James IV Article

Dentistry and the medically compromised patient

R.A. Seymour
School of Dental Sciences, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne NED2 4BW

Correspondence to: R.A. Seymour, School of Dental Sciences, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne NED2 4BW

Introduction Infective endocarditis Joint prosthesis infections Corticosteroids

Co-morbidity Conclusions References

Keywords: Infective endocarditis, chemoprophylaxi’s corticosteroids, gingival overgrowth
Surg J R Coll Surg Edinb Irel., 1 August 2003, 207-214

Certain medical conditions and their accompanying drug treatment do have an impact upon oral structures and the delivery of dental care. Recent evidence suggests that oral health could be a significant risk factor for coronary artery disease. Many medical conditions can affect dental care are often over-stated and lack an evidence base. Examples include the need for antibiotic cover in patients at risk from infective endocarditis and the necessity to provide supplementary corticosteroids for those patients on longterm steroid therapy. By contrast, certain systematic drug treatments can have a profound affect on the oral tissue. The most obvious is drug-induced gingival overgrowth. Drugs frequently implicated in this unwanted effect include phenytoin, ciclosporin and the calcium channel blockers. Several risk factors for drug-induced overgrowth have been identified and include age, sex, peridontal variables and a range of drug pharmaco kinetic variables. The relationship between oral health and coronary artery disease opens up a potentially new vista for the delivery of oral care. Although the association is convincing, casualty has not been established. If casualty for this relationship can be confirmed then the delivery of dental care and the promotion of oral health will receive a significant impetus

INTRODUCTION
The improvement in environmental conditions, public health measures and medical care over the past 50 years has significantly increased life expectancy. This improvement is also paralleled in oral health with many patients retaining their teeth into old age.¹ One aspect of these changes that is translated into dental practice is an increase in both the number and complexity of medically compromised patients attending for routine dental care. Such patients are of concern to the dental practitioner and their management problems can be categorised as follows:

• Effect of the patient's medical problem and drug therapy on the delivery of dental treatment

• Specific oral and dental problems that can arise from either the underlying medical condition or from a the patient's medication

• Possible interaction between the patient's oral health and their general health

For each of these categories, it is possible to identify specific examples which have a significant impact upon dental practice.

Two common examples that will be addressed under this heading are the need for chemoprophylaxis in patients at risk from dental-induced bacteraemia and the management of patients on long-term corticosteroids. In the former, the two main categories are the prevention of infective endocarditis and antibiotic prophylaxis for patients with hip and joint prostheses.

INFECTIVE ENDOCARDITIS

Chemoprophylaxis for the prevention of infective endocarditis
Chemoprophylaxis to prevent infective endocarditis arising from a dental-induced bacteraemia remains one of the most controversial subjects in dental practice. The main questions raised on this topic include:

• Is infective endocarditis caused by a dental procedure-induced bacteraemia or spontaneous bacteraemia? 

• Which patients are at risk from infective endocarditis?

• Which procedures require antibiotic cover?

• Are the risks of providing such cover greater than the risks of contracting infective endocarditis?

• Are the antibiotic regimens effective?

Although these questions are frequently asked, there is little evidence-based material to address the issues. A major problem with trying to provide answers to these questions is the lack of randomised controlled trials to evaluate the efficacy of antibiotic cover. Such a study would require at least 6000 patients and would raise considerable ethical issues.²

Dental procedures and infective endocarditis
Poor oral health, especially periodontal status, is an important risk for infective endocarditis. In theory, any procedure that involves manipulation of the gingival tissues can result in a bacteraemia. The magnitude of the bacteraemia will vary according to the procedure (Table 1). It has now been shown that similar bacteraemia can arise from chewing and various oral hygiene practices (Table 1), and these activities are responsible for so-called random or spontaneous cases of bacteraemia.³ Dental treatment is often regarded as a cause of infective endocarditis. In many instances, the occurrence of endocarditis does not relate to the so-called dentalinduced bacteraemia. It may well transpire that random or spontaneous bacteraemia may be more causative in infective endocarditis than dental surgeons carrying out treatment.

It has been estimated that 4% or less of all infective endocarditis cases are related to dental-induced bacteraemia.^4,5 Whether such bacteraemia arises from dental treatment or were spontaneous is not discernible. It is suggested that if spontaneous random bacteraemia causes 96% of all cases of infective endocarditis, then random oral bacteraemia, as opposed to those arising from dental treatment, may also have caused the remaining.⁶

Three major studies have investigated the link between dental procedures and infective endocarditis.^7-9 The conclusion from the Dutch studies suggested that strict adherence to the generally accepted recommendations for chemoprophylaxis might do little to decrease the total number of patients with endocarditis in the community. The findings from the Strom et al (1998) study are far more reaching. ⁹ They found that dental treatment was no more frequent among cases of infective endocarditis than controls (adjusted odds ratio 0.8), and that among cases with known cardiac lesions (the target of antibiotic cover) dental treatment was significantly less common than amongst controls. The authors concluded that the lack of a link between dental treatment and infective endocarditis, together with the rare occurrence of this disease, does not justify the routine use of antibiotic prophylaxis.

Identifying patients at risk from infective endocarditis
The most detailed list of patients at risk from infective endocarditis has been published by the American Heart Association (AHA).¹⁰ They categorise patients as either high, moderate or negligible risk based upon their cardiac history. The main problem with categorising patients or their cardiac history relates to mitral valve prolapse (MVP). This is a common condition that affects about 5% of the adult population.¹¹ 

However, it is only those patients who have valvular prolapse with regurgitation and/or thickened leaflets that are at risk from endocarditis. Mitral valve prolapse can only be diagnosed/confirmed by angiography or from echocardiograms. In the majority of cases neither the patient nor the dental surgeon will be aware of any mitral valve disorders and will receive treatment without antibiotic cover. Guidelines on identifying patients at risk from infective endocarditis vary from country to country. The consensus view is that antibiotic cover is often over prescribed for many seemingly innocuous cardiac conditions.

Which procedures require cover?
The AHA guidelines are prescriptive in identifying the various dental procedures that require cover.¹⁰ There may be concern amongst dental surgeons over procedures such as probing periodontal pockets, endodontics within the confines of the root canal, placement of subgingival antibiotics fibres and prophylactic cleaning of the teeth. Whilst bacteraemia arising from such procedures have not been quantified, they are likely to be similar in magnitude to the bacteraemia arising from toothbrushing or other oral hygiene practices. This does question whether such dental procedures require cover whilst patient generated bacteraemia are not covered. Whilst the AHA guidelines to provide cover for certain dental procedures may be an overstatement, they do need to be adhered to until evidence becomes available that will refute them.

Comparing the risk of antibiotic cover with the risk of contracting infective endocarditis
When antibiotics are given prophylatically to prevent infective endocarditis, the dental surgeon needs to consider the risk and cost benefit of such treatment. The most significant adverse event associated with the penicillins is hypersensitivity reactions. The chance of a penicillin reaction following administration of the drug is in the range of 0.7-5%.¹² This prevalence does vary with the route of drug administration, with the intramuscular route causing a 5% prevalence and oral penicillin a 0.3% prevalence of a hypersensitivity reaction. However, high doses of oral amoxicillin can cause an allergic response rate similar to intramuscular penicillin.¹³

Data from the USA show that 400-800 deaths are caused each year by anaphylactic reactions to penicillin, although only a portion of these will arise from penicillin prophylaxis to prevent infective endocarditis.¹⁴

To put the risk-benefit into perspective, it has been estimated that 1.36 people per million population are likely to die from penicillin-induced anaphylaxis to prevent infective endocarditis, whereas only 0.26 deaths per million population are due to dental procedure-induced endocarditis.¹⁵ Put another way, patients receiving penicillin (amoxicillin) prophylaxis to prevent infective endocarditis are five times more likely to die from an anaphylactic reaction to the drug than to die from contracting endocarditis if no cover was provided. Thus, it would appear from these statistics that the risk of providing cover to prevent infective endocarditis is far greater than not providing cover.

Are the antibiotic regimens effective?
The overall prevalence of infective endocarditis is approximately 15 per million patients per year.4 It is interesting to note that this figure has not changed with the advent of antibiotic prophylaxis. On a global scale, at least, the provision of such prophylaxis has had little impact on the occurrence of the disease.

The efficacy of antibiotic prophylaxis to prevent infective endocarditis has not been subjected to a randomised, placebocontrolled study. Evidence, to date, on efficacy has come from case-controlled studies, animal experiments and antibiotic efficacy studies on bacteraemia after tooth extractions.¹⁶ There is now a growing consensus that antibiotic prophylaxis may not prevent infective endocarditis by a bactericidal blood activity, but it does so by decreasing microbial adherence to damaged cardiac valves or by eliminating bacteria after their attachment to valves.^17-19

The inter-relationship between dentistry, oral health, chemoprophylaxis and infective endocarditis is a complex issue which will continue to cause confusion within the dental profession. Current guidelines issued by the British Society for Antimicrobial Chemotherapy need to be adhered to, despite the fact that there are many holes in the evidence. It is the spectra of litigation that often clouds our thinking on the need to provide antibiotic cover. Further investigations are required to try and resolve the many issues raised so far. It may well transpire that simple local measures (such as the local application of antiseptics) may be more beneficial and considerably safer than exposing patients to high doses of systemic antibiotics.

JOINT PROSTHESIS INFECTIONS

Chemoprophylaxis for patients with hip and joint prostheses
Chemoprophylaxis prior to dental treatment for patients with joint prostheses still remains a contentious issue. As with infective endocarditis the following questions need to be addressed:

• Does dental-induced bacteraemia cause haematogenous infections in patients with joint prostheses?

• Does antibiotic prophylaxis prevent such infections?

• What is the cost-risk benefit of providing such cover?

Does dental-induced bacteraemia cause haematogenous infections in patients with joint prostheses?
It is now regarded as routine practice to give antibiotic prophylaxis prior to hip or other joint replacements. Such use of antibiotics has reduced the prevalence of post-operative infection to about 1%. This suggests that nearly all joint infection arises from wound contamination and not from haematogenous spread.

To establish whether a dental-induced bacteraemia has caused a joint infection, it is necessary to confirm the following criteria: (a) the same organism must be isolated from the oral site and infected joint; (b) the presence of the organism must be confirmed with a positive blood culture; (c) the timing of the dental event and the procedure carried out must relate to the onset of the joint infection. DNA fingerprinting techniques have to be utilised to confirm that isolates from infected joints are the same as those found in the mouth.

The evidence linking dental treatment to joint infections is sparse and inconclusive. It has been shown in a six-year prospective study that the incidence of joint infections is low (3 per 1000 patients). Of these 1000 patients, 224 had undergone an invasive dental procedure, with chemoprophylaxis, and none of the 1000 patients experienced a joint infection.²¹ Two further reviews of patients with joint infections implicated skin on soft tissue infections as being the most likely primary cause.^22,23 Four out of the 110 cases were attributable to Viridans streptococci.²³ It is interesting to note that all four patients had a recent experience of an acute dental infection, which emphasises the need for good oral health before patients are fitted with a joint prosthesis.

An analysis of 2,693 patients, in whom four total prosthetic hip joints had been placed, showed an incidence of joint infections of approximately 1%.²⁴ In only one of these patients was the infection temporally associated with previous dental treatment. As with so many cases, the imprecise microbiological data were unable to confirm whether the infection arose from an oral source. The authors concluded that the data did not support the practice of chemoprophylaxis for patients with prosthetic joints prior to dental treatment.

Although the evidence linking dental treatment-induced bacteraemia to prosthetic joint infection is somewhat tenuous, such infections are serious. Most of the infections are caused by staphylococci (> 66%) and only 4.9% are due to Viridans streptococci of possible oral origin. Again, it has not been determined whether such bacteria enter the circulation spontaneously or from dental treatment. It should be emphasised that Viridans streptococci can come from non-oral sources such as the colon. Thus, from an analysis of joint infections, it is difficult to justify antibiotic prophylaxis prior to dental treatment.

Risk-benefit of providing antibiotic cover

If antibiotics are justified to prevent haematogenous infections then benefits have to outweigh the risks that are associated with these drugs.

It has been estimated that approximately 70,000 hip and knee replacements are performed in the UK every year and the number is likely to increase. The value of providing antibiotic cover to these patients needs to be evaluated against the risk of both joint infections when no cover is provided and adverse reactions to the antibiotics utilised. Such information has been subjected to a decision utility analysis, and the results are shown in Table 2.²⁵ A safer, but more costly option appears to be provided by cephalexin, but the reduced prevalence of joint infections needs to be balanced against the risk of an anaphylactic reaction to the drug.

Other cost-effectiveness studies have been carried out in which the cost of treating a joint infection, should it arise from dental treatment, was compared with the cost of providing antibiotic cover for such dental treatment.²⁶ The calculated risk of an infection from dental treatment in these patients is 0.03 per 100,000 patients with joint prostheses. Treating such infections (which also includes joint replacements) is approximately £15,000 per patient, giving a total cost of £450,000. Providing these patients with antibiotic cover will cost just under £1 million. If penicillin or amoxicillin is the drug of choice, then in this cohort of patients there is likely to be 5000 possible adverse reactions to penicillin and 40 cases of anaphylaxis would be expected to occur. The evidence on cost-benefit seems to demonstrate that antibiotic cover with either amoxicillin or penicillin is not cost-effective when compared with no prophylaxis. On purely financial terms, it is cheaper to provide no prophylaxis and treat joint infections as and when they arise as opposed to providing antibiotic cover. Other factors that need to be entered into the equation include litigation costs of the joint infection and  replacement. However, this needs to be considered against the background of the cost associated with the life threatening condition of anaphylaxis, the development of resistant strains arising from antibiotic misuse and the increased risk of super infection in an ageing population.

The need for antibiotic cover prior to dental treatment for patients with prosthetic joints seems to be driven exclusively by orthopaedic surgeons. The supportive evidence for such an indication appears equivocal at best and does not seem based upon a clear understanding of oral bacteraemia arising either spontaneously or from dental treatment. It has not been established in a randomised, placebo controlled study whether any of the antibiotic regimens recommended are efficacious. The low prevalence of joint infections and the high occurrence of dental treatment would suggest, as with infective endocarditis, a large number of patients will be required to provide meaningful information.

Antibiotics recommended are not without risks and anaphylaxis from amoxicillin is a much more likely event than a joint infection. Even on a cost basis, it is more expensive to provide cover than to treat a joint infection.

Thus, the case for antibiotic cover prior to dental treatment in patients with joint prosthesis is weak or virtually non-existent. If the risk of cover is greater than the risk of joint infection, and this is added into the equation, then the whole argument falls apart. Litigation and potential conflict with patients and their orthopaedic surgeon does cloud the issue. Certainly, when dental surgeons are placed in such a situation they would benefit from National Guidelines that all parties have to adhere to.

CORTICOSTEROIDS
A further dilemma for the dental surgeon is whether to prescribe steroid cover to patients on long-term corticosteroids prior to any stressful dental treatment and, thus, prevent an adrenocortical crisis. Although physiological adrenocortical suppression does occur when exogenous steroids are taken, evidence from recent studies suggests that such suppression is not clinically significant.^27,28

We have subsequently tested this hypothesis in a group of organ transplant patients on long-term prednisolone, who required bilateral gingival surgery (gingivectomy). Such patients often have the need for two surgical episodes, and this affords the opportunity to carry out a randomised, placebo-controlled study with patients acting as their own controls.²⁹ In brief, 20 patients who required bilateral gingivectomy participated in the investigation. Before one surgical episode they received 100mg of hydrocortisone hemisuccinate IV and for the subsequent surgery they received a placebo injection. Blood pressure was measured throughout a three-hour investigation period. The results showed that both systolic and diastolic measures were practically identical after each treatment.

The conclusions from the study were that organ transplant patients on long-term immunosuppression with prednisolone showed no significant changes in their blood pressure measurements when subjected to gingival surgery under local anaesthesia. Furthermore, these patients do not require supplementary corticosteroids prior to surgery.

Whilst these conclusions apply to organ transplant patients we feel they can be extrapolated to all patients on long-term corticosteroids who need to undergo dental treatment. It would seem that the need for steroid cover is very overstated and from the dental perspective has little or no relevance in the management of patients on long-term steroids. However, such a statement would not be applicable to those patients with Addison's disease.

CO-MORBIDITY AND MEDICATION
Specific oral and dental problems can arise from either the underlying medical condition or the patient's medication. It is the latter category which causes problems to the dental surgeon.

Drug-induced gingival overgrowth
Drug-induced gingival overgrowth is a troublesome, unwanted effect  associated with the chronic usage of phenytoin , cyclosporin and the calcium channel blockers.³⁰ Of the latter, nifedipine is the drug most frequently implicated, but this may be a reflection on its widespread use. Our research on this unwanted effect has been focused on the prevalence and risk factors for its development and expression.^31,32 Risk factors for the prevalence of drug-induced gingival overgrowth include age, and gender, with young people, and males being more susceptible.

A range of drug variables have been suggested as risk factors, ranging from dose, duration of therapy, serum, salivary and concentrations of the drug in gingival creviculer fluid.³³ Other drugs taken by the patient can also affect the expression of overgrowth. For example, nifedipine increases the expression of cyclosporininduced gingival overgrowth, whilst azathioprine and prednisolone seem to have a protective action.³⁴ For phenytoin-induced gingival overgrowth, concomitant medication with either carbamazepine or primidone increases the severity of this unwanted effect.³⁵

A variety of periodontal variables can affect the extent of drug-induced gingival overgrowth.³² The more plaque-induced inflammatory changes in the tissues, the more pronounced the overgrowth. Genetic variables may also influence the drug-induced gingival changes, as well as other factors including P450 polymorphism and histocompatability lymphocyte antigen expression.³⁶

Management of drug-induced gingival overgrowth remains a significant challenge. Surgery is the principal option and the improved gingival contours facilitate plaque control. Despite good oral hygiene, some patients appear to be particularly susceptible to this unwanted effect and undergo repeated surgical procedures to resolve the problem.^37,38

Peridontal disease is a risk factor for coronary artery disease
In the early 1990s, evidence was emerging that suggested poor oral health, especially the extent and severity of periodontal disease, was significantly associated with coronary artery disease and myocardial infarction. This evidence was summarised in a review article and subsequent studies have reinforced the association.³⁹

In the late 1980s and early 1990s, small cross-sectional studies showed that patients with a recent history of myocardial infarction or coronary artery disease had poorer oral health than age- and sex-matched controls.³⁹ The significance of oral health as a risk factor for coronary artery disease (CAD) remained after adjustments were allowed for other risk factors. Two further longitudinal studies provided further evidence that poor oral health, especially periodontal disease, was a significant risk factor for CAD.^40,41 The study by Beck et al (1996)⁴¹ generated odds ratios for periodontal disease as a risk factor for CAD. Such calculations enable the risk of periodontal disease to be put into perspective for other recognised risks for CAD. The extent and severity of periodontal disease generated odds ratios of 1.5 and 1.9 for CAD and death arising from CAD. These values are very similar to those generated from smoking histories in the same patients.

The only study at variance with those reported above arose from a questionnaire delivered to 44,000 male health professionals, 50% of these were dentists.⁴² Their conclusion was that tooth loss may be associated with an increased risk of CAD where there is a positive history of periodontal disease. However, a reported history of periodontal disease per se was not a significant risk factor for CAD.

To date, some 17 studies have been published on the association between periodontal disease and heart disease (for review see Seymour et al (2003).⁴³ These  studies have used a range of outcome measures to assess the increased risk of CAD or atherosclerosis in individuals with poor oral or periodontal health, often concentrating on fatal coronary events or further myocardial infarctions. The scale of the risk has varied according to the study methods, but the increased  risk quoted is typically in the order of around a 50% increase.

The primary problem when attempting to measure the presence or the scale of a risk to cardiovascular health from poor oral health is one of confounding variables. Periodontal disease, in particular, shares known risk factors with CAD (such as smoking, stress and lifestyle). Before a realistic risk can be identified and calculated, all of the likely confounding variables need to be accounted for.

In an attempt to rationalise what is becoming a bit of an epidemiological soup, two recent approaches are worthy of specific mention. A meta-analysis by Danesh (1999) looked only at prospective longitudinal studies (five in total).⁴⁴ The  analysis revealed that individuals with dental disease yielded a combined risk ratio for CAD of 1.24 (95% confidence intervals of 1.11.38), compared with those who were free from dental disease. This is equivalent to a 24% increase in the risk, so those with periodontal disease were nearly one quarter as likely again to have CAD. This suggests that the observed relationship was real, but only rather weak.

The other study of particular note is that by Hujoel et al (2000).⁴⁵ This was a very carefully modelled analysis based on epidemiological follow-up of the first US National Health and Nutritional Examination Survey (NHANES 1) data set. In this study, the confounding variables are much more carefully and sensitively modelled than in any of the other previous follow-up studies. There was an increased risk of serious CAD events where there was periodontal disease, but this just failed to reach a level of statistical significance. While the modelling of confounding variables in this study was very careful, there was a major problem with the quality of the periodontal data which, by current standards, is relatively crude. By contrast, the study by Arbes et al (1996), based on a cross-sectional analysis of NHANES III data, suggested a close response relationship between carefully measured periodontal variables and CAD.⁴⁶ They showed that the more severe the periodontal destruction the greater the likelihood of CAD.

The question that needs to be addressed is whether the association between periodontitis and CAD is causal? Epidemiological evidence has shown that 12 out of 14 studies show a significant association. The two remaining studies showed a weak or non-significant association. It should be emphasised that the nature of both periodontitis and CAD is multi-factorial and some degree of caution should be exercised when implicating periodontal disease in the causation of CAD and further coronary events.

Several putative mechanism have been explored to explain the association between periodontal disease and CAD. These include a periodontallydiseaseinduced increase in white blood cell count, fibrinogen and C-reactive protein; bacterial plaque-induced enhancement of platelet aggregation; the invasion of aortic and heart endothelial cells with P gingivalis; a periodontitis-induced hyperlipidaemia and a periodontitisinduced oxidative stress that could contribute to the formation of oxidised low density lipoproteins.^47-54

Despite elucidating such mechanism, there still remains the question of causality. Dental Practitioners need to know whether improving a patient's periodontal health has an impact on preventing CAD or reducing further coronary events in those with established disease. Correctly designed and executed studies need to be completed to ascertain whether periodontal intervention has an effect on preventing CAD. If the results of such studies are positive, then the dental profession will play a major role in preventing the most significant life-threatening disease in the Western World.

CONCLUSIONS
I have tried to identify those various medical conditions that can impact upon the oral and dental tissues and also affect the delivery of routine dental care. In many instances where medical problems have the potential to affect dental treatment (e.g. patients at risk from infective endocarditis, and those on long-term corticosteroid therapy), the case is often overstated and not evidence-based. By contrast, systemic drug therapy does have a marked effect on the oral and dental structures and strategies need to be put in place to try and reduce such unwanted effects. Finally, there is evidence that oral health may be a risk factor for important conditions such CAD. If causality for this relationship can be confirmed then delivery of dental care and promotion of oral health will receive a significant impetus.

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Copyright: 28 April 2003