Is intravenous lidocaine protective against myocardial ischaemia and reperfusion injury after cardiac surgery?

A best evidence topic was constructed using a described protocol. The three-part question addressed was: In patients undergoing cardiac surgery, does intravenous lidocaine exert a cardioprotective effect against postoperative myocardial ischaemia and reperfusion injury? Using the reported search, 461 papers were found, of which 5 studies represented the best evidence to answer the question. In 3 studies, lidocaine was associated with a postoperative fall in biomarkers of myocardial injury. An additional study lacked power, but the difference in biomarkers was marginally non-significant with a trend in favour of lidocaine. A final study evaluating ischaemic changes on continuous and 12 lead ECG found no benefit with lidocaine. The limited evidence suggests that lidocaine may be cardioprotective, although no study has demonstrated improvement in clinical outcomes. Furthermore, all trials were small studies with a multitude of dosing regimens in heterogenous patient populations. There is insufficient data to correlate dose with effect and not all studies measured plasma lidocaine concentration. The narrow therapeutic index and our current evidence base does not support lidocaine prophylaxis.


Introduction
A best evidence topic was constructed according to a structured framework outlined in the International Journal of Surgery [1].

Clinical scenario
A 75-year old man is referred to you for elective cardiac surgery. You know that lidocaine has been reported to protect the myocardium from ischaemia and reperfusion injury in animal models. You consider whether a perioperative lidocaine infusion will reduce the incidence of postoperative myocardial ischaemia. To answer this question, you carry out a literature search for the evidence. MEDLINE to June 2020 using the OVID interface.

Search outcome
461 papers were found using the reported search. In total, 5 randomised controlled trials (RCTs) were identified that provided the best evidence to answer the question. These are summarised in Table 1.

Results
Sunamori et al. [2] compared no treatment (n = 24) with lidocaine infusion (n = 24) at 1 mg min − 1 from induction of anaesthesia to 24 h after aorto-coronary saphenous vein bypass surgery under cardiopulmonary bypass (CPB). They found that serum creatine kinase   myocardial band (CK-MB) measured 18-24 h following initiation of reperfusion was significantly lower in the lidocaine treated group (P < 0.05) ( Table 1). In addition, the lidocaine treated group had a higher stroke volume index (P < 0.001) and cardiac index (P < 0.01) at 24 h after surgery. However, CK-MB levels peak at 6-8 h after injury and can decline to normal levels in 24-48 h. Thus, late measurements which fall on the declining part of the CK-MB curve may have missed or underestimated reperfusion injury.
King et al. [3] showed a significant reduction in ventricular arrhythmias (33% vs 67%; P < 0.005) in patients given 100 mg lidocaine bolus after CPB followed by 2 mg min − 1 infusion for 24 h (n = 40) compared to placebo control (n = 43). Myocardial injury was measured through 12 lead ECG on arrival to intensive care and at 12 and 24 h. CK-MB was measured in patients with ECG changes or when clinically indicated. There was no significant difference between numbers of new myocardial infarction or ST changes on ECG (Table 1). However, studies have shown that ECG changes may be limited or absent despite significant ischaemia with an estimated sensitivity of only 45% in acute myocardial infarction diagnosed by troponin and CK-MB assays [4]. Furthermore, it is not known whether these studies achieved the therapeutic range for lidocaine as dosing was not weight based and there was no measurement of serum levels.
Rinne et al. [5] compared 1 mg kg − 1 lidocaine bolus before cardiac cannulation followed by a 20 h 1.2 mg − 1 kg − 1 h − 1 infusion (n = 50) with no treatment control (n = 50) in patients undergoing CABG with CPB. There was a clear trend towards lower CK-MB (p = 0.09), Troponin T (TnT) values (p = 0.06) and myocardial infarctions (p = 0.20) in the lidocaine treated group, but these did not reach statistical significance ( Table 1). The study was underpowered by 50 patients in both groups when retrospective analysis was performed using the observed TnT difference. Serum lidocaine concentration was only measured in one patient who developed severe postoperative bradycardia with the level at the lower limit of the therapeutic range.
The therapeutic range for lidocaine when used for analgesia is described as 2.5-3.5 μg ml − 1 whereas 2-6 μg ml − 1 is usually quoted for its anti-arrhythmic effects [7]. It is unclear what levels should be targeted for myocardial protection. Systemic lidocaine has a narrow therapeutic index with serum levels >5 μg ml − 1 resulting in central nervous system (CNS) toxicity. Cardiovascular toxicity can also occur when levels exceed 10 μg ml − 1 . Furthermore, lidocaine may be cardiotoxic opposed to cardioprotective at higher concentrations. In vitro studies on arterial and venous grafts have demonstrated vasodilation at low concentrations and dose-dependent vasoconstriction at higher doses [8]. Serum lidocaine concentration will also fall abruptly upon initiation of CPB due to haemodilution and increased volume of distribution. This may necessitate a significant loading dose, which may risk local anaesthetic toxicity, in order to achieve therapeutic plasma levels after bypass.
Kim et al. [9] compared lidocaine (n = 36) and dexmedetomidine (n = 40) alone and in combination (n = 39), against no infusion control (n = 38) in off-pump CABG. Lidocaine bolus of 1.5 mg kg − 1 at induction of anaesthesia was followed by a 2 mg kg − 1 h − 1 infusion continued for 24 h from the end of surgery. Dexmedetomidine infusion was adjusted between 0.3 and 0.7 μg kg − 1 h − 1 to maintain mean arterial blood pressure within 20% of the preoperative value. Serum CK-MB and TnI were measured the day before surgery, immediately after surgery and on postoperative day one and two (Table 1). Median CK-MB concentrations on both postoperative days were significantly lower for the lidocaine (P = 0.003) and combined group (P = 0.015) compared to control. Troponin I was significantly lower for the lidocaine (P = 0.003) and combined group (P = 0.048) on postoperative day two only. The area under the curve with these time points was significantly lower for the  lidocaine (P = 0.048) and combined group (P = 0.006) compared to control for CK-MB but not TnI.
There is a biochemical signal across studies grounded in scientific plausibility for lidocaine cardioprotection. Lidocaine inhibits the ischaemic induced accumulation of sodium and loss of potassium in myocardial cells [10]. Animal models have demonstrated an antiapoptotic effect after myocardial ischaemia reperfusion with reduction of infarct size and post-ischaemic improvement in functional and metabolic recovery [11,12]. However, while studies have shown significant differences in cardiac enzyme levels in favour of lidocaine, there is no direct correlate with clinical outcomes. These observed differences in biomarkers of cardiac injury therefore needs to be interpreted with caution. Studies have not been powered to detect differences in clinical outcome measures such as myocardial infarction, mortality or length of hospital stay. Those that reported rates of myocardial infarction were also poorly specified with studies utilising different definitions and methods of detection.
Lidocaine has a high hepatic extraction ratio and therefore requires dose reduction in patients with liver disease and reduced cardiac output states. Metabolites can also cause toxicity in those with heart failure and accumulate in renal failure [12]. Population studies in cardiac surgery with CPB have modelled pharmacokinetics based on body weight [13]. Prolonged infusions also require dose reduction to prevent accumulation as the active metabolite monoethylglycinexylidide (MEGX) has an inhibitory effect on lidocaine clearance. These factors were not fully explored with huge variation in dosing regimens between studies. Not all studies administered an initial bolus and concerningly, some did not consider patient weight and co-morbidities in dosing calculations.
Furthermore, not all studies measured serum lidocaine concentration making it difficult to relate dose to effect. CPB also needs to be considered as a distinct category of analysis as the pharmacokinetic differences between on-pump and off-pump surgery mandates a different approach to dosing. In addition, the risk of bias with inadequate blinding in three studies in combination with small sample sizes makes results difficult to generalise. Studies also failed to evaluate the effect of lidocaine in obtunding perioperative stress and sympathetically mediated haemodynamic changes. While hypertension, tachycardia and increased myocardial oxygen demand is clearly undesirable, any substantial drop in blood pressure will compromise coronary perfusion pressure and risk ischaemic injury.

Clinical bottom line
The available evidence is suggestive that lidocaine may be cardioprotective as there is an association with lower biochemical markers of myocardial injury in the postoperative period. However, studies were missing crucial clinical outcome data which is of practical importance to patient care. All studies were small, exclusively in coronary artery bypass surgery and with significant differences between patient groups including co-morbidities, lidocaine dosing regimen and use of CPB. This substantial heterogeneity between studies makes these findings difficult to pool or generalise. Furthermore, the optimum dosing regimen has not been established and there is a concern that inappropriately high serum lidocaine levels may be cardiotoxic. Measurement of plasma lidocaine concentrations is essential and future studies need to correlate these with not only biochemical but also clinical end points. These studies also need to be pragmatically designed and powered to prioritise objective patient-relevant clinical outcomes. With these reservations, we are unable to recommend lidocaine prophylaxis for postoperative myocardial ischaemia and reperfusion injury.

Declaration of competing interest
No conflicts of interest to declare.

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Guarantor
Chengyuan Zhang is guarantor for this paper.