Evaluation of the AirgloveTM, An Air-Regulated Thermal-Venodilatory Device Facilitating the Cannulation of Patients With Dicult Venous Access

Dicult venous access (DVA) can prevent delivery of life-saving intravenous (IV) uids and medication. The Airglove ™ was developed to facilitate IV access, circumventing DVA in chemotherapy patients, as current warm-water immersion (WWI) methods are sub-optimal. This study had two parts; EAGLE-1, an observational, proof-of-concept study and EAGLE-2, a prospective, cross-sectional comparative study. EAGLE-1 recruited 80 adult participants undergoing chemotherapy for cancer with DVA where venous cannula insertion success rate was evaluated using Airglove ™ . EAGLE-2 was carried out on 34 adult healthy participants where the degree of venodilation by WWI and AirGlove ™ in three veins; cubital-fossa cephalic vein, cubital-fossa median vein and the third dorsal carpal vein on both arms were measured using the GE Logic S8 multi-frequency linear-array transducer (L6-15MHz), two-dimension B-mode ultrasound. Baseline measurements were taken at 23 o C, forearms were warmed to 38 o C using the two modalities prior to ultrasound assessment.


Introduction
Failure in gaining intravenous (IV) access is common in those undergoing chemotherapy, the obese population, IV drug users and patients with chronic medical problems leading to peripheral venous collapse. The importance of IV access is highlighted in the 2010 National Hospital Ambulatory Care Survey, where over one quarter (35.2 million) of all emergency-department attendances in the United States result in the placement of an IV cannula for parenteral uid administration 1 . However, when traditional routes are compromised, additional methods such as intraosseous infusion, central IV catheters and other more invasive approaches are available 2 .
Previous studies have shown where IV access failure occurs, in patients who have "di cult venous access" (DVA), ultrasound-guided methods have proven superior 3,4,5,6,7 . However, ultrasound equipment is expensive, not widely available at most hospitals for this purpose and very few clinical staff are trained in its use. Furthermore, bedside ultrasound equipment in most hospitals in the UK are only able to image in a single plane, meaning that the operator is only able to either view the vein in the short or long axis but not both simultaneously. There have been advances in bi-plane imaging, however this is costly and not widely available 8 . Thus, there is scope for more simple, cost-effective tools to facilitate venous access in DVA patients in an outpatient setting.
For DVA patients, most chemotherapy units in the United Kingdom immerse the patient's forearm in a container of warmed-water or by running the patient's arm under a warm-water tap. Convection of heat from warmed water onto skin causes vasodilation on activation of the sympathetic pathway, thus dissipating excess heat from the surface of the skin 9 . Venodilation by this method is transient but serves the primary purpose of allowing staff to gain IV access, enabling administration of drugs for chemotherapy, and delivering life-saving uids, nutrition and medication.
There are important limitations to the warm-water immersion (WWI) method; maintaining accurate and safe temperature controls (risk of scalding) can be challenging, sterility of the method cannot be ensured especially within a cohort with signi cant risks of immune-compromise, risks of water spillage and the potential distress to patients. For this reason, the Airglove™ (Fig. 1a, b, c, d) was developed. This device directs warmed air over the forearm within a single-use polyurethane-glove, causing venodilation with precise thermal regulation in three-minutes, to facilitate easier venepuncture or cannulation without the need for specialist training.
A "Medical Technologies Innovation brie ng" document has been developed by The National Institute for Health and Care Excellence (NICE) on the recommended use and application of the Airglove™ 10 . In the EAGLE study, we evaluated the utility of the Airglove™ in a cohort of patients undergoing chemotherapy and subsequently compared the degree of venodilation by the Airglove™ relative to the WWI method in the upper limbs of healthy individuals.

EAGLE-1
The median age of participants from the cancer-chemotherapy group in EAGLE-1 was 68.5 years and 67.5% of the participants were women (Table 1). Unexplained weight loss is a common feature in patients upon initial cancer diagnosis thus no participant in this cohort had a BMI > 25. Most (81.25%) of the cancer-chemotherapy participants were within the normal BMI range (18.5-25.0), Mann-Whitney U analysis indicated that BMI was not a contributory factor to cannulation failure in EAGLE-1 (p = 0.784) and adiposity, a feature normally contributing to DVA was not relevant in this cohort (Table 1).
Participants were on various chemotherapy treatments for a variety of cancer presentations (Table 1).
Extravasation is a known risk factor during venous access and delivery of chemotherapy drugs, with vesicant drugs carrying the highest risk 11,12 .
The common observation of participants with DVA in EAGLE-1 was that the forearm of those participants was cold-to-touch (80%), and clinicians involved in EAGLE-1 proposed the cause may be peripheral venoconstriction (Table 1). Another subjective observation by clinical staff in EAGLE-1 was that two patients had very fragile veins (Table 1). "Fragile veins" is a fairly common clinical feature noted in elderly patients undergoing chemotherapy in whom there is a loss of subcutaneous fat or lack of tone, causing the veins to move and roll under the skin when a venous cannula is inserted.
Five patients had multiple IV lines delivering chemotherapy with multiple bruises from past venepuncture attempts, therefore limiting the number of IV-accessible veins for chemotherapy (Table 1). Two patients also had lymphadenectomy or axillary lymph node clearance (Table 1); usually the insertion of peripheral venous cannula is contraindicated in the ipsilateral arm where axillary lymph-node clearance has been performed, due to increased risk of infection 13 . IV-access for chemotherapy is therefore carried out mainly in the contralateral arm for those patients.
Success in IV cannulation deployment in participants with DVA following use of Airglove TM.
The use of Airglove™ resulted in an 87.5% success rate in deployment of a venous cannula among participants with DVA undergoing chemotherapy for cancer (Table 1). A comparative study investigating the use of WWI vs Airglove™ was not carried out in EAGLE-1 since ethical approval was only granted for a proof-of-concept observational study solely for the use of Airglove™. Discussions with colleagues from other chemotherapy centres using WWI placed the overall success rate of IV-cannula placement after WWI in patients with DVA at around 65% (LGD personal communication).
The failure rate of Airglove™ in enabling insertion of a venous cannula in the forearm was 12.5% (Table 1). A total of 21.25% of patients undergoing chemotherapy were also on treatment with corticosteroids. Corticosteroids are frequently prescribed in patients undergoing chemotherapy and this class of drugs also causes venoconstriction, thus potentially further complicating IV-access in patients with DVA. However, we were able to gain venous access in 15 of these patients on the rst attempt with the use of the Airglove™. Only two patients could not be cannulated, even after a second attempt, due to poorly visible and impalpable veins. With the Airglove™, 77.50% of participants with DVA in EAGLE-1 showed visibly enhanced dilation of their veins.
Survey questionnaires by clinical staff involved in EAGLE-1 using the Airglove™ to deploy venous cannula suggested various subjective factors contributing to the success or failure in cannulation ( Table 2). These factors are subjective viewpoints of 25 members of experienced clinical staff with an average of over 15 years of clinical experience.

EAGLE-2 demonstration of the degree of venous dilatation by ultrasound
Baseline demographics of participants in EAGLE-2 are shown in Table 3. The median age of participants was 40.6 ± 12.36 years, 69% of participants were women (total number of participants = 34). The Shapiro-Wilks test showed that age, BMI and percentage body-fat data was normally distributed. The independent means T-test (p < 0.05, 95% C.I.) showed no observable effect of age-bias, BMI or percentage body-fat on the degree of venodilation by the two methods (Airglove™ or the WWI method).
Increases were noted in the median diameter from baseline values in all veins measured by both modalities, although signi cantly enhanced venodilation was noted using Airglove™ (Fig. 2). Increases in average diameter of all veins (both arms) being measured in this study, subtracted from baseline values are shown in Fig. 3, the Airglove™ showed signi cant difference in venodilation compared to the WWI in all veins (p < 0.001 95% C.I.).

Discussion
The results of this study are an important prelude for future in conducting a nationwide-randomised clinical trial where the e cacy of Airglove™ will be evaluated in patients undergoing chemotherapy. The device may be of potential use in emergency departments, PET-scanning labs, radiology and cardiaccatheterisation suites, general wards, care of the elderly wards and paediatric units, and whenever patients with DVA are encountered.
The median age-group of participants in EAGLE-1 was in the seventh decade, this conforms to the median age of participants in other adult chemotherapy units in the UK 14 . Younger age-group chemotherapy patients are not treated at MTW-Trust, since this subset of patients have unique needs due to the rapid development in their physical, cognitive, psychological, social, and experiential framework 15 , such needs are best addressed at other specialist centres, explaining why this subset was underrepresented in this study.
The use of corticosteroids is common in cancers as an anti-in ammatory and adjuvant in treatment 16 , to offset the effects of spinal cord compression in cancer metastasis 17 , to reduce the feeling of nausea and vomiting in cancer 18 , and sometimes to enhance appetite and wellbeing 19 . However, the use of corticosteroids is also well-known to cause systemic vasoconstriction via the adrenergic system 20 which could potentially decrease the chances of a successful cannulation. A total of 17 out of 80 participants in EAGLE-1 were prescribed corticosteroids for various clinical reasons. Only two patients from this cohort did not respond to Airglove TM -mediated venodilation.
One widely known cause for failure in gaining venous access is the increased level of adiposity which is directly correlated with BMI 21,22,23 . Approximately, 81.25% of the cancer-chemotherapy cohort in our study (EAGLE-1), had an average BMI between 18.5-25 (Table 1), therefore adiposity was not a signi cant confounding factor in that cohort. It also appears that adiposity was not a signi cant confounding factor in our healthy cohort population in EAGLE-2 since the average BMI among participants was 25. However, we acknowledge that further studies are warranted to investigate the venodilatory effect in participants with signi cant adiposity to establish optimal parameters in that cohort.
Although the use of Airglove™ was demonstrated to be successful in EAGLE-1, it was appropriate to carry out an empirical study where the actual degree of venodilation by Airglove™ was determined in comparison with WWI, the current widely used standard venodilation method in chemotherapy units across the UK. In EAGLE-2, we show that the Airglove™ causes statistically signi cant venodilation, measurable by ultrasound, compared to the WWI method ( Fig. 3, p < 0.001, CI: 95%).
While the WWI method is widely used, it has numerous issues of concern which are obviated by the Airglove™ including: i. water spillage on clothing of patients is common and distressing.
ii. di culty adjusting to a suitable temperature reproducibly, without risk of scalding.
iii. it is non-sterile, while the Airglove™ method employs a double-walled, single-use-glove.
iv. it is a signi cant inconvenience due to need for removal of some clothing; patients who are peripherally venoconstricted often complain of feeling cold.
v. the convection cooling effect from moisture causes constriction of vessels after immersion.
vi. vi) it is di cult to maintain minimal contact during the current pandemic using the WWI method, whereas the Airglove™ method allows use and disposal of the sterile glove.
Venous or arterial access devices in patient groups that require regular venous access for transfusions or delivery of medication are available, such as use of tunnelled central venous catheters (e.g. Hickman®, Broviac®, Groshong® or Neostar® lines) 24 , arterio-venous stula, peripherally inserted central catheters (PICC) 25 , central vascular access devices (CVAD) 26 or portacaths 27 . However, these methods are invasive, require specialist medical or surgical team intervention and considerable post-procedural, specialist-nurse-led after-care is often warranted. Furthermore, insertion of some of these ex-vivo devices have been associated with increased risk for deep vein thrombosis (DVT) 28,29 , although these risks can be reduced with appropriate patient-centred risk-strati cation and prior medical management; DVT prophylaxis with intravenous heparin 30 . Other devices have been reported to facilitate easy venous access, such as the AccuVein AV300, which uses infrared light to highlight haemoglobin within bloodvessels, however it does not venodilate veins 31 . However, subsequent trials that have been conducted produced con icting results 32,33 .
This study has demonstrated that while enhanced venous dilatation is achieved using both modes of forearm-warming, the Airglove™ showed a signi cant advantage over the WWI method in all the vessels measured ( Figs. 2 and 3). The additional major bene ts of the Airglove™ are that it is reproducible, sterile, patient-friendly, and simple to use, without the need for specialist training. The Airglove™ has been evaluated by the NICE Medical Technologies Evaluation Programme (MTEP), producing a MedTech Innovation Brie ng (MIB) which supports NHS and social care commissioners and staff when they are evaluating new medical devices 10 . The MIBs are commissioned by NHS England in line with the 5-year Forward View policy documents, which help accelerate innovation in new treatments and diagnostics and help key personnel in decision making. We anticipate that although use of the Airglove™ in this study has been slanted towards the chemotherapy cohort with DVA, it could be considered in other clinical situations where DVA is encountered. Particularly, we envisage that since the design of the Airglove™ uses a sterile-single use in atable-glove, it will be pertinent in the current coronavirus pandemic (COVID- 19) where sterility is paramount.

Methods
Study design, institutional review, ethical approvals and participants' eligibility criteria The study acronym: the EAGLE study, was shortened from "E cacy of Air-GLovE in di cult venous access". The study was carried out in two parts (Fig. 4). The rst, an observational, proof-of-concept study for Airglove™ (EAGLE-1), recruited a total of 80 informed and consented participants from patients (inclusion-exclusion criteria; Table 4) attending the chemotherapy unit at Maidstone Hospital, Kent. Approvals for the EAGLE-1 study were granted by the local research ethics committee and the R&D Department at MTW Trust, Kent, England, UK.
The second part, EAGLE-2, was a prospective, cross-sectional, comparative study on 34 appropriately consented participants, where the degree of venodilation of the Airglove™ vs. WWI was determined by ultrasound in three veins of the forearm (Fig. 5). EAGLE-2 was approved by the institutional ethics committee (reference number: HLS/PSWAHP/18/168) and run at the clinical simulation unit of Glasgow Caledonian University, Scotland, UK. All participants to the study (EAGLE-1 and EAGLE-2) met the inclusion-exclusion criteria (Table 4)

EAGLE-1 study
Evaluation of the Airglove™ on participants undergoing chemotherapy The Airglove™ was evaluated on a total of 80 participants (demographics described in Table 1) undergoing chemotherapy at the Chemotherapy unit, Maidstone Hospital (MTW Trust), Kent, with DVA (inclusion-exclusion criteria in Table 4). The endpoint was set as the overall successful insertion of a venous-cannula (maximum two attempts) following the use of Airglove™. Total number of participants were recruited to the study over a period of one month and cannulation was carried out by a single quali ed nurse to avoid operator bias. EAGLE-1 study questionnaires were completed by the operator of the Airglove™ and a total of 25 clinical staff in the chemotherapy unit normally performing venouscannulation. Aspects and features frequently contributing to cannulation success or failure from the questionnaires are tabulated in Table 2.

EAGLE-2 study
Pre-assessment of volunteers Blood-pressure (from both arms), age, height, weight, BMI, percentage of body-fat (using bioimpedanceanalysis (BIA) measured with a Tanita Body composition analyser (TBF-300M) across the lower limbs) and hydration status (assessed clinically by capillary re ll, dryness of mucus membranes, jugular-venouspressure) were recorded prior to venodilation and ultrasound measurements.

Warmed-water Immersion (WWI) method of venodilation
The upper limbs (to the level of mid-humerus) of participants were immersed in a container lled with a mix of cold-and warm tap-water to 38.5 o C for 3 minutes in the WWI method. Water temperature was veri ed using a Tanma 72-2060 digital thermometer. Arms were towel-dried, and the degree of venodilation was assessed by ultrasound.

Airglove™ method of venodilation
A single-use, double-walled, polyurethane-balloon (Green Cross Medico, Scotland) was in ated around the forearm using the Airglove™ to 38.5 o C at setting number-3 ( Fig. 1c) for 3 minutes and then removed. The degree of venodilation was assessed by ultrasound.

Ultrasound assessment of venous dilation by Airglove™ vs. WWI
No invasive procedure, such as cannulation or venepuncture, was carried out on participants in EAGLE-2. Ultrasound assessment of veins was performed prior to and following the Airglove™ and WWI warming methods. Volunteers were placed in a semi-recumbent position while ultrasound measurements were taken from each arm, devoid of external circumferential compression-pressures such as tight clothing or watches.
Three markings, aligning with common IV cannulation sites, were made on the upper limbs: i) the prominent veins proximal to the base of the middle-digit on the dorsum of the hand (dorsal-metacarpal), ii) lateral side of arm, 5 cm proximal to the skin crease of cubital fossa, to mark cephalic vein in arm (CV at cubital fossa), and iii) medial side of arm at the skin crease of cubital fossa to mark the mediancubital vein (MCV near cubital fossa).
Ultrasound examination of the veins in the forearm was performed by a single sonographer, using a GE Logic S8, (software version R2, revision 1.1, GE Healthcare, USA) with multi-frequency linear array transducer (L6-15MHz). Measurements of each vein were recorded to 0.01 cm accuracy, using twodimensional B-mode scanning in a transverse plane. On frozen annotated images, antero-posterior (AP) measurements were recorded at the skin-marked vessel sites, from inner anterior wall to inner posterior wall (or intima to intima) to facilitate repeatability (Fig. 2).
Baseline ultrasound measurements were recorded at 23°C ambient room temperature. The WWI method was deployed as described above and ultrasound measurements conducted on all three marked sites.
Participants were rested for 30 mins before testing with Airglove™ and ultrasound measurements were recorded on the same three marked sites. This process was repeated on the opposite limb. WWI and Airglove™ venodilation (temperature setting #3, Fig. 1c) were set at 38.5 o C for uniformity, enabling comparison. The rst warming method used rst on each participant was randomised and carried out by one of our team members.

Blinding in EAGLE-2
Blinding was achieved by physical concealment of onscreen diameter measures at time of scan, also ensuring the sonographer was unaware of the venodilation warming method used for participants. Vein diameter measurements were retrospectively recorded for statistical analysis.    Boxplots showing comparison between baseline venous diameter and increase in venous dilatation via the warm water immersion (WWI) method and AirgloveTM. The bottom and top edges of the boxes represent the rst (25%) and the third (75%) quartile of the long-axis diameter measurements by ultrasound. Veins typically are elliptical; the long axis diameter was selected for preserving consistency in measurements. The whiskers represent the minimum and the maximum measurements in the dataset.
The dark-rimmed open-circles represent suspected outlier measurements of the long-axis venous diameter and were determined with the threshold of less than or greater than 1.5 times the lower and upper interquartile range (IQR) limits, respectively. Median values are displayed next to the middle line of each box, re ecting the mid-point of each dataset. The increase in venous diameter from the AirgloveTM is more pronounced in all the veins measured compared to the WWI method.  Overall owchart summarising the EAGLE study.