In this prospective, placebo-controlled, randomized study of lidocaine during adult cardiac surgery with CPB, no neuroprotective effect of lidocaine was found. In addition, we found that diabetic subjects receiving lidocaine were more likely to suffer cognitive decline at 6 weeks. In secondary analyses, an association between higher total dose of lidocaine and increased neurocognitive decline was detected in the lidocaine treated group; a total dose of 35 mg/kg approximated the threshold for this cognitive decline. Furthermore, when the study sample was restricted to only nondiabetic subjects who received a dose of lidocaine < 42.6 mg/kg (75th percentile), a protective effect of lidocaine upon cognition was seen. A marginally significant improvement in cognition was also detected at 1 year after surgery in subjects receiving lidocaine, although this finding is limited by substantial loss to follow-up. There was no diminution of the perioperative cytokine response in lidocaine treated subjects.
Lidocaine is a cationic amide that blocks the sodium channel and has achieved widespread use as a local anesthetic and antiarrhythmic. The use of lidocaine as cerebral protectant largely arose from its assessment as a treatment for decompression illness. Evans et al14
were the first to demonstrate that cerebral somatosensory evoked response was preserved to a greater degree in anesthetized cats pretreated with lidocaine before a single bolus of air in the vertebral artery. Since then, numerous studies have attempted to define the neuroprotective mechanisms of lidocaine; these include reduction in activation and residual cerebral metabolism, deceleration of ischemic ion fluxes, preservation of CBF, and modulation of inflammatory mediators.13
During neuronal ischemia, Astrup et al22
in a canine model of global ischemia demonstrated that large doses of lidocaine (100-160 mg/kg) reduced the metabolic rate by 15-20% beyond that achieved by barbiturates, thus preserving cellular energy stores. Of note, the effects of lidocaine and hypothermia were additive. These investigators attributed their findings to lidocaine’s ability to block anoxic sodium influx and potassium efflux that lead to cellular edema and loss of cell function. Similarly, in rat hippocampal slices exposed to varying concentrations of lidocaine, anoxic depolarization was less frequent and delayed when it did occur.23
With more conventional dosing of lidocaine (0.2 mg/kg/min) administered to rabbits undergoing global ischemia, anoxic depolarization was again delayed.24
As a consequence, secondary neurotoxic events such as intracellular edema,25
cytosolic calcium accumulation,26
release are attenuated.
In conventional doses, lidocaine also has been reported to preserve CBF29
and reduce intracranial pressure30
but the existing data are conflicting. Depending on the dose of lidocaine and the vascular bed of interest, both vasodilatory and vasoconstrictive responses have been described.31-33
Furthermore, Lei et al34
in a rat model of focal cerebral ischemia demonstrated that an antiarrhythmic dose of lidocaine reduced infarct size 24 hours after ischemia but had no significant effect on CBF in the penumbra or the core during ischemia and reperfusion. The infarct-reducing effect of lidocaine was thought to be related to the inhibition of apoptotic cell death in the penumbra. Finally, neuroprotection with lidocaine may be a consequence of inflammatory modulation, largely manifested as a reduction in neutrophil adherence to injured endothelium, transmigration into the ischemic zone, and release of proinflammatory cytokines.35, 36
On the basis of the animal data presented above and case reports37
suggesting a beneficial effect of lidocaine in the treatment of cerebral arterial gas embolism, Mitchell and colleagues13
assessed the effect of lidocaine in 55 evaluable patients undergoing left heart valve surgery. Lidocaine was administered intravenously to 28 patients for a total duration of 48 hours. Significantly fewer lidocaine patients had a deficit in at least one neuropsychological test at 10 days and 10 weeks (p<0.025) and lidocaine patients achieved superior percentage change scores in 6 of the 11 tests (p<0.05). Of note, only 3 of the 55 patients (5.5%) in this study were diabetic and body mass index was lower in the lidocaine group. In a second study, Wang et al38
administered lidocaine until the end of surgery in 88 patients undergoing coronary revascularization. Patients treated with lidocaine again had a lower incidence of cognitive deficit (18.6% vs 40%, p=0.028); body weight was not different between treatment groups but only 9 subjects in each group were diabetic.
In the largest lidocaine study to date, our primary analysis revealed only a treatment by diabetes interaction such that diabetic subjects treated with lidocaine were more likely to experience cognitive decline. Post hoc
analyses, however, revealed not only a detrimental effect of higher total dose of lidocaine but also a potential protective effect of lidocaine when administered to nondiabetics at lower doses. The plasma concentration of lidocaine has been related to therapeutic and side effects; an accepted therapeutic range is 2-5 mcg/ml, with central nervous system toxicity manifested as visual disturbances, confusion, impaired concentration, tinnitus, tremors, dysarthria, or even seizures, psychosis, and coma at levels above 6-10 mcg/ml.39, 40
The distribution half life of lidocaine is typically short (6.8-9.3 minutes) and hepatic metabolism is the primary route of elimination, being highly dependent on hepatic blood flow with 60-70% of the drug extracted in the first pass. The pharmacokinetics of lidocaine, however, appear to change with prolonged infusions of lidocaine. When lidocaine is given as a constant infusion for more than 24 hours, the elimination rate constant and clearance decrease by approximately one half while the hepatic extraction rate decreases by almost two-thirds.41-43
Lidocaine disposition is also altered by disease states common to cardiac surgical patients such as congestive heart failure.44
In such patients, the volume of distribution of the central compartment is smaller so that the same dose will achieve a higher plasma concentration while a diminished cardiac index results in a decrease in clearance. Finally, lidocaine has active metabolites whose pharmacokinetics should be considered. Lidocaine is de-ethylated to monoethyglycinexylidide (MEGX), with further de-ethylation to glycinexylidide (GX). MEGX and GX have 83% and 10-26%, respectively of the antiarrhythmic potency of lidocaine and both may contribute to central nervous system toxicity.39, 43-45
The ratio of serum levels of MEGX to lidocaine and of GX to lidocaine averaged 0.36 + 0.26 and 0.11 + 0.11 in 33 cardiac patients receiving lidocaine for more than 24 hours.46
In the same study, MEGX levels were reported to be higher in patients with manifestations of lidocaine toxicity compared to the nontoxic patients. The importance of metabolites in toxicity is also highlighted by a study in normal volunteers where side effects were most common when lidocaine and MEGX were administered in combination.47
Lidocaine clearance also appeared to be inhibited by MEGX, a finding that may explain the delayed elimination seen with prolonged infusion.47
Therefore, despite normal plasma lidocaine levels, accumulation of metabolites may account for the development of toxicity.
The detrimental effect of lidocaine in diabetic subjects may also be related to its metabolism. Gawronska-Szklarz et al48
evaluated the effect of streptozotocin-induced diabetes on the elimination kinetics of lidocaine in male Wistar rats and found that experimental diabetes enhanced lidocaine elimination. In contrast, MEGX elimination was impaired with the MEGX half-life increasing from 0.34 hours in the control group to 0.89 hours in rats with diabetes. In an isolated perfused liver model (removing variations in hepatic flow), however, these same investigators reported that diabetes reduces lidocaine elimination possibly due to an impairment in the de-ethylation pathway.49
Unfortunately, pharmacokinetic data during extended lidocaine infusion and corroborating human data are lacking. Aside from differences in lidocaine pharmacokinetics, it has been reported that ATP-sensitive potassium channels, which are activated during cerebral hypoxia or ischemia to produce arteriolar dilation, demonstrate diminished responsiveness in diabetics50
and may be further impaired by lidocaine.51
However, the net effect of these findings are uncertain as channel function has not been compared with and without lidocaine in diabetic and nondiabetic subjects.
Methodological limitations to neuropsychological testing in the setting of cardiac surgery include the difficulty in obtaining corroborating brain imaging studies, the lack of control groups, and the often arbitrary nature of the definition of postoperative cognitive decline. While we also lack imaging measures, our placebo group serves as a control group and to partially overcome the arbitrary nature of our dichotomous outcome variable, we have also examined the continuous change scores. The principal limitation to our study is the loss to follow-up, particularly at the 1 year timepoint. Twenty-five percent of our subjects allocated to treatment did not return for follow-up testing at 6 weeks, rising to 42.5% at 1 year. At 6 weeks non-returning subjects had lower baseline cognitive scores and lower levels of education than returnees while at 1 year they had lower levels of education and were more likely to be diabetic. However, the other demographic characteristics listed in were not different and importantly, the rate of loss to follow-up was not different between the 2 treatment groups. The loss of diabetic subjects to follow-up at 1 year likely accounts for the marginally protective effect of lidocaine seen at 1 year. Another limitation to our study is the lack of lidocaine levels after 24 hours or lidocaine metabolite data in any of the enrolled subjects; thus, we are left to speculate that impaired elimination with prolonged infusion and accumulation of metabolites may be responsible for the observed detrimental effects. Finally, all posthoc analyses were considered exploratory and are unadjusted for multiple comparisons.
In summary, our study is the largest trial to date to evaluate the effect of lidocaine on neurocognitive outcomes following adult cardiac surgery in a prospective randomized manner. Lidocaine administration to the entire study population had no neuroprotective benefit and in fact was detrimental when given to diabetic subjects and at higher doses. Lidocaine also did not diminish the inflammatory response associated with CPB. When given to nondiabetics at reduced doses, a protective effect of lidocaine was observed, suggesting that further study in nondiabetic subjects is warranted.