Cooling Anesthesia for Intravitreal Injections-A Review

Various methods of anesthesia have been used prior to giving IVT injections in patients. These include topical anesthetic agents (TA) in the form of drops, pledgets, gel forms and subconjunctival anesthetic agents. TA drops block cell membrane depolarization by reducing the cell membrane permeability of sodium ions in affected cells and thus halting pain signaling in cornea, conjunctiva and sclera. The most common TA agents that are used include proparacaine hydrochloride (HCL), tetracaine HCL and less commonly lidocaine. Formulations of tetracaine and lidocaine aims at a pH between 7.6 and 7.8 to aid in tear film penetration while proparacaine has benzalkonium chloride to aid in the same. The effect lasts for nearly 15 minutes taking effect from 15 to 20 seconds after application. TA drops cause burning sensation and long-term use leads to reduced corneal sensation causing keratitis, corneal opacity and vision loss. TA gel forms include 0.5% tetracaine HCL gel, lidocaine HCL and preservative-free lidocaine HCL gel. Gel anesthetics stay in the eye for a longer duration without getting diluted by tears unlike TA drops. Local anesthetic (LA) gel forms are well tolerated. However, LA gel forms were associated with high rates of endophthalmitis when given prior to povidone-iodine for IVT injections.

Following application of topical anesthetics, TA pledgets are applied with pressure on the intended injection site ranging from 20 seconds to 1 minute. TA pledgets produced similar pain scores with no adverse events reported compared to other modes of anesthetic use. Subconjunctival injections can cause subconjunctival hemorrhages, which worsen following IVT injections. In all forms of anesthesia, the pain was well tolerated with the most distressing step being needle insertion.

LA can be divided into Esther and amide types based on the structure of their intermediate chain. Allergy to LA is more common with the Esther group, particularly associated with the constituent methylparaben (a bacteriostatic preservative) or hyaluronidase (enhances the spread of anesthetic agent and speeds up action) or metabisulfite (a stabilizer for sympathomimetic agents) used in the anesthetic preparation.10 Periorbital allergic contact dermatitis and sight-threatening periorbital swelling due to Esther anesthetic types have been reported following peribulbar anesthesia. The metabolite p-aminobenzoic acid (PABA – from Esther anesthetics and methylparaben) is believed to be antigenic causing sensitization of T-lymphocytes and this leads to cell-mediated immunity on second exposure. The cross-reaction between Esther anesthetic group and methylparaben can cause anaphylaxis due to cross-reaction and hence preservative free amide group anesthetic can be used.

This review article by Chandrasekaran et al addressed the need for such an anesthetic that will lessen patient’s anxiety at the most crucial step and reduce pain score. Hence, cooling anesthesia might mitigate the above concerns of the patient and prove to be effective.

Ultra-Rapid Non-Pharmacological Cooling Anesthesia for IVT Injections

The primary outcome was to measure subjective pain at the time of IVT injection using a visual analog scale (VAS) which ranged from 0 to 10, with zero being no pain and 10 being severe pain. The secondary outcome was to measure post injection pain and discomfort 4 hours after IVT injection and adverse events as reported by the patients 7 days after the injection.

Within each group, post-injection pain scores measured 4 hours after IVT injection were similar between CA within each group and SOC groups (P = 0.3–0.8). The mean ± SEM for combined SOC arms and combined – 10°C. A 4 hours post IVT injection were 1.6 ± 0.4 and 1.2 ± 0.5 (P = 0.56), post-injection pain score in group 5 (−10°C for 20 seconds) in CA was the least, mean ± SEM post-injection pain score difference between combined SOC (n = 22) and group 5 of CA (n = 5) was 1.2 ± 0.5 that was statistically significant (P = 0.02), mean ± SEM IVT injection time was 395 ± 40 seconds in those in SOC and that of CA was 124 ± 5 seconds (P < 0.0001).

COOL-1 Trial

There was no statistically significant difference pairwise at the time of injection in the groups but significant difference among the 3 groups in aggregate (P = 0.047) at the time of injection, no statistical difference 5 minutes and 24 to 48 hours post-injection among the groups (0.676 and 0.32 respectively). P values were 0.13, 0.27 and 0.53, respectively, in all three groups at the time of injection, 5 minutes and 24–48 hours post IVT injection, statistically significant pain scores at the time of injection and 5 minutes post injection (P =0.00008, 0.003 and 0.005, respectively) in groups −10°C for 20 seconds, - 15°C for 15 seconds and −15°C for 20 seconds, statistically significant difference in the 5 minutes post-injection and in −10°C for 10 seconds and –15°C for 15 seconds only (P = 0.00001, 0.018 respectively). Average procedural time was 2.05 minutes with an SD of 1.75 minutes.

COOL-2 Trial

The primary outcome measure was to measure pain using a visual analog scale (VAS) with 0 being least and 10 being most severe pain. The secondary outcome was to look for

1. Patient movement during injection and particularly during needle penetration (1 - mild movement and 2 - marked movement).

2. Time taken to perform the entire IVT procedure.

3. Anesthetic preference by the patient by the end of 24 to 48 hours – standard of care or cooling anesthesia.

4. Pain during follow-up – 24 to 48 hours after IVT injection using VAS score.

Use of IVT injections for various retinal diseases have increased exponentially in the last few years. Various theories of freeze damage have been speculated to be due to hypertonicity of intra- and extracellular fluids, physical destruction at the site by the extracellular ice crystals, attainment of minimum cell volume, cell protein damage, rapid water loss leading to membrane rupture, ischemic necrosis and production of autoantibodies predominantly in vitro. It has been shown that cryo causes complete tissue destruction at the center where there is recovery in the periphery. Reversible conduction block happens when cold is applied to peripheral nerves either by direct cooling of few segments or complete immersion of the entire tissue. This in turn is dependent upon the duration of exposure and the temperature attained in the tissues. There is breakdown of myelin sheath with disintegration of axons and Wallerian degeneration occurs with perineurium and epineurium remaining intact. Nerve regeneration not only depends on the temperature reached but also on the degree of hypoxia, buildup of metabolites, histamine release and its action and finally inactivation of enzymes due to cold exposure. The reappearance of sensory and motor activity is dependent on the rate of nerve regeneration and the distance between cryo lesion and end organ. Studies have speculated the temperature drop to −20°C for adequate pain relief that produces only a brief interruption of conduction of nerve impulses.

Various factors are associated with increased pain score during intravitreal injections including being female, patients not undergoing anterior chamber paracentesis and those who had more waiting time

The COOL-1 study showed that there was no statistical difference in pain scores among groups at the time of injection, 5 minutes after injection and 24–48 hours later. The use of single drop of topical 0.5% proparacaine used before placing the CA device added additional benefit by anesthetizing the ocular surface initially and paving way for rapid and adequate anesthetic effect for the injection. This is considered much faster than other types of anesthesia for IVT such as lidocaine gel or subconjunctival lidocaine. However, the confounding contribution from topical 0.5% proparacaine towards the NRS pain scores cannot be overlooked. These findings were consistent with reduced pain scores following prolonged duration of exposure (12 minutes with topical tetracaine gel or 6 minutes with subconjunctival lidocaine).

Cooling anesthesia may provide an efficient, efficacious, and safe anesthesia strategy prior to intravitreal injections. Multiple early-stage trials have clearly shown the potential of cooling anesthesia prior to intravitreal injections for retinal diseases. These results have so far shown that cooling anesthesia would mitigate the pain, apprehension and possibly hypersensitivity or anaphylaxis associated with certain groups and compounds used as additives. However, further randomized controlled trials are required to prove the efficacy and safety of cooling anesthesia compared to the current standard of care anesthetic strategies for patients undergoing intravitreal injections.

Source: Chandrasekaran et al; Clinical Ophthalmology 2023:17 https://doi.org/10.2147/OPTH.S388327