Introduction
Methods
This study is a prospective, randomized, controlled, non-inferiority trial involving blinded outcome analyses to ensure objective results. Approval for the study was obtained from the Institutional Review Board of Zhongshan Ophthalmic Center, Sun Yat-sen University (Approval Number: 2019KYPJ154). This research was registered at the Chinese Clinical Trial Registry (Registration No. ChiCTR1900028088) to promote transparency in clinical research. The study strictly adheres to the Consolidated Standards of Reporting Trials (CONSORT) statement. We ensured that written informed consent was acquired from all participants or their legal guardians prior to enrollment.
Participants included patients aged between 16 and 65 years, classified as American Society of Anesthesiologists (ASA) physical status 1, 2, or 3, scheduled to undergo primary reconstruction of extensive orbital floor and medial wall fractures under general anesthesia. Recruitment occurred between December 2019 and November 2020. Exclusions applied to patients with known allergies to any study-related medications, contraindications for regional ophthalmic blocks, gastrointestinal bleeding or peptic ulcer conditions, operational histories of opiate abuse, chronic pain disorders, or cognitive impairments that could affect outcome measurement. Other exclusionary factors included any additional conditions potentially influencing study results.
Study Procedures
Potential participants were identified and screened by anesthesiologists in the preoperative evaluation clinic a day prior to surgery. An investigator explained the study protocol to eligible patients, detailing the associated risks and benefits. Following the acquisition of written informed consent, patients were randomly allocated into either group OFA or group OSA using a computer-generated randomization sequence concealed within opaque envelopes. On surgery day, a nurse, who was independent from the research team, opened the envelope to disclose group allocation. The randomization list was securely maintained by personnel not involved in any other study activities.
General anesthesia for participants was administered using total intravenous anesthesia in accordance with the established hospital protocols for adult patients. Induction utilized propofol, fentanyl, and rocuronium, followed by the establishment of the airway using a flexible laryngeal mask. Anesthesia maintenance involved administering propofol and remifentanil in target-controlled infusion mode, aiming for a bispectral index value of 40–60 while maintaining intraoperative blood pressure and heart rate within 20% of baseline preanesthesia values. Intravenous atropine and ephedrine were administered when clinically indicated to address bradycardia or hypotension. Unless contraindications existed, patients received prophylactic dexamethasone (5 mg) and tropisetron (5 mg) to mitigate postoperative nausea and vomiting (PONV). Fifteen minutes prior to surgical completion, a slow injection of flurbiprofen axetil (50 mg) was administered in both patient groups. Propofol and remifentanil were discontinued at surgery conclusion. Once spontaneous breathing resumed, the laryngeal mask airway was removed, and patients were subsequently transferred to the postanesthesia care unit (PACU) for comprehensive monitoring.
Postoperative Care
In the PACU, pain levels were quantified using an 11-point numeric rating scale (NRS), where 0 indicates no pain and 10 signifies the worst imaginable pain. Patients reporting NRS scores exceeding 3/10 received an additional flurbiprofen axetil dose of 50 mg as a rescue measure. Patients were eligible for discharge from the PACU once they met the discharge criteria and achieved pain scores≤3/10. The analgesic rescue regimen applied during the surgical ward stay and at home encompassed scheduled doses of oral acetaminophen (1 g) administered if NRS exceeded 3/10. Additionally, oral metoclopramide (10 mg) was prescribed to manage PONV on an as-needed basis, barring any contraindications.
Outcomes Measures
The primary outcomes consisted of the area under the curve (AUC) of the NRS pain scores alongside the incidence of postoperative nausea and vomiting (PONV) within 24 hours post-surgery. Pain assessment employed NRS pain scores at 2, 6, 12, 24, and 48 hours postoperatively, ultimately illustrated by calculating the AUC of NRS points (AUCNRS) for the preliminary 24 hours. The incidence of combined symptoms of PONV, which included nausea, retching, and vomiting, was analyzed as the primary outcome, with individual symptom incidences documented.16
Secondary outcomes encompassed the duration to first analgesic request, defined as the time from surgery conclusion until the initial oral paracetamol intake, and the number of patients necessitating analgesic rescue during their hospital stay. Each patient completed the Self-rating Anxiety Scale (SAS) to gauge preoperative anxiety levels, while baseline characteristics such as age, sex, weight, height, ASA classification, past general anesthesia and ophthalmic surgery histories, smoking and alcohol use history, and preoperative morbidity were documented. The length of surgery was defined as the interval between surgical incision initiation and wound suturing completion, along with the cumulative consumption of fentanyl and remifentanil during the procedure (using a 1:1.2 conversion ratio for fentanyl to an equivalent remifentanil dose).
The time to achieve out-of-bed activity was measured as the interval between the conclusion of surgery and patients’ first attempt to get out of bed on the ward. Each patient completed a QoR-40 questionnaire on postoperative day 1 to assess recovery status following surgery.17
Sample Size Considerations
The minimum difference necessary for detecting non-inferiority on the two primary outcomes was established as 24 (point·h) pertaining to AUCNRS and 13% regarding PONV incidence.21,22 To ensure a power of 0.8 with a one-sided α-value of 0.025, an estimated 19 patients per group was required for AUCNRS, based on a non-inferiority margin (NIM) of 24 (point·h) with an assumed common SD of 24.3 (derived from unpublished preliminary data, October 2019; n = 16). In contrast, 52 patients per group were necessary for PONV incidence, with expectation of a NIM of 13% and a reference incidence of 6% in the PCIA group. Thus, a total sample size of 104 subjects was determined. Calculations for sample size were conducted using PASS version 15.0 (NCSS, LLC).
Statistical Analysis
This intention-to-treat analysis utilized descriptive statistics to present baseline characteristics across the two groups. Data were rigorously examined for distribution using the Kolmogorov–Smirnov test and histogram analysis. For normally distributed variables, data are expressed as mean ± standard deviation (SD); non-normally distributed variables are reported as median (interquartile range [IQR]), while categorical variables are described as frequencies with percentages. Comparisons for normally distributed data between two groups utilized independent t tests, while non-normally distributed data comparisons employed the Mann–Whitney U-test. Categorical variables underwent analysis through the chi-squared test or Fisher exact test, as deemed appropriate. During the primary outcome analysis, we assessed the non-inferiority of group OFA relative to group OSA concerning AUCNRS and PONV incidence over the initial 24 postoperative hours using one-tailed non-inferiority t tests. Non-inferiority would be accepted if the upper limit of the two-sided 95% confidence interval (CI) for the differences between the two groups was below the predefined NIM.
Results
We successfully included 122 out of 130 eligible patients for randomization and analysis (Figure 2). Six participants were withdrawn based on pre-established criteria, while two opted against providing informed consent. Additionally, the visual assessments of 14 patients indicating presurgical “light perception” or “no light perception” were deemed unsuitable for analysis, with their visual outcomes excluded from the study. Comprehensive patient and surgical characteristics are summarized in Table 1.
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Table 1 Patient and Surgical Characteristics
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Figure 2 Consolidated Standards of Reporting Trials Statement Flow Diagram.
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Postoperative Analgesic Effects
Postoperative pain control was adequately managed within both OFA and OSA groups, with median pain scores remaining low (Table 2). The AUCNRS for pain scores across the 24 hours post-surgery revealed no significant differences among the groups. The calculated median difference accompanied by a 95% confidence interval (CI) was −6 (95% CI, −12 to 6; P = 0.65), confirming that the upper limit fell beneath the predetermined NIM of 24 (point·h). Therefore, it was established that OFA is non-inferior to OSA (Figure 3). Upon discharge to the surgical ward, only 4 patients from the OFA group required additional analgesic rescue, compared to 3 patients in the OSA group.
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Table 2 Comparison of Primary and Secondary Outcomes Between the Groups
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Figure 3 Treatment Differences for AUCNRS (A) and the Incidence of PONV (B) during the First 24 hours after Surgery. Abbreviations: AUC, area-under-the-curve; NRS, numerical rating scale; PONV, postoperative nausea and vomiting; NIM, non-inferiority margin; OSA, opioid-sparing analgesia; OFA, opioid-free analgesia. Notes: The dashed line designates the NIM (∆). The spot shows the median and ratio difference between the two groups for the AUCNRS of pain scores and the incidence of PONV, respectively. The error bars designate the two-sided 95% CI of the differences between the OFA and OSA groups.
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Postoperative Complication and Recovery
PONV is a prevalent postoperative complication closely tied to opioid utilization. The incidence of PONV during the first 24 hours post-surgery revealed that the OFA group did not demonstrate non-inferiority when compared to the OSA group. Specifically, PONV incidence in the OFA group was 6.6%, versus 9.8% in the OSA group (ratio difference of 3%; 95% CI, −7% to 14%; P = 0.51), as the upper limit exceeded the predefined NIM of 13% (Figure 3). Despite these statistics, the incidences of nausea (1.6% vs 3.3%, respectively) and vomiting (4.9% vs 6.6%, respectively) depicted comparable outcomes across both groups (Table 2).
No significant differences in other postoperative in-hospital complications, including dizziness, headache, and urinary retention, were found, but 18% of patients in the OSA group experienced dizziness, compared to only 6.6% in the OFA group. No patients in either cohort required unexpected medical interventions or readmissions due to complications after discharge. In terms of recovery quality, time to ambulation was similar between both groups. Notably, QoR-40 scores exhibited a statistical difference between the OFA and OSA groups on postoperative day 1, with scores of 188 [178–196] versus 181 [169–191], respectively; this yields a median difference of 6 with a 95% CI of 2 to 10, P = 0.005. Among the five dimensions of QoR-40, emotional status, physical comfort, and physical independence scores were significantly elevated in the OFA group when contrasted with the OSA group (P = 0.004, P = 0.03 and P = 0.001, respectively) (Figure 4).
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Figure 4 Box Plots of QoR-40 Scores at 24 hours after Surgery. Abbreviations: OSA, opioid-sparing analgesia; OFA, opioid-free analgesia; QoR, quality of recovery; IQR, interquartile range. Notes: Box plots illustrate the median (solid lines) and IQR (boxes, representing the 25th and 75th percentiles), with whiskers marking the 10th and 90th percentiles while dark spots identify the fifth and 95th percentiles, respectively. P |
The Influence on Ocular Features on the Eye to Be Operated
Discussion
This randomized controlled trial compared low-dose postoperative opioid use with OFA on short-term outcomes following primary orbital fracture reconstruction. While our results do not definitively confirm the non-inferiority of OFA in preventing PONV compared with OSA, data suggest that OFA using the MCPB provides adequate postoperative pain relief alongside enhanced recovery. These findings imply that an opioid-free analgesic strategy comprising MCPB and NSAIDs can optimize short-term outcomes in primary reconstructions of significant orbital fractures, ultimately facilitating early postoperative recovery.
Effective regional blocks and multimodal non-opioid analgesic approaches are critical components of enhanced recovery pathway protocols, minimizing opioid reliance and fostering improved recovery outcomes.23 Regional blocks in ophthalmology have a well-established tradition in facilitating pain management during orbital surgeries. The medial canthus block is a progression of PB, with Deruddre and Benhamou’s initial implementation marking it as an effective alternative for cataract operations. A singular MCPB injection has been reported to achieve efficacy on par with double-injection percutaneous peribulbar anesthesia while necessitating a lower volume of local anesthetic.12 Consequently, we formulated a multimodal non-opioid analgesic strategy integrating MCPB and non-opioid agents to address pain from both inflammatory and signaling pathways comprehensively. To prolong analgesia, a single-injection MCPB using 1% ropivacaine (noted for its extended action with a duration of approximately 21.5 hours) was employed, yielding sustained analgesic effects comparable to the continuous intravenous analgesia of the OSA protocol.24
We observed a superior recovery quality in patients administered OFA over OSA, indicated by enhanced scores in emotional wellbeing, physical comfort, and independence as recorded in the QoR-40.25 This suggests that patients undergoing a non-opioid multimodal analgesic regimen tend to evade opioid-related side effects, as evidenced by diminished dizziness incidence in the OFA compared to the OSA cohort. Dizziness can cause discomfort, significantly impairing the return to independent activities post-surgery.
Existing research indicates a strong correlation between PONV and opioid administration.26 Given that many surgical patients encounter their first opioid exposure perioperatively, the potential benefits of applying OFA techniques become evident. It has been posited that employing MCPB combined with non-opioid analgesics may preemptively mitigate PONV.27 Nevertheless, despite our findings suggesting a low incidence of PONV in both groups, we did not affirm non-inferiority in terms of PONV incidence for the OFA group relative to the OSA group. This may be owed to the multimodal prophylactic drug regimen encompassing propofol anesthesia and antiemetic prophylaxis provided to every participant.28
With non-specific postoperative symptoms like headache and nausea, the potential rise in intraocular pressure (IOP) and Porb attributed to local anesthetic administration warrants consideration. Our study indicated that MCPB utilization did not lead to a marked increase in IOP or Porb.
This investigation is subject to several limitations. Firstly, the true effects of the MCPB regarding akinesia and pain perception couldn’t be assessed due to performance of blocks under general anesthesia. We opted to perform blocks at the conclusion of surgery to avert disruption of orbital architecture. Secondly, injecting local anesthetic into the orbit (3 to 5 mL) could potentially increase periorbital pressure significantly, demanding vigilance concerning IOP and Porb changes during the injection.29 Thirdly, while using fentanyl may not be standard protocol following orbital fracture reconstruction, no optimal multimodal analgesic methods have been identified in the contemporary literature.
In conclusion, both OFA and OSA strategies provide effective postoperative pain management post-orbital fracture reconstruction. However, the opioid-free multimodal analgesia strategy integrating MCPB and NSAIDs can significantly enhance the quality of early recovery.
Data Sharing Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics Approval
This study was performed in line with the principles of the Declaration of Helsinki. Approval was secured from the Institutional Review Board of Zhongshan Ophthalmic Center (Approval Number: 2019KYPJ154). Informed consent was obtained from participants or their legal guardians before participation.
Acknowledgments
We extend our gratitude to Prof. Ling Jin, senior statistician at Zhongshan Ophthalmic Center, for aiding in statistical analysis of the study. The project found support from the Natural Science Foundation of Guangdong Province, China (2021A1515010553) and the clinical research project of Zhongshan Ophthalmic Center of Sun Yat-sen University (3030901011175). The sponsors had no role in the design, method, analysis, or preparation of the manuscript. Rui Zhang, Yongjian Mai, and Huijing Ye share co-first authorship for this research.
Disclosure
The authors report no conflicts of interest in this work.
References
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A Cheeky Commentary on a Surgical Study: The Perils of Pain and the Quest for Nausea Freedom
Ah, the world of medical studies—a realm bursting with spreadsheets, ethical dilemmas, and a dash of morbidity! And here we have a delightful piece about a randomized controlled trial tackling—hold onto your hats—postoperative pain management in ophthalmic surgeries! Trust me, this is about to get as exciting as watching paint dry, but with more opioids and medical jargon.
The Setup: Gentlemen, Start Your Anesthesia!
Right, let’s dive in. The researchers have pulled off a classic double-blind RCT, and it’s startling how many ethics committees had to sign off on this merry adventure. Just think of the boardroom full of serious-faced doctors deliberating over the ins and outs of consent forms like it’s the New Year’s Eve party planning—all hats off to the Institutional Review Board of Zhongshan Ophthalmic Center.
Now, they specifically enlisted a demographic of patients aged 16 to 65 with various health statuses. You’ve got to admire the thoroughness! Allergy-prone folks should steer clear of the studies, as should those who have a tasty penchant for opiate misuse—sensible enough. What’s next? An exclusion for those who brought their mothers in to the consent procedure?
Study Procedures: A Game of Randomized musical Chairs
We’ve got strategies galore! Participants were tossed into two groups faster than you can say “postoperative nausea and vomiting.” Let’s make it a fun experiment where we blindfold our "nurse" as they unravel envelopes and hope nobody accidentally picks a card for ‘general hilarity.’
A typical anesthesia procedure followed, but instead of your regular pre-surgery chit-chat, I imagined propofol, fentanyl, and rocuronium having a little pow-wow: “Well, chaps, we’ve got a surgical fiesta to prepare these fellows for!” How charming!
What did they do next? A lovely stroll to the PACU for “further monitoring.” Sounds like a fancy way of saying they’d keep an eye on you until you sobered up from your surgical cocktail.
Postoperative Care: Pain Relief that Makes You Wonder
Once you’re done with surgery, your pain is assessed on the delightful NRS scale (who knew numbers could be this thrilling?). You want a pain score below 3/10 to escape this post-surgical purgatory! And what’s popping up now? An additional dose of flurbiprofen—a drug so snazzy that even its name sounds like it should be hosting a talk show! Imagine pitching that to your mates: “Oh, I was on flurbiprofen last night and boy, was I bouncing back from that orbital floor reconstruction!”
Post-op, eight patients required rescue analgesics—probably crying out “SAVE ME” as they realized they weren’t in a Michelin-star restaurant but rather, the more unglamorous realm of postoperative care.
Outcomes: Nausea and Other Unpleasant Verticals
The researchers threw around acronyms like they were confetti—AUC, PONV, QoR-40! What a cocktail of statistics! In short, the study found no difference between opioid-free and opioid therapies. They managed to confuse the term “non-inferiority” with the term “equivalence,” which one must admit is not quite the same!
As for PONV, a not-so-fancy acronym for postoperative woes, our dear old opioid-free crew didn’t win a prize. Those suffering from postoperative nausea were not significantly reduced despite their best “flurbiprofen” efforts.
Can you imagine the blokes at the pub talking about their surgeries? “Oh, I went under for a bit of eye work and came out without the need for opioids, but the nausea was a right bother, mate." And there you have it, ‘the joys of surgery’ in a nutshell!
The Big Conclusion: Opioid-Free, Pain-Free or Just a Free-for-All?
In the grand scheme of things, we see the authors concluding that both approaches are rather effective—well, that’s a bit anticlimactic, isn’t it? But, hey, opioid-free might keep you from feeling like a Eddie Murphy movie, post-surgery!
Ultimately, this trial would tantalize the medical minds while ensuring the average punter at the pub remains utterly confused. "You mean I could have surgery and skip the opioids, but end up slightly queasy instead?" Ahh, medical trials—where your chances of pain relief can sometimes verge on the absurd!
So, kudos to the researchers, hats off to the ethics committees, and let’s give a round of applause for postoperative care sessions out there; a blend of discomfort and recovery—the real ‘pain-ting’ of medical research! Cheers!
P>But let’s not overlook the true hero of this tale: the MCPB (Medial Canthus Block). It’s like the unsung artist who suddenly becomes a household name! This little technique is like a one-hit wonder in the world of anesthesia—delivers impressive results and keeps the pain at bay longer than your average local anesthetic. Break out the confetti for ropivacaine, which apparently has a longer duration than most relationships!
Results: The Aftermath of the Recovery Battle Royale
And how did our brave participants fare? The results show that patients on the OFA (Opioid-Free Analgesia) side felt like champions compared to their OSA (Opioid-Sparring Analgesia) counterparts. Higher scores in emotional well-being, physical comfort, and independence are the kind of results that make trials like these worth their weight in medical journals! One might think of it as a reality TV show where the former contestants—no opioids allowed!—are living their best post-op lives. Dizziness, you say? Not on their watch!
The Sour notes: PONV, IOP, and Limitations
Ah, but every tale has its twists. The specter of PONV (Postoperative Nausea and Vomiting) lurks behind the curtains, waiting to ruin the post-surgery celebration. While the study hinted at decreased incidence, it didn’t quite seal the deal to prove OFA is a PONV-slaying superhero. Perhaps those propofol-infused mint juleps provided as prophylaxis had something to do with it!
And then there’s the matter of increased intraocular pressure (IOP) and Porb (presumably some fancy moniker we’ve concocted for the ocular blood pressure)—but rejoice, for our intrepid researchers found no alarming spikes in these after the MCPB! The study claims to have traversed the murky waters of local anesthetic risks with panache.
This adventure also came with a disclaimer: the limitations voice the usual suspects—general anesthesia covering up the nitty-gritty details of akinesia and pain perception are like the fog in a good mystery novel. And don’t even get me started on the potential pressures of injecting local anesthetic—one might need a sturdy eyeball-watching assistant on standby! Could we ask for a little more research here? One’s curiosity is piqued, indeed!
Final Curtain: A Conclusion Worth Celebrating
And there you have it, a robust bow on a study that managed to inject a little excitement into the postoperative realm—a rare gem of research! So, hats off to this team for bravely navigating the stormy seas of pain management with an opioid-free treasure map. With increased comfort and fewer side effects, we can only wonder: when will they greaten the scope of their research to include, say, flashy new anesthetics or even the secret dreams of reclining chairs for postoperative bliss?
Until then, we can rest easy—after all, the quest for optimal postoperative care is an exhilarating journey, filled with equally thrilling jargon and delightful discoveries.
