On day 1, the low dose of caffeine was 2.5 mg/kg, the high dose of caffeine was 5 mg/kg, and the neutralizing dose of propranolol was 0.6 mg/kg. On day 2, the low dose of propranolol was 0.2 mg/kg, the high dose of propranolol was 0.6 mg/kg, and the neutralizing dose of caffeine was 5 mg/kg.
eTable 1. Median Differences Between Days 1 and 2 With Corresponding P-value for the Eyesi Surgical-Generated Score
eTable 2. Median Differences Between Days 1 and 2 With the Corresponding P-value for the Eyesi Tremor-Specific Task Score
eTable 3. Median Difference Between Days 1 and 2 With the Corresponding P-value for the Intraocular Trajectory (Odometer)
eTable 4. Median Difference Between Days 1 and 2 With the Corresponding P-value for the Total Time for Task Completion
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Roizenblatt M, Dias Gomes Barrios Marin V, Grupenmacher AT, et al. Association of Weight-Adjusted Caffeine and β-Blocker Use With Ophthalmology Fellow Performance During Simulated Vitreoretinal Microsurgery. JAMA Ophthalmol. 2020;138(8):819–825. doi:10.1001/jamaophthalmol.2020.1971
Is there an association of weight-adjusted doses of caffeine alone, a β-blocker (propranolol) alone, or a β-blocker and caffeine combination with surgical performance by novice vitreoretinal surgeons?
In this cross-sectional study of 15 vitreoretinal surgical fellows, propranolol alone was associated with improved surgical performance compared with caffeine alone and the combination of caffeine and propranolol.
The findings suggest that caffeine is negatively associated with surgical performance among novice vitreoretinal surgeons but that addition of propranolol is associated with improved performance.
Vitreoretinal surgery can be technically challenging and is limited by physiologic characteristics of the surgeon. Factors that improve accuracy and precision of the vitreoretinal surgeon are invaluable to surgical performance.
To establish weight-adjusted cutoffs for caffeine and β-blocker (propranolol) intake and to determine their interactions in association with the performance of novice vitreoretinal microsurgeons.
Design, Settings, and Participants
This single-blind cross-sectional study of 15 vitreoretinal surgeons who had less than 2 years of surgical experience was conducted from September 19, 2018, to September 25, 2019, at a dry-laboratory setting. Five simulations were performed daily for 2 days. On day 1, performance was assessed after sequential exposure to placebo, low-dose caffeine (2.5 mg/kg), high-dose caffeine (5.0 mg/kg), and high-dose propranolol (0.6 mg/kg). On day 2, performance was assessed after sequential exposure to placebo, low-dose propranolol (0.2 mg/kg), high-dose propranolol (0.6 mg/kg), and high-dose caffeine (5.0 mg/kg).
Surgical simulation tasks were repeated 30 minutes after masked ingestion of placebo, caffeine, or propranolol pills during the 2 days.
Main Outcomes and Measures
An Eyesi surgical simulator was used to assess surgical performance, which included surgical score (range, 0 [worst] to 700 [best]), task completion time, intraocular trajectory, and tremor rate (range, 0 [worst] to 100 [best]). The nonparametric Friedman test followed by Dunn-Bonferroni post hoc test was applied for multiple comparisons.
Of 15 vitreoretinal surgeons, 9 (60%) were male, with a mean (SD) age of 29.6 (1.4) years and mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 23.15 (2.9). Compared with low-dose propranolol, low-dose caffeine was associated with a worse total surgical score (557.0 vs 617.0; difference, –53.0; 95% CI, –99.3 to –6.7; P = .009), a lower antitremor maneuver score (55.0 vs 75.0; difference, –12.0; 95% CI, –21.2 to –2.8; P = .009), longer intraocular trajectory (2298.6 vs 2080.7 mm; difference, 179.3 mm; 95% CI, 1.2-357.3 mm; P = .048), and increased task completion time (14.9 minutes vs 12.7 minutes; difference, 2.3 minutes; 95% CI, 0.8-3.8 minutes; P = .048). Postcaffeine treatment with propranolol was associated with performance improvement; however, surgical performance remained inferior compared with low-dose propranolol alone for total surgical score (570.0 vs 617.0; difference, –51.0; 95% CI, –77.6 to –24.4; P = .01), tremor-specific score (50.0 vs 75.0; difference, –16.0; 95% CI, –31.8 to –0.2; P = .03), and intraocular trajectory (2265.9 mm vs 2080.7 mm; difference, 166.8 mm; 95% CI, 64.1-269.6 mm; P = .03).
Conclusions and Relevance
The findings suggest that performance of novice vitreoretinal surgeons was worse after receiving low-dose caffeine alone but improved after receiving low-dose propranolol alone. Their performance after receiving propranolol alone was better than after the combination of propranolol and caffeine. These results may be helpful for novice vitreoretinal surgeons to improve microsurgical performance.
Vitreoretinal surgery is one of the most technically challenging microsurgical procedures,1 derived in part from inherent human physiologic limits including tremor, precision, visual resolution, ability to sense microforces on underlying tissue, and fatigue. The level of surgical difficulty is also associated with innate properties of the target retinal tissues, which are delicate, transparent, nonregenerative, and critical to visual function.2-4
Virtual training simulators provide quantitative feedback on parameters of surgical precision, such as surgeon microtremor and accuracy of task completion, among other relevant measurements. Of importance, the use of the device allows better preparation for surgical performance and is associated with improvement in the individual skills required of novice surgeons.5,6 To be most useful, a simulator for vitreoretinal surgery requires a realistic retinal image and retinal tissue response to instrument manipulation.7,8 The ophthalmic surgical simulator Eyesi Surgical (VRmagic Holding AG) is a widely used virtual simulator for anterior segment and vitreoretinal surgical procedures.9,10
Consistent with the goal of improving microsurgical performance, the literature11,12 describes potential factors associated with surgical precision. Among these, all individuals have upper extremity physiologic oscillations that manifest as a fine tremor and may become more pronounced during stressful periods. Previous reports13,14 have described strategies to reduce physiologic oscillations and enhance manual dexterity, most of which can be categorized broadly into either postural considerations or pharmacologic interventions.13,14 Pharmacologic intervention with β-blockers (eg, propranolol and timolol)15,16 has been studied for its association with decreasing anxiety and hand tremor, thereby improving surgical precision. In contrast, an apparent correlation was reported between coffee consumption and impaired microsurgical performance by surgeons who identified as normally having a low-caffeine diet.17
The current study was designed to objectively analyze the individual performance of novice vitreoretinal surgeons exposed to various weight-adjusted doses of caffeine alone, propranolol alone, or a combination of caffeine and propranolol, 2 potentially opposing factors. The primary objective was to assess weight-based doses of propranolol and caffeine that would be associated with change of microsurgical skills during vitreoretinal surgery. The secondary outcome was to assess whether there was a potential role for the addition of propranolol to neutralize the caffeine effects in this setting.
The Committee of Ethics of the Universidade Federal de São Paulo in Brazil approved this single-blind cross-sectional study, which was conducted according to the tenets of the Declaration of Helsinki.18 All participants provided written informed consent. No incentives or financial compensation were offered to participants to join the study. From September 19, 2018, to September 25, 2019, 15 vitreoretinal fellows from the Retinal Division of the Ophthalmology Department of the Universidade Federal de São Paulo with fewer than 2 years of surgical experience were enrolled. The exclusion criteria included daily caffeine consumption exceeding two 8-oz cups or systemic medical conditions (eg, asthma, cardiac or neurologic disease, or mental illness). Before entry into the research protocol, electrocardiography was performed for each surgeon and an oral dose of propranolol (0.6 mg/kg) was administered to test for adverse reactions.
The current study19 was conducted using the commercially available Eyesi software, version 3.4.2 (VRMagic Holding AG). The simulator combines training of basic skills with challenging surgical procedures in increasing levels of difficulty. The surgeon must meet a required performance level for each task to advance successfully to the next step. In this study, we established in advance that any score higher than 0 was sufficient for the operator to go to the next step. At the end of each training module, the Eyesi simulator presents a total score of 100 for each task together with a detailed performance summary.20-23
The surgical skills were assessed during 2 nonsequential days. Blood pressure and heart rate were measured before and after each drug exposure followed by a scored simulated surgical performance analysis. The following fixed sequence of 7 tasks for posterior-segment surgery was repeated throughout the study: navigation exercise, antitremor maneuver, bimanual dumbbells touching, bimanual scissors task, posterior hyaloid detachment, epiretinal membrane peeling, and inner limiting membrane peeling. The antitremor maneuver was a task that was part of the simulation sequence that focused on quantifying tremor. Evaluation of the microsurgical technique occurred 30 to 60 minutes after ingestion of caffeine or propranolol to guarantee sufficient time for each intervention to reach a peak plasma drug concentration. The timing was in accordance with protocols of previously published and well-accepted work.17,24-26
To become familiar with the technology, all surgeons underwent a training period of at least 2 hours in the posterior-segment training module on the simulator. The training occurred on the day before the day of data collection. Surgeons were instructed to maintain their daily coffee consumption routine on the day of analysis because acute caffeine withdrawal may be associated with tremor in acclimated users.27 The research team administered placebo, caffeine, and propranolol pills, all of which were visually identical, making this a single-blinded experiment. The adjustment of the propranolol and caffeine doses based on weight were in accordance with a previously published study.24
Figure 1 summarizes the study flowchart for day 1 and day 2 of analysis. The main outcome measures evaluated for all 7 tasks were the total task score generated by the Eyesi platform, which ranges from 0 (worst) to 700 (best); the total time to task completion (minutes); and the total intraocular trajectory of the surgical tool tip, also called odometer (mm). The amount of hand tremor was assessed by the antitremor maneuver score ranging from 0 (worst) to 100 (best).
The sample size calculation was performed using PASS, version 14 (NCSS Statistical Software). A sample size of 14 was calculated to detect a 10-point difference in Eyesi mean score for each task after drug ingestion compared with placebo, with an SD of 14.5 points. The study was powered for 0.80 and P = .05. The data were analyzed by repeated measures analysis of variance with the Geisser-Greenhouse Corrected F.
Statistical analysis was performed using Stata, version 12 (StataCorp LLC) and SPSS, version 20 (IBM Corp). The nonparametric Friedman test followed by the Dunn-Bonferroni post hoc test was applied for multiple comparisons. As a paired analysis, the differences in medians were calculated as the median of day 1 minus day 2 (median [day 1 – day 2]) and not the median of day 1 minus the median of day 2 (median [day 1] – median [day 2]). The values are expressed as the median and correspondent 95% CI. All statistical tests were 2-sided using a significance level set at P < .05.
A total of 15 vitreoretinal fellows (9 [60%] men; mean [SD] age, 29.6 [1.4] years; mean [SD] body mass index, 23.15 [2.9] [calculated as weight in kilograms divided by height in meters squared]) with less than 2 years of surgical experience were recruited for the study. No surgeon was excluded, and no adverse effects were reported or observed for any surgeon. All surgeons were right handed. The mean (SD) baseline caffeine consumption reported was 1.27 (1.03) cups per day. There were no differences in demographic characteristics or daily caffeine intake. Systemic blood pressure and heart rate were measured before and after each external exposure, and the values were always equal or above 120/80 mm Hg for blood pressure and 60 beats/min for heart rate.
No differences in performance between the 2 days of testing were seen after the combined medication intake and placebo pill ingestion in the following parameters: Eyesi total score, tool intraocular trajectory, time to task completion, or amount of tremor (Figure 2). When treated with low-dose caffeine vs low-dose propranolol, surgeons had a lower total score (557.0 vs 617.0; difference, –53.0; 95% CI, –99.3 to –6.7; P = .009), a lower antitremor maneuver score (55.0 vs 75.0; difference, –12.0; 95% CI, –21.2 to –2.8; P = .009), longer intraocular trajectory (2298.6 vs 2080.7 mm; difference, 179.3 mm; 95% CI, 1.2-357.3 mm; P = .048), and increased task completion time (14.9 minutes vs 12.7 minutes; difference, 2.3 minutes; 95% CI, 0.8-3.8 minutes; P = .048). Median differences between days 1 and 2 with corresponding P values for Eyesi surgical-generated score (eTable 1 in the Supplement), tremor-specific task score (eTable 2 in the Supplement), intraocular trajectory (eTable 3 in the Supplement), and task completion time (eTable 4 in the Supplement) are recorded.
Propranolol administered after caffeine was associated with enhanced overall hand dexterity. However, this improvement remained inferior to that observed with low-dose propranolol alone for total surgical score (570.0 vs 617.0; difference, –51.0; 95% CI, –77.6 to –24.4; P = .01), tremor-specific score (50.0 vs 75.0; difference, –16.0; 95% CI, –31.8 to –0.2; P = .03), and pathway inside the eye (2265.9 vs 2080.7 mm; difference, 166.8 mm; 95% CI, 64.1 mm to 269.6 mm; P = .03). After exposure to the final neutralizing agent, there were no differences between day 1 and day 2 in the generated surgical score, total time to task completion, and intraocular trajectory.
The results of our prospective cross-sectional study showed that overall the combined ingestion of caffeine and propranolol was associated with surgeons achieving their own placebo-level performance. These data also suggest that preoperative ingestion of caffeine by a novice surgeon can neutralize to a large extent the deleterious association with hand dexterity by receiving a 0.6 mg/kg dose of propranolol. However, receiving propranolol after caffeine was not associated with improved overall hand dexterity compared with propranolol alone. The current results provide supporting evidence for avoiding even low-dose caffeine in the hours before performing surgical procedures by nonhabitual caffeine users to maintain overall performance capability.
Arnold et al28 obtained similar results when studying hand movement, amplified by a handheld laser pointer, among ophthalmology trainees after their ingestion of fixed low-dose caffeine (200 mg), 12.5 mg of timolol (another β-blocker), a combination of caffeine and timolol, or placebo. The authors described increased hand steadiness after consumption of timolol combined with caffeine compared with caffeine alone.
Similarly, Jacobson et al24 analyzed nonphysician, caffeine-naive women by recording the error time and frequency in static and dynamic delicate manual tasks. The experiments occurred 30 to 60 minutes after caffeine ingestion, a time of the peak plasma caffeine concentrations. The authors24 found differences in the hand steadiness error time and tracing error time and frequency for the 5-mg/kg dose of caffeine but not for the 2.5-mg/kg dose or placebo. Changes occurred with both the 5.0-mg/kg and 2.5-mg/kg doses for only the hand steadiness error frequency. The authors24 concluded that both low- and high-dose caffeine were negatively associated with selected performance skills. The low dose of caffeine established in that study (2.5 mg/kg) and in the current study represents approximately a 25-mL cup of espresso29 or an 8-oz cup of drip or percolated coffee30,31 for a person weighing 70 kg. Regarding very low doses of caffeine, Mürbe et al32 found no change in the tremor amplitude after consumption of 50 mg of caffeine.
The terms low dose and high dose in the current protocol simply standardized the amount of weight-adjusted caffeine and propranolol intake because high and low doses of these medications are different in the treatment of other diseases. The dose of propranolol for a person weighing 70 kg that is used to treat benign essential tremor ranges from 1.7 mg/kg to 3.4 mg/kg,33 whereas it ranges from 0.8 mg/kg to 9.1 mg/kg for systemic hypertension.34 Therefore, high-dose propranolol in this protocol of 0.6 mg/kg would be considered low dose in other clinical disease settings.
Propranolol is widely used to treat tremor-related diseases, systemic hypertension, heart rhythm disorders, and other heart or circulatory conditions. The most common adverse effects are nausea, diarrhea, bradycardia, hypotension, paresthesia, lightheadedness, and lethargy.35 However, because propranolol-related adverse effects are dose dependent, at low doses, most of these effects are mild and transient.36 No adverse effects associated with propranolol were reported among the participants in this study, which is likely because of the low dose of the medication used.
Our finding that propranolol use was associated with improved surgical performance and decreased surgical tremor can be explained by β-blocker pharmacologic characteristics. β-Blockers bind competitively to heart and smooth muscle β-receptors, thereby diminishing the sympathetically mediated cardiovascular effects of stress, peripheral muscle tremor, and central anxiety. Left untreated, these sympathetic responses may jeopardize performance when a complex task is being performed.37 It is important to emphasize that β-blockers may be unsuitable for surgeons with underlying asthma, cardiac conduction disorders, diabetes, and peripheral vascular disease.38
Although there was no difference between low-dose exposure of propranolol or caffeine and baseline Eyesi-generated surgical score, there was a progressive dose-dependent difference in scores between the 2 days. Our results agree with those of Pointdujour et al,13 who reported that administration of a fixed amount of propranolol (10 mg) or caffeine (200 mg) was not associated with the Eyesi score compared with the baseline performance among physicians who were more experienced than an ophthalmology resident.
The cumulative trajectory length of the instrument tip inside the eye was shorter after receiving low-dose propranolol compared with receiving low-dose caffeine (suggesting conservation of movement associated with use of propranolol). Receiving low-dose propranolol was also associated with shortened time to task completion compared with low-dose caffeine. Foster et al39 reported a potential confounding effect (ie, increase in time of surgeon’s reaction time after receiving 40 mg of oxprenolol, a different class of β-blocker) but no association with accuracy or tremor.
We found that the doses of caffeine and propranolol associated with modification of surgical microtremor were similar to those associated with changes in intraocular trajectory and total time for task completion (low-dose propranolol vs low-dose caffeine). In contrast, Lubahn et al40 did not find a beneficial association between hand tremor and a fixed dose of timolol 12.5 mg. However, Elman et al41 reinforced the hypothesis of the beneficial association with high-dose propranolol and reported a subjective decrease in tremor and anxiety by ophthalmology residents, but the group could not demonstrate improved surgical outcome.
In contrast to our study results, Humayun et al15 reported a mean decrease in hand tremor associated with oral propranolol at a fixed low dose (10 mg) compared with baseline performance. However, there were fundamental differences in the methods between the studies. Their study15 did not adjust the medication dose according to the participant’s weight; both men and women were included. Their study results15 focused on measuring static hand steadiness by asking surgeons to hold an endoillumination probe at a preset target location, whereas in our protocol, tremor was quantified during a dynamic surgical task. In accordance with our study, their study results15 confirmed no difference in performance between low-dose caffeine and placebo.
The associations of high-dose propranolol and high-dose caffeine were neutralized by exposure to the high dose of the combined drug (caffeine and propranolol); on completion of the final protocol step, the performance was the same on days 1 and 2, which suggests the difference in performance was associated with the prescribed external exposure.
Despite the knowledge that caffeine is associated with decreased surgical performance and increased hand tremor,11 its negative association with microsurgery appears to be partially attenuated by tolerance. Caffeine-naive individuals have a more pronounced decrease in dexterity compared with those who are regular coffee drinkers.15,42 Caffeinated beverages are widely consumed by surgeons and residents sometimes because of their long working hours and consequent fatigue.43 Therefore, to avoid bias, we recommended that all study participants maintain their regular daily caffeine intake routine.
In addition, the requirement for 2 hours of previous nonconsecutive surgical training with the Eyesi surgical simulator in the posterior-segment module was adopted by this protocol to avoid bias. Urso-Baiarda et al17 reported that the results of a crossover study that investigated the adverse effect of low-dose caffeine intake by novice microsurgeons was affected by a learning curve. Their protocol allocated participants to receive either placebo in the morning and caffeine in the afternoon or the reverse treatment. Receiving caffeine followed by placebo was associated with improved microsurgical skills from the morning to the afternoon, whereas the reverse treatment was associated with no improvement.
A strength of this research is that the physiologic association with vitreoretinal surgical performance is described in the context of a balanced interaction between caffeine and β-blockers. The current study has some limitations. First, when performing a multifactorial comparison on the same day of analysis, a higher dose of propranolol was associated with progressive score improvement, a reduction in the total time to task completion, a shorter trajectory inside the eye, and reduced tremor. An opposite phenomenon occurred after exposure to progressively higher caffeine doses. The significance of these findings might require an increase in the sample size, even though the current study was adequately powered to detect the external exposure association among vitreoretinal fellows. Second, our results were restricted to novice surgeons; future studies are required to assess whether the findings translate to more experienced vitreoretinal surgeons. Third, although Eyesi is the only simulator model for ophthalmologic training that has undergone comprehensive investigation, no published evidence supports the transfer of skills from the simulator to the operating room, to our knowledge.44 Consequently, there is still insufficient evidence to support propranolol intake by novice surgeons before performing surgical procedures, and further investigations are required to confirm the association between the performance changes demonstrated in this study and clinically significant differences in surgical outcomes.
This study suggests that young vitreoretinal surgeons who ingest caffeine before performing a surgical procedure may benefit from receiving a partially neutralizing dose of propranolol. However, the expected beneficial association of caffeine and propranolol combination may be no greater than the surgeon’s baseline performance. Moreover, receiving propranolol without caffeine may be associated with enhanced microsurgical performance by novice vitreoretinal surgeons. In this study, surgical performance after receiving caffeine and propranolol combination was inferior compared with receiving low-dose propranolol alone. These data may provide guidance regarding the association of receiving propranolol alone and the neutralization potential of receiving the propranolol and caffeine combination by novice microsurgeons who wish to improve their surgical performance.
Accepted for Publication: April 20, 2020.
Corresponding Author: Marina Roizenblatt, MD, Department of Ophthalmology, Universidade Federal de São Paulo, Rua Botucatu 821, First Floor, São Paulo–SP 04023-062, Brazil (email@example.com).
Published Online: June 11, 2020. doi:10.1001/jamaophthalmol.2020.1971
Author Contributions: Dr Roizenblatt had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Roizenblatt, Dias Gomes Barrios Marin, Grupenmacher, Muralha, Gehlbach, Farah, Belfort, Maia.
Acquisition, analysis, or interpretation of data: Roizenblatt, Dias Gomes Barrios Marin, Grupenmacher, Muralha, Faber, Jiramongkolchai, Gehlbach, Maia.
Drafting of the manuscript: Roizenblatt, Maia.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Roizenblatt, Faber.
Obtained funding: Farah, Belfort, Maia.
Administrative, technical, or material support: Roizenblatt, Dias Gomes Barrios Marin, Muralha, Gehlbach, Farah, Belfort, Maia.
Supervision: Roizenblatt, Jiramongkolchai, Gehlbach, Farah, Belfort, Maia.
Conflict of Interest Disclosures: Dr Belfort reported receiving grants from the Brazilian Council of Research outside the submitted work. Dr Maia reported receiving grants from the Brazilian Council of Research during the conduct of the study. No other disclosures were reported.
Funding/Support: Dr Roizenblatt received research funding from Lemann Foundation, Instituto da Visão, Latinofarma, and Coordination for the Improvement of Higher Education Personnel. Dr Gehlbach received research funding from Research to Prevent Blindness and gifts from the J. Willard and Alice S. Marriott Foundation, the Gale Trust, Herb Ehlers, Bill Wilbur, and Rajandre Shaw, Helen Nassif, Mary Ellen Keck, Don and Maggie Feiner, and Ronald Stiff. Drs Belfort Jr and Maia received research funding from the National Council for Scientific and Technological Development. This funding was not specifically given to the present study.
Role of the Funder/Sponsor: The above-mentioned institutions had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation or review of the manuscript.
Additional Contributions: We thank all of the research participants who voluntarily agreed to participate in this study without any compensation or incentives.