Objectives
This is a protocol for a Cochrane Review (intervention). The objectives are as follows:
To evaluate the effectiveness of the LipiFlow Thermal Pulsation System on dry eye signs and symptoms compared to placebo or other commercially available treatments for meibomian gland dysfunction in adults.
Background
Description of the condition
Description of dry eye disease and meibomian gland dysfunction
Dry eye disease (DED) is a common condition (Stapleton 2017), that causes significant discomfort and negatively impacts quality of life (Uchino 2013). DED can result from a lack of tear production (aqueous deficiency DED), excessive tear evaporation (evaporative DED), or a combination of both (Wolffsohn 2017).
Meibomian glands are situated within the upper and lower eyelid, and they secrete oils (meibum) through openings at the eyelid margins (Knop 2011). Meibum mixes with tears to form a thin oil layer on top of the tear film, which functions to prevent evaporation of the aqueous tears while stabilizing the thin spreading of the tear film during blinking (Georgiev 2017). However, in meibomian gland dysfunction (MGD), the composition and quantity of meibum are pathologically altered, reducing its ability to retard evaporation and stabilize the tear film, which results in evaporative DED (Knop 2011).
Epidemiology of dry eye disease and meibomian gland dysfunction
There have been several studies that have evaluated the prevalence of DED, as summarized in The Dry Eye Workshop (DEWS) II report (Stapleton 2017) and the more recent review by Papas 2021. Between 5% to 50% of people globally suffer from some degree of DED (Stapleton 2017). A large range of reported prevalences is likely due to the field using an inconsistent definition of DED (Papas 2021; Stapleton 2017). However, these suggest a DED global distribution that impacts all ages, sexes, and racial groups (Papas 2021; Stapleton 2017). Risk factors for DED include female sex, advancing age (over 50 years), and Asian ethnicity (Farrand 2017; Rapoport 2016; Schaumberg 2003; Schaumberg 2009). There are few studies on the prevalence of DED in children, but current research indicates children with certain conditions including Sjögren's Syndrome, graft versus host disease, or environmental allergies are more likely to have the condition (Alves 2008). DED can be classified into evaporative DED and aqueous deficient DED with most DED patients having the evaporative form (Lemp 2012). Evaporative DED most commonly stems from MGD (Lemp 2012). Evaporative DED is driven primarily by MGD (Lemp 2012).
Diagnosis of meibomian gland dysfunction
There are many different strategies to diagnose MGD. The International Workshop on MGD concluded that meibomian gland dropout (atrophy) quantification, and quality or expressibility of meibum assessments, are the most frequent and appropriate factors for diagnosing MGD (Tomlinson 2011). MGD can sometimes affect focal areas of the eyelid, but it has been suggested that there is a high correlation between disease severity across the upper and lower eyelids (McCann 2009), so some diagnostic protocols allow diagnosis based on the lower eyelid evaluation alone.
Meibomian gland expression is typically performed by applying digital pressure to the outer eyelid surface. Some methods and devices have been designed, however, to provide a more standardized force (Meadows 2012). Meibum quality (clear, opaque, etc.) and ease of expressibility can be considered when grading gland expression. Meibomian gland morphology can likewise be evaluated with a digital imaging system called meibography. Various grading scales exist to quantify gland atrophy, expressibility, and meibum quality (Tomlinson 2011).
Other clinical features may aid in diagnosing and evaluating the severity of MGD. Symptom assessment using validated questionnaires is helpful in quantifying symptoms before and after treatment. Objective clinical assessments of tear osmolarity, tear volume, ocular surface staining, and grading of eyelid morphology may also be used in conjunction with gland atrophy and expressibility assessments to diagnose and grade MGD severity (Tomlinson 2011).
Description of the intervention
The LipiFlow Thermal Pulsation System is a medical device used in the office by eye care professionals to treat MGD. It aims to provide controlled, repeatable heat and compression to the eyelid and meibomian glands. The device applies heat to the upper and lower palpebral conjunctival tissues that lie directly over the meibomian glands, while also applying graded pulsatile pressure to the outer eyelid to express the meibomian glands. The meibomian glands are massaged in the direction of the gland orifices, allowing expression during the heating procedure (Lane 2012).
The system consists of the disposable or activator (the component that meets the eye and ocular surface) and the handheld control system. The disposable consists of the lid warmer and the eyecup. The lid warmer is similar in size and shape to a scleral contact lens. The concave edges rest on the bulbar conjunctiva and the concave center vaults the cornea, shielding the cornea from direct heat exposure. On the convex lid warmer surface, a heater regulates the temperature administered to the inner eyelid surface and palpebral conjunctiva to between 41 °C and 43 °C. The eyecup component contains an inflatable air bladder that sits on the external eyelid surface and inflates, allowing compression of the eyelid (Lane 2012).
It is suggested that prior to insertion of the disposable, two drops of topical anesthetic be applied to each eye. The disposable can be inserted, like a scleral contact lens or corneal surgical shield. The patient is instructed to close their eyes (Lane 2012). Once the disposable is properly inserted, the 12‐minute treatment begins. It consists of a programmed compression cadence that includes cycles of constant, increasing, and alternating pressure, which results in the eyelids being heated and massaged for the entire 12‐minutes (Finis 2014).
How the intervention might work
The LipiFlow Thermal Pulsation System is an automated, thermal pulsation system that applies pressure in a pulsed sequence to the eyelids while delivering heat to the eyelids targeting the meibomian glands (Friedland 2011). A single‐use sterile eyecup is placed on the eye, which vaults over the cornea and rests on the bulbar conjunctiva. The convex side of the eyecup delivers heat to the palpebral surfaces of the upper eyelids. An inflatable air bladder attached to the outer surface of the eyecup rests on the external skin of the upper eyelids as the eye is closed. The air bladder inflates and deflates at regular intervals during the treatment, compressing the eyelid between the eyelid warming surface and the bladder, and applying pressure. Thus, the combination of heat, which attempts to liquefy hardened meibum in MGD, and pressure pushes meibum out of the meibomian glands, alleviating obstruction (Li 2020).
In comparison with LipiFlow, other treatments that aim to provide local heat and compression, such as manual warm compress techniques, heating pads, and goggles may be less effective, because of difficulties in maintaining a temperature that can diffuse from the outer eyelid to the location of the meibomian glands near the inner palpebral conjunctiva and/or apply the appropriate amount of pressure in the correct eyelid location (Korb 2011).
Why it is important to do this review
MGD is estimated to affect 35% of the world population, so having effective treatments are vital to combat this condition (Hassanzadeh 2021). The LipiFlow Thermal Pulsation System has been touted as an effective treatment for alleviating obstructive MGD (Lane 2012). To date, only one systematic review has compared the LipiFlow Thermal Pulsation System to placebo or other commercially available dry eye treatments (Hu 2022). Thus, this systematic review is important as it will provide an updated, objective review of the current research available on the efficacy and safety of the LipiFlow Thermal Pulsation System for the treatment of DED.
Objectives
To evaluate the effectiveness of the LipiFlow Thermal Pulsation System on dry eye signs and symptoms compared to placebo or other commercially available treatments for meibomian gland dysfunction in adults.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomized controlled trials (RCTs). We will exclude cross‐over trials because the LipiFlow Thermal Pulsation System is thought to have variable long‐term benefits with no consensus on the duration of potential carry‐over effects.
Types of participants
We will include studies conducted with adults (over 18 years old) who have DED, as defined by the study investigators. No restrictions on race, ethnicity, or sex will be imposed. Contact lens wearers will be considered if they are equally represented between groups.
Types of interventions
We will include studies that compare LipiFlow Thermal Pulsation System to no treatment, placebo (e.g. non‐activated device), or any DED treatment, including:
artificial tears;
topical dry eye medications (e.g. corticosteroids, cyclosporine, lifitegrast);
oral intervention (e.g. doxycycline, azithromycin, omega‐3, omega‐6);
local eyelid manipulation (e.g. warm compresses);
eyelid hygiene products (e.g. eyelid scrubs); and
other devices for meibomian gland dysfunction (e.g. iLux, Mibo Thermoflo).
Studies that combine the LipiFlow Thermal Pulsation System with other treatments will be included if clear distinctions in treatment effects can be determined.
Types of outcome measures
Primary outcomes
Critical outcomes
The critical outcome will be the mean change from baseline in symptom scores as measured by validated questionnaires such as the Standard Patient Evaluation of Eye Dryness Questionnaire (SPEED; Korb 2005), Ocular Surface Disease Index (OSDI; Schiffman 2000), or Dry Eye Questionnaire 5 (DEQ‐5; Begley 2001), at one to four weeks, with the longest time point within this time frame being reported by the included studies.
Secondary outcomes
Important outcomes
We will evaluate the following outcomes, measured as the proportion of participants with improvement at one to four weeks post‐treatment, with the longest time point within this time frame being used in the analysis:
meibomian gland expression, assessed by any integer scale with a grade of 1 or more classified as clinically meaningful (Bron 1991; Foulks 2003; Meadows 2012);
meibum quality, assessed by any integer scale with a grade of 1 or more classified as clinically meaningful (Bron 1991; Meadows 2012; Shimazaki 1998);
meibomian gland atrophy, as determined with meibography and assessed by any integer scale with a grade of 2 or more classified as clinically meaningful (Arita 2008; Pult 2013);
tear breakup time, assessed in seconds with times faster than 10 seconds classified as abnormal (Korb 2001; Lemp 1973);
-
adverse events:
intervention‐related, vision‐threatening adverse events, which have the potential to lead to permanent vision loss, such as microbial keratitis or corneal abrasions;
progression of dry eye, as quantified by increases in corneal fluorescein staining compared to baseline using any validated scale (e.g. the National Eye Institute (NEI) scoring system ranged 0 to 15 (Lemp 1995); the Oxford scales ranged 0 to 5 (Bron 1997), with higher numbers being worse) with a grade increase by one compared to baseline classified as clinically meaningful.
We will evaluate the following outcome, measured at between 6 months and 12 months compared to baseline, with the longest time point within this time frame as reported by the included studies:
patient‐reported symptom scores as measured by validated questionnaires (Begley 2001; Korb 2005; Schiffman 2000).
Search methods for identification of studies
Electronic searches
The Cochrane Eyes and Vision Information Specialist will search the following electronic databases without restrictions on language or date of publication.
Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (latest issue) (Appendix 1);
MEDLINE Ovid (1946 to present) (Appendix 2);
Embase.com (1947 to present) (Appendix 3);
PubMed (1948 to present) (Appendix 4);
LILACS (Latin American and Caribbean Health Science Information database (1982 to present) (Appendix 5);
US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.ClinicalTrials.gov) (Appendix 6); and
World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp) (Appendix 7).
Searching other resources
We will search reference lists of included studies and review articles to identify additional relevant studies that may not have been identified by our primary search. We will impose no restriction on language or date of publication. We will also contact experts in the field regarding information about any ongoing studies on the LipiFlow Thermal Pulsation System.
Data collection and analysis
Selection of studies
Two review authors, following removing duplicate records, will independently screen the titles and abstracts of potential studies using the internet‐based review management software Covidence. We will classify each record as 'definitely relevant', 'possibly relevant', or 'not relevant' for full‐text review. We will retrieve the full‐text reports for records classified as 'definitely relevant' or 'possibly relevant'. Two review authors will then independently review the full‐text articles for eligibility, excluding ineligible articles. If there are questions regarding the eligibility of the studies, we will contact the study investigators to obtain further information. If the study investigators do not respond within two weeks, we will use the information available from publications and trial registers to determine eligibility. We will record reasons for exclusion for each report assessed as 'ineligible' after assessment of the full‐text articles, in a characteristics of excluded studies table. We will classify studies that meet eligibility criteria but have not yet been completed as 'ongoing', and any relevant studies that have been completed but whose results are unavailable as awaiting classification. We will resolve any disagreements between the review authors at each stage of the screening process by discussion and consensus.
Data extraction and management
Two review authors will independently extract data from included studies using the data collection form developed and piloted in Covidence software. One review author will export data from Covidence into Review Manager Web (RevMan Web), and a second review author will verify all data entries to ensure that data are consistent and free of errors. We will extract the following information:
methods: study design, study setting, location, sample size, study duration;
participants: number of participants, age, sex, ethnicity, inclusion criteria and exclusion criteria;
interventions: intervention, comparison interventions, co‐intervention ;
outcomes: primary, secondary, time points; and
other: sources of funding, and potential conflicts of interest.
We will collect and use the most detailed numerical data available from the included studies to facilitate analyses. We will contact study investigators or organizations to obtain missing data or clarify information. If the investigators do not respond within two weeks, we will proceed with the existing information. Where data are only available in graphical displays, two review authors will independently extract the data electronically with an appropriate program such as ImageJ. In case of any discrepancies in data extraction between review authors, a consensus will be reached through discussion or by consulting a third review author.
Assessment of risk of bias in included studies
Two review authors will independently assess the risk of bias of symptom scores, as measured with any validated symptom questionnaire at one to four weeks post‐treatment, for each of the included studies using RoB 2, as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022a). We will consider the following domains of bias:
bias arising from the randomization process;
bias due to deviations from intended interventions;
bias due to missing outcome data;
bias in measurement of the outcome; and
bias in selection of the reported result.
We will evaluate the risk of bias in every bias domain as well as the overall risk of bias as either 'low risk of bias', 'high risk of bias' or 'some concerns'. The assessment of each domain is guided by signaling questions (Sterne 2019).
For an overall risk of bias judgement, we will consider a study to have:
low risk of bias if it is of low risk of bias for all domains for this result;
some concerns if the trial is judged to raise some concerns in at least one domain for this result, but not to be at high risk of bias for any domain; and
high risk of bias if the trial is judged to be at high risk of bias in at least one domain, or to have some concerns for multiple domains in a way that substantially lowers confidence in the result.
In case of disagreement or discrepancy between review authors, a consensus will be reached through discussion or by consulting a third review author.
Measures of treatment effect
For continuous outcomes measured using the same scales, we will calculate mean differences (MDs) with 95% confidence intervals (CIs) where outcomes are normally distributed. Where studies measured continuous outcomes using difference scales, we will calculate standardized mean differences (SMDs).
For dichotomous outcomes, we will calculate risk ratios (RR) with 95% CIs. We will consider the proportion of participants with an adverse event to be a dichotomous outcome. We will check data for skewness and will analyze skewed data using guidance outlined in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2022).
Unit of analysis issues
For this review, the participant will be the primary unit of analysis; however, results will be analyzed by eye when contralateral eye studies are being evaluated. If we include studies with more than two groups, we will evaluate each relevant comparison separately, and select one pair‐wise comparison that is relevant to the review to avoid double counting the studies in the analysis (Higgins 2022b).
Dealing with missing data
We will analyze outcomes on an intention‐to‐treat (ITT) basis. We will contact the study authors whenever outcome data are missing and will use the best information available to analyze data if we receive no response from authors within two weeks. We will only analyze available data and will not impute missing data for the purposes of this review.
Assessment of heterogeneity
We will assess clinical and methodological heterogeneity among studies by assessing the potential differences in participants, interventions compared (LipiFlow Thermal Pulsation System versus other dry eye treatment or placebo), and study design features. We will also assess statistical heterogeneity among outcomes by examining the overlap in CIs of forest plots, and by using the Chi2 and I2 statistics (Higgins 2003) to determine the proportion of total variation due to statistical heterogeneity, as described in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2022). We will consider the following thresholds for the interpretation of the I2 statistic:
0% to 40%: might not be important;
30% to 60%: may represent moderate heterogeneity;
50% to 90%: may represent substantial heterogeneity; and
75% to 100%: considerable heterogeneity.
Assessment of reporting biases
We will assess selective result reporting for ocular symptoms guided by the signaling questions in the RoB 2 tool (Higgins 2022a). We will assess selective outcome reporting for each study using methods outlined in Chapter 13 of the Cochrane Handbook (Higgins 2022c). We will assess small‐study effects, which could be due to publication bias, using a funnel plot when 10 more studies contribute to a meta‐analysis (Egger 1997).
Data synthesis
We will synthesize and analyze data following the guidelines in Chapter 9 (McKenzie 2022a), and Chapter 10 (Deeks 2022), of the Cochrane Handbook for Systematic Reviews of Interventions. When we have more than two studies that contribute data to the same outcome or where there is statistical or clinical heterogeneity, we will use a random‐effects model to estimate intervention effects. If the direction of treatment effects is inconsistent across studies, or we detect the presence of substantial or considerable statistical heterogeneity, we will not combine results in a meta‐analysis and will present a narrative summary of results instead, following guidance in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 12 (McKenzie 2022b).
Subgroup analysis and investigation of heterogeneity
We will conduct subgroup analysis on the following two outcomes: changes in symptom scores at post‐treatment weeks 1 to 4, and changes in symptom scores at post‐treatment months 6 to 12, by the following factors, depending on the availability of data:
comparison interventions;
sex;
race and ethnicity; and
number of LipiFlow Thermal Pulsation System treatment sessions performed.
Sensitivity analysis
To assess the robustness of the effect estimates, we will perform a sensitivity analysis excluding studies with an overall high risk of bias, and studies that failed to handle the unit of analysis issue properly.
Summary of findings and assessment of the certainty of the evidence
We will prepare a summary of findings table according to the methods described in Chapter 14 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2022), and present the estimated effects of the LipiFlow Thermal Pulsation System at one to four weeks, with the longest time point within this time frame being used in analysis. We will include the following outcomes:
mean change from baseline in symptom scores, as measured with any validated symptom questionnaire (e.g. SPEED, OSDI, DEQ‐5);
proportion of participants who have abnormal meibomian gland expression, assessed by any integer scale (e.g. 0 to 3, with higher numbers being worse) with a grade of 1 or more classified as clinically meaningful;
proportion of participants who have abnormal meibum quality, assessed by any integer scale (e.g. 0 to 3, 0 to 4, with higher numbers being worse) with a grade of 1 or more classified as clinically meaningful;
proportion of participants who have meibomian gland atrophy, as determined with meibography and assessed by any integer scale (e.g. 0 to 3, 0 to 4, with higher numbers being worse) with a grade of 2 or more classified as clinically meaningful; and
proportion of participants with intervention‐related, vision‐threatening adverse events, that have the potential to lead to permanent vision loss, such as microbial keratitis or corneal abrasions.
Two review authors will independently judge the certainty of the evidence for each outcome using the GRADE approach. We will judge the certainty of evidence as 'very low',' low', 'moderate', or 'high' (Schünemann 2022). We will resolve any disagreements by discussion or consultation with a third review author.
Acknowledgements
We thank Lori Rosman, Information Specialist for Cochrane Eyes and Vision (CEV), who created and executed the electronic search strategies.
We also thank Alison Su‐Hsun Liu and Louis Leslie, methodologists of CEV@US; Genie Han, Assistant Managing Editor for CEV@US; Anupa Shah, Managing Editor for CEV, for support and guidance in the preparation of this protocol. We thank Lindsay Robertson for copy editing the protocol.
We would also like to thank the following clinical peer reviewers for their comments on the protocol: Viral Juthani (Montefiore Medical Center) and Richard Gibralter (Montefiore Medical Center). We thank Robin Featherstone (Cochrane Central Editorial Service) for peer review of the search strategy.
This protocol was managed by CEV@US and was signed off for publication by Tianjing Li and Gianni Virgili.
Appendices
Appendix 1. CENTRAL search strategy
#1 lipiflow* #2 MeSH descriptor: [Dry Eye Syndromes] explode all trees #3 (dry* near/2 eye*) #4 (ocular near/2 dry*) #5 MeSH descriptor: [Tears] explode all trees #6 tear* #7 xerophthalmi* #8 (Keratoconjunctiv* NEAR/2 sicca) or ("kerato conjunctivitis" NEAR/2 sicca) #9 ((Sjogren* or Sjoegren*) near/2 (syndrom* or disease*)) #10 (sicca next/1 syndrom*) #11 blepharoconjunctiviti* #12 MeSH descriptor: [Meibomian Glands] explode all trees #13 MeSH descriptor: [Meibomian Gland Dysfunction] explode all trees #14 (meibomian or tarsal or MGD) #15 MeSH descriptor: [Lacrimal Apparatus] explode all trees #16 MeSH descriptor: [Lacrimal Apparatus Diseases] this term only #17 MeSH descriptor: [Lacrimal Duct Obstruction] explode all trees #18 (lacrima* or epiphora) #19 MeSH descriptor: [Eyelids] explode all trees #20 (eye next/1 lid*) or eyelid* #21 {OR #2‐#20} #22 ((vector* or puls* or system* or therap* or treatment* or device*) NEAR/3 (therm* or heat* or warm*)) #23 (puls* NEAR/3 (therap* or system* or treatment* or device*)) #24 {OR #22‐#23} #25 #21 AND #24 #26 #1 OR #25 in Trials
Appendix 2. MEDLINE (Ovid) search strategy
1. Randomized Controlled Trial.pt. 2. Controlled Clinical Trial.pt. 3. (randomized or randomised).ab,ti. 4. placebo.ab,ti. 5. drug therapy.fs. 6. randomly.ab,ti. 7. trial.ab,ti. 8. groups.ab,ti. 9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 10. exp animals/ not humans.sh. 11. 9 not 10 12. lipiflow* 13. exp Dry Eye Syndromes/ 14. (dry* adj2 eye*).tw. 15. (ocular adj2 dry*).tw. 16. exp Tears/ 17. tear*.tw. 18. xerophthalmi*.tw. 19. ((Keratoconjunctiv* adj2 sicca) or ("kerato conjunctivitis" adj2 sicca)).tw. 20. ((Sjogren* or Sjoegren*) adj2 (syndrom* or disease*)).tw. 21. (sicca adj1 syndrom*).tw. 22. blepharoconjunctiviti*.tw. 23. exp Meibomian Glands/ 24. exp Meibomian Gland Dysfunction/ 25. (meibomian or tarsal or MGD).tw. 26. exp Lacrimal Apparatus/ 27. Lacrimal Apparatus Diseases/ 28. exp Lacrimal Duct Obstruction/ 29. (lacrima* or epiphora).tw. 30. exp Eyelids/ 31. ("eye lid*" or eyelid*).tw. 32. or/13‐31 33. ((vector* or puls* or system* or therap* or treatment* or device*) adj3 (therm* or heat* or warm*)).tw. 34. (puls* adj3 (therap* or system* or treatment* or device*)).tw. 35. or/33‐34 36. 12 or (32 and 35) 37. 11 and 36
The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville et al (Glanville 2006).
Appendix 3. EMBASE.com search strategy
#1 'randomized controlled trial'/exp #2 'randomization'/exp #3 'double blind procedure'/exp #4 'single blind procedure'/exp #5 random*:ab,ti #6 #1 OR #2 OR #3 OR #4 OR #5 #7 'animal'/exp OR 'animal experiment'/exp #8 'human'/exp #9 #7 AND #8 #10 #7 NOT #9 #11 #6 NOT #10 #12 'clinical trial'/exp #13 (clin* NEAR/3 trial*):ab,ti #14 ((singl* OR doubl* OR trebl* OR tripl*) NEAR/3 (blind* OR mask*)):ab,ti #15 'placebo'/exp #16 placebo*:ab,ti #17 random*:ab,ti #18 'experimental design'/exp #19 'crossover procedure'/exp #20 'control group'/exp #21 'latin square design'/exp #22 #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 #23 #22 NOT #10 #24 #23 NOT #11 #25 'comparative study'/exp #26 'evaluation'/exp #27 'prospective study'/exp #28 control*:ab,ti OR prospectiv*:ab,ti OR volunteer*:ab,ti #29 #25 OR #26 OR #27 OR #28 #30 #29 NOT #10 #31 #30 NOT (#11 OR #23) #32 #11 OR #24 OR #31 #33 lipiflow*:ab,ti,kw #34 'dry eye syndrome'/exp #35 (dry* NEAR/2 eye*):ab,ti,kw #36 (ocular NEAR/2 dry*):ab,ti,kw #37 'lacrimal fluid'/exp #38 xerophthalmi*:ab,ti,kw #39 ((keratoconjunctiv* NEAR/2 sicca):ab,ti,kw) OR (('kerato conjunctivitis' NEAR/2 sicca):ab,ti,kw) #40 ((sjogren* OR sjoegren*) NEAR/2 (syndrom* OR disease*)):ab,ti,kw #41 (sicca NEXT/1 syndrom*):ab,ti,kw #42 blepharoconjunctiviti*:ab,ti,kw #43 'eyelid'/exp #44 'meibomian gland dysfunction'/exp #45 meibomian:ab,ti,kw OR tarsal:ab,ti,kw OR mgd:ab,ti,kw #46 'lacrimal gland disease'/de #47 'lacrimal duct occlusion'/exp #48 'lacrimation disorder'/exp #49 'lacrimal apparatus'/exp #50 lacrima*:ab,ti,kw OR epiphora:ab,ti,kw #51 ((eye NEXT/1 lid*):ab,ti,kw) OR eyelid*:ab,ti,kw #52 #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49 OR #50 OR #51 #53 'thermal pulsation system'/exp #54 ((vector* OR puls* OR system* OR therap* OR treatment* OR device*) NEAR/3 (therm* OR heat* OR warm*)):ab,ti,kw #55 (puls* NEAR/3 (therap* OR system* OR treatment* OR device*)):ab,ti,kw #56 #53 OR #54 OR #55 #57 #52 AND #56 #58 #33 OR #57 #59 #32 AND #58
The search filter for trials at the beginning of the Embase strategy is adapted from the published paper by Lefebvre et al (Lefebvre 2008).
Appendix 4. PubMed search strategy
1. ((randomized controlled trial[pt]) OR (controlled clinical trial[pt]) OR (randomised[tiab] OR randomized[tiab]) OR (placebo[tiab]) OR (drug therapy[sh]) OR (randomly[tiab]) OR (trial[tiab]) OR (groups[tiab])) NOT (animals[mh] NOT humans[mh]) 2. lipiflow*[tw] 3. (dry[tw] OR dryness[tw]) AND (eye[tw] OR eyes[tw] OR eyelid*[tw] OR ocular[tw]) 4. tear*[tw] OR xerophthalmi*[tw] 5. ((Keratoconjunctiv*[tw] OR "kerato conjunctivitis"[tw]) AND sicca[tw]) 6. ((Sjogren*[tw] OR Sjoegren*[tw]) AND (syndrom*[tw] OR disease*[tw])) 7. "sicca syndrom*"[tw] OR blepharoconjunctiviti*[tw] 8. (meibomian[tw] OR tarsal[tw] OR MGD[tw]) 9. (lacrima*[tw] OR epiphora[tw]) 10. ("eye lid*"[tw] OR eyelid*[tw]) 11. #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 12. ((vector*[tw] OR puls*[tw] OR system*[tw] OR therap*[tw] OR treatment*[tw] OR device*[tw]) AND (therm*[tw] OR heat*[tw] OR warm*[tw])) 13. (puls*[tw] AND (therap*[tw] OR system*[tw] OR treatment*[tw] OR device*[tw])) 14. #12 OR #13 15. #11 AND #14 16. #2 OR #15 17. #1 AND #16 18. medline[sb] 19. #17 NOT #18
Appendix 5. LILACS search strategy
Lipiflow$ OR ((MH:C11.496.260$ OR (dry$ AND eye$) OR (dry$ AND ocular) OR MH:A12.200.882$ OR tear$ OR xerophthalmi$ OR (Keratoconjunctiv$ AND sicca) OR ("kerato conjunctivitis" AND sicca) OR ((Sjogren$ OR Sjoegren$) AND (syndrome$ OR disease$)) OR "sicca syndrome" OR "sicca syndromes" OR blepharoconjunctiviti$ OR MH:A09.371.337.614$ OR MH:A10.336.827.600$ OR MH:C11.338.780$ OR meibomian OR tarsal OR MGD OR MH:A09.371.463$ OR MH:A10.336.422$ OR MH:C11.496 OR MH:C11.496.456$ OR lacrima$ OR epiphora OR MH:A01.456.505.420.504$ OR MH:A09.371.337$ OR "eye lid" OR "eye lids" OR eyelid$) AND (((vector$ OR puls$ OR system$ OR therap$ OR treatment$ OR device$) AND (therm$ OR heat$ OR warm$)) OR (puls$ AND (therap$ OR system$ OR treatment$ OR device$))))
Appendix 6. ClinicalTrials.gov search strategy
lipiflow OR ((dry eye OR tear OR xerophthalmia OR Keratoconjunctivitis Sicca OR Sjogren's OR Sjoegren's OR sicca syndrome OR blepharoconjunctivitis OR meibomian OR MGD OR tarsal OR lacrimal OR epiphora OR eyelid) AND (((vector OR pulse OR system OR therapy OR treatment OR device) AND (thermal OR thermo OR heat OR warm)) OR (pulse AND (therapy OR system))))
Appendix 7. ICTRP search strategy
lipiflow
dry eye AND thermal OR dry eye AND thermo OR dry eye AND heat OR dry eye AND warm OR dry eye AND pulse OR dry eye AND pulsation OR dry eye AND thermodynamic
tear AND thermal OR tear AND thermo OR tear AND heat OR tear AND warm OR tear AND pulse OR tear AND pulsation OR tear AND thermodynamic
xerophthalmia AND thermal OR xerophthalmia AND thermo OR xerophthalmia AND heat OR xerophthalmia AND warm OR xerophthalmia AND pulse OR xerophthalmia AND pulsation OR xerophthalmia AND thermodynamic
meibomian AND thermal OR meibomian AND thermo OR meibomian AND heat OR meibomian AND warm OR meibomian AND pulse OR meibomian AND pulsation OR meibomian AND thermodynamic
MGD AND thermal OR MGD AND thermo OR MGD AND heat OR MGD AND warm OR MGD AND pulse OR MGD AND pulsation OR MGD AND thermodynamic
lacrimal AND thermal OR lacrimal AND thermo OR lacrimal AND heat OR lacrimal AND warm OR lacrimal AND pulse OR lacrimal AND pulsation OR lacrimal AND thermodynamic
epiphora AND thermal OR epiphora AND thermo OR epiphora AND heat OR epiphora AND warm OR epiphora AND pulse OR epiphora AND pulsation OR epiphora AND thermodynamic
eyelid AND thermal OR eyelid AND thermo OR eyelid AND heat OR eyelid AND warm OR eyelid AND pulse OR eyelid AND pulsation OR eyelid AND thermodynamic
Contributions of authors
Conception and design of protocol and review: Andrew D Pucker.
Drafting the protocol/review or commenting on them critically for intellectual content: Andrew D Pucker, Erin Rueff, William Ngo, Anna A Tichenor, John E Conto.
Final approval of the document to be published: Andrew D Pucker, Erin Rueff, William Ngo, Anna A Tichenor, John E Conto.
Sources of support
Internal sources
-
None, Other
No internal source of support.
External sources
-
National Eye Institute, National Institutes of Health, USA
Cochrane Eyes and Vision US Project, supported by grant 1 U01 EY020522‐01, National Eye Institute, National Institutes of Health.
-
Public Health Agency, UK
The HSC Research and Development (R&D) Division of the Public Health Agency funds the Cochrane Eyes and Vision editorial base at Queen's University Belfast.
-
Queen's University Belfast, UK
Gianni Virgili, Co‐ordinating Editor for Cochrane Eyes and Vision’s work is funded by the Centre for Public Health, Queen’s University of Belfast, Northern Ireland.
Declarations of interest
Andrew D Pucker: Dr. Pucker has received research support from Alcon Research, LLC., Art Optical, ScienceBased Health, and the National Eye Institute. Dr. Pucker has served as a consultant for Alcon Research, LLC., CooperVision, EpiTech, EyeGate Pharmaceuticals Inc., Kala Pharmaceuticals, Lexitas Pharam Services, Nevakar Inc., and Optikal Care Inc. Dr. Pucker is currently an employee of Lexitas Pharam Services.
Erin Rueff: consultant for Johnson & Johnson Vision, Inc.
William Ngo: currently consultant for Alcon and Sun Pharma. Previous employee at the Centre for Ocular Research & Education, where research funding has been received from the following companies: Alcon, Allergan, Allied Innovations, Aurinia Pharma, Azura Ophthalmics, Bausch Health Canada, Brien Holden Vision Institute, CooperVision, GL Chemtec, i‐Med Pharma, Johnson & Johnson Vision, Lubris, Menicon, Nature's Way, Novartis, Ophtecs, Ote Pharma, PS Therapy, Santen, SightGlass, SightSage, Visioneering Tec.h
Anna A Tichenor: no declarations of interest.
John E Conto: no declarations of interest.
New
References
Additional references
Alves 2008
- Alves M, Dias AC, Rocha EM. Dry eye in childhood: epidemiological and clinical aspects. Ocular Surface 2008;6(1):44-51. [DOI] [PubMed] [Google Scholar]
Arita 2008
- Arita R, Itoh K, Inoue K, Amano S. Noncontact infrared meibography to document age-related changes of the meibomian glands in a normal population. Ophthalmology 2008;115(5):911-5. [DOI] [PubMed] [Google Scholar]
Begley 2001
- Begley CG, Chalmers RL, Mitchell GL, Nichols KK, Caffery B, Simpson T, et al. Characterization of ocular surface symptoms from optometric practices in North America. Cornea 2001;20(6):610-8. [DOI] [PubMed] [Google Scholar]
Bron 1991
- Bron AJ, Benjamin L, Snibson GR. Meibomian gland disease. Classification and grading of lid changes. Eye 1991;5 (Pt 4):395-411. [DOI] [PubMed] [Google Scholar]
Bron 1997
- Bron AJ. The Doyne Lecture. Reflections on the tears. Eye 1997;11 (Pt 5):583-602. [DOI] [PubMed] [Google Scholar]
Covidence [Computer program]
- Veritas Health Innovation Covidence. Version accessed 22 March 2022. Melbourne, Australia: Veritas Health Innovation. Available at covidence.org.
Deeks 2022
- Deeks JJ, Higgins JP, Altman DG. Chapter 10: Analysing data and undertaking meta-analyses. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.3 (updated February 2022). Cochrane, 2022. Available from www.training.cochrane.org/handbook.
Egger 1997
- Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315(7109):629-34. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]
Farrand 2017
- Farrand KF, Fridman M, Stillman IO, Schaumberg DA. Prevalence of diagnosed dry eye disease in the United States among adults aged 18 years and older. American Journal of Ophthalmology 2017;182:90-8. [DOI] [PubMed] [Google Scholar]
Finis 2014
- Finis D, Hayajneh J, Konig C, Borrelli M, Schrader S, Geerling G. Evaluation of an automated thermodynamic treatment (LipiFlow®) system for meibomian gland dysfunction: a prospective, randomized, observer-masked trial. Ocular Surface 2014;12(2):146-54. [DOI] [PubMed] [Google Scholar]
Foulks 2003
- Foulks GN, Bron AJ. Meibomian gland dysfunction: a clinical scheme for description, diagnosis, classification, and grading. Ocular Surface 2003;1(3):107-26. [DOI] [PubMed] [Google Scholar]
Friedland 2011
- Friedland BR, Fleming CP, Blackie CA, Korb DR. A novel thermodynamic treatment for meibomian gland dysfunction. Current Eye Research 2011;36(2):79-87. [DOI] [PubMed] [Google Scholar]
Georgiev 2017
- Georgiev GA, Eftimov P, Yokoi N. Structure-function relationship of tear film lipid layer: a contemporary perspective. Experimental Eye Research 2017;163:17-28. [DOI] [PubMed] [Google Scholar]
Glanville 2006
- Glanville JM, Lefebvre C, Miles JN, Camosso-Stefinovic J. How to identify randomized controlled trials in MEDLINE: ten years on. Journal of the Medical Library Association 2006;94(3):354. [PMC free article] [PubMed] [Google Scholar]
Hassanzadeh 2021
- Hassanzadeh S, Varmaghani M, Zarei-Ghanavati S, Heravian SJ, Azimi KA. Global prevalence of meibomian gland dysfunction: a systematic review and meta-analysis. Ocular Immunology and Inflammation 2021;29(1):66-75. [DOI] [PubMed] [Google Scholar]
Higgins 2003
- Higgins 2003: Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60. [DOI] [PMC free article] [PubMed] [Google Scholar]
Higgins 2022a
- Higgins JP, Savović J, Page MJ, Elbers RG, Sterne JA. Chapter 8: Assessing risk of bias in a randomized trial. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.3 (updated February 2022). Cochrane, 2022. Available from www.training.cochrane.org/handbook.
Higgins 2022b
- Higgins JP, Li T, Deeks JJ. Chapter 6: Choosing effect measures and computing estimates of effect. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.3 (updated February 2022). Cochrane, 2022. Available from www.training.cochrane.org/handbook.
Higgins 2022c
- Page MJ, Higgins JPT, Sterne JAC. Chapter 13: Assessing risk of bias due to missing results in a synthesis. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.3 (updated February 2022). Available from www.training.cochrane.org/handbook.
Hu 2022
- Hu J, Zhu S, Liu X. Efficacy and safety of a vectored thermal pulsation system (Lipiflow®) in the treatment of meibomian gland dysfunction: a systematic review and meta-analysis. Graefe's Archive for Clinical and Experimental Ophthalmology 2022;260(1):26-39. [DOI] [PubMed] [Google Scholar]
ImageJ [Computer program]
- U. S. National Institutes of Health ImageJ: Image Processing and Analysis in Java. Version 1.8.0. Bethesda, Maryland, USA: U. S. National Institutes of Health, 2018. Available at imagej.nih.gov/ij/.
Knop 2011
- Knop E, Knop N, Millar T, Obata H, Sullivan DA. The international workshop on meibomian gland dysfunction: report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland. Investigative Ophthalmology and Visual Science 2011;52(4):1938-78. [DOI] [PMC free article] [PubMed] [Google Scholar]
Korb 2001
- Korb DR, Greiner JV, Herman J. Comparison of fluorescein break-up time measurement reproducibility using standard fluorescein strips versus the Dry Eye Test (DET) method. Cornea 2001;20(8):811-5. [DOI] [PubMed] [Google Scholar]
Korb 2005
- Korb DR, Herman JP, Greiner JV, Scaffidi RC, Finnemore VM, Exford JM, et al. Lid wiper epitheliopathy and dry eye symptoms. Eye and Contact Lens 2005;31(1):2-8. [DOI] [PubMed] [Google Scholar]
Korb 2011
- Korb DR, Blackie CA. Meibomian gland therapeutic expression: quantifying the applied pressure and the limitation of resulting pain. Eye and Contact Lens 2011;37(5):298-301. [DOI] [PubMed] [Google Scholar]
Lane 2012
- Lane SS, DuBiner HB, Epstein RJ, Ernest PH, Greiner JV, Hardten DR, et al. A new system, the LipiFlow, for the treatment of meibomian gland dysfunction. Cornea 2012;31(4):396-404. [DOI] [PubMed] [Google Scholar]
Lefebvre 2008
- Lefebvre C, Eisinga A, McDonald S, Paul N. Enhancing access to reports of randomized trials published world-wide: the contribution of Embase records to the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library. Emerging Themes in Epidemiology 2008;30(5):13. [DOI] [PMC free article] [PubMed] [Google Scholar]
Lemp 1973
- Lemp MA, Hamill JR Jr. Factors affecting tear film breakup in normal eyes. Archives of Ophthalmology 1973;89(2):103-5. [DOI] [PubMed] [Google Scholar]
Lemp 1995
- Lemp MA. Report of the National Eye Institute/Industry workshop on clinical trials in dry eyes. Contact Lens Association of Ophthalmologists 1995;21(4):221-32. [PubMed] [Google Scholar]
Lemp 2012
- Lemp MA, Crews LA, Bron AJ, Foulks GN, Sullivan BD. Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: a retrospective study. Cornea 2012;31(5):472-8. [DOI] [PubMed] [Google Scholar]
Li 2020
- Li B, Fu H, Liu T, Xu M. Comparison of the therapeutic effect of Meibomian Thermal Pulsation LipiFlow® on obstructive and hyposecretory meibomian gland dysfunction patients. International Ophthalmology 2020;40(12):3469-79. [DOI] [PMC free article] [PubMed] [Google Scholar]
McCann 2009
- McCann LC, Tomlinson A, Pearce EI, Diaper C. Tear and meibomian gland function in blepharitis and normals. Eye and Contact Lens 2009;35(4):203-8. [DOI] [PubMed] [Google Scholar]
McKenzie 2022a
- McKenzie JE, Brennan SE, Ryan RE, Thomson HJ, Johnston RV. Chapter 9: Summarizing study characteristics and preparing for synthesis. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.3 (updated February 2022). Cochrane, 2022. Available from www.training.cochrane.org/handbook.
McKenzie 2022b
- McKenzie JE, Brennan SE. Chapter 12: Synthesizing and presenting findings using other methods. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.3 (updated February 2022). Cochrane, 2022. Available from www.training.cochrane.org/handbook.
Meadows 2012
- Meadows JF, Ramamoorthy P, Nichols JJ, Nichols KK. Development of the 4-3-2-1 meibum expressibility scale. Eye and Contact Lens 2012;38(2):86-92. [DOI] [PubMed] [Google Scholar]
Papas 2021
- Papas EB. The global prevalence of dry eye disease: a Bayesian view. Ophthalmic and Physiological Optics 2021;41(6):1254-66. [DOI] [PubMed] [Google Scholar]
Pult 2013
- Pult H, Riede-Pult B. Comparison of subjective grading and objective assessment in meibography. Contact Lens and Anterior Eye 2013;36(1):22-7. [DOI] [PubMed] [Google Scholar]
Rapoport 2016
- Rapoport Y, Singer JM, Ling JD, Gregory A, Kohanim S. A comprehensive review of sex disparities in symptoms, pathophysiology, and epidemiology of dry eye syndrome. Seminars in Ophthalmology 2016;31(4):325-36. [DOI] [PubMed] [Google Scholar]
RevMan Web [Computer program]
- The Cochrane Collaboration Review Manager Web (RevMan Web). Version 4.2.1. The Cochrane Collaboration, 2022. Available at revman.cochrane.org.
Schaumberg 2003
- Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. American Journal of Ophthalmology 2003;136(2):318-26. [DOI] [PubMed] [Google Scholar]
Schaumberg 2009
- Schaumberg DA, Dana R, Buring JE, Sullivan DA. Prevalence of dry eye disease among US men: estimates from the Physicians' Health Studies. American Journal of Ophthalmology 2009;127(6):763-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
Schiffman 2000
- Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the Ocular Surface Disease Index. American Journal of Ophthalmology 2000;118(5):615-21. [DOI] [PubMed] [Google Scholar]
Schünemann 2022
- Schünemann HJ, Higgins JP, Vist GE, Glasziou P, Akl EA, Skoetz N, et al. Chapter 14: Completing ‘Summary of findings’ tables and grading the certainty of the evidence. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.3 (updated February 2022). Cochrane, 2022. Available from www.training.cochrane.org/handbook.
Shimazaki 1998
- Shimazaki J, Goto E, Ono M, Shimmura S, Tsubota K. Meibomian gland dysfunction in patients with Sjögren syndrome. Ophthalmology 1998;105(8):1485-8. [DOI] [PubMed] [Google Scholar]
Stapleton 2017
- Stapleton F, Alves M, Bunya VY, Jalbert I, Lekhanont K, Malet F, et al. TFOS DEWS II epidemiology report. Ocular Surface 2017;15(3):334-65. [DOI] [PubMed] [Google Scholar]
Sterne 2019
- Sterne JA, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898. [DOI: 10.1136/bmj.l4898] [DOI] [PubMed] [Google Scholar]
Tomlinson 2011
- Tomlinson A, Bron AJ, Korb DR, Amano S, Paugh JR, Pearce EI, et al. The international workshop on meibomian gland dysfunction: report of the diagnosis subcommittee. Investigative Ophthalmology and Visual Science 2011;52(4):2006-49. [DOI] [PMC free article] [PubMed] [Google Scholar]
Uchino 2013
- Uchino M, Schaumberg DA. Dry eye disease: impact on quality of life and vision. Current Ophthalmology Reports 2013;1(2):51-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
Wolffsohn 2017
- Wolffsohn JS, Arita R, Chalmers R, Djalilian A, Dogru M, Dumbleton K, et al. TFOS DEWS II diagnostic methodology report. Ocular Surface 2017;15(3):539-74. [DOI] [PubMed] [Google Scholar]