Reaction of periradicular tissuesto root canal treatment: benefitsand drawbacksJOSE F. SIQUEIRA JR

Tissue injury induced by intra-canal procedures and substances extruded through the apical foramen may influence

the development of post-operative pain as well as the outcome of root canal treatment. While the development of

pain is related to the intensity of tissue damage, treatment outcome is more dependent on the persistence of the

source of injury. Procedural errors are the main causative agents of either post-operative pain or persistent

periradicular lesions. However, even when the treatment has followed the highest standards, post-operative pain

can occur and periradicular disease can persist, albeit at a lower incidence when compared to teeth treated to a poor

technical standard. This paper critically reviews the effects of intra-canal procedures on the periradicular tissues,

with special emphasis on the occurrence of post-operative pain and the outcome of the root canal treatment. The

possible systemic effects stemming from root canal procedures are also discussed in the light of current knowledge.

The overwhelming scientific evidence demonstrates

that periradicular lesions are diseases of infectious

origin (1–4), and that endodontic procedures should

be directed towards the prevention and/or the

elimination of the pulpal and periradicular microor-

ganisms. The prevention or healing of periradicular

disease will depend on how effective the clinician is in

achieving these goals (5–7). Root canal treatment of

teeth containing irreversibly inflamed pulps is essen-

tially a prophylactic treatment, since the radicular vital

pulp is usually free of infection and the rationale is to

prevent further infection of the root canal system (8).

On the other hand, in cases of infected necrotic pulps

or in root filled teeth associated with periradicular

disease, an intra-radicular infection is established and,

as a consequence, endodontic procedures should focus

not only on prevention of the introduction of new

microorganisms in the root canal system, but also on

the elimination of those located therein (9, 10).

Root canal procedures involve the use of instruments

and substances to clean, shape and disinfect the root

canal system, as well as materials to fill the root canal

space. These procedures inevitably cause some level of

damage to the periradicular tissues. Because tissue

injury induced by intra-canal procedures may result in

unfavorable responses to treatment, the practitioner’s

choice on procedures to be used during root canal

treatment should rely on those that are known to cause

as little damage as possible. This review paper focuses

on the reaction of the periradicular tissues to root canal

procedures with special emphasis to the influence of

those procedures on the development of post-opera-

tive pain and the outcome of the root canal treatment.

Post-operative pain and post-treatment disease

The worst-case scenario for periradicular tissue re-

sponse to intracanal procedures is represented mainly

by post-operative pain and/or the emergence/persis-

tence of disease. While the development of pain is

conceivably more dependent on the intensity of tissue

damage, the outcome of the root canal treatment is

more influenced by the persistence of the source of

injury. This can be explained by the fact that post-

123

Endodontic Topics 2005, 10, 123–147All rights reserved

Copyright r Blackwell Munksgaard

ENDODONTIC TOPICS 20051601-1538

operative pain is usually a result of an acute inflamma-

tory response in the tissues, whilst post-treatment

disease is usually characterized by the emergence or

persistence of chronic inflammation. The intensity of

acute inflammation is directly proportional to the

extent of the injury (11); chronic inflammation is

usually a result of a persistent low-grade injury (12).

It is well established that microorganisms are the

most common aetiologic agents of post-operative pain

and post-treatment disease, and their participation in

these events will obviously depend on the intensity or

the persistence of the injury caused to the periradicular

tissues, respectively. In some way, root canal procedures

can allow or precipitate the involvement of micro-

organisms in these events.

Microorganisms persisting in the root canal system

after treatment are the major causative agents of

therapy-resistant periradicular lesions (13–16), inas-

much as they usually represent a persistent source of

irritation to periradicular tissues. In addition, micro-

organisms are usually regarded as the most common

cause of post-operative pain (17, 18); a clear indication

of this relationship is that flare-ups are more likely to

occur in necrotic cases (infected) than in vital cases

(non-infected) (19). Apical extrusion of infected

debris and perturbations in the endodontic micro-

biota induced by intracanal procedures are the main

situations in which microorganisms are involved with

the development of inter-appointment pain (18, 20).

The involvement of microorganisms with post-opera-

tive pain and post-treatment disease has been reviewed

recently (18, 20–23).

Non-microbial factors can also induce periradicular

inflammation, but since the source of non-microbial

irritation is usually transient the reaction is not

maintained. As a consequence, although some authors

suggest an exclusive involvement of intrinsic or

extrinsic non-microbial factors in causation of persis-

tent periradicular lesions (24–27), it remains to be

proved and confirmed by studies using microbiological

techniques more sensitive and specific than microscopy.

However, in spite of being transient, inflammation

generated by non-microbial factors can be of enough

intensity to cause pain.

Non-microbial factors are represented by chemical or

mechanical injury generated by intracanal procedures.

When the use of instruments, irrigants, medications,

and filling materials is restricted to the confines of the

root canal system, the intensity of the reaction in the

periradicular tissues is low. Only a small volume of

tissue will be injured and even then in a transient way.

On the other hand, when root canal procedures or

substances are intentionally or accidentally extended

beyond the boundaries of the apical foramen, undesir-

able events can ensue (28–33).

Examples of mechanical irritation to the periradicular

tissues include over-instrumentation and over-exten-

sion of filling materials. In the event of over-instru-

mentation, there is a risk of post-operative pain

developing, the intensity of which is usually propor-

tional to the extent of tissue damage (18): The larger

the instrument size, the larger the area of periradicular

tissue destruction. Moreover, in infected cases, over-

instrumentation can be coupled with extrusion of

infected debris, which may not only induce pain (18)

but also impair healing (21, 34). Over-extended filling

materials can induce pain by mechanical compression of

the periradicular tissues (18).

Examples of chemical irritation include apical extru-

sion of irrigants, intra-canal medicaments and filling

materials. Most irrigants and medicaments are cyto-

toxic to host tissues (35, 36), and as a consequence

their use should be restricted to the root canal. In spite

of being cytotoxic, clinical trials have shown that

substances used for irrigation or intra-canal medication

have no influence on the occurrence of post-operative

symptoms (37–40). There is no proven benefit in

intentionally extruding irrigants or medicaments. In

fact, severe reactions have been reported after extrusion

of some commonly used substances into the periradi-

cular tissues (28–33). Overextended filling materials

also represent chemical irritation to the periradicular

tissues, as virtually all endodontic sealers have a certain

degree of cytotoxicity, at least before setting (41–43).

Furthermore their irritating effects conceivably in-

crease as the material/tissue contact surface area

increases. Thus, the larger the volume of over-extended

material, the larger the surface of contact between the

filling material and the tissue and the greater the

intensity of chemical damage to the periradicular

tissues. Therefore, large overfillings are likely to

increase the risk of pain. However, because tissue

irritation induced by over-extended filling materials is

arguably transient (provided that there is no damage to

anatomical structures such as the mandibular nerve or

the maxillary sinus), the impact on the outcome of the

treatment without concomitant infection is question-

able. This issue will be addressed later in this paper.

Siqueira

124

The working length debate

One of the most controversial issues in root canal

treatment is related to the point where the chemome-

chanical and filling procedures terminate. This is an

important discussion, since the response of the

periradicular tissues to intra-canal procedures is ob-

viously influenced by the length at which they are

restricted. While the termination point of root canal

procedures appears to have no significant influence on

the development of post-operative pain (except in cases

of over-instrumentation), the same is apparently not

true for the outcome of the root canal treatment, and

here resides the main reason for controversy.

In addition to the fact that the anatomy of each root

canal system is unique, which makes any standardiza-

tion prone to error, the pathological conditions of the

root canal should also be taken into consideration in

any discussion on working length. In daily practice,

clinicians usually face three diagnostic endodontic

conditions that require professional intervention – vital

pulps, necrotic pulps and retreatment cases (Fig. 1).

The recognition of the differences between these

conditions and the reliance of the clinical decision-

making on these differences represents the basis on

which the outcome of root canal treatment is founded.

The major difference between these conditions resides

in the fact that while in vital pulps infection is absent,

necrotic pulps and retreatment cases present a micro-

biological challenge that should be treated appropri-

ately. A diseased vital pulp, although irreversibly

inflamed, is free of microorganisms colonizing the root

canal. Infection is for the most part restricted to the

surface of the pulp exposed to the oral cavity. The

radicular pulp, as long as it remains vital, usually

succeeds in protecting itself against microbial invasion

and colonization. On the other hand, necrotic pulps

lack the essential defense apparatus against infection,

and are therefore characterized by the presence of

microorganisms colonizing the root canal system.

Fig. 1. Diagnostic endodontic conditions commonly faced by clinicians. The major difference between them resides inthe microbiological conditions of the root canal. Prevention of infection is paramount for a favorable outcome of vitalcases (asepsis). Because necrotic cases and retreatment cases are characterized by an intra-radicular infection, treatmentsuccess will also rely on effective eradication of intracanal microorganisms (anti-sepsis).

Reaction of periradicular tissues

125

The fact that a periradicular radiolucency may not be

visible on a radiograph does not necessarily mean that

an inflammatory periradicular lesion is absent (44).

Therefore, regardless of the presence of radiographi-

cally detected periradicular pathosis, root canals con-

taining necrotic pulp tissue should be treated as

infected canals. Retreatment cases are usually associated

with a persistent or secondary root canal infection by

therapy-resistant microorganisms, which may be more

difficult to eradicate when compared to primary

infections (21–23). Several studies have reported on a

role of infection on the outcome of the root canal

treatment, and demonstrated that various factors

associated with the presence of microorganisms have

a substantial influence on the outcome, including the

preoperative pulpal status (5, 45–48), presence of a

periradicular lesion (5, 45, 46, 49–52), and retreatment

cases (5, 47, 48, 53).

The difference between these clinical conditions is

obvious and now accepted within the endodontic

community. As a consequence it is also recognized

that treatment techniques should be customized to

meet the specific challenges they present in terms

of infection control. Thus, the presence of infection

should be the most important factor that should

be taken into account when deciding whether the

root canal should be treated in one or more visits,

what intracanal medicaments should be applied to the

canal or at what level the apical canal preparation

should terminate.

Vital cases (Non-Infected)

It has been claimed that the ideal outcome of root canal

treatment is closure of the apical foramen by newly

formed hard tissue (54) (Fig. 2). Animal studies have

described some procedures and materials that may

predictably favor the occurrence of periradicular

tissue repair associated with deposition of cementum-

like tissue sealing the apical foramen (55–58).

However, apical sealing by hard tissue formation is

not always complete and predictable (59, 60) and it

remains questionable as to whether it can be attained in

most cases.

Absence of inflammation in the periradicular tissues is

arguably the major histological picture to be achieved

in successfully treated teeth. From a clinical standpoint,

success is better characterized by absence of a radio-

graphically detectable periradicular lesion accompanied

by absence of signs and symptoms of infection, such as

pain, swelling or draining sinus tract (5, 61, 62).

Clinical healing does not necessarily correlate well with

histological healing, as many teeth classified as clinically

healed can show inflammation in the periradicular

tissues adjacent to the apical foramen (63). However,

the implications of residual inflammation in the period-

ontal ligament without any clinical or radiographic

manifestation remain to be elucidated, as well as for

how much longer the inflammation persist in the

absence of microbial challenge.

In teeth with vital pulps, some authors recommend

that canals should be instrumented up to 1 mm short

of the canal terminus in an attempt to preserve the

vitality of the apical pulp tissue (‘pulp stump’),

which might play a role in periradicular tissue repair.

Studies have shown that the procedure of preserving

the health of the ‘pulp stump’ in vital pulps allows

natural healing processes to occur, most often with

apical closure by hard tissue formation, even when

dentinal chips have been packed against the ‘pulp

stump’ (56, 64, 65).

Nonetheless, it must be appreciated that maintain-

ing such a small tissue fragment in a healthy condition

is not predictable, particularly during the instrumen-

tation of curved narrow root canals. Moreover,

irrigation with sodium hypochlorite solution in differ-

ent concentrations may lead to severe inflammation or

necrosis of the ‘pulp stump’ (66), as a result of its

Fig. 2. Closure of the apical foramen by newly formedhard tissue has been considered as the ideal histologicaloutcome of the endodontic treatment (courtesy ofFrancisco Souza-Filho).

Siqueira

126

cytotoxicity (67). Considering that asepsis is the major

decisive factor in preventing the development of disease

in the treatment of vital pulps, it could be argued

that sodium hypochlorite irrigation should not be

used in order to reduce the potential of damaging the

‘pulp stump’. Admittedly, keeping the root canal

flooded with sodium hypochlorite during chemome-

chanical preparation can help maintain asepsis during

treatment. Furthermore, irritation to the periradicular

tissues caused by sodium hypochlorite is usually

transient and restricted to a small tissue area, which

will result in no substantial adverse effect, provided

the irrigant is prevented from extruding through the

apical foramen.

It is important to point out that the repair of the

periradicular tissues after the treatment of vital pulps is

accomplished by cells and molecules of the periodontal

ligament. This is a soft specialized connective tissue,

which ranges in width from 0.15 to 0.38 mm, with its

thinnest portion around the middle third of the root

(68). As with any other connective tissue, the period-

ontal ligament consists of cells, extracellular matrix,

vessels and nerves. The major cells found are fibroblasts

(the prevailing cells), osteoblasts and osteoclasts (lining

the bone surface of the ligament), cementoblasts

(lining the cementum surface of the ligament),

epithelial cells, macrophages and undifferentiated

mesenchymal cells. The extracellular matrix is com-

posed principally of collagen fibre bundles embedded

in a ground substance consisting of glycosaminogly-

cans, glycoproteins and glycolipids. In vivo, period-

ontal ligament constituents are constantly being

synthesized, removed and replaced. Fibroblasts are

the major cells responsible for the matrix turnover,

being able to simultaneously synthesize and degrade

collagen, which is continuously remodeled (68). The

high turnover is not exclusive to the extracellular

matrix, as cells are frequently being renewed as well.

The periodontal ligament is exceptionally well vascu-

larized, which reflects the high rate of turnover of its

cellular and extracellular constituents. Its main blood

supply comes from the superior and inferior alveolar

arteries. The ligament also possesses an efficient lymph

drainage system. Because the periodontal ligament has

a high turnover rate, it can easily adapt to changing

local conditions (69). All these features point to an

Fig. 3. Periradicular tissue response after overinstrumentation in vital teeth of dogs. (A) Radiograph taken at the time ofinstrumentation beyond the apical foramen. (B and C) Histological picture after 180 days showing tissue ingrowth intothe canal and hard tissue deposition along the canal walls and closing the apical foramen. (D) Higher magnification ofthe specimen showed in C (courtesy of Francisco Souza-Filho).

Reaction of periradicular tissues

127

excellent ability of the periodontal ligament to repair

itself after injury.

Maintenance of the vitality of the ‘pulp stump’ is

unpredictable during chemomechanical procedures

(70, 71) and evidence indicates that it is not paramount

for periradicular tissue repair to take place. Studies

have demonstrated that even after the mechanical

removal of the ‘pulp stump’ by instrumentation at or

beyond the apical foramen, repair by hard tissue

formation is not precluded, particularly when calcium

hydroxide is used as intra-canal medication or it is

present in formulations of root canal sealers (55, 57–

60). In addition, studies in dogs (72–74) revealed that

enlargement of the apical foramen with consequent

removal of the ‘pulp stump’ was followed by periradi-

cular tissue ingrowth into the root canals, sometimes

associated with deposition of cementum-like tissue

over the canal walls (Fig. 3). This confirms the healing

potential of the periodontal ligament, which is con-

ceivably a consequence of its intense metabolic activity.

However, although some studies have shown that even

under extreme conditions the periodontal ligament can

be repaired in the absence of concomitant infection,

one should be aware that, in clinical situations,

enlargement of the apical foramen is undesirable and

unnecessary, as it can result in lack of apical control and

severe post-operative pain.

The outcome of treatment of teeth with vital pulps

does not appear to be substantially affected by the

apical limit of the root canal procedures, provided

microorganisms are prevented from gaining entry into

the root canal before filling (8). Obviously, over-

extension should be avoided as it can predispose to

post-operative pain. The recommended working

length in teeth with vital pulps is 1–2 mm short of the

radiographic apex. The use of apical patency files has

been advocated to clean the apical foramen and to keep

it free of debris, without enlarging it. The price paid by

using patency files in such cases may be the removal of

the ‘pulp stump’. The reasons to maintain the apical

foramen patent in teeth with vital pulps are almost

exclusively based on mechanical factors, i.e., to pre-

vent apical blockage with dentinal debris that

could lead to loss of apical control and give rise to

procedural errors during chemomechanical prepara-

tion, particularly of curved and narrow root canals.

However, from a biological perspective, it seems that it

does not matter whether the ‘pulp stump’ is removed

by the use of small patency files, since the main entity

responsible for the periradicular tissue repair is the

apical periodontal ligament.

Necrotic pulp and retreatment cases(Infected)

Root canals containing necrotic pulp tissue associated

or not with a periradicular lesion as well as root-

filled teeth with recalcitrant lesions are a different

matter because of the presence of infection. In these

cases, microorganisms may reach the apical part of the

canal and be near or at the apical foramen and accessory

foramina, in close contact with the periradicular tissues

(14, 75–77) (Fig. 4). Thus, the length of instrumenta-

tion in infected cases is critical (78) and it is reasonable

to assume that it would be preferable to clean the canal

to its terminus. Nevertheless, the risks of instrumenting

the canal to this position includes the possibility of

over-instrumentation, which can force infected debris

and filling materials into the periradicular tissues.

Fig. 4. (A) Scanning electron micrograph showingextensive bacterial colonization in the very apical part ofthe canal, near and at the apical foramen. (B) Highermagnification of the inset in A. Modified with permissionfrom Siqueira and Lopes (77).

Siqueira

128

One of the requisites for microorganisms to partici-

pate in the pathogenesis of periradicular diseases is that

they should be spatially located in the root canal system

in such a way that they or their virulence factors can

gain access to the periradicular tissues (79). A region

that fulfills this requisite is the apical third of the root

canal, since microorganisms colonizing this region are

in intimate contact with the host tissues through the

apical foramen and accessory foramina, which have

been demonstrated to be more frequently found in the

apical third of the root (80).

Microorganisms infecting the apical region of necro-

tic pulps are predominantly anaerobic and the time of

infection can influence such a dominance. A study in

monkeys (81) investigated the distribution of different

microbial species in root canal samples after different

periods of time and in different parts of the root canal

system. The numbers of anaerobic bacterial cells

significantly increased with time and outnumbered

facultative bacterial cells after 90 days. After 90 or 180

days of infection, 85–98% of the bacterial cells infecting

the apical root canal were anaerobic. Baumgartner and

Falkler (82) cultured the apical 5 mm of root canals of

10 teeth with carious exposures and reported that the

most prevalent species were Prevotella intermedia/

nigrescens, Prevotella buccae, Peptostreptococcus anaero-

bius and Veillonella parvula, all of them being isolated

from one-half of the examined cases. Of a total of 50

bacterial isolates, 68% were strict anaerobes. All cases

harbored anaerobes. The number of colony forming

units in the apical 5 mm of root canals ranged from

5.6 � 104 to 4.3 � 106.

Dougherty et al. (83) investigated the occurrence of

black-pigmented anaerobic bacteria in the apical and

coronal segments of infected root canals and found

these bacteria in 12 of 18 cases (67%). Prevotella

nigrescens was isolated from 9/12 apical segments,

Prevotella melaninogenica from 3/12, P. intermedia

from 1/12, and Porphyromonas gingivalis from 1/12.

Siqueira et al. (84) surveyed samples taken from the

apical third of infected root canals associated with

periradicular lesions for the presence of 11 anaerobic

bacterial species using the polymerase chain reaction

method. All cases were positive for the presence of

bacteria. Of the 23 teeth, Pseudoramibacter alactolyti-

cus was detected in 10, Treponema denticola in 6,

Fusobacterium nucleatum in 6, Porphyromonas endo-

dontalis in 4, and Filifactor alocis in 2 (Fig. 5).

Occurrence of these bacterial species in the apical third

of infected root canals can be indicative of their role in

the pathogenesis of periradicular lesions.

The apical part of the root canal can be regarded as a

‘critical territory’ for the pathogenic bacteria, for the

host, and for the clinician (84). It is critical for

pathogenic bacteria, because in this region they are in

close contact with the periradicular tissues from which

they can obtain nutrients and to which they can induce

damage. It is also critical to the host, because the host

defense must concentrate in this area and wall off the

microbes in an attempt to prevent spreading of the

infection. It is finally critical for the clinician, because

the outcome of the treatment will depend on how

effective s/he is in eradicating the infection and in

promoting both fluid-tight and bacteria-tight seal in

this area.

Given its strategic anatomic position as well as its

complex anatomy, the apical portion of the root canal

system can be considered as the most critical element of

the whole system with regard to the need for cleaning,

disinfection and sealing (85). Because it is not known

how many microbial cells remaining in the apical

portion can be managed by the host defenses, the

length of the chemomechanical procedures should

presumably not be shorter than the apical level of the

infection. Thus, the apical limit of chemomechanical

preparation should ideally reach the full extent of the

apical root canal up to the canal terminus, in an attempt

to remove or at least significantly reduce the microbial

counts before the filling is placed. In fact, the need for

control of apical preparation within infected canals has

been demonstrated by clinical studies of treatment

outcomes (5, 86).

Fig. 5. Bacterial prevalence in the apical portion ofinfected root canals as evaluated by a molecular method.Data according to Siqueira et al. (84).

Reaction of periradicular tissues

129

During instrumentation of infected root canals,

dentinal debris containing microorganisms is produced

and may be packed in the apical region or extruded into

the periradicular tissues. When packed in the canal,

dentine debris may reduce the working length and may

hinder repair because of the presence of residual

microorganisms (87). Infected dentine debris, which

is extruded into the periradicular tissues may also be

responsible for persistent periradicular inflammation

and consequent treatment failure (34).

To effectively clean and disinfect the most apical part

of root canals, the use of patency files that reach or even

pass through the apical foramen have been proposed.

The apical patency concept is based on the placement of

a small file (size 10 or 15) to 1 mm longer than the canal

terminus in an attempt to remove dentinal debris from

the apical portion of the canal (88). It is recommended

that this small file should be passively moved through

the apical constricture without widening it. This

concept is currently taught in 50% of the United States

dental schools (89).

Clinical experience demonstrates that patency with

small files can be of great value in maintaining control

of the working length. This is because the use of

patency files ensures that the apical foramen remains

unblocked and patent, and when used repeatedly, tends

to prevent accumulation of pulpal and dentinal debris

that can cause blockages that often lead to ledges and

perforations, which, particularly in infected cases, put

the outcome at risk. Moreover, it has been suggested,

but remains to be proved, that keeping the foramen

patent allows penetration of irrigants deeper into the

apical portions of the root canal system (90). Also,

irrigant exchange is supposed to occur, when irrigation

fluids are displaced by patency files (90). However,

although patency files can actually prevent the blockage

of the apical foramen by dentinal debris, it also remains

to be clarified as to whether the use of patency files can

remove a significant amount of dentinal debris packed

in the apical canal.

In essence, the reasons proposed for the establish-

ment and maintenance of apical patency during

preparation of infected cases are based on biological

and mechanical factors. From a mechanical point of

view, when the instrument prepares a root canal to its

terminus and is repeatedly taken to that point, the risks

of procedural accidents are theoretically reduced. This

is because the accumulation of debris in this area is

prevented or reduced. Such accumulation may lead to

blockage of the apical root canal, with consequent loss

of the working length.

Attempts to regain working length should it be lost

may result in other accidents, such as file breakage,

ledge formation and perforation (Fig. 6). In this

regard, the principle is also applicable to non-infected

cases, as alluded to earlier. However, from a biological

point of view, the use of patency files arguably enhances

cleaning and disinfection of the entire extension of the

root canal up to the canal terminus, eliminating

microorganisms and preventing accumulation of in-

fected debris in this area, which could jeopardize the

outcome of the endodontic treatment (Fig. 7). Even if

instruments and irrigants do not succeed in completely

eliminating microorganisms in the apical segment of

the canal, they can conceivably disturb the environment

and promote an imbalance that may be conducive to

the successful action of host defense mechanisms.

To restrict apical cleaning and shaping procedures to

1–2 mm short of the apical foramen may leave behind

sufficient numbers of microorganisms to maintain

periradicular disease. Theoretically, the use of patency

files may assist in elimination of bacteria located near or

even at the apical foramen. A study (45) compared the

outcome of root canal treatment performed by an

endodontist using different protocols and evaluated

the influence of factors affecting outcome. A relatively

high rate of complete healing was observed for different

protocols. Although patency files were used, they were

Fig. 6. Blockage of the root canal during chemo-mechanical procedures and consequent attempts to regainthe initial working length may result in proceduralaccidents, such as perforations, which can jeopardize theoutcome of the treatment of infected cases.

Siqueira

130

not included as a variable. Therefore, the impact of the

patency concept on the bacterial elimination and on the

outcome of the endodontic treatment remains elusive.

Ideally, there is no apparent reason to extend the use

of patency files beyond the confines of the canal.

Reaching the canal terminus would appear to be

sufficient to perform the effects expected for a patency

file. Even so, because of the inherent difficulties in

establishing the precise location of the canal terminus

clinically, patency files are likely to pass through the

apical foramen in many cases. It is entirely unlikely that

they can cause significant mechanical damage to the

periradicular lesions, provided small instruments are

used. On the other hand, in infected canal systems,

instruments can become contaminated by microorgan-

isms on their passage to the patency length. Thus,

patency files could theoretically carry bacteria from the

canal to the periradicular tissues. However, an ex vivo

study (91) analyzed the effectiveness of 5.25% NaOCI

in preventing inoculation of periradicular tissues

with contaminated patency files and concluded

that the NaOCl present in the canal after irrigation

was sufficient to kill the test bacteria used to

contaminate files.

Because patency files can dislodge debris accumulated

in the apical part of the canal, it is possible that infected

dentinal debris is pushed into the periradicular tissues.

Apically extruded infected dentinal debris can play a

role in induction of post-operative pain and can cause

persistence of periradicular lesions after root canal

treatment. However, the participation of infected

dentinal debris in these processes will depend on the

amount of debris as well as on the virulence and/or

numbers of bacteria present. The fact that there is no

apparent influence on the development of post-

operative pain when using patency files (39, 92)

suggests that apical extrusion of debris during patency

filing may not be important, provided small files are

Fig. 7. The use of patency files can be justified by mechanical (non-infected and infected cases) and biological (infectedcases) reasons. (A) Instrumentation short of the apical foramen without reaching it can result in blockage of debris andloss of the working length, particularly in curved canals. (B) The use of small patency files can prevent accumulation ofdebris in the most apical segment of root canals. It can also help eliminate microorganisms located in this region. (C andD) Radiographs showing establishment of the patency length.

Reaction of periradicular tissues

131

used gently and passively. The impact of apically

extruded debris during the use of patency files on the

outcome of root canal treatment remains elusive.

As mentioned previously, retreatment cases should

also be regarded as infected. Persistent infection in the

most apical portion of the root canal is the major

cause of the persistence of post-treatment disease

(14, 76). Remaining microorganisms may be locat-

ed in uninstrumented areas of the main root canal,

in dentinal debris, in ramifications, in apical deltas,

in dentinal tubules, and in voids of the root canal filling.

If those microorganisms contact the periradicular

tissues and they are in sufficient numbers to be

pathogenic, an inflammatory lesion can develop or be

maintained. Using light and transmission electron

microscopy, Nair et al. (14) reported that microorgan-

isms may sometimes persist in the filled root canal and

survive beyond the apical constriction. Fukushima et al.

(76) examined root-filled teeth with periradicular

lesions by means of scanning electron microscopy

and bacteriological methods. In over 60% of the

cases, bacterial aggregates were visualized between

the terminus of the root canal filling and the apical

foramen. Those bacteria were likely to be members of a

persistent or secondary infection. These findings

indicated that bacteria can persist in the apical portion

of the root canal and can be responsible for recalcitrant

periradicular lesions. Therefore, the same principles

applied to the length of the chemomechanical proce-

dures in cases of necrotic pulps should also be applied to

retreatment cases.

Therefore, it appears but has not been proven that

small patency files can help clean up to the canal

terminus during chemomechanical procedures, with-

out enlarging it. Short of the canal terminus (0.5–

1 mm), the root canal should then be sufficiently

enlarged to maximize cleaning and disinfection, as

well as to accommodate the filling material (Fig. 8).

Studies have demonstrated that the larger the apical

preparation of infected root canals, the greater the

reduction of the bacterial numbers within the canal

(93–97). Debris is also more effectively removed when

the apical preparation size is relatively large (98).

Sufficiently large preparations can incorporate more

anatomic irregularities and allow the removal of a

substantial volume of bacterial cells and debris from the

root canal (Fig. 9). In addition, instrumentation to

larger file sizes can also result in increased penetration

of the irrigating needle and facilitate better irrigant

exchange in the apical third of the root canal (98, 99).

Although there are contradictory findings in the

literature regarding the effects of apical enlargement

on the outcome of the treatment (45, 46, 51, 52, 86),

it is fair to assume that if increased elimination of

microorganisms is achieved, so are the chances for a

better outcome of the treatment.

Obviously, enlargement of infected canals should be

compatible with the tooth anatomy to avoid weakening

of the root and procedural errors, such as ledges and

perforations. NiTi instruments allow the attainment of

larger preparations in curved root canals with reduced

risks of procedural accidents (100–103). Because of

this, they should be the instruments of choice to

Fig. 8. Ideal apical limit of root canal procedures.

Fig. 9. For instrumentation to touch all root canal wallsand to remove substantial amounts of pulp tissue andbacteria, the size of preparation should ideallyincorporate anatomic irregularities, which can bedifficult and sometimes impossible to carry out in canalsthat are not round in cross-section.

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132

prepare curved root canals. Less post-treatment disease

has been reported for teeth instrumented with hand

NiTi files when compared with teeth prepared with

hand stainless-steel files (104). NiTi file utilization was

five times more likely to achieve healing than using

stainless-steel files (104). This probably occurred

because of the improved ability of NiTi files in

maintaining the original canal path during instrumen-

tation and so facilitate removal of microorganisms.

One should be mindful that enlargement must be

restricted to the root canal without reaching the canal

terminus. As discussed above, the latter should be

cleaned, disinfected and maintained patent, but it must

not be enlarged. The clinician should be aware of the

risks when using large instruments beyond the canal

terminus, as this procedure can result in severe

periradicular injury, lack of an apical stop, and extrusion

of a large amount of infected debris, which predispose

to the occurrence of post-operative discomfort and

poses a potential threat to the long-term outcome of

the treatment.

Establishing the working length

In his classic study, Kuttler (105) found that the root

canal usually narrows toward the apex and then expands

to form the apical foramen. The narrowest part of the

canal formed the apical constriction, which is located

just short of the apical foramen. This area is generally

believed to be located at the cementum–dentinal

junction (CDJ) and its distance to the apical foramen

varies from 0.5 to 1 mm for teeth of different ages

(105–107). In more than 60% of root canals, the apical

foramen is not located at the apex, and the distance

between the apical foramen and the radiographic apex

ranges from 0 to 3 mm (105, 108). Kuttler (105)

reported that the mean apex to foramen distance was

0.48 mm for young individuals and 0.6 mm for older

ones. Dummer et al. (106) reported the mean apex to

foramen distance in anterior teeth to be 0.36 mm.

Traditionally, the apical constriction has been con-

sidered as the ideal termination for root canal

procedures (109, 110) (Fig. 10). However, the greatest

problem to accept this area as a landmark, to which

endodontic procedures should be limited, is that the

CDJ is very often impossible to detect clinically, even by

experienced practitioners (111). This is because the

CDJ does not always represent the most constricted

area of the root canal and/or because it is not always

present. Alternatively, the apical foramen could be a

more useful landmark, but it is also difficult and many

times impossible to locate clinically and radiographi-

cally. This is because the position of the apical foramen

in most cases does not coincide with the root apex

(105). To complicate matters further, when the apical

foramen exits to the side of the root in a buccal or

lingual direction it is virtually impossible to identify on

a radiograph. Consequently, the exact determination of

where the root canal ends is a difficult if not impossible

task (112). In addition to the anatomical variability, the

apical root canal can be sclerosed or the apical

constriction can have been modified or lost due apical

root resorption, as a result of an inflammatory

periradicular lesion (113). In many cases, the very

apical part of the root canal may contain an extension of

inflammatory tissue (75), which can be derived from an

ingrowth of inflamed periradicular tissues into the canal

or it can be due to the fact that in some cases a

periradicular lesion develops even before the entire

pulp tissue is necrotic (114). Although this inflamma-

tory tissue may temporarily prevent microorganisms

from reaching the most apical part of the root canal, its

presence is unpredictable and virtually impossible to

determine in the clinical situation.

Because the root apex is usually visible radiographi-

cally, it has been widely used as a reference for

determination of the working length. However, even

though 0.5–1 mm short of the radiographic apex is

commonly used and recommended as the termination

point, this remains only an estimate. It can be argued

Fig. 10. Scanning electron micrograph of the apicalforamen. Note the apical constriction (courtesy of HelioLopes).

Reaction of periradicular tissues

133

that instrumenting and filling to an arbitrary measure-

ment short of the apex is not treating the root canal

system in its entirety. But if infection is absent (e.g.,

vital cases), this may not be necessary. On the other

hand, the entire infected root canal should ideally be

instrumented, and the clinician should take advantage

of the available methods to assess where the root

canal terminates.

Radiographs have been used widely for working

length determination. Other methods have also been

proposed, such as tactile sensation and the paper point

technique (90), but they are imprecise, unreliable,

empirical and fraught with limitations. In recent years,

electronic length measurement devices have been used

for determination of the root canal terminus with a

satisfactory degree of accuracy and reliability (115–

117). A long-term retrospective study used an electro-

nic apex locator to determine the working length in

infected root canals associated with periradicular

lesions and reported a high rate of healing (118).

Commercially available electronic apex locators direc-

ted to the analysis of several impedance values at

different frequencies concurrently have been reported

to be accurate to within 0.5 mm from the apical

foramen in more than 90% of cases, irrespective of the

pulpal diagnosis (117, 119–123). The working length

can then be established by subtracting 0.5 mm from

measurements of electronic devices, which would result

in theory in the corrected working length being 1 mm

short of the apical foramen. Afterwards, a radiograph

should be taken to confirm measurements. As a matter

of fact, the combined use of electronic apex locators

and radiographs of a trial file has been shown to be

more accurate than the use of radiographs alone (124,

125). Because of their accuracy, apex locators allow for

a reduction in the number of radiographs necessary to

determine the working length particularly in teeth

where the apex is difficult to visualize on the radio-

graph. Even though electronic apex locators appear to

be excellent tools for the determination of the working

length, they should be used as an adjunct not as a

substitute for radiographs.

What happens in the apical region ofthe canal after filling?

Different events can occur in the most apical segment

of the root canal after filling. The most common are:

(a) The apical segment can be blocked by dentinal

debris (Fig. 11). In non-infected vital pulps, this

usually does not represent a problem as dentinal

chips can function as a nidus for calcification and

closure of the apical foramen (56, 65). On the other

hand, in infected necrotic pulps and retreatment

cases, dentinal debris can contain microorganisms

and their products. In these cases, the outcome of

root canal treatment will depend on the virulence

and numbers of remaining microorganisms as well as

on the host ability to cope with them (21, 22).

(b) The apical segment may remain filled with pulp

tissue. In non-infected pulps, if microorganisms

were not introduced in the canal during treatment,

tissue repair will be uneventful. In infected pulps,

microorganisms can remain in the necrotic tissue

and dentinal debris in the most apical portion of the

Fig. 11. Blockage of the very apical part of the canal bydentin chips after instrumentation. In non-infected cases,this may not affect the outcome of the treatment. On theother hand, in infected cases, microorganisms embeddedin debris may pose a threat to the treatment outcome(courtesy of Helio Lopes).

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134

canal. Again, the outcome of treatment will depend

on the virulence and numbers of remaining micro-

organisms as well as on the host resistance (21, 22).

(c) The apical segment of the root canal cleaned by

patency files can remain unfilled. In this situation, if

the apical segment is free of microorganisms, the

periodontal ligament can ingrow and occupy this

space (72, 74). If microorganisms remain, the

inflamed tissue can ingrow and the persistence of

inflammation will depend on the number and

virulence of microbial species and the host capability

to reach and eliminate remaining microorganisms.

(d) The apical portion can remain filled with the intra-

canal medicament, such as a calcium hydroxide

paste. As time goes by, calcium hydroxide paste can

be solubilized or phagocytosed, and then be

replaced by ingrowing periodontal ligament (126).

(e) The apical portion can be filled, which is the most

common situation observed when patency is

established. In this case, a biocompatible sealer

can occupy and seal this space. Theoretically, if the

filling material has antimicrobial properties, it may

help eliminate remaining microorganisms. Most

endodontic sealers have some antimicrobial activity

during setting, although this property is not as

pronounced as intracanal irrigants and medica-

ments (127–135). If the sealer is solubilized or

phagocytized, it can be replaced by tissue ingrowth.

There is a belief that the extrusion of sealer beyond

the radiographic terminus confirms that the apical

foramen is patent and has been sealed (136) (Fig. 12).

Although minor extrusion of sealer is unlikely to cause

discomfort and may not compromise the outcome of

treatment, the presence of sealer in the apical part of the

canal does not necessarily guarantee that the root canal

is properly sealed or that success will ensue. Bacterial

colonies can remain unaffected in the apical root canal

in spite of overfilling and can lead to treatment failure

(14, 137). In fact, the radiographic quality of the root

filling is in no way indicative that the root canal was well

sealed, particularly when canals are oval or ribbon-

shaped in transverse section (138) (Fig. 13). In

addition, disinfection of the root canal system cannot

be determined from radiographs and, as a consequence,

even apparently well-filled canals can remain infected

(14, 21). Therefore, the belief that the quality of root

canal treatment is determined by the presence of sealer

‘puffs’ visible on a post-obturation radiograph is based

on opinion rather than on facts, which is in clear

contrast with the current trend of evidence-based

endodontic treatment. There is no evidence supporting

this belief.

Influence of overfilling on treatmentoutcome

It has been demonstrated that a better outcome for the

root canal treatment is observed when the intracanal

procedures terminate within the confines of the root

canal system. A histological study (54) reported that

the most favorable response of the periradicular tissues

occurred when both instrumentation and filling

remained short of the apical constriction. A clinical

Fig. 12. Formation of sealer ‘puffs’ gives a good ‘esthetic’appearance on radiographs and has been regarded asindicative that proper treatment has been accomplished.However, even though a tiny extrusion of sealer isunlikely to cause discomfort and may not compromisethe outcome of the treatment, sealer ‘puffs’ does notnecessarily guarantee that the root canal is properly sealedor that the case will result in success.

Reaction of periradicular tissues

135

study showed that an optimal treatment outcome in

infected teeth with periradicular lesions was achieved

when the apical terminus was 0–2 mm short of the

radiographic apex (5). The same study revealed that the

prognosis was markedly decreased with significant

underfill and with overfill. These findings corroborated

earlier reports (61, 139).

The toxicity of the root filling materials has been

considered to play an important role in failures

associated with overfillings (140). However, it has

been reported that the apical extent of root fillings

seems to have no correlation with treatment failure,

provided infection is absent (6, 7, 13, 141). Apart from

the paraformaldehyde-containing materials, most of

the materials used in root fillings are either biocompa-

tible or show cytotoxicity only prior to setting (41–43,

142, 143). Therefore, it is highly unlikely that most of

the contemporary endodontic materials by themselves

are able to sustain a periradicular inflammation when

overfilled in the absence of a concomitant endodontic

infection. This is because tissue injury caused by

extruded sealers is usually only transient but not

persistent. This statement is reinforced by the high

success rate of the treatment of teeth without

periradicular lesions even in cases of overfilling (6,

13). In addition, one should bear in mind that when

the apical terminus of the root canal filling is at the

radiographic apex, it actually is in many cases passing

through the apical foramen, but the rate of healing

in those cases is rather high (5).

Obviously, overfilling should be prevented since post-

operative complications, such as post-filling pain, can

develop, particularly when a substantial amount of

filling material extrudes through the apical foramen.

Sealers are cytotoxic before setting and thereby have

the ability to induce tissue damage and consequent

inflammation. Gross overfillings allow the introduction

of a large volume of sealer (and its cytotoxic compo-

nents) into the periradicular tissues with a consequent

large area of contact with them, maximizing damage

and inflammation. The risk of pain in those cases is

consequently high (20).

However, disease associated with overfilled root

canals is usually caused by concomitant infections and

may occur mainly due to:

Fig. 14. Apical percolation as a result of overfilling can bethe main responsible for failures in the treatment ofpreviously infected teeth. Note the space between thegutta-percha filling and the root canal walls clearly visibleon radiographs.

Fig. 13. The quality of the root canal obturation asvisualized on a buccal–lingual radiograph is in no wayindicative that the root canal was well sealed, particularlywhen canals are oval or ribbon-shaped in transversesection. Note the discrepancy of the image taken in abuccal–lingual direction as compared to that taken ina mesio-distal direction.

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136

Apical percolation

In most cases, the apical seal is inadequate in overfilled

root canals (Fig. 14). Percolation of tissue fluids rich in

proteins and glycoproteins into the root canal system

can supply substrate to residual microorganisms, which

can proliferate and reach sufficient numbers to

induce or perpetuate a periradicular lesion. If fluid

penetrating into a previously non-infected canal or in a

properly disinfected one finds no residual microorgan-

isms, a periradicular lesion will not be induced or

maintained.

Previous overinstrumentation

Another phenomenon is likely to occur in most of the

overfilled teeth. It is well known that over-instrumen-

tation usually precedes over-filling. In infected cases,

over-instrumentation carries the risk of contamination

of the periradicular tissues by displacement of infected

debris into the periradicular tissues. Embedded in

debris, microorganisms can be physically protected

from the host defense mechanisms and thereby can

survive within the periradicular tissues and induce or

maintain periradicular inflammation. The presence of

infected dentine or cementum chips in the periradicular

lesion has been associated with impaired healing (34).

Theoretically, this can be regarded as a type of extra-

radicular infection. In fact, this may be one of the ways

Actinomyces species and Propionibacterium propioni-

cum reach the periradicular tissues to induce periradi-

cular actinomycosis (144).

Extra-radicular infection – clinicalimplications

Periradicular lesions are formed in response to intra-

radicular infection and comprise an effective barrier

against spreading of the infection to the alveolar bone

and to other body sites. In most situations, inflamma-

tory periradicular lesions succeed in preventing micro-

organisms from gaining access to the periradicular

tissues. Nevertheless, in some specific circumstances,

microorganisms can overcome this barrier and establish

an extra-radicular infection. The most common form of

extra-radicular infection is the acute periradicular

abscess, characterized by purulent inflammation in

the periradicular tissues in response to the egress of

virulent bacteria from the root canal (144). There is,

however, another form of extra-radicular infection

which, unlike the acute abscess, is usually characterized

by absence of overt symptoms. This condition en-

compasses the establishment of microorganisms in the

periradicular tissues, either by adherence to the apical

external root surface in the form of biofilm-like

structures (145) or by formation of cohesive colonies

within the body of the inflammatory lesion (146, 147).

Extra-radicular microorganisms have been discussed as

one of the etiologies of persistence of periradicular

lesions in spite of a well-performed root canal treatment

(21, 148).

Conceivably, the extra-radicular infection can be

dependent on, or independent of the root canal

infection (144). For instance, the acute periradicular

abscess is for the most part clearly dependent on the

intra-radicular infection – once the intra-radicular

infection is properly eradicated by root canal treatment

or tooth extraction and drainage of pus is achieved, the

extra-radicular infection usually subsides. However, it

should be appreciated that in some cases, bacteria that

have participated in acute periradicular abscesses may

persist in the periradicular tissues following resolution

of the acute response and establish a persistent extra-

radicular infection associated with a chronic periradi-

cular inflammation. This would then characterize an

extra-radicular infection independent of the intra-

radicular infection.

Studies using cultivation (147, 149, 150) or mole-

cular methods (151–153) for microbial identification

have reported the extra-radicular occurrence of a

complex microbiota associated with periradicular le-

sions that not respond favorably to the root canal

treatment. Anaerobic bacteria have been reported to be

the dominant microorganisms in several of those

lesions (151, 152). Because those studies did not

evaluate the bacteriological conditions of the apical part

of the root canal, it is difficult to ascertain whether

those extra-radicular infections were dependent on or

independent of an intra-radicular infection.

In the light of recent evidence brought about by

culture and molecular studies (147, 150–153), the fact

that bacteria can be located outside the root canal and

within the inflamed periradicular tissues cannot be

denied. However, the clinical implications of such

findings are far from clear. An important question is:

what is the fate of extra-radicular bacteria after proper

chemomechanical and intracanal medication procedures?

The presence of bacterial colonies outside the root

canal usually characterizes a borderline between the

Reaction of periradicular tissues

137

intra-radicular infection and the inflamed periradicular

tissues. Even so, their presence outside the canal

indicates an extra-radicular infection, which may be

dependent on the intra-radicular infection in the sense

that if the latter is eradicated the, the former can be

eliminated by the host.

In fact, most oral microorganisms are opportunistic

pathogens and only a few species have the ability to

challenge and overcome the host defenses, to acquire

nutrients and to thrive in the inflamed periradicular

tissues and, then, to establish an extra-radicular

infection. Several species of putative oral pathogens

have been detected in recalcitrant periradicular lesions

(147, 151–157). Some of them are recognized to

possess an apparatus of virulence that theoretically can

allow them to invade and to survive in a hostile

environment, such as the inflamed periradicular lesion.

For instance, it is currently recognized that some

Actinomyces species and P. propionicum are able to

participate in extra-radicular infections and to cause a

pathological entity called periradicular actinomycosis,

which is successfully treated only by periradicular

surgery (144). Some other putative oral pathogens,

such as Treponema species, Porphyromonas endodonta-

lis, Porphyromonas gingivalis, Tannerella forsythia,

Prevotella species and Fusobacterium nucleatum, have

also been detected in chronic periradicular diseases by

culture, immunological or molecular studies (149,

151–153, 155). Most of these species possess virulence

traits that can allow them to avoid or overcome the host

defenses in the periradicular tissues (158–166).

The incidence of extra-radicular infections in un-

treated teeth is rather low (75, 77), which is congruent

with the high success rate of non-surgical root canal

treatment. Even in root filled teeth with recalcitrant

lesions, in which a higher incidence of extra-radicular

bacteria has been reported, a high rate of healing

following retreatment (5) indicates that the major cause

of endodontic disease is located within the root canal

system, characterizing a persistent or secondary intra-

radicular infection. This has been confirmed by studies

investigating the microbiological conditions of root

canals associated with post-treatment disease (15, 16,

141, 167, 168). Based on this, one may assume that

most of the extra-radicular infections observed in root

filled teeth could have been fostered by the intra-

radicular infection. Thus, the usual origin of bacteria

involved with extra-radicular infections is the intra-

radicular infection.

There are some situations that permit intra-radicular

bacteria to reach the periradicular tissues and establish

an extra-radicular infection. This may be a result of

direct advance of some bacterial species that are able to

overcome host defenses concentrated near the apical

foramen or that manage to penetrate into the lumen of

pocket (bay) cysts (169, 170), which is in direct

communication with the apical foramen. This may

also be due to bacterial persistence in the periradi-

cular lesion after remission of acute abscesses. Finally,

root canal procedures can also in some way favor

the establishment of an extra-radicular infection, in

the event of apical extrusion of debris during root

canal instrumentation (particularly after overinstru-

mentation).

As discussed above, bacteria embedded in dentinal

chips can be physically protected from the host defense

cells and therefore can persist in the periradicular tissues

and sustain periradicular inflammation. The virulence

and the quantity of the involved bacteria as well as the

host ability to deal with infection will be the decisive

factors dictating whether an extra-radicular infection

will develop or not. Because there is a potential risk of

treatment failure in the event of apical extrusion of

infected debris (not to mention the recognized risk of

post-operative pain), the clinician’s choice of instru-

mentation techniques should ideally rely on those that

allow minimal extrusion. In addition, accurate estab-

lishment of the working length is paramount in

prevention of debris extrusion.

Possible systemic effects stemmingfrom endodontic infections

A revived interest in the focal infection theory has been

generated in the last few decades due to reports from

epidemiological studies suggesting the involvement of

oral microorganisms in systemic diseases (171, 172). A

focal infection is a localized or generalized infection

caused by the dissemination of microorganisms or their

products from a focus of infection, which is a confined

area that contains pathogenic microorganisms (173).

Although there is a plethora of focal infections having

the oral cavity as suspected focus, the most documen-

ted examples are bacterial endocarditis (174), brain

abscess (175) and orthopedic joint infections (173).

Oral bacteria have also been implicated in aspiration

pneumonia (176), preterm low birth weight (177), and

coronary heart disease (178). Infected root canals and

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138

periradicular lesions have been considered as potential

foci of infection (173).

There is no evidence showing that bacteremia

spontaneously arises from infected root canals asso-

ciated with a chronic periradicular lesion. On the other

hand, bacteremia can occur in cases of acute periradi-

cular abscesses and during the treatment of infected

root canals or periradicular surgery (179–185). Studies

revealed that it was far more probable that a bacteremia

occurs if root canal procedures were performed beyond

the apical foramen than when maintained within the

confines of the root canal system (182, 183). Bender

et al. (182) reported that the incidence of bacteremia

was none if the instrumentation remained within the

canal and 15% if it extended beyond the apical foramen.

Even so, the bacteremia following endodontic proce-

dures was shown to last no longer than 10 min (182)

due to clearance of microorganisms from within the

circulation. Using improved anaerobic cultivation

methods, Baumgartner et al. (184, 185) revealed that

non-surgical root canal treatment resulted in a lower

incidence of bacteremia (3%, as a result of over-

instrumentation) than surgical flap reflection (83%),

periradicular curettage (33%) or tooth extraction

(100%). In a study that performed intentional instru-

mentation beyond the apex, a 34–54% incidence of

bacteremia was detected (186).

However, it has been recently demonstrated that

bacteremia can occur even if instrumentation is

maintained within the root canal system. Debelian

et al. (187) investigated the incidence of bacteremia

following endodontic treatment of teeth with perira-

dicular lesions. In the treatment of one-half of the

patients, the first three reamers (sizes 15, 20 and 25)

were used to a level 2 mm beyond the root apex, while

in the other half, instrumentation ended inside the root

canal, 1 mm short of the apex. They found no statistical

difference when the frequency of bacteremias in the

two groups was compared. The most common micro-

organisms present within the associated bacteremia

were anaerobic bacteria. This can be explained by the

fact that all instrumentation techniques induce apical

extrusion of debris, some more than others, even when

instrumentation is confined to the interior of the canal

(188–190). If debris is infected, bacteria are launched

into the periradicular tissues and then can gain entry

into the circulation.

Therefore, there is no doubt that root canal

procedures can induce bacteremia. The questions

now are how frequently and at what magnitude

(number of bacterial cells in the blood) bacteremia

occurs, how long it persists and whether endodontic

bacteria are able to cause disease at distant sites. It is

difficult to prove that a given oral microorganism is the

causative agent of a focal infection, unless it is of the

same clonal type as that present in the oral cavity.

Although it has been demonstrated that the microbial

species present in the blood of patients undergoing

root canal treatment are of the same clonal types as

those present in their root canals (191), such findings

only mean that root canal treatment can cause

bacteremia, but not that microorganisms from the

root canal cause disease in remote sites of the body. For

bacteria present in the bloodstream to reach other body

sites and induce disease, they have to survive the host

defenses in the blood vessels as well as in the distant

body site, they have to encounter predisposing condi-

tions in the distant body site for their attachment and

further colonization, and they have to be in sufficient

numbers to induce disease.

It is apparent from well-conducted studies that oral

bacteria are rarely a cause of systemic disease (173). For

instance, periodontal pathogens are very rarely a cause

of endocarditis, with 102 reported cases due to

Actinobacillus actinomycetemcomitans, two due to

Prevotella oralis, one due to Prevotella bivia, one due

to black-pigmented anaerobic bacteria, and five due to

Veillonella species (192, 193). Except for A. actinomy-

cetemcomitans, which has been infrequently found in

endodontic infections (194, 195), the other species

have been isolated from infected root canals or

periradicular abscesses. As a matter of fact, obligate

anaerobic bacteria from the oral cavity do not appear to

survive well in other body locations and viridans group

streptococci, considered the principal oral culprits in

endocarditis, are not primary pathogens but rather

opportunistic bacteria that usually require altered

biologic tissue to induce disease (173).

Cultivation-independent procedures for bacterial

identification have revealed previously unsuspected

degrees of diversity in the microbiota present in

environmental and human-associated sites (196–

200). Studies using sophisticated molecular methods

have demonstrated that about 40–50% of the oral

microbiota is composed of as-yet uncultivable bacteria

(201–203). A similar picture has been demonstrated

for the root canal microbiota of teeth associated with

periradicular lesions (204, 205). Since many bacteria

Reaction of periradicular tissues

139

are still uncultivable, their pathogenicity and involve-

ment in causation of disease remain unknown. A study

using molecular technology revealed a large amount of

bacterial DNA in blood specimens from healthy

individuals (206) and many of the DNA sequences

detected were from unknown bacteria. The presence of

bacterial DNA in the blood has important implications

for a possible, previously uncharacterized role of some

bacterial species in some diseases, sometimes distant

from the focus of infection. It would appear that to date

no molecular study has been performed to detect the

occurrence of uncultivable bacterial phylotypes from

the oral cavity in bacteremias following endodontic

procedures. In addition, no study has evaluated the

presence of those phylotypes in remote diseases in the

body. Therefore, future research is warranted to

ascertain whether uncultivable bacteria from the oral

cavity can be involved in focal diseases.

Although there is no definitive evidence that bacteria

from infected root canals can cause systemic diseases

after bacteremia, there is a potential risk in some special

patients. Consequently, it would be prudent to avoid

certain situations that could predispose to bacteremias,

such as over-instrumentation. Over-instrumentation

induces damage to the periradicular tissues, affecting

cells, extracellular matrix and vessels. When over-

instrumentation occurs during preparation of infected

root canals, large numbers of bacteria can also be

carried into the periradicular tissues. Bacteria intro-

duced in the periradicular tissues can then enter injured

vessels and a bacteremia ensues. It has been postulated

that lymphatics, and not blood vessels (where the

pressure gradient is outward and not inward after

trauma), may be the primary means of entry of oral

bacteria into the blood (173). In addition to a higher

risk of bacteremia, as alluded to earlier, bacteria present

in the periradicular tissues may cause postoperative pain

or even the failure of root canal treatment due to an

extra-radicular infection. For all these reasons, over-

instrumentation should be avoided.

The focal infection theory has remained controversial

due to the lack of indisputable evidence regarding the

causal relationship between oral infections and other

medical conditions. In fact, non-surgical endodontics is

perhaps the least likely of dental treatment procedures

to produce a significant bacteremia in either incidence

or magnitude (173). One should bear in mind that

bacteremia can occur naturally as a result of normal

daily activities, including toothbrushing and mastica-

tion (207). Because of the 1000–8000 times greater

chance of any bacteremia originating from normal daily

activities, it is equally impossible to determine if the

bacteremia emanated from the endodontic interven-

tion or a time before or after it (173). Whatever the

origin, bacteremias are usually transient. Even so, in the

absence of clear evidence regarding the effects of

bacteremia in some compromised patients and before

elucidation of the speculative involvement of unculti-

vable bacteria, empirical consensus indicates that

antibiotic prophylaxis should be performed in patients

at risk to develop infective endocarditis. In addition,

antibiotic prophylaxis should also be considered for

immunosuppressed patients, individuals with indwel-

ling catheters or patients with orthopoedic prosthetic

devices (208).

Concluding remarks

Some of the problems that dentists face in their clinical

practice are caused or facilitated by improper (but

sometimes even proper) treatment of the root canal

system. In an attempt to accomplish the major goals of

root canal treatment, namely to prevent and/or to

control endodontic infections, clinicians use proce-

dures, substances and materials that may induce some

degree of injury to the periradicular tissues. Invariably,

periradicular tissue healing will occur uneventfully in

cases where microorganisms were successfully elimi-

nated from and/or prevented from gaining entry into

the root canal system and minimal or no damage was

inflicted on the periradicular tissues during therapy.

The worst-case scenario for periradicular tissue re-

sponse to intra-canal procedures is reflected largely in

post-operative pain and persistence of periradicular

disease despite treatment. While the development of

post-operative pain is largely a short-term response

related to the extent of tissue injury, post-treatment

disease is a long-term response influenced by the

persistence of the source of injury. Even though

chemical and mechanical factors can be involved with

unfavorable responses of the periradicular tissues to

intracanal procedures, microorganisms are the major

causative agents of post-operative pain and post-

treatment disease. In this regard, microorganisms can

be favoured when intra-canal procedures are carried

out ineffectively. For example, over-instrumentation

during treatment of infected root canals can create

conditions for both post-operative pain and post-

Siqueira

140

treatment disease. In addition, there is a higher risk of

bacteremia after over-instrumentation; the systemic

effects of this in compromised patients remain to be

clarified. The clinician should be aware of the proce-

dures and substances that can offer a better outcome

for their patients with a minimum risk of post-operative

sequelae and systemic involvement. Because micro-

organisms are the major factor related to a poor

response by the periradicular tissues to treatment, all

efforts should be directed towards prevention and

eradication of the root canal infection. Proper establish-

ment of the working length is an important step in the

pursuit of these goals. Antimicrobial treatment should

be accomplished by intra-canal procedures and sub-

stances that cause no or as little damage as possible to

the periradicular tissues, avoiding further injury of

chemical and/or mechanical origin, which could also

evoke undesirable periradicular tissue responses.

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