Crystallization of Local Anesthetics when mixed with adjuvants
Myron Yaster MD and Lynne G. Maxwell MD
Before beginning today’s PAAD, a quick review of local anesthetic pharmacology and pharmacokinetics is needed. Local anesthetics are tertiary amines and weak bases that reversibly bind to intracellular voltage-gated sodium channels and thereby inhibit sodium influx leading to a blockade of nerve depolarization. Local anesthetics can inhibit Na+ channels in both the ionized (B)and nonionized forms (BH). However, to reach the sodium channel, the local anesthetic must cross the nerve membrane and it is primarily the non-ionized (BH) form of the drug that can do this. How much drug is available to cross the nerve membrane depends on the pKa of the drug and the pH of the fluid surrounding the nerve.
The pKa of a drug is defined as the pH at which half of the drug exists in the ionic form and the other half in the non-ionized form. All local anesthetics are weak bases with a pKa greater than physiologic pH (7.4)); indeed, the pKa for most local anesthetics lie between 7.7 and 9.1. Thus, these agents predominantly exist in the ionized (cationic) form in biologic fluids at physiologic pH. The lower the pKa of a drug, the more non-ionized drug is available to cross the nerve membrane at physiologic pH. For example, 28% of lidocaine exists in the base (non-ionized) form at pH 7.4 compared to only 2.5% for chloroprocaine because the pKa of these drugs are 7.9 and 9.0, respectively. Acidosis and hypercarbia in the environment in which a local anesthetic is injected will further increase the ionized fraction of local anesthetic. This explains the poor analgesia that results when local anesthetics are infiltrated into infected or ischemic tissues, as might occur when local anesthetics are injected into traumatic lacerations prior to suturing.
In order to preserve the shelf life of these drugs, manufacturers produce these drugs as acids and because they are acids they are painful on injection (think of a bee sting). To reduce the pain of local anesthetic infiltration, many clinicians mix bicarbonate into the bottle of local in order to raise the pH and thereby lessen pain. Additionally, raising the pH speeds up the onset of the block. To demonstrate this and to increase the use of local infiltration prior to IV and art line insertion, in the past, I would have students and residents perform subcutaneous injections of straight and bicarbonated lidocaine on each other. Of course, once they learned that bicarbonated local anesthetics were completely painless many changed their practice and began to infiltrate the skin routinely prior to IV insertion. Of course, using students and housestaff to self inject would probably lead to immediate dismissal if done today.
One of the problems of adding bicarbonate to local anesthetic solutions was crystallization. For example, adding 1 mL of bicarb to 9 mL lidocaine was OK (10:1 dilution), but adding the same amount to bupivacaine would instantly produce crystallization. Beyond bicarbonate, many adjuvants are added to local anesthetics. Do they crystallize? Does it matter? Myron Yaster MD
Original article
Hoerner E, Stundner O, Putz G, Steinfeldt T, Mathis S, Gasteiger L. Crystallization of ropivacaine and bupivacaine when mixed with different adjuvants: a semiquantitative light microscopy analysis. Reg Anesth Pain Med. 2022;47: 625-9. Jun 23:rapm-2022-103610. doi: 10.1136/rapm-2022-103610. PMID: 35738668.
Original article
Hoerner E, Stundner O, Fiegl H, Gasteiger L. Crystallization of short-acting and intermediate-acting local anesthetics when mixed with adjuvants: a semiquantitative light microscopy analysis. Reg Anesth Pain Med. 2023;Oct;48(10):508-512. doi: 10.1136/rapm-2023-104398. PMID: 36928300.
In today’s PAAD, Hoerner et al.1, 2 took short, intermediate, and long acting local anesthetics and mixed them with a variety of adjuvants including clonidine, dexamethasone, dexmedetomidine, fentanyl, sodium bicarbonate (8.4%), epinephrine, or morphine (the latter two only in the short and intermediate acting local anesthetics) in clinically established ratios. “For each mixture, they measured initial pH and recorded crystallization patterns at 0, 15, 30 and 60min using a standardized, semiquantitative light microscopy approach.”1, 2
What did they find? In the long acting local anesthetic study, “all pure substances-except the reference standards sterile water and triamcinolon-showed crystallization grades ranging from grade 1 to grade 4. Addition of adjuvants led to variable, unpredictable changes in crystal depositions. Addition of sodium bicarbonate 8.4% produced heavy crystallization in all combinations. Grade of crystallization was weakly positively related to the pH of the solution in 1:1 mixtures and clinically relevant concentrations, but not in pure substances.”1 In the short to intermediate acting local anesthetic study, “lidocaine 2% and mepivacaine 2% plus sodium bicarbonate 8.4%, and mepivacaine 2% plus dexamethasone developed delayed grade 5 crystallization over 1 hour. Prilocaine-based, procaine-based and chloroprocaine-based mixtures showed much less pronounced crystallization, with a maximum of grade 2. Initial pH and grade of crystallization showed weak monotonic relationships at time points t0, t15 and t30 (ρ=-0.17, 0.31 and 0.32, (all p>0.05)) and a moderate relationship time point t60 (ρ=0.57 (p=0.0003))”2 Finally, because crystallization increased over time, the authors “cast doubt on the safety of preparing these formulations for later use.”2
We have many questions about the meaning of these studies. This was an in vitro study and not done in vivo. In clinical practice, does the presence of crystallization in these solutions matter? Does it affect the onset or duration of blockade? Is it safe? Does the presence of crystallization affect the safety of administering these drugs particularly in the epidural or perineural spaces? If mixed in advance, does the presence of crystallization affect the local anesthetic’s shelf life stability? Are all of the mixed adjuvants preservative free? This is an issue that may be of much greater concern than the presence of crystals.
What are your thoughts? Do you add bicarbonate to local anesthetics for local anesthetic infiltration or for peripheral or central nerve blocks? Have you seen crystallization in local anesthetic solutions and if you did, did you throw it away or use it? Send your responses to Myron who will post in a Friday Reader response.
References
1. Hoerner E, Stundner O, Putz G, Steinfeldt T, Mathis S, Gasteiger L. Crystallization of ropivacaine and bupivacaine when mixed with different adjuvants: a semiquantitative light microscopy analysis. Regional anesthesia and pain medicine. Jun 23 2022; 47; 625-9. doi:10.1136/rapm-2022-103610
2. Hoerner E, Stundner O, Fiegl H, Gasteiger L. Crystallization of short-acting and intermediate-acting local anesthetics when mixed with adjuvants: a semiquantitative light microscopy analysis. Regional anesthesia and pain medicine. Oct 2023;48(10):508-512. doi:10.1136/rapm-2023-104398