Contraindications for Vasoconstrictors

Contraindications for Vasoconstrictors

Below, we review the contraindications for sympathomimetic vasoconstrictors (epinephrine, norepinephrine, and levonordefrin) in three sections: absolute contraindications, relative contraindications, and contraindications of little relevance. In the last part, we examine the contraindications to felypressin. We also explain that, although there is potential for further research, including well‐designed studies on the effects of local anesthetics with vasoconstrictors, most clinical studies on the doses and regimens used in dentistry have shown that these solutions are very safe and that relatively few cases of adverse effects have been reported (Brown and Rhodus 2005).

Absolute Contraindications

Below, we analyze some situations in which sympathomimetic vasoconstrictors, especially epinephrine, are absolutely contraindicated and cannot be used (Table 10.1).

Uncontrolled Insulin‐dependent Diabetes Mellitus

Administration of epinephrine in healthy patients increases plasma levels of the drug, therefore when levels of 150–200 pg/ml are reached (as with administration of two cartridges of a 1:100 000 solution [10 μg/ml]) (Annex 16), the blood sugar level increases (Clutter et al. 1980) as glucose is released by the liver as a result of increased neoglycogenesis (Christensen 1979; Hamburg et al. 1980). Furthermore, when blood epinephrine levels greater than 400 pg/ml are reached (as with administration of five cartridges of a 1:100 000 solution [10 μg/ml]) (Annex 16), release of insulin is inhibited through the direct action of epinephrine on the cells of the pancreas (Christensen 1979; Hamburg et al. 1980), thus aggravating the increase in plasma glucose (Clutter et al. 1980).

Studies on intraoral injection of anesthetic solutions with epinephrine confirm this data (Meechan et al. 1991a; Meechan 1996). In addition, the anxiety felt by the patient (as is often the case in the dentist’s office) worsens the situation by activating the sympathetic nervous system and increasing the release of glucose to the bloodstream (Christensen 1979; Hamburg et al. 1980; Berk et al. 1985). Increased blood glucose (glycemia) for 20–30 minutes is well tolerated by healthy persons (Meechan et al. 1991a; Meechan 1991b, 1996).

Such situations are very serious in diabetic patients (Christensen 1979) and are worse for patients with insulin‐dependent diabetes mellitus (Berk et al. 1985). Nevertheless, both types of patients can be treated at the dentist’s office and receive anesthetic solutions with epinephrine, provided they are carefully monitored (Dos Santos‐Paul et al. 2015). It is important to remember that these patients, and any patients with uncontrolled systemic disease, are considered ASA (American Society of Anesthesiologists) III (Wilson et al. 2008). However, most insulin‐dependent diabetic patients are young and need considerable discipline to administer insulin, maintain a balanced diet, and take regular and well‐planned physical exercise. These requirements are often difficult to meet owing to the fact that young people participate in sports, group activities, and activities that do not facilitate the necessary discipline for appropriate insulin treatment (Munroe 1983). In these circumstances, there is an increased risk of diabetic ketoacidosis or hyperglycemic reaction or worsening of an ongoing one (onset of these reactions is slow, usually hours or days) (Munroe 1983; Perusse et al. 1992b).

In conclusion, in patients with poorly controlled or uncontrolled insulin‐dependent diabetes, dental local anesthetic solutions with epinephrine are absolutely contraindicated (Munroe 1983; Perusse et al. 1992b). Furthermore, since these patients are considered ASA IV (Malamed 2007; Wilson et al. 2008), only emergency dental treatment (analgesics, antibiotics, etc.) is indicated for control of pain and infection (Munroe 1983).

Table 10.1 Summary of absolute contraindications for sympathomimetic vasoconstrictors.

  1. Poorly controlled or uncontrolled insulin‐dependent diabetes mellitus.
  2. Intolerance to sulfites.
  3. Severe asthma controlled by corticosteroids.
  4. Arterial hypertension due to pheochromocytoma.
  5. Consumption of cocaine in the previous 24 hours.
  6. Consumption of psychostimulants by patients with cardiovascular disease
  7. Allergy to vasoconstrictors.

Intolerance to Sulfites

Sulfites (sulfite, bisulfite, sodium/potassium metabisulfite, and sulfur dioxide) are used as antimicrobial drugs, reducing agents, and antibrowning agents in foods such as fruit, vegetables, salads, mushrooms, potatoes, shellfish, wine, beer, and juices; in addition, they are used in foods that do not contain thiamine, such as red meat (Bush et al. 1986; Simon 1986; Seng and Gay 1986). Sulfites are also used as antioxidants in various medicines, including local anesthetic solutions containing sympathomimetic vasoconstrictors (Huang and Fraser 1984; Schwartz and Sher 1985; Bush et al. 1986; Simon 1986; Seng and Gay 1986), therefore all dental local anesthetic solutions with epinephrine, norepinephrine, and levonordefrin contain sulfites (Huang and Fraser 1984; Schwartz and Sher 1985; Seng and Gay 1986). The United States Food and Drug Administration (FDA) includes sulfites in the Generally Recognized As Safe category (Bush et al. 1986; Simon 1986; Seng and Gay 1986).

Little is known about the mechanism of sensitization to sulfites (Schwartz and Sher 1985; Bush et al. 1986; Simon 1986). It is thought to result from the following: (i) release of histamine via a nonimmune pathway, (ii) action of the parasympathetic nervous system and gastrin, and (iii) deficiency of the enzyme sulfite oxidase (responsible for oxidizing sulfite to inactive sulfate). It is therefore more appropriate to talk of intolerance or reactions to sulfites than allergy until we can better determine to what extent these reactions are immunological.

The prevalence of intolerance to sulfites in the general population is unknown, although the condition is considered extremely rare (except in the case of asthmatic patients [see below]) (Bush et al. 1986). Furthermore, although it has been demonstrated that subcutaneous sensitization to sulfites is very difficult (the oral route and, even more so, the inhaled route are the most common routes of sensitization) (Goldfarb and Simon 1984; Bush et al. 1986), there have been reports of reactions (urticaria, angioedema, inflammation, dyspnea, etc.) after administration of dental local anesthesia with epinephrine solutions caused by the sulfites they contain (Huang and Fraser 1984; Schwartz and Sher 1985; Schwartz et al. 1989; Dooms‐Goossens et al. 1989; Campbell et al. 2001).

In conclusion, anesthetic solutions containing adrenergic vasoconstrictors are absolutely contraindicated in patients who do not tolerate sulfites, since these solutions contain sulfites as antioxidants.

Asthma Controlled with Corticosteroids

For reasons that remain unknown, asthmatic patients are particularly sensitive to sulfites, and it has been estimated that around 5% of asthmatics could be very sensitive to these drugs (Seng and Gay 1986; Simon 1986). Although other authors have reported this figure to be excessive (Bush et al. 1986), a more selective study has shown that not all asthmatics are the same. Thus, 8% of patients with severe asthma controlled by corticosteroids are sensitized to sulfites, whereas fewer than 1% of asthmatics who do not need corticosteroids are sensitized (Bush et al. 1986). In addition, the literature shows that most asthmatics who experience bronchospasms and reactions to sulfites are patients who need corticosteroids (Bush et al. 1986; Schwartz et al. 1989).

In conclusion, in patients with severe asthma whose disease is controlled with corticosteroids, local anesthetic solutions containing adrenergic vasoconstrictors are absolutely contraindicated, since 8% do not tolerate the sulfites used as antioxidants in these solutions. Furthermore, asthma patients whose disease is difficult to control and have frequent attacks that require admission to hospital and corticosteroids are classed as ASA IV, therefore only immediate dental treatment is indicated (analgesics, antibiotics, etc.) for control of pain and infection (Perusse et al. 1992b; Steinbacher and Glick 2001; Malamed 2007).

Pheochromocytoma‐induced Arterial Hypertension

Pheochromocytoma is an unusual tumor of the medulla of the adrenal gland that is generally benign and produces epinephrine and norepinephrine (Hickler and Thorn 1977; Cryer 2001; Keiser 2001). The most typical symptom in most cases is arterial hypertension, and the tumor is thought to cause fewer than 0.1–0.5% of diagnosed cases of hypertension (Sutton et al. 1981; Plouin et al. 1981).

The arterial hypertension produced by this tumor is permanent in 50–60% of cases, although 25–50% of cases involve paroxysmal hypertension (Hickler and Thorn 1977; Keiser 2001), that is, hypertension that takes the form of crises lasting minutes or even hours that are usually spontaneous or caused by physical effort, emotional tension, or abdominal palpation. Attacks of paroxysmal hypertension, which result from release of catecholamines, can lead to death from myocardial infarction (even in the absence of heart disease), from arrhythmias, or from brain hemorrhage (Hickler and Thorn 1977; Keiser 2001).

In conclusion, sympathomimetic vasoconstrictors are contraindicated in patients with pheochromocytoma owing to the risk of fatal heart abnormalities or cerebrovascular accidents (Perusse et al. 1992b). In addition, these patients can be considered ASA III or IV depending on the degree of severity.

Recent Consumption of Cocaine

Cocaine was addressed in Chapter 1, since it was the first local anesthetic, and in Chapter 12, since it is a topical anesthetic that is still in use. Illegal consumption of and addiction to cocaine in developed countries cause serious medical and social problems (Friedlander and Gorelick 1988; Goulet et al. 1992).

Cocaine taken intranasally is quickly inactivated on entering the bloodstream by plasma pseudocholinesterase. However, it remains in blood for more than 6 hours, with a peak at 60 minutes and a half‐life of 1.5 hours (Annex 11). This is because the drug remains in the mucosa for more than 3 hours owing to its vasoconstrictive effect (Van Dyke et al. 1976). Consumption stimulates the central nervous system (CNS) and peripheral sympathetic nervous system (Benchimol et al. 1978; Pasternack et al. 1985) with generalized sensitization of the body to the action of catecholamines (Tainter et al. 1949; Tye et al. 1967; Benchimol et al. 1978; Kossowosky and Lyon 1984; Nanji and Filipenko 1984; Howard et al. 1985; Goulet et al. 1992). Therefore, high doses can produce a direct toxic effect on the heart, with possible coronary spasm (Benchimol et al. 1978; Kossowosky and Lyon 1984; Schachne et al. 1984; Friedlander and Gorelick 1988). Ingestion results in increased arterial blood pressure and heart rate, with increased oxygen consumption by the heart that can in turn lead to the following:

  • Hypertensive crises with a risk of cerebrovascular accidents (Friedlander and Gorelick 1988).
  • Arrhythmias (Benchimol et al. 1978; Nanji and Filipenko 1984; Friedlander and Gorelick 1988).
  • Angina pectoris (Pasternack et al. 1985) or acute myocardial infarction, even in young patients with no previous history of heart disease (Kossowosky and Lyon 1984; Schachne et al. 1984; Cregler and Mark 1985; Howard et al. 1985; Pasternack et al. 1985; Weiss 1986).

The dentist should try to identify recent consumption of cocaine based on suspicious behavior (mania, restlessness, irritability, or depression, dilated pupils, red eyes, runny, or bloody nose, frequent intakes of breath through the nose without allergy or having a cold, etc.), careless appearance (Friedlander and Gorelick 1988), or as part of taking a medical history and asking about recreational drug use (Goulet et al. 1992), although patients may not disclose their consumption.

In conclusion, anesthetic solutions containing sympathomimetic vasoconstrictors, especially epinephrine, are contraindicated in patients who have consumed cocaine during the previous 24 hours (Goulet et al. 1992), given that plasma levels of the drug are maintained for more than 6 hours (Van Dyke et al. 1976).

Patients with Cardiovascular Diseases Who Take Amphetamines and Psychostimulants

Children with psychological disorders, such as attention‐deficit hyperactivity disorder, are generally treated with amphetamine and other psychostimulants (atomoxetine, dexamfetamine, modafinil, etc.) (Table 10.2) (Moore and Hersh 2006). If these patients also have cardiovascular problems such as arrhythmia or arterial hypertension, then local anesthetic solutions with sympathomimetic vasoconstrictors (mainly epinephrine and levonordefrin) are contraindicated (Moore and Hersh 2006; Hersh and Moore 2008).

Note: For some authors, selegiline, an antiparkinson and antidepressant monoamine oxidase inhibitor (MAOI), is absolutely contraindicated in patients receiving sympathomimetic amines such as epinephrine. Selegiline can cause increases in arterial pressure since it produces amphetamine compounds (L‐metamfetamine and L‐amfetamine) during metabolism in the liver (Friedlander et al. 2009).

Allergy to Vasoconstrictors

We generally think of vasoconstrictors as epinephrine and norepinephrine. Given that these drugs are natural neurotransmitters and hormones, there are no cases of allergy to their base forms, as this would not be compatible with human life. However, exogenous forms administered in local anesthetics include bitartrates and hydrochlorides, and two cases of allergy to epinephrine have been reported (Kohase and Umino 2004).

Table 10.2 Amphetamines and psychostimulants.

Amphetamine Atomoxetine
Dexamphetamine Dexmethylphenidate
Methamphetamine Methylphenidate
Modafinil Pemoline

Felypressin (Octapressin®), which is used in many countries in the European Union, and levonordefrin (synthetic vasoconstrictor), which is used in the United States, are artificial drugs, therefore they can cause allergic sensitization. In fact, one case of allergy to levonordefrin has been reported (Germishuys and Anderson 1982). Allergy is an absolute contraindication for these drugs.

Of note, these situations are exceptional since, despite years of experience with these drugs, only three cases of allergy have been reported.

Relative Contraindications

Below, we present those situations (mainly drug interactions) where sympathomimetic vasoconstrictors such as norepinephrine and levonordefrin are absolutely contraindicated, but where epinephrine can be administered, albeit with important restrictions. In such situations, we have two alternatives:

  1. Solutions with epinephrine where limitations are applied, as follows:
    • The maximum concentration is 1:100 000 (10 μg/ml), therefore higher concentrations are contraindicated (1:80 000 [12.5 μg/ml] and 1:50 000 [20 μg/ml]), but not lower concentrations (1:200 000 [5 μg/ml]) (McCarthy 1982; American Dental Association 2003; Malamed 2004).
    • The current maximum dose of epinephrine is no longer 200 μg, although much lower doses of 27–50 μg can be administered depending on the case.

      A suitable alternative in these cases is articaine 4% with epinephrine 1:200 000 (5 μg/ml) and an anesthetic parameter of 92%‐45′/190′‐260′.

  2. Solutions that do not contain epinephrine or any other sympathomimetic vasoconstrictor, such as the following (see Chapter 7):
    • Solutions that do not contain a vasoconstrictor, such as mepivacaine 3% with an anesthetic parameter of 91%‐15′/100′‐190′ or prilocaine 4% with an anesthetic parameter of 87%‐10′/75′‐180′.
    • Prilocaine 3% with felypressin 0.03 IU (0.54 μg/ml) and an anesthetic parameter of 88%‐25′/180′‐220′.

The problem with an epinephrine‐free alternative is that the anesthetic parameter is not very potent (see Chapter 7), and we must remember that onset of pain owing to deficient anesthesia leads to a more marked reaction of the sympathetic nervous system, with an increased risk for the patient (Annex 17).

The maximum number of 1.8‐ml cartridges that can be administered with epinephrine in these circumstances is summarized in Table 10.3.

Nonselective Beta‐blockers

Beta‐blockers, also known as beta‐adrenergic antagonists and beta‐adrenergic receptor blockers, are classified into two types (Table 10.4): (i) cardioselective beta‐blockers, which only act on β1 receptors, mainly in the heart, and (ii) nonselective beta‐blockers, which act by blocking both cardioselective β1 receptors and β2 vasodilators in the arterioles of skeletal muscle and via many other actions (Table 6.7, Chapter 6). These drugs are used in patients with disease such as arterial hypertension, angina pectoris or myocardial infarction, arrhythmias, vascular headaches (migraine), hyperthyroidism, pheochromocytoma, etc. (Foster and Aston 1983; Goulet et al. 1992; Yagiela 1999).

Clinical trials in hypertensive patients (Houben et al. 1982) and with healthy volunteers (Hjemdahl et al. 1983; Reeves et al. 1984; Dzubow 1986; Rehling et al. 1986; Sugimura et al. 1995; Niwa et al. 1996) have demonstrated the following:

  • Administration of epinephrine in patients who take cardioselective beta‐blockers produces very moderate hemodynamic effects (Houben et al. 1982; Hjemdahl et al. 1983; Rehling et al. 1986); the same can be said of norepinephrine (Hjemdahl et al. 1983). The selective beta blockers block β1 effects, leaving the alpha effects and β2 effects, namely vasoconstriction and vasodilatation, respectively, and therefore there is less of a hypertensive response to epinephrine.
  • Administration of epinephrine in patients taking nonselective beta‐blockers produces severe hemodynamic effects, with increased arterial pressure and a reflex decrease in heart rate (bradycardia) (Houben et al. 1982; Hjemdahl et al. 1983; Reeves et al. 1984; Dzubow 1986; Rehling et al. 1986; Sugimura et al. 1995; Niwa et al. 1996). The same is true of norepinephrine (Hjemdahl et al. 1983; Reeves et al. 1984), although with lesser intensity, given that the vasodilatory β2 effect of norepinephrine is much less pronounced than that of epinephrine (Reeves et al. 1984). The same is true of levonordefrin (Mito and Yagiela 1988). The nonselective beta blockers block all β1 and β2 effects, leaving the alpha effects, namely vasoconstriction, unopposed, and therefore there is a risk for a hypertensive response to epinephrine.

Table 10.3 Summary of the maximum doses of epinephrine and maximum number of cartridges in situations of relative contraindication.

Number of 1.8‐ml cartridges
Maximum doses of epinephrine 1:100 000 (10 μg/ml) 1:200 000 (5 μg/ml) Clinical situations
27 μg 1.5 3 Nonselective beta‐blockers
Antiparkinson COMTi
40 μg 2.2 4.5 ASA III cardiovascular
50 μg 2.7 5.5 Amphetamines and psychostimulants
Tricyclic antidepressants
Older antihypertensive
Halothane and thiopental
Example LASa Lidocaine 2% + epinephrine 1:100 000 Articaine 4% + epinephrine 1:200 000
Anesthetic parameter 95%‐45′/190′‐200´ 92%‐45′/190′‐260´
Example LAS Articaine 4% + epinephrine 1:100 000 Bupivacaine 0.5% + epinephrine 1:200 000
Anesthetic parameter 98%‐60′/190′‐260′ 80%‐35′/410′‐490′

Epinephrine can be used, albeit at lower doses (lower number of cartridges). Articaine 4% with epinephrine 1:200 000 (5 μg/ml) is very useful in these cases since, as it contains half the amount of epinephrine as the 1:100 000 solution (10 μg/ml), we can administer double the amount of solution with similar potency and efficacy, although this is somewhat lower than the standard solution of lidocaine 2% with epinephrine 1:100 000, as indicated in its anesthetic parameter.

a LAS, local anesthetic solution.

Table 10.4 Beta‐blockers.

Cardioselective Nonselective
Atenolol Carteolol
Bisoprolol Carvedilol
Celiprolol Labetalol
Esmolol Nadolol
Metoprolol Oxprenolol
Nebivolol Pindolol

The most common drugs are shown in bold.

The mechanism underlying the interaction between sympathomimetic vasoconstrictors (epinephrine and norepinephrine) and nonselective beta‐blockers is based on blockade of the vasodilatory β2 receptors of the arterioles of skeletal muscle by the beta‐blocker, which increases arterial pressure (systolic and diastolic). Given that only the vasoconstrictor α effect remains, there is a risk of cerebrovascular accidents (Hansbrough and Near 1980) and a reflex decrease in heart rate (bradycardia) resulting from blockade of the cardioselective β1 receptors, thus increasing the risk of cardiac arrest (Foster and Aston 1983). Furthermore, this effect is more intense, given that nonselective beta‐blockers reduce clearance of epinephrine and, to a lesser extent, norepinephrine, thus extending the duration of action of the exogenous catecholamines (Hjemdahl et al. 1983). It is interesting that, even though these reactions are thought to be dose‐dependent, there may be idiopathic cases in which specific sensitivity to these adrenergic receptors aggravates the reaction (Dzubow 1986). A curious effect is that by blocking the vasodilatory β2 effect, nonselective beta‐blockers indirectly increase the vasoconstrictor α affect, thus increasing the anesthetic potency of local anesthetic solutions with epinephrine and the duration of soft tissue and pulpal anesthesia (Zhang et al. 1999).

A review of the literature reveals case reports of patients treated with propranolol (nonselective beta‐blocker) who were given epinephrine at 40–320 μg (Kram et al. 1974; Hansbrough and Near 1980; Foster and Aston 1983) or levonordefrin at 75 μg (Mito and Yagiela 1988). After a few minutes, the patients experienced an episode of arterial hypertension accompanied by bradycardia lasting 10–15 minutes, which, in some cases, was complicated by a cerebrovascular accident (Hansbrough and Near 1980) or cardiac arrest (Foster and Aston 1983).

The measure proposed in these cases was not to use local anesthetic solutions containing epinephrine (Goulet et al. 1992) or if they did contain epinephrine, then the dose had to be very low (Dzubow 1986), namely, the equivalent of 1.5 cartridges of epinephrine 1:100 000 (10 μg/ml), which represents 27 μg (Yagiela 1999; Naftalin and Yagiela 2002). In addition, arterial pressure and heart rate had to be monitored after 5 minutes (Yagiela 1999; Naftalin and Yagiela 2002; Malamed 2004).

In conclusion, in these patients, local anesthetic solutions containing epinephrine can be used, although at a maximum concentration of 1:100 000 (10 μg/ml) and an absolute maximum dose of 27 μg (1.5 × 1.8‐ml cartridges). Heart rate and arterial pressure should be monitored before administration of local anesthetic containing vasopressor as well as 5 minutes following administration.

COMT Inhibitor‐type Antiparkinson Drugs

The new antiparkinson medicines tolcapone (Tasmar®) and entacapone produce reversible blockade of catechol‐O‐methyltransferase (COMT), an enzyme that inactivates peripheral levodopa, therefore these drugs are dopaminergics since they increase dopamine levels. However, they also inhibit inactivation of exogenously administered catecholamines (e.g., epinephrine, norepinephrine, and levonordefrin) by COMT, leading to increased arterial pressure, increased heart rate, and risk of arrhythmias (Illi et al. 1995; Ganzberg 2003; Friedlander et al. 2009). There have been no reports of this interaction to date, probably because the drugs are new and little experience is available.

In conclusion, epinephrine should be reduced to 1.5–3 cartridges of epinephrine 1:100 000 (10 μg/ml), that is, an absolute maximum dose of 27–50 μg (Hersh and Moore 2008; Friedlander et al. 2009).

ASA III Patients with Cardiovascular Conditions

ASA III patients have severe systemic disease that limits activity but is not disabling (no symptoms at rest or with standard exercise). They have reduced tolerance to physical stress (pain) and psychological stress (anxiety). Cardiovascular disorders affecting this group include the following:

  • Uncontrolled arterial hypertension with moderate blood pressure (95–115/160–200 mmHg) (McCarthy 1982; Abraham‐Inpijn et al. 1988; Malamed 2007
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Feb 17, 2024 | Posted by in Oral and Maxillofacial Surgery | Comments Off on Contraindications for Vasoconstrictors

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