Jason C. Vernon

Cardiac resuscitation after incremental overdosage with lidocaine, bupivacaine, levobupivacaine, and ropivacaine in anesthetized dogs

There is no information comparing the ability to reverse the cardiotoxic effects associated with incremental overdosage of bupivacaine (BUP) to levobupivacaine (LBUP), ropivacaine (ROP), or lidocaine (LIDO). Open-chest dogs were randomized to receive incremental escalating infusions of BUP, LBUP, ROP, and LIDO to the point of cardiovascular collapse (mean arterial pressure [MAP] ≤45 mm Hg). Hypotension and arrhythmias were treated with epinephrine, open-chest massage, and advanced cardiac life support protocols, respectively. Outcomes were defined as the following: successful (stable rhythm and MAP ≥55 mm Hg for 20 min), successful with continued therapy (stable rhythm and MAP <55 mm Hg after 20 min), or death. Continued therapy was required in 86% of LIDO dogs compared with only 10%–30% of the other dogs (P < 0.002). Mortality from BUP, LBUP, ROP, and LIDO was 50%, 30%, 10%, and 0%, respectively. Myocardial depression was primarily responsible for the profound hypotension, as the occurrence of lethal arrhythmias preceding resuscitation was not different among local anesthetics. Epinephrine-induced ventricular fibrillation occurred more frequently in BUP-intoxicated dogs than in dogs given LIDO or ROP (P < 0.05). The unbound plasma concentrations at collapse were larger for ROP, 19.8 &mgr;g/mL (10–39 &mgr;g/mL), compared with BUP, 5.7 &mgr;g/mL (3–11 &mgr;g/mL); whereas the concentrations of LBUP, 9.4 &mgr;g/mL (5–18 &mgr;g/mL) and BUP were not significantly different from each other. IMPLICATIONS There were consistent differences among the local anesthetics, the sum of which suggests that larger doses and blood concentrations of ropivacaine (ROP) and lidocaine will be tolerated as compared with bupivacaine (BUP) and levobupivacaine (LBUP). Lidocaine intoxication results in myocardial depression from which resuscitation is consistently successful but will require continuing drug support. After BUP, LBUP, or ROP, resuscitation is not always successful, and the administration of epinephrine may lead to severe arrhythmias. The unbound plasma concentrations at collapse were larger for ROP compared with BUP, whereas the concentrations of LBUP and BUP were not significantly different from each other. Furthermore, larger plasma concentrations of ROP than BUP are present after resuscitation, suggesting a wider margin of safety when large volumes and large concentrations are used to establish upper or lower extremity nerve blocks for surgical anesthesia and during long-term infusions for pain management.

Ischemic preconditioning reduces neurologic injury in a rat model of spinal cord ischemia

Background. Ischemic preconditioning (IPC) is an endogenous cellular protective mechanism whereby brief, noninjurious periods of ischemia render a tissue more resistant to a subsequent, more prolonged ischemic insult. We hypothesized that IPC of the spinal cord would reduce neurologic injury after experimental aortic occlusion in rats and that this improved neurologic benefit could be induced acutely after a short reperfusion interval separating the IPC and the ischemic insult. Methods. Forty male Sprague-Dawley rats under general anesthesia were randomly assigned to one of two groups. The IPC group (n 5 20) had 3 minutes of aortic occlusion to induce spinal cord ischemia 30 minutes of reperfusion, and 12 minutes of ischemia, whereas the controls (n 5 20) had only 12 minutes of ischemia. Neurologic function was evaluated 24 and 48 hours later. Some animals from these groups were perfusion-fixed for hematoxylin and eosin staining of the spinal cord for histologic evaluation. Results. Survival was significantly better at 48 hours in the IPC group. Sensory and motor neurologic function were significantly different between groups at 24 and 48 hours. Histologic evaluation at 48 hours showed severe neurologic damage in rats with poor neurologic test scores. Conclusions. Ischemic preconditioning reduces neurologic injury and improves survival in a rat model of spinal cord ischemia. The protective benefit of IPC is acutely invoked after a 30-minute reperfusion interval between the preconditioning and the ischemic event. (Ann Thorac Surg 1999;68:874 ‐ 80)

Ventricular arrhythmias with or without programmed electrical stimulation after incremental overdosage with lidocaine, bupivacaine, levobupivacaine, and ropivacaine.

It is unclear whether the mechanism of death from local anesthetic (LA) intoxication is primarily a consequence of cardiac arrhythmias or myocardial contractile depression, and whether LAs might differ in this susceptibility to these two mechanisms. By using programmable electrical stimulation (PES) protocols in anesthetized, ventilated dogs, we compared the arrhythmogenic potential of bupivacaine (BUP), ropivacaine (ROP), levobupivacaine (LBUP), and lidocaine (LIDO). Open-chest dogs were randomized to receive escalating incremental infusions of the four local anesthetics until cardiovascular collapse. We assumed a concentration relationship of 4:1 for LIDO/BUP, LBUP, and ROP. The effective refractory period did not change significantly until the dose increment corresponding to target concentrations of 8 and 32 &mgr;g/mL for BUP, LBUP, ROP, and LIDO, respectively. Thirty percent to 50% increases in effective refractory period oc-curred in surviving dogs at this dose. The incidence ofspontaneous or PES-induced ventricular tachycardia and ventricular fibrillation did not differ among groups. Compared with LIDO, the incidence of PES-induced extrasystoles was more frequent for BUP- and LBUP-treated dogs (P < 0.05). ROP-treated dogs did not differ from LIDO-treated dogs with respect to PES-induced extrasystoles. At the dose increment preceding cardiovascular collapse, all LAs produced significant increases in heart rate and reductions in blood pressure compared with their respective baseline values. The incidence of programmable electrical stimulation-induced ventricular tachycardia and fibrillation with BUP does not differ from the incidence that occurs with the single S (−) enantiomers LBUP and ROP, providing further evidence against stereoselective arrhythmogenesis as a primary component of local anesthetic-induced cardiotoxicity. Implications Progressive bupivacaine intoxication in anesthetized, ventilated dogs does not produce early arrhythmogenic events. The incidence of programmable electrical stimulation-induced ventricular tachycardia and fibrillation with bupivacaine does not differ from the incidence that occurs with the single S (−) enantiomers levobupivacaine and ropivacaine, providing further evidence against stereoselective arrhythmogenesis as a primary component of local anesthetic-induced cardiotoxicity.

Does vacuum-assisted venous drainage increase gaseous microemboli during cardiopulmonary bypass?

BACKGROUND Vacuum-assisted venous drainage enables adequate drainage through small-diameter cannulas but concerns are that it results in more gaseous microemboli delivered to the patient. METHODS Five identical embolus detectors monitored the propagation of entrained air through a cardiopulmonary bypass (CPB) model. The ability of the CPB circuit to remove gaseous microemboli was studied with vacuum-assisted venous drainage and gravity siphon venous drainage using different pump speeds and rates of gaseous microemboli delivery. RESULTS Under all conditions entrained venous air resulted in the detection of gaseous microemboli in the perfusate after the arterial filter. In blood-primed circuits, increased flow rates and higher levels of vacuum-assisted venous drainage were independently associated with increased gaseous microemboli counts in the arterial line. Vacuum-assisted venous drainage at -40 mm Hg did not significantly increase gaseous microemboli activity when compared with gravity siphon venous drainage at 4 L/min flow rate. CONCLUSIONS Vacuum-assisted venous drainage at -40 mm Hg does not statistically reduce the ability of the CPB circuit to remove gaseous microemboli at lower pump rates. High levels of vacuum and increased pump flow rates should be avoided. Air should not be introduced into the venous line.

Does local anesthetic stereoselectivity or structure predict myocardial depression in anesthetized canines

Background and Objectives It is unclear whether the susceptibility to myocardial depression from an accidental intravascular local anesthetic (LA) administration is associated with LA stereoselectivity or structure. By using direct left ventricular pressure monitoring and echocardiographic indices of contractile function in anesthetized, ventilated dogs, we compared the cardiac depressant effects of bupivacaine, ropivacaine, levobupivacaine, and lidocaine. Methods Open-chest dogs were randomized to receive escalating incremental infusions of the 4 local anesthetics until cardiovascular collapse. We assumed a concentration relationship for potency of 4:1 for lidocaine/bupivacaine, ropivacaine, and levobupivacaine. Results All LAs produced concentration-dependent increases in left ventricular end diastolic pressure (LVEDP) and decreases in dP/dtmax, ejection fraction % (EF), fractional shortening (%) (FS), and cardiac output (CO). When comparing the long-acting agents, the effect was least for ropivacaine. The effective concentration estimates for ropivacaine that produced 35% reductions in dP/dtmax and FS were 4.0 μg/mL (95% confidence intervals [CI95]: 3.1 to 5.2 μg/mL) and 3.0 μg/mL (CI95: 2.1 to 4.2 μg/mL), respectively. The concentrations of levobupivacaine that produced these same end points of contractile dysfunction were significantly less: 2.4 μg/mL (CI95: 1.9 to 3.1 μg/mL) and 1.3 μg/mL (CI95: 0.9 to 1.8 μg/mL), respectively, and these were not different from bupivacaine. As expected, the concentrations of lidocaine that produced 35% reductions in dP/dtmax and FS were significantly greater than the longer acting agents; 8.0 μg/mL (CI95: 5.7 to 11.0 μg/mL) and 5.5 μg/mL (CI95: 3.5 to 8.7 μg/mL), respectively. Conclusions This study suggests that smaller molecular size and possibly a piperidine-free structure as opposed to stereoselectivity may be the more important factor in reducing the risk of LA-induced myocardial depression.

Intrathecal morphine reduces infarct size in a rat model of ischemia-reperfusion injury

Systemically-administered morphine reduces infarct size in rat models of myocardial ischemia-reperfusion. We sought to determine whether much smaller doses of spinally-administered morphine offer a similar cardioprotective benefit. Barbiturate-anesthetized, open-chested, Wistar rats with chronic indwelling thoracic intrathecal catheters were instrumented for hemodynamic measurements and subjected to 30 min of coronary occlusion and 90 min of reperfusion. Myocardial infarct size was determined using triphenyl-tetrazolium staining. Rats were randomly assigned to receive intrathecal (IT) 0.9% saline (vehicle), IV morphine (0.3 mg/kg) plus IT saline, small-dose IT morphine (0.3 &mgr;g/kg), or large-dose IT morphine (3 &mgr;g/kg) 20 min before occlusion. IV and both doses of IT morphine reduced infarct size, defined as area of necrosis expressed as a percentage of area at risk (%AN/AAR), as compared with vehicle. The %AN/AAR group means were as follows: IV (n = 7), 30% ± 6%; ITsmall-dose (n = 9), 30% ± 5%; ITlarge-dose (n = 9), 18% ± 4%; and vehicle (n = 10), 47% ± 5%. There were no significant differences in infarct size among the morphine-pretreated rats. During ischemia-reperfusion, heart rate was unchanged from baseline in the ITlarge-dose group, whereas in the ITsmall-dose, IV and vehicle groups, significant declines in heart rate occurred. Changes in arterial blood pressure were similar among groups. These results indicate that IT morphine reduces infarct size in rats, and this benefit is as great as that provided by IV morphine administration.

Thoracic epidural anesthesia reduces infarct size in a canine model of myocardial ischemia and reperfusion injury.

OBJECTIVE To determine the effects of thoracic epidural anesthesia on myocardial infarct size, regional myocardial blood flow (RMBF), and plasma norepinephrine in an anesthetized canine model of ischemia reperfusion injury with infarction. DESIGN Blinded, randomized, placebo-controlled animal study. SETTING Experiments were performed in the cardiothoracic research laboratory at Wake Forest University Baptist Medical Center. PARTICIPANTS Anesthetized, open-chest mongrel dogs were used in these studies. METHODS Dogs were instrumented for measurement of aortic pressure (AP) and left ventricular systolic pressure (LVSP), dP/dt, and RMBF Epidural catheters were inserted at thoracic segment T5. Three groups received epidural 0.5% bupivacaine: low-dose (n = 7; 0.3 mg/kg bolus, 0.15 mg/kg/ h), mid-dose (n = 7; 0.6 mg/kg bolus, 0.3 mg/kg/h), high-dose (n = 7; 1.2 mg/kg bolus, 0.6 mg/kg/h). The vehicle (VEH) group received epidural saline. Bolus followed by maintenance infusions began 30 minutes before the onset of ischemia (60 min) and continued through reperfusion (180 min). RESULTS Myocardial infarct size was significantly reduced in the high-dose group versus the VEH and low-dose groups (p < 0.05). After initiation of the mid and high dose, AP, LVSP, and dP/dt decreased 7% to 16% (high vVEH; p < 0.05). VEH dogs showed a 130% increase from control in early postischemic RMBF. There was a dose-dependent attenuation in this reflow response: 72%, 31%, and 6% increase in RMBF in the low, mid, and high groups, relative to controls (p < 0.05 high v VEH). Although there was no significant difference in plasma norepinephrine, fewer surges occurred in the high-dose group. CONCLUSIONS Thoracic epidural anesthesia reduces infarct size and postischemic hyperemia in a model of ischemia reperfusion injury.

Cloricromene reduces infarct size and alters postischaemic blood flow defects in dog myocardium

1. The aim of the present investigation was to evaluate the effect of cloricromene on myocardial infarct size, regional myocardial blood flow and neutrophil accumulation in a canine model of ischaemia‐reperfusion.

Spinal Cord Blood Flow after Ischemic Preconditioning in a Rat Model of Spinal Cord Ischemia

Spinal cord blood flow after ischemic preconditioning is poorly characterized. This study is designed to evaluate spinal cord blood flow patterns in animals after acute ischemic preconditioning. Experiment 1: After a laminectomy and placement of a laser Doppler probe over the lumbar spinal cord to measure spinal cord blood flow, 16 male Sprague-Dawley rats were randomized into two groups: ischemic preconditioning (IPC, n = 8), and control (CTRL, n = 8). Rats in the CTRL and the IPC groups were subjected to 12 min of ischemia directly followed by 60 min of reperfusion. IPC rats received 3 min of IPC and 30 min of reperfusion prior to the 12-min insult period. Experiment 2: After instrumentation, the rats were randomized into three groups: control (CTRL, n = 7), ischemic preconditioning (IPC, n = 7), and time control (TC, n = 4). Rats in the CTRL and the IPC groups were subjected to the same ischemia and reperfusion protocol as above. The TC group was anesthetized for the same time period as the CTRL and the IPC groups, but had no ischemic intervention. Microspheres were injected at baseline and at 15 and 60 min into the final reperfusion. All rats were euthanized and tissue harvested for spinal cord blood flow analysis. In Experiment 1, there was a slight, significant difference in spinal cord blood flow during the ischemic period; however, this difference soon disappeared during reperfusion. In experiment 2, there was no difference in blood flow at any experimental time. The results of these experiments demonstrate that IPC slightly enhances blood flow to the spinal cord during ischemia; however, this effect is not sustained during the reperfusion period.

ISCHEMIC PRECONDITIONING REDUCES NEUROLOGIC INJURY IN A RAT MODEL OF SPINAL CORD ISCHEMIA

BACKGROUND Ischemic preconditioning (IPC) is an endogenous cellular protective mechanism whereby brief, noninjurious periods of ischemia render a tissue more resistant to a subsequent, more prolonged ischemic insult. We hypothesized that IPC of the spinal cord would reduce neurologic injury after experimental aortic occlusion in rats and that this improved neurologic benefit could be induced acutely after a short reperfusion interval separating the IPC and the ischemic insult. METHODS Forty male Sprague-Dawley rats under general anesthesia were randomly assigned to one of two groups. The IPC group (n = 20) had 3 minutes of aortic occlusion to induce spinal cord ischemia 30 minutes of reperfusion, and 12 minutes of ischemia, whereas the controls (n = 20) had only 12 minutes of ischemia. Neurologic function was evaluated 24 and 48 hours later. Some animals from these groups were perfusion-fixed for hematoxylin and eosin staining of the spinal cord for histologic evaluation. RESULTS Survival was significantly better at 48 hours in the IPC group. Sensory and motor neurologic function were significantly different between groups at 24 and 48 hours. Histologic evaluation at 48 hours showed severe neurologic damage in rats with poor neurologic test scores. CONCLUSIONS Ischemic preconditioning reduces neurologic injury and improves survival in a rat model of spinal cord ischemia. The protective benefit of IPC is acutely invoked after a 30-minute reperfusion interval between the preconditioning and the ischemic event.