Maxillary sinus augmentation – relative performance of available biomaterials and the challenge of small studies

To allow dental implant placement in the posterior maxilla, it is sometimes necessary to increase the height of the residual alveolar bone of the maxillary sinus floor by undertaking a sinus lift procedure. The historical material of choice has been autogenous bone (AB), but this can lead to donor-site morbidity following harvesting. To simplify this process of sinus augmentation, several substitute materials have been studied, such as xenografts in the form of deproteinised bovine bone, synthetic grafts, growth factors, and platelet concentrates. There have been three recent systematic reviews utilising standard pairwise meta-analyses to investigate the efficacy of these biomaterials as a substitute for AB (Corbella et al., 2016; Danesh-Sani et al., 2017; Ting et al., 2017). The authors chose to undertake a Bayesian network meta-analysis (NMA) to evaluate and rank all these materials simultaneously in their capacity to form new bone. (Trimmel et al., 2021)

Methods

The study protocol was registered in PROSPERO (International Prospective Register of Systematic Reviews) and followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis for Network Meta-analysis (PRISMA-NMA) guidelines (Hutton et al., 2015). A systematic search for suitable randomised control trials (RCTs) was performed in the  Cochrane Library (CENTRAL), EBSCO, Embase, MEDLINE (via PubMed), and Web of Science Core Collection electronic databases with records published up to October 1, 2019. The risk of bias was assessed using the Cochrane Risk of Bias Tool.

The Bayesian approach for NMAs describes the range and probability of the parameter of interest (e.g., treatment effect here being bone % bone regeneration). The posterior distribution produced by this method predicts the new range and probability of plausible values for these parameters with the representation of uncertainty in the form of a 95% credibility interval. The interventions were ranked by their posterior probability by calculating the surface under the cumulative ranking (SUCRA) curve values.

Results

  • 34 RCTs (842 maxillary sinus augmentations) with an average healing period of 5–8 months were included in the NMA. 31 were two-arm studies, and 3 were three-arm studies.
  • There were 28 treatment options, 378 possible pairwise comparisons, and 31 pairwise comparisons using direct data.
  • The overall assessment for risk of bias showed low risk in 5 studies, unclear risk in 20 studies, and high risk in 9 studies.
  • There were significant differences favouring the bovine bone + bone marrow concentrate (BMC) composite graft and the biodegradable copolymer; and between the bovine + BMC composite graft and the allograft.
  • From the 376 pairwise comparisons, no significant differences were detected, leading to a rejection of the null hypothesis that AB alone is the most favourable material for bone regeneration.
  • The SUCRA ranking probability for the most effective bone grafting material for new bone regeneration:-
Top Five Grafting MaterialsSUCRA ranking
Bovine xenograft + bone marrow concentrate (BMC)81%
Bovine xenograft + platelet-rich plasma (PRP)77%
Bioactive glass ceramic + autologous bone 1:170%
Nanocrystalline hydroxyapatite in silica gel70%
Bioactive glass-ceramic70%
Autologous bone graft57%

Conclusions

The authors concluded:-

The results of the present NMA suggest that the use of biomaterials does not result in a statistically significant difference in the rate of NB formation compared to AB alone as grafting material. However, their use can significantly reduce the amount of AB graft required for MSA, resulting in a less invasive surgical intervention and shorter surgical time. The combination of biomaterials with AB or autologous cell concentrates, such as BMC, PRP, and platelet-rich fibrin, represents a feasible alternative for AB substitution to achieve high NB formation. The superiority of AB compared to biomaterials for MSA in a healing time frame of 5–8 months cannot be justified.

Comments

Network meta-analyses are highly complex statistical tools to evaluate multiple treatment options. This complexity can limit the strength and certainty of the inferences produced even when the NMA is well done, as in this case. In a two-part paper by Foote, Chaudhry and co-workers, they outline a practical guide on interpreting NMAs (Foote et al., 2015; Chaudhry et al., 2015). It should be noted that even though this NMA had a high number of treatment nodes, it was a sparse network with a network density of about 10%, whereas a full connected (dense) network would achieve 100%. The sparsity of connections increases the reliance on indirect evidence and the effects of heterogeneity within the included studies, leading to extremely wide confidence/credibility intervals and questionable results (Brignardello-Petersen et al., 2019). To explore this potential problem, the primary data in Table 2 of Trimmels paper was extracted and reanalysed using the R package called “BUGSnet” (Bayesian inference Using Gibbs Sampling to conduct a Network meta-analysis) in R (Béliveau et al., 2019). The initial reanalysis duplicated Trimmels results, as can be seen in the netplot (Figure 1).

Figure 1. Netplot of Trimmel original data.

The material and methods section of the original paper mentioned that each intervention would be presented compared to a placebo in a forest plot; however, the forest plot was not shown in the paper. In the reanalysis, the forest plot is given below. It clearly shows the very wide credibility intervals. Almost all the treatment options cross the null effect line, confirming the problems created by incorporating many small poorly networked studies and the resultant indirect estimates the model generates (Figure 2.).

Figure 2. Forest plot relative to autogenous bone

To explore this further, the simplest method was to undertake a sensitivity meta-analysis and remove those studies considered to be at high risk of bias. These studies would be the most likely to result in misleading results (Chaudhry et al., 2015). The 9 papers the authors considered to be a high risk of bias were removed from the NMA database, and 2 further papers that appeared to share a control group. The rankings were then recalculated and presented alongside the original ranking data to observe any changes. The reanalysis removed 3 treatments from the ranking (autogenous bone plus autologous platelet concentrate, bovine plus bone marrow aspirates, and porcine bone), plus bone marrow concentrate was dropped 18 places from 81% to 40%. The top five highest-ranking treatments now include bovine bone mixed with autologous bone, bovine bone plus platelet-rich fibrin (PRF), and biphasic calcium phosphate (HA/β-TCP = 60/40) combined with fibrin sealant (FS). (Table 1.)

Table 1. Change in top 5 ranked augmentation materials.

RankSensitivity meta-analysisScoreOriginal meta-analysisScore
1Bovine+AB4:185Bovine+BMC81
2Bovine+AB1:183Bovine+PRP77
3Bovine+AB1:1+laser stimulation77Bioglass+AB1:170
4Bovine+PRP76HA+silicalgel70
5BCP+FS73Bioglass70

We could conclude that the sensitivity analysis confirmed the authors finding that autologous bone did not show superiority to composite grafting material. Significantly, however, the ranking of those materials changes at the extremes, with the first six highest rankings being substantially downgraded and three treatments being removed from the meta-analysis altogether (Figure 3).

Figure 3. Change in SUCRA scores with sensitivity analysis.

In summary, both the researcher and the reader must exercise caution when undertaking a network meta-analysis. Leaving aside the issue of transitivity assumptions, consistency and statistical complexity,  network analysis will not eliminate the problems associated with combining multiple small, severely underpowered studies that could be potentially at high risk of bias. To quote Foote and co-authors: –

Assessing the credibility of the methodology is an important first step in critically appraising an NMA. As with conventional systematic reviews, assessing credibility involves evaluating the article for a sensible research question, an exhaustive search, reproducible selection and assessment of articles, presenting clinically relevant results, and addressing certainty in effect estimates (Foote et al., 2015).

Primary paper

Trimmel, B., Gede, N., Hegyi, P., et al. 2021. Relative Performance of Various Biomaterials Used for Maxillary Sinus Augmentation: A Bayesian Network Meta‐Analysis. Clinical Oral Implants Research, 32, 135-153.

Review protocol in PROSPERO

Other references

Béliveau, A., Boyne, D. J., Slater, J., et al. 2019. Bugsnet: An R Package to Facilitate the Conduct and Reporting of Bayesian Network Meta-Analyses. BMC Medical Research Methodology, 19.

Brignardello-Petersen, R., Murad, M. H., Walter, S. D., et al. 2019. Grade Approach to Rate the Certainty from a Network Meta-Analysis: Avoiding Spurious Judgments of Imprecision in Sparse Networks. J Clin Epidemiol, 105, 60-67.

Chaudhry, H., Foote, C. J., Guyatt, G., et al. 2015. Network Meta-Analysis: Users’ Guide for Surgeons: Part Ii – Certainty. Clinical Orthopaedics & Related Research, 473, 2172-2178.

Corbella, S., Taschieri, S., Weinstein, R., et al. 2016. Histomorphometric Outcomes after Lateral Sinus Floor Elevation Procedure: A Systematic Review of the Literature and Meta-Analysis. Clinical Oral Implants Research, 27, 1106-1122.

Danesh-Sani, S. A., Engebretson, S. P. & Janal, M. N. 2017. Histomorphometric Results of Different Grafting Materials and Effect of Healing Time on Bone Maturation after Sinus Floor Augmentation: A Systematic Review and Meta-Analysis. Journal of Periodontal Research, 52, 301-312.

Foote, C. J., Chaudhry, H., Bhandari, M., et al. 2015. Network Meta-Analysis: Users’ Guide for Surgeons: Part I – Credibility. Clinical Orthopaedics & Related Research, 473, 2166-2171.

Hutton, B., Salanti, G., Caldwell, D. M., et al. 2015. The Prisma Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-Analyses of Health Care Interventions: Checklist and Explanations. Ann Intern Med, 162, 777-784.

Ting, M., Rice, J. G., Braid, S. M., et al. 2017. Maxillary Sinus Augmentation for Dental Implant Rehabilitation of the Edentulous Ridge: A Comprehensive Overview of Systematic Reviews. Implant Dent, 26, 438-464.

Powered Air-Purifying Respirator (PAPR) use for prevention of highly infectious viral disease in healthcare workers

IMG_1132

Link to the Dental Elf

There has been a considerable amount of literature developed over the Coronavirus CoV-2 pandemic regarding the dental profession, aerosol generating procedures (AGP), airborne spread of the virus and the need for enhanced personal protective equipment (PPE).Though there is evidence that dental AGPs cause significant environmental contamination there is very little evidence linking this to direct infection of staff or patients (HPS, 2020).

To reduce the potential risk of infection via the airborne route most national and international regulations (Clarkson et al., 2020) require that dental teams wear Face Filtering Piece level respiratory protection (FFP2/FFP3) in addition to standard PPE when performing AGPs. Following the SARS-Cov-1 outbreak in Toronto, Canada, powered air-purifying respirators (PAPRs) superseded the use of FFP respirators in the respiratory PPE protocols (Peng et al., 2003) however there is no mention of their existence as an alternative to FFP3 respirator in the PPE guidance from the Office of the Chief Dental Officer (England) (OCDO, 2020). This review is important due to limited information available regarding the practical efficacy between FFP2/FFP3 and PAPRs in the clinical environment.

Methods

This systematic review was reported according to the standards for the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), and the protocol was prospectively registered with the International Register of Systematic Reviews (PROSPERO). Searches were undertaken using the electronic databases: Medline; Embase; Cochrane Library (Cochrane Database of Systematic Reviews and CENTRAL). Grey literature was sought through: Google Scholar, OpenGrey, and GreyNet. Searches were repeated up to June 2020, and only English language studies were included.

Studies were screened by two reviewers. Risk of bias in randomized controlled studies was assessed using the Cochrane Risk of Bias tool, and the ROBINS-I (Risk of Bias in Non-randomized Studies of Interventions) tool to assess the risk of bias in non-randomized studies. Quality of evidence was classified according to Grading of Recommendations, Assessment, Development and Evaluation (GRADE). Due to the heterogeneity of the small number of studies a narrative review was undertaken.

Results

  • 10 studies fulfilled the inclusion criteria out of a total of 690.
  • There was no difference in the primary endpoint of COVID-19 infection in respective observational studies in the airway proceduralists utilizing PAPR versus other protective respiratory equipment.
  • Healthcare workers reported Improved comfort with regards to heat tolerance and visibility with PAPR technology.
  • Decreased effort was needed to maintain the work of breathing compared to conventional filtering face pieces.
  • Lower contamination rates of skin and clothing in simulation studies of participants utilising PAPRs.
  • Decrease in audibility and communication difficulties due to increased weight of the equipment and noise generated by positive airflow.

Conclusions

The authors concluded: –

Field observational studies do not indicate a difference in healthcare worker infection utilizing PAPR devices versus other compliant respiratory equipment. Greater heat tolerance accompanied by lower scores of mobility and audibility in PAPR were identified. Further pragmatic studies are needed in order to delineate actual effectiveness and provider satisfaction with PAPR technology.

Comments

This was a well conducted systematic review considering the limitation in the number of studies. Due to the global nature of the pandemic more papers could possibly have been identified if the authors had not restricted the language search. There would appear to be numerous advantages identified in this review regarding the use of PAPRs such as increased assigned protection factors (APF >25), inbuilt eye protection, reusable, they don’t need fit testing, improved heat tolerance and comfort if worn for longer than 1 hour, and they can be worn without limiting facial hair.

Limitations include challenges in verbal communication due to the hum of the motor, maintenance and battery life, decontamination after use, and cost. Given the lack of demonstrable advantage in terms of infection prevention, institutional decision makers may be applying a pragmatic choice to use FFP3 over PAPR respirators, however there may be considerable physical and financial advantage for health care workers and dental staff who are required to work for extended periods.

Links

Primary Paper

Use of Powered Air-Purifying Respirator (PAPR) by healthcare workers for preventing highly infectious viral diseases -a systematic review of evidence. Ana Licina, Andrew J Silvers, Rhonda Stuart. medRxiv 2020.07.14.20153288;

Review protocol on PROSPERO

Other references

CLARKSON, J., RICHARDS, D. & RAMSAY, C. 2020. Aerosol Generating Procedures and their Mitigation in International Dental Guidance Documents – A Rapid Review.

OCDO. 2020. Standard operating procedure Transition to recovery  first published 4th June.[Online].  Accessed 1st Aug 2020].

PENG, P. W., WONG, D. T., BEVAN, D. & GARDAM, M. 2003. Infection control and anesthesia: lessons learned from the Toronto SARS outbreak. Canadian Journal of Anesthesia, 50, 989-997.

HPS 2020. SBAR: Assessing the evidence base for medical procedures which create a higher risk of respiratory infection transmission from patient to healthcare worker.

Aerosol generating procedures (AGPs) and their mitigation in international guidelines: Fallow time

330px-Dental_aerosols

Link to Dental Elf

Bottom line

The recommendations for  fallow time in dental practice following an AGP appears almost random in its application across half of international guidelines. Its basic idea appears to be centred on a single precautionary principle based on simulation studies that are only weakly supported by evidence. Policy makers will need to take a more balanced approach when assessing the benefits and harms fallow time creates.

Introduction

With the publication of, ‘Aerosol Generating Procedures and their Mitigation in International Dental Guidance Documents – A Rapid Review’ by the  COVID-19 Dental Services Evidence Review (CoDER) Working Group (Clarkson et al., 2020) it was interesting to note their finding regarding fallow time for non Covid-19 patients:

  • 48% of the guidelines recommend having a fallow period.
  • The amount of time recommended varied (2-180 mins) between guidelines and also within guidelines, depending on environmental mitigation.
  • None of the fallow period recommendations referenced any scientific evidence.

The fallow period is the ‘time necessary for clearance of infectious aerosols after a procedure before decontamination of the surgery can begin’ (FGDP, 2020), and this has caused considerable discussion/stress amongst the dentist returning to practice after lockdown in the UK (BAPD, 2020, Heffernan, 2020).

The fallow times following an AGP for both Covid-19 negative patients and Covid-19 positive patients are presented in Figure 1 and Table 2 using the data from the CoDER rapid review:

Figure 1. Stacked bar chart representing fallow times for both Covid negative and positive patients

Fallow times

Since the fallow times are not normally distributed the median value was utilised and the 95% confidence limit approximated according to Hill (Hill, 1987).

Table 1. Median fallow time

Aerosol generating procedure Median Fallow time (mins)
Non Covid-19 patient 15 (95% CI: 15 to 30)
Covid-19 positive patient 20 (95% CI: 10 to 60)

Much of the theory around the need for fallow time is based on the aerosol transmission of the Coronavirus SARS-CoV-2 and the need to allow the aerosol to settle or be physically removed from the room via ventilation or filtration. Initially the WHO supported the idea that spread was predominantly caused by large droplets and contact (WHO, 2020a) but under increased lobbying from the scientific community to include airborne transmission as a significant factor (Morawska and Milton, 2020) the WHO amended their position (WHO, 2020b) on the 9th July.

The evidence for airborne transmission of Coronavirus SARS-CoV-2 is uncertain and mostly based on mathematical modelling (Buonanno et al., 2020) but where there has been limited observational data Hota and co-workers concluded that the virus was not well transmitted by the airborne route compared to measles, SARS-1 or Tuberculosis  (Hota et al., 2020).

The reason there is no strong scientific evidence for fallow time and airborne transmission is possibly because it is based on two conceptual arguments:

The Precautionary Principle (PP)

The precautionary principle (PP) states that if an action or policy has a suspected risk of causing severe harm to the public domain (affecting general health or the environment globally), the action should not be taken in the absence of scientific near-certainty about its safety. Under these conditions, the burden of proof about absence of harm falls on those proposing an action, not those opposing it (Taleb et al., 2020). The confusion at the moment is that the PP has been reversed and the action is evidence-based ‘normal/enhanced PPE and cross infection policy’ rather than the imposition of untested application of ‘fallow time’ in general practice.

The Independent Action Hypothesis (IAH)

The IAH states that each virion has an equal, non-zero probability of causing a fatal infection especially where airborne spread via small droplets (5μm) is the proposed method of transmission (Stadnytskyi et al., 2020). The reality of the IAH is that evidence supporting this theory is oversimplified and indirect, based mainly on small sample studies of moth larvae, and tobacco mosaic virus (Zwart et al., 2009, Cornforth et al., 2015).

Discussion

The main problem for anyone challenging the PP and IAH is having to prove a ‘near certainty of safety’ when there are many confounding factors in play, and the application of a ‘non-zero’ probability of a single inhaled virus causing death results in an ill-defined probability of risk (Taleb et al., 2020). Unfortunately, once the PP was been invoked designing challenge studies to create the scientific proof that the action is safe can be unethical in humans or experimentally impossible due to the effect of low viral prevalence in the community on statistical power.

One solution may be to rapidly assess the retrospective infection rates associated with the provision of dental care in those countries with extended fallow times and compare then to countries of similar demographics that do not have fallow time (Table 1). Policy makers may need to revise their current interpretation of the precautionary principle and IAH  based on the fact that in a pandemic situation there may be multiple interacting factors that can cause significantly more second and third order harm to the public domain than the virus itself.

 

Table 2. Countries with/without(bold) fallow time. ND – no data

Country Non Covid-19 Covid-19   Country Non Covid-19 Covid-19
Ireland 0 60 Burkina Faso ND ND
Poland 0 0 Canada ND 180
Bolivia 2 2 Chile ND ND
Philippines 5 5 Columbia ND ND
Dominican Republic 10 10 Costa Rica ND ND
Ecuador 10 10 Croatia ND ND
Brazil 15 15 Denmark ND ND
France 15 15 Finland ND 30
Italy 15 ND Greece ND ND
Morocco 15 15 Guatemala ND ND
Romania 15 15 Honduras ND ND
Spain 15 ND India ND ND
Switzerland 15 30 Kenya ND ND
Tunisia 15 ND Kosovo ND ND
UAE 20 ND Malaysia ND ND
Germany 30 30 Mexico ND ND
Malta 30 ND Mozambique ND ND
Ukraine 30 ND Myanmar ND ND
Estonia 45 ND Netherlands ND ND
Singapore 45 ND New Zealand ND 20
Argentina 60 60 Norway ND ND
Bulgaria 60 60 Panama ND ND
Montenegro 60 60 Peru ND ND
UK 60 60 Portugal ND ND
UK – NI 60 60 Slovakia ND ND
UK – Wales 60 60 Slovenia ND 10
China 90 ND South Africa ND ND
Paraguay 180 180 UK – Scotland ND ND
Australia ND ND Uruguay ND ND
Austria ND ND USA ND ND
Belgium ND ND Zimbabwe ND ND

 

References

BAPD. 2020. BAPD urges government to reconsider PPE requirements for dentistry [Online]. Dentistry. [Accessed 30th July 2020 ].

BUONANNO, G., STABILE, L. & MORAWSKA, L. 2020. Estimation of airborne viral emission: Quanta emission rate of SARS-CoV-2 for infection risk assessment. Environ Int, 141, 105794.

CLARKSON J, RAMSAY C, RICHARDS D, ROBERTSON C, & ACEVES-MARTINS M; on behalf of the CoDER Working Group (2020). Aerosol Generating Procedures and their Mitigation in International Dental Guidance Documents – A Rapid Review.

CORNFORTH, D. M., MATTHEWS, A., BROWN, S. P. & RAYMOND, B. 2015. Bacterial Cooperation Causes Systematic Errors in Pathogen Risk Assessment due to the Failure of the Independent Action Hypothesis. PLoS Pathog, 11, e1004775.

FGDP. 2020. Implications of COVID-19 for the safe management of general dental practice A practical guide [Online]. [Accessed 30th July 2020 ].

HEFFERNAN, M. 2020. Is a one hour fallow period really necessary for dentistry in England? [Online]. Dentistry. [Accessed 30th July 2020 ].

HILL, I. 1987. 95% Confidence limits for the median. Journal of Statistical Computation and Simulation, 28, 80-81.

HOTA, B., STEIN, B., LIN, M., TOMICH, A., SEGRETI, J. & WEINSTEIN, R. A. 2020. Estimate of airborne transmission of SARS-CoV-2 using real time tracking of health care workers.

MORAWSKA, L. & MILTON, D. K. 2020. It is time to address airborne transmission of COVID-19. Clin Infect Dis, 6,ciaa939.

STADNYTSKYI, V., BAX, C. E., BAX, A. & ANFINRUD, P. 2020. The airborne lifetime of small speech droplets and their potential importance in SARS-CoV-2 transmission. Proc Natl Acad Sci U S A, 117, 11875-11877.

TALEB, N., READ, R. & DOUADY, R. 2020. The Precautionary Principle (with Application to the Genetic Modification of Organisms).

WHO 2020a. Modes of transmission of virus causing COVID-19: implications for IPC precaution recommendations: scientific brief, 27 March 2020. World Health Organization.

WHO 2020b. Transmission of SARS-CoV-2: implications for infection prevention precautions 9th July. World Health Organization.

ZWART, M. P., HEMERIK, L., CORY, J. S., DE VISSER, J. A., BIANCHI, F. J., VAN OERS, M. M., VLAK, J. M., HOEKSTRA, R. F. & VAN DER WERF, W. 2009. An experimental test of the independent action hypothesis in virus-insect pathosystems. Proc Biol Sci, 276, 2233-42.