Table 2.
Summary of controlled trials evaluating the use of reduced eyedrop volume compared with standard drops
| Author, year | Design | Population (sample size) |
Regimen(s) | Instilled drop volumes (level of comparison, i.e., eyes or subjects) | Method of instilling microdrops | Efficacy outcome(s) | Safety outcome(s) |
|---|---|---|---|---|---|---|---|
| a1-adrenergic agonists and muscarinic antagonists | |||||||
| Brown 1978 [11] | Non-randomized controlled trial |
Adults (41) |
Group A - µ-drop of PHE 5% & TRO 0.5%, in a mixture, in one eye (1 drop, 3 doses, 5 min interval) - s-drop of PHE 10% & TRO 1%, sequentially, in the other eye (1 drop, 3 doses, 5 min interval) Group B - µ-drop of PHE 5% & TRO 0.5%, in a mixture, in one eye (1 drop, 3 doses, 5 min interval) - s-drop of PHE 10% & TRO 1% in the other eye (1 drop, 3 doses, 5 min interval) |
A) 5 µl vs. 70 µl (in either eye of the same subject) B) 10 µl vs. 70 µl (in either eye of the same subject) |
A) Sterile PE-160 polyethylene tubing wrapped at least four times around the barrel of a 1-ml tuberculin plastic syringe and attached to the syringe through an 18-gauge needle B) Calibrated micropipette |
A) Mean pupil diameter at T45 increased from 2.09 mm to 7.10 mm after µ-drop, and from 2.10 mm to 7.39 mm after s-drop B) No difference in mydriasis between µ-drop and s-drop |
Tearing and ocular irritation experienced only after s-drop (percentages are not reported) |
| Brown 1987 [130] | Crossover RCT |
Adults (10) |
- µ-drop of PHE 10% (1 drop, 2 doses, 10 min interval) - s-drop of PHE 2.5% (1 drop, 2 doses, 10 min interval) |
8 µl vs. 32 µl (subjects, at least one-week washout period) |
Calibrated micropipette | Larger increase from baseline in pupil diameter at T45 after µ-drop (p = 0.0001) | No difference in the average plasma concentration of PHE at T10, T20, T40 |
| Lynch 1987 [13] | RCT |
Preterm infants (11 for efficacy and 17 for safety outcome) |
PHE 2.5% (1 drop, 3 doses, 2–5 min interval) |
8 µl vs. 30 µl (eyes for the efficacy and subjects for the safety outcome) |
Calibrated micropipette | No difference in the percent change from baseline in pupil diameter at T60 | Lower plasma levels of PHE at T10 after µ-drop (p = 0.01) |
| Craig 1991 [131] | Crossover non-randomized controlled trial |
Healthy volunteers (20) |
PHE 10% (regimen NR) |
10 ± 2 µl vs. 30 ± 4 µl (subjects, one week washout period) |
22G Venflon iv cannula attached to the end of a Minim after removal of the central stylette | No difference in the change from baseline in pupil diameter at T60 | Less discomfort was self-reported after µ-drop (percentages are not reported) |
| Gray 1991 [132] | RCT |
Patients requiring diagnostic pupil dilation (60) |
Group A: PHE 10% & TRO 1% (1 drop of each, 2 min apart) Group B: TRO 1% (1 drop) Group C: TRO 0.5% (1 drop) |
5 µl vs. 26 µl (in either eye of each subject in all three groups) |
30G Rycroft cannula attached to the minim |
A) Larger increase in pupil diameter at T20 after s-drop B) No difference in the change from baseline in pupil diameter at T20 C) Larger increase in pupil diameter at T20 after s-drop |
Less ocular discomfort was reported after µ-drop (percentages are not reported) |
| Gray 1992 [133] | Crossover non-randomized controlled trial |
Healthy adult volunteers (20) |
TRO 1% (Regimen NR) |
5 µl vs. 26 µl (subjects; only one eye was tested in each individual, at least one-week washout period) |
Narrow bore cannula attached to the minim | No difference in the change in pupil: cornea diameter ratio at T30, T60, T120 and T240 | Improved rate of recovery of distance and near visual acuity at T30 after µ-drops compared with s-drops (p < 0.05) |
| Noske 1993 [14] | Crossover non-randomized controlled trial |
Children with uncorrected or undercorrected hypermetropia (15) |
Atropine 0.5% (< 2 years) − 1 µ-drop, 3 doses, 5 min interval − 1 s-drop, 6 doses (twice daily for 3 days) Atropine 1% (> 2 years) − 1 µ-drop, 3 doses, 5 min interval − 1 s-drop, 6 doses (twice daily for 3 days) |
5 µl vs. 30–36 µl (eyes, without washout period) |
Calibrated micropipette |
Higher by 0.25 D mean spherical equivalent of cycloplegic refraction at T90 after s-drop (p < 0.05) No difference in cylindrical power and axis after s-drop and µ-drop |
Increased change from baseline in HR at T90 after s-drop (p < 0.05) Typical flushing observed in some children after both s-drop and µ-drop |
| Wheatcroft 1993 [134] | Non-randomized controlled trial |
Preterm infants (26) |
PHE 2.5% & CYCLO 0.5% (1 drop of each, 5 min apart) |
5 µl vs. 26 µl (in either eye of the same subject) |
30-gauge Rycroft intraocular cannula attached to the minim | No difference in pupil diameter at T40-T60 | Not assessed |
| Whitson 1993 [12] | Crossover RCT |
Healthy adults (13) |
PHE 10% (1 drop, 2 doses, 10 min interval) +/- eyelid closure for 1 min |
10 µl vs. 30 µl (subjects, at least one-week washout period) |
Calibrated micropipette |
No difference in pupil diameter at T60 For both s-drop and µ-drop, eyelid closure produced greater pupil dilation |
No difference in plasma concentration at T20 |
| Elibol 1997 [135] | Crossover non-randomized controlled trial |
Infants (53) |
Group A: PHE 10% (1 drop, 2 doses, 5 min interval) Group B: CYCLO 1% (1 drop, 2 doses, 5 min interval) Group C: TRO 0.5% (1 drop, 2 doses, 5 min interval) |
A) 5.1 µl vs. 33 µl (subjects, 3–7 days washout period) B) 6.5 µl vs. 39.2 µl (subjects, 3–7 days washout period) C) 5.4 µl vs. 33.8 µl (subjects, 3–7 days washout period) |
24-gauge intravenous cannula attached to the end of a minim after removal of the central stylette |
A) No difference in pupil diameter at T15, T30, T45, T60 B) No difference in pupil diameter at T15, T30, T45, T60 C) Increased pupil diameter at T30, T45, T60 after s-drops compared with µ-drops (p < 0.01) |
A, B, C) Increased change from baseline in mean BP at T15, T30, T45, T60 after s-drop (p < 0.01) A, B, C) No difference in the change from baseline in HR at T60 B, C) Significant flushing after s-drop of CYCLO and TRO compared with µ-drop (p < 0.01) |
| Ianchulev 2016 [136] | RCT |
Healthy adults (102) |
PHE 2.5% & TRO 1%, sequentially Group A: 1 µ-drop * 1.5 µl of each drug in one eye Group B: 2 µ-drops * 3 µl of each drug in one eye (3-min interval) Group C: 1 µ-drop * 6 µl of each drug in one eye In all three groups: 1 s-drop (26 µl) of each drug in the other eye |
1.5–3 µl or 6 µl vs. 26 µl (in either eye of the same subject) |
Piezoelectric device | No difference in pupil diameter at T10, T20, T60 min after instillation of 2*3 µl and 1*6 µl compared with s-drops | Participants preferred piezoelectric self-delivery to s-drops, reporting better head-positioning comfort, reduced tearing/overflow and increased likelihood of adhering to ocular medication regimens (p < 0.0001) |
| Ianchulev 2018 [137] | Crossover non-randomized controlled trial |
Healthy adults (12) |
Group A: s-drop of PHE 10% (Regimen NR) Group B: s-drop of PHE 2.5% (Regimen NR) Group C: µ-drop of PHE 10% (Regimen NR) |
8 µl vs. 32 µl (subjects, one-week washout period) |
Microdroplet spray device |
No difference in the change from baseline in pupil diameter at T30, T45, T60 µ-drop of PHE 10% achieved comparable pupil dilation as s-drop of PHE 10%, and superior pupil dilation to s-drop of PHE 2.5% at T75 (p = 0.009) |
No difference in HR and BP at T60 No difference in PHE plasma levels at T20 after µ-drop of PHE 10% or s-drop of PHE 10% Higher PHE plasma levels at T20 after µ-drop of PHE 10% compared with s-drop of PHE 2.5% (p = 0.021) |
| Seliniotaki 2022 [125] | Pilot crossover RCT |
Preterm infants (25) |
PHE 1.67% & TRO 0.33% (mixture) (1 drop, 3 doses, 5 min interval) |
6–7 µl vs. 28–34 µl (subjects, one-week washout period) |
27-gauge irrigating cannula attached to a disposable 2.5 ml syringe | No difference in pupil diameter at T45, T90, T120 |
No difference in HR at T45, T90 Lower levels of HR at T120 after µ-drop (p = 0.046) No difference in BP and oxygen saturation at T45, T90, T120 No difference in 24-h cardiorespiratory and gastrointestinal AE |
| Hoppe 2023 [138] | Non-inferiority RCT |
Children (50) |
PHE 2.5% & CYCLO 1% & TRO 1% (1 drop of each drug sequentially) |
10.4 µl vs. 50 µl (eyes) |
Nanodropper adaptor |
Inconclusive trial regarding spherical equivalent and pupil constriction percentage** at T30 Non-inferiority of µ-drop compared with s-drop regarding pupil diameter at T30 (non-inferiority margin: −0.20) |
Inconclusive trial regarding IOP after dilation |
| Seliniotaki 2024 [139] | Non-inferiority crossover RCT |
Preterm infants (83) |
PHE 1.67% & TRO 0.33% (mixture) (1 drop, 3 doses, 5 min interval) |
6.5 µl vs. 28–34 µl (subjects, at least one-week washout period) |
Calibrated micropipette |
Superiority of µ-drop regarding pupil dilation at T45 (p = 0.008) Non-inferiority of µ-drop regarding pupil dilation at T90 and T120 (Bonferroni-corrected 95%CI at T90: −0.10, 0.17; at T120: −0.18, 0.14; non-inferiority margin: −0.4 mm) |
Lower levels of oxygen saturation at T45 (p = 0.03) and T90 (p = 0.04) after s-drop Higher percentage of 24 h hypertensive episodes (p = 0.01) after s-drop Pooled pharmacokinetic data of PHE within 3-hours post-instillation, insufficient to compare µ-drop with s-drop |
| beta-blockers | |||||||
| Montoro 1990 [94] | RCT |
Adults (20) |
Timolol maleate 0.5% (Regimen NR) |
29.12 ± 1.2 µl vs. 49.26 ± 1.4 µl (subjects; before-after) |
NR |
Significant reduction in IOP in each separate group (time-point not specified) |
Decrease in HR from baseline in each separate group – larger decrease observed after s-drop (0.05 < p < 0.10) No difference in BP compared with baseline in each separate group |
| Steger 2024 [98] | Non-inferiority RCT |
Adults with open angle glaucoma and ocular hypertension (419) |
Timolol maleate 0.5% (1 drop) |
12.5 µl vs. 28 µl (subjects) |
Nanodropper adaptor |
Significant reduction in IOP in each separate group at all time-points (1-, 2-, 5- and 8-hours post-instillation) Non-inferiority of µ-drop regarding IOP at 1-, 2-, and 8-hours post-instillation (non-inferiority margin: 1.5 mmHg) Inconclusive trial at 5-hours post-instillation |
Significant reduction in systolic BP in each separate group at 1-, 2-, and 5- hours post-instillation) No difference in diastolic BP change from baseline in each group at any time-point Greater absolute and relative HR decrease from baseline after s-drop |
| a2-adrenergic agonists | |||||||
| Petursson 1984 [15] | Crossover RCT |
Adults (16) |
Placebo in one eye & Clonidine 0.25% or Clonidine 0.5% in the other eye (1 drop) |
15 µl vs. 70 µl (eyes) |
Calibrated pipette | Both s-drop and µ-drop of 0.25% and 0.50% clonidine lowered the IOP at 1–5 h compared with the placebo |
Only s-drop of 0.50% clonidine lowered systemic BP at 1–5 h Transient “burning in the eye” after µ-drop of clonidine 0.25% (one patient) |
| Vocci 1992 [140] | Crossover RCT |
Healthy adult volunteers (29) |
Apraclonidine 0.5% (1 drop) |
16 µl vs. 30 µl (subjects, one-week washout period) |
A potentially commercially available eyedrop bottle that delivers 16 µl |
No difference in mean IOP at 1, 3, 8, 12 h Reduced IOP at 1, 3, 8, 12 h after s-drop and µ-drop compared with placebo |
No difference in the % change from baseline in BP No difference in the number of subjects experiencing AE including blurred vision, dry mouth, drowsiness, tiredness |
| muscarinic agonists | |||||||
| File 1980 [16] | Crossover RCT |
Healthy adult volunteers (10) |
Pilocarpine 0.5% (1 drop) |
20 µl vs. 50 µl (subjects; only one eye was tested in each individual, one-week washout period) |
Micropipette with sterile disposable tips | No difference in the change from baseline in pupil diameter up to 2 h post-instillation | Not formally assessed |
| Lal 1995 [141] | Crossover RCT |
Healthy volunteers (12) |
Pilocarpine 2% (1 drop) after the drop administration, the inner punctum was pressed for 1 min |
10 µl vs. 20 µl vs. 40 µl vs. 80 µl (subjects, 7-days washout period) |
Micropipette | Larger decrease in pupil diameter at T15, T30, T45, T60, T90, T120, T180, T240, T300 after 10 µl, compared with 20 µl, 40 µl and 80 µl |
No difference in HR at T15, T30, T45, T60, T90, T120, T180, T240, T300 Fewer subjects experiencing frontal headache or ocular irritation after 10–20 µl (statistical analysis not performed) |
| allogeneic serum | |||||||
| Vermeulen 2023 [142] | Multi-center non-inferiority crossover RCT |
Adults with dry eye disease (49) |
Allogeneic serum (6 drops daily for 1 month) |
7 µl vs. 50 µl (hospitals, one-month washout period) |
mu-Drop system | Non-inferiority of µ-drop compared with s-drop regarding the Ocular Surface Disease Index score (mean difference − 2.60; 95%CI −9.16 to 3.97; p = 0.006; non-inferiority margin = 6) | Not formally assessed |
µ-drop microdrop instillation, s-drop standard drop instillation, PHE phenylephrine, TRO tropicamide, CYCLO cyclopentolate, RCT randomized controlled trial, BP blood pressure, HR heart rate, NR not reported, IOP intraocular pressure, AE adverse events, ROP retinopathy of prematurity, CI confidence interval
**Pupillary constriction percentage was calculated by the pupillometer in response to a 180-mW flash: (maximum - minimum) / maximum