Comparing the Impact of Diluents and Injection Techniques on Patient Comfort During Indocyanine Green Lymphangiography: A Prospective Study

Introduction

Lymphedema is a condition characterized by the accumulation of lymphatic fluid in the interstitial spaces, resulting in chronic swelling of the affected area.^1,2 It can be primary or secondary, and can occur in various parts of the body, including the upper and lower extremities. The diagnosis of lymphedema is primarily based on clinical examination, and imaging studies are often used to confirm the diagnosis and to assess the severity of the disease.

Indocyanine green (ICG) lymphography is a relatively new imaging modality that has gained popularity in recent years for the diagnosis of lymphedema. ³ ICG is a fluorescent dye that is injected into the affected area, and the transportation of the dye through the lymphatic vessels can be visualized using near-infrared imaging. ⁴ ICG lymphography allows for visualization of the lymphatic vessels and helps in identifying areas of obstruction or damage, which is important for guiding treatment decisions.

Although ICG lymphography is generally considered a safe and well-tolerated diagnostic procedure for lymphedema investigation, some patients may experience discomfort during the injection, which rarely can lead to vasovagal episodes.^5–8 Several authors have investigated methods of reducing patients' discomfort during injection, including the addition of local anesthetic such as Xylocaine^® to water for injection (WFI) solution or the dilution of ICG with WFI (with and without Xylocaine) and Dextrose^® 5% w/v.^9,10

However, to our knowledge, no studies have directly compared the pain score of patients injected with ICG diluted in normal saline (NS) with those of patients receiving the aforementioned interventions. This study aims to compare different ICG diluents for optimal patient experience and efficacy in lymphography.

Materials and Methods

In this prospective study, we tested three ICG diluents, such as WFI, NS, and Dextrose 5% w/v Dextrose plus 5% human albumin (Dx+Alb). The ICG dye used came in stock of 5 mg/mL (Diagnostic Green GmbH, Aschheim-Dornach, Germany). These three diluents were injected into two different planes (subdermal or intradermal) in five healthy volunteers, aged between 20 and 50 years, who were willing to participate in all procedures and provide informed consent.

We excluded those with known allergies to ICG dye, a history of severe allergic reactions to diagnostic dyes, current skin diseases, recent trauma or edema in the examination area, use of medications affecting lymphatic function or pain perception, and those who were pregnant or breastfeeding. Sequential enrollment was followed, adhering to these criteria.

Each volunteer underwent a different diluent testing with an interval of 1 week. The three groups were created as follows:

Group A had ICG diluted in 10 mL WFI (ICG+WFI).

Group B had ICG diluted in 10 mL of NS (ICG+NS).

Group C had ICG diluted in 9.5 mL 5% w/v Dextrose and 0.5 mL of 5% albumin (Baxalta Innovations GmbH, Vienna, Austria) (ICG+Dx+Alb).

To achieve good dilution of the ICG on each case, the mixture was vortexed using a table vortex mixer (Kartell TK3S; Kartell Labware, Italy). In addition, to prevent undiluted dye clusters to be injected into the patients' skin, we used blunt filter needles (BD Switzerland Sarl) to aspirate the diluted dye into 1 mL syringes. We always use 29G syringes (opening 0.33 and 13 mm length) for the injection of the ICG and our common practice is to inject 0.2 mL of dye on each of the first and fourth webspaces in a slow manner with metacarpophalangeal joints flexed for better visualization of the small regional veins. No massaging was applied after injection into either site.

For the purposes of the study, at one hand of the volunteers, the injections were made intradermally (ID), while at the contralateral hand, the injections were made subdermally (SD). The patients were asked to mark a point on the line that best represents their pain on a visual pain score (VAS) for each injection. The average of the two measurements was used as the final score for this plane of injection (Table 1). Moreover, the duration between the initial injection point and the moment of the ICG dye identified at the axilla was calculated in our study (Table 2).

The study received an institutional review board approval and all volunteers had consented before the procedure.

Results

Our findings suggest that, overall, Group B (i.e., injection with ICG+NS) experienced the least discomfort during the injections (mean values of 1.4 and 0.6 for intradermal and subdermal injections, respectively), followed by Group C (ICG+Dx+Alb, mean values of 2 and 1.2 for intradermal and subdermal injections, respectively). In contrast, the VAS in Group A (ICG+WFI) was the highest among groups. Furthermore, comparing intradermal versus subdermal injection planes, the latter is associated with lower or same VASs (in 80% and 20% of the cases, respectively).

As far as it concerns the transport time of ICG from the injection site to the axilla, we noticed that intradermal injections were associated with faster transport times when compared with subdermal injections. This finding can be explained by the rich lymphatic network within the dermis that facilitates a more compact delivery of the dye to lymphatic vessels from intradermal injection and is in consistency with previous studies where the authors noticed that intradermal injection delivers radiotracers more rapidly to lymphatic structures.^11–13 The mean fastest time among all groups was seen in Groups A and B when the dye was injected intradermally (9.4 minutes), whereas the mean time recorded for Group C was 10.2 minutes.

Mixing of ICG with NS is our current preferred method of formulation resulting in great patient experience.

Discussion

The results of our study provide important insights into the optimal method for dilution of ICG dye in lymphography and the associated injection technique. Our findings suggest that diluting ICG with NS or a mixture of 5% w/v Dx and 5% albumin results in significantly less discomfort during injection, compared with diluting with WFI. Furthermore, subdermal injections were found to be less painful than intradermal injections in most cases. This may be due to the relative loose space in the subdermal tissue, resulting in less pressure at the sensory nerve endings.

Regarding the transport time of ICG dye from the injection site to the axilla, intradermal injections were found to be associated with superior transport times than subdermal injections, likely due to the rich lymphatic network within the dermis and relative paucity of lymphatic vessels in the subdermal tissue, resulting in a less compact delivery of the dye to the lymphatic vessels. This finding is consistent with previous research that found intradermal injections delivered radiotracers more rapidly to lymphatic structures. ¹³

However, it is important to acknowledge that different studies ¹⁴ explore varying aspects of lymphatic mapping and surgery, employing distinct methodologies. Although our research emphasizes the efficiency of intradermal injections in dye transport, the study by Gentileschi et al. ¹⁴ focuses on the use of SPECT/CT for targeted lymph node identification. This highlights the diversity of approaches in lymphatic imaging, underscoring the need for a comprehensive understanding of various techniques and their specific applications in the field of lymphedema management.

In our study we decided not to include in the dilution mixtures lidocaine (plain or in combination with adrenaline) due to the effects that these two components may have on the contractility of lymphatics as shown by Kwon and Sevick-Muraca. ¹⁵ Specifically, the authors showed that the administration of lidocaine led to a reduction in lymphatic function, whereas the combined use of epinephrine and lidocaine resulted in an overall increase in contractile activity. The efficacy of local anesthetics for mitigating immediate pain during the needle penetration and ICG solution infiltration may be limited due to their slow onset of action.

Consequently, the duration of time it takes for the anesthetic to take effect may not be sufficient in reducing the pain during this stage as it is likely that the pain would have already subsided by the time the anesthetic takes effect. In this study, our findings demonstrate that NS or a mixture of 5% w/v dextrose and 5% albumin can minimize patient discomfort during lymphography when used as diluents for ICG dye. It is noteworthy that other studies have also employed NS as a diluent for ICG in lymphatic imaging.^16,17 One other study has demonstrated the effect that different concentrations of ICG dye may have in mice lymphatics contractility and amplitude. ⁴ These findings, diluents, and their final concentrations were also taken into account during our experimental setup.

To provide further insight into the optimal ICG dilution method and injection technique, we deliberately avoided the use of cryogenic numbing devices in our study contrarily to the previous study mentioned. This approach was taken to minimize any external parameters that may have influenced the pain perception of patients during the procedure, and has several benefits, including (1) a direct comparison between the different diluents, (2) a more patient-centered perspective, and (3) potential reductions in cost and procedural time.

In conclusion, our study provides important insights into the optimal method for dilution of ICG dye and the associated injection technique for lymphography. Our findings suggest that using NS or a mixture of 5% w/v Dx and 5% albumin for dilution and subdermal injection technique can minimize patient discomfort during lymphography. These results may have important implications for clinical practice and ultimately improve patient experience and outcomes.