Ann Thorac Surg 2009;87:820-825. doi:10.1016/j.athoracsur.2008.12.042
© 2009 The Society of Thoracic Surgeons
Original Articles: Adult Cardiac
Cerebral Protection by Lidocaine During Cardiac Operations: A Follow-Up Study
Simon J. Mitchell, FANZCA, PhDa,c,*,
Alan F. Merry, FANZCAa,c,
Christopher Frampton, PhDb,
Elaine Daviesa,
Diana Grieve, MAa,
Brigid P. Mills, MHSc(Hons)a,
Craig S. Webster, PhDa,
F. Paget Milsom, FRACSd,
Timothy W. Willcox, CCPe,
Desmond F. Gorman, MD, PhDa
a Department of Anaesthesiology, University of Auckland, Auckland, New Zealand
b StatistEcol, Mount Eden, Auckland, New Zealand
c Department of Anaesthesia, Auckland City Hospital, Auckland, New Zealand
d Department of Surgery, Auckland City Hospital, Auckland, New Zealand
e Department of Clinical Perfusion, Auckland City Hospital, Auckland, New Zealand
Accepted for publication December 5, 2008.
* Address correspondence to Dr Mitchell, Department of Anaesthesiology, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand (Email: sj.mitchell{at}auckland.ac.nz).
 |
Abstract
|
|---|
Background: A previous study showed less postoperative neurocognitive impairment in open-chamber cardiac surgery patients given lidocaine for 48 hours after induction of anesthesia. In the present study, we aimed to test the benefit of a 12-hour infusion in a broader group of cardiac surgery patients, including those undergoing coronary artery bypass graft surgery.
Methods: This was a randomized, double-blind, intention-to-treat trial. Before cardiac surgery, 158 patients completed 7 neurocognitive tests and a self-rating scale for memory. They received a 12-hour infusion of either lidocaine in a standard antiarrhythmic dose or placebo, beginning at induction of anesthesia. The cognitive tests and memory scale were repeated at postoperative weeks 10 and 25. A deficit in any cognitive test was defined as a decline in score by more than or equal to the preoperative group standard deviation.
Results: All tests were completed by 118 and 107 patients at 10 and 25 weeks, respectively. The proportions of patients in the lidocaine and placebo groups exhibiting a deficit in one or more tests were as follows: 45.8% versus 40.7% at 10 weeks, and 35.2% versus 37.7% at 25 weeks (not significant). There were no significant differences between groups in self-ratings of memory function or length of intensive care unit or hospital stay.
Conclusions: Lidocaine was not neuroprotective. The result of the previous trial may represent a type 1 error. Alternatively, benefit may be more likely for open-chamber surgery patients exposed to larger numbers of emboli or with a longer lidocaine infusion.
|
Introduction
|
|---|
Cardiac surgery and cardiopulmonary bypass (CPB) result in exposure to gaseous and particulate arterial emboli and, potentially, to periods of cerebral hypoperfusion that may result in perioperative brain injury. While the reported incidence varies according to injury definitions and the method and timing of surveys, contemporary review suggests that new stroke occurs in 1% to 3%, and significant neurocognitive deficits (NCDs) in 30% to 65% of patients [1]. The NCDs may persist for at least 5 years in 42% of affected patients [2]. Not surprisingly, the prevention of these injuries has been the subject of considerable research [1]. Much of this has focused on means of preventing exposure to arterial emboli [3], but there has also been interest in neuroprotective drugs.
Lidocaine is a sodium-channel–blocking drug utilized as an antiarrhythmic agent (class Ib) and a local anesthetic. Investigations of its neuroprotective properties have been reviewed elsewhere [4], but in summary, lidocaine preserves neuronal function and reduces damage in in vivo models of arterial gas embolism, focal ischemia, and global ischemia when administered either before or early after the injury. A study performed in our group of patients undergoing cardiac operations showed that lidocaine reduced the incidence of NCDs at 10 days and 10 weeks after left-side heart valve surgery when infused in standard antiarrhythmic doses for 48 hours after induction of anesthesia [5]. A second study by a separate group also showed a reduction in NCDs at 10 days after coronary artery bypass graft surgery (CABG) [6]. However, both studies had weaknesses. Our original study [5] was small, restricted to valve surgery patients or combined valve and graft procedures, and involved a 48-hour lidocaine infusion. The consequent 48-hour requirement for a monitored bed poses practical difficulties given the modern trend toward fast-tracking patients through intensive care units. Although the second study [6] was larger, enrolled patients undergoing CABG, and restricted lidocaine administration to the duration of surgery, the patients were only followed for 10 days postoperatively.
The present study was designed to revisit prevention of NCDs after cardiac surgery with an appropriately powered design, a typical mix of cardiac surgical procedures, a 12-hour lidocaine infusion, and medium-term patient follow-up.
|
Patients and Methods
|
|---|
This study was conducted in the Departments of Cardiothoracic Surgery and Anesthesiology at Auckland City Hospital, Auckland, New Zealand, after Institutional Review Board approval. The format was a randomized, double-blind, controlled trial analyzed on an intention-to-treat basis. Eligible patients were 20 to 75 years old; resident in the greater Auckland area; English speakers as their first or preferred language; undergoing CABG (with or without cardiopulmonary bypass), valve surgery, or combined procedures; and with no preexisting cerebral dysfunction, no history of sensitivity to lidocaine, and no condition the procedural anesthesiologist would normally consider to be a contraindication to lidocaine administration. Patients were approached on the day before surgery, and provided written informed consent for participation.
Neurocognitive Testing
The neurocognitive tests were administered by appropriately trained personnel under the direction of a registered psychologist on the day before surgery, and were repeated at 10 and 25 weeks postoperatively. Where applicable, parallel forms of the tests were used at each postoperative follow-up. The test battery for our primary outcome measure consisted of seven test scales, described by Lezak [7], and chosen to interrogate the cognitive domains considered important in the 1995 statement of consensus on the assessment of neurobehavioral outcomes after cardiac surgery [8]. We did not include a motor skills assessment in our battery. The seven test scales are as follows: (1) Auditory-Verbal Learning Test—in this study, the total score for trials 1 to 5 was recorded; this is primarily a test of short-term verbal memory. (2 and 3) Digit Span Forward and Backward—this is a subtest of the Wechsler Adult Intelligence Scale–Revised (WAIS-R); the forward iteration primarily tests attention with overlay from short-term numerical memory, whereas the backward iteration sharpens the focus on short-term numerical memory and associated integration and manipulation functions. (4 and 5) Digit Symbol and Digit Symbol A—these are also subtests of the WAIS-R that primarily test psychomotor performance and the inherent requirement for integration of multiple cognitive processes; they are considered very sensitive to brain injury. (6 and 7) Thurstone Word Fluency (two lists)—this is another test of integrated cognition requiring organized thought and generation of associations to achieve a good score; it is particularly sensitive to frontal lobe dysfunction.
A significant decline in postoperative performance in any test scale was defined as a decline in score by 1 or more SD from the preoperative group mean for that test. Subjects were considered to exhibit a cognitive function deficit if they showed a significant decline in one or more test.
At the preoperative evaluation and at both follow-up evaluations, patients also completed the Memory Assessment Clinics Self-Rating Scale (MAC-S) [9], which provides a structured tool for measuring patients' own perceptions of their memory function; and the Hospital Anxiety and Depression Scale [10], to control for any effects of changes in anxiety or depression on postoperative cognitive performance. Finally, and in addition to the cognitive function tests, we employed the National Adult Reading Test [11] as a means of comparing preoperative intellectual function between the two groups. This test was not repeated postoperatively.
Trial Medication Administration
A collaborator who had no other role in the trial generated a block-randomized sequence of allocations to lidocaine or placebo stratified by surgeon, thus ensuring each surgeon operated on approximately equal numbers of patients in each study group. This sequence was concealed from the patients, all medical staff in contact with the patients, and from all other trial collaborators. Trial solutions (2% lidocaine or normal saline for placebo) were repackaged into generic vials by a licensed pharmaceutical company (Biomed, Auckland, New Zealand). The infusion was started at induction of anesthesia and was designed so patients allocated to the lidocaine group would receive a "bolus" of 1 mg · kg–1 over 5 minutes, followed by 2 mg · min–1 for 2 hours, and 1 mg · min–1 thereafter, for a total of 12 hours. As in our previous study [5], this regimen aimed to produce a plasma lidocaine concentration of 6 to 12 µmol · L–1, which corresponds to the lower half of the therapeutic range for antiarrhythmic effect. All patients (whether allocated to the lidocaine or placebo groups) had blood specimens taken for plasma lidocaine level measurements at 2 hours and 10 hours after initiation of the infusion. These levels were not reported to any staff involved in managing or evaluating the patient during or after surgery.
Anesthesia and Surgery
There was no attempt to rigidly standardize the anesthetic technique, but practice among anesthesiologists was confluent, and no significant changes occurred over the course of the study. Patients were almost invariably premedicated on the day of surgery with midazolam and ranitidine. Induction of general anesthesia was undertaken with tailored doses of propofol or etomidate, fentanyl, and a nondepolarizing muscle relaxant. Anesthesia was maintained with isoflurane. Where applicable, CPB was established with an extracorporeal circuit containing a roller pump (Stockert Instrumente, Munich, Germany), hard shell venous reservoir, and hollow fiber membrane oxygenator, and a 40-µm arterial line filter with continuous purge. Indexed nonpulsatile flow rates were 2.0 to 3.0 L · m2–1 · min–1 during cooling and rewarming, falling no lower than 2.0 L · m2–1 · min–1 during stable CPB. The target range for CPB perfusion pressure was 50 to 80 mm Hg. All patients undergoing CPB were cooled within the range 28° to 34°C. Arterial line inflow temperatures were not allowed to exceed 37°C during rewarming.
Physiological measurements were automatically recorded using electronic data logging devices. In view of the link between emboli exposure and postoperative cognitive dysfunction, we used a Doppler ultrasound emboli counting device (MultiDop; DWL Doppler, Singen, Germany) to count emboli in the right common carotid artery from 5 minutes before cannulation of the great vessels until 20 minutes after withdrawal of CPB.
At the end of surgery, patients were taken sedated and intubated to a dedicated cardiothoracic intensive care unit for protocol-based withdrawal of sedation and extubation, and other supportive care as appropriate.
Outcomes, Statistical Methods, and Sample Size Estimation
The primary outcome measure was comparison of the proportion of patients in the two groups exhibiting a significant deficit (as previously defined) in one or more of the seven neurocognitive test scales at each postoperative follow-up. These proportions were compared using the Pearson 
2 test. Secondary outcome measures were comparisons between the groups with respect to the length of stay in the intensive care unit, the length of stay in hospital, and the change in postoperative scores for the MAC-S self-rating memory inventory at each follow-up. Length of stay in the intensive care unit and hospital was compared with Mann-Whitney U tests. The percentage changes in sequential postoperative scores in MAC-S were compared using independent sample t tests. A p value of 0.05 or less was taken to indicate statistical significance.
The study groups were sized on the basis of the difference in the incidence of NCDs in the lidocaine and control groups at 10 weeks (46% versus 75%, respectively) and 25 weeks (28% versus 48%, respectively) in our previous study [5]. It was calculated that for 80% power at 
= 0.05, we would need 36 patients in each group for the 10-week evaluation, and 91 patients in each group for the 25-week evaluation. The recruitment target was, therefore, 182 patients.
|
Results
|
|---|
Recruitment numbers, treatment allocation, and losses to follow-up are documented in Figure 1. Recruitment of patients was dependent on the availability of a research associate trained to administer the neurocognitive tests. In addition, many patients failed to meet eligibility criteria (Fig 1), especially with respect to age, language, and place of residence. Throughout the study there were other trials concomitantly under way that competed for the same patient population, and our Institutional Review Board approval forbade recruitment of patients into more than one trial. These issues resulted in a 6-year recruitment period to achieve 158 patients, and it was decided to curtail the trial at that point, having recruited slightly fewer patients than required for our sample size estimation for the analysis at 25 weeks, but well within the number required for 10 weeks.
View larger version (40K):
[in this window]
[in a new window]
|
Fig 1. Patient allocations and losses to follow-up. "Missing" implies that a patient could not be contacted. "Unavailable" denotes patients who were not available for follow-up at 10 weeks, but who subsequently were "available" at 25 weeks.
|
|
Eighty-one patients and 77 patients were randomly assigned to receive lidocaine and the placebo, respectively. Lidocaine blood levels were congruent with allocated treatment groups except that 1 lidocaine patient had plasma levels below detectable limits in both samples, and 1 placebo patient had levels of 4 µmol · L–1, also in both samples. This may represent a procedural error that resulted in swapping of medication vials, but we remain uncertain about the cause. Eight placebo patients had detectable but very low lidocaine levels (
1 µmol · L–1). All patients were analyzed according to their original treatment group allocations except for 1 patient who received lidocaine but was subject to a code break intraoperatively and was excluded from further analysis because the neurocognitive testing was thereby unblinded for this case. In the lidocaine group, the mean plasma levels at 2 and 10 hours were 9 and 7 µmol · L–1, respectively. The two groups were adequately matched with respect to important preoperative variables (Table 1) and perioperative variables (Table 2).
Four patients in the lidocaine group died before the 10-week review versus none in the placebo group (statistically nonsignificant). These deaths were attributed to multiorgan failure (3 cases) and acute graft occlusion (1 case), and occurred between 5 and 9 days postoperatively. Thus, none occurred during the lidocaine infusions, and none could be plausibly linked to lidocaine administration. Losses to follow-up (Fig 1) were otherwise similar between the groups and reflect the difficulties inherent in medium-term outpatient follow-up in a mobile patient population. Comparison between the groups with respect to the proportion of patients exhibiting a NCD at each follow-up (the primary outcome variable) is shown in Table 3. The average intensive care unit and hospital stays (secondary outcome measures) are compared for the two groups in Table 4. The percentage changes in score (from the preoperative baseline) in the two scales of the MAC-S (the final secondary outcome measure) are compared between the groups in Table 5. There were no significant differences between the groups in any of these measures at either follow-up point. Finally, although both groups exhibited significant postoperative reductions in anxiety and depression as measured by the Hospital Anxiety and Depression Scale, there were no significant differences between the groups.
View this table:
[in this window]
[in a new window]
|
Table 3 Comparison of Study Groups With Respect to Proportion of Patients Exhibiting a Neurocognitive Deficit at Each Follow-Up
|
|
View this table:
[in this window]
[in a new window]
|
Table 5 Comparison of Study Groups With Respect to Percentage Changes in Score (From Preoperative Baseline) at Follow-Up in Two Scales of Memory Assessment Clinics Self-Rating Scale
|
|
|
Comment
|
|---|
There has been interest in lidocaine as a neuroprotective agent since the first relevant study demonstrated preservation of neuroelectrical function after cerebral arterial gas embolism in cats [12]. Subsequent studies spanning multiple animal models, injury types, and outcome measures were summarized in 2001 [4], and other studies have continued to emerge since then [13–15]. The overwhelming majority of studies conducted in carefully controlled experimental settings have demonstrated neuroprotection. That is not surprising. Sodium channel blockade is a rational neuroprotective strategy [16], and may be especially so in the transient ischemia typically caused by gas emboli [4] because it delays the loss of ion homeostasis and neuronal depolarization that are the precursors to virtually all subsequent injurious processes. In addition, lidocaine in standard antiarrhythmic doses is known to lower the cerebral metabolic rate for oxygen [17] and to inhibit white cell activation in inflammation [18]; both effects may be neuroprotective.
The first reported use of lidocaine for clinical neuroprotection occurred in diving medicine [19], but this was limited to case reporting of apparent benefit for divers who had refractory neurologic decompression illness. It is hardly surprising that neuroprotection by lidocaine was eventually tested formally in humans since, as an old, safe, inexpensive, and well-understood drug, there would have been considerable utility if it proved effective in this new and important indication. The first formal evaluation was our own small randomized, double-blind trial in patients undergoing open-chamber cardiac operations [5], which was followed by the study by Wang and others [6]. Both studies reported benefit, but as described in the introduction, both had methodologic weaknesses. The present study was undertaken in an attempt to revisit the issue in a study with appropriate power, involving a typical mix of cardiac surgery patients, utilizing a lidocaine infusion of intermediate (12-hour) duration, and incorporating medium-term follow-up.
In contrast to our first study (and that of Wang and colleagues [6]), the present investigation found no evidence of neuroprotection in the lidocaine group despite several small (and statistically nonsignificant) between-group differences that favor the lidocaine group in respect of potentially important variables such as previous cardiac surgery, combined valve and graft procedures, and exposure to arterial emboli (Tables 1 and 2). Potential explanations for this include methodologic differences between the studies or the possibility that our previous result represented a type 1 error. In respect of the methodologies, there are several potentially relevant differences:
First, the vast majority of patients entered into the present study were undergoing CABG without cardiotomy, unlike our previous study [5], in which all patients underwent cardiotomy for valve replacement. Not surprisingly, emboli counts recorded in both studies show that, on average, patients in the previous study were exposed to an order of magnitude more emboli. Greater emboli exposure in open-chamber procedures has been recorded previously [20]. However, there is controversy over whether this imposes greater risk of perioperative brain injury. Although typical CABG patients may be exposed to fewer emboli, they may have different risk factors for postoperative NCDs; for example, they are usually older [21]. The relevant point in the present context is that while NCDs may occur in both open-chamber and CABG groups, the mechanism of injury may be subtly or even significantly different. There are plausible grounds for suggesting that lidocaine may be most protective in an injury caused mainly by exposure to the showers of small bubbles more typically seen in cardiotomy patients [4]. Unfortunately, we are unable to further elucidate this issue in the present study as there were insufficient numbers of cardiotomy patients to allow a meaningful subanalysis for benefit of lidocaine by surgical group.
Second, the 12-hour lidocaine infusion in the present study was considerably shorter than the 48-hour infusion used in our previous investigation. The latter was chosen because of the potential contribution of anti-inflammatory effects of lidocaine to neuroprotection, and the possibility that this might remain relevant for a prolonged period after exposure to emboli. It is also possible that a longer infusion might provide neuroprotection during any early postoperative hemodynamic disturbances, or other adverse events. However, a 48-hour lidocaine infusion is somewhat impractical, in part because of the associated need for a bed with cardiac monitoring and we wished to investigate the efficacy of a shorter infusion. It remains possible that the shorter infusion resulted in less neuroprotection, although this is inconsistent with the demonstration of benefit by Wang and coworkers [6], who maintained the infusion only for the period of surgery.
Third, the data we chose to collect and the neurocognitive test battery we utilized were different in the present study. Although our previous study was small, it was relatively cumbersome methodologically, involving collection of more descriptive data about each patient and the administration of a larger number of neurocognitive tests, some of which were nondiscriminating. We attempted a more efficient design on this occasion by collecting fewer data and performing a smaller number of sensitive tests chosen to interrogate those domains considered important [8] and in which benefit was most apparent in the previous study [5]. In particular, we retained the use of the Digit Symbol Test, the Auditory Verbal Learning Test, and the MAC-S for memory function, all of which strongly indicated benefit for lidocaine in the previous study. That benefit was not apparent in the same tests used in the present study. Nevertheless, it remains possible that by reducing numbers of tests we have inadvertently reduced the discriminating power of our method. Although this seems unlikely, it is notable that the incidence of NCDs in the control group is considerably lower at both follow-ups in the present study. However, this may be influenced by the different make-up of the patient population as discussed above, or even a genuine reduction in the incidence of NCDs among all patients in our unit over the 4 years that intervened between studies and the 6-year period of the study. A great deal more is understood about minimizing the risk of NCD today.
Our present study has failed to confirm a neuroprotective benefit from perioperative lidocaine administration in cardiac surgery. In addition, another negative trial of lidocaine in brain protection during cardiac surgery was reported in abstract form by the Duke group [22], but in the absence of a full description, it is difficult to further interpret this result. Despite these results, caution should be exercised before completely discounting clinical neuroprotection by lidocaine because our study has several limitations. First, there were traces of lidocaine in the blood samples from 8 patients in the placebo group that were probably attributable to the use of local anesthetic (perhaps topically in the trachea). Although we strongly doubt that this would bias the results, we cannot exclude the possibility. The presumed swap of one lidocaine for one placebo vial is regrettable, but again very unlikely to substantially influence the outcome overall. Second, there was a moderate number of losses to follow-up (Fig 1). However, there is no evidence here of any systematic bias related to study group allocation in the pattern of loss. Third, we stopped the study after reaching the sample size estimate for 10-week analysis. In fact, our estimates were based on a higher underlying incidence of NCD than we actually detected in our current patient population. The incidence of NCDs with placebo at 10 weeks was 41% instead of the 75% we reported in our earlier study [5] (and upon which our power calculation was based). On this basis, to demonstrate significance for an improvement proportionately similar to that seen in the previous study would require approximately 300 patients (about 150 per group). Even more (approximately 1,200) would be required for the 25-week assessment. Therefore, as it turned out, the study was considerably underpowered. However, there were no trends toward benefit from lidocaine at either follow-up, so we doubt that larger numbers would have made any difference. There is no indication for further study of this lidocaine protocol in this specific patient population implied by our results.
Despite this, on the strength of carefully controlled in vitro and in vivo experiments [4, 13–15], it seems clear that lidocaine is almost invariably neuroprotective when present in clinically relevant concentrations at the time of neuronal insult. The difficulty in consistently demonstrating such a benefit in humans has some parallels with hypothermia: hypothermia is unequivocally neuroprotective in carefully controlled in vivo experiments, but demonstration of benefit in clinical studies has been inconsistent. As with hypothermia, it remains possible that lidocaine may in the future be shown to have a clinically relevant neuroprotective role when used in appropriate dosage regimens and specific clinical situations. For the present, however, the data published to date do not justify the use of lidocaine for neuroprotection in clinical practice.
|
Acknowledgments
|
|---|
Doctor Dorothy Gronwall acted as consultant in neuropsychology to the investigating team during inception of the trial, and guided the choice and administration of the tests used in this study. Tragically, she died during the period of recruitment, which was a devastating loss to our team. We would like thank Dr Jenni Ogden for providing subsequent advice in Dr Gronwall's place. We acknowledge the support and logistic contributions of Drs James Cheeseman and Guy Warman. This work was supported by medical equipment grant AP72364 from the Lottery Grants Board of New Zealand, grants 81354 and 81399 from the Auckland Medical Research Foundation, and by a grant from the English Freemasons of New Zealand.
|
References
|
|---|
- Hogue CW, Palin CA, Arrowsmith JE. Cardiopulmonary bypass management and neurologic outcomes: an evidence based appraisal of current practices Anesth Analg 2006;103:21-37.[Abstract/Free Full Text]
- Newman MF, Kirchner JL, Phillips-Bute, et al. Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery N Engl J Med 2001;344:395-402.[Medline]
- Shann KG, Likosky DS, Murkin JM, et al. An evidence based review of the practice of cardiopulmonary bypass in adults: a focus on neurological injury, glycemic control, hemodilution, and the inflammatory response J Thorac Cardiovasc Surg 2006;132:283-290.[Free Full Text]
- Mitchell SJ. Lidocaine in the treatment of decompression illness: a review of the literature Undersea Hyperbaric Med 2001;28:165-174.
- Mitchell SJ, Pellett O, Gorman DF. Cerebral protection by lidocaine during cardiac operations Ann Thorac Surg 1999;67:1117-1124.[Medline]
- Wang D, Wu X, Li J, Xiao F, Liu X, Meng M. The effect of lidocaine on early postoperative cognitive dysfunction after coronary artery bypass surgery Anesth Analg 2002;95:1134-1141.[Abstract/Free Full Text]
- Lezak MD. Neuropsychological Assessment3rd ed.. Oxford, UK: Oxford University Press; 1995.
- Murkin JM, Newman SP, Stump DA, Blumenthal JA. Statement of consensus on assessment of neurobehavioural outcomes after cardiac surgery Ann Thorac Surg 1995;59:1289-1295.[Free Full Text]
- Crook TH, Larrabee GJ. S self-rating scale for evaluating memory in everyday life Psychology Aging 1990;5:48-57.
- Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale Acta Psychiatr Scand 1983;67:361-370.[Medline]
- Bright P, Jaldow E, Kopelman, MD. The National Adult Reading Test as a measure of premorbid intelligence: a comparison with estimates derived from demographic variables J Int Neuropsych Soc 2002;8:847-854.[Medline]
- Evans DE, Kobrine AI, LeGrys DC, Bradley ME. Protective effect of lidocaine in acute cerebral ischaemia induced by air embolism J Neurosurg 1984;60:257-263.[Medline]
- Lei B, Cottrell JE, Kass IS. Neuroprotective effect of low-dose lidocaine in a rat model of transient focal ischemia Anesthesiology 2001;95:445-451.[Medline]
- Lei B, Popp S, Capuano-Waters C, Cottrell JE, Kass IS. Lidocaine attenuates apoptosis in the ischemic penumbra and reduces infarct size after transient focal cerebral ischemia in rats Neuroscience 2004;125:691-701.[Medline]
- Niiyama S, Tanaka E, Tsuji S, et al. Neuroprotective mechanisms of lidocaine against in vitro ischemic insult of the rat hippocampal CA1 pyramidal neurons Neurosci Res 2005;53:271-278.[Medline]
- Urenjak J, Obrenovitch TP. Pharmacological modulation of voltage-gated Na+ channels: a rational and effective strategy against ischemic brain damage Pharmacol Rev 1996;48:21-67.[Medline]
- Sakabe T, Maekawa T, Ishikawa T, Takeshita H. The effects of lidocaine on canine cerebral metabolism and circulation related to the EEG Anesthesiology 1974;40:433-441.[Medline]
- MacGregor RR, Thorner RE, Wright DM. Lidocaine inhibits granulocyte adherence and prevents granulocyte delivery to inflammatory sites Blood 1980;56:203-209.[Free Full Text]
- Drewry A, Gorman DF. Lidocaine as an adjunct to hyperbaric therapy in decompression illness: a case report Undersea Biomed Res 1992;19:187-190.[Medline]
- Stump DA, Stein CS, Tegeler CH, et al. Validity and reliability of an ultrasound device for detecting carotid emboli J Neuroimag 1991;1:18-22.[Medline]
- Nussmeier NA. Adverse neurological events: risks of intracardiac versus extracardiac surgery J Cardiothorac Vasc Anesth 1996;10:31-37.[Medline]
- Mathew JP, Grocott HP, Phillips-Bute B, Newman MF. Lidocaine does not prevent cognitive dysfunction after cardiac surgeryhttp://outcomeskeywest.com/Portals/16/Abstracts/2004/3-6.pdf 1996Accessed July 18, 2008.
Top
Abstract
Introduction
