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Irrigants for non-surgical root canal treatment in mature
permanent teeth (Review)
Fedorowicz Z, Nasser M, Sequeira-Byron P, de Souza RF, Carter B, Heft M
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2012, Issue 9
http://www.thecochranelibrary.com
Irrigants for non-surgical root canal treatment in mature permanent teeth (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Analysis 1.1. Comparison 1 Sodium hypochlorite versus chlorhexidine, Outcome 1 The proportion of teeth with positive
bacterial culture following intervention (up to 48 hrs). . . . . . . . . . . . . . . . . . . . . 46
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 55
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Irrigants for non-surgical root canal treatment in mature permanent teeth (Review) i
[Intervention Review]
Irrigants for non-surgical root canal treatment in mature

permanent teeth
Zbys Fedorowicz1 , Mona Nasser2 , Patrick Sequeira-Byron3 , Raphael Freitas de Souza4 , Ben Carter5 , Marc Heft6
1 UKCC (Bahrain Branch), Head of Research College of Medicine, AMA International University of Bahrain, Awali, Bahrain. 2 Peninsula
Dental School, University of Plymouth, Plymouth, UK. 3 Department of Preventive, Restorative and Pediatric Dentistry, School of
Dental Medicine, Bern 10, Switzerland. 4 Department of Dental Materials and Prosthodontics, Ribeiro Preto Dental School, University
of So Paulo, Ribeiro Preto, Brazil. 5 North Wales Centre for Primary Care Research, Bangor University, Wrexham, UK. 6 Department
of Oral and Maxillofacial Surgery, University of Florida College of Dentistry, Gainesville, USA
Contact address: Patrick Sequeira-Byron, Department of Preventive, Restorative and Pediatric Dentistry, School of Dental Medicine,
Freiburgstrasse 7, Postfach 64, Bern 10, Bern, CH-3010, Switzerland. patrick.sequeira@zmk.unibe.ch.
Editorial group: Cochrane Oral Health Group.

Publication status and date: New, published in Issue 9, 2012.
Review content assessed as up-to-date: 24 July 2012.
Citation: Fedorowicz Z, Nasser M, Sequeira-Byron P, de Souza RF, Carter B, Heft M. Irrigants for non-surgical root canal
treatment in mature permanent teeth. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD008948. DOI:
10.1002/14651858.CD008948.pub2.
ABSTRACT
Background
Root canal treatment is carried out on teeth in which irreversible pulpitis has led to necrosis of the dental pulp. As a treatment option it
is an alternative to dental extraction. Mechanical preparation and irrigation with antiseptic or antibacterial solutions destroys bacteria
and cleans the infected root canal. Irrigants should be effective in deactivating bacteria in the entire root canal space without causing
any adverse tissue reactions. Sodium hypochlorite (NaOCl) and chlorhexidine are commonly used but there is uncertainty as to which
solution, concentration or combination is the most effective.
Objectives
To assess the effects of irrigants used in the non-surgical root canal treatment of mature permanent teeth.
Search methods
We searched the Cochrane Oral Health Groups Trials Register (to 5 July 2012), the Cochrane Central Register of Controlled Trials
(CENTRAL) (The Cochrane Library 2012, Issue 4), MEDLINE via Ovid (1950 to 5 July 2012), EMBASE via Ovid (1980 to 5 July
2012), LILACS via BIREME (1980 to 5 July 2012). There were no restrictions regarding language or date of publication.
Selection criteria
Randomised controlled trials in single or multi-rooted permanent teeth with pulpal or periapical pathology or both, which require root
canal treatment. Irrigants either against each other or against inactive irrigant or placebo. Combinations of irrigants were allowed and
if used in conjunction with EDTA (ethylenediaminetetra-acetic acid) or similar chelating agents.
Data collection and analysis
Two review authors independently assessed risk of bias of included trials and extracted data.
Irrigants for non-surgical root canal treatment in mature permanent teeth (Review) 1
Main results
We included 11 trials involving 851 participants with 879 teeth which had undergone root canal treatment and involved the use of
irrigants. Two trials were assessed as being at low risk of bias, with six unclear and three high. Four trials compared sodium hypochlorite
versus chlorhexidine, however, no primary outcomes and only one secondary outcome, bacterial growth cultures, was reported for
two of these trials (20% and 50% of teeth in the control group had positive bacterial culture). The meta-analysis indicated no strong
evidence of a difference in the existence of bacterial growth between the interventions (risk ratio 0.73; 95% condence interval 0.34
to 1.56; P = 0.41).
The seven remaining trials each compared different interventions and only two of these trials included useable data on the primary
outcomes of swelling and pain. One trial compared sodium hypochlorite 5.25% alone versus sodium hypochlorite 5.25% combined
with hydrogen peroxide 3%, and versus normal saline and reported pain at 3 to 14 days after the procedure. There was no evidence
of a difference in pain between the three groups. The other trial compared sodium hypochlorite 5% versus sodium hypochlorite with
proteolytic enzyme, and there was no evidence of a difference in swelling between the groups. Two further trials reported bacterial
growth, and three trials failed to report any data which could be used in the review. None of the included trials reported any data on
adverse effects nor radiological changes in periapical radiolucency.
Authors conclusions
Although root canal irrigants such as sodium hypochlorite and chlorhexidine appear to be effective at reducing bacterial cultures when
compared to saline, most of the studies included in this review failed to adequately report these clinically important and potentially
patient-relevant outcomes. There is currently insufcient reliable evidence showing the superiority of any one individual irrigant. The
strength and reliability of the supporting evidence was variable and clinicians should be aware that changes in bacterial counts or pain
in the early postoperative period may not be accurate indicators of long-term success. Future trials should report both clinician-relevant
and patient-preferred outcomes at clearly dened perioperative, as well as long-term, time points.
PLAIN LANGUAGE SUMMARY

Irrigating solutions for use in root canal treatment of teeth
Root canal treatment may be carried out as an alternative to dental extraction on a tooth in which the nerve has been injured or has
died. Root canal treatment is carried out because the offending canal is infected or the pulp severely inamed. The aim of root canal
treatment is to eliminate bacteria from, and prevent their further entry to the root canal system. The technique involves cleaning and
removal of any remaining bacteria and nerve canal contents. Elimination of any remaining infection improves the chance of success,
and irrigation of the canal with certain types of solutions during the procedure can be helpful in achieving this. A range of antiseptic
and antibacterial irrigating solutions are available. Sodium hypochlorite (NaOCl) in a variety of strengths has been used by dentists for
many years, but concerns have been raised about its toxicity and the occasional report of pain when higher concentrations are used.
Chlorhexidine, an antimicrobial, has also been used in a variety of concentrations as either a solution or gel. Combinations of antibiotic
and a detergent (MTAD) have been recently developed and are being used increasingly.
This review evaluated 11 studies which included 851 participants with 879 front and back teeth which had undergone root canal
treatment. Sodium hypochlorite in a range of strengths was the most commonly used irrigating solution, followed by chlorhexidine
as a solution or a gel. The amount of pain experienced immediately after treatment and between appointments did not appear to
differ either between some of the irrigants or between the different strengths of individual irrigants. Limited data suggested that higher
strength concentrations of sodium hypochlorite solution and a nal rinse with chlorhexidine may be more effective than other irrigants
at destroying bacteria.
BACKGROUND
should help achieve a successful obturation of the root canal, it is
Endodontic treatment of root canals or root canal treatment is a rel- of paramount importance that the surrounding vital tissues of the
atively complex dental procedure which is carried out principally root are not harmed by the irrigant, that the process is both safe
on teeth in which irreversible pulpitis has led to necrosis (death) for the patient and clinician and that it will ultimately enable the
of the dental pulp (nerve) (Fedorowicz 2005). As a treatment op- tooth to be restored to full function (Hlsmann 2009).
tion it offers an alternative to dental extraction. Orthograde root
canal treatment entails drilling into the pulp chamber (inside) of
the tooth which contains the dental pulp. The pulp, which may
Why it is important to do this review
be inamed or necrotic, is removed and the root canal is then
cleaned and prepared. The objectives of root canal treatment are Disinfection of root canals during their treatment is believed to
the elimination of infection from the root canal and the preven- directly affect long-term success. This may be even more important
tion of its re-infection by the lling and sealing of the root canal when single-visit root canal treatment is performed (Figini 2007).
space (Gagliani 2005; Orstavik 1998). The control of the pulp The challenge for the clinician is to select and use an irrigant, and
space infection is believed to be associated with the success of non- in particular one which is supported by the best evidence for its
surgical root canal treatment. Pulp spaces are complex and provide effectiveness. At present there is uncertainty as to which solutions,
niches where residual micro-organisms may hide (Nair 2004). It is at what concentration and the methods of their delivery, are the
generally assumed that a cleaner root canal system should lead to most effective. Indeed the answers to these questions have the
improved outcomes (Gutarts 2005), and that successful root canal potential to change practice and ultimately improve outcomes that
treatment may prolong the retention of the tooth as a functional are relevant to both clinicians and patients.
unit in the mouth. Thus the effective control of infective agents
within the root canal space pervades all aspects of root canal treat-
ment from the initial opening of the canal, to subsequent cleaning
and shaping of the canal and nally to the appropriate obturation OBJECTIVES
(lling) of the canal space.
To assess the effects of irrigants used in the non-surgical root canal
The indications for root canal therapy are most commonly caries- treatment of mature permanent teeth.
related i.e. when the pulp is irreversibly damaged or there is evi-
dence of periapical infection or both. However, elective root canal
therapy may also be required, in particular if the crown of a tooth
METHODS
requires extensive modication e.g. as a bridge pontic or under
an overdenture as a retaining root or in order to achieve retention
from the root canal for a crown. Root canal treatment may also be
required when the pulp has been injured as a result of trauma to Criteria for considering studies for this review
a tooth.
Types of studies
Description of the intervention Randomised controlled trials (RCT) in which the unit of randomi-
sation was an individual participant or tooth. If the unit of analysis
Mechanical preparation will remove many of the micro-organisms was an individual person with more than one treated tooth this
in an infected root canal. However, mechanical preparation may study would be considered a cluster RCT.
not be sufcient to ensure a clean and bacteria-free canal and, for
this reason, an active irrigant is routinely added to the treatment
regimen (Bystrm 1983). Types of participants
Any age, involving single or multi-rooted permanent teeth with
pulpal or periapical pathology or both, which required root canal
How the intervention might work treatment (single or multiple visit). Only teeth with fully formed
roots were considered.
By irrigating the canal during the course of treatment it may be
possible to: further reduce the number of micro-organisms; ush
out infected debris; and to remove potential organic growth sub- Types of interventions
strates which may support re-infection of the root space. The chal- Any irrigants either against each other or against inactive agent
lenge is to deliver the irrigant to the entire root canal space so that (irrigant) or placebo. Combinations of irrigants were acceptable
all of the micro-organisms are deactivated (by means of a bacteri- and if they had been used in conjunction with EDTA (ethylenedi-
cidal or bacteriostatic effect or both). Albeit the use of the irrigant aminetetra-acetic acid) or similar chelating agents. Concomitant
administration of antibiotics or any pain medication which may for MEDLINE (Appendix 1) but revised appropriately for each
inuence any of the outcomes was acceptable providing these were database.
available equally to both the treatment and control group. The following databases were searched.
The Cochrane Oral Health Groups Trials Register (to 5
July 2012) Appendix 2;
Types of outcome measures
The Cochrane Central Register of Controlled Trials
(CENTRAL) (The Cochrane Library, to Issue 4, 2012) Appendix
Primary outcomes 3;
MEDLINE (1950 to 5 July 2012) Appendix 1;
1. Proportion of participants with moderate to severe pain in
EMBASE (1980 to 5 July 2012) Appendix 4;
the time period: 72 hours to 14 days following the procedure.
Latin American and Caribbean Literature on Health
2. Proportion of participants with new or worsening signs,
Sciences (LILACS) (via BIREME) (1980 to 5 July 2012)
symptoms or both, of inammation i.e. pain, redness, swelling,
Appendix 5.
heat, or loss of function, requiring a revisit at any time point up
to 14 days following the procedure. For the MEDLINE search, we ran the subject search with the
Persistent pain at time points beyond these may be due to a number Cochrane Highly Sensitive Search Strategy (CHSSS) for identify-
of other reasons e.g. incompletely obturated canal, failed coronal ing randomised trials in MEDLINE: sensitivity maximising ver-
seal or tooth fracture, and which are less likely to be associated sion (2008 revision) as referenced in Chapter 6.4.11.1 and detailed
directly with the effectiveness or otherwise of the irrigants used, in box 6.4.c of the Cochrane Handbook for Systematic Reviews of In-
and therefore these other time points were not included for this terventions Version 5.1.0 [updated March 2011] (Higgins 2011).
outcome. The search of EMBASE was linked to the Cochrane Oral Health
Group lter for identifying RCTs, and the search of LILACS was
linked to the Brazilian Cochrane Center lter.
Secondary outcomes
1. Proportion of participants with moderate to severe pain up
to 6 hours following the procedure. Searching other resources
2. The mean change in health-related quality of life, or The reference lists of relevant articles were examined and we con-
participant-expressed satisfaction with the procedure. tacted the investigators of included studies by electronic mail to
3. Proportion of participants or samples with positive ask for details of additional published and unpublished trials. One
bacterial growth culture following the procedure and until 72 of the review authors (PS) handsearched the following journals
hours at follow-up in accordance with the recommendations of the Cochrane Oral
4. Change in periapical radiolucency as assessed by Health Group.
radiography or cone beam computed tomography (CBCT) at The International Endodontic Journal (to June 2011)
any clinically relevant time points and up to 1 year post- Journal of Endodontics (from 2004 to June 2011)
endodontic treatment. Oral Surgery, Oral Pathology, Oral Radiology, and
Endodontics (from 2003 to June 2011)
Adverse outcomes Dental Traumatology (from 2003 to June 2011)
Australian Endodontic Journal (from 2003 to June 2011)
We planned to record any reported adverse effects related to any of
the active interventions during the treatment phase. These might
include events affecting the operator or the patient i.e. damage Ongoing Trials Registers
to skin and clothing, injection into periradicular tissues, allergic We used free-text terms to search the following ongoing trial reg-
reactions to irrigating agents, or air emphysema during root canal isters on 13 September 2011:
drying. The metaRegister of Controlled Trials www.controlled-trials.com.
The U.S. National Institutes of Health Ongoing Trials Register
www.clinicaltrials.gov.
Search methods for identification of studies The World Health Organization International Clinical Trials Reg-
istry platform www.who.int/trialsearch.
Electronic searches
Language
For the identication of studies included or considered for this
review, detailed search strategies were developed for each database There were no language restrictions on included studies. Studies
to be searched. These were based on the search strategy developed not in the English language were translated.
Data collection and analysis 1. Sequence generation
2. Allocation concealment
3. Blinding (of participants, personnel and outcome assessors,
Selection of studies data analysts)
Two review authors independently assessed the abstracts of stud- 4. Incomplete outcome data
ies resulting from the searches. We obtained full text copies of all 5. Selective outcome reporting
relevant and potentially relevant studies, those appearing to meet 6. Free of other bias
the inclusion criteria, or for which there were insufcient data in These assessments were reported in the Risk of bias tables within
the title and abstract to make a clear decision. Two review authors the Characteristics of included studies tables for each individual
independently assessed full text papers and any disagreements on study.
the eligibility of potentially included studies were resolved through In addition, the overall risk of bias in each included study was
discussion and consensus with the other review authors. After as- categorised according to the following.
sessment, any duplicate publications or remaining studies that did Low risk of bias (plausible bias unlikely to seriously alter the
not match the inclusion criteria were excluded from further review results) if all criteria were met.
and the reasons for their exclusion noted in the Characteristics of Unclear risk of bias (plausible bias that raises some doubt
excluded studies table. about the results) if one or more criteria were assessed as unclear.
High risk of bias (plausible bias that seriously weakens
condence in the results) if one or more criteria were not met.
Data extraction and management
Two review authors collected study details and outcomes data in-
dependently and in duplicate using a data extraction form specif- Measures of treatment effect
ically designed for this purpose. We entered study details into the We calculated risk ratios (RR) and their associated 95% condence
Characteristics of included studies table and outcomes data into intervals (CIs) for dichotomous outcomes. No data were available
RevMan 5.1 (RevMan 2011). Any disagreements were discussed for continuous outcomes, but in future updates we will report the
and data was only included if there was an independently reached mean change from baseline or the mean post-intervention value
consensus. as well as the difference in means between treatment groups, and
1. Trial methods: (a) method of allocation; (b) masking of their corresponding 95% CIs.
participants and outcomes; (c) exclusion of participants after
randomisation and proportion of losses at follow-up.
Unit of analysis issues
2. Participants: (a) country of origin; (b) sample size; (c) age;
(d) gender; (e) inclusion and exclusion criteria. Cluster randomised controlled trials allocate groups of correlated
3. Intervention: (a) type; (b) sequence of irrigants, units e.g. teeth within the same mouth. Appropriate analysis of
concentrations, amounts and temperatures; (c) delivery system; these studies needs to reect the correlated structure of the data.
(d) length of time in follow-up. If these types of studies had been included, and where this had
4. Control: (a) type; (b) sequence of irrigants, concentrations, not been carried out, we would attempt to inate the standard
amounts and temperatures; (c) delivery system; (d) length of errors to account for the clustering. Where this was not possible,
time in follow-up. all meta-analyses would report outcomes with, and without these
5. Outcomes: primary and secondary outcomes outlined in studies.
the Types of outcome measures section of this review protocol. Studies that had randomised multiple teeth in the same individual
If stated, we recorded the sources of funding of any of the included were examined to assess: if the study design was reported correctly;
studies. for the possibility of cross-contamination of the individual teeth
This information was used to help assess heterogeneity and the by the interventions and for awed analysis. If any evidence of
generalisability of any included trials. these risks was found in any of these studies this was reported in
the Other potential sources of bias domain for the individual
study, and the judgement of risk of bias was amended accordingly.
Assessment of risk of bias in included studies Any studies included in this review which used a split-mouth de-
Two review authors graded the selected trials following the do- sign would be analysed as paired data and according to the recom-
main-based evaluation described in Chapter 8 of the Cochrane mendations in the Cochrane Handbook (Higgins 2011).
Handbook (Higgins 2011). The evaluations were compared and
any inconsistencies between the review authors were discussed and
resolved. Dealing with missing data
The following domains were assessed as low risk of bias, unclear Attempts were made to retrieve missing data from several of the
(i.e. uncertain risk of bias) or high risk of bias. investigators in the included trials (Table 1). In dealing with miss-
ing data we have followed the advice provided in section 16.1.2 (as dened above) are identied, we will carry out the following
of the Cochrane Handbook (Higgins 2011). subgroup analyses.
1. Irrigant concentration.
2. The method of irrigant delivery i.e. automatic pump/
Assessment of heterogeneity suction and with or without ultrasonic instrumentation.
We assessed clinical heterogeneity by examining the characteris- 3. The initial infective status of the pulp space i.e. infected or
tics of the studies, the similarity between the types of participants, vital pulp space.
the interventions and the outcomes as specied in the criteria for
included studies. Statistical heterogeneity was assessed using a Chi Sensitivity analysis
2 test and the I2 statistic where I2 values of 30% to 60% indicate
If sufcient studies had been included we planned to conduct
moderate to high heterogeneity, and 50% to 90% substantial het- sensitivity analyses to assess the robustness of our review results by
erogeneity (Higgins 2011). repeating the analysis with the following adjustments: exclusion of
studies with unclear or inadequate allocation concealment; unclear
or inadequate blinding of outcomes assessment; and completeness
Assessment of reporting biases
of follow-up.
If sufcient numbers of trials had been identied for inclusion in
this review, publication bias would have been assessed according to
the recommendations on testing for funnel plot asymmetry (Egger
1997) as described in section 10.4.3.1 of the Cochrane Handbook RESULTS
(Higgins 2011), and if asymmetry was identied we would have
tried to assess other possible causes and these would be explored
in the discussion if appropriate.
Description of studies
See: Characteristics of included studies; Characteristics of excluded
Data synthesis studies; Characteristics of studies awaiting classication.
Two review authors analysed the data and reported them as spec- See Characteristics of included studies and Characteristics of
ied in Chapter 9 of the Cochrane Handbook (Higgins 2011). excluded studies.
Pooling of data to provide estimates of the effects of the interven-
tions was only undertaken if the included studies had similar in- Results of the search
terventions received by similar participants. A xed-effect model The electronic searches retrieved 1429 references to studies. Af-
would be used but, if there was substantial clinical diversity be- ter examination of the titles and abstracts of these references, all
tween the included studies, the random-effects model, with stud- of those which did not match our inclusion criteria and were
ies grouped by action, was to be tted. If there were insufcient clearly ineligible were eliminated. We obtained full text copies of
trials for any specic intervention or insufcient study data that the remaining studies and subjected them to further evaluation.
could be pooled, a narrative synthesis was provided. Although we handsearched the journals which had been recom-
mended by the Cochrane Oral Health Group, we did not retrieve
any additional studies over and above those that had already been
Subgroup analysis and investigation of heterogeneity identied in the electronic search. The searches of the WHO In-
In view of the small number of studies examining similar inter- ternational Clinical Trials Registry Platform, the Current Clinical
ventions that were included in this review, we did not carry out a Trials ISRCTN Register and the ClinicalTrials.gov databases did
subgroup analysis. In future updates and if a sufcient number of not identify any ongoing trials.
studies with moderate, substantial or considerable heterogeneity For further details see Study Flow diagram (Figure 1).
Figure 1. Study flow diagram.
Characteristics of the interventions
Included studies
A range of interventions and comparisons were examined, with
Eleven studies were included in this review (Bashetty 2010; Bebek the majority of the studies evaluating head-to-head comparisons
2009; Ercan 2004; Harrison 1978; Malkhassian 2009; Ringel of irrigants and two which considered irrigants combined with
1982; Soares 2006; Taschieri 2009; Torabinejad 2005; Vianna chelating agents such as EDTA and MTAD, and only one study
2006; Zamany 2003). with a single comparison of irrigant against normal saline.
Sodium hypochlorite (NaOCl) versus chlorhexidine (four
trials) (Bashetty 2010; Ercan 2004; Ringel 1982; Vianna 2006).
Characteristics of the trial settings, investigators and Sodium hypochlorite: 1% versus 2.5% and versus 5% (one
methods trial) (Soares 2006).
Sodium hypochlorite 5.25% alone versus sodium
All of the studies were parallel group randomised controlled trials
hypochlorite 5.25% combined with hydrogen peroxide 3%, and
which had been conducted in Brazil, Canada, Croatia, India, Italy,
versus normal saline (one trial) (Harrison 1978).
Turkey and the USA. A university or dental school was the setting
Sodium hypochlorite 5% versus sodium hypochlorite with
in most of the studies, with the exception of one study which was
proteolytic enzyme (one trial) (Taschieri 2009).
conducted in a private practice (Taschieri 2009). In nine of the
Sodium hypochlorite 1% with additional irrigation of either
studies, two or more visits were required for obturation, whereas
chlorhexidine 2% or normal saline (one trial) (Zamany 2003).
in two studies the root canal treatment was completed at the same
Sodium hypochlorite 1.3% with MTAD (doxycycline,
visit (Taschieri 2009; Vianna 2006).
citric acid and Tween 80) versus normal saline (one trial)
In two of the studies, multiple teeth in several of the participants
(Malkhassian 2009).
received one or other intervention and, although it was not clear if
Sodium hypochlorite 5.25% with EDTA (17%) versus
the individual teeth were the unit of randomisation, the possibility
sodium hypochlorite 1.3% with MTAD (one trial) (Torabinejad
of unintentionally biased recruitment or allocation to interven-
2005).
tion or both, cannot be discounted (Ercan 2004; Ringel 1982). In
Chlorhexidine 0.2% versus normal saline (one trial) (Bebek
addition, neither study reported if these multiple teeth were con-
2009).
tiguous, whether the alternative treatments were carried out at the
same visit and if so what if any measures were taken to limit chem-
ical or biological cross-contamination. Although multiple within-
Characteristics of the outcomes measures
participant measurements at different time points (repeated mea-
sures) were conducted on the individual teeth in these two studies, Only two studies evaluated the pain outcomes prespecied for this
it is possible that these observations are not independent and are review (Harrison 1978; Taschieri 2009). Inter-appointment as-
likely to be correlated and subject to a clustering effect. sessments of pain rated as none, slight, or moderate to severe were
undertaken in Harrison 1978, but were inadequately reported,
and although the use of medication for pain relief was specied as
one of the criteria to be used in rating the level of pain, nothing
Characteristics of the participants was reported. Self-assessment of pain and swelling was undertaken
A total of 851 participants were investigated and provided 879 by the participants in Taschieri 2009 with a 5-point (rated: 1 =
teeth in the eleven studies. The age of the participants ranged from 0 to 5 = very much) questionnaire. These self-assessments were
14 to 78 years and included both genders. In three of the studies, to be undertaken at specic postoperative time points: at days
over half of the participants were either experiencing spontaneous 1, 2 and days 3 to 7 but a number of the questionnaires were
pain (Malkhassian 2009), had mild to moderate pain at enrolment not returned for analysis. Although the use of pain medication
(Bashetty 2010) or included a mix of participants with and with- by the participants was one of the outcomes prespecied and to
out symptoms (Torabinejad 2005), whereas in the remainder of be recorded in this questionnaire, neither the type of analgesic,
the studies the teeth were asymptomatic. Anterior and posterior the dose or frequency of its use were reported. Two studies used
teeth, both single and multi-rooted, were investigated. Clinical identical patient-reported questionnaires which assessed discom-
and radiographic assessments were carried out on all of the teeth fort but with a pain rating scale (0 = no pain to 9 = severe), and
in the included studies, but the preoperative assessment of pulp which were completed at intervals between the rst and second
vitality was only clearly reported in four studies (Harrison 1978; visits (Bashetty 2010; Torabinejad 2005).
Ringel 1982; Torabinejad 2005; Vianna 2006) but in Harrison The seven remaining studies carried out assessments of bacterial
1978 a third of the teeth were vital at enrolment. load and used a wide range of sampling and microbiological meth-
ods of assessment. In one study, colony forming unit (CFU) counts A list of the studies excluded from this review and the reasons
were used to compare the percentage of growing and non-grow- for their exclusion are reported in the Characteristics of excluded
ing bacterial species before and after irrigation (Ercan 2004). In studies table.
another study, bacterial levels were assessed before and after irriga-
tion using epiuorescence microscopy (EFM) and colony form-
ing unit (CFU) counts (Malkhassian 2009). In four studies, bac- Studies awaiting assessment
teriologic cultures of the canals taken at the beginning and end Data for a subset of participants relevant to this systematic re-
of each appointment were compared (Bebek 2009; Ringel 1982; view which were included in Blome 2008 have been requested
Soares 2006; Zamany 2003). In the nal study, the total micro- from the investigators, and therefore this study is awaiting assess-
bial content was assessed by a laboratory technique utilising real- ment pending a response (see Characteristics of studies awaiting
time quantitative-polymerase chain reaction (RTQ-PCR) meth- classication).
ods designed to quantify targeted DNA molecules in the bacteria
(Vianna 2006).
Risk of bias in included studies
For further details of outcomes measures in the included studies
see Table 2. Details of these assessments are reported in the relevant sections of
the Characteristics of included studies table and are also presented
in the Risk of Bias graph (Figure 2) and the Risk of Bias summary
Excluded studies (Figure 3).
Figure 2. Risk of bias graph: review authors judgements about each risk of bias item presented as
percentages across all included studies.
Figure 3. Risk of bias summary: review authors judgements about each risk of bias item for each included
study.
We assessed the overall risk of bias in each study and have cate-
gorised two of the studies as being at low risk of bias (Malkhassian studies, it was unclear to what extent the nature of the interven-
2009; Zamany 2003). Three studies were rated as being at high tion coupled with the uncertainty in the blinding of participants
risk of bias (plausible bias that seriously weakens condence in and self-assessed outcomes, are likely to lead to biased outcome as-
the results) because one or more domain received a judgement of sessment, and therefore these studies have been judged as unclear
high risk (Bashetty 2010; Ercan 2004; Taschieri 2009), and the risk of bias (Bashetty 2010; Harrison 1978). After email contact
remaining six studies were rated as being at unclear risk of bias with the principal investigator in Torabinejad 2005, we were able
(plausible bias that raises some doubt about the result) because to amend the judgement for this domain from unclear to low
one or more criteria were assessed as unclear risk. risk of bias. In six of the remaining studies, in which there were
no participant-assessed outcomes, it was not reported if personnel
Allocation
were blinded to the allocations or were involved in the microbio-
logic assessment or data analysis (Bebek 2009; Ercan 2004; Ringel
1982; Soares 2006; Vianna 2006; Zamany 2003). It remains un-
Randomisation
clear therefore if the outcome or its assessment, in these studies, is
The method used to generate the sequence was only clearly likely to be inuenced by the lack of blinding. Athough none of
reported in three studies (Bashetty 2010; Malkhassian 2009; the outcomes in Malkhassian 2009 were participant-assessed, the
Zamany 2003). After electronic mail contact with the principal investigators were effectively blinded and therefore this domain
investigators in four further studies (Bebek 2009; Taschieri 2009; was judged as low risk of bias in this study.
Torabinejad 2005; Vianna 2006), we were able to further clarify
the methods used and therefore a judgement of low risk of bias
was given for this domain in these seven studies. The remaining Incomplete outcome data
four studies were classied as unclear risk (Ercan 2004; Harrison
Two of the studies provided ow diagrams charting the path of
1978; Ringel 1982; Soares 2006).
participants through each study (Malkhassian 2009; Taschieri
2009), however, reporting inconsistencies were noted in one of
Allocation concealment them (Taschieri 2009), some of which we were able to clarify with
The method used to conceal the allocation sequence was only the investigators. In addition, data were unavailable for 34/200 of
clearly reported in one study (Malkhassian 2009) which was the participants in this study; half (17) of these losses were due
graded low risk of bias for this domain. We successfully corre- to protocol deviation i.e. exclusions after randomisation, and only
sponded (see Table 1) with the investigators in four studies and 166 out of a total number of 183 pain assessment questionnaires
were subsequently able to amend the judgements for this domain were returned. As not all of the randomised participants were
in these studies, from unclear risk to low risk of bias (Bebek 2009; analysed, a judgement of high risk of bias was given for this
Taschieri 2009; Vianna 2006; Zamany 2003). No further infor- domain in this study. There was no evidence of missing data in
mation was made available from the investigators in Torabinejad any of the remaining studies and these were judged as low risk of
2005 and therefore the judgement for this domain remains un- bias for this domain.
clear. All remaining studies were assigned a judgement of unclear
risk of bias.
Selective reporting
Although the overall level of data reporting was poor, most of
Blinding the studies, with the exception of Bashetty 2010, reported all ex-
The measures used to blind study participants and personnel pected outcomes including those that were prespecied in the cor-
from knowledge of which intervention a participant received were responding methods sections of the reports. The study protocol
only clearly reported in two studies (Malkhassian 2009; Taschieri was unavailable for Bashetty 2010, but one of the outcomes listed
2009). One study was reported as triple blinded but the investi- in the methods section of the study, and of interest in this review
gators did not clearly specify how blinding was achieved and, be- i.e. clinical evaluations, was not reported. The objectives of these
cause we were unable to receive a response from the investigators, evaluations were to assess the status of the periapical region using
this domain was judged as unclear risk of bias (Bashetty 2010). routine palpation and percussion tests seven days after the rst
The operator was blinded in another study but the method used visit. Selective reporting of only the subjective outcomes in this
was not clearly reported, however, we made successful contact with study as opposed to the more objective clinical signs and symp-
the principal investigator and were subsequently able to amend toms, irrespective of the direction and magnitude of treatment
our judgement to one of low risk of bias (Zamany 2003). In two effect, represents a potential threat to the validity of this study
which was judged high risk of bias for this domain. The remain- Primary outcomes
ing studies were all assessed as being at low risk of bias.
Proportion of participants with moderate to severe pain in

the time period: 72 hours to 14 days following the procedure
Other potential sources of bias
None of the studies reported data for this outcome.
Other potential sources of bias were those associated with trial
conduct e.g. subjects being randomised and then being excluded
as a result of unsatisfactory screening methodology, as was the case Proportion of participants with new or worsening signs,
in Taschieri 2009, which was assessed as high risk of bias. Pain was symptoms or both, of inflammation i.e. pain, redness,
the principal outcome in two studies (Bashetty 2010; Torabinejad swelling, heat, or loss of function, requiring a revisit at any
2005), but not all of the teeth were asymptomatic at enrolment time point up to 14 days following the procedure
nor were the key variables balanced across intervention groups. None of the studies reported data for this outcome.
In general, patients should be matched for preoperative pain if
they are to be studied for postoperative pain (OKeefe 1976), and
therefore in these two studies the impact of the baseline imbal- Secondary outcomes
ance in pain on the effect estimate remains unclear and they were
assessed as unclear risk of bias. In two of the studies, multiple
teeth in several of the participants received one or other interven- Proportion of participants with moderate to severe pain up
tion and there was some evidence to suggest that the outcomes to 6 hours following the procedure
may be clustered within these individual participants (Ercan 2004; None of the studies reported data for this outcome.
Ringel 1982). In Ercan 2004, 30 teeth from 20 participants were
randomised and the distribution and spread of growth and no-
growth outcome data as reported, was suggestive of a possible The mean change in health related quality of life, or
chemical cross-contamination of interventions. Similar clustered participant-expressed satisfaction with the procedure
outcomes were reported in Ringel 1982, in which 60 individual None of the studies reported data for these outcomes.
teeth were randomised from 52 participants. After evaluation of
the potential risk of bias in these studies, Ercan 2004 received a
judgement of high risk and Ringel 1982 an unclear risk of bias Proportion of participants or samples with positive bacterial
for this domain. growth culture following the procedure and until 72 hours at
In the remaining six studies there were no concerns about other follow-up
potential sources of bias that had not been addressed in the other The data for this outcome were not clearly reported in Ringel 1982
domains, and therefore this domain was judged as low risk of bias and were deemed to be unreliable and have not been entered into
in these studies. the meta-analysis.
In Vianna 2006, positive bacterial cultures were obtained in 4/16
samples following a 20 minute irrigation with sodium hypochlo-
Effects of interventions rite (2.5%) compared to 8/16 after irrigation with chlorhexidine
gel (2%): risk ratio (RR) 0.50 (95% condence interval (CI) 0.2
to 1.3; P = 0.17).
Positive bacterial growth in Ercan 2004 assessed by CFU counts
1. Sodium hypochlorite (NaOCl) versus chlorhexidine
from samples taken after irrigation occurred in 3/15 samples after
Four studies evaluated these two irrigants (Bashetty 2010; Ercan chlorhexidine (2%) as opposed to 4/15 with sodium hypochlorite
2004; Ringel 1982; Vianna 2006). A solution of sodium hypochlo- (5.25%): RR 1.33 (95% CI 0.4 to 5.0; P = 0.67).
rite (2.5%) was compared with a solution of chlorhexidine (0.2%) After pooling of the two studies: RR 0.74 (95% CI 0.3 to 1.6; P
in Ringel 1982, and with a 2% chlorhexidine gel in Vianna = 0.41; I2 = 27%) (see Analysis 1.1 and Figure 4). Based on this
2006. The two remaining studies compared solutions of sodium data there is insufcient evidence to conclude that there was any
hypochlorite (5.25%) with chlorhexidine (2%) (Bashetty 2010; difference between the two irrigants in reducing the proportion of
Ercan 2004). samples with positive bacterial growth.
Figure 4. Forest plot of comparison: 1 Sodium hypochlorite (NaOCl) versus chlorhexidine, outcome: 1.1
The proportion of teeth with positive bacterial culture following intervention (up to 48 hrs).
Change in periapical radiolucency as assessed by radiography

Adverse events
or cone beam computed tomography (CBCT) at any
clinically relevant time points and up to 1 year post- None were reported in the single study included in this compari-
endodontic treatment son.
None of the studies reported data for this outcome.

3. Sodium hypochlorite 5.25% alone versus sodium
hypochlorite 5.25% combined with hydrogen peroxide
Adverse events 3%, and versus normal saline
None were reported in any of the studies included in this compar- The effects of irrigating solutions of normal saline or sodium
ison. hypochlorite (5.25%) used alone or in combination with hydro-
gen peroxide (3%) were compared in Harrison 1978.
2. Sodium hypochlorite: 1% versus 2.5% and versus 5%

Primary outcomes
One study compared these three strengths of sodium hypochlorite
solutions and provided data for only one of our secondary out-
comes (Soares 2006).
Proportion of participants with moderate to severe pain in
Moderate to severe inter-appointment pain at follow-up (2 to 14
Primary outcomes
days) was reported in 7/86 of participants in the saline group, 6/
No data were reported for any of these outcomes. 92 in the sodium hypochlorite group and in 4/75 of participants
in the sodium hypochlorite combined with hydrogen peroxide
group (see Table 3). Based on these data there was no evidence
Secondary outcomes that the inter-appointment pain was different between any of the
intervention groups. The risk ratio and corresponding P values for
each pairwise comparison are reported in Table 4.
Proportion of participants or samples with positive bacterial

growth culture following the procedure and until 72 hours at Proportion of participants with new or worsening signs,
follow-up symptoms or both, of inflammation i.e. pain, redness,
swelling, heat, or loss of function, requiring a revisit at any
The proportion of samples with a positive culture after nal irriga-
time point up to 14 days following the procedure
tion were 10/39 for sodium hypochlorite (1%); 5/36 for sodium
hypochlorite (2.5%) and 2/36 for sodium hypochlorite (5%). The No data were reported for this outcome.
investigators concluded that sodium hypochlorite (5%) used as an
irrigant reduced the proportion of samples with positive cultures
when compared to sodium hypochlorite (1%): RR 4.62 (95% CI Secondary outcomes
1.1 to 19.7; P = 0.04). No data were reported for any of these outcomes.
Adverse events Proportion of participants or samples with positive bacterial
None were reported in the single study included in this compari- growth culture following the procedure and until 72 hours at
son. follow-up
No data were reported for this outcome.
4. Sodium hypochlorite 5% versus sodium

hypochlorite with proteolytic enzyme Change in periapical radiolucency as assessed by radiography
This comparison was evaluated in a single study which only re- or cone beam computed tomography (CBCT) at any
ported patient-assessed pain and swelling as primary outcomes clinically relevant time points and up to 1 year post-
(Taschieri 2009). endodontic treatment
Primary outcomes
Adverse events
None were reported in the single study included in this compari-
Proportion of participants with moderate to severe pain in son.
None of the participants in either intervention group reported
5. Sodium hypochlorite 1% with additional irrigation
moderate to severe pain persisting after day 2.
of either chlorhexidine 2% or normal saline
A single study compared the effects of a nal irrigation with ei-
Proportion of participants with new or worsening signs, ther a 2% chlorhexidine or normal saline solution following initial
symptoms or both, of inflammation i.e. pain, redness, biomechanical preparation with a 1% sodium hypochlorite irrig-
swelling, heat, or loss of function, requiring a revisit at any ant (Zamany 2003).
time point up to 14 days following the procedure
On day 1, swelling was reported in 23/84 participants in the
Primary outcomes
sodium hypochlorite group and 25/82 in the sodium hypochlorite
combined with proteolytic enzyme group: RR 0.9 (95% CI 0.6 No data were reported for these outcomes.
to 1.5; P = 0.66). There was no evidence of swelling persisting
beyond day 3 in either group.
Secondary outcomes
Secondary outcomes
Proportion of participants with moderate to severe pain up
to 6 hours following the procedure
Proportion of participants with moderate to severe pain up No data were reported for this outcome.
Although the report did not indicate the specic time of outcome
measurement on day 1, it would not be unreasonable to assume The mean change in health related quality of life, or
that the data covered the proportion of participants with moderate participant-expressed satisfaction with the procedure
to severe pain up to as well as beyond the 6 hour time point No data were reported for this outcome.
specied for this outcome. This was reported in 6/84 participants
in the sodium hypochlorite and 4/82 participants in the sodium
hypochlorite with proteolytic enzyme group: RR 1.5 (95% CI 0.4 Proportion of participants or samples with positive bacterial
to 5.0; P = 0.54). growth culture following the procedure and until 72 hours at
follow-up
Samples taken at the end of the rst appointment provided posi-
The mean change in health related quality of life, or tive bacterial cultures in 1/12 samples in the chlorhexidine group
participant-expressed satisfaction with the procedure compared to 7/12 in the saline group: RR 0.14 (95% CI 0.02 to
No data were reported for this outcome. 0.99; P = 0.05).
Change in periapical radiolucency as assessed by radiography 7. Sodium hypochlorite 5.25% with EDTA (17%)
or cone beam computed tomography (CBCT) at any versus sodium hypochlorite 1.3% with MTAD
clinically relevant time points and up to 1 year post- Only one study compared these two interventions (Torabinejad
endodontic treatment 2005).
Adverse events
None were reported in the single study included in this compari- Primary outcomes
son. The report provided only a graph plot of the average pain at time
points over the 7-day postoperative period in each intervention
group, but this could not be transformed into usable data to address
6. Sodium hypochlorite 1.3% with MTAD (doxycycline,
the prespecied outcomes for this review.
citric acid and Tween 80) versus normal saline
The effects of MTAD or saline as a nal irrigating rinse when added
to a conventional 1.3% sodium hypochlorite irrigant were com- Secondary outcomes
pared in only one study, but which did not satisfactorily address
No data were reported for any of the secondary outcomes.
any of this reviews prespecied outcomes (Malkhassian 2009).
Adverse events
Primary outcomes
No data were reported for these outcomes. None were reported in the single study included in this compari-
son.
Secondary outcomes
8. Chlorhexidine 0.2% versus normal saline
The effects of chlorhexidine (0.2%) were compared to normal
Proportion of participants with moderate to severe pain up saline in one study (Bebek 2009).
Primary outcomes
No data were reported for these outcomes.
The mean change in health related quality of life, or
participant-expressed satisfaction with the procedure
No data were reported for this outcome. Secondary outcomes
Proportion of participants or samples with positive bacterial

Proportion of participants with moderate to severe pain up
growth culture following the procedure and until 72 hours at
follow-up
Although the report concluded that vital bacterial counts decreased
after the active intervention, live bacteria were present in all of the
samples. No further data relevant to this outcome were reported.
The mean change in health related quality of life, or
participant-expressed satisfaction with the procedure
Change in periapical radiolucency as assessed by radiography No data were reported for this outcome.
or cone beam computed tomography (CBCT) at any
clinically relevant time points and up to 1 year post-
endodontic treatment Proportion of participants or samples with positive bacterial
No data were reported for this outcome. growth culture following the procedure and until 72 hours at
follow-up
Samples taken at the end of the rst appointment provided positive
Adverse events bacterial cultures in 65% of the samples in the chlorhexidine group
None were reported in the single study included in this compari- compared with 89% in the saline group but no further data were
son. reported.
Change in periapical radiolucency as assessed by radiography Overall completeness and applicability of
or cone beam computed tomography (CBCT) at any evidence
clinically relevant time points and up to 1 year post-
The studies included in this review which evaluated a range of in-
endodontic treatment
terventions including their strengths, combinations and methods
No data were reported for this outcome. and duration of administration, did not provide sufcient data to
enable fair and reasonable comparisons to be made for any one
single intervention against another for a specic outcome.
Adverse events Despite the fact that pain remains one of the primary reasons pa-
None were reported in the single study included in this compari- tients seek endodontic treatment, only four out of the eleven in-
son. cluded studies considered pain as an outcome. In this context it
was not possible to fully and reliably clarify the effects of these
interventions on any change in pain scores from pre to postoper-
ative time points nor to establish the likelihood of an association
between the incidence and severity of inter-appointment pain and
DISCUSSION the possible irritant effect of sodium hypochlorite on the periapi-
cal tissues.
It is unclear whether the data from the two studies which examined
Summary of main results similar interventions and reported a reduction in the proportion
Whilst recognising the challenges of conducting in vivo studies for of samples with positive cultures, rather than estimates of a reduc-
these interventions, the authors consider that the body of evidence tion in bacterial load, are able to provide reliable evidence for the
summarised in this review allows a limited set of conclusions to be effectiveness or otherwise of these interventions. Furthermore, the
drawn. From a single underpowered study there was no difference diversity of techniques used to estimate change in bacterial load in
in the level or incidence of moderate to severe inter-appointment several of the included studies provided data which was heteroge-
pain when a 5.25% sodium hypochlorite (NaOCl) irrigating so- nous and therefore did not enable ready comparisons to be made
lution was used alone or when it was combined with 3% hydro- between the interventions, or permit any correlation of this data
gen peroxide. A further underpowered study reported the level with the other bacteriological assessments, and thus limited the
of inter-appointment pain and incidence of swelling over a 3-day overall completeness of the evidence.
postoperative period and that there was no difference when 5%
sodium hypochlorite was used alone, or in combination with a pro-
teolytic enzyme, however, the evidence was considered weak and Quality of the evidence
unreliable. The self-assessed level of pain 6 hours postoperatively
was reported to be greater with a sodium hypochlorite (5.25%)
irrigating solution than with chlorhexidine (2%), however, these
conclusions could not be clearly substantiated and provide poor Limitations in study design and implementation
and unreliable evidence. Although study design in the included studies appeared to have
There was a reduction in the proportion of samples with posi- been at best adequate, our study-level assessments of the risk of
tive bacterial cultures when a nal rinse of chlorhexidine 2% was bias for a number of the domains in several of these studies revealed
compared to normal saline; or a higher concentration of sodium some of the limitations in their implementation, which have been
hypochlorite (5%) was compared to a lower concentration (1%). reported in the Risk of bias in included studies section of this
Similar results, i.e. proportionally fewer positive bacterial cultures, review. Wide variation in the inclusion criteria i.e. symptomatic
were obtained when a 20 minute irrigation with sodium hypochlo- versus asymptomatic teeth, and an appreciable baseline imbalance
rite (2.5%) was compared to chlorhexidine gel (2%), and a so- in level of pain between intervention groups in one study ensured
lution of chlorhexidine (0.2%) was compared to normal saline. a clinically diverse population of participants within and between
Although these results may be seen as potentially benecial, it re- the included trials (Bashetty 2010). Exclusion of participants after
mains unclear to what extent this reduction in positive bacterial randomisation and the challenges faced in the follow-up of partic-
cultures is associated with changes in patient-relevant outcomes ipants, in particular the large number of missing post-procedure
such as level of inter-appointment pain and incidence of swelling, questionnaires which assessed our primary outcomes, were several
particularly in the immediate postoperative period. of the limitations in a further study (Taschieri 2009).
None of the included studies provided longer term assessments Pain was one of the key outcomes in this review but its assessment,
of the radiologically assessed periapical status of the root treated which although not indicative of any intentional subversion by
tooth or reported any adverse effects associated with any of the the investigators, was somewhat disordered and the data was im-
irrigants. plausibly analysed in Bashetty 2010. The tool used for assessment
consisted of a numerical category scale which did not appear to Publication bias
have any empirical basis and exhibited no denitive metric prop- It would be reasonable to assume that the comprehensive elec-
erties and had also been used previously in Torabinejad 2005. The tronic searches employed in this review will have identied all ex-
trialists confused pain intensity assessment (none, mild, moderate isting randomised controlled trials and thereby helped to limit bias
and severe) with pain effect (not discomforting, discomforting but in the conduct of this review. However, even though only a small
bearable, severe discomfort) and unpleasantness, which are dis- number of trials were identied and an assessment of publication
tinctive attributes and not necessarily correlated. In addition, the bias could not be made, one cannot condently discount the pos-
assessment tool was based on one which had been developed for sible existence of some unpublished studies with either similar i.e.
use in a prior study (Habib 1990), but there was no indication of null to minimally benecial results or perhaps studies that report
how the tool had been modied and if it was subsequently retested side effects. In view of the low number of trials included in this
prior to application. review, an assessment of publication bias was not carried out.
Uncertainity continues to surround the reliability, accuracy and
sensitivity of laboratory tests used to quantify bacterial load
whether simply as colony forming unit (CFU) counts or using
Potential biases in the review process
more complex real-time quantitative-polymerase chain reaction
(RTQ-PCR) or epiuoresence microscopy (EFM) technology, We made every attempt to limit bias in the review process by ensur-
which was demonstrated by the inconsistency of results when dif- ing a comprehensive search for potentially eligible studies. The au-
fering sampling techniques and enumeration methods were com- thors independent assessments of study eligibility and subsequent
pared in several of the studies (Malkhassian 2009; Vianna 2006). data extraction minimised the potential for additional bias beyond
that detailed in the Risk of bias tables in the Characteristics of
included studies section. The incompleteness of some of the re-
Inconsistency ports and our inability to obtain clarication of certain trial details
Although none of the studies evaluated both of the key outcomes or to resolve ambiguities in the reports may have contributed to
of inter-appointment pain and microbiological counts, those stud- some bias in their assessment, but where these conditions applied
ies which reported pain failed to show any difference between the this was explicitly stated in the text of our review.
intervention groups as compared to those reporting microbiolog-
ical counts, implying a measure of inconsistency between the re-
sults of the two outcome measures. Agreements and disagreements with other
studies or reviews
We identied four additional reviews, only one of which carried
Indirectness of evidence
out a comprehensive literature search (Mohammadi 2009). Al-
Only indirect evidence, consisting of microbiological counts or though the investigators reached a number of conclusions on the
bacteriological cultures of samples taken from the root canal, was effectiveness of chlorhexidine as an endodontic irrigant they failed
available for most of the comparisons considered in the included to provide any indication of how studies, on which their conclu-
studies. Direct evidence relating to patient-relevant outcomes such sions were based, were selected, evaluated and could be designated
as pain and swelling was very limited and was covered by the as reliable sources of evidence. An earlier review of different as-
comparisons of sodium hypochlorite (5.25%) alone or combined pects of sodium hypochlorite use in endodontics also reached a
with hydrogen peroxide (3%), and by sodium hypochlorite (5%) wide range of conclusions but similarly did not critically appraise
with or without the proteolytic enzyme. the primary research nor provide clear evidentiary support for the
conclusions (Mohammadi 2008). A more recent literature review
(Singla 2011) of MTAD concluded that the irrigant had less than
Imprecision optimal antimicrobial activity which was largely in agreement with
The small number and low quality of studies that were included in the results reported in one of the studies which was evaluated in
this review provided very limited data which could be pooled. Data our systematic review (Malkhassian 2009).
were pooled for only one comparison which had been evaluated in The classic review of endodontic irrigants provides a valuable and
two of the included studies; one of which was assessed as high risk comprehensive background to their biochemical properties in ad-
and the other as unclear risk of bias. In both of these studies the dition to summarising what evidence for their effectiveness was
lack of precision in the effect of the intervention was illustrated by available at that time (Zehnder 2006). Six randomised controlled
the wide condence intervals about the point estimate (see Analysis trials have been conducted since and these have been included in
1.1). We have described the ndings and reported data from the this review. These studies provide opportunities for a re-evalua-
individual studies and have indicated where there is uncertainty tion of the strength and direction of the evidence underpinning
with the reliability of the evidence. some of those conclusions such that they can be supported by the
current best evidence available. This would apply in particular to cultures (1/12), in comparison with normal saline (7/12) when
the availability of some evidence indicating a possibility of higher used as a nal irrigant.
concentrations of sodium hypochlorite solutions to further reduce
the proportion of root canal samples with positive bacterial cul-
tures and without any apparent increase in either the incidence or Different concentration of endodontic irrigants
level of inter-appointment pain. against each other
One study compared three different concentrations (5%, 2.5%
and 1%) of sodium hypochlorite against each other. The higher
concentration of sodium hypochlorite (5%) was responsible for a
greater reduction in the number of positive bacterial samples when
AUTHORS CONCLUSIONS
compared to the lower concentrations, however, these results were
based on a single underpowered study.
Implications for practice
Eleven studies, which examined a total of 879 teeth in 851 partic-
ipants were included in this review. A range of interventions and Other endodontic irrigant protocols against each
comparisons were evaluated. Although there is a current trend to- other
wards the use of newer irrigants and combinations of irrigants, we The smear layer removing properties of MTAD and its effect on
conclude that there was insufcient clear evidence to support the postoperative discomfort were examined in two studies. Whilst
outright superiority of any specic individual irrigant or irrigating taking into account the possible confounding of the different con-
regime. centrations of sodium hypochlorite used, there was no difference
in mean postoperative pain scores in a comparison of the two pro-
tocols using either MTAD or EDTA (ethylenediaminetetra-acetic
Endodontic irrigants versus normal saline acid). However, the absence of a sample-size calculation suggests
Sodium hypochlorite (NaOCl) is currently the most commonly a degree of uncertainty if the study had in fact included a suf-
used irrigant in the preparation of root canals. Only one study, ciently large enough number of participants to detect a modest
which was conducted over 30 years ago and compared sodium and statistically signicant difference, if indeed there was one.
hypochlorite (5.25%) with normal saline, was identied. No dif- In a further but adequately powered study, vital bacterial counts
ferences were reported between the intervention groups for the decreased after a nal rinse of MTAD compared with normal saline
incidence or degree of inter-appointment pain. In addition to in- but live bacteria were present in all of the samples at the follow-
vestigating sodium hypochlorite (5.25%), this study also com- up visit.
pared hydrogen peroxide (3%) to normal saline and also failed None of the studies included in this review reported any adverse
to demonstrate any difference in inter-appointment pain between effects associated with the interventions and it was not clear if
these irrigants. there were none or that they were just not reported, and thus the
A comparison of the effects of chlorhexidine (0.2%) and normal safety prole for each of the irrigants remains unclear.
saline on bacterial growth indicated that only 65% of the samples Based on the results of this systematic review clinicians should take
taken from patients in the chlorhexidine group had positive bacte- into consideration both the benets and potential harms when
rial cultures compared to 89% from the normal saline group. The selecting irrigants to be used for non-surgical root canal treatment
investigators in this small study maintained that a positive bacte- in mature permanent teeth.
rial culture was a potential long-term surrogate outcome for the
failure of endodontic treatment. However, the strength of the as- Implications for research
sociation between these surrogate outcomes and treatment failure This systematic review demonstrates the potential of some en-
or success remains unclear and therefore it is not possible to infer dodontic irrigants to contribute to the success of non-surgical root
whether these differences were of clinical relevance to patients. canal treatment in mature permanent teeth. However, the extent
of their effects and whether these outweigh some of the potential
adverse consequences for patients is still unclear. Future research
Different type of endodontic irrigants against each should be directed towards well-designed randomised controlled
other trials which compare the different endodontic irrigants against
No major differences were found between the different types of each other and normal saline, and also include adverse conse-
endodontic irrigants used in most of the included studies. In a quences as outcomes. In addition, any trials comparing the effec-
single small study, chlorhexidine (2%) was added as a nal irrigant tiveness of chlorhexidine used as a stand alone or add-on irrigant
following a solution of sodium hypochlorite (1%) and was shown to sodium hypochlorite should also consider including costs as
to be more effective in reducing the number of positive bacterial outcomes. Sodium hypochlorite is well established as a preferred
irrigant not only because of its perceived effectiveness but also due results, and accurate judgements to be made about the risk of bias,
to its availability and low cost. Chlorhexidine and some of the and the overall quality of the evidence. Although it is uncertain
newer irrigants are more expensive and potentially more difcult whether reported quality mirrors actual study conduct, it is note-
to handle, both of which may be issues of importance and rele- worthy that studies with unclear methodology have been shown to
vance in resource-limited settings. produce biased estimates of treatment effects (Schulz 1995). Ad-
herence to guidelines, such as the CONSORT statement, would
Although in vitro studies may be easier to conduct they are unable help ensure complete reporting.
to demonstrate the effect of these irrigants on patient-relevant
outcomes. Further in vitro studies on endodontic irrigants that See Table 5 for further research recommendations based on the
are already in general use could be considered to be a waste of EPICOT format (Brown 2006).
resources, especially as there is an urgent need for clinical research
which has a clear focus on providing a better understanding of the
clinical effectiveness of these interventions, and which would be
best examined by studies carried out in vivo. ACKNOWLEDGEMENTS
Future randomised controlled trials must be well-designed, well- The review authors would like to thank the Cochrane Oral Health
conducted, and adequately delivered with subsequent reporting, Group and the peer reviewers and referees for their help in con-
including high-quality descriptions of all aspects of methodol- ducting this systematic review. We would like to acknowledge the
ogy. Reporting should conform to the Consolidated Standards of help we received from Abdulkadir Taskin, Sales Support Specialist,
Reporting Trials (CONSORT) statement (http://www.consort- Librarian at Mikro Bilgi Kayit Dagitim AS Turkey who translated
statement.org/) which will enable appraisal and interpretation of one of the studies in the Turkish language.
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Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical 2006;32(5):38998.

evidence of bias. Dimensions of methodological quality Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Bashetty 2010
Methods Randomised controlled trial. Setting: Department of Endodontics, Oxford Dental Col-
lege and Hospital, Bangalore, India. Date of commencement and duration not reported
Participants 40, gender not specied, age range 21 to 40 years

Teeth: 40 mandibular rst premolars
INCLUSION CRITERIA:
irreversible pulpitis, necrotic pulp and non vital
non vital teeth with acute periapical periodontitis
EXCLUSION CRITERIA:
history of allergy to specic medications
re-treatment cases
patients taking medications for pain
acute abscess
RANDOMISED: 20 (CHX); 20 (NaOCl)
WITHDRAWALS/LOSSES TO FOLLOW-UP:
No drop outs were reported
BASELINE CHARACTERISTICS:
Preoperative status number of participants by intervention group:
pain: 15/20 (CHX); 11/20 (NaOCl)
necrotic pulp: 4/20 (CHX);10/20 (NaOCl)
irreversible pulpitis: 8/20(CHX); 3/20 (NaOCl)
acute apical periodontitis: 7/20 (CHX); 8/20 (NaOCl)
Interventions Orthograde root canal treatment (2) visit, crown-down technique to an apical ISO size
of 30
Antiseptic preparation of teeth and operating eld unreported
INTERVENTION:
2% chlorhexidine solution (Consepsis, Ultradent USA)
COMPARISON:
5.25% sodium hypochlorite
Irrigation with 30-gauge Max-i-Probe syringe 3 mm short from apex, unclear if irrigant at
all instrument change, dried with paper points, dry sterile cotton pellet in pulp chamber
and closed with Cavit (ESPE Dental AG, Germany)
No inter-appointment intracanal medications placed
Outcomes Pain and discomfort participant-assessed with modied VAS rated 0 to 9 (9 =

severe) at 6 hours, 24 hours, days 4, 7 and reported as mean pain scores/intervention
group *
Clinical evaluation by investigator, to assess the status of the periapical region
using routine palpation and percussion tests at day 7 *
* Although pain was an outcome for this review the data reported as mean pain scores were
not amenable to transformation. See Types of outcome measures. No clinical evaluations
by the investigator were reported
Bashetty 2010 (Continued)
Notes
Risk of bias
Bias Authors judgement Support for judgement
Random sequence generation (selection Low risk Quote: random assignment by coin toss
bias) method was done by another endodontic
resident who enrolled participants and also
assigned them to their groups page 524
Comment: Probably done
Allocation concealment (selection bias) Unclear risk The method used to conceal the allocation
sequence, that is to determine whether in-
tervention allocations could have been fore-
seen in advance of, or during enrolment,
was not reported
Comment: Insufcient information to per-
mit a clear judgement
[Email to PI no response]
Blinding of participants and personnel Unclear risk Quote: this was a triple blinded study....
(performance bias) page 525
All outcomes Comment: The measures used to blind
study participants and personnel from
knowledge of which intervention a partic-
ipant received were not clearly reported
Both participants and personnel were out-
come assessors. Review authors judge it is
unclear if the outcome is likely to be inu-
enced by the lack of blinding
Insufcient information to permit a clear
judgement
Blinding of outcome assessment (detection Unclear risk Quote: this was a triple blinded study in
bias) which the study participants including pa-
All outcomes tients, endodontic residents and statistician
were blinded page 525
Comment: The measures used to blind the
outcome assessors (participants and per-
sonnel) from knowledge of which interven-
tion a participant received were not clearly
reported
Outcomes assessment:
participant-assessed pain
personnel-assessed clinical evaluation
Lack of blinding is likely to exert an in-
Bashetty 2010 (Continued)
uence on outcome measurement, but in-

sufcient detail reported to permit a clear
judgement
Incomplete outcome data (attrition bias) Low risk No evidence of missing or incomplete data
All outcomes due to attrition or exclusions for the pri-
mary outcome in the study
Selective reporting (reporting bias) High risk Study protocol unavailable but one of the
outcomes listed in the methods section of
the study, and of interest in this review, was
not reported i.e. clinical evaluations; to as-
sess the status of the periapical region using
routine palpation and percussion tests at
day 7 (page 524)
Comment: Report of the study not free of
selective outcome reporting
Other bias Unclear risk Pain was the principal outcome, not all
teeth asymptomatic and not balanced
across intervention groups. Possible impact
of baseline imbalance in pain, a principal
outcome measure, on the intervention ef-
fect-estimate is unclear
Bebek 2009
Methods Randomised controlled trial. Setting: Department of Endodontics, School of Dental

Medicine, University of Zagreb, Croatia. Date of commencement and duration not
reported
Participants 44 (13 male, 31 female), age range 21 to 63 years

INCLUSION CRITERIA:
single-rooted asymptomatic (no pain) teeth
pulpal necrosis and apical periodontitis
EXCLUSION CRITERIA:
periodontal pockets > 4 mm
root fracture
mobile
use of antibiotics in prior 4 weeks
RANDOMISED: 44 (25 + 19)
None reported
Interventions Orthograde root canal treatment (2) visit, step-back technique

Antiseptic preparation of teeth and operating eld with 10% povidone-iodine solution
INTERVENTION:
0.2% chlorhexidine solution (Plivasept Glukonat, Pliva Zagrebl) (25)
Bebek 2009 (Continued)
COMPARISON:
0.9% saline solution (19)
Irrigation three times (27-gauge needle syringe) during instrumentation with 2 mL 0.
2% CHX solution or 2 mL of saline for 30 seconds, dried with paper points, sterile
cotton pellet in canal orice and sealed with Cavit G
No intracanal medications placed
Obturation after 48 hours
Outcomes Bacterial counts identication by macro and micromorphology no further

details reported: Sampling at access before irrigation and 48 hours after biomechanical
preparation prior to obturation
Notes No other irrigant used other than 5.25% NaOCl after last sample and prior to obturation
Risk of bias
Random sequence generation (selection Low risk Quote: randomly selected... randomly di-
bias) vided in two groups page 1160
Comment: Insufcient information in the
report to make a clear judgement
Following email communication with the
PI:
envelopes with numbers, in a box and the
patient selected an envelope
Allocation concealment (selection bias) Low risk The method used to conceal the allocation
was not reported
PI:
External co-worker held code
Blinding of participants and personnel Unclear risk The measures used to blind study partic-
(performance bias) ipants and personnel from knowledge of
All outcomes which intervention a participant received
were not reported
No participant-assessed outcomes and un-
reported if personnel were blinded or were
involved in data analysis. Review authors
judge it is unclear if the outcome is likely to
be inuenced by the uncertainty in blind-
Bebek 2009 (Continued)
ing
Blinding of outcome assessment (detection Unclear risk Unclear if investigators were involved with
bias) the microbiologic evaluations or data anal-
All outcomes ysis. Review authors judge it is unclear if
the outcome assessment is likely to be in-
uenced by the uncertainty in blinding
All outcomes due to attrition or exclusions for the pri-
mary outcome in the study
Selective reporting (reporting bias) Low risk Although the study protocol was unavail-
able and the outcomes sought were not
clearly specied in the methods section
there was no evidence of selective reporting
Other bias Low risk There were no concerns about bias not ad-
dressed in the other domains in this tool
Ercan 2004
Methods Randomised controlled trial. Setting: University of Dicle, Diyarbakir City, Turkey. Date
of commencement and duration not reported
Participants 20 participants gender unspecied, age range 20 to 52 years

30 incisors and premolars single root canal
INCLUSION CRITERIA:
not clearly specied other than pulpal necrosis, apical pathosis or both
only teeth with single canal
EXCLUSION CRITERIA:
not specied
RANDOMISED: 30 (15 + 15) teeth
None reported
Interventions Orthograde root canal treatment (2) visit, step-back technique

Antiseptic preparation of teeth and operating eld with 10% povidone-iodine solution
INTERVENTION:
2% chlorhexidine solution (Farmacia Ensino, FCFRP USP Brazil)
COMPARISON:
5.25% sodium hypochlorite solution (Clorox Oakland Ca USA)
Irrigation with 2 mL of either intervention or comparison at instrument change, dried
with paper points, dry sterile cotton pellet in pulp chamber and closed with Cavex
(Holland)
No intracanal medications placed
Obturation after 48 hours
Ercan 2004 (Continued)
Outcomes Bacterial counts (CFU) Enterococcus faecalis, Actinomyces israelii, Staphylococcus

aureus and Streptococcus salivarius
First appointment: Sampling at access before irrigation, after irrigation and 48 hours
after biomechanical preparation prior to obturation
Notes
Risk of bias
Random sequence generation (selection Unclear risk Quote: Randomly divided into two
bias) groups... page 84
was not reported
were not reported
reported if personnel were blinded or were
involved in data analysis. Review authors
judge it is unclear if the outcome is likely to
be inuenced by the uncertainty in blind-
ing
All outcomes ysis. Review authors judge it is unclear if
the outcome assessment is likely to be in-
uenced by the uncertainty in blinding
All outcomes due to attrition or exclusions for the out-
comes in the study
Ercan 2004 (Continued)
able and the outcomes sought were not
clearly specied in the methods section
there was no evidence of selective reporting
Other bias High risk Half of the participants had multiple teeth
randomised within this study. Given the
clustered outcome data, it was unclear if
the teeth were randomised individuals, or
subject to contamination
Harrison 1978
Methods Randomised controlled trial conducted in USA. Setting date of commencement and
duration not reported
Participants Endodontic referrals

253 participants, age unspecied
Maxillary: anterior (80), premolar (33), molar (33)
Mandibular: anterior (18), premolar (23), molar (66)
Vital teeth (78), non vital teeth (175), 138/253 teeth previously opened but not instru-
mented
INCLUSION CRITERIA:
completely symptom free
canals closed to oral cavity
EXCLUSION CRITERIA:
None reported
RANDOMISED: 253
No drop outs were reported
Interventions Orthograde root canal treatment (2) visit, 2 dentists

INTERVENTIONS:
Group 1 = 86
Normal saline 1 mL irrigant used between each instrument
Group 2 = 92
5.25% NaOCl 1 mL irrigant used between each instrument
Group 3 = 75
3% H2 O2 0.5 mL and 5.25% NaOCl 0.5 mL used between each instrument
Canal dried with sterile paper cones, no inter-appointment intracanal medication, closed
with cotton pellet and Cavit
Follow-up visit 2 to 14 days and obturation if no pain
Outcomes PRIMARY OUTCOME:

Assessed at second appointment within 2 to 14 days
Inter-appointment pain (none, slight or moderate to severe)
Pain incidence (no pain versus pain)
Harrison 1978 (Continued)
Pain degree (no pain versus slight pain versus moderate to severe pain)
Type of measurement tool unreported, not clear if self-assessed or participant adminis-
tered
Rated as
Slight: any brief discomfort, no medication, no delay with obturation at follow-
up appointment
Moderate to severe: required medication
Notes
Risk of bias
Random sequence generation (selection Unclear risk Quote: patients were randomly placed
bias) into three groups according to the type of
irrigant to be used during canal prepara-
tion page 7
was not reported
were not reported
Comment: Only participant-assessed out-
comes, unclear whether the outcome is
likely to be inuenced by a lack of blinding
Blinding of outcome assessment (detection Unclear risk Participants were outcome assessors, un-
bias) clear whether the outcome assessment is
All outcomes likely to be inuenced by a lack of blinding
comes in the study
able there was no evidence of selective re-
porting. Outcomes listed in the methods
section were comparable to those reported
Harrison 1978 (Continued)
Malkhassian 2009
Methods Randomised controlled trial. Setting: Graduate Endodontics Clinic at the Faculty of
Dentistry, University of Toronto, Canada. From November 2005 to December 2006
Participants 30 (15 male, 15 female), age 25 to 78 (mean 51.9) years

Maxillary 15 (6 anterior, 9 premolars)
Mandibular 15 (4 anterior, 7 premolars, 4 molars)
INCLUSION CRITERIA:
age > 18 years, ASA I or II (ASA 1963)
adequate remaining crown structure
negative response to cold test
radiographic evidence of apical periodontitis
gingival probing depth 4 mm
EXCLUSION CRITERIA:
previous endodontic treatment
maxillary molar
radiographic evidence of internal/external root resorption
pregnancy, nursing mother
ASA III or higher
allergy to chlorhexidine, doxycycline, citric acid, Tween 80
No losses reported
One sample in each group excluded from analysis
Interventions Orthograde root canal treatment (2) visit 7 days apart

Antiseptic preparation of teeth 30% H2 O2 and 5% tincture of iodine and inactivated
with 5% sodium thiosulphate
FIRST VISIT:
Both groups: At instrument change canal irrigated 1.5 mL NaOCl 1.3% (30-gauge
needle) < 10.5 mL
INTERVENTION (nal rinse): MTAD: doxycycline, citric acid and Tween 80 (BioPure
MTAD Dentsply Tulsa USA)
1 mL solution delivered in 5 mL (30-gauge needle) syringe, with up-down motion and
manual agitation with #15 K-le. After 5 minutes further 4 mL of MTAD and nal
rinse 3 mL saline
COMPARISON (nal rinse): Normal saline
Inter-appointment intracanal medication: Both groups CHX gel (2%) injected into
canal. Sterile sponge pellet in pulp chamber, closed resin modied glass-ionomer (Photac
Fil ESPE St Paul USA)
SECOND VISIT:
Canal ushed with 3 mL saline, CHX gel inactivated 3 mL L-lecithin (Sigma Aldrich),
ushed with saline. Irrigated with 1.3% NaOCl
Obturated with Gutta Percha
Malkhassian 2009 (Continued)

Bacterial counts by epiuorescence microscopy (EFM) of residual bacteria
expressed as mean EFM bacterial densities
Absence or presence (CFU) of bacterial growth expressed as number of bacteria per
microlitre RCV
Sampling (rst appointment), at access at preliminary ling, at completion of ling.
Sampling (second appointment), at access, after ushing, after nal irrigation
Notes
Risk of bias
Random sequence generation (selection Low risk Quote: randomly assigned ...by drawing
bias) from a pool of lots page 1484
Allocation concealment (selection bias) Low risk Quote: preparation of the solutions car-
ried out in advance by a laboratory techni-
cian in advance and delivered to the treat-
ment provider page 1484
Comment: Reasonable attempts made to
ensure intervention allocations could not
have been foreseen in advance of, or during,
enrolment
Blinding of participants and personnel Low risk Quote: the saline control was colored to
(performance bias) mimic MTAD page 1484
All outcomes Comment: No participant-assessed out-
comes, and reasonable attempts made to
blind personnel
Blinding of outcome assessment (detection Low risk Adequate measures taken to blind person-
bias) nel who were responsible for the outcome
All outcomes assessment
Incomplete outcome data (attrition bias) Low risk One sample in each group excluded from
All outcomes analysis (no bacterial growth in one and
contamination of culture plate). Balanced
across intervention groups and review au-
thors judge the proportion of missing data
is unlikely to have an impact on the inter-
vention effect estimate
No evidence of other missing or incomplete
data due to attrition for the outcomes in
the study
Malkhassian 2009 (Continued)
Other bias Low risk Sponsorship included Dentsply Tulsa Den-

tal Specialities the level and extent of which
was not stated. But there were no concerns
about bias not addressed in the other do-
mains in this tool
Ringel 1982
Methods Randomised controlled trial conducted in USA. Setting date of commencement and
duration not reported
Participants 52 participants (60 teeth), no further demographic details reported

INCLUSION CRITERIA:
asymptomatic
uniradicular
necrotic pulps
EXCLUSION CRITERIA:
none reported
None reported
Interventions Orthograde endodontic treatment (3) visit

Antiseptic preparation of teeth and operating eld with 30% H2 O2 for 1 to 2 minutes
INTERVENTION:
0.2% chlorhexidine gluconate solution (30)
CONTROL:
2.5% sodium hypochlorite (30)
FIRST VISIT:
Initial irrigation for a minimum of 30 minutes, further instrumentation, irrigation sterile
de-ionised water, canal dried with paper points, sterile cotton pellet in pulp chamber,
sealed with Cavit G and zinc phosphate cement
SECOND VISIT:
Similar irrigation protocol
THIRD VISIT:
Repeat irrigation protocol and obturation if pain and symptom free (up to maximum of
5 visits)
No inter-appointment intracanal medications placed

Dental lings and paper point specimens taken pre and post-irrigation at each
visit for aerobic/anaerobic culture
The ability of irrigants to yield negative cultures according to the number of
Ringel 1982 (Continued)
appointments
Notes Supported by Grant-in-Aid of Research from the Endowment and Memorial Founda-
tion of the American Association of Endodontists
Risk of bias
Random sequence generation (selection Unclear risk Quote: Thirty teeth were randomly as-
bias) signed to the experimental group, and
the other 30 were assigned to the control
group
was not reported
were not reported
reported if the personnel were blinded. Re-
view authors judge that it is unclear if the
outcome is likely to be inuenced by the
lack of blinding
All outcomes ysis. Review authors judge that it is unclear
if the outcome measurement is likely to be
inuenced by the lack of blinding
comes in the study
Ringel 1982 (Continued)
Other bias Unclear risk Eight of the participants had multiple teeth
randomised within this study. Given the
clustered outcome data, it was unclear if
the teeth were randomised individuals, or
subject to contamination
Soares 2006
Methods Randomised controlled trial. Setting: Clinic of Endodontics of Federal University of

Vales do Jequitinhonha e Mucuri (Brazil). Date of commencement and duration not
reported
Participants 83 gender unspecied, age range 14 to 53 years

93 anterior teeth and premolars with advanced carious lesions, necrotic pulp and peri-
apical radiolucencIes (111 root canals)
INCLUSION CRITERIA:
asymptomatic
EXCLUSION CRITERIA:
none specied
RANDOMISED:
canals randomly assigned to 3 groups: I (n = 39), II (n = 36) and III (n = 36), with 31,
32 and 30 teeth, respectively
None reported
Interventions Orthograde endodontic treatment, only one visit reported. Step-down followed by step-
back technique
Antiseptic preparation of operating eld 5% iodated alcohol solution and neutralised
with alcohol/ether
INTERVENTIONS:
Group 1: 1% NaOCl
Group 2: 2.5% NaOCl
Group 3: 5% NaOCl
Canals explored, irrigated with 3 mL of either solution in between les. Removal of

smear layer 3 mL EDTA (17%), irrigation with NaOCl and 5 mL sterile saline for 5
minutes

Microbiological evaluation of micro-organisms, paper point specimens taken pre
and post-irrigation
Notes
Risk of bias
Soares 2006 (Continued)
Random sequence generation (selection Unclear risk Quote: randomly assigned.. page 311
bias) Comment: Insufcient information in the
was not reported
were not reported
lack of blinding
comes in the study
Taschieri 2009
Methods Randomised controlled trial. Setting: multicentre two clinic (Milan, Rome) in Italy.
Enrollment of participants June 2007 to June 2008
Participants 200 (127 Milan clinic, 73 Rome clinic), gender, age and tooth unreported
INCLUSION CRITERIA:
> 18 years, ASA I or II ASA 1963
with pulpal and/or periradicular pathosis
only single visit procedure
EXCLUSION CRITERIA:
taking pain medications i.e. anti-inammatory drugs or antibiotics
pregnant females
history of allergy e.g. NaOCl
root canal retreatment
RANDOMISED: 200, active intervention (101), control (99)
17 excluded from analysis (non single-visit), active intervention (3/101), control
(10/99) [gure on page 417 claried with PI]
17 excluded from analysis (protocol deviation failed to return questionnaire),
active intervention (10/94), control (7/89)
Final analysis: active intervention (84/101), control (82/99) [per protocol analysis 17%
drop out]
Interventions Orthograde root canal treatment single visit including canal obturation
INTERVENTION:
solution of NaOCl (Niclor 5, Giovanni Ogna & gli S.p.A.,Muggi, Milan, Italy)
plus enzyme (Bacillus subtilis Protease 9014-01-1, Giovanni Ogna & gli S.p.A)
CONTROL:
solution of NaOCl (Niclor 5, Giovanni Ogna & gli S.p.A.,Muggi, Milan, Italy)
Canals explored, irrigated with either solution between les (quantity/volume timing un
reported). Removal of smear layer, nal irrigation EDTA 17% (Giovanni Ogna & gli
S.p.A.), for 2 minutes
Canals dried with sterile paper points, ushed assigned irrigating solution. Dried and
obturated gutta percha
Outcomes Postoperative pain and tissue swelling by self-assessed questionnaire (5-point

Likert-type scale: 1 = none to 5 = very much) daily for a week
Pain-killer and antibiotic usage
Pre and postoperative radiographs to ensure no extrusion of root lling
Notes
Risk of bias
Random sequence generation (selection Low risk Quote: The patients in each center were
bias) randomly assigned to two different treat-
ment groups page 416
Taschieri 2009 (Continued)

PI:
Quote: a computer-generated random se-
quence was adopted...
Comment: Judgement amended to low
risk
was not reported
PI:
Quote: Each of the two centers received
a number of labeled samples, numbered
in sequence, containing the irrigating solu-
tion. Neither the operators nor the patients
were aware of the type of irrigant used.
Only the biostatistician that generated the
sequence and the manufacturer which pro-
vided the labelled samples were aware of it.
The code was held by the manufacturer
risk
Blinding of participants and personnel Low risk Quote: To ensure masking of the oper-
(performance bias) ators, the endodontic treatment was per-
All outcomes formed using a black syringe page 417
Comment: Although only participant-as-
sessed outcomes, blinding of both partici-
pants and investigators appears to be ade-
quate
Blinding of outcome assessment (detection Low risk Participants were outcome assessors, and
bias) blinding of outcome assessment appears to
All outcomes be adequate
Incomplete outcome data (attrition bias) High risk Available case analysis, incomplete data for
All outcomes 34/200 (17%) due to protocol deviation
Only 166/183 pain outcomes assessments
were returned
Taschieri 2009 (Continued)

albeit with minimal data
Other bias High risk Quote: 17 required a multiple-visit treat-

ment and had to be excluded page 418
Comment: Other potential sources of bias
were those associated with trial conduct i.
e. subjects being randomised in error as a
result of poor screening methodology or
inadequate follow-up resulting in missing
data
Torabinejad 2005
Methods Randomised controlled trial. Setting: Endodntic residency clinic of Loma Linda Uni-
versity (USA). Date of commencement and duration not reported. Conducted by 7
endodontic residents
Participants 73 teeth (symptomatic and asymptomatic) unclear if single or multi-rooted

INCLUSION CRITERIA:
> 18 yr
no medications affecting pain perception, inammation, or infection
EXCLUSION CRITERIA:
pregnant patients
allergy to any of the interventions
root canal retreatment
concurrent use of drugs that might increase or decrease the effects of the test
solutions
RANDOMIZED: 73 (group 1 = 40, group 2 = 33)
None reported
Interventions Orthograde root canal treatment two visit, canal obturation at 7 days
Antiseptic preparation of teeth and operating eld unreported. Passive step back tech-
nique including use of rotary instruments
GROUP 1:
solution of NaOCl (5.25%) 1 mL between les, EDTA 17% for 1 minute,
followed by 5 mL rinse NaOCl (5.25%)
GROUP 2:
solution of NaOCl (1.3%) 1 mL between les, MTAD for 5 minutes
Canals dried with sterile paper points, sterile cotton pellet in pulp chamber, sealed with
Cavit no inter-appointment canal medication
Outcomes Pain and severity of discomfort participant-assessed with modied VAS rated
0 to 9 (9 = severe) at 6, 12, 18, 24 hours and days 2 to 7 and reported as mean pain
scores/intervention group*
* Although pain was an outcome for this review the data reported in this study as mean
pain scores were not amenable to transformation (see Types of outcome measures)
Torabinejad 2005 (Continued)
Notes
Risk of bias
Random sequence generation (selection Low risk Quote: At random, canals were cleaned
bias) and shaped and at random each resident
assigned his or her patients to two differ-
ent protocols for debriding the root canals
page 172
PI:
Quote: we used a randomization table...
risk
Allocation concealment (selection bias) Unclear risk Nothing reported

PI:
Nothing further reported
Blinding of participants and personnel Low risk Nothing reported

(performance bias) Following email communication with the
All outcomes PI:
Quote: masked syringes and labelled nu-
merically...
risk
Blinding of outcome assessment (detection Low risk Participants were outcome assessors, and
bias) blinding of outcome assessment appears to
All outcomes be adequate
comes in the study
albeit with minimal data
Other bias Unclear risk Potential confounding by NaOCl concen-

tration, non direct comparison for the ef-
fectiveness of MTAD
Torabinejad 2005 (Continued)
Pain was the principal outcome, not all

teeth asymptomatic and not balanced
across intervention groups. Possible impact
of baseline imbalance in pain, a principal
outcome measure, on the intervention ef-
fect-estimate is unclear
Vianna 2006
Methods Randomised controlled trial. Setting: Piracicaba Dental School SP (Brazil). Date of
commencement and duration not reported
Participants 32 gender unreported, age range 19 to 63 years

INCLUSION CRITERIA:
single-rooted
asymptomatic
not responsive to sensitivity testing
EXCLUSION CRITERIA:
antibiotic medication in prior 3 months
retreatment
None reported
Interventions Orthograde root canal treatment appears to be single visit including canal obturation
Antiseptic preparation of teeth and operating eld with 30% H2 O2 for 30 seconds, 2.
5% NaOCl for 30 seconds and inactivated with 5% sodium thiosulphate
INTERVENTION:
2.5% NaOCl solution canals irrigated with 5 mL in between les. Inactivation
with 5 mL 0.5% sodium thiosulphate for 1 minute
CONTROL:
2% CHX gel canals irrigated 1 mL (27-gauge needle), followed by 4 mL saline.
Inactivation with 5 mL; 0.5% Tween 80 and lecithin for 1 minute

Evaluation of bacterial load by the RTQ-PCR and total number of CFU by
conventional culture methods, paper point specimens taken pre and post-
chemomechanical procedure
Notes
Risk of bias
Random sequence generation (selection Low risk Quote: ...were randomly divided into two
bias) groups.. page 486
Vianna 2006 (Continued)

PI:
Quote: The randomisation was per-
formed using permuted block of randomi-
sation (8 blocks), each block had equal
amount 4 samples per 2 per group, the
blocks were chosen at random and treat-
ments allocated according to that block un-
til complete the required sample size (32)
risk
was not reported
PI:
Quote: After the randomisation, treat-
ment options were placed in sealed en-
velopes and opened only during the session
after access cavity
risk
were not reported
lack of blinding
comes in the study
Vianna 2006 (Continued)
Zamany 2003
Methods Randomised controlled trial. Setting: referrals to the Department of Endodontology,

University of Connecticut School of Dental Medicine, USA. Date of commencement
and duration not reported
Participants 24 gender unreported, age range 12 to 70 years

INCLUSION CRITERIA:
radiographically demonstrable apical periodontitis
single-rooted tooth with a necrotic pulp
EXCLUSION CRITERIA:
antibiotic medication previous 2 weeks
tooth unsuitable for good rubber dam isolation
retreatment
presence of a sinus tract
no growth in the initial culture
None reported
Interventions Orthograde root canal treatment (2) visit. Crown-down technique

Antiseptic preparation of tooth 30% H2 O2 and 5% tincture of iodine on the operating
eld
INTERVENTION:
Canal instrumentation; irrigated 1% NaOCl, dried and inactivated 5 mL 10%
sodium thiosulfate. 2% CHX, canals irrigated 4 mL delivered in a syringe 30 seconds
agitated with a le
CONTROL:
Canal instrumentation; irrigated 1% NaOCl, dried and inactivated 5 mL 10%
sodium thiosulfate. Normal saline, canals irrigated 4 mL delivered in a syringe 30
seconds agitated with a le
Inactivation with 3 mL 0.3% L--lecithin in 3%Tween 80 (Sigma, St Louis, Mo)
Canal dried inter-appointment dressing Ca(OH)2 paste (Dental Therapeutics, Nacka,
Sweden)
Revisit appointment for obturation within 7 to 10 days

Microbiological evaluation of bacterial load, paper point specimens taken pre and
post-chemomechanical procedure (3 time points)
Number of cultures with growth
Zamany 2003 (Continued)
Notes
Risk of bias
Random sequence generation (selection Low risk Quote: a dental assistant randomly as-
bias) signed the tooth... by drawing from a pool
of lots. page 579
was not reported
PI:
Quote: dental reception personnel not di-
rectly Involved with the study was trained
to use a list of numbers and randomly as-
sign research patients into two groups A or
B
risk
Blinding of participants and personnel Low risk Quote: the operator was blinded to the
(performance bias) solutions being used page 579
All outcomes Comment: The measures used to blind
study participants and personnel from
knowledge of which intervention a partici-
pant received were not clearly reported. In-
sufcient information in the report to per-
PI:
Quote: the dental assistant would provide
the operator with a container of unmarked
syringes either A or B
As there were no participant-assessed out-
comes and it appears that reasonable at-
tempts were made to blind study personnel
the judgement was amended to low risk
Blinding of outcome assessment (detection Low risk Although unclear if the investigators were
bias) involved with the microbiologic evalua-
All outcomes tions or data analysis, the review authors
Zamany 2003 (Continued)
judge that this is unlikely to inuence out-

come measurement
Incomplete outcome data (attrition bias) Low risk Although minimally reported all outcomes
All outcomes data appear to have been presented in the
report of the study
ASA = American Society of Anesthesiologists Physical Status Classication System [Class I healthy patient to Class V moribund patient
not expected to survive 24 hours]; Ca(OH)2 = calcium hydroxide; CFU = colony forming units; CHX = chlorhexidine solution;
EDTA = ethylenediaminetetra-acetic acid; H2 O2 = hydrogen peroxide solution; NaOCl = sodium hypochlorite solution; RCV =
root canal volume; RTQ-PCR = real-time quantitative-polymerase chain reaction; Tween 80 = non ionic surfactant and emulsier;
VAS = visual analogue scale
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bayirli 1968 Comparative study, non RCT [translated from the Turkish by Abdulkadir Taskin, Librarian at Mikro Bilgi Kayit
Dagitim AS Turkey]
Bonsor 2006 CCT, teeth randomly selected, no evidence of random allocation to intervention
Gondim 2010 Comparison of two different irrigation devices, same irrigant for both groups
Huffaker 2010 Comparison of irrigation devices, same irrigant for both groups
Paudel 2011 After email communication with PI participants allocated by alternation: CCT
RCT = randomised controlled trial

CCT = controlled clinical trial (quasi-randomised)
Characteristics of studies awaiting assessment [ordered by study ID]
Blome 2008
Methods Randomised controlled trial. Setting: Department of Operative Dentistry and Periodontology at the University of
Bonn Germany. Date of commencement and duration not reported
Participants 40 (18 male, 22 female), age range 21 to 77 years referred for root canal treatment
28 single root canal; 12 multi-rooted teeth, 2 with 2 canals and 10 with three canals
2 groups; without previous endodontic treatment, re-treatment
INCLUSION CRITERIA:
single or multi-rooted tooth
radiographic evidence of chronic apical periodontitis
teeth caries-free at the time of endodontic treatment
nil response to sensitivity testing
no pocketing > 4 mm
EXCLUSION CRITERIA:
antibiotic treatment previous 3 months
RANDOMISED:
2 groups; without previous endodontic treatment, re-treatment (40); 10 in each group randomised to either inter-
vention
Interventions As part of the chemomechanical root canal preparation, in each group 10 teeth were randomly assigned to irrigation
with either 2% sodium hypochlorite or 0.1% chlorhexidine for 30 minutes
Outcomes Focus on adjunctive benets of inter-appointment intracanal medication, no IPD available for the 10 participants in
each group
Notes [Email to PI 28th July 2011 no response]

This study was supported by GABA International a European branded manufacturer of innovative top-quality oral
care products
IPD = individual patient data
DATA AND ANALYSES
Comparison 1. Sodium hypochlorite versus chlorhexidine
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 The proportion of teeth with 2 62 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.34, 1.56]
positive bacterial culture
following intervention (up to
48 hrs)
Analysis 1.1. Comparison 1 Sodium hypochlorite versus chlorhexidine, Outcome 1 The proportion of teeth
with positive bacterial culture following intervention (up to 48 hrs).
Review: Irrigants for non-surgical root canal treatment in mature permanent teeth
Comparison: 1 Sodium hypochlorite versus chlorhexidine
Outcome: 1 The proportion of teeth with positive bacterial culture following intervention (up to 48 hrs)
Study or subgroup Favours NaOCl Chlorhexidine Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Ercan 2004 4/15 3/15 27.3 % 1.33 [ 0.36, 4.97 ]
Vianna 2006 4/16 8/16 72.7 % 0.50 [ 0.19, 1.33 ]
Total (95% CI) 31 31 100.0 % 0.73 [ 0.34, 1.56 ]

Total events: 8 (Favours NaOCl), 11 (Chlorhexidine)
Heterogeneity: Chi2 = 1.38, df = 1 (P = 0.24); I2 =27%
Test for overall effect: Z = 0.82 (P = 0.41)
Test for subgroup differences: Not applicable
0.01 0.1 1 10 100

Favours NaOCl Favours chlorhexidine
ADDITIONAL TABLES
Table 1. Contact with investigators of included studies
Study ID Response Additional comment

Yes or No
Bashetty 2010 No Email: June 29th drbashetty@gmail.com
Bebek 2009 Yes Email: Sept 15th bago@sfzg.hr

Response Sept 21st. patients selected/chose numbered envelopes from box. Ex-
ternal co-worker held code
Blome 2008 No Email: July 28th BennyBlome@gmx.net
Ercan 2004 No Email: July 11th ertugrulercan@hotmail.com
Harrison 1978 No Unable to contact PI
Taschieri 2009 Yes Email: July 24th massimo.delfabbro@unimi.it

Response July 2nd further details re: sequence generation and concealment
Response Aug 2nd
[Data in Fig 1 Pg 417 claried with PI] 17 excluded from analysis (non single-
visit)
Torabinejad 2005 Yes Email: December 17th mtorabinejad@llu.edu

Response December 17th further details re: sequence generation and blinding no
response re: allocation concealment
Soares 2006 No Email: July 18th and August 20th janirsoares@citell.com.br
Vianna 2006 Yes Email July 24th m.vianna@eastman.ucl.ac.uk

Response: July 25th
The randomisation was performed using permuted block of randomisation (8
blocks), each block had equal amount 4 samples per 2 per group, the blocks were
chosen at random and treatments allocated according to that block until complete
the required sample size (32). The randomisation was based on permuted block as
described by Beller et al 2002 (The Medical Journal of Australia 177: 565-567)
After the randomisation, treatment options were placed in sealed envelopes and
opened only during the session after access cavity.
Zamany 2003 Yes Email July 27th and July 30th safavi@nso1.uchc.edu
Response to blinding, allocation sequence concealment and clarication of inter-
ventions
Table 2. Table of review outcomes
Primary outcomes Secondary outcomes Adverse effects
Moderate to New or wors- Moderate to Health related Positive bacte- Change in pe-
severe pain af- ening signs severe pain up quality of life, rial growth riapical radi-
ter 72 hours to and/or symp- to 6 hours or patient sat- culture olucency
14 days (pro- toms or of in- (proportion of isfaction until 72 hours
portion of par- ammation or participants) (proportion of
ticipants) loss of func- participants)
tion (propor-
tion of partici-
pants)
Bashetty 2010 - - - - - - -
Bebek 2009 - - - - Data - -
Ercan 2004 - - - - Data - -
Harrison Data Data - - - - -

1978
Malkhassian - - - - Data - -
2009
Ringel 1982 - - - - Data - -
Soares 2006 - - - - Data - -
Taschieri Data Data Data - - - -

2009
Torabinejad - - - - - - -
2005
Vianna 2006 - - - - Data - -
Zamany 2003 - - - - Data - -
Table 3. Proportion of participants with inter-appointment pain (Harrison 1978)
Pain rating Saline 5.25% NaOCl H2 02 combined with NaOCl
None 51/86
62/92 53/75
Slight 28/86 24/92 18/75
Table 3. Proportion of participants with inter-appointment pain (Harrison 1978) (Continued)
Moderate to severe 7/86 6/92 4/75
Table 4. Inter-appointment pain comparison of NaOCl, NaOCl with H2 O2 and saline (Harrison 1978)
Group 1 Group 2 RR 95% CI P value
Saline Sodium hypochlorite 1.25 (0.4 to 3.7) 0.68
Saline Sodium hypochlorite 1.53 (0.5 to 5.0) 0.49

with hydrogen peroxide
Sodium hypochlorite Sodium hypochlorite 1.22 (0.4 to 4.2) 0.75

with hydrogen peroxide
H2 O2 = hydrogen peroxide; NaOCl = sodium hypochlorite
Table 5. Research recommendations based on a gap in the evidence of the effects of irrigants for non-surgical root canal
treatment in mature permanent teeth
Core Issues to consider Status of research for this review

elements
Evidence (E) What is the current state of the evidence? This systematic review identied eleven randomised
controlled trials. Four partially addressed one of the
main outcomes i.e. inter-appointment pain but pro-
vided limited evidence for the comparative effects of the
irrigants considered
There was no difference in the incidence or
degree of inter-appointment pain when sodium
hypochlorite (5.25%) was used alone or when
combined with hydrogen peroxide (3%), or when
compared with normal saline.
Although the occurrence of pain and swelling at
two days post-intervention was reportedly not
dissimilar between sodium hypochlorite (5%) with
and without a proteolytic enzyme, the evidence should
be considered unreliable due to study protocol
deviation in a large number of participants and
missing outcome data.
Self-reported level of pain at 6 hours was greater
with sodium hypochlorite (5.25%) irrigating solution
than with chlorhexidine (2%). However, these
conclusions could not be substantiated in view of the
high likelihood of bias as result of baseline imbalance
in the study and, because they were based on outcome
treatment in mature permanent teeth (Continued)
measures which used an assessment scale without any

empirical basis i.e. capable of reecting the qualitative
or quantitative dimensions of pain.
Evidence for the comparative effects of several irrig-
ants on the number of samples with positive bacterial
growth
There were proportionately less samples with
positive bacterial growth when a nal rinse of
chlorhexidine (2%) rather than saline was added to a
standard regimen of sodium hypochlorite (1%).
Sodium hypochlorite (5%) reduced the
proportion of samples with positive cultures when
compared to sodium hypochlorite (1%)
There was no difference in the proportion of
samples with positive bacterial growth after irrigation
with solutions of chlorhexidine (2%) compared to
sodium hypochlorite (5.25%).
MTAD added as a nal irrigating rinse to a
conventional 1.3% sodium hypochlorite regimen was
more effective than saline at reducing vital bacterial
counts but live bacteria were present in all of the
samples.
Proportionately less samples had a positive
bacterial culture following a 20-minute irrigation with
sodium hypochlorite (2.5%) than with chlorhexidine
gel (2%).
A low strength solution of chlorhexidine (0.2%)
provided a smaller proportion of samples with positive
culture when compared to normal saline.
Population Diagnosis, disease stage, comorbidity, risk Any age, involving single or multi-rooted permanent
(P) factor, sex, age, ethnic group, specic inclusion teeth with pulpal or periapical pathology or both, which
or exclusion criteria, clinical setting require root canal treatment (single or multiple visit).
Root formation must have been completed in all treated
teeth. If possible teeth with irreversible pulpitis and a
vital pulp should be stratied and evaluated separately
to teeth with necrotic non-vital pulps
Retreated teeth should not be included. To obviate unit
of analysis issues and the confounding effects of cross-
contamination, cluster randomised trials and the use of
multiple teeth in individuals should be avoided
Intervention Type, frequency, dose, duration, prognostic Any irrigants or combinations of irrigants if they have
(I) factor been used in conjunction with EDTA (ethylenedi-
aminetetra-acetic acid) or similar chelating agents. The
volume of irrigant, method of delivery, timing i.e. at in-
strument change or nal rinse, and if relevant the tem-
perature should be reported. Inter-appointment intra-
canal medications, if any, must be recorded
treatment in mature permanent teeth (Continued)
Concomitant administration of antibiotics or any pain

medication providing these are available equally to both
the treatment and control group
Comparison Type, frequency, dose, duration, prognostic Irrigants against saline, each other or against inactive
(C) factor agent (irrigant) or placebo. The volume of irrigant,
method of delivery, timing i.e. at instrument change or
nal rinse should be reported
Outcome (O) Which clinical or patient related outcomes will Direct patient-reported/centred measures as well as in-
the researcher need to measure, improve, direct measures (such as identication of the type and
inuence or accomplish? Which methods of counts of analgesic)
measurement should be used? PRIMARY OUTCOMES:
Baseline and postoperative pain assessments (e.g. 6
hourly for the rst day and then daily for the next 3
days). Pain rating scales should be internationally recog-
nised, valid and reliable for the clinical pain of interest.
SECONDARY OUTCOMES:
The measures should provide information about pain
impact e.g. type, number and frequency of analgesic
usage to reduce the pain/discomfort of the intervention.
Also include a checklist of potential impacts (e.g. YES/
NO: pain is increased by chewing. Pain is increased by
eating/biting; as subsets of quality of life measures)
Satisfaction with the treatment/outcome (e.g. Likert
scale: How satised with the treatment are you? very
dissatised, dissatised, neither dissatised nor satis-
ed, very satised, very satised)
Counts of total anaerobes and aerobes isolated from
root canals before and after irrigation, as well as the
detection of clinically important species
Time Stamp Date of literature search or recommendation 5 July 2012

(T)
Study Type What is the most appropriate study design to Randomised controlled trial (adequately powered/mul-
address the proposed question? ticentred)
Methods: concealment of allocation sequence
Blinding: patients, trialists, outcomes assessors, data an-
alysts
Setting: hospital/university or general practice with ade-
quate follow-up. A general dental practice setting would
be preferable as it more closely resembles a real life
experience
APPENDICES
Appendix 1. MEDLINE via OVID search strategy

1. ENDODONTICS/
2. exp ROOT CANAL THERAPY/
3. APICOECTOMY/
4. endodontic$.mp.
5. (apical and (surgery or surgical$)).mp.
6. (apicectom$ or apicoectom$).mp.
7. ((orthograd$ adj6 ll$) or (root adj6 therap$) or (root-end adj6 resect$) or (root-end adj6 ll$)).mp.
8. ((root canal adj (prepar$ or obturat$)) or dental pulp devitali$).mp.
9. ((orthograd$ adj6 ll$) or (retrograd$ adj ll$)).mp.
10. (retrograd$ adj6 ll$).mp.
11. or/1-10
12. ROOT CANAL IRRIGANTS/
13. irrigat$ or irrigant$
14. clean$ or disinfect$ or rins$
15. or/12-14
16. 11 AND 15
The above subject search was linked to the Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying randomized trials in
MEDLINE: sensitivity maximising version (2008 revision) as referenced in Chapter 6.4.11.1 and detailed in box 6.4.c of The Cochrane
Handbook for Systematic Reviews of Interventions, Version 5.1.0 [updated March 2011] (Higgins 2011).
1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
3. randomized.ab.
4. placebo.ab.
5. drug therapy.fs.
6. randomly.ab.
7. trial.ab.
8. groups.ab.
9. or/1-8
10. exp animals/ not humans.sh.
11. 9 not 10
Appendix 2. Cochrane Oral Health Groups Trials register search strategy

((endodont* or root canal or apicoectomy or apical surgery or apicectomy or orthograd* ll* or root-end* ll* or retrograd*
ll* or dental pulp devitali*) AND (irrigat* or irrigant* or clean* or disinfect* or rins*))
Appendix 3. CENTRAL search strategy

#1 MeSH descriptor Endodontics explode all trees
#2 MeSH descriptor Apicoectomy, this term only
#3 MeSH descriptor Root Canal Therapy explode all trees
#4 endodontic*
#5 (apical and (surgical* or surgery))
#6 (apicectom* or apicoectom*)
#7 ((orthograd* near/6 ll*) or (root* near/6 therap*) or (root-end* near/6resect*) or (root-end* near/6 ll*))
#8 ((root canal near/6 prepar*) or (root canal near/6 obturat*))
#9 dental pulp devitali*
#10 (retrograd* near/6 ll*)
#11 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10)
#12 MeSH descriptor Root Canal Irrigants, this term only
#13 (irrigat* or irrigant*)
#14 (clean* or disinfect* or rins* or clens*)
#15 (#12 OR #13 OR #14)
#16 (#11 AND #15)
Appendix 4. EMBASE via OVID search strategy

1. exp Endodontics/
2. endodontic$.mp.
3. (apical and (surgery or surgical$)).mp.
4. (apicectom$ or apicoectom$).mp.
5. ((orthograd$ adj6 ll$) or (root adj6 therapy) or (root-end adj6 resect$) or (root-end adj6 ll$)).mp.
6. (root canal adj5 (prepar$ or obturat$ or ll$)).mp.
7. dental pulp devitali$.mp.
8. (retrograd adj6 ll$).mp.
9. or/1-8
10. Root Canal Irrigants/
11. (irrigat$ or irrigant$).mp.
12. (clean$ or disinfect$ or rins$ or clens$).mp.
13. or/10-12
14. 9 and 13
The above subject search was linked to the Cochrane Oral Health Group lter for EMBASE via OVID:
1. random$.ti,ab.
2. factorial$.ti,ab.
3. (crossover$ or cross over$ or cross-over$).ti,ab.
4. placebo$.ti,ab.
5. (doubl$ adj blind$).ti,ab.
6. (singl$ adj blind$).ti,ab.
7. assign$.ti,ab.
8. allocat$.ti,ab.
9. volunteer$.ti,ab.
10. CROSSOVER PROCEDURE.sh.
11. DOUBLE-BLIND PROCEDURE.sh.
12. RANDOMIZED CONTROLLED TRIAL.sh.
13. SINGLE BLIND PROCEDURE.sh.
14. or/1-13
15. ANIMAL/ or NONHUMAN/ or ANIMAL EXPERIMENT/
16. HUMAN/
17. 16 and 15
18. 15 not 17
19. 14 not 18
Appendix 5. LILACS via BIREME search strategy
(endodontic$ or root canal or apicectom$ or apicoectom$ or apical surg$ or orthograd$ ll$ or retrograd$ ll or root-end$
resect$ or root-end ll$) [Words] and (irrigant$ or irrigat$ or rins$ or clean$ or clens$ or disinfect$) [Words]
The above subject search was linked to the Brazilian Cochrane Center lter for LILACs via BIREME:
((Pt randomized controlled trial OR Pt controlled clinical trial OR Mh randomized controlled trials OR Mh random allocation OR Mh
double-blind method OR Mh single-blind method) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Pt clinical
trial OR Ex E05.318.760.535$ OR (Tw clin$ AND (Tw trial$ OR Tw ensa$ OR Tw estud$ OR Tw experim$ OR Tw investiga$))
OR ((Tw singl$ OR Tw simple$ OR Tw doubl$ OR Tw doble$ OR Tw duplo$ OR Tw trebl$ OR Tw trip$) AND (Tw blind$ OR
Tw cego$ OR Tw ciego$ OR Tw mask$ OR Tw mascar$)) OR Mh placebos OR Tw placebo$ OR (Tw random$ OR Tw randon$ OR
Tw casual$ OR Tw acaso$ OR Tw azar OR Tw aleator$) OR Mh research design) AND NOT (Ct animal AND NOT (Ct human and
Ct animal)) OR (Ct comparative study OR Ex E05.337$ OR Mh follow-up studies OR Mh prospective studies OR Tw control$ OR
Tw prospectiv$ OR Tw volunt$ OR Tw volunteer$) AND NOT (Ct animal AND NOT (Ct human and Ct animal))) [Words]
HISTORY
Protocol rst published: Issue 1, 2011
Review rst published: Issue 9, 2012
CONTRIBUTIONS OF AUTHORS
Zbys Fedorowicz (ZF) was responsible co-ordinating the review.
Patrick Sequeira-Byron (PSB), (ZF), Mona Nasser (MN) and Raphael Freitas de Souza (RF) were responsible for: screening search
results; organising the retrieval of papers; writing to authors of papers for additional information; screening retrieved papers against
inclusion criteria; appraising the quality of papers.
ZF, Ben Carter (BC), PSB and Marc Heft (MH) were responsible for: extracting outcome data from the papers and entering them into
RevMan; assessing the risk of bias; writing the effects of interventions and analysing the data.
All review authors contributed to the interpretation of the data and writing the review.
PSB and ZF conceived the idea for the review and are the guarantors for the review.
DECLARATIONS OF INTEREST
There are no nancial conicts of interest and the review authors declare that they do not have any associations with any parties who
may have vested interests in the results of this review.
SOURCES OF SUPPORT
Internal sources
No sources of support supplied
External sources
New York University (NYU), USA.
NYU have provided funding for the Cochrane Oral Health Group Global Alliance (http://ohg.cochrane.org/)
British Orthodontic Society (BOS), UK.
The BOS have provided funding for the Cochrane Oral Health Group Global Alliance (http://ohg.cochrane.org/)
British Society of Paediatric Dentistry (BSPD), UK.
The BSPD have provided funding for the Cochrane Oral Health Group Global Alliance (http://ohg.cochrane.org/)
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

The most widely used irrigation protocol is sodium hypochlorite (5.25%) at instrument change in combination with EDTA (17%)
to remove the bacteria laden smear layer (Dutner 2011). To enable further comparisons with other protocols we have widened the
inclusion criteria for this review, which will permit evaluation of combinations of irrigants and adjunct irrigants e.g. MTAD, EDTA
against the standard protocol.
INDEX TERMS
Medical Subject Headings (MeSH)

Bacterial Infections [therapy]; Chlorhexidine [administration & dosage]; Hydrogen Peroxide [administration & dosage]; Randomized
Controlled Trials as Topic; Root Canal Irrigants [ administration & dosage]; Root Canal Preparation [ methods]; Sodium Chloride
[administration & dosage]; Sodium Hypochlorite [administration & dosage]; Therapeutic Irrigation [methods]
MeSH check words

Humans

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Irrigants for non-surgical root canal treatment in mature

permanent teeth (Review)

Fedorowicz Z, Nasser M, Sequeira-Byron P, de Souza RF, Carter B, Heft M

Irrigants for non-surgical root canal treatment in mature

Editorial group: Cochrane Oral Health Group.

PLAIN LANGUAGE SUMMARY

Proportion of participants with moderate to severe pain in

Change in periapical radiolucency as assessed by radiography

None of the studies reported data for this outcome.

2. Sodium hypochlorite: 1% versus 2.5% and versus 5%

Proportion of participants or samples with positive bacterial

4. Sodium hypochlorite 5% versus sodium

Proportion of participants or samples with positive bacterial

Blome 2008 {published data only} Higgins 2011

Characteristics of included studies [ordered by study ID]

Participants 40, gender not specied, age range 21 to 40 years

Outcomes Pain and discomfort participant-assessed with modied VAS rated 0 to 9 (9 =

Bias Authors judgement Support for judgement

uence on outcome measurement, but in-

Methods Randomised controlled trial. Setting: Department of Endodontics, School of Dental

Participants 44 (13 male, 31 female), age range 21 to 63 years

Interventions Orthograde root canal treatment (2) visit, step-back technique

Outcomes Bacterial counts identication by macro and micromorphology no further

Bias Authors judgement Support for judgement

Participants 20 participants gender unspecied, age range 20 to 52 years

Interventions Orthograde root canal treatment (2) visit, step-back technique

Outcomes Bacterial counts (CFU) Enterococcus faecalis, Actinomyces israelii, Staphylococcus

Bias Authors judgement Support for judgement

Participants Endodontic referrals

Interventions Orthograde root canal treatment (2) visit, 2 dentists

Outcomes PRIMARY OUTCOME:

Bias Authors judgement Support for judgement

Participants 30 (15 male, 15 female), age 25 to 78 (mean 51.9) years

Interventions Orthograde root canal treatment (2) visit 7 days apart

Outcomes PRIMARY OUTCOME:

Bias Authors judgement Support for judgement

Other bias Low risk Sponsorship included Dentsply Tulsa Den-

Participants 52 participants (60 teeth), no further demographic details reported

Interventions Orthograde endodontic treatment (3) visit

Outcomes PRIMARY OUTCOME:

Bias Authors judgement Support for judgement

Methods Randomised controlled trial. Setting: Clinic of Endodontics of Federal University of

Participants 83 gender unspecied, age range 14 to 53 years

Canals explored, irrigated with 3 mL of either solution in between les. Removal of

Outcomes PRIMARY OUTCOME:

Bias Authors judgement Support for judgement

Outcomes Postoperative pain and tissue swelling by self-assessed questionnaire (5-point

Bias Authors judgement Support for judgement

Comment: Insufcient information in the

section were comparable to those reported

Other bias High risk Quote: 17 required a multiple-visit treat-

Participants 73 teeth (symptomatic and asymptomatic) unclear if single or multi-rooted

Bias Authors judgement Support for judgement

Allocation concealment (selection bias) Unclear risk Nothing reported

Blinding of participants and personnel Low risk Nothing reported

Other bias Unclear risk Potential confounding by NaOCl concen-

Pain was the principal outcome, not all

Participants 32 gender unreported, age range 19 to 63 years

Outcomes PRIMARY OUTCOME:

Bias Authors judgement Support for judgement

Following email communication with the

Methods Randomised controlled trial. Setting: referrals to the Department of Endodontology,

Participants 24 gender unreported, age range 12 to 70 years