Local Anesthetic Mixtures with Adjuvants: Risks, Benefits, and Insights from the Anesthesiology Review

The key point is: recent in vitro evidence has demonstrated microscopic crystallization/precipitation in routinely used combinations, including mixtures previously considered "safe" (e.g., lidocaine + bicarbonate).

Key takeaways#

Compatibility and crystallization: the alert has changed scale

• In vitro evidence shows precipitation/crystallization in several combinations, including "traditionally safe" mixtures.
• Most mixtures with bicarbonate resulted in high-grade crystallization, including lidocaine + bicarbonate; despite guideline recommendations for rapid epidural augmentation, caution is advised.
• Among anesthetic-adjuvant mixtures, ropivacaine has a higher propensity to crystallize, especially with bicarbonate or dexamethasone, including "in situ" mixtures through sequential injection (as in epidural top-up).
• Ropivacaine + short-acting local anesthetic (with or without adjuvant) showed substantial crystallization; given the low pharmacological plausibility and limited efficacy evidence, caution/avoidance is recommended, especially with ropivacaine.

Clinical benefit: when it exists, it comes at the cost of duration

• Mixing short- and long-acting anesthetics may shorten onset time in large nerves; in smaller nerves and neuraxial anesthesia, the benefit tends to be small (a few minutes) and likely clinically insignificant.
• Regardless of the scenario, mixing short- and long-acting anesthetics significantly reduces block duration (by hours).
• Adjuvants such as dexmedetomidine, epinephrine, and dexamethasone can increase duration; alkalinization may not be as effective as previously thought, but still accelerates onset by a few minutes compared to lidocaine without bicarbonate and about 10 min compared to long-acting drugs.

Safety and gaps: toxicity, selectivity, and research

• Systemic toxicity is additive: calculate and limit each component, considering different cardiovascular profiles of short- vs. long-acting anesthetics.
• Sensory selectivity does not improve with anesthetic mixtures or adjuvants: true selectivity for pain fibers has not been achieved; selectivity differences between local anesthetics are often overshadowed by potency differences.
• More research is needed on safer and more selective formulations/adjuvants; neosaxitoxin is cited as a promising agent requiring further investigation.
• It is urgent to elucidate the composition of precipitates and the consequences of perineural/epidural injection (including chemical approaches, animal models, and epidemiological studies).

The journal Anesthesiology published a narrative review ("Is It Time to Reassess Local Anesthetic and Adjuvant Mixtures?") that compiles available evidence on local anesthetic mixtures with each other and with adjuvants, discussing chemical/pharmacological fundamentals, in vitro data, clinical outcomes, and a practical risk-versus-benefit analysis.

Below, we analyze the main points of the article.

1) Pharmacodynamics of local anesthetics#

Local anesthetics in use are weak bases that interact, among other targets, with voltage-gated sodium channels.

Three properties define efficacy regarding blockade of these channels:

• pKa: the closer to physiological extracellular pH, the greater membrane permeability and, therefore, faster onset.
• lipophilicity: associated with analgesic potency.
• protein binding: influences metabolism and systemic toxicity; the unbound fraction is metabolized more rapidly.

Any addition of substances to the formulation can alter the pharmacodynamic profile and chemical composition, sometimes desirably (e.g., accelerating onset through alkalinization), but with possible physicochemical costs.

2) pH and solubility#

The solubility of weak acids/bases in water is primarily determined by the degree of ionization and the state of the carrier medium. It is a dynamic equilibrium.

Local anesthetics are often formulated as hydrochloride salts in aqueous solution with "stabilizing" agents.

The review revisits Le Chatelier's principle: changes in conditions/constituents of a system at equilibrium shift the system to a new equilibrium. This is central to understanding why mixtures can become unstable.

3) pH change and crystallization#

Alkalinizing (e.g., with bicarbonate) alters the proportion of ionized vs. non-ionized drug and, theoretically, can accelerate onset.

A quantitative example presented: in the 9/10 lidocaine + 1/10 bicarbonate 8.4% mixture, pH can rise from about 6.4 (lidocaine "pure") to about 7.7 (lidocaine + bicarbonate).

The critical point is that pH change also alters solubility, potentially exceeding solubility constants. Anesthetics with higher pKa (e.g., bupivacaine and ropivacaine) can precipitate grossly when alkalinized.

Although bicarbonate is not recommended for ropivacaine and bupivacaine, this practice repeatedly appears in clinical trials and reviews.

Even combinations historically considered safe (e.g., lidocaine + bicarbonate, due to absence of "visible" precipitate) are now questioned when evaluated under microscopy, as we will see later.

4) In vitro evidence of crystallization/precipitation

The "new" core of this discussion comes from in vitro microscopy analyses that detected precipitation at the microscopic level in:

• anesthetic-adjuvant mixtures, and
• anesthetic-anesthetic mixtures (with or without adjuvant).

Two operational findings are particularly relevant:

1. Precipitation can be delayed: in some mixtures (e.g., lidocaine 2% + bicarbonate), precipitates appeared after up to 30 minutes, suggesting that preparing the mixture in advance may increase risk.
2. Not everything is explained by pH alone: the review describes examples with very similar pH but different crystallization behaviors, and cites water solubility constants varying widely among local anesthetics.

Crystallization studies used a 6-point semiquantitative scale to grade crystallization, with sterile water and triamcinolone as negative/positive standards (grades 0 and 5).

Among long-acting anesthetics, ropivacaine showed the most evident capacity to form crystals when mixed with adjuvants and also when combined with any short-acting anesthetic.

5) Clinical efficacy of local anesthetic mixtures#

The classic rationale is to "combine the best of both worlds": mixing a short/intermediate-acting agent with a long-acting one to accelerate onset while preserving duration.

The review highlights that, in practice, the scenario is more complex, including due to the dilution effect and physicochemical properties of solutions.

With the introduction of ultrasound, block latency time has substantially decreased. In this context, the question becomes whether there is still a need to mix for this purpose.

Clinical studies cited and the recurring pattern

Other points described:

• Adding mepivacaine to bupivacaine in ultrasound-guided interscalene block did not produce clinically significant difference in onset time, but reduced duration.
• In axillary block and obstetric epidural, the pattern reappears: onset reductions coexist with duration reductions, including motor block reduction (1.5 vs 3 h).
• In larger nerves, as in the sciatic nerve study under dual guidance, latency reduction can be more pronounced.

Proposed clinical synthesis: mixtures to reduce onset tend to provide small benefit in smaller nerves and neuraxial anesthesia, but may be useful in larger nerves. Regardless of the scenario, mixing short- and long-acting anesthetics significantly reduces block duration.

6) Toxicity of local anesthetic mixtures#

The practical premise is that systemic toxicity is additive when drugs are administered together.

The review exemplifies: if the injectable solution contains 60% of the maximum lidocaine dose, the other component (e.g., bupivacaine) should be around 40% of the recommended maximum dose for that patient.

Additionally, there are hemodynamic/cardiotoxic differences:

• lidocaine/mepivacaine manifest toxicity more as reduced inotropy;
• bupivacaine has greater arrhythmogenic potential and is traditionally more difficult to resuscitate.

In translational models (piglets), a lidocaine-bupivacaine mixture may behave like lidocaine in hemodynamic variables but approach bupivacaine regarding arrhythmogenic potential.

7) Clinical efficacy of adjuvants: overview#

Adjuvants used in regional anesthesia are drugs not primarily developed for nerve block. Much of their use is off-label in neuraxial and peripheral blocks, with different profiles of systemic effects.

The central clinical objectives when using adjuvants are to increase duration and "density" of the block (intensifying while using lower anesthetic concentrations). The main adjuvants discussed follow.

8) Alpha-2 agonists: clonidine and dexmedetomidine#

Alpha-2 agonists appear as highlights.

Assumed mechanism: activation of receptors in the dorsal horn with subsequent blockade of potassium and calcium channels, inhibiting nociceptive receptors and substance P. Dexmedetomidine has alpha-2 affinity about 8 times greater than clonidine.

Evidence described:

• Clonidine in spinal anesthesia: increased block duration by about 2 hours without significant increase in hypotension when used in cesarean sections.
• Intrathecal dexmedetomidine: more prolonged sensory and motor blocks versus clonidine.
• In peripheral blocks: clonidine added to ropivacaine without effect in one study, but increased duration when added to mepivacaine or bupivacaine.
• In volunteers (ulnar nerve): 20 mcg of dexmedetomidine added to 0.75% ropivacaine increased sensory block duration by 60%; intravenous administration of 20 mcg increased it by 10%.
• Dose escalation study in volunteers identified 100 mcg as optimal dose added to ropivacaine for perineural use, balancing sedation and analgesic effect. The review summarizes "optimal" dose as about 1 mcg/kg in peripheral blocks and 3-10 mcg for neuraxial use.

9) Dexamethasone#

Assumed perineural mechanisms include direct transmission inhibition in C fibers, local anti-inflammatory effect and vasoconstriction, plus central analgesic effect.

The review acknowledges that systematic reviews and meta-analyses suggest block prolongation with dexamethasone added to local anesthetics, but also notes inconsistency in volunteer studies and conflicting results regarding systemic administration.

• In a meta-analysis of 100 trials (n=5,728), Sehmbi et al. report greater prolongation with intravenous dexamethasone, followed by perineural.
• Desai et al. found moderate superiority of perineural use, but the difference was considered not clinically relevant.

Decisive point for mixing practice: corticosteroids can lead to relevant crystallization when added to local anesthetics. Therefore, "with current knowledge," dexamethasone (and other corticosteroids) should not be mixed with local anesthetics for regional anesthesia.

10) Vasoconstrictor agents#

Epinephrine is used to prolong block and reduce systemic absorption of the local anesthetic.

Data presented:

• Brachial plexus: 200 mcg of epinephrine is "equi-effective" to 1 mcg/kg of dexmedetomidine when added to 1% mepivacaine, increasing sensory and motor block by about 20% versus local anesthetic alone.
• Femoral nerve: epinephrine 1:200,000 added to 0.2% or 0.5% ropivacaine did not influence block duration.

The review also discusses the pharmacokinetic rationale (reduction of absorption rate) and notes that the hypothesis of reducing neural blood flow perineurally has not been confirmed in experimental studies.

11) Opioids#

Opioids are used as additives in epidural/intrathecal analgesia.

Hydrophilic and lipophilic opioids differ in onset and duration, and both can cause respiratory depression, with greater relevance for morphine and no observed risk with fentanyl in certain neuraxial contexts.

For peripheral regional anesthesia, the position is direct: opioids added to local anesthetic have no role, as opioid receptors are not expressed in peripheral nerves. Perineural use in chronic pain is noted as a topic requiring additional scientific evaluation.

12) Alkalinization#

The most sensitive practical issue for bicarbonate use is converting obstetric epidural analgesia to surgical anesthesia in cesarean section, often under time pressure.

The review delimits: the alkalinization discussed applies to intermediate-acting anesthetics (e.g., lidocaine, mepivacaine), as adding bicarbonate to long-acting anesthetics (e.g., bupivacaine) precipitates before reaching physiological pH.

Clinical evidence is described as heterogeneous:

• Study with volunteers: inconsistent evidence of nerve block acceleration with alkalinization.
• In elective cesarean, reported difference of 22 vs 13 min (9 min gain) favoring bicarbonate, with denser block.
• In epidural lidocaine-fentanyl, reduction from 19 to 15 min (4 min gain).
• Network meta-analysis (Reschke et al.) in obstetric epidural anesthesia: 2% lidocaine + bicarbonate is the fastest form for surgical anesthesia; still, time for conversion to full anesthesia in cesarean was 13.4 min.
• There are also studies showing no significant difference in obstetric and non-obstetric populations, and an ongoing trial (QETAL) is cited as a future information source.

Regarding prior preparation, the review notes that bicarbonate may reduce epinephrine content over prolonged periods, without appreciable effect on local anesthetic concentration.

The risk of injecting precipitates into the epidural space is described as uncertain. The potential time benefit must be weighed against potential risk, especially when an alkalinized intermediate-acting anesthetic is injected sequentially after a long-acting anesthetic, a combination that produced massive crystallization in an in vitro model.

13) Risk and benefit of mixtures: how to weigh them in practice#

The practice of mixing anesthetics (with each other or with adjuvants) has been widespread for decades. Recent preclinical evidence suggests that chemical incompatibility is not limited to "traditional culprits" (such as bupivacaine + bicarbonate) and can occur in mixtures considered safe.

The review proposes weighing these findings against possible benefits:

• Mixing short + long-acting anesthetics may shorten onset in large nerves. In smaller nerves, the effect tends to be a few minutes and likely clinically insignificant, while block duration decreases by hours.
• Adjuvants such as dexmedetomidine, epinephrine, and dexamethasone can increase duration; alkalinization may not be as effective as previously thought, but still accelerates onset by a few minutes compared to lidocaine without bicarbonate and about 10 min compared to long-acting drugs.

Conclusion#

Final message: in each scenario, a critical and evidence-based assessment of the risk vs. benefit of any proposed mixture should be made, considering compatibility, selectivity, and toxicity.