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Most neuromodulators are provided as powders that require reconstitution prior to use.
Preserved saline is the most common diluent used in clinical practice; however, other diluents have also proven to be safe and effective.
While package inserts state that reconstituted botulinum toxin should be used within 4 to 24 hours, stored at 2°C to 8°C, and not refrozen, these recommendations are strict.
Neuromodulators that are reconstituted to yield a low concentration and high volume result in greater diffusion than toxin that is reconstituted to have a high concentration and a low volume.
A successful botulinum toxin (BoNT-A) treatment begins with correct reconstitution and precise knowledge of all variables involved in this process. Published data on BoNT-A reconstitution methods will be reviewed in this chapter. In addition, we will share our preferred method of toxin reconstitution.
OnabotulinumtoxinA and prabotulinumtoxinA are provided as vacuum-dried powders, whereas incobotulinumtoxinA and abobotulinumtoxinA are provided as lyophilized powders. Daxibotulinumtoxin A, a new neuromodulator, is also provided as a lyophilized powder. Alternatively, rimabotulinumtoxinB is provided as a ready-to-use sterile liquid, and no reconstitution is required. All powders require reconstitution, and although package inserts recommend preservative-free 0.9% sodium chloride as the diluent, other potential diluents have been shown to be safe and effective. No matter what diluent is used, care must be taken to avoid residual undiluted powder in the vial as this can affect the final concentration of the reconstituted product ( Fig. 13.1 ).
Sodium chloride: Given that the initial pivotal trials on BoNT-A were performed using preservative-free saline as the diluent, the US Food and Drug Administration has approved the reconstitution of BoNT-A with preservative-free saline. However, in clinical practice, preserved saline is more commonly used given it significantly decreases patient discomfort on injection. Preserved saline, also known as bacteriostatic saline, contains benzyl alcohol. Benzyl alcohol has anesthetic properties and does not affect the potency of the neuromodulator. In accordance with the 2013 Consensus Panel’s Assessment and Recommendations on the Use of 3 Botulinum Toxin Type A Products in Facial Aesthetics , preserved saline is our diluent of choice.
Saline plus hyaluronidase: In 2003, Goodman demonstrated that BoNT-A mixed with hyaluronidase may increase toxin diffusion without a compromise in efficacy. The study concluded that addition of hyaluronidase to BoNT-A could potentially allow for a lower dose of toxin needed for the treatment of axillary hyperhidrosis given the increase in diffusion. While compelling, long-term data were not collected, and further studies investigating this concept have not been performed.
Ringer acetate: Dressler et al. reported that reconstituted BoNT-A products are acidic and that normalization of the pH can be achieved with the use of Ringer acetate as the diluent. This study found that BoNT-A reconstituted with Ringer acetate decreased injection site pain (with no compromise in clinical efficacy) when compared to BoNT-A reconstituted with normal saline.
Epinephrine: A randomized, double-blind, split face study found that the addition of a 1-mL ampule of epinephrine 1:100,000 to onabotulinumtoxinA diluted with preservative-free saline allowed for a faster onset of action and enhanced-short term efficacy when compared with onabotulinumtoxinA without epinephrine. No long-term change in effect was observed. Given the vasoconstrictive properties of epinephrine, it is hypothesized that epinephrine localizes BoNT-A to the appropriate site of injection and can decrease the risk of bruising.
Lidocaine: A double-blinded, side-by-side, randomized controlled trial of 29 patients with axillary hyperhidrosis compared the efficacy and tolerance profile of saline-diluted BoNT-A and 2% lidocaine-diluted BoNT-A. The study showed equal effectiveness between the two study arms but decreased pain with the 2% lidocaine-diluted BoNT-A. We, however, do not add lidocaine to BoNT-A when treating axillary hyperhidrosis and, when needed, prefer to use forced cool air or topical anesthetic creams to minimize pain.
Bupivacaine: In a randomized, double-blinded, split-face study for the treatment of glabellar lines, Yen et al. compared the use of onabotulinumtoxinA reconstituted with 0.75% bupivacaine to onabotulinumtoxinA reconstituted with unpreserved saline. The authors found the use of bupivacaine as the diluent resulted in decreased pain with injection, faster onset of paresis, and no long-term reduction in efficacy.
Albumin: Mohammadi et al. found that the use of albumin-supplemented abobotulinumtoxinA for the treatment of cervical dystonia, blepharospasm, and hemifacial spasms could allow for dose reduction without a decrease in therapeutic efficacy or safety. The mechanism by which albumin allows for dose reduction is not fully understood but some believe that albumin may prevent toxin loss caused by adhesion to the syringe walls.
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