Evidence Report/Technology Assessment

Number 48

Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
2101 East Jefferson Street
Rockville, MD 20852

http://www.ahrq.gov/

Contract No. 290-97-0011

Prepared by:
Research Triangle Institute
James D. Bader, D.D.S., M.P.H.
Principal Investigator

Arthur J. Bonito, Ph.D.
Daniel A. Shugars, D.D.S., Ph.D.
Investigators

AHRQ Publication No. 02-E006

July 2002

On December 6, 1999, under Public Law 106-129, the Agency for Health Care Policy and Research (AHCPR) was reauthorized and renamed the Agency for Healthcare Research and Quality (AHRQ). The law authorizes AHRQ to continue its research on the cost, quality, and outcomes of health care and expands its role to improve patient safety and address medical errors.

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Bader JD, Bonito AJ, Shugars DA. Cardiovascular Effects of Epinephrine on Hypertensive Dental Patients. Evidence Report/Technology Assessment Number 48. (Prepared by Research Triangle Institute under Contract No. 290-97-0011.) AHRQ Publication No. 02-E006 Rockville, MD: Agency for Healthcare Research and Quality. July 2002.

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.

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Hypertension affects one quarter of the adult U.S. population. A systematic review of the literature was conducted to identify the additional risks of adverse cardiovascular outcomes to controlled and uncontrolled hypertensive individuals represented by the use of epinephrine-containing anesthetic solutions and epinephrine-impregnated retraction cords during dental treatment.

Two parallel searches of MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were conducted to identify reports involving cardiovascular and hemodynamic outcomes associated with the use of epinephrine in the dental treatment of hypertensive individuals. One search identified reports involving epinephrine in local anesthetic solutions, the other epinephrine in gingival retraction materials. The gray literature was not searched, and only reports in English were included in the search. We included any report where epinephrine was administered, and one or more cardiovascular parameters (blood pressure, heart rate, cardiac output, plasma epinephrine concentration, EKG changes including transient arrhythmias) or adverse events (headache, syncope, angina, hypertensive crisis, longer-term arrhythmia, cerebral vascular accident, myocardial infarction) was reported for hypertensive individuals. We selected studies for inclusion in the evidence table from among 373 local anesthetic and 33 retraction cord reports identified in the searches using independent dual review of titles, abstracts, and full papers. We abstracted data into the table for six reports for local anesthesia. No studies of retraction cord met the inclusion criteria.

Five of the studies reported blood pressure and heart rate changes associated with use of epinephrine in local anesthetics in uncontrolled hypertensive patients. One study reported results among controlled hypertensives. We did not meta-analyze these results due to incomplete information describing variability. In general, hypertensive subjects receiving an extraction experience small increases in systolic blood pressure and heart rate associated with the use of a local anesthetic containing epinephrine (4 mm Hg and 6 bpm). These increases associated with the use of epinephrine occur in addition to increases in systolic and diastolic blood pressure and heart rate associated with undergoing the procedure without epinephrine (11.7 and 3.3 mm Hg and 4.7 bpm) that are larger for hypertensives than for normotensives. No adverse outcomes were reported in these studies, and only one case report of an adverse outcome associated with the use of epinephrine in local anesthetic in a hypertensive patient was identified in the literature. However, we judged the strength of the evidence for answering the question addressed by the review as poor. The available studies did not address effects of gingival retraction cord, and only one study examined effects of epinephrine in anesthetics on controlled hypertensive subjects, where additional risks due to interactions with antihypertensive medications are possible. Further, the five studies examining effects in uncontrolled hypertensive subjects examined a narrow range of outcomes, and their designs made it unlikely that three of the studies could detect transient changes in outcomes that might indicate increased risk for adverse events.

The quantity and quality of the pertinent literature is problematic. The reported occurrence of adverse events in hypertensives associated with the use of epinephrine in local anesthetics is minimal, and the increased risk for adverse events among uncontrolled hypertensives is low, according to the authors of the studies that have examined this issue. However, these studies, as a group, do not offer strong evidence for this conclusion because the ability of the studies to detect signs of increased risk, mainly transient changes in cardiovascular and hemodynamic parameters, was limited. Further, no information is available to quantify the risk of using epinephrine-impregnated gingival retraction cord in hypertensive individuals, or epinephrine-containing local anesthetics in controlled hypertensives.

The question addressed by this systematic review is whether there is evidence of added risk of adverse events posed by the hemodynamic and cardiovascular effects of epinephrine when it is used in the dental treatment of hypertensive individuals. About 24 percent of the U.S. adult population is hypertensive, when hypertension is defined by a mean systolic blood pressure of 140 mm Hg or greater, a diastolic blood pressure of 90 mm Hg or greater, or use of prescription antihypertensive medication. Of this hypertensive population, 48 percent are untreated, 24 percent are successfully treated, and 28 percent are inadequately treated. Thus, hypertensive individuals, both controlled and uncontrolled, will represent a substantial proportion of a typical dental practice's adult patients.

Epinephrine is widely used as an additive in local anesthetics (typically in concentrations of 1:100,000) to improve the depth and duration of the anesthesia, as well as to reduce bleeding in the operative field. Epinephrine counteracts the anesthetic's localized vasodilator effects in subcutaneous and submucosal vessels, thereby reducing the risk of anesthetic toxicity by decreasing the rate of systemic absorption from the site of injection. Epinephrine is also impregnated in cotton cord that is inserted into the sulcus between a tooth and the surrounding gingiva, improving access for tooth preparation and allowing dental impression material to more readily flow into the sulcus to record details of teeth prepared for crowns. The epinephrine also constricts the blood supply to adjacent tissue, thereby permitting the impression to be secured without contamination by bleeding.

Despite these benefits, which may not be as readily achievable through use of non-epinephrine preparations, the clinical significance of cardiovascular and hemodynamic changes caused by the introduction of exogenous epinephrine makes its use among hypertensive individuals a controversial subject in dentistry. The added risks attributed to the use of epinephrine in hypertensive patients include greater probability of acute hypertensive crisis, angina pectoris, and myocardial infarction, as well as cardiac arrthymias through the direct action of epinephrine; and acute hypertensive or hypotensive crisis brought about by the interaction of epinephrine and some antihypertensive medications.

Recommendations for the use of epinephrine in clinical dental practice are not in full agreement. Most recommendations advise caution in using local anesthetics with epinephrine in hypertensive patients. However, some indicate that epinephrine is contraindicated in controlled hypertensive patients taking medications with known epinephrine interactions, while others indicate that epinephrine use is acceptable with appropriate precautions and monitoring. Opinion about the use of epinephrine in uncontrolled hypertensives is also divided, with some cautioning against it, while others indicate that it is appropriate in most instances. Virtually all recommendations discourage the use of epinephrine-impregnated gingival retraction cord in uncontrolled hypertensives, including those of manufacturers.

The key question for this systematic review is stated as, "What additional risks of adverse cardiovascular outcomes do epinephrine-containing local anesthetic solutions and epinephrine-impregnated gingival retraction cords represent for controlled and uncontrolled hypertensive individuals receiving dental treatment?" Because adverse events are relatively rare, we examined the literature for studies reporting changes in risk indicators for adverse events, as well as for adverse events themselves. We defined adverse events as headache, syncope, angina, hypertensive crisis, longer-term arrhythmia, cerebrovascular accident, and myocardial infarction. We considered risk indicators to include changes in blood pressure, heart rate, and stroke volume, and plasma epinephrine concentration, and EKG disturbances including transient arrhythmias.

We conducted separate literature searches focusing on effects of epinephrine in anesthetic solutions and in gingival retraction cord. In both instances we searched MEDLINE initially, with additional searching conducted in EMBASE and the Cochrane Controlled Trials Register. No attempt was made to search the gray literature, i.e., dissertations, theses, unpublished studies, abstracts, industry reports, and other nontraditional sources. We limited the searches to English-language reports. Subsequently, we examined reference lists of studies identified in these searches to include additional reports of possible interest. We identified 373 reports addressing the use of epinephrine-containing local anesthetics and 33 addressing epinephrine-impregnated gingival retraction cord. We then reviewed these studies for possible inclusion in the evidence table. We used essentially identical inclusion criteria in both reviews that addressed the inclusion and separate analysis of known hypertensive subjects, exposure to known concentrations of epinephrine through receipt of an intraoral injection or application of gingival retraction cord, recording of at least one cardiovascular or hemodynamic outcome, and a dental setting with dental treatment provided. We used independent dual review and eventually identified six local anesthetic studies that met the criteria for inclusion. No retraction cord papers met the criteria because no studies included hypertensive subjects.

We abstracted data from the included studies directly into the evidence table. We did not meta-analyze the results because two of the studies reported no information describing variation about the mean. We rated the quality of each included study using a rating scale that assessed several elements of internal and external validity, including sample size, presence of a comparison group of normotensive subjects, use of control groups (without epinephrine), outcomes reported, measurement methods, statistical testing, determination of hypertensive status, and reporting issues. We then graded the strength of the combined evidence, using a three-category system. The evidence was considered to be good if the numbers of studies and subjects were large (10 or more studies, 500 or more subjects); the quality of the studies was generally high (median quality score of 70 or higher); the results of these studies were consistent; and, taken together, the results were comprehensive with respect to risks examined. The evidence was considered to be fair if the numbers of studies and subjects were adequate overall (5 or more studies, 200 or more subjects); the quality of the studies was generally acceptable (median of 55 or higher); the results of these studies were reasonably consistent, with inconsistencies reflected as quantitative rather than qualitative differences; and the principal known risks were adequately examined. The evidence was considered to be poor if the numbers of studies and/or subjects were small (fewer than 5 studies or 200 subjects) or the quality of the studies was generally low (median of less than 55); or there were substantial inconsistencies in the results, or the risks examined among the studies did not represent a reasonably complete assessment of known risks.

The six included studies comprised 325 subjects, of whom 177 were identified as hyper-tensive. Of these, 14 percent were identified as taking medication for control of hypertension. In all studies the local anesthetic involved was 2 percent lidocaine, and epinephrine concentrations were divided between 1:100,000 (n=3 studies) and 1:80,000 (n=3 studies). Quantities of anesthetic solution injected were reported in four studies, with means ranging from 2 ml to 4.5 ml. The outcomes examined in these studies consisted principally of systolic and diastolic blood pressures and heart rate. EKG recordings were collected in two studies. The dental procedure involved was tooth extraction in five of the six studies, and "minor oral surgery" in the sixth.

The results suggest that hypertensive subjects receiving an extraction experience small increases in systolic blood pressure and heart rate associated with the use of a local anesthetic containing epinephrine (4 mm Hg and 6 bpm). These increases associated with the use of epinephrine occur in addition to increases in systolic and diastolic blood pressure and heart rate associated with undergoing the procedure without epinephrine (11.7 and 3.3 mm Hg and 4.7 bpm) that are larger for hypertensives than for normotensives. No adverse outcomes were reported among any of the subjects in the studies included in the review, and only one report of an adverse event associated with the use of epinephrine in local anesthetic in a hypertensive patient was identified in the literature.

We rated the strength of the evidence as poor for describing additional risks among controlled and uncontrolled hypertensives due to epinephrine-containing local anesthetic solutions and gingival retraction cords. These ratings result from both the number of available studies and their quality. For outcomes of the administration of local anesthetic solutions containing epinephrine to patients taking medications for the control of hypertension, one study comprising 14 subjects and two medications was available. Two other studies included patients taking antihypertensive medications, but outcomes were not reported separately. No studies described outcomes of the use of gingival retraction cord either for hypertensive patients or for those taking medications for the control of hypertension. There were five studies addressing outcomes of the use of epinephrine-containing anesthetic solutions in hypertensive patients. The strength of this evidence was rated as poor because the outcomes considered in the studies did not represent a reasonably complete assessment of risk indicators, and because transient effects in blood pressure and heart rate, the principal outcomes reported, might have remained undetected in three of five studies.

Based on the available evidence, which suggests that adverse outcomes among hypertensive patients are infrequent and that hemodynamic outcomes, which may be viewed as risk indicators, reflect only minimal change, replication of existing studies does not represent an efficient method to further our knowledge of the risks for adverse cardiovascular outcomes associated with use of local anesthetics containing epinephrine. Rather, a large-scale descriptive study of adverse outcomes of the use of epinephrine-containing local anesthetics would seem to be indicated. A long-term protocol initiated in one or more large dental clinics that involves electronic capture of pre-existing cardiovascular diagnoses and medication status of all patients, together with information describing all adverse outcomes occurring during treatment, could begin to quantify the magnitude of additional risk represented by the use of epinephrine in hypertensive dental patients with minimal outlay of effort and expense. Only if the results of such an investigation indicate that the added risk is greater than deemed acceptable would additional trials to develop more sensitive methods for identifying patients at increased risk be justified.

With respect to the use of epinephrine-impregnated gingival retraction cord, studies are needed to quantify the absorption of epinephrine from gingival tissues. The effects of time, tissue condition, cord construction, and epinephrine concentration on plasma concentration of epinephrine should be determined in these studies. Once a better understanding of the possible range of epinephrine concentrations is gained, the risks associated with the use of these cords in hypertensive patients can be evaluated. At present, a single human study reports absorption levels.