Liberal use of local anaesthetic and the risk of toxicity in elective arthroplasties at a tertiary teaching hospital

Abstract

Background

Local anaesthetic systemic toxicity (LAST) is a life-threatening potential complication that may follow the administration of local anaesthetic (LA) drugs, and is cumulative across the drug class. Local anaesthetics are commonly administered via different routes for elective orthopaedic procedures – both by anaesthetists and surgeons. We hypothesized that total doses of LA may be routinely encroaching upon toxicity.

Methods

All total hip or knee arthroplasties (THAs and TKAs) performed within a 3 month period at the John Hunter Hospital (tertiary referral centre and teaching hospital) were audited to assess total administration of LA. Demographics, surgical characteristics, use of general anaesthesia or sedation, and use of local anaesthetic via any route of administration was recorded. For each patient, a weight-based theoretical maximum safe dose was calculated and compared against the dose they received. Data is presented as mean ± SD, percentages. Statistical significance was determined at p < 0.05.

Results

130 THAs and TKAs were identified within the audit period. 52 patients exceeded their drug-class theoretical maximum safe dose. 49 patients exceeded their weight-based maximum dose for a single LA agent, in all cases ropivacaine. Non-obese individuals receive significantly higher mean dose than obese individuals (119.4% [98.6–140.3] vs 78.82% [65.95–91.69], p = 0.001). No LAST events were identified.

Conclusions

Patients who received elective total hip or knee arthroplasties were exposed to concerningly high total doses of local anaesthetic, suggesting that greater awareness of the additive toxicity of drugs within this class is required.

Keywords

Local anaesthesia nerve block local infiltration analgesia arthroplasty

Introduction

Local anaesthetic systemic toxicity (LAST) is a life-threatening potential complication of the increasingly prevalent and varied local anaesthetic (LA) regional analgesic techniques being performed for common orthopaedic procedures. The growing myriad of LA-dependent techniques available – including neuroaxial anaesthesia (NA), peripheral nerve blocks (PNB), continuous catheter-infusion, fascial plane techniques, and local infiltration analgesia (LIA) – coupled with an increasing enthusiasm for utilising concurrent LA techniques in the same patient contribute to the risk of LAST.^1–4

Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are commonly performed elective surgical procedures in Australia, and are commonly and increasingly performed using at least one LA anaesthetic approach.^2,5 Peripheral nerve block utilisation in TKA has increased two-fold in the last decade.⁶ LA-based regional anaesthesia offer advantages for these procedures in terms of perioperative, surgical, and economic outcomes.^3,4 Amongst these techniques, LIA is becoming an increasingly popular adjunct to other LA techniques in total joint arthroplasty, consisting of surgeon-administered high-volume periarticular LA infiltration.⁷

Available literature suggests that LA plasma concentrations do not encroach upon toxic thresholds in patients receiving LIA in the context of TKA or THA procedures.^8–11 However, individual cases of LAST have been reported, highlighting that individual patient and surgical factors contribute to significant pharmacokinetic variation that must be considered when using multiple LAs by multiple routes of administration in the same patient.¹² It has been shown, for example, that LA absorption is significantly higher in THA than in TKA.¹¹

Total arthroplasties are common at our centre, with greater than 200 THA and 350 TKA procedures being performed annually. Anecdotal evidence suggested that concurrent LA techniques was routine practice for these operations. This study sought to retrospectively audit the anaesthetic practice for all elective hip and knee arthroplasties performed at our centre following a case of LAST developing in an otherwise healthy twenty-four year old male who received concurrent ultrasound-guided adductor canal block and local anaesthetic infiltration under general anaesthesia for anterior cruciate ligament. Our aim was to describe standard practice at our centre; assess the cumulative dose of LA received by any route for patients undergoing TKA or THA; and to identify whether LA dose routinely encroached upon theoretical toxic levels.

Pharmacokinetics and pathophysiology of LAST

LAST is a syndrome characterised by cardiovascular (CVS) and central nervous system toxicity (CNS). CNS symptoms - typically in the form of seizures – are the most common presentation of LAST (68–77%), although LAST may be difficult to diagnose as 40% presents atypically.^13–15 The development of LAST is a function of LA plasma concentration.⁷ LA molecules primarily act via a common mechanism of intracellular-mediated blockade of Na_v channels, inhibiting neuronal transmission.¹⁶ Other targets of LA blockade include Ca²⁺ channels, K⁺ channels, Na⁺- K⁺ ATPase channels.^17–21 LAs are also known to modulate intracellular and transmembrane signaling via inhibition of second messenger pathways in metabotropic systems, and through inhibitory modulation of sarcoplasmic-mediated contractility via PKA and RyR.^22–24 Increasing plasma concentrations of LA cause increasing blockade of the aforementioned LA targets, resulting in a complex picture of combined CVS and CNS toxicity.

When multiple LA types and routes of administration are being employed for a single patient these techniques are specifically chosen for their pharmacokinetic properties. However, as LAs share a common mechanism of action, each separate agent and route of administration contributes to net LA plasma concentration. In the absence of evidence to the contrary, it is suggested that toxicities should be presumed to be additive.^25,26 The authors hypothesised that this audit would reveal that it would be uncommon for TKA and THA patients to receive doses of individual agents encroaching upon their weight-based maximum safe dose, but that cumulative toxicity may be routinely approached via the use of multiple LA agents concurrently, complicated by independent administration by both the surgical and anaesthetic teams.

Material and methods

This study was performed at the John Hunter Hospital (University of Newcastle-affiliated tertiary hospital), New South Wales, Australia. Hip and knee arthroplasties are common procedures performed at our centre, and are performed by a number of different surgeons and anaesthetists.

This study is a retrospective audit of all patients who received total hip or knee arthroplasties at the John Hunter Hospital between 1st October and 31st December 2018. This audit was granted exemption from formal ethics review by the Hunter New England Human Research Ethics Committee (AU201910-08). Subjects were identified via extraction of medical record numbers from the HNE Master Disease Index searching by the following procedure codes: Total arthroplasty of knee, unilateral; Total arthroplasty of knee, bilateral; Total arthroplasty of hip, unilateral; and, Total arthroplasty of hip, bilateral.

All patients extracted database were reviewed for eligibility. All patients who received a TKA or THA performed within the specified time period were included in this audit. Patient demographics (age and sex) and date of procedure were retrieved from this database. Further information was retrieved from the local electronic patient record system, including patient characteristics (height and weight) and surgical characteristics (site of procedure). Data regarding the anaesthetic technique employed for each patient was retrieved from a combination of the patient's anaesthetic record, surgical operation report, nursing operation report, and routine additional documentation in the case of neuroaxial analgesia or catheter infusion order. Anaesthetic data points collected were those identified to be pertinent to assessing LA plasma concentration, and included: use of general anaesthesia or sedation; use of neuraxial analgesia, and its agents’ concentrations, volumes, and dose; use of peripheral nerve blockade(s), block location and technique (catheter infusion vs single-shot), block agent(s), concentration(s), volume(s), dose(s); and, use of local infiltration analgesia, infiltration agent(s), concentration(s), volume(s), and dose(s). General anaesthesia was defined by the use of a laryngeal-mask airway or endotracheal tube. Patient medical records day zero and day one postoperatively were reviewed for evidence of LAST.

Data regarding local infiltration analgesia was retrieved from nursing operation reports. All documented LA doses were interpreted as being administered in their entirety.

Patients who received bilateral arthroplasties recorded on the same anaesthetic record were considered to have undergone one procedure.

Patients were non-exclusively categorised into sub-groups depending on their procedure, BMI, sex, and combination of anaesthetic techniques received.

For each patient, a weight-based theoretical maximum dose for each individual LA agent was calculated using commonly accepted standard maximum doses as included in the Australian Medicines Handbook; 3 mg kg⁻¹ for lidocaine and ropivacaine, and 2 mg kg⁻¹ for bupivacaine.^27–29 The net dose received for each LA agent across all routes of administration was calculated, and expressed as a percentage of the agent-specific theoretical maximum (referred to as Agent % Max Dose). A cumulative percentage maximum dose was calculated as the sum of every agent-specific percentage for each individual patient (referred to as Patient % Max Dose).

Data is presented as mean ± standard deviation in the text and tables, unless otherwise specified. Statistical analysis was performed using a commercially available statistical software suite. Comparison between patient sub-groups was performed with ANOVA, and correlations assessed using linear regression modelling. Significance was established at p < 0.05.

Results

We identified 130 TKA or THA procedures performed within our audit period; consisting of 84 TKAs (65%), and 46 THAs (35%). Patient demographics and surgical characteristics are further described in Table 1.

Table 1.

Patient demographics and surgical characteristics.

Procedure	Number of Procedures	% of Total Procedures	% Right-side	Mean Age	% Male	Mean Weight (kg)	Mean BMI
Total Knee and Hip Arthroplasties	130	100.0	54.6	67.4 ± 10.9	40.0	91.1 ± 22.1	33.8 ± 8.0
Total Knee Arthroplasties, unilateral	80	61.5	55.0	68.7 ± 9.6	37.5	95.1 ± 21.6	35.6 ± 8.1
Total Hip Arthroplasties, unilateral	46	35.4	50.0	66.2 ± 12.8	45.6	83.4 ± 21.5	30.4 ± 7.1
Total Knee Arthroplasties, bilateral	4	3.1	100	57.0 ± 5.8	25.0	98.0 ± 21.1	35.4 ± 6.0

BMI: body mass index.

Among the 130 lower limb arthroplasties within our audit period, we identified 63 (48%) procedures performed under a planned general anaesthetic (and one case of intra-operative conversion to general anaesthesia), 109 (84%) procedures employing a neuroaxial technique, 37 (28%) utilising peripheral nerve blocks, and 105 (81%) in which local infiltration anaesthesia was performed. Further data is presented in Table 2.

Table 2.

Use of local anaesthetic in hip and knee arthroplasties.

Procedure	All Arthroplasties	Total Knee Arthroplasties	Total Hip Arthroplasties
Number Performed (% total arthroplasties)	130 (100%)	84 (65%)	46 (35%)
Anaesthetic Technqiue
N General Anaesthetic (GA)	63 (48%)	29 (35%)	34 (74%)
N Neuraxial Anaesthesia (NA)	109 (84%)	70 (83%)	36 (78%)
N Peripheral Nerve Block (PNB)	37 (28%)	34 (40%)	3 (7%)
N Local Infiltration Analgesia (LIA)	105 (81%)	69 (82%)	36 (78%)
≥ any one of NA, PNB, or LIA	129 (99%)	84 (100%)	45 (98%)
≥ any two of NA, PNB, or LIA	99 (76%)	71 (85%)	28 (61%)
NA + PNB + LIA	20 (15%)	18 (21%)	2 (4%)
Lidocaine in Hip and Knee Arthroplasties
N Lidocaine Use	3 (2%)	3 (3%)	0
Mean Lidocaine Dose (mg)	90.0 ± 65.6	90.0 ± 65.6	—
Mean Lidocaine % Max Dose	26.4 ± 18.6	26.4 ± 18.6	—
Ropivacaine in Hip and Knee Arthroplasties
N Ropivacaine Use	105 (81%)	71 (84%)	34 (74%)
Mean Ropivacaine Dose (mg)	260.4 ± 121.8	259.2 ± 128.6	262.9 ± 107.9
Mean Ropivacaine % Max Dose	100.71 ± 53.73	96.74 ± 53.71	109.01 ± 53.63
Bupivacaine in Hip and Knee Arthroplasties
N Bupivacaine Use	105 (81%)	71 (84%)	34 (74%)
Mean Bupivacaine Dose (mg)	12.5 ± 1.99	12.2 ± 1.81	13.0 ± 2.26
Mean Bupivacaine % Max Dose	7.40 ± 2.18	6.97 ± 1.99	8.314 ± 2.78
Cumulative Local Anaesthetic Doses in in Hip and Knee Arthroplasties
Mean Cumulative % Max Dose	90.01 ± 62.60	88.60 ± 61.95	92.77 ± 64.51
Median Cumulative % Max Dose [IQR]	82.77 [36.36–130.45]	82.19 [32.27–131.03]	83.33 [41.59–127.87]

GA: general anaesthetic; NA: neuraxial anaesthesia; PNB: peripheral nerve block; LIA: local infiltration analgesia; IQR: interquartile range.

Neuraxial anaesthesia was common (n = 109), and similarly prevalent in TKAs and THAs. Bupivacaine (as Marcain 0.5%) was used almost exclusively as the LA agent in this context. One patient received lidocaine-based neuroaxial anaesthesia. Overall, hyperbaric bupivacaine (Marcain Heavy) was used more frequently compared to isobaric bupivacaine (Marcain Plain). Hyperbaric solution was used in a total of 79 arthroplasties (72.5%: 56 TKA, 23 THA); whereas isobaric was used in 29 (26.6%: 15 TKA, 14 THA). There was no statistically significant difference in mean drug volume reported for hyperbaric vs isobaric bupivacaine (2.49 ± 0.39 mL, p = 0.109).

Opioids were commonly included in the neuroaxial cocktail, morphine (n = 94; 128.4 mcg ± 59.30) being more frequently used than fentanyl (n = 61; 18.525 mcg ± 2.936).

Peripheral nerve blocks were used less frequently than the other techniques identified (n = 37), with a significant preponderance in TKAs compared to THAs (34 vs 3). PNBs identified in TKAs consisted of 28 adductor canal blocks; 2 combined femoral nerve and obturator; and, 4 saphenous nerve blocks. Amongst the 28 adductor canal blocks (ACBs) performed for TKAs, 19 were documented as single shot blocks, and 9 as catheter infusions. Ropivacaine was used as the LA agent in all except one, in which ropivacaine and lidocaine were used concurrently. Ropivacaine was used in varying concentrations: 15 ACBs performed with 0.2%; 7 with 0.375%; 3 with 0.5%; 2 with 0.75%, and 1 with 1%. All three PNBs reported in THAs were documented as fascia iliaca blocks.

Local infiltration anaesthesia was used in 81% of total arthroplasties, and was similarly common amongst TKAs and THAs. Across all arthroplasties the mean volume of infiltration was 127.45 ± 56.30 mL. Amongst the 105 patients who received LIA, the mean documented dose of ropivacaine that these patients received was 259.9 ± 103.8 mg. Within this cohort, by LIA alone, the mean dose of ropivacaine documented as administered was in excess of the Ropivacaine %Maximum dose calculated for each patient (101.78 ± 47.38 Ropivacaine %Maximum).

Across all arthroplasties audited, 52 patients exceeded their Patient %Maximum LA dose. All of these patients received LIA. No patient who did not receive LIA exceeded their Patient %Maximum LA dose. Within this patient group, 49 of these patients also exceeded their weight-based maximum dose for a single LA agent alone, in all cases ropivacaine. An additional 19 patients (total = 71) received cumulative LA doses in excess of 80% of their calculated maximum safe LA dose. Figure 1 illustrates the distribution of Patient %Maximum dose across all LA agents and all arthroplasties within our audit. Further data is presented in Table 2 detailing the use of local anaesthetic across all arthroplasties and by subgroup.

Figure 1.

Histogram of patient % maximum dose.

We identified no statistically significant difference in mean Patient %Maximum dose for patients receiving TKA vs THA (p = 0.939); nor in male vs female arthroplasty patients (p = 0.377); nor in those whose arthroplasty was performed under general anaesthetic vs sedation (p = 0.410).

Non-obese individuals receive significantly higher mean Patient %Maximum dose than obese individuals (119.4% [98.6–140.3] vs 78.82% [65.95–91.69], p = 0.001). This is shown in Figure 2. Obesity was defined as a BMI of 30 or greater. Within the obese group (n = 93) the average BMI was 37.36 ± 6.44, and within the non-obese group 24.91 ± 2.61 (n = 36). 44.4% of the non-obese group was male vs 38.7% of the obese group. Obese patients were significant younger than non-obese patients (65.12 ± 9.96 vs 73.30 ± 11.14, p < 0.001).

Figure 2.

Interval plot of patient % maximum dose for obese vs non-obese patients.

Linear regression analysis further revealed that increased patient % maximum LA dose was correlated with increasing age (β = 1.274, p = 0.012); decreasing weight (β = −0.892, p < 0.001), and decreasing BMI (β = −2.504, p < 0.001).

No LAST events were identified upon review of medical records for day zero and day one postoperatively.

Discussion

The aim of this study was to examine and quantify the use of local anaesthetic in THA and TKA procedures at our centre. We hypothesized significant intra-patient variability in the LA agent of choice, regional techniques, and cumulative dose of LA for lower limb arthroplasties – reflective of the numerous similarly efficacious techniques that are currently in vogue. However, our findings suggest less striking variation in anaesthetic technique than hypothesise, and reveal an alarmingly liberal use of local anaesthetic across all patient subgroups. Key findings relevant to the specific aims were that across the 130 arthroplasties audited, 52 patients exceeded their Patient %Maximum LA dose. A total of 71 patients received cumulative LA doses in excess of 80% of their calculated maximum safe LA dose. When looking at the contribution of a single agent in Ropivacaine, 49 patients exceeded their weight-based maximum dose for this single LA agent. All of these patients received LIA. No patient who did not receive LIA exceeded their Patient %Maximum LA dose. In the context of a routinely performed orthopaedic procedure, this raises concern for the potential of multiple near-miss LAST events.

Within this cohort, by LIA alone, the mean dose of ropivacaine documented as administered was in excess of the Ropivacaine %Maximum dose calculated for each patient (101.78 ± 47.38 Ropivacaine %Maximum). This may represent an opportunity for examining the factors that have resulted in this finding; be it poor documentation, communication between surgeons and anaesthetists, or a poor understanding of LA doses and LAST risk on behalf of the surgical teams involved.

With respect to subgroups, non-obese individuals received significantly higher mean Patient %Maximum dose than obese individuals (119.4% [98.6–140.3] vs 78.82% [65.95–91.69], p = 0.001) hence putting this group at a theoretical higher risk of LAST than the obese group, as has been previously described by Christie et al.³⁰

Particular strengths of this project were that it has been able to quantify the additive and cumulative doses of LA in a very common elective surgical procedure at our institution. This is on the background or a recent case report of LAST in a healthy patient undergoing elective orthopaedic surgery. We were then able to compare the total LA dose given against the suggested benchmark of a maximum safe dose that aims to avoid the risk of a life threatening LAST event. We acknowledge that one limitation of this study is the use of relatively conservative maximum safe doses for each local anaesthetic agent, with maximum safe doses of up to 4.5 mg/kg of lignocaine frequently described elsewhere. However from a risk-management perspective, we believed it was sensible to audit our practice against the recommendations of our national reference prescribing guide.

The results are concerning especially given the LA used for skin infiltration for a neuroaxial block was not included. Anecdotally this is up to 5 mL of 1% lignocaine (50 mg), with a theoretical maximum safe dose of 3 mg/kg.

It may be surprising given the doses of LA reported that no patients were identified as having experienced a LAST event. The authors acknowledge that retrospective diagnosis of LAST is difficult given its many varied presentations, and that medical records are a problematic source for data collection in this regards. However, whilst delayed presentations of LAST are increasingly described, LAST most frequently presents immediately following injection of LA.³¹ The American Society of Regional Anesthesia and Pain Medicine recently published a practice advisory highlighting a shift towards increasing delayed presentations of LAST, presenting up to an hour post-injection.³¹ As this time frame spans the immediately pre-, intra-, and post-operative periods, in which the patient will have been in theatre or recovery, we suggest that LAST would have been appropriately identified and documented in these settings.

The authors hypothesise that the two most likely explanations for the seemingly incongruous doses of LA reported and the lack of identified LAST are as follows. Firstly, it was assumed that all of the LA recorded on the surgical and scrub nursing documentation was actually administered by the surgeon, as there was no evidence to the contrary. One possible explanation for the lack of LAST events identified may lie in reconciling the amount of LIA ‘drawn up’ versus ‘administered’ by the surgeon. Anecdotally, it was felt that all of the LA was actually administered as the ‘cocktail’ of LIA commonly contained other pharmacological adjuncts. The authors suggest that more vigilant documentation of the volume discarded or volume infiltrated, as opposed to simply the volume ‘drawn up’, is in the best interest of both patient safety and minimising medicolegal risk. Moving forward, a heightened awareness to, and increasingly precise documentation of the LA administered would enhance patient safety by permitting accurate calculations of total LA dose to best assess patients’ LAST risk.

Secondly, we identified a lack of clear documentation regarding the time of and between the administration of LA by different routes. This is a potential limitation to the results of our study, as it is possible that one of the reasons such a high number of patients exceeded maximum safe doses of LA but did not develop LAST may be due to the time elapsed between administration of LA via different routes being sufficient to avoid peak plasma concentrations exceeding the toxic threshold. We found, for example, that the elapsed time between the anaesthetist placing a neuraxial block or PNB at the commencement of the case, and the surgeon administering the LIA at the end was not clearly documented. There is clearly an opportunity to improve documentation regarding the total amount of LA used and when with reference to the patient's maximum safe dose, and communication of this information between surgical and anaesthetic teams responsible for administering LA to the same patient. Whether accountability for this documentation falls on anaesthetists or surgeons is unclear, and will likely be a source of debate going forward.

It is important to clarify that, as authors, we recognise that local anaesthetic plasma concentrations are dependent on a number of pharmacokinetic and pharmacodynamic factors, and that the commonly accepted standard maximum doses of 3 mg kg⁻¹ for lidocaine and ropivacaine and 2 mg kg⁻¹ for bupivacaine^27–29 are a conservative guide, and – as our study has identified – the administration of far higher per kilogram doses would appear to be quite safe. However, these conservative guides should be kept in mind whilst considering patient safety and medicolegal risk. Further investigation via a prospective study to establish the true incidence and safety threshold for LAST amongst patients undergoing arthroplasties may be required to establish a new evidence-based per kilogram dose limit appropriate for this cohort.

Conclusions

Local anaesthetic systemic toxicity (LAST) is potential life-threatening complication in patients who receive in excess of a recommended dose of LA. In recent years the management of patients undergoing total joint arthroplasties has moved toward techniques that utilise more LA, LIA by the surgeons and PNB by the anaesthetist This audit has provided useful and concerning information over the total LA dose in patients undergoing elective THA and TKA at a tertiary teaching hospital. An opportunity exits to improve awareness, documentation and communication between surgical and anaesthetic teams prior to a further audit to ensure patients are receiving more conservative total LA doses in the interest of patient safety and risk management.

Footnotes

Declaration of conflicting interests

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

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

James Bulman

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