Serum lidocaine (lignocaine) concentrations during prolonged perioperative infusion in patients undergoing breast cancer surgery: A secondary analysis of a randomised controlled trial

Abstract

Perioperative lidocaine (lignocaine) infusions are being employed with increasing frequency. The determinants of systemic lidocaine concentrations during prolonged administration are unclear. In the Long-term Outcomes after Lidocaine Infusions for PostOperative Pain (LOLIPOP) pilot trial, the impact of infusion duration and body size metrics on serum lidocaine concentrations was examined with regression models in 48 women undergoing breast cancer surgery. Lidocaine was delivered as an intravenous bolus (1.5 mg/kg) and infusion (2 mg/kg per h) intraoperatively, followed by a 12-h subcutaneous infusion (1.33 mg/kg per h) postoperatively. Dosing was based on total body weight. Wound infiltration with other long-acting local anaesthetics was permitted. Protein binding and pharmacogenomic data were also collected. Lidocaine concentrations (median (interquartile range) (range)) during prolonged administration were in the safe and potentially therapeutic range: post-anaesthesia care unit 2.16 (1.73–2.82) (1.12–6.06) µg/ml; ward 1.41 (1.22–1.75) (0.64–2.81) µg/ml. Concentrations increased non-linearly during the early intravenous phase of administration (mean rise 1.21 µg/ml per hour of infusion, P = 0.007) but reached a pseudo steady-state during the later subcutaneous phase. Higher dose rates received per kilogram of lean (P = 0.004), adjusted (P = 0.006) and ideal body weight (P = 0.009) were associated with higher steady-state concentrations. The lidocaine free fraction was unaffected by the presence of ropivacaine, and phenotypes linked to slow metabolism were infrequent. Serum lidocaine concentrations reached a pseudo steady-state during a 12-h postoperative infusion. Greater precision in steady-state concentrations can be achieved by dosing on lean body weight versus adjusted or ideal body weight (equivalent lean body weight doses: intravenous bolus 2.5 mg/kg; intravenous infusion 3.33 mg/kg per h; subcutaneous infusion 2.22 mg/kg per h.

Keywords

Breast cancer surgery intravenous infusion lidocaine concentration perioperative subcutaneous infusion opioid-free

Introduction

Systemic lidocaine (lignocaine) infusions have been used for more than 50 years to treat or prevent a variety of conditions including cardiac arrhythmias,¹ chronic neuropathic pain,² cancer pain³ and, more recently, acute⁴ and chronic post-surgical pain.⁵ For many of these clinical indications, prolonging the duration of lidocaine infusion offers a therapeutic advantage and minimisation of opioid-related side-effects.⁶ However, maintaining safety reliably during prolonged intravenous infusion has proven problematic due to the risk of inadvertent intravenous bolus⁷ and unrecognised systemic accumulation.^8–11 As a consequence, many institutional guidelines advise that postoperative lidocaine infusions take place in critical care areas with continuous cardiac monitoring, and few clinicians are comfortable outside of these restrictions.¹²

A recent development in perioperative trials is the use of the subcutaneous route to deliver a prolonged postoperative lidocaine infusion after intraoperative loading via the intravenous route.^13,14 This offers a safety advantage by eliminating the risk of inadvertent intravenous bolus outside of the theatre environment. In addition, subcutaneous lidocaine has previously been shown to achieve appropriate systemic concentrations after a single bolus¹⁵ and during titrated infusions lasting days to weeks in terminal cancer patients.¹⁶ However, data in the surgical setting around the determinants of systemic lidocaine concentrations during prolonged subcutaneous infusion and the risk of unrecognised accumulation remain sparse. In particular, the influence of infusion duration,¹⁷ obesity,¹⁸ parallel local anaesthetic techniques¹⁹ and inherited phenotypes linked to slow lidocaine metabolism²⁰ are under-explored. We therefore conducted this planned secondary analysis of our recently completed Long-term Outcomes after Lidocaine Infusions for PostOperative Pain (LOLIPOP) pilot trial²¹ to evaluate the impact of these variables on systemic lidocaine concentrations during intravenous and prolonged subcutaneous administration.

Material and methods

This is a planned secondary analysis of the LOLIPOP pilot trial following on from the primary analysis published in 2021.²¹ LOLIPOP was approved by the South Metropolitan Health Service Human Research Ethics Committee on 22 December 2017 and registered on 29 March 2018 (ACTRN12618000463279).¹³ Briefly, women undergoing breast cancer surgery were randomised to lidocaine (n = 74) or placebo (n = 76) infusions starting intraoperatively and continuing for up to 12 h postoperatively. Intraoperative lidocaine 2% was delivered intravenously via a pre-programmed Alaris PK Pump (BD systems, New Jersey, USA), starting with a 1.5 mg/kg bolus over 5 min after induction of anaesthesia, followed immediately by an infusion of 2 mg/kg per h that continued into the post-anaesthesia care unit (PACU). In PACU, the intravenous infusion was replaced with a subcutaneous infusion of lidocaine 10%, delivered via a Niki T34 (BD systems, New Jersey, USA), a wearable syringe driver, at a rate of 1.33 mg/kg per h for up to 12 h, unless stopping or hospital discharge criteria were met at an earlier juncture. These doses and dosing rates represent 86.5% of lidocaine base and were calculated based on total (actual) body weight, capped at 100 kg. Doses were selected to target steady-state concentrations of 1.5 µg/ml based on results from equivalent perioperative trials^14,22 and therapeutic thresholds identified in chronic pain populations.²³ Routine surgical practice with respect to long-acting local anaesthetics for wound infiltration or field blocks intraoperatively was permitted, with dose limits applied for ropivacaine (2 mg/kg) and bupivacaine (1 mg/kg).

Serum samples and assays

Blood samples were collected twice where possible; once in PACU during the intravenous infusion within 1 h of arrival (the PACU sample), and once on the ward during the subcutaneous infusion within a time-window of 4–12 h from the end of surgery (the ward sample). Serum was obtained then stored at –80°C in three aliquots (minimum 0.5 ml) and batch transferred to the laboratory. Samples were then assayed to quantify total serum lidocaine, the main metabolite monoethylglycinexylidide (MEGX) and the secondary metabolite glycinexylidide (GX), using a validated ultra performance liquid chromatography (UPLC) mass spectrometry method (coefficient of variation <10%). Total serum ropivacaine and bupivacaine were also quantified using UPLC mass spectrometry. Unbound local anaesthetics and lidocaine metabolites were extracted using temperature-controlled ultrafiltration and measured again with UPLC mass spectrometry. Finally, alpha-1 acid glycoprotein was quantified using an immunonephelometry assay on the IMMAGE system from Beckman Coulter.

This secondary analysis focuses on patients who were randomised to lidocaine and had at least one valid serum sample.

Dose rate calculations

In order to evaluate dosing strategies based on different body size metrics, the average dose rate received in mg/kg per h at each sampling point was calculated. For these calculations, the total lidocaine dose administered was divided by the infusion duration in hours, then divided again by one of four measures of body size commonly used in pharmacokinetic studies: total body weight, ideal body weight, adjusted body weight and lean body weight. Body size formulae evaluated by Green and Duffull were applied,¹⁸ alongside a simpler formula for ideal body weight based on recent recommendations for easy bedside application (height in centimetres minus 105 for women).⁸

Pharmacogenomics

At study conclusion, cheek swabs were mailed to participants allocated to the lidocaine arm. These were forwarded to myDNA (Melbourne, Australia) for pharmacogenomic single-nucleotide polymorphism analysis of CYP1A2 (rs76255, rs2069514, rs35694136), CYP3A4 (rs35599367) and CYP3A5 (rs776746, rs10264272, rs41303343). From the genotype results, individual phenotypes were summarised as follows: CYP1A2 normal, ultra rapid with inducer present, or unknown; CYP3A4 and CYP3A5 normal or intermediate. The dominant combined CYP1A2/CYP3A phenotype was ranked in order of the anticipated metabolism speed from slow to fast: Group 1, normal/intermediate; Group 2, normal/normal; Group 3, ultrarapid/intermediate; Group 4, ultrarapid/normal. If the CYP1A2 phenotype was unknown, no combined phenotype was assigned. The CYP3A4 and CYP3A5 categories were also combined to reflect an overall CYP3A phenotype²⁴ of poor, intermediate or extensive, and these in turn were explored in combination with CYP1A2 phenotype.

Statistical analysis

Continuous variables were tested for normality using D’Agostino’s omnibus test. All descriptive data for continuous variables are expressed as median (interquartile range (IQR)) (range) or number (percentage) because of skewed distributions.

To ensure adequate power, the analysis focused on regression models exploring covariates associated with lidocaine concentrations where there were at least 10 observations per covariate. Additional exploratory analyses were performed without a multiplicity adjustment of the statistical significance threshold.

Spearman’s rank correlation coefficient was used to identify covariates associated with the total serum lidocaine concentration in PACU during intravenous infusion, and the total serum lidocaine concentration on the ward during subcutaneous infusion. Backwards elimination linear regression models with natural log transformation were constructed to examine covariates in a multivariable context. Covariates entered into these models included age, infusion duration (from time of initial bolus) and average lidocaine dose administered per kilogram of body weight (mg/kg per h). These covariates were retained at a threshold of P < 0.1. Separate models were used for each body size metric.

The metabolic ratio for MEGX and GX was calculated by dividing the total lidocaine concentration by the metabolite concentrations. Changes in serum lidocaine and alpha-1 acid glycoprotein concentrations, metabolic ratios and protein binding in the early postoperative period were assessed in patients with both a PACU and a ward value, using the Mann–Whitney U test.

Serum lidocaine concentration-time profiles using the described drug delivery systems were evaluated with mixed-effects models incorporating non-linear fitting with fractional polynomials assessed using the χ² test. All patients were assumed to have a lidocaine concentration of zero at time zero (the start of the lidocaine bolus).

To evaluate whether lidocaine is displaced from binding sites by the presence of other amide local anaesthetics, any correlation between the lidocaine free fraction and the serum concentration of ropivacaine and alpha-1 acid glycoprotein was assessed using linear regression.

The distribution of CYP phenotypes was summarised descriptively. Exploratory analyses of the impact of CYP phenotype on lidocaine concentration were conducted with the Mann–Whitney and Kruskal–Wallis tests as appropriate.

Analyses were completed in Stata (Stata Statistical Software: Release 16. 2019. StataCorp LLC, College Station, TX, USA) with a significance threshold of P < 0.05.

Results

Patient and procedural characteristics are summarised in Table 1. Lidocaine data were available for 48 patients and demonstrated a positively skewed distribution that normalised after natural log transformation.

Table 1.

Patient and treatment characteristics.

	PACU n = 41	Ward n = 48
Patient characteristics
Age, years	60 (55–68) (35–71)	61 (55–68) (35–71)
Total body weight, kg	78 (67–85) (53–115)	80 (67–88) (53–122)
Adjusted body weight, kg	64 (57–68) (50–79)	65 (60–70) (50–86)
Ideal body weight, kg	57 (52–62) (45–78)	58 (54–63) (45–78)
Lean body weight, kg	47 (44–51) (40–57)	48 (45–51) (40–57)
Height, cm	162 (157–167) (150–183)	163 (159–168) (150–183)
BMI, kg/m²	30 (24–24) (20–43)	28 (24–34) (20–43)
BMI ≥30 kg/m², n (%)	17 (41)	21 (51)
ASA 1, n (%)	3 (7)	5 (10)
ASA 2, n (%)	25 (61)	30 (63)
ASA 3, n (%)	13 (32)	13 (27)
White/Caucasian, n (%)	36 (88)	42 (88)
Index surgery
Breast conserving surgery, n (%)	36 (88)	43 (90)
Mastectomy, n (%)	5 (12)	5 (10)
Duration of surgery, min	60 (44–89) (27–289)	57 (43–85) (24–289)
Wound infiltration with ropivacaine, n (%)	26 (63)	28 (58)
Ropivacaine dose when given, mg	133 (106–150) (16–200)	139 (112–150) (16–200)
Wound infiltration with bupivacaine, n (%)	15 (37)	20 (42)
Bupivacaine dose when given, mg	75 (60–89) (20–100)	78 (60–96) (20–100)
Lidocaine infusion
Infusion duration at sampling point, min	122 (94–144) (54–305)	369 (320–426) (235–597)
Total dose at sampling point, mg	364 (288–444) (193–954)	839 (720–1048) (511–1262)

Data presented as median (interquartile range) (range) or number (percentage).

PACU: post-anaesthesia care unit; BMI: body mass index; ASA: American Society of Anesthesiologists Physical Status Classification.

Modelling of total serum lidocaine concentration

In the multivariable models at the PACU timepoint, infusion duration was the only variable associated with lidocaine concentration; coefficient = 1.21, R² = 17.0%, P = 0.007 (Table 2). This relationship between intravenous infusion duration and lidocaine concentration was non-linear.

Table 2.

Univariable correlation and multivariable linear regression (backward elimination) for lidocaine concentrations in the post-anaesthesia care unit and on the ward.

	Univariate		Multivariable
	Spearman’s rho	P value	Coefficient	R ²	P value
PACU models (n = 41)
Age, years	–0.080	0.621
Infusion duration, h	0.417	0.007	1.21	17.0%	0.007
Dose per TBW, mg/kg per h^a	–0.215	0.177
Dose per ABW, mg/kg per h^a	0.087	0.589
Dose per IBW, mg/kg per h^a	0.178	0.265
Dose per LBW, mg/kg per h^a	0.138	0.391
Ward model with dose per TBW (n = 48)
Age, years	0.214	0.144
Infusion duration, h	0.186	0.206
Dose per TBW, mg/kg/ per h	0.109	0.461
Ward model with dose per ABW (n = 48)
Age, years	0.214	0.144
Infusion duration, h	0.186	0.206	1.08	18.1%	0.039
Dose per ABW, mg/kg per h	0.297	0.041	1.57	18.1%	0.006
Ward model with dose per IBW (n = 48)
Age, years	0.214	0.144
Infusion duration, h	0.186	0.206	1.07	16.9%	0.066
Dose per IBW, mg/kg per h	0.303	0.036	1.24	16.9%	0.009
Ward model with dose per LBW (n = 48)
Age, years	0.214	0.144
Infusion duration, h	0.186	0.206	1.08	19.5%	0.052
Dose per LBW, mg/kg per h	0.335	0.020	1.30	19.5%	0.004

PACU models were constructed separately for each body size metric, with the addition of age and infusion duration.

PACU: post-anaesthesia care unit; TBW: total body weight; IBW: ideal body weight; ABW: adjusted body weight; LBW: lean body weight.

In the multivariable models of concentrations at the ward timepoint, the average lidocaine dose rate received per kilogram of adjusted body weight (ABW), ideal body weight (IBW) or lean body weight (LBW), but not total body weight, was associated with the serum lidocaine concentration (Table 2). The LBW model explained the most variance (R² = 19.5%, P = 0.004); every 1 mg/kg per h increase in the average dose rate resulted in a 0.30 µg/ml increase in the lidocaine concentration. The relationships between doses received per body size metric and the resulting ward lidocaine concentrations are further described in Supplementary material Figure 1 online. Infusion duration was not a consistently significant covariate in the ward models.

Figure 1.

Non-linear fitted fractional polynomial curve of the relationship between infusion duration and total lidocaine concentration measured in the first 10 postoperative hours, with raw data included (mixed-effect model: R² = 17.0%; P < 0.0001).

The exploratory mixed-effects model analysis of lidocaine concentrations across the perioperative infusion period incorporated two infusion duration covariates describing an early rise during the intravenous infusion followed by a gradual decline towards steady-state during the subcutaneous phase (Figure 1).

Paired samples

Data from participants with paired serum samples in PACU and on the ward (n = 39) are summarised in Table 3. Consistent with the higher doses during the intravenous phase, median (IQR) (range) total lidocaine concentrations were significantly higher in PACU than on the ward: 2.16 (1.73–2.82) (1.12–6.06) µg/ml versus 1.41 (1.22–1.75) (0.64–2.81) µg/ml, P < 0.0001. Only three patients had a higher lidocaine concentration at the later timepoint (+0.10, +0.44, +0.63 µg/ml).

Table 3.

Serum concentrations of lidocaine, monoethylglycinexylidide, glycinexylidide and alpha-1 acid glycoprotein in the post-anaesthesia care unit and on the ward (paired samples only).

	PACU n = 39	Ward n = 39	P value
Lidocaine
Total lidocaine, µg/ml	2.16 (1.73–2.82) (1.12–6.06)	1.41 (1.22–1.75) (0.64–2.81)	<0.0001
Unbound lidocaine, µg/ml	0.58 (0.47–0.78) (0.33–2.04)	0.40 (0.34–0.44) (0.14–1.11)	<0.0001
Lidocaine protein binding, %	70 (67–75) (55–84)	73 (69–79) (46–82)	0.176
Primary metabolite
Total MEGX, µg/ml	0.29 (0.23–0.42) (0.08–0.66)	0.36 (0.26–0.45) (0.12–0.81)	0.271
Unbound MEGX, µg/ml	0.22 (0.17–0.33) (0.04–0.61)	0.24 (0.17–0.34) (0.09–0.59)	0.348
Total lidocaine:total MEGX ratio	7.00 (5.56–10.31) (2.06–17.41)	4.35 (3.26–5.61) (2.19–12.08)	<0.0001
Secondary metabolite
Unbound GX^a, µg/ml	0.03 (0.02–0.04) (0.00–0.15)	0.08 (0.05–0.12) (0.00–0.34)	<0.0001
Total lidocaine:unbound GX ratio	76.65 (49.01–109.66) (11.47–352.63)	14.70 (10.53–34.56) (4.07–73.06)	<0.0001
Alpha-1 acid glycoprotein
Alpha-1 acid glycoprotein, µg/ml	0.80 (0.65–0.85) (0.43–1.18)	0.74 (0.66–0.85) (0.51–1.20)	0.589

Data presented as median (interquartile range) (range).

^aSerum values of the secondary metabolite, GX, were low and better quantified by the unbound assay.

PACU: post-anaesthesia care unit; MEGX: monoethylglycinexylidide; GX: glycinexylidide.

Neither alpha-1 acid glycoprotein concentration nor lidocaine protein binding changed significantly in the early postoperative period (Table 3). First-step metabolism to MEGX increased between PACU and the ward, reflected in a decreased metabolic ratio. Similarly, second-step metabolism to GX also increased between PACU and the ward, reflected in a decreased metabolic ratio.

Other amide local anaesthetics and protein binding

Serum ropivacaine and bupivacaine were detectable in less than 65% patients in PACU and on the ward (Supplementary Table 1). Total concentrations were low and did not exceed 0.39 and 0.14 µg/ml respectively. Protein binding (%) for ropivacaine and bupivacaine was considerably higher than for lidocaine. The lidocaine free fraction was not correlated with total ropivacaine or bupivacaine concentrations but was correlated with the alpha-1 acid glycoprotein concentration (Figure 2).

Figure 2.

Scatterplots with linear regression for: (a) lidocaine free fraction versus total ropivacaine in post-anaesthesia care unit (PACU) (coefficient = –2.65, R² = 0.12%, P = 0.886, n = 20) and (b) lidocaine free fraction versus alpha-1 acid glycoprotein in PACU (coefficient = –24.9, R² = 43.4%, P < 0.001, n = 41).

Pharmacogenomics

Total lidocaine concentrations at the PACU and ward sampling points are summarised according to cytochrome P450 phenotypes in Supplementary Table 2. Phenotypes linked to slow metabolism were uncommon (≤12%). No statistically significant differences in lidocaine concentrations were apparent between phenotype groups at either timepoint.

Discussion

This secondary analysis of the LOLIPOP pilot study demonstrates that intraoperative intravenous lidocaine infusion, followed by a reduced postoperative subcutaneous infusion, results in relatively stable systemic drug concentrations 4–10 h after the initial drug bolus. Lidocaine exposure with our dosing strategy was highest and most variable in PACU, during a period of careful monitoring and one-to-one nursing. Thereafter, serum concentrations dropped slowly towards a pseudo steady-state. No ward lidocaine concentrations exceeded values purportedly linked to systemic toxicity (5 µg/ml).⁸

The parameters we identified as significant determinants of systemic lidocaine concentrations at the early and later measurement points were consistent with pharmacokinetic studies in non-surgical settings. First, Bassan and colleagues have shown that it takes 6 h of lidocaine administration to approximate steady-state when a bolus and infusion combination is employed.²⁵ It is therefore unsurprising that infusion duration was the main determinant of lidocaine concentration in the PACU models, with sampling times ranging between one and five hours from the initial drug bolus. Clinicians using intravenous lidocaine intraoperatively with equivalent dosing schedules should be aware that longer operations will result in higher systemic concentrations.

Second, lidocaine metabolism observes first-order kinetics,²⁶ whereby the steady-state concentration (µg/ml) is determined by the fixed infusion rate (µg/kg per h) divided by the clearance rate (ml/kg per h). In surgical populations with lidocaine dosing per kilogram of total body weight, obese patients will receive a higher fixed infusion rate. They will not, however, exhibit a proportionally higher clearance rate, as this is largely determined by liver blood flow²⁷ that changes little with increased adiposity. Lidocaine clearance for a given individual is better reflected by alternative body size metrics such as LBW, which is well-established as a means of chronic drug dosing.¹⁸ Indeed, obese patients in our study were observed to receive a higher fixed infusion rate per kilogram of lean, adjusted and ideal body weight and consequently exhibited higher steady-state concentrations (Supplementary Figure 1). Future studies should consider dosing lidocaine according to LBW to reduce some of the inter-individual variability in steady-state concentrations and avoid overshoot in obese patients (equivalent LBW doses: intravenous bolus 2.5 mg/kg; intravenous infusion 3.33 mg/kg per h; subcutaneous infusion 2.22 mg/kg per h).

In our models of lidocaine concentrations measured on the ward between 4 h and 10 h from the initial bolus, infusion duration was not a consistently significant covariate (ABW model, coefficient = 1.08, P = 0.039; IBW model, coefficient = 1.07, P = 0.066; LBW model, coefficient = 1.08, P = 0.052). However, these data remain consistent with small concentration increases over time, representing either the final approach towards steady-state, or autoinhibition of lidocaine metabolism by its own metabolites during prolonged exposure.²⁸ Consequently, gradual rises beyond 10 h cannot be ruled out. Indeed, Bauer and colleagues demonstrated falling lidocaine clearance rates in the first 30 h of drug infusion in healthy volunteers,¹⁷ and many clinical studies have also reported lidocaine concentration rises during fixed rate infusions, well beyond the time required to reach steady-state.^29,30 Importantly, the rises observed in these studies are gradual and unlikely to encroach on minor toxicity thresholds (5 µg/ml) when doses similar to those employed in our study are used for up to 24 h.¹⁴ As longer-duration infusions may ultimately be necessary to maximise the antinociceptive,⁴ antihyperalgesic³¹ and anti-inflammatory³² lidocaine effects in surgical patients, future work should evaluate whether autoinhibition is a robust and quantifiable phenomenon in the perioperative period.

The use of additional long-acting local anaesthetic agents was permitted in the pilot study in order to assess the added value of lidocaine over and above routine practice. Serum concentrations of ropivacaine and bupivacaine were low in PACU and on the ward, reflecting limited systemic absorption, and no major safety events were detected.¹³ The absence of a correlation between the lidocaine free fraction and total ropivacaine suggests that significant competition for protein binding sites was not taking place, and the potential for synergistic toxicity demonstrated in vitro¹⁹ is not a concern at these low concentrations. In this light, our data support the concept that recommendations to universally avoid other local anaesthetic techniques alongside lidocaine infusions⁸ appear unnecessarily restrictive.^33,34 Consistent with other breast surgery studies,³⁵ we observed no significant changes in concentrations of alpha-1 acid glycoprotein or lidocaine protein binding over time. Thus, total and unbound lidocaine concentrations are highly correlated in the very early postoperative period, and either can be used to probe efficacy and safety in breast cancer surgery patients.

In our pharmacogenomic analysis, phenotypes potentially linked to slow lidocaine metabolism via CYP systems were infrequent. The CYP3A4*22 variant, present in about 10% of European populations, has gained prominence due to its association with considerably reduced CYP3A4 protein expression and function.³⁶ The CYP1A2*1F variant is also common (over 50% in Europeans) and leads to rapid metabolism in the presence of inducers such as smoking.³⁷ The frequencies of these polymorphisms in the pilot study reflected the general population and were not associated with markedly different lidocaine concentrations. Although these data are only preliminary and based on a limited sample size, it remains reassuring that large fluctuations in lidocaine concentrations were not observed. Definitive pharmacogenomic studies can now be embedded within clinical trials based on these frequencies in a predominantly European-heritage cohort.

Finally, our data confirm that there is considerable inter-individual variation in lidocaine concentrations during perioperative administration, up to 80% of which remains unexplained. This variability is likely to pertain to inter-individual differences in liver blood flow and CYP function that are dynamic due to the impact of anaesthesia and surgery,^38,39 and difficult to measure with conventional approaches. Even on the postoperative ward where haemodynamics are very stable in patients after breast surgery, we observed a positively skewed range of lidocaine concentrations spanning 2.17 µg/ml. At present, ensuring that the individuals creating this positive skew do not exceed toxic thresholds requires restraint in dosing regimens applied to whole populations. Ultimately, more population-specific data on lidocaine concentrations and safety are required to guide better precision.

This secondary analysis of the LOLIPOP pilot study has several limitations. First, we did not employ any population pharmacokinetic analyses to formally derive or test pharmacokinetic parameters. Second, the sample size was limited and no a priori power calculations were performed. Consequently, many of our analyses remain exploratory in the absence of formal multiplicity adjustments. Finally, our results cannot be generalised to other surgical populations, where postoperative liver blood flow and lidocaine metabolism are less predictable.⁴⁰

In conclusion, in patients undergoing routine care for breast cancer surgery we have shown that infusion of intravenous lidocaine intraoperatively followed by a lower dose subcutaneous infusion postoperatively resulted in pseudo steady-state concentrations 4–10 h after the initial bolus. Such steady-state concentrations were determined in part by the dose rate administered per kilogram of lean, adjusted or ideal body weight. Perioperative lidocaine concentrations exceeded or approximated therapeutic thresholds previously described in chronic pain cohorts²³ and those achieved in equivalent randomised trials.⁸ Conversely, all ward concentrations were below the threshold traditionally linked to minor toxicity (5 µg/ml). Thus, in combination with reassuring safety data from the pilot study,¹³ this dosing approach appears to balance efficacy and safety concerns. The definitive LOLIPOP trial (NCT05072314) is therefore employing a similar dosing regimen for up to 24 h, modified to a LBW approach. To evaluate the scope for further precision in lidocaine delivery, pre-specified sub-studies will fully explore autoinhibition and pharmacogenomic effects.

Supplemental Material

sj-pdf-1-aic-10.1177_0310057X231194833 - Supplemental material for Serum lidocaine (lignocaine) concentrations during prolonged perioperative infusion in patients undergoing breast cancer surgery: A secondary analysis of a randomised controlled trial

Supplemental material, sj-pdf-1-aic-10.1177_0310057X231194833 for Serum lidocaine (lignocaine) concentrations during prolonged perioperative infusion in patients undergoing breast cancer surgery: A secondary analysis of a randomised controlled trial by Andrew J Toner in Anaesthesia and Intensive Care

Supplemental Material

sj-pdf-2-aic-10.1177_0310057X231194833 - Supplemental material for Serum lidocaine (lignocaine) concentrations during prolonged perioperative infusion in patients undergoing breast cancer surgery: A secondary analysis of a randomised controlled trial

Supplemental material, sj-pdf-2-aic-10.1177_0310057X231194833 for Serum lidocaine (lignocaine) concentrations during prolonged perioperative infusion in patients undergoing breast cancer surgery: A secondary analysis of a randomised controlled trial by Andrew J Toner in Anaesthesia and Intensive Care

Footnotes

Author Contributions

Andrew J Toner: Conceptualization; Data curation; Formal analysis; Funding acquisition; Writing – original draft.

Martin A Bailey: Conceptualization; Writing – review & editing.

Stephan A Schug: Conceptualization; Writing – review & editing.

Michael Phillips: Formal analysis; Writing – review & editing.

Jacobus PJ Ungerer: Formal analysis; Writing – review & editing.

Andrew A Somogyi: Formal analysis; Writing – review & editing.

Tomas B Corcoran: Conceptualization; Writing – review & editing.

Acknowledgements

At Royal Perth Hospital, Perth, the following research fellows assisted with data collection: F Droste, K Fisher, A Ganska, E Sethi-Chaudhary, M De Avila, D Ishak, C Fellingham, Y Yew. In-kind equipment support was received from REM Systems (North Ryde, Australia), including loan of Niki T34 syringe drivers and associated disposables, with no involvement in study design, data collection, analysis or interpretation.

Data sharing statement

Data are available from the corresponding author upon reasonable request.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Australian and New Zealand College of Anaesthetists (19/040); the Royal Perth Hospital Research Foundation (Springboard Grant 2019); and a Raine Medical Research Foundation/Department of Health Clinician Research Fellowship (CRF011-R7) to AT.

ORCID iDs

Andrew J Toner

Andrew A Somogyi

Supplemental material

Supplemental material for this article is available online.

References

Collinsworth

Kalman

Harrison

DC.

The clinical pharmacology of lidocaine as an antiarrhythmic drug. Circulation 1974; 50: 1217–1230. doi:10.1161/01.cir.50.6.1217

Tremont-Lukats

Challapalli

McNicol

, et al. Systemic administration of local anesthetics to relieve neuropathic pain: A systematic review and meta-analysis. Anesth Analg 2005; 101: 1738–1749. doi:10.1213/01.ANE.0000186348.86792.38

Lee

Sanderson

Xuan

, et al. Lidocaine for cancer pain in adults: A systematic review and meta-analysis. J Palliat Med 2019; 22: 326–334. doi:10.1089/jpm.2018.0257

Weibel

Jokinen

Pace

, et al. Efficacy and safety of intravenous lidocaine for postoperative analgesia and recovery after surgery: A systematic review with trial sequential analysis. Br J Anaesth 2016; 116: 770–783. doi:10.1093/bja/aew101

Bailey

Corcoran

Schug

, et al. Perioperative lidocaine infusions for the prevention of chronic postsurgical pain: A systematic review and meta-analysis of efficacy and safety. Pain 2018; 159: 1696–1704. doi:10.1097/j.pain.0000000000001273

McLott

Stahel

PF.

Opioid-free anesthesia: the next frontier in surgical patient safety. Patient Saf Surg 2022; 16: 38. doi:10.1186/s13037-022-00346-5

De Oliveira

Eipe

Intravenous lidocaine for acute pain: A single-institution retrospective study. Drugs Real World Outcomes 2020; 7: 205–212. doi:10.1007/s40801-020-00205-8

Foo

Macfarlane

AJR

Srivastava

, et al. The use of intravenous lidocaine for postoperative pain and recovery: International consensus statement on efficacy and safety. Anaesthesia 2021; 76: 238–250. doi:10.1111/anae.15270

Greenwood

Nimmo

Paterson

, et al. Intravenous lidocaine infusion as a component of multimodal analgesia for colorectal surgery-measurement of plasma levels. Perioper Med (Lond) 2019; 8: 1. doi:10.1186/s13741-019-0112-4

10.

Pandit

McGuire

Unlicensed intravenous lidocaine for postoperative pain: Always a safer ‘licence to stop’ than to start. Anaesthesia 2021; 76: 156–160. doi:10.1111/anae.15286

11.

Schuler

Lupi

Szumita

, et al. Evaluating the safety of continuous infusion lidocaine for postoperative pain. Clin J Pain 2021; 37: 657–663. doi:10.1097/AJP.0000000000000960

12.

Bailey

Toner

Corcoran

TB.

A survey of perioperative intravenous lidocaine use by anaesthetists in Australia and New Zealand. Anaesth Intensive Care 2020; 48: 53–58. doi:10.1177/0310057X19889367

13.

Toner

Bailey

Schug

, et al. A pilot multicentre randomised controlled trial of lidocaine infusion in women undergoing breast cancer surgery. Anaesthesia 2021; 76: 1326–1341. doi:10.1111/anae.15440

14.

Weinberg

Rachbuch

Ting

, et al. A randomised controlled trial of peri-operative lidocaine infusions for open radical prostatectomy. Anaesthesia 2016; 71: 405–410. doi:10.1111/anae.13368

15.

Scott

Jebson

Braid

, et al. Factors affecting plasma levels of lignocaine and prilocaine. Br J Anaesth 1972; 44: 1040–1049. doi:10.1093/bja/44.10.1040

16.

Brose

Cousins

MJ.

Subcutaneous lidocaine for treatment of neuropathic cancer pain. Pain 1991; 45: 145–148. doi:10.1016/0304-3959(91)90180-6

17.

Bauer

Brown

Gibaldi

, et al. Influence of long-term infusions on lidocaine kinetics. Clin Pharmacol Ther 1982; 31: 433–437. doi:10.1038/clpt.1982.56

18.

Green

Duffull

SB.

What is the best size descriptor to use for pharmacokinetic studies in the obese?

Br J Clin Pharmacol 2004; 58: 119–133. doi:10.1111/j.1365-2125.2004.02157.x

19.

Goolkasian

Slaughter

Edwards

, et al. Displacement of lidocaine from serum alpha 1-acid glycoprotein binding sites by basic drugs. Eur J Clin Pharmacol 1983; 25: 413–417. doi:10.1007/BF01037957

20.

Bill

Clayman

Morgan

, et al. Lidocaine metabolism pathophysiology, drug interactions, and surgical implications. Aesthet Surg J 2004; 24: 307–311. doi:10.1016/j.asj.2004.05.001

21.

Toner

Bailey

Schug

, et al. A pilot multicentre randomised controlled trial of lidocaine infusion in women undergoing breast cancer surgery. Anaesthesia 2021; 76: 1326–1341. doi:10.1111/anae.15440

22.

Kaba

Laurent

Detroz

, et al. Intravenous lidocaine infusion facilitates acute rehabilitation after laparoscopic colectomy. Anesthesiology 2007; 106: 11–18; discussion 5-6. doi:10.1097/00000542-200701000-00007

23.

Wallace

Dyck

Rossi

, et al. Computer-controlled lidocaine infusion for the evaluation of neuropathic pain after peripheral nerve injury. Pain 1996; 66: 69–77. doi:10.1016/0304-3959(96)02980-6

24.

Elens

van Gelder

Hesselink

, et al. CYP3A4*22: promising newly identified CYP3A4 variant allele for personalizing pharmacotherapy. Pharmacogenomics 2013; 14: 47–62. doi:10.2217/pgs.12.187

25.

Bassan

Weinstein

Mandel

WJ.

Use of lidocaine by continuous infusion. Am Heart J 1974; 87: 302–303. doi:10.1016/0002-8703(74)90069-6

26.

Struys

De Smet

Glen

, et al. The history of target-controlled infusion. Anesth Analg 2016; 122: 56–69. doi:10.1213/ANE.0000000000001008

27.

Stenson

Constantino

Harrison

DC.

Interrelationships of hepatic blood flow, cardiac output, and blood levels of lidocaine in man. Circulation 1971; 43: 205–211. doi:10.1161/01.cir.43.2.205

28.

Thomson

Elliott

Kelman

, et al. The pharmacokinetics and pharmacodynamics of lignocaine and MEGX in healthy subjects. J Pharmacokinet Biopharm 1987; 15: 101–115. doi:10.1007/BF01062338

29.

Hsu

Somma

Newman

, et al. Population pharmacokinetics of lidocaine administered during and after cardiac surgery. J Cardiothorac Vasc Anesth 2011; 25: 931–936. doi:10.1053/j.jvca.2011.03.008

30.

LeLorier

Grenon

Latour

, et al. Pharmacokinetics of lidocaine after prolonged intravenous infusions in uncomplicated myocardial infarction. Ann Intern Med 1977; 87: 700–706. doi:10.7326/0003-4819-87-6-700

31.

Koppert

Zeck

Sittl

, et al. Low-dose lidocaine suppresses experimentally induced hyperalgesia in humans. Anesthesiology 1998; 89: 1345–1353. doi:10.1097/00000542-199812000-00011

32.

Hollmann

Durieux

ME.

Local anesthetics and the inflammatory response: A new therapeutic indication?

Anesthesiology 2000; 93: 858–875. doi:10.1097/00000542-200009000-00038

33.

Dubowitz

Toner

Riedel

, et al. The use of intravenous lidocaine for postoperative pain and recovery. Anaesthesia 2021; 76: 719–720. doi:10.1111/anae.15400

34.

Shanthanna

Weinberg

Intravenous lidocaine, regional blockade, or both: Considerations for multiple interventions involving local anaesthetics. Br J Anaesth 2021; 127: 497–501. doi:10.1016/j.bja.2021.04.024

35.

Rygnestad

Brevik

Samdal

Plasma concentrations of lidocaine and alpha1-acid glycoprotein during and after breast augmentation. Plast Reconstr Surg 1999; 103: 1267–1272. doi:10.1097/00006534-199904040-00027

36.

Okubo

Murayama

Shimizu

, et al. CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) is associated with reduced CYP3A4 protein level and function in human liver microsomes. J Toxicol Sci 2013; 38: 349–354. doi:10.2131/jts.38.349

37.

Ghotbi

Christensen

Roh

, et al. Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype relationship in Swedes and Koreans. Eur J Clin Pharmacol 2007; 63: 537–546. doi:10.1007/s00228-007-0288-2

38.

Gelman

Fowler

Smith

LR.

Regional blood flow during isoflurane and halothane anesthesia. Anesth Analg 1984; 63: 557–565.

39.

Gelman

SI.

Disturbances in hepatic blood flow during anesthesia and surgery. Arch Surg 1976; 111: 881–883. doi:10.1001/archsurg.1976.01360260049012

40.

Feely

Wade

McAllister

, et al. Effect of hypotension on liver blood flow and lidocaine disposition. N Engl J Med 1982; 307: 866–869. doi:10.1056/NEJM198209303071406

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.34 MB

0.07 MB