Reviews

Akathisia—from the Greek for “inability to sit”—is a neuropsychiatric syndrome characterized by subjective and objective psychomotor restlessness. Patients typi­cally experience feelings of unease, inner restlessness mainly involving the legs, and a compulsion to move. Most engage in repetitive movement. They might swing or cross and uncross their legs, shift from one foot to the other, continuously pace, or persistently fidget.

In clinical settings, akathisia usually is a side effect of medi­cation. Antipsychotics, serotonin reuptake inhibitors, and buspirone are common triggers, but akathisia also has been associated with some antiemetics, preoperative sedatives, calcium channel blockers, and antivertigo agents. It also can be caused by withdrawal from an antipsychotic or related to a substance use disorder, especially cocaine. Akathisia can be acute or chronic, occurring in a tardive form with symptoms that last >6 months.^1-3

Much isn’t known about drug-induced akathisia
Our understanding of the pathophysiology of akathisia is incomplete. Some have suggested that it results from an imbal­ance between the dopaminergic/cholinergic and dopaminer­gic/serotonergic systems⁴; others, that the cause is a mismatch between the core and the shell of the nucleus accumbens, due in part to overstimulation of the locus ceruleus.⁵

More recently, researchers established a positive asso­ciation between higher scores on the Liverpool University Neuroleptic Side Effects Rating Scale and D2/D3 receptor occupancy in the ventral striatum (nucleus accumbens and olfactory tubercle).⁶ The D2/D3 receptor occupancy model might explain withdrawal symptoms associated with cocaine,⁷ as well as rela­tive worsening of symptoms after tapering or discontinuing stimulants in attention-deficit/hyperactivity disorder (ADHD).

Elements of a clinical evaluation
When akathisia is suspected, evaluation by a clinician familiar with its phenom­enology is crucial. A validated tool, such as the Barnes Akathisia Rating Scale (at out cometracker.org/library/BAS.pdf) can aid in the detection and assessment of severity.⁸

In evaluating patients, keep in mind that the inner restlessness that characterizes akathisia can affect the trunk, hands, and arms, as well as the legs, and can cause dys­phoria and anxiety. Akathisia has been linked to an increased likelihood of developing sui­cidal ideation and behavior.⁹

Less common subjective symptoms include rage, fear, nausea, and worsening of psychotic symptoms. Because of its asso­ciation with aggression and agitation, drug-induced akathisia has been cited—with little success—as the basis for an insanity defense by people who have committed a violent act.¹⁰

Or is akathisia another psychiatric disorder?
Akathisia might go undetected for several reasons. One key factor: Its symptoms resem­ble and often overlap with those of other psy­chiatric disorders, such as mania, psychosis, agitated depression, and ADHD. In addition, akathisia often occurs concurrently with, and is masked by, akinesia, a common extrapy­ramidal side effect of many antipsychotics. Such patients might have the inner feeling of restlessness and urge to move but do not exhibit characteristic limb movements. In some cases, cognitive or intellectual limita­tions prevent patients from communicating the inner turmoil they feel.¹¹

Medication nonadherence further compli­cates the picture, sometimes prompting a cli­nician to increase the dosage of the drug that is causing akathisia (Box 1¹²).

Managing drug-induced akathisia
Akathisia usually resolves when the drug causing it is discontinued; decreasing the dosage might alleviate the symptoms. Whenever akathisia is detected, careful revision of the current drug regimen— substituting an antipsychotic with a lower prevalence of akathisia, for example— should be considered (Box 2^13-16). Treatment of drug-induced akathisia, which should be tailored to the patient’s psycho­pathology and comorbidities, is needed as well (Table^17-25).

Low-dose mirtazapine (15 mg/d) was found to be as effective as propranolol, 80 mg/d, in a placebo-controlled study, and to be more effective than a beta blocker in treating akathisia induced by a first-gener­ation antipsychotic. The authors concluded that both propranolol and mirtazapine should be first-line therapy.²³ Others have suggested that these results be interpreted with caution because mirtazapine (at a higher dosage) has been linked to akathi­sia.³³ Mirtazapine blocks α-adrenergic receptors, resulting in antagonism of 5-HT2 and 5-HT3 receptors and consequent enhancement of 5-HT1A serotonergic trans­mission.³⁴ In one study, it was shown to reduce binding of the D2/D3 receptor ago­nist quinpirole.³⁵

Serotonin antagonists and agonists. Blockade of 5-HT2 receptors can attenuate D2 blockade and mitigate akathisia symp­toms. Mianserin, 15 mg/d, can be helpful, and ritanserin, 5 to 20 mg/d, produced about a 50% reduction in akathisia symp­toms in 10 patients taking neuroleptics.36 Neither is available in the United States, however.

Cyproheptadine, a potent 5-HT2A and 5-HT2C antagonist with anticholinergic and antihistaminic action, improved akathisia symptoms in an open trial of 17 patients with antipsychotic-induced akathisia.³⁷ The recommended dose is 8 to 16 mg/d.

A study using the selective inverse ago­nist pimavanserin (not FDA-approved) decreased akathisia in healthy volunteers taking haloperidol.^14,24,33

Zolmitriptan, a 5-HT1D agonist, also can be used³⁸; one study found that 7.5 mg/d of zolmitriptan is as effective as propranolol.³⁹

A 2010 study showed a statistically signifi­cant improvement in 8 patients taking trazo­done, compared with 5 patients on placebo, all of whom met criteria for at least mild akathisia. Trazodone’s antiakathitic effect is attributed to its 5-HT2A antagonism.²⁵

Anticholinergics. Traditionally, benztropine, biperiden, diphenhydramine, and trihexy­phenidyl have been used for prevention and treatment of extrapyramidal side effects. A Cochrane review concluded, however, that data are insufficient to support use of anticho­linergics for akathisia.⁴⁰ Although multiple case reports have shown anticholinergics to be effective in treating drug-induced akathi­sia,^12,17,33 their association with cognitive side effects suggests a need for caution.¹⁸

Benzodiazepines. Through their sedative and anxiolytic properties, benzodiazepines are thought to partially alleviate akathisia symptoms. Two small trials found clonaz­epam helpful for akathisia symptoms^2,20; and 1 case report revealed that a patient with akathisia improved after coadministration of clonazepam and baclofen.⁴¹

Anticonvulsants. Valproic acid has not been found to be useful in antipsychotic-induced tardive akathisia.⁴² However, a case report described a patient with schizophrenia whose akathisia symptoms improved after the dosage of gabapentin was increased.⁴³ Last, carbamazepine was found to be effec­tive in reducing akathisia symptoms in 3 patients with schizophrenia who were resis­tant to beta blockers, anticholinergics, anti­histaminergics, and benzodiazepines.¹⁹

α-adrenergic agonists. In an open trial, akathisia symptoms in 6 patients improved with clonidine, 0.2 to 0.8 mg/d.¹⁷ Speculation is that strong α1 antagonism might help pre­vent akathisia, which could be why this con­dition is not associated with iloperidone.⁴⁴

D2 agonists. Akathisia and restless legs syndrome have similar pathophysiology,^1,2 and patients with akathisia could ben­efit from D2 agonists such as cabergoline, pramipexole, rotigotine, and ropinirole. One case study revealed that a patient with aripiprazole-induced akathisia improved with ropinirole.⁴⁵ D2 agonists can precipi­tate or worsen psychosis, however, and would be a relative contraindication in patients with psychotic disorders.²²


Bottom Line
Failure to detect drug-induced akathisia can increase morbidity and delay recovery in patients undergoing psychiatric care. Knowing what to look for and how to tailor treatment to the needs of a given patient is an essential component of good care.

Related Resources
• Ferrando SJ, Eisendrath SJ. Adverse neuropsychiatric effects of dopamine antagonist medications. Misdiagnosis in the medical setting. Psychosomatics. 1991;32(4):426-432.
• Vinson DR. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. J Emerg Med. 2004;26(3):265-270.

Drug Brand Names
Aripiprazole • Abilify                  Haloperidol • Haldol
Baclofen • Lioresal                     Iloperidone • Fanapt
Benztropine • Cogentin              Lurasidone • Latuda
Biperiden • Akineton                  Mirtazapine • Remeron
Buspirone • BuSpar                   Pramipexole • Mirapex
Cabergoline • Dostinex              Propranolol • Inderal
Carbamazepine • Tegretol          Quetiapine • Seroquel
Clonazepam • Klonopin              Ropinirole • Requip
Clonidine • Catapres                  Rotigotine • Neupro
Clozapine • Clozaril                    Trazodone • Desyrel, Oleptro
Cyproheptadine • Periactin          Trihexyphenidyl • Artane
Diphenhydramine • Benadryl       Valproic acid • Depakene
Gabapentin • Neurontin               Zolmitriptan • Zomig


Acknowledgement
Mandy Evans, MD, assisted with editing the manuscript of this article.

Disclosure
Dr. Forcen reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Akathisia—from the Greek for “inability to sit”—is a neuropsychiatric syndrome characterized by subjective and objective psychomotor restlessness. Patients typi­cally experience feelings of unease, inner restlessness mainly involving the legs, and a compulsion to move. Most engage in repetitive movement. They might swing or cross and uncross their legs, shift from one foot to the other, continuously pace, or persistently fidget.

In clinical settings, akathisia usually is a side effect of medi­cation. Antipsychotics, serotonin reuptake inhibitors, and buspirone are common triggers, but akathisia also has been associated with some antiemetics, preoperative sedatives, calcium channel blockers, and antivertigo agents. It also can be caused by withdrawal from an antipsychotic or related to a substance use disorder, especially cocaine. Akathisia can be acute or chronic, occurring in a tardive form with symptoms that last >6 months.^1-3

Much isn’t known about drug-induced akathisia
Our understanding of the pathophysiology of akathisia is incomplete. Some have suggested that it results from an imbal­ance between the dopaminergic/cholinergic and dopaminer­gic/serotonergic systems⁴; others, that the cause is a mismatch between the core and the shell of the nucleus accumbens, due in part to overstimulation of the locus ceruleus.⁵

More recently, researchers established a positive asso­ciation between higher scores on the Liverpool University Neuroleptic Side Effects Rating Scale and D2/D3 receptor occupancy in the ventral striatum (nucleus accumbens and olfactory tubercle).⁶ The D2/D3 receptor occupancy model might explain withdrawal symptoms associated with cocaine,⁷ as well as rela­tive worsening of symptoms after tapering or discontinuing stimulants in attention-deficit/hyperactivity disorder (ADHD).

Elements of a clinical evaluation
When akathisia is suspected, evaluation by a clinician familiar with its phenom­enology is crucial. A validated tool, such as the Barnes Akathisia Rating Scale (at out cometracker.org/library/BAS.pdf) can aid in the detection and assessment of severity.⁸

In evaluating patients, keep in mind that the inner restlessness that characterizes akathisia can affect the trunk, hands, and arms, as well as the legs, and can cause dys­phoria and anxiety. Akathisia has been linked to an increased likelihood of developing sui­cidal ideation and behavior.⁹

Less common subjective symptoms include rage, fear, nausea, and worsening of psychotic symptoms. Because of its asso­ciation with aggression and agitation, drug-induced akathisia has been cited—with little success—as the basis for an insanity defense by people who have committed a violent act.¹⁰

Or is akathisia another psychiatric disorder?
Akathisia might go undetected for several reasons. One key factor: Its symptoms resem­ble and often overlap with those of other psy­chiatric disorders, such as mania, psychosis, agitated depression, and ADHD. In addition, akathisia often occurs concurrently with, and is masked by, akinesia, a common extrapy­ramidal side effect of many antipsychotics. Such patients might have the inner feeling of restlessness and urge to move but do not exhibit characteristic limb movements. In some cases, cognitive or intellectual limita­tions prevent patients from communicating the inner turmoil they feel.¹¹

Medication nonadherence further compli­cates the picture, sometimes prompting a cli­nician to increase the dosage of the drug that is causing akathisia (Box 1¹²).

Managing drug-induced akathisia
Akathisia usually resolves when the drug causing it is discontinued; decreasing the dosage might alleviate the symptoms. Whenever akathisia is detected, careful revision of the current drug regimen— substituting an antipsychotic with a lower prevalence of akathisia, for example— should be considered (Box 2^13-16). Treatment of drug-induced akathisia, which should be tailored to the patient’s psycho­pathology and comorbidities, is needed as well (Table^17-25).

Low-dose mirtazapine (15 mg/d) was found to be as effective as propranolol, 80 mg/d, in a placebo-controlled study, and to be more effective than a beta blocker in treating akathisia induced by a first-gener­ation antipsychotic. The authors concluded that both propranolol and mirtazapine should be first-line therapy.²³ Others have suggested that these results be interpreted with caution because mirtazapine (at a higher dosage) has been linked to akathi­sia.³³ Mirtazapine blocks α-adrenergic receptors, resulting in antagonism of 5-HT2 and 5-HT3 receptors and consequent enhancement of 5-HT1A serotonergic trans­mission.³⁴ In one study, it was shown to reduce binding of the D2/D3 receptor ago­nist quinpirole.³⁵

Serotonin antagonists and agonists. Blockade of 5-HT2 receptors can attenuate D2 blockade and mitigate akathisia symp­toms. Mianserin, 15 mg/d, can be helpful, and ritanserin, 5 to 20 mg/d, produced about a 50% reduction in akathisia symp­toms in 10 patients taking neuroleptics.36 Neither is available in the United States, however.

Cyproheptadine, a potent 5-HT2A and 5-HT2C antagonist with anticholinergic and antihistaminic action, improved akathisia symptoms in an open trial of 17 patients with antipsychotic-induced akathisia.³⁷ The recommended dose is 8 to 16 mg/d.

A study using the selective inverse ago­nist pimavanserin (not FDA-approved) decreased akathisia in healthy volunteers taking haloperidol.^14,24,33

Zolmitriptan, a 5-HT1D agonist, also can be used³⁸; one study found that 7.5 mg/d of zolmitriptan is as effective as propranolol.³⁹

A 2010 study showed a statistically signifi­cant improvement in 8 patients taking trazo­done, compared with 5 patients on placebo, all of whom met criteria for at least mild akathisia. Trazodone’s antiakathitic effect is attributed to its 5-HT2A antagonism.²⁵

Anticholinergics. Traditionally, benztropine, biperiden, diphenhydramine, and trihexy­phenidyl have been used for prevention and treatment of extrapyramidal side effects. A Cochrane review concluded, however, that data are insufficient to support use of anticho­linergics for akathisia.⁴⁰ Although multiple case reports have shown anticholinergics to be effective in treating drug-induced akathi­sia,^12,17,33 their association with cognitive side effects suggests a need for caution.¹⁸

Benzodiazepines. Through their sedative and anxiolytic properties, benzodiazepines are thought to partially alleviate akathisia symptoms. Two small trials found clonaz­epam helpful for akathisia symptoms^2,20; and 1 case report revealed that a patient with akathisia improved after coadministration of clonazepam and baclofen.⁴¹

Anticonvulsants. Valproic acid has not been found to be useful in antipsychotic-induced tardive akathisia.⁴² However, a case report described a patient with schizophrenia whose akathisia symptoms improved after the dosage of gabapentin was increased.⁴³ Last, carbamazepine was found to be effec­tive in reducing akathisia symptoms in 3 patients with schizophrenia who were resis­tant to beta blockers, anticholinergics, anti­histaminergics, and benzodiazepines.¹⁹

α-adrenergic agonists. In an open trial, akathisia symptoms in 6 patients improved with clonidine, 0.2 to 0.8 mg/d.¹⁷ Speculation is that strong α1 antagonism might help pre­vent akathisia, which could be why this con­dition is not associated with iloperidone.⁴⁴

D2 agonists. Akathisia and restless legs syndrome have similar pathophysiology,^1,2 and patients with akathisia could ben­efit from D2 agonists such as cabergoline, pramipexole, rotigotine, and ropinirole. One case study revealed that a patient with aripiprazole-induced akathisia improved with ropinirole.⁴⁵ D2 agonists can precipi­tate or worsen psychosis, however, and would be a relative contraindication in patients with psychotic disorders.²²


Bottom Line
Failure to detect drug-induced akathisia can increase morbidity and delay recovery in patients undergoing psychiatric care. Knowing what to look for and how to tailor treatment to the needs of a given patient is an essential component of good care.

Related Resources
• Ferrando SJ, Eisendrath SJ. Adverse neuropsychiatric effects of dopamine antagonist medications. Misdiagnosis in the medical setting. Psychosomatics. 1991;32(4):426-432.
• Vinson DR. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. J Emerg Med. 2004;26(3):265-270.

Drug Brand Names
Aripiprazole • Abilify                  Haloperidol • Haldol
Baclofen • Lioresal                     Iloperidone • Fanapt
Benztropine • Cogentin              Lurasidone • Latuda
Biperiden • Akineton                  Mirtazapine • Remeron
Buspirone • BuSpar                   Pramipexole • Mirapex
Cabergoline • Dostinex              Propranolol • Inderal
Carbamazepine • Tegretol          Quetiapine • Seroquel
Clonazepam • Klonopin              Ropinirole • Requip
Clonidine • Catapres                  Rotigotine • Neupro
Clozapine • Clozaril                    Trazodone • Desyrel, Oleptro
Cyproheptadine • Periactin          Trihexyphenidyl • Artane
Diphenhydramine • Benadryl       Valproic acid • Depakene
Gabapentin • Neurontin               Zolmitriptan • Zomig


Acknowledgement
Mandy Evans, MD, assisted with editing the manuscript of this article.

Disclosure
Dr. Forcen reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Akathisia—from the Greek for “inability to sit”—is a neuropsychiatric syndrome characterized by subjective and objective psychomotor restlessness. Patients typi­cally experience feelings of unease, inner restlessness mainly involving the legs, and a compulsion to move. Most engage in repetitive movement. They might swing or cross and uncross their legs, shift from one foot to the other, continuously pace, or persistently fidget.

In clinical settings, akathisia usually is a side effect of medi­cation. Antipsychotics, serotonin reuptake inhibitors, and buspirone are common triggers, but akathisia also has been associated with some antiemetics, preoperative sedatives, calcium channel blockers, and antivertigo agents. It also can be caused by withdrawal from an antipsychotic or related to a substance use disorder, especially cocaine. Akathisia can be acute or chronic, occurring in a tardive form with symptoms that last >6 months.^1-3

Much isn’t known about drug-induced akathisia
Our understanding of the pathophysiology of akathisia is incomplete. Some have suggested that it results from an imbal­ance between the dopaminergic/cholinergic and dopaminer­gic/serotonergic systems⁴; others, that the cause is a mismatch between the core and the shell of the nucleus accumbens, due in part to overstimulation of the locus ceruleus.⁵

More recently, researchers established a positive asso­ciation between higher scores on the Liverpool University Neuroleptic Side Effects Rating Scale and D2/D3 receptor occupancy in the ventral striatum (nucleus accumbens and olfactory tubercle).⁶ The D2/D3 receptor occupancy model might explain withdrawal symptoms associated with cocaine,⁷ as well as rela­tive worsening of symptoms after tapering or discontinuing stimulants in attention-deficit/hyperactivity disorder (ADHD).

Elements of a clinical evaluation
When akathisia is suspected, evaluation by a clinician familiar with its phenom­enology is crucial. A validated tool, such as the Barnes Akathisia Rating Scale (at out cometracker.org/library/BAS.pdf) can aid in the detection and assessment of severity.⁸

In evaluating patients, keep in mind that the inner restlessness that characterizes akathisia can affect the trunk, hands, and arms, as well as the legs, and can cause dys­phoria and anxiety. Akathisia has been linked to an increased likelihood of developing sui­cidal ideation and behavior.⁹

Less common subjective symptoms include rage, fear, nausea, and worsening of psychotic symptoms. Because of its asso­ciation with aggression and agitation, drug-induced akathisia has been cited—with little success—as the basis for an insanity defense by people who have committed a violent act.¹⁰

Or is akathisia another psychiatric disorder?
Akathisia might go undetected for several reasons. One key factor: Its symptoms resem­ble and often overlap with those of other psy­chiatric disorders, such as mania, psychosis, agitated depression, and ADHD. In addition, akathisia often occurs concurrently with, and is masked by, akinesia, a common extrapy­ramidal side effect of many antipsychotics. Such patients might have the inner feeling of restlessness and urge to move but do not exhibit characteristic limb movements. In some cases, cognitive or intellectual limita­tions prevent patients from communicating the inner turmoil they feel.¹¹

Medication nonadherence further compli­cates the picture, sometimes prompting a cli­nician to increase the dosage of the drug that is causing akathisia (Box 1¹²).

Managing drug-induced akathisia
Akathisia usually resolves when the drug causing it is discontinued; decreasing the dosage might alleviate the symptoms. Whenever akathisia is detected, careful revision of the current drug regimen— substituting an antipsychotic with a lower prevalence of akathisia, for example— should be considered (Box 2^13-16). Treatment of drug-induced akathisia, which should be tailored to the patient’s psycho­pathology and comorbidities, is needed as well (Table^17-25).

Low-dose mirtazapine (15 mg/d) was found to be as effective as propranolol, 80 mg/d, in a placebo-controlled study, and to be more effective than a beta blocker in treating akathisia induced by a first-gener­ation antipsychotic. The authors concluded that both propranolol and mirtazapine should be first-line therapy.²³ Others have suggested that these results be interpreted with caution because mirtazapine (at a higher dosage) has been linked to akathi­sia.³³ Mirtazapine blocks α-adrenergic receptors, resulting in antagonism of 5-HT2 and 5-HT3 receptors and consequent enhancement of 5-HT1A serotonergic trans­mission.³⁴ In one study, it was shown to reduce binding of the D2/D3 receptor ago­nist quinpirole.³⁵

Serotonin antagonists and agonists. Blockade of 5-HT2 receptors can attenuate D2 blockade and mitigate akathisia symp­toms. Mianserin, 15 mg/d, can be helpful, and ritanserin, 5 to 20 mg/d, produced about a 50% reduction in akathisia symp­toms in 10 patients taking neuroleptics.36 Neither is available in the United States, however.

Cyproheptadine, a potent 5-HT2A and 5-HT2C antagonist with anticholinergic and antihistaminic action, improved akathisia symptoms in an open trial of 17 patients with antipsychotic-induced akathisia.³⁷ The recommended dose is 8 to 16 mg/d.

A study using the selective inverse ago­nist pimavanserin (not FDA-approved) decreased akathisia in healthy volunteers taking haloperidol.^14,24,33

Zolmitriptan, a 5-HT1D agonist, also can be used³⁸; one study found that 7.5 mg/d of zolmitriptan is as effective as propranolol.³⁹

A 2010 study showed a statistically signifi­cant improvement in 8 patients taking trazo­done, compared with 5 patients on placebo, all of whom met criteria for at least mild akathisia. Trazodone’s antiakathitic effect is attributed to its 5-HT2A antagonism.²⁵

Anticholinergics. Traditionally, benztropine, biperiden, diphenhydramine, and trihexy­phenidyl have been used for prevention and treatment of extrapyramidal side effects. A Cochrane review concluded, however, that data are insufficient to support use of anticho­linergics for akathisia.⁴⁰ Although multiple case reports have shown anticholinergics to be effective in treating drug-induced akathi­sia,^12,17,33 their association with cognitive side effects suggests a need for caution.¹⁸

Benzodiazepines. Through their sedative and anxiolytic properties, benzodiazepines are thought to partially alleviate akathisia symptoms. Two small trials found clonaz­epam helpful for akathisia symptoms^2,20; and 1 case report revealed that a patient with akathisia improved after coadministration of clonazepam and baclofen.⁴¹

Anticonvulsants. Valproic acid has not been found to be useful in antipsychotic-induced tardive akathisia.⁴² However, a case report described a patient with schizophrenia whose akathisia symptoms improved after the dosage of gabapentin was increased.⁴³ Last, carbamazepine was found to be effec­tive in reducing akathisia symptoms in 3 patients with schizophrenia who were resis­tant to beta blockers, anticholinergics, anti­histaminergics, and benzodiazepines.¹⁹

α-adrenergic agonists. In an open trial, akathisia symptoms in 6 patients improved with clonidine, 0.2 to 0.8 mg/d.¹⁷ Speculation is that strong α1 antagonism might help pre­vent akathisia, which could be why this con­dition is not associated with iloperidone.⁴⁴

D2 agonists. Akathisia and restless legs syndrome have similar pathophysiology,^1,2 and patients with akathisia could ben­efit from D2 agonists such as cabergoline, pramipexole, rotigotine, and ropinirole. One case study revealed that a patient with aripiprazole-induced akathisia improved with ropinirole.⁴⁵ D2 agonists can precipi­tate or worsen psychosis, however, and would be a relative contraindication in patients with psychotic disorders.²²


Bottom Line
Failure to detect drug-induced akathisia can increase morbidity and delay recovery in patients undergoing psychiatric care. Knowing what to look for and how to tailor treatment to the needs of a given patient is an essential component of good care.

Related Resources
• Ferrando SJ, Eisendrath SJ. Adverse neuropsychiatric effects of dopamine antagonist medications. Misdiagnosis in the medical setting. Psychosomatics. 1991;32(4):426-432.
• Vinson DR. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. J Emerg Med. 2004;26(3):265-270.

Drug Brand Names
Aripiprazole • Abilify                  Haloperidol • Haldol
Baclofen • Lioresal                     Iloperidone • Fanapt
Benztropine • Cogentin              Lurasidone • Latuda
Biperiden • Akineton                  Mirtazapine • Remeron
Buspirone • BuSpar                   Pramipexole • Mirapex
Cabergoline • Dostinex              Propranolol • Inderal
Carbamazepine • Tegretol          Quetiapine • Seroquel
Clonazepam • Klonopin              Ropinirole • Requip
Clonidine • Catapres                  Rotigotine • Neupro
Clozapine • Clozaril                    Trazodone • Desyrel, Oleptro
Cyproheptadine • Periactin          Trihexyphenidyl • Artane
Diphenhydramine • Benadryl       Valproic acid • Depakene
Gabapentin • Neurontin               Zolmitriptan • Zomig


Acknowledgement
Mandy Evans, MD, assisted with editing the manuscript of this article.

Disclosure
Dr. Forcen reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

“It takes 20 years to build a reputation and 5 minutes to ruin it. If you think about that, you’ll do things differently.”          
—Warren Buffet

CASE: Decline in new patients
A well-respected physician—one of the best in his field—notices that the number of new patients in his practice has fallen off drastically over the past year. Baffled, he hires a consultant, who discovers that the doctor’s online reputation has plummeted, thanks to four negative reviews and no positive ones.

What can the physician do to remedy the situation and restore his reputation?

The problem can be fixed, but it takes time—like major surgery. Rather than wait until negative reviews are posted, we recommend that you become proactive and take steps as soon as possible to secure your online reputation. That way, you won’t get caught by surprise when one or two unhappy patients try to smear your good name. In this article, we step you through a number of remedies and proactive strategies for boosting positive online reviews and combating negative ones.

The Internet: A one-stop source of information
The Internet has become everyone’s go-to source for pretty much any kind of data, including details on products, services, and people. Anyone can access all kinds of information simply by asking.

Today, people research medical conditions on the Web, often using Google. If you have done your search engine optimization, your Web site will come up in the first page of search results, making it possible for prospective patients to click through to your homepage. (For the scoop on search engine optimization, see Part 3 of this series, “Maximizing your online reach through SEO and pay-per-click,” which appeared in the September 2014 issue of OBG Management.)

If visitors like what they see at your site, they may make an appointment. But they are more likely to visit three or four other sites before making a decision. And in all likelihood, they will research each physician to find out what patients have to say about her or him. It’s no different than looking at the reviews of hotels or products you are considering.

You are an open book on the Internet. Only a few short years ago, your peers and patients knew your reputation primarily through word of mouth, which traveled at the speed of molasses. For the most part, that information was favorable. Today your exposure is much greater, and negative comments about you can be viewed by thousands of potential patients. The speed of information has increased, as well. What is posted on the Internet can become readily available to hundreds, thousands, and even millions of Web users in a nanosecond.

The Internet provides a forum for people to say whatever they want about their experiences, both positive and negative. Regrettably, the positive experiences do not find their way online nearly as often as the negative ones!

The bottom line? In today’s Internet-­savvy world, you need to pay regular attention to your online reputation. You need to take steps to ensure that your name and practice look their best and to negate any complaints that may appear.

What patients share about their experience with you
Many online review sites provide an opportunity for your patients to describe their experience with you and your practice. To name a few: RateMDs.com, Vitals.com, ­ZocDoc.com, healthgrades.com, ­UcompareHealth.com, Citysearch.com, yelp.com, and, of course, Google Plus reviews.

And when patients post comments on the Internet, you likely will be rated on:

• the patient’s wait time
• how your staff treated the patient
• the diagnosis
• your attitude
• the level of trust in your decisions
• treatment and outcome.

The online surfer searching for a reputable physician is likely to believe whatever he or she finds on the leading review sites.

The good news: Most physicians have a very favorable rating, averaging 9.3 out of 10 on a scale of 1 to 10. In fact, 70% of doctors have perfect scores!¹

The bad news: Someone who is unhappy with her treatment or outcome will go out of her way to find every online review site possible and proclaim your faults to the cyber-world, using the Internet as a forum, whether her facts are straight or not. Patients who are pleased and satisfied rarely bother to place a positive review.

How you can control your online reputation
It is incumbent upon you to keep an eye on your online reputation at all times. Here are some tips for taking charge:

• If someone posts a negative review, respond to them directly in the review site. Doing so does not violate privacy laws as long as you do not mention the patient’s name or give other identifying details. Explain your side of the story without confirming or denying that the reviewer is or was a patient. Do not mention the specifics of any patient’s condition.
• If you feel that a negative review is completely unjustified, file a dispute with the review site. Many review sites will remove the unfavorable content if you can convince them that the patient is merely ranting.
• To protect your reputation over the long term, use your name or practice name to set up an alert with Google Alerts by visiting the site Google.com/alerts.
• Do a Google search of your name and the name of your practice at least once a month and check out all the review sites that come up. Read the comments!

Develop a proactive system
You have a lot of control when it comes to protecting your online reputation, provided you are willing to take the time to set up a system to regularly request feedback or testimonials from your patients.

Regrettably, this is where most medical practices fall short, by failing to establish a system to solicit positive reviews.

The process need not be complicated. Such a system can be set in motion by scheduling a quick meeting with your staff to announce your plans to solicit testimonials from patients. Often there will be a flurry of activity for a couple of weeks before the task is forgotten. To keep your system from falling through the cracks, make a checklist and decide who on your staff is responsible for each step in the process. Go over the results in your staff meetings on a regular basis—ie, at least monthly.

You want to solicit positive reviews for use in two places:

• your Web site
• the review sites we mentioned earlier.

Posting testimonials on your Web site

Your site is the place prospective patients visit when they are looking for information about you and your services. Here are a few tips on gathering and posting testimonials:

• The best time to solicit feedback from the patient is after the follow-up appointment, when her needs have been met and she has had at least two experiences with your practice. If she is happy with her outcome, she is likely to be receptive to the idea of providing a testimonial while the details are fresh in her mind.
• Post testimonials on your homepage and every other page at your site. They should be visible when each page loads without the need to scroll down. A testimonial is worthless if it can’t be easily seen.
• Post testimonials in italics, with quotation marks around the comments to distinguish them from other elements on the page.
• Give each testimonial a headline in bold italics. Use key words likely to resonate with the reader. For example, if the patient reports: “I had a surgical procedure and it was a game changer. You turned my life around! Thank you!” the headline might be: “You turned my life around.”
• Create a Web page just for testimonials and order the comments and headlines so that they will appeal to a diversity of prospective patients. The visitor may not read every testimonial, but she will at least read and scroll through the headlines.

Gathering feedback: Your options

• One option for automating the gathering of feedback is to include a patient feedback survey on your Web site. It’s a convenient way to ask for comments. When the patient is in the office, you or your staff can simply ask her to visit the survey page on your site and answer the questions. The problem with this approach is that many patients will agree to complete the survey but few will actually follow through.
• A far more effective way to get patients to complete a survey while they are still in your office is to have the receptionist hand the patient an iPad after her appointment and ask her to take a couple of minutes to complete the survey. You can then transcribe her comments and post them on your site.
• Asking patients to post positive comments on review sites such as healthgrades.com is another option—but, again, patients are unlikely to follow through unless you make it as easy and fast as possible. The best way to do this is to provide your patient with a blueprint for how to proceed. We offer a “patient feedback” form that contains four or five questions (FIGURE). The answers to these questions will provide a great testimonial for the doctor and the practice. Providing your patients with the right questions to elicit an emotional response will help them describe their experiences more fully. If you let the patient create a testimonial on her own, you’ll probably just receive comments such as, “I’m very happy with my results” or “She is a great doctor.”
• Also provide patients with a step-by-step process for entering their feedback on the desired review sites. This can be a daunting task for your patient, so your instructions should be clear and simple. Better yet, have someone on your staff sit with the patient at a computer or iPad to help her through the process.
• Another way to control your online reputation is to capture positive comments at the point of service. In our practice, we have a testimonial poster in every exam room as well as the reception area. It contains a quick response (QR) code that can be scanned to allow the patient to submit a testimonial about her experience with the practice. With this system, we are able to collect three to five positive reviews every day.
  
  

FIGURE: Patient follow-up satisfaction survey

CASE: Resolved
The physician institutes a process in his practice to gather testimonials and positive feedback, and his staff takes time to help willing patients post their reviews online. He also disputes the negative comments that have already been posted online, offering an objective response to the complaints and asking the Web sites to take down the reviews that are merely ranting. In addition, he posts selected testimonials on the homepage of his Web site and adds a page that is just for testimonials.

Within a few weeks, the number of new patients scheduling appointments with him begins to increase until he once again enjoys a bustling practice.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

“It takes 20 years to build a reputation and 5 minutes to ruin it. If you think about that, you’ll do things differently.”          
—Warren Buffet

CASE: Decline in new patients
A well-respected physician—one of the best in his field—notices that the number of new patients in his practice has fallen off drastically over the past year. Baffled, he hires a consultant, who discovers that the doctor’s online reputation has plummeted, thanks to four negative reviews and no positive ones.

What can the physician do to remedy the situation and restore his reputation?

The problem can be fixed, but it takes time—like major surgery. Rather than wait until negative reviews are posted, we recommend that you become proactive and take steps as soon as possible to secure your online reputation. That way, you won’t get caught by surprise when one or two unhappy patients try to smear your good name. In this article, we step you through a number of remedies and proactive strategies for boosting positive online reviews and combating negative ones.

The Internet: A one-stop source of information
The Internet has become everyone’s go-to source for pretty much any kind of data, including details on products, services, and people. Anyone can access all kinds of information simply by asking.

Today, people research medical conditions on the Web, often using Google. If you have done your search engine optimization, your Web site will come up in the first page of search results, making it possible for prospective patients to click through to your homepage. (For the scoop on search engine optimization, see Part 3 of this series, “Maximizing your online reach through SEO and pay-per-click,” which appeared in the September 2014 issue of OBG Management.)

If visitors like what they see at your site, they may make an appointment. But they are more likely to visit three or four other sites before making a decision. And in all likelihood, they will research each physician to find out what patients have to say about her or him. It’s no different than looking at the reviews of hotels or products you are considering.

You are an open book on the Internet. Only a few short years ago, your peers and patients knew your reputation primarily through word of mouth, which traveled at the speed of molasses. For the most part, that information was favorable. Today your exposure is much greater, and negative comments about you can be viewed by thousands of potential patients. The speed of information has increased, as well. What is posted on the Internet can become readily available to hundreds, thousands, and even millions of Web users in a nanosecond.

The Internet provides a forum for people to say whatever they want about their experiences, both positive and negative. Regrettably, the positive experiences do not find their way online nearly as often as the negative ones!

The bottom line? In today’s Internet-­savvy world, you need to pay regular attention to your online reputation. You need to take steps to ensure that your name and practice look their best and to negate any complaints that may appear.

What patients share about their experience with you
Many online review sites provide an opportunity for your patients to describe their experience with you and your practice. To name a few: RateMDs.com, Vitals.com, ­ZocDoc.com, healthgrades.com, ­UcompareHealth.com, Citysearch.com, yelp.com, and, of course, Google Plus reviews.

And when patients post comments on the Internet, you likely will be rated on:

• the patient’s wait time
• how your staff treated the patient
• the diagnosis
• your attitude
• the level of trust in your decisions
• treatment and outcome.

The online surfer searching for a reputable physician is likely to believe whatever he or she finds on the leading review sites.

The good news: Most physicians have a very favorable rating, averaging 9.3 out of 10 on a scale of 1 to 10. In fact, 70% of doctors have perfect scores!¹

The bad news: Someone who is unhappy with her treatment or outcome will go out of her way to find every online review site possible and proclaim your faults to the cyber-world, using the Internet as a forum, whether her facts are straight or not. Patients who are pleased and satisfied rarely bother to place a positive review.

How you can control your online reputation
It is incumbent upon you to keep an eye on your online reputation at all times. Here are some tips for taking charge:

• If someone posts a negative review, respond to them directly in the review site. Doing so does not violate privacy laws as long as you do not mention the patient’s name or give other identifying details. Explain your side of the story without confirming or denying that the reviewer is or was a patient. Do not mention the specifics of any patient’s condition.
• If you feel that a negative review is completely unjustified, file a dispute with the review site. Many review sites will remove the unfavorable content if you can convince them that the patient is merely ranting.
• To protect your reputation over the long term, use your name or practice name to set up an alert with Google Alerts by visiting the site Google.com/alerts.
• Do a Google search of your name and the name of your practice at least once a month and check out all the review sites that come up. Read the comments!

Develop a proactive system
You have a lot of control when it comes to protecting your online reputation, provided you are willing to take the time to set up a system to regularly request feedback or testimonials from your patients.

Regrettably, this is where most medical practices fall short, by failing to establish a system to solicit positive reviews.

The process need not be complicated. Such a system can be set in motion by scheduling a quick meeting with your staff to announce your plans to solicit testimonials from patients. Often there will be a flurry of activity for a couple of weeks before the task is forgotten. To keep your system from falling through the cracks, make a checklist and decide who on your staff is responsible for each step in the process. Go over the results in your staff meetings on a regular basis—ie, at least monthly.

You want to solicit positive reviews for use in two places:

• your Web site
• the review sites we mentioned earlier.

Posting testimonials on your Web site

Your site is the place prospective patients visit when they are looking for information about you and your services. Here are a few tips on gathering and posting testimonials:

• The best time to solicit feedback from the patient is after the follow-up appointment, when her needs have been met and she has had at least two experiences with your practice. If she is happy with her outcome, she is likely to be receptive to the idea of providing a testimonial while the details are fresh in her mind.
• Post testimonials on your homepage and every other page at your site. They should be visible when each page loads without the need to scroll down. A testimonial is worthless if it can’t be easily seen.
• Post testimonials in italics, with quotation marks around the comments to distinguish them from other elements on the page.
• Give each testimonial a headline in bold italics. Use key words likely to resonate with the reader. For example, if the patient reports: “I had a surgical procedure and it was a game changer. You turned my life around! Thank you!” the headline might be: “You turned my life around.”
• Create a Web page just for testimonials and order the comments and headlines so that they will appeal to a diversity of prospective patients. The visitor may not read every testimonial, but she will at least read and scroll through the headlines.

Gathering feedback: Your options

• One option for automating the gathering of feedback is to include a patient feedback survey on your Web site. It’s a convenient way to ask for comments. When the patient is in the office, you or your staff can simply ask her to visit the survey page on your site and answer the questions. The problem with this approach is that many patients will agree to complete the survey but few will actually follow through.
• A far more effective way to get patients to complete a survey while they are still in your office is to have the receptionist hand the patient an iPad after her appointment and ask her to take a couple of minutes to complete the survey. You can then transcribe her comments and post them on your site.
• Asking patients to post positive comments on review sites such as healthgrades.com is another option—but, again, patients are unlikely to follow through unless you make it as easy and fast as possible. The best way to do this is to provide your patient with a blueprint for how to proceed. We offer a “patient feedback” form that contains four or five questions (FIGURE). The answers to these questions will provide a great testimonial for the doctor and the practice. Providing your patients with the right questions to elicit an emotional response will help them describe their experiences more fully. If you let the patient create a testimonial on her own, you’ll probably just receive comments such as, “I’m very happy with my results” or “She is a great doctor.”
• Also provide patients with a step-by-step process for entering their feedback on the desired review sites. This can be a daunting task for your patient, so your instructions should be clear and simple. Better yet, have someone on your staff sit with the patient at a computer or iPad to help her through the process.
• Another way to control your online reputation is to capture positive comments at the point of service. In our practice, we have a testimonial poster in every exam room as well as the reception area. It contains a quick response (QR) code that can be scanned to allow the patient to submit a testimonial about her experience with the practice. With this system, we are able to collect three to five positive reviews every day.
  
  

FIGURE: Patient follow-up satisfaction survey

CASE: Resolved
The physician institutes a process in his practice to gather testimonials and positive feedback, and his staff takes time to help willing patients post their reviews online. He also disputes the negative comments that have already been posted online, offering an objective response to the complaints and asking the Web sites to take down the reviews that are merely ranting. In addition, he posts selected testimonials on the homepage of his Web site and adds a page that is just for testimonials.

Within a few weeks, the number of new patients scheduling appointments with him begins to increase until he once again enjoys a bustling practice.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

“It takes 20 years to build a reputation and 5 minutes to ruin it. If you think about that, you’ll do things differently.”          
—Warren Buffet

CASE: Decline in new patients
A well-respected physician—one of the best in his field—notices that the number of new patients in his practice has fallen off drastically over the past year. Baffled, he hires a consultant, who discovers that the doctor’s online reputation has plummeted, thanks to four negative reviews and no positive ones.

What can the physician do to remedy the situation and restore his reputation?

The problem can be fixed, but it takes time—like major surgery. Rather than wait until negative reviews are posted, we recommend that you become proactive and take steps as soon as possible to secure your online reputation. That way, you won’t get caught by surprise when one or two unhappy patients try to smear your good name. In this article, we step you through a number of remedies and proactive strategies for boosting positive online reviews and combating negative ones.

The Internet: A one-stop source of information
The Internet has become everyone’s go-to source for pretty much any kind of data, including details on products, services, and people. Anyone can access all kinds of information simply by asking.

Today, people research medical conditions on the Web, often using Google. If you have done your search engine optimization, your Web site will come up in the first page of search results, making it possible for prospective patients to click through to your homepage. (For the scoop on search engine optimization, see Part 3 of this series, “Maximizing your online reach through SEO and pay-per-click,” which appeared in the September 2014 issue of OBG Management.)

If visitors like what they see at your site, they may make an appointment. But they are more likely to visit three or four other sites before making a decision. And in all likelihood, they will research each physician to find out what patients have to say about her or him. It’s no different than looking at the reviews of hotels or products you are considering.

You are an open book on the Internet. Only a few short years ago, your peers and patients knew your reputation primarily through word of mouth, which traveled at the speed of molasses. For the most part, that information was favorable. Today your exposure is much greater, and negative comments about you can be viewed by thousands of potential patients. The speed of information has increased, as well. What is posted on the Internet can become readily available to hundreds, thousands, and even millions of Web users in a nanosecond.

The Internet provides a forum for people to say whatever they want about their experiences, both positive and negative. Regrettably, the positive experiences do not find their way online nearly as often as the negative ones!

The bottom line? In today’s Internet-­savvy world, you need to pay regular attention to your online reputation. You need to take steps to ensure that your name and practice look their best and to negate any complaints that may appear.

What patients share about their experience with you
Many online review sites provide an opportunity for your patients to describe their experience with you and your practice. To name a few: RateMDs.com, Vitals.com, ­ZocDoc.com, healthgrades.com, ­UcompareHealth.com, Citysearch.com, yelp.com, and, of course, Google Plus reviews.

And when patients post comments on the Internet, you likely will be rated on:

• the patient’s wait time
• how your staff treated the patient
• the diagnosis
• your attitude
• the level of trust in your decisions
• treatment and outcome.

The online surfer searching for a reputable physician is likely to believe whatever he or she finds on the leading review sites.

The good news: Most physicians have a very favorable rating, averaging 9.3 out of 10 on a scale of 1 to 10. In fact, 70% of doctors have perfect scores!¹

The bad news: Someone who is unhappy with her treatment or outcome will go out of her way to find every online review site possible and proclaim your faults to the cyber-world, using the Internet as a forum, whether her facts are straight or not. Patients who are pleased and satisfied rarely bother to place a positive review.

How you can control your online reputation
It is incumbent upon you to keep an eye on your online reputation at all times. Here are some tips for taking charge:

• If someone posts a negative review, respond to them directly in the review site. Doing so does not violate privacy laws as long as you do not mention the patient’s name or give other identifying details. Explain your side of the story without confirming or denying that the reviewer is or was a patient. Do not mention the specifics of any patient’s condition.
• If you feel that a negative review is completely unjustified, file a dispute with the review site. Many review sites will remove the unfavorable content if you can convince them that the patient is merely ranting.
• To protect your reputation over the long term, use your name or practice name to set up an alert with Google Alerts by visiting the site Google.com/alerts.
• Do a Google search of your name and the name of your practice at least once a month and check out all the review sites that come up. Read the comments!

Develop a proactive system
You have a lot of control when it comes to protecting your online reputation, provided you are willing to take the time to set up a system to regularly request feedback or testimonials from your patients.

Regrettably, this is where most medical practices fall short, by failing to establish a system to solicit positive reviews.

The process need not be complicated. Such a system can be set in motion by scheduling a quick meeting with your staff to announce your plans to solicit testimonials from patients. Often there will be a flurry of activity for a couple of weeks before the task is forgotten. To keep your system from falling through the cracks, make a checklist and decide who on your staff is responsible for each step in the process. Go over the results in your staff meetings on a regular basis—ie, at least monthly.

You want to solicit positive reviews for use in two places:

• your Web site
• the review sites we mentioned earlier.

Posting testimonials on your Web site

Your site is the place prospective patients visit when they are looking for information about you and your services. Here are a few tips on gathering and posting testimonials:

• The best time to solicit feedback from the patient is after the follow-up appointment, when her needs have been met and she has had at least two experiences with your practice. If she is happy with her outcome, she is likely to be receptive to the idea of providing a testimonial while the details are fresh in her mind.
• Post testimonials on your homepage and every other page at your site. They should be visible when each page loads without the need to scroll down. A testimonial is worthless if it can’t be easily seen.
• Post testimonials in italics, with quotation marks around the comments to distinguish them from other elements on the page.
• Give each testimonial a headline in bold italics. Use key words likely to resonate with the reader. For example, if the patient reports: “I had a surgical procedure and it was a game changer. You turned my life around! Thank you!” the headline might be: “You turned my life around.”
• Create a Web page just for testimonials and order the comments and headlines so that they will appeal to a diversity of prospective patients. The visitor may not read every testimonial, but she will at least read and scroll through the headlines.

Gathering feedback: Your options

• One option for automating the gathering of feedback is to include a patient feedback survey on your Web site. It’s a convenient way to ask for comments. When the patient is in the office, you or your staff can simply ask her to visit the survey page on your site and answer the questions. The problem with this approach is that many patients will agree to complete the survey but few will actually follow through.
• A far more effective way to get patients to complete a survey while they are still in your office is to have the receptionist hand the patient an iPad after her appointment and ask her to take a couple of minutes to complete the survey. You can then transcribe her comments and post them on your site.
• Asking patients to post positive comments on review sites such as healthgrades.com is another option—but, again, patients are unlikely to follow through unless you make it as easy and fast as possible. The best way to do this is to provide your patient with a blueprint for how to proceed. We offer a “patient feedback” form that contains four or five questions (FIGURE). The answers to these questions will provide a great testimonial for the doctor and the practice. Providing your patients with the right questions to elicit an emotional response will help them describe their experiences more fully. If you let the patient create a testimonial on her own, you’ll probably just receive comments such as, “I’m very happy with my results” or “She is a great doctor.”
• Also provide patients with a step-by-step process for entering their feedback on the desired review sites. This can be a daunting task for your patient, so your instructions should be clear and simple. Better yet, have someone on your staff sit with the patient at a computer or iPad to help her through the process.
• Another way to control your online reputation is to capture positive comments at the point of service. In our practice, we have a testimonial poster in every exam room as well as the reception area. It contains a quick response (QR) code that can be scanned to allow the patient to submit a testimonial about her experience with the practice. With this system, we are able to collect three to five positive reviews every day.
  
  

FIGURE: Patient follow-up satisfaction survey

CASE: Resolved
The physician institutes a process in his practice to gather testimonials and positive feedback, and his staff takes time to help willing patients post their reviews online. He also disputes the negative comments that have already been posted online, offering an objective response to the complaints and asking the Web sites to take down the reviews that are merely ranting. In addition, he posts selected testimonials on the homepage of his Web site and adds a page that is just for testimonials.

Within a few weeks, the number of new patients scheduling appointments with him begins to increase until he once again enjoys a bustling practice.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Patients with cancer can have many hematologic complications. One of the most serious is bleeding, which can range in severity from laboratory abnormalities to life-threatening hemorrhage. The bleeding can be due to complications of the cancer, its therapy, or treatment for complications of cancer such as thrombosis. This manual discusses an approach to the cancer patient with bleeding, with a specific focus on issues such as coagulation defects, thrombocytopenia, and platelet dysfunction. Bleeding complications of specific cancers and their treatment will be discussed as well.

To read the full article in PDF:

Click here

Patients with cancer can have many hematologic complications. One of the most serious is bleeding, which can range in severity from laboratory abnormalities to life-threatening hemorrhage. The bleeding can be due to complications of the cancer, its therapy, or treatment for complications of cancer such as thrombosis. This manual discusses an approach to the cancer patient with bleeding, with a specific focus on issues such as coagulation defects, thrombocytopenia, and platelet dysfunction. Bleeding complications of specific cancers and their treatment will be discussed as well.

To read the full article in PDF:

Click here

Patients with cancer can have many hematologic complications. One of the most serious is bleeding, which can range in severity from laboratory abnormalities to life-threatening hemorrhage. The bleeding can be due to complications of the cancer, its therapy, or treatment for complications of cancer such as thrombosis. This manual discusses an approach to the cancer patient with bleeding, with a specific focus on issues such as coagulation defects, thrombocytopenia, and platelet dysfunction. Bleeding complications of specific cancers and their treatment will be discussed as well.

To read the full article in PDF:

Click here

Prostate cancer remains the second leading cause of death in men in the United States as of 2012. It is estimated that prostate cancer affected more than 241,000 new men in 2012, with 15% of these patients presenting with advanced disease. As one would expect, compared to localized prostate cancer, metastatic disease remains the more challenging type to treat. In 1941 Huggins and Hodges demonstrated the dependence of prostatic tissues on androgens and from this work hormonal therapy was developed as the primary treatment for metastatic prostate cancer. Since then, significant progress has been made in the treatment of metastatic prostate cancer, including advances in androgen deprivation therapy and in the treatment of castrationresistant prostate cancer (CRPC), with many advances yet to come. CPRC has been an exciting topic for recent research and advancement, as our understanding of how prostate cancer utilizes very low levels of androgen has evolved considerably.

To read the full article in PDF:

Click here

Prostate cancer remains the second leading cause of death in men in the United States as of 2012. It is estimated that prostate cancer affected more than 241,000 new men in 2012, with 15% of these patients presenting with advanced disease. As one would expect, compared to localized prostate cancer, metastatic disease remains the more challenging type to treat. In 1941 Huggins and Hodges demonstrated the dependence of prostatic tissues on androgens and from this work hormonal therapy was developed as the primary treatment for metastatic prostate cancer. Since then, significant progress has been made in the treatment of metastatic prostate cancer, including advances in androgen deprivation therapy and in the treatment of castrationresistant prostate cancer (CRPC), with many advances yet to come. CPRC has been an exciting topic for recent research and advancement, as our understanding of how prostate cancer utilizes very low levels of androgen has evolved considerably.

To read the full article in PDF:

Click here

Prostate cancer remains the second leading cause of death in men in the United States as of 2012. It is estimated that prostate cancer affected more than 241,000 new men in 2012, with 15% of these patients presenting with advanced disease. As one would expect, compared to localized prostate cancer, metastatic disease remains the more challenging type to treat. In 1941 Huggins and Hodges demonstrated the dependence of prostatic tissues on androgens and from this work hormonal therapy was developed as the primary treatment for metastatic prostate cancer. Since then, significant progress has been made in the treatment of metastatic prostate cancer, including advances in androgen deprivation therapy and in the treatment of castrationresistant prostate cancer (CRPC), with many advances yet to come. CPRC has been an exciting topic for recent research and advancement, as our understanding of how prostate cancer utilizes very low levels of androgen has evolved considerably.

To read the full article in PDF:

Click here

Syncope is a transient loss of consciousness and postural tone with spontaneous, complete recovery. There are three major types: neurally mediated, orthostatic, and cardiac (Table 1).

NEURALLY MEDIATED SYNCOPE

Neurally mediated (reflex) syncope is the most common type, accounting for two-thirds of cases.^1–3 It results from autonomic reflexes that respond inappropriately, leading to vasodilation and bradycardia.

See related patient-education handout

Neurally mediated syncope is usually preceded by premonitory symptoms such as lightheadedness, diaphoresis, nausea, malaise, abdominal discomfort, and tunnel vision. However, this may not be the case in one-third of patients, especially in elderly patients, who may not recognize or remember the warning symptoms. Palpitations are frequently reported with neurally mediated syncope and do not necessarily imply that the syncope is due to an arrhythmia.^4,5 Neurally mediated syncope does not usually occur in the supine position^4,5 but can occur in the seated position.⁶

Subtypes of neurally mediated syncope are as follows:

Vasovagal syncope

Vasovagal syncope is usually triggered by sudden emotional stress, prolonged sitting or standing, dehydration, or a warm environment, but it can also occur without a trigger. It is the most common type of syncope in young patients (more so in females than in males), but contrary to a common misconception, it can also occur in the elderly.⁷ Usually, it is not only preceded by but also followed by nausea, malaise, fatigue, and diaphoresis^4,5,8; full recovery may be slow. If the syncope lasts longer than 30 to 60 seconds, clonic movements and loss of bladder control are common.⁹

Mechanism. Vasovagal syncope is initiated by anything that leads to strong myocardial contractions in an "empty" heart. Emotional stress, reduced venous return (from dehydration or prolonged standing), or vasodilation (caused by a hot environment) stimulates the sympathetic nervous system and reduces the left ventricular cavity size, which leads to strong hyperdynamic contractions in a relatively empty heart. This hyperdynamic cavity obliteration activates myocardial mechanoreceptors, initiating a paradoxical vagal reflex with vasodilation and relative bradycardia.¹⁰ Vasodilation is usually the predominant mechanism (vasodepressor response), particularly in older patients, but severe bradycardia is also possible (cardioinhibitory response), particularly in younger patients.⁷ Diuretic and vasodilator therapies increase the predisposition to vasovagal syncope, particularly in the elderly.

On tilt-table testing, vasovagal syncope is characterized by hypotension and relative bradycardia, sometimes severe (see Note on Tilt-Table Testing).^10–12

Situational syncope

Situational syncope is caused by a reflex triggered in specific circumstances such as micturition, defecation, coughing, weight-lifting, laughing, or deglutition. The reflex may be initiated by a receptor on the visceral wall (eg, the bladder wall) or by straining that reduces venous return.

Carotid sinus hypersensitivity

Carotid sinus hypersensitivity is an abnormal response to carotid massage, predominantly occurring in patients over the age of 50. In spontaneous carotid sinus syndrome, syncope clearly occurs in a situation that stimulates the carotid sinus, such as head rotation, head extension, shaving, or wearing a tight collar. It is a rare cause of syncope, responsible for about 1% of cases. Conversely, induced carotid sinus syndrome is much more common and represents carotid sinus hypersensitivity in a patient with unexplained syncope and without obvious triggers; the abnormal response is mainly induced during carotid massage rather than spontaneously. In the latter case, carotid sinus hypersensitivity is a marker of a diseased sinus node or atrioventricular node that cannot withstand any inhibition. This diseased node is the true cause of syncope rather than carotid sinus hypersensitivity per se, and carotid massage is a "stress test" that unveils conduction disease.

Palpitations do not necessarily imply that syncope is due to an arrhythmia

Thus, carotid massage is indicated in cases of unexplained syncope regardless of circumstantial triggers. This test consists of applying firm pressure over each carotid bifurcation (just below the angle of the jaw) consecutively for 10 seconds. It is performed at the bedside, and may be performed with the patient in both supine and erect positions during tilt-table testing; erect positioning of the patient increases the sensitivity of this test.

An abnormal response to carotid sinus massage is defined as any of the following^13–15:

• Vasodepressor response: the systolic blood pressure decreases by at least 50 mm Hg
• Cardioinhibitory response: sinus or atrioventricular block causes the heartbeat to pause for 3 or more seconds
• Mixed vasodepressor and cardioinhibitory response.

Overall, a cardioinhibitory component is present in about two-thirds of cases of carotid sinus hypersensitivity.

Carotid sinus hypersensitivity is found in 25% to 50% of patients over age 50 who have had unexplained syncope or a fall, and it is seen almost equally in men and women.¹³

One study correlated carotid sinus hypersensitivity with the later occurrence of asystolic syncope during prolonged internal loop monitoring; subsequent pacemaker therapy reduced the burden of syncope.¹⁴ Another study, in patients over 50 years old with unexplained falls, found that 16% had cardioinhibitory carotid sinus hypersensitivity. Pacemaker placement reduced falls and syncope by 70% compared with no pacemaker therapy in these patients.¹⁵

On the other hand, carotid sinus hypersensitivity can be found in 39% of elderly patients who do not have a history of fainting or falling, so it is important to rule out other causes of syncope before attributing it to carotid sinus hypersensitivity.

Postexertional syncope

While syncope on exertion raises the worrisome possibility of a cardiac cause, postexertional syncope is usually a form of vasovagal syncope. When exercise ceases, venous blood stops getting pumped back to the heart by peripheral muscular contraction. Yet the heart is still exposed to the catecholamine surge induced by exercising, and it hypercontracts on an empty cavity. This triggers a vagal reflex.

Postexertional syncope may also be seen in hypertrophic obstructive cardiomyopathy or aortic stenosis, in which the small left ventricular cavity is less likely to tolerate the reduced preload after exercise and is more likely to obliterate.

ORTHOSTATIC HYPOTENSION

Orthostatic hypotension accounts for about 10% of cases of syncope.^1–3

Normally, after the first few minutes of standing, about 25% to 30% of the blood pools in the veins of the pelvis and the lower extremities, strikingly reducing venous return and stroke volume. Upon more prolonged standing, more blood leaves the vascular space and collects in the extravascular space, further reducing venous return. This normally leads to a reflex increase in sympathetic tone, peripheral and splanchnic vasoconstriction, and an increase in heart rate of 10 to 15 beats per minute. Overall, cardiac output is reduced and vascular resistance is increased while blood pressure is maintained, blood pressure being equal to cardiac output times vascular resistance.

Vasovagal syncope is initiated by anything that leads to strong contractions in an 'empty' heart

Orthostatic hypotension is characterized by autonomic failure, with a lack of compensatory increase in vascular resistance or heart rate upon orthostasis, or by significant hypovolemia that cannot be overcome by sympathetic mechanisms. It is defined as a drop in systolic blood pressure of 20 mm Hg or more or a drop in diastolic pressure of 10 mm Hg or more after 30 seconds to 5 minutes of upright posture. Blood pressure is checked immediately upon standing and at 3 and 5 minutes. This may be done at the bedside or during tilt-table testing.^2,4

Some patients have an immediate drop in blood pressure of more than 40 mm Hg upon standing, with a quick return to normal within 30 seconds. This "initial orthostatic hypotension" may be common in elderly patients taking antihypertensive drugs and may elude detection during standard blood pressure measurement.² Other patients with milder orthostatic hypotension may develop a more delayed hypotension 10 to 15 minutes later, as more blood pools in the periphery.¹⁶

Along with the drop in blood pressure, a failure of the heart rate to increase identifies autonomic dysfunction. On the other hand, an increase in the heart rate of more than 20 to 30 beats per minute may signify a hypovolemic state even if blood pressure is maintained, the lack of blood pressure drop being related to the excessive heart rate increase.

Orthostatic hypotension is the most common cause of syncope in the elderly and may be due to autonomic dysfunction (related to age, diabetes, uremia, or Parkinson disease), volume depletion, or drugs that block autonomic effects or cause hypovolemia, such as vasodilators, beta-blockers, diuretics, neuropsychiatric medications, and alcohol.

Since digestion leads to peripheral vasodilation and splanchnic blood pooling, syncope that occurs within 1 hour after eating has a mechanism similar to that of orthostatic syncope.

Supine hypertension with orthostatic hypotension. Some patients with severe autonomic dysfunction and the inability to regulate vascular tone have severe hypertension when supine and significant hypotension when upright.

Postural orthostatic tachycardia syndrome, another form of orthostatic failure, occurs most frequently in young women (under the age of 50). In this syndrome, autonomic dysfunction affects peripheral vascular resistance, which fails to increase in response to orthostatic stress. This autonomic dysfunction does not affect the heart, which manifests a striking compensatory increase in rate of more than 30 beats per minute within the first 10 minutes of orthostasis, or an absolute heart rate greater than 120 beats per minute. Unlike in orthostatic hypotension, blood pressure and cardiac output are maintained through this increase in heart rate, although the patient still develops symptoms of severe fatigue or near-syncope, possibly because of flow maldistribution and reduced cerebral flow.²

While postural orthostatic tachycardia syndrome per se does not induce syncope,² it may be associated with a vasovagal form of syncope that occurs beyond the first 10 minutes of orthostasis in up to 38% of these patients.¹⁷

In a less common, hyperadrenergic form of postural orthostatic tachycardia syndrome, there is no autonomic failure but the sympathetic system is overly activated, with orthostasis leading to excessive tachycardia.^10,18

CARDIAC SYNCOPE

Accounting for 10% to 20% of cases of syncope, a cardiac cause is the main concern in patients presenting with syncope, as cardiac syncope predicts an increased risk of death and may herald sudden cardiac death.^1,2,8,19,20 It often occurs suddenly without any warning signs, in which case it is called malignant syncope. Unlike what occurs in neurally mediated syncope, the postrecovery period is not usually marked by lingering malaise.

There are three forms of cardiac syncope:

Syncope due to structural heart disease with cardiac obstruction

In cases of aortic stenosis, hypertrophic obstructive cardiomyopathy, or severe pulmonary arterial hypertension, peripheral vasodilation occurs during exercise, but cardiac output cannot increase because of the fixed or dynamic obstruction to the ventricular outflow. Since blood pressure is equal to cardiac output times peripheral vascular resistance, pressure drops with the reduction in peripheral vascular resistance. Exertional ventricular arrhythmias may also occur in these patients. Conversely, postexertional syncope is usually benign.

Syncope due to ventricular tachycardia

Ventricular tachycardia can be secondary to underlying structural heart disease, with or without reduced ejection fraction, such as coronary arterial disease, hypertrophic cardiomyopathy, hypertensive cardiomyopathy, or valvular disease. It can also be secondary to primary electrical disease (eg, long QT syndrome, Wolff-Parkinson-White syndrome, Brugada syndrome, arrhythmogenic right ventricular dysplasia, sarcoidosis).

Occasionally, fast supraventricular tachycardia causes syncope at its onset, before vascular compensation develops. This occurs in patients with underlying heart disease.^2,8,19

Syncope from bradyarrhythmias

Bradyarrhythmias can occur with or without underlying structural heart disease. They are most often related to degeneration of the conduction system or to medications rather than to cardiomyopathy.

Caveats

When a patient with a history of heart failure presents with syncope, the top considerations are ventricular tachycardia and bradyarrhythmia. Nevertheless, about half of cases of syncope in patients with cardiac disease have a noncardiac cause,¹⁹ including the hypotensive or bradycardiac side effect of drugs.

As noted above, most cases of syncope are neurally mediated. However, long asystolic pauses due to sinus or atrioventricular nodal block are the most frequent mechanism of unexplained syncope and are seen in more than 50% of syncope cases on prolonged rhythm monitoring.^1,21 These pauses may be related to intrinsic sinus or atrioventricular nodal disease or, more commonly, to extrinsic effects such as the vasovagal mechanism. Some experts favor classifying and treating syncope on the basis of the final mechanism rather than the initiating process, but this is not universally accepted.^1,22

OTHER CAUSES OF SYNCOPE

Acute medical or cardiovascular illnesses can cause syncope and are looked for in the appropriate clinical context: severe hypovolemia or gastrointestinal bleeding, large pulmonary embolus with hemodynamic compromise, tamponade, aortic dissection, or hypoglycemia.

Bilateral critical carotid disease or severe vertebrobasilar disease very rarely cause syncope, and, when they do, they are associated with focal neurologic deficits.² Vertebrobasilar disease may cause "drop attacks," ie, a loss of muscular tone with falling but without loss of consciousness.²³

Severe proximal subclavian disease leads to reversal of the flow in the ipsilateral vertebral artery as blood is shunted toward the upper extremity. It manifests as dizziness and syncope during the ipsilateral upper extremity activity, usually with focal neurologic signs (subclavian steal syndrome).²

Psychogenic pseudosyncope is characterized by frequent attacks that typically last longer than true syncope and occur multiple times per day or week, sometimes with a loss of motor tone.² It occurs in patients with anxiety or somatization disorders.

SEIZURE: A SYNCOPE MIMIC

Certain features differentiate seizure from syncope:

• In seizure, unconsciousness often lasts longer than 5 minutes
• After a seizure, the patient may experience postictal confusion or paralysis
• Seizure may include prolonged tonic-clonic movements; although these movements may be seen with any form of syncope lasting more than 30 seconds, the movements during syncope are more limited and brief, lasting less than 15 seconds
• Tongue biting strongly suggests seizure.

Urinary incontinence does not help distinguish the two, as it frequently occurs with syncope as well as seizure.

DIAGNOSTIC EVALUATION OF SYNCOPE

Table 2 lists clinical clues to the type of syncope.^2–5,8

Underlying structural heart disease is the most important predictor of ventricular arrhythmia and death.^20,24–26 Thus, the primary goal of the evaluation is to rule out structural heart disease by history, examination, electrocardiography, and echocardiography (Figure 1).

Initial strategy for finding the cause

The cause of syncope is diagnosed by history and physical examination alone in up to 50% of cases, mainly neurally mediated syncope, orthostatic syncope, or seizure.^2,3,19

Always check blood pressure with the patient both standing and sitting and in both arms, and obtain an electrocardiogram.

Perform carotid massage in all patients over age 50 if syncope is not clearly vasovagal or orthostatic and if cardiac syncope is not likely. Carotid massage is contraindicated if the patient has a carotid bruit or a history of stroke.

Electrocardiography establishes or suggests a diagnosis in 10% of patients (Table 3, Figure 2).^1,2,8,19 A normal electrocardiogram or a mild nonspecific ST-T abnormality suggests a low likelihood of cardiac syncope and is associated with an excellent prognosis. Abnormal electrocardiographic findings are seen in 90% of cases of cardiac syncope and in only 6% of cases of neurally mediated syncope.²⁷ In one study of syncope patients with normal electrocardiograms and negative cardiac histories, none had an abnormal echocardiogram.²⁸

If the heart is normal

If the history suggests neurally mediated syncope or orthostatic hypotension and the history, examination, and electrocardiogram do not suggest coronary artery disease or any other cardiac disease, the workup is stopped.

If the patient has signs or symptoms of heart disease

If the patient has signs or symptoms of heart disease (angina, exertional syncope, dyspnea, clinical signs of heart failure, murmur), a history of heart disease, or exertional, supine, or malignant features, heart disease should be looked for and the following performed:

• Echocardiography to assess left ventricular function, severe valvular disease, and left ventricular hypertrophy
• A stress test (possibly) in cases of exertional syncope or associated angina; however, the overall yield of stress testing in syncope is low (< 5%).²⁹

If electrocardiography and echocardiography do not suggest heart disease

Often, in this situation, the workup can be stopped and syncope can be considered neurally mediated. The likelihood of cardiac syncope is very low in patients with normal findings on electrocardiography and echocardiography, and several studies have shown that patients with syncope who have no structural heart disease have normal long-term survival rates.^20,26,30

The following workup may, however, be ordered if the presentation is atypical and syncope is malignant, recurrent, or associated with physical injury, or occurs in the supine position¹⁹:

Carotid sinus massage in patients over age 50, if not already performed. Up to 50% of these patients with unexplained syncope have carotid sinus hypersensitivity.¹³

24-hour Holter monitoring rarely detects significant arrhythmias, but if syncope or dizziness occurs without any arrhythmia, Holter monitoring rules out arrhythmia as the cause of the symptoms.³¹ The diagnostic yield of Holter monitoring is low (1% to 2%) in patients with infrequent symptoms^1,2 and is not improved with 72-hour monitoring.³⁰ The yield is higher in patients with very frequent daily symptoms, many of whom have psychogenic pseudosyncope.²

Tilt-table testing to diagnose vasovagal syncope. This test is positive for a vasovagal response in up to 66% of patients with unexplained syncope.^1,19 Patients with heart disease taking vasodilators or beta-blockers may have abnormal baroreflexes. Therefore, a positive tilt test is less specific in these patients and does not necessarily indicate vasovagal syncope.

Event monitoring. If the etiology remains unclear or there are some concerns about arrhythmia, an event monitor (4 weeks of external rhythm monitoring) or an implantable loop recorder (implanted subcutaneously in the prepectoral area for 1 to 2 years) is placed. These monitors record the rhythm when the rate is lower or higher than predefined cutoffs or when the rhythm is irregular, regardless of symptoms. The patient or an observer can also activate the event monitor during or after an event, which freezes the recording of the 2 to 5 minutes preceding the activation and the 1 minute after it.

In a patient who has had syncope, a pacemaker is indicated for episodes of high-grade atrioventricular block, pauses longer than 3 seconds while awake, or bradycardia (< 40 beats per minute) while awake, and an implantable cardioverter-defibrillator is indicated for sustained ventricular tachycardia, even if syncope does not occur concomitantly with these findings. The finding of nonsustained ventricular tachycardia on monitoring increases the suspicion of ventricular tachycardia as the cause of syncope but does not prove it, nor does it necessarily dictate implantation of a cardioverter-defibrillator device.

An electrophysiologic study has a low yield in patients with normal electrocardiographic and echocardiographic studies. Bradycardia is detected in 10%.³¹

If heart disease or a rhythm abnormality is found

If heart disease is diagnosed by echocardiography or if significant electrocardiographic abnormalities are found, perform the following:

Pacemaker placement for the following electrocardiographic abnormalities^1,2,19:

• Second-degree Mobitz II or third-degree atrioventricular block
• Sinus pause (> 3 seconds) or bradycardia (< 40 beats per minute) while awake
• Alternating left bundle branch block and right bundle branch block on the same electrocardiogram or separate ones.

Telemetric monitoring (inpatient).

An electrophysiologic study is valuable mainly for patients with structural heart disease, including an ejection fraction 36% to 49%, coronary artery disease, or left ventricular hypertrophy with a normal ejection fraction.³² Overall, in patients with structural heart disease and unexplained syncope, the yield is 55% (inducible ventricular tachycardia in 21%, abnormal indices of bradycardia in 34%).³¹

However, the yield of electrophysiologic testing is low in bradyarrhythmia and in patients with an ejection fraction of 35% or less.³³ In the latter case, the syncope is often arrhythmia-related and the patient often has an indication for an implantable cardioverter-defibrillator regardless of electrophysiologic study results, especially if the low ejection fraction has persisted despite medical therapy.³²

If the electrophysiologic study is negative

If the electrophysiologic study is negative, the differential diagnosis still includes arrhythmia, as the yield of electrophysiologic study is low for bradyarrhythmias and some ventricular tachycardias, and the differential diagnosis also includes, at this point, neurally mediated syncope.

The next step may be either prolonged rhythm monitoring or tilt-table testing. An event monitor or an implantable loop recorder can be placed for prolonged monitoring. The yield of the 30-day event monitor is highest in patients with frequently recurring syncope, in whom it reaches a yield of up to 40% (10% to 20% will have a positive diagnosis of arrhythmia, while 15% to 20% will have symptoms with a normal rhythm).^31,34 The implantable recorder has a high overall diagnostic yield and is used in patients with infrequent syncopal episodes (yield up to 50%).^1,35,36

In brief, there are two diagnostic approaches to unexplained syncope: the monitoring approach (loop recorder) and the testing approach (tilt-table testing). A combination of both strategies is frequently required in patients with unexplained syncope, and, according to some investigators, a loop recorder may be implanted early on.²¹

Heart disease with left ventricular dysfunction and low ejection fraction

Carotid massage is indicated in cases of unexplained syncope regardless of circumstantial triggers

In patients with heart disease with left ventricular dysfunction and an ejection fraction of 35% or less, an implantable cardioverter-defibrillator can be placed without the need for an electrophysiologic study. These patients need these devices anyway to prevent sudden death, even if the cause of syncope is not an arrhythmia. Patients with a low ejection fraction and a history of syncope are at a high risk of sudden cardiac death.³² Yet in some patients with newly diagnosed cardiomyopathy, left ventricular function may improve with medical therapy. Because the arrhythmic risk is essentially high during the period of ventricular dysfunction, a wearable external defibrillator may be placed while the decision about an implantable defibrillator is finalized within the ensuing months.

In patients with hypertrophic cardiomyopathy, place an implantable cardioverter-defibrillator after any unexplained syncopal episode.

Valvular heart disease needs surgical correction.

If ischemic heart disease is suspected, coronary angiography is indicated, with revascularization if appropriate. An implantable cardioverter-defibrillator should be placed if the ejection fraction is lower than 35%. Except in a large acute myocardial infarction, the substrate for ventricular tachycardia is not ameliorated with revascularization.^32,37 Consider an electrophysiologic study when syncope occurs with coronary artery disease and a higher ejection fraction.

A note on left or right bundle branch block

Patients with left or right bundle branch block and unexplained syncope (not clearly vasovagal or orthostatic) likely have syncope related to intermittent high-grade atrioventricular block.³⁸

One study monitored these patients with an implanted loop recorder and showed that about 40% had a recurrence of syncope within 48 days, often concomitantly with complete atrioventricular block. About 55% of these patients had a major event (syncope or high-grade atrioventricular block).³⁹ Many of the patients had had a positive tilt test; thus, tilt testing is not specific for vasovagal syncope in these patients and should not be used to exclude a bradyarrhythmic syncope. Also, patients selected for this study had undergone carotid sinus massage and an electrophysiology study with a negative result.

Underlying structural heart disease is the most important predictor of ventricular arrhythmia and death

In another analysis, an electrophysiologic study detected a proportion of the bradyarrhythmias but, more importantly, it induced ventricular tachycardia in 14% of patients with right or left bundle branch block. Although it is not sensitive enough for bradyarrhythmia, electrophysiologic study was highly specific and fairly sensitive for the occurrence of ventricular tachycardia on follow-up.³⁸ Thus, unexplained syncope in a patient with right or left bundle branch block may warrant carotid sinus massage, then an electrophysiologic study to rule out ventricular tachycardia, followed by placement of a dual-chamber pacemaker if the study is negative for ventricular tachycardia, or at least placement of a loop recorder.

INDICATIONS FOR HOSPITALIZATION

Patients should be hospitalized if they have severe hypovolemia or bleeding, or if there is any suspicion of heart disease by history, examination, or electrocardiography, including:

• History of heart failure, low ejection fraction, or coronary artery disease
• An electrocardiogram suggestive of arrhythmia (Table 3)
• Family history of sudden death
• Lack of prodromes; occurrence of physical injury, exertional syncope, syncope in a supine position, or syncope associated with dyspnea or chest pain.^2,40

In these situations, there is concern about arrhythmia, structural heart disease, or acute myocardial ischemia. The patient is admitted for immediate telemetric monitoring. Echocardiography and sometimes stress testing are performed. The patient is discharged if this initial workup does not suggest underlying heart disease. Alternatively, an electrophysiologic study is performed or a device is placed in patients found to have structural heart disease. Prolonged rhythm monitoring or tilt-table testing may be performed when syncope with underlying heart disease or worrisome features remains unexplained.

Several Web-based interactive algorithms have been used to determine the indication for hospitalization. They incorporate the above clinical, electrocardiographic, and sometimes echocardiographic features.^{2,24,25,40–42} A cardiology consultation is usually necessary in patients with the above features, as they frequently require specialized cardiac testing.

Among high-risk patients, the risk of sudden death, a major cardiovascular event, or significant arrhythmia is high in the first few days after the index syncopal episode, justifying the hospitalization and inpatient rhythm monitoring and workup in the presence of the above criteria.^24,40,42

SYNCOPE AND DRIVING

A study has shown that the most common cause of syncope while driving is vasovagal syncope.⁶ In all patients, the risk of another episode of syncope was relatively higher during the first 6 months after the event, with a 12% recurrence rate during this period. However, recurrences were often also seen more than 6 months later (12% recurrence between 6 months and the following few years).⁶ Fortunately, those episodes rarely occurred while the patient was driving. In a study in survivors of ventricular arrhythmia, the risk of recurrence of arrhythmic events was highest during the first 6 to 12 months after the event.⁴³

Thus, in general, patients with syncope should be prohibited from driving for at least the period of time (eg, 6 months) during which the risk of a recurrent episode of syncope is highest and during which serious cardiac disease or arrhythmia, if present, would emerge. Recurrence of syncope is more likely and more dangerous for commercial drivers who spend a significant proportion of their time driving; individualized decisions are made in these cases.

Syncope is a transient loss of consciousness and postural tone with spontaneous, complete recovery. There are three major types: neurally mediated, orthostatic, and cardiac (Table 1).

NEURALLY MEDIATED SYNCOPE

Neurally mediated (reflex) syncope is the most common type, accounting for two-thirds of cases.^1–3 It results from autonomic reflexes that respond inappropriately, leading to vasodilation and bradycardia.

See related patient-education handout

Neurally mediated syncope is usually preceded by premonitory symptoms such as lightheadedness, diaphoresis, nausea, malaise, abdominal discomfort, and tunnel vision. However, this may not be the case in one-third of patients, especially in elderly patients, who may not recognize or remember the warning symptoms. Palpitations are frequently reported with neurally mediated syncope and do not necessarily imply that the syncope is due to an arrhythmia.^4,5 Neurally mediated syncope does not usually occur in the supine position^4,5 but can occur in the seated position.⁶

Subtypes of neurally mediated syncope are as follows:

Vasovagal syncope

Vasovagal syncope is usually triggered by sudden emotional stress, prolonged sitting or standing, dehydration, or a warm environment, but it can also occur without a trigger. It is the most common type of syncope in young patients (more so in females than in males), but contrary to a common misconception, it can also occur in the elderly.⁷ Usually, it is not only preceded by but also followed by nausea, malaise, fatigue, and diaphoresis^4,5,8; full recovery may be slow. If the syncope lasts longer than 30 to 60 seconds, clonic movements and loss of bladder control are common.⁹

Mechanism. Vasovagal syncope is initiated by anything that leads to strong myocardial contractions in an "empty" heart. Emotional stress, reduced venous return (from dehydration or prolonged standing), or vasodilation (caused by a hot environment) stimulates the sympathetic nervous system and reduces the left ventricular cavity size, which leads to strong hyperdynamic contractions in a relatively empty heart. This hyperdynamic cavity obliteration activates myocardial mechanoreceptors, initiating a paradoxical vagal reflex with vasodilation and relative bradycardia.¹⁰ Vasodilation is usually the predominant mechanism (vasodepressor response), particularly in older patients, but severe bradycardia is also possible (cardioinhibitory response), particularly in younger patients.⁷ Diuretic and vasodilator therapies increase the predisposition to vasovagal syncope, particularly in the elderly.

On tilt-table testing, vasovagal syncope is characterized by hypotension and relative bradycardia, sometimes severe (see Note on Tilt-Table Testing).^10–12

Situational syncope

Situational syncope is caused by a reflex triggered in specific circumstances such as micturition, defecation, coughing, weight-lifting, laughing, or deglutition. The reflex may be initiated by a receptor on the visceral wall (eg, the bladder wall) or by straining that reduces venous return.

Carotid sinus hypersensitivity

Carotid sinus hypersensitivity is an abnormal response to carotid massage, predominantly occurring in patients over the age of 50. In spontaneous carotid sinus syndrome, syncope clearly occurs in a situation that stimulates the carotid sinus, such as head rotation, head extension, shaving, or wearing a tight collar. It is a rare cause of syncope, responsible for about 1% of cases. Conversely, induced carotid sinus syndrome is much more common and represents carotid sinus hypersensitivity in a patient with unexplained syncope and without obvious triggers; the abnormal response is mainly induced during carotid massage rather than spontaneously. In the latter case, carotid sinus hypersensitivity is a marker of a diseased sinus node or atrioventricular node that cannot withstand any inhibition. This diseased node is the true cause of syncope rather than carotid sinus hypersensitivity per se, and carotid massage is a "stress test" that unveils conduction disease.

Palpitations do not necessarily imply that syncope is due to an arrhythmia

Thus, carotid massage is indicated in cases of unexplained syncope regardless of circumstantial triggers. This test consists of applying firm pressure over each carotid bifurcation (just below the angle of the jaw) consecutively for 10 seconds. It is performed at the bedside, and may be performed with the patient in both supine and erect positions during tilt-table testing; erect positioning of the patient increases the sensitivity of this test.

An abnormal response to carotid sinus massage is defined as any of the following^13–15:

• Vasodepressor response: the systolic blood pressure decreases by at least 50 mm Hg
• Cardioinhibitory response: sinus or atrioventricular block causes the heartbeat to pause for 3 or more seconds
• Mixed vasodepressor and cardioinhibitory response.

Overall, a cardioinhibitory component is present in about two-thirds of cases of carotid sinus hypersensitivity.

Carotid sinus hypersensitivity is found in 25% to 50% of patients over age 50 who have had unexplained syncope or a fall, and it is seen almost equally in men and women.¹³

One study correlated carotid sinus hypersensitivity with the later occurrence of asystolic syncope during prolonged internal loop monitoring; subsequent pacemaker therapy reduced the burden of syncope.¹⁴ Another study, in patients over 50 years old with unexplained falls, found that 16% had cardioinhibitory carotid sinus hypersensitivity. Pacemaker placement reduced falls and syncope by 70% compared with no pacemaker therapy in these patients.¹⁵

On the other hand, carotid sinus hypersensitivity can be found in 39% of elderly patients who do not have a history of fainting or falling, so it is important to rule out other causes of syncope before attributing it to carotid sinus hypersensitivity.

Postexertional syncope

While syncope on exertion raises the worrisome possibility of a cardiac cause, postexertional syncope is usually a form of vasovagal syncope. When exercise ceases, venous blood stops getting pumped back to the heart by peripheral muscular contraction. Yet the heart is still exposed to the catecholamine surge induced by exercising, and it hypercontracts on an empty cavity. This triggers a vagal reflex.

Postexertional syncope may also be seen in hypertrophic obstructive cardiomyopathy or aortic stenosis, in which the small left ventricular cavity is less likely to tolerate the reduced preload after exercise and is more likely to obliterate.

ORTHOSTATIC HYPOTENSION

Orthostatic hypotension accounts for about 10% of cases of syncope.^1–3

Normally, after the first few minutes of standing, about 25% to 30% of the blood pools in the veins of the pelvis and the lower extremities, strikingly reducing venous return and stroke volume. Upon more prolonged standing, more blood leaves the vascular space and collects in the extravascular space, further reducing venous return. This normally leads to a reflex increase in sympathetic tone, peripheral and splanchnic vasoconstriction, and an increase in heart rate of 10 to 15 beats per minute. Overall, cardiac output is reduced and vascular resistance is increased while blood pressure is maintained, blood pressure being equal to cardiac output times vascular resistance.

Vasovagal syncope is initiated by anything that leads to strong contractions in an 'empty' heart

Orthostatic hypotension is characterized by autonomic failure, with a lack of compensatory increase in vascular resistance or heart rate upon orthostasis, or by significant hypovolemia that cannot be overcome by sympathetic mechanisms. It is defined as a drop in systolic blood pressure of 20 mm Hg or more or a drop in diastolic pressure of 10 mm Hg or more after 30 seconds to 5 minutes of upright posture. Blood pressure is checked immediately upon standing and at 3 and 5 minutes. This may be done at the bedside or during tilt-table testing.^2,4

Some patients have an immediate drop in blood pressure of more than 40 mm Hg upon standing, with a quick return to normal within 30 seconds. This "initial orthostatic hypotension" may be common in elderly patients taking antihypertensive drugs and may elude detection during standard blood pressure measurement.² Other patients with milder orthostatic hypotension may develop a more delayed hypotension 10 to 15 minutes later, as more blood pools in the periphery.¹⁶

Along with the drop in blood pressure, a failure of the heart rate to increase identifies autonomic dysfunction. On the other hand, an increase in the heart rate of more than 20 to 30 beats per minute may signify a hypovolemic state even if blood pressure is maintained, the lack of blood pressure drop being related to the excessive heart rate increase.

Orthostatic hypotension is the most common cause of syncope in the elderly and may be due to autonomic dysfunction (related to age, diabetes, uremia, or Parkinson disease), volume depletion, or drugs that block autonomic effects or cause hypovolemia, such as vasodilators, beta-blockers, diuretics, neuropsychiatric medications, and alcohol.

Since digestion leads to peripheral vasodilation and splanchnic blood pooling, syncope that occurs within 1 hour after eating has a mechanism similar to that of orthostatic syncope.

Supine hypertension with orthostatic hypotension. Some patients with severe autonomic dysfunction and the inability to regulate vascular tone have severe hypertension when supine and significant hypotension when upright.

Postural orthostatic tachycardia syndrome, another form of orthostatic failure, occurs most frequently in young women (under the age of 50). In this syndrome, autonomic dysfunction affects peripheral vascular resistance, which fails to increase in response to orthostatic stress. This autonomic dysfunction does not affect the heart, which manifests a striking compensatory increase in rate of more than 30 beats per minute within the first 10 minutes of orthostasis, or an absolute heart rate greater than 120 beats per minute. Unlike in orthostatic hypotension, blood pressure and cardiac output are maintained through this increase in heart rate, although the patient still develops symptoms of severe fatigue or near-syncope, possibly because of flow maldistribution and reduced cerebral flow.²

While postural orthostatic tachycardia syndrome per se does not induce syncope,² it may be associated with a vasovagal form of syncope that occurs beyond the first 10 minutes of orthostasis in up to 38% of these patients.¹⁷

In a less common, hyperadrenergic form of postural orthostatic tachycardia syndrome, there is no autonomic failure but the sympathetic system is overly activated, with orthostasis leading to excessive tachycardia.^10,18

CARDIAC SYNCOPE

Accounting for 10% to 20% of cases of syncope, a cardiac cause is the main concern in patients presenting with syncope, as cardiac syncope predicts an increased risk of death and may herald sudden cardiac death.^1,2,8,19,20 It often occurs suddenly without any warning signs, in which case it is called malignant syncope. Unlike what occurs in neurally mediated syncope, the postrecovery period is not usually marked by lingering malaise.

There are three forms of cardiac syncope:

Syncope due to structural heart disease with cardiac obstruction

In cases of aortic stenosis, hypertrophic obstructive cardiomyopathy, or severe pulmonary arterial hypertension, peripheral vasodilation occurs during exercise, but cardiac output cannot increase because of the fixed or dynamic obstruction to the ventricular outflow. Since blood pressure is equal to cardiac output times peripheral vascular resistance, pressure drops with the reduction in peripheral vascular resistance. Exertional ventricular arrhythmias may also occur in these patients. Conversely, postexertional syncope is usually benign.

Syncope due to ventricular tachycardia

Ventricular tachycardia can be secondary to underlying structural heart disease, with or without reduced ejection fraction, such as coronary arterial disease, hypertrophic cardiomyopathy, hypertensive cardiomyopathy, or valvular disease. It can also be secondary to primary electrical disease (eg, long QT syndrome, Wolff-Parkinson-White syndrome, Brugada syndrome, arrhythmogenic right ventricular dysplasia, sarcoidosis).

Occasionally, fast supraventricular tachycardia causes syncope at its onset, before vascular compensation develops. This occurs in patients with underlying heart disease.^2,8,19

Syncope from bradyarrhythmias

Bradyarrhythmias can occur with or without underlying structural heart disease. They are most often related to degeneration of the conduction system or to medications rather than to cardiomyopathy.

Caveats

When a patient with a history of heart failure presents with syncope, the top considerations are ventricular tachycardia and bradyarrhythmia. Nevertheless, about half of cases of syncope in patients with cardiac disease have a noncardiac cause,¹⁹ including the hypotensive or bradycardiac side effect of drugs.

As noted above, most cases of syncope are neurally mediated. However, long asystolic pauses due to sinus or atrioventricular nodal block are the most frequent mechanism of unexplained syncope and are seen in more than 50% of syncope cases on prolonged rhythm monitoring.^1,21 These pauses may be related to intrinsic sinus or atrioventricular nodal disease or, more commonly, to extrinsic effects such as the vasovagal mechanism. Some experts favor classifying and treating syncope on the basis of the final mechanism rather than the initiating process, but this is not universally accepted.^1,22

OTHER CAUSES OF SYNCOPE

Acute medical or cardiovascular illnesses can cause syncope and are looked for in the appropriate clinical context: severe hypovolemia or gastrointestinal bleeding, large pulmonary embolus with hemodynamic compromise, tamponade, aortic dissection, or hypoglycemia.

Bilateral critical carotid disease or severe vertebrobasilar disease very rarely cause syncope, and, when they do, they are associated with focal neurologic deficits.² Vertebrobasilar disease may cause "drop attacks," ie, a loss of muscular tone with falling but without loss of consciousness.²³

Severe proximal subclavian disease leads to reversal of the flow in the ipsilateral vertebral artery as blood is shunted toward the upper extremity. It manifests as dizziness and syncope during the ipsilateral upper extremity activity, usually with focal neurologic signs (subclavian steal syndrome).²

Psychogenic pseudosyncope is characterized by frequent attacks that typically last longer than true syncope and occur multiple times per day or week, sometimes with a loss of motor tone.² It occurs in patients with anxiety or somatization disorders.

SEIZURE: A SYNCOPE MIMIC

Certain features differentiate seizure from syncope:

• In seizure, unconsciousness often lasts longer than 5 minutes
• After a seizure, the patient may experience postictal confusion or paralysis
• Seizure may include prolonged tonic-clonic movements; although these movements may be seen with any form of syncope lasting more than 30 seconds, the movements during syncope are more limited and brief, lasting less than 15 seconds
• Tongue biting strongly suggests seizure.

Urinary incontinence does not help distinguish the two, as it frequently occurs with syncope as well as seizure.

DIAGNOSTIC EVALUATION OF SYNCOPE

Table 2 lists clinical clues to the type of syncope.^2–5,8

Underlying structural heart disease is the most important predictor of ventricular arrhythmia and death.^20,24–26 Thus, the primary goal of the evaluation is to rule out structural heart disease by history, examination, electrocardiography, and echocardiography (Figure 1).

Initial strategy for finding the cause

The cause of syncope is diagnosed by history and physical examination alone in up to 50% of cases, mainly neurally mediated syncope, orthostatic syncope, or seizure.^2,3,19

Always check blood pressure with the patient both standing and sitting and in both arms, and obtain an electrocardiogram.

Perform carotid massage in all patients over age 50 if syncope is not clearly vasovagal or orthostatic and if cardiac syncope is not likely. Carotid massage is contraindicated if the patient has a carotid bruit or a history of stroke.

Electrocardiography establishes or suggests a diagnosis in 10% of patients (Table 3, Figure 2).^1,2,8,19 A normal electrocardiogram or a mild nonspecific ST-T abnormality suggests a low likelihood of cardiac syncope and is associated with an excellent prognosis. Abnormal electrocardiographic findings are seen in 90% of cases of cardiac syncope and in only 6% of cases of neurally mediated syncope.²⁷ In one study of syncope patients with normal electrocardiograms and negative cardiac histories, none had an abnormal echocardiogram.²⁸

If the heart is normal

If the history suggests neurally mediated syncope or orthostatic hypotension and the history, examination, and electrocardiogram do not suggest coronary artery disease or any other cardiac disease, the workup is stopped.

If the patient has signs or symptoms of heart disease

If the patient has signs or symptoms of heart disease (angina, exertional syncope, dyspnea, clinical signs of heart failure, murmur), a history of heart disease, or exertional, supine, or malignant features, heart disease should be looked for and the following performed:

• Echocardiography to assess left ventricular function, severe valvular disease, and left ventricular hypertrophy
• A stress test (possibly) in cases of exertional syncope or associated angina; however, the overall yield of stress testing in syncope is low (< 5%).²⁹

If electrocardiography and echocardiography do not suggest heart disease

Often, in this situation, the workup can be stopped and syncope can be considered neurally mediated. The likelihood of cardiac syncope is very low in patients with normal findings on electrocardiography and echocardiography, and several studies have shown that patients with syncope who have no structural heart disease have normal long-term survival rates.^20,26,30

The following workup may, however, be ordered if the presentation is atypical and syncope is malignant, recurrent, or associated with physical injury, or occurs in the supine position¹⁹:

Carotid sinus massage in patients over age 50, if not already performed. Up to 50% of these patients with unexplained syncope have carotid sinus hypersensitivity.¹³

24-hour Holter monitoring rarely detects significant arrhythmias, but if syncope or dizziness occurs without any arrhythmia, Holter monitoring rules out arrhythmia as the cause of the symptoms.³¹ The diagnostic yield of Holter monitoring is low (1% to 2%) in patients with infrequent symptoms^1,2 and is not improved with 72-hour monitoring.³⁰ The yield is higher in patients with very frequent daily symptoms, many of whom have psychogenic pseudosyncope.²

Tilt-table testing to diagnose vasovagal syncope. This test is positive for a vasovagal response in up to 66% of patients with unexplained syncope.^1,19 Patients with heart disease taking vasodilators or beta-blockers may have abnormal baroreflexes. Therefore, a positive tilt test is less specific in these patients and does not necessarily indicate vasovagal syncope.

Event monitoring. If the etiology remains unclear or there are some concerns about arrhythmia, an event monitor (4 weeks of external rhythm monitoring) or an implantable loop recorder (implanted subcutaneously in the prepectoral area for 1 to 2 years) is placed. These monitors record the rhythm when the rate is lower or higher than predefined cutoffs or when the rhythm is irregular, regardless of symptoms. The patient or an observer can also activate the event monitor during or after an event, which freezes the recording of the 2 to 5 minutes preceding the activation and the 1 minute after it.

In a patient who has had syncope, a pacemaker is indicated for episodes of high-grade atrioventricular block, pauses longer than 3 seconds while awake, or bradycardia (< 40 beats per minute) while awake, and an implantable cardioverter-defibrillator is indicated for sustained ventricular tachycardia, even if syncope does not occur concomitantly with these findings. The finding of nonsustained ventricular tachycardia on monitoring increases the suspicion of ventricular tachycardia as the cause of syncope but does not prove it, nor does it necessarily dictate implantation of a cardioverter-defibrillator device.

An electrophysiologic study has a low yield in patients with normal electrocardiographic and echocardiographic studies. Bradycardia is detected in 10%.³¹

If heart disease or a rhythm abnormality is found

If heart disease is diagnosed by echocardiography or if significant electrocardiographic abnormalities are found, perform the following:

Pacemaker placement for the following electrocardiographic abnormalities^1,2,19:

• Second-degree Mobitz II or third-degree atrioventricular block
• Sinus pause (> 3 seconds) or bradycardia (< 40 beats per minute) while awake
• Alternating left bundle branch block and right bundle branch block on the same electrocardiogram or separate ones.

Telemetric monitoring (inpatient).

An electrophysiologic study is valuable mainly for patients with structural heart disease, including an ejection fraction 36% to 49%, coronary artery disease, or left ventricular hypertrophy with a normal ejection fraction.³² Overall, in patients with structural heart disease and unexplained syncope, the yield is 55% (inducible ventricular tachycardia in 21%, abnormal indices of bradycardia in 34%).³¹

However, the yield of electrophysiologic testing is low in bradyarrhythmia and in patients with an ejection fraction of 35% or less.³³ In the latter case, the syncope is often arrhythmia-related and the patient often has an indication for an implantable cardioverter-defibrillator regardless of electrophysiologic study results, especially if the low ejection fraction has persisted despite medical therapy.³²

If the electrophysiologic study is negative

If the electrophysiologic study is negative, the differential diagnosis still includes arrhythmia, as the yield of electrophysiologic study is low for bradyarrhythmias and some ventricular tachycardias, and the differential diagnosis also includes, at this point, neurally mediated syncope.

The next step may be either prolonged rhythm monitoring or tilt-table testing. An event monitor or an implantable loop recorder can be placed for prolonged monitoring. The yield of the 30-day event monitor is highest in patients with frequently recurring syncope, in whom it reaches a yield of up to 40% (10% to 20% will have a positive diagnosis of arrhythmia, while 15% to 20% will have symptoms with a normal rhythm).^31,34 The implantable recorder has a high overall diagnostic yield and is used in patients with infrequent syncopal episodes (yield up to 50%).^1,35,36

In brief, there are two diagnostic approaches to unexplained syncope: the monitoring approach (loop recorder) and the testing approach (tilt-table testing). A combination of both strategies is frequently required in patients with unexplained syncope, and, according to some investigators, a loop recorder may be implanted early on.²¹

Heart disease with left ventricular dysfunction and low ejection fraction

Carotid massage is indicated in cases of unexplained syncope regardless of circumstantial triggers

In patients with heart disease with left ventricular dysfunction and an ejection fraction of 35% or less, an implantable cardioverter-defibrillator can be placed without the need for an electrophysiologic study. These patients need these devices anyway to prevent sudden death, even if the cause of syncope is not an arrhythmia. Patients with a low ejection fraction and a history of syncope are at a high risk of sudden cardiac death.³² Yet in some patients with newly diagnosed cardiomyopathy, left ventricular function may improve with medical therapy. Because the arrhythmic risk is essentially high during the period of ventricular dysfunction, a wearable external defibrillator may be placed while the decision about an implantable defibrillator is finalized within the ensuing months.

In patients with hypertrophic cardiomyopathy, place an implantable cardioverter-defibrillator after any unexplained syncopal episode.

Valvular heart disease needs surgical correction.

If ischemic heart disease is suspected, coronary angiography is indicated, with revascularization if appropriate. An implantable cardioverter-defibrillator should be placed if the ejection fraction is lower than 35%. Except in a large acute myocardial infarction, the substrate for ventricular tachycardia is not ameliorated with revascularization.^32,37 Consider an electrophysiologic study when syncope occurs with coronary artery disease and a higher ejection fraction.

A note on left or right bundle branch block

Patients with left or right bundle branch block and unexplained syncope (not clearly vasovagal or orthostatic) likely have syncope related to intermittent high-grade atrioventricular block.³⁸

One study monitored these patients with an implanted loop recorder and showed that about 40% had a recurrence of syncope within 48 days, often concomitantly with complete atrioventricular block. About 55% of these patients had a major event (syncope or high-grade atrioventricular block).³⁹ Many of the patients had had a positive tilt test; thus, tilt testing is not specific for vasovagal syncope in these patients and should not be used to exclude a bradyarrhythmic syncope. Also, patients selected for this study had undergone carotid sinus massage and an electrophysiology study with a negative result.

Underlying structural heart disease is the most important predictor of ventricular arrhythmia and death

In another analysis, an electrophysiologic study detected a proportion of the bradyarrhythmias but, more importantly, it induced ventricular tachycardia in 14% of patients with right or left bundle branch block. Although it is not sensitive enough for bradyarrhythmia, electrophysiologic study was highly specific and fairly sensitive for the occurrence of ventricular tachycardia on follow-up.³⁸ Thus, unexplained syncope in a patient with right or left bundle branch block may warrant carotid sinus massage, then an electrophysiologic study to rule out ventricular tachycardia, followed by placement of a dual-chamber pacemaker if the study is negative for ventricular tachycardia, or at least placement of a loop recorder.

INDICATIONS FOR HOSPITALIZATION

Patients should be hospitalized if they have severe hypovolemia or bleeding, or if there is any suspicion of heart disease by history, examination, or electrocardiography, including:

• History of heart failure, low ejection fraction, or coronary artery disease
• An electrocardiogram suggestive of arrhythmia (Table 3)
• Family history of sudden death
• Lack of prodromes; occurrence of physical injury, exertional syncope, syncope in a supine position, or syncope associated with dyspnea or chest pain.^2,40

In these situations, there is concern about arrhythmia, structural heart disease, or acute myocardial ischemia. The patient is admitted for immediate telemetric monitoring. Echocardiography and sometimes stress testing are performed. The patient is discharged if this initial workup does not suggest underlying heart disease. Alternatively, an electrophysiologic study is performed or a device is placed in patients found to have structural heart disease. Prolonged rhythm monitoring or tilt-table testing may be performed when syncope with underlying heart disease or worrisome features remains unexplained.

Several Web-based interactive algorithms have been used to determine the indication for hospitalization. They incorporate the above clinical, electrocardiographic, and sometimes echocardiographic features.^{2,24,25,40–42} A cardiology consultation is usually necessary in patients with the above features, as they frequently require specialized cardiac testing.

Among high-risk patients, the risk of sudden death, a major cardiovascular event, or significant arrhythmia is high in the first few days after the index syncopal episode, justifying the hospitalization and inpatient rhythm monitoring and workup in the presence of the above criteria.^24,40,42

SYNCOPE AND DRIVING

A study has shown that the most common cause of syncope while driving is vasovagal syncope.⁶ In all patients, the risk of another episode of syncope was relatively higher during the first 6 months after the event, with a 12% recurrence rate during this period. However, recurrences were often also seen more than 6 months later (12% recurrence between 6 months and the following few years).⁶ Fortunately, those episodes rarely occurred while the patient was driving. In a study in survivors of ventricular arrhythmia, the risk of recurrence of arrhythmic events was highest during the first 6 to 12 months after the event.⁴³

Thus, in general, patients with syncope should be prohibited from driving for at least the period of time (eg, 6 months) during which the risk of a recurrent episode of syncope is highest and during which serious cardiac disease or arrhythmia, if present, would emerge. Recurrence of syncope is more likely and more dangerous for commercial drivers who spend a significant proportion of their time driving; individualized decisions are made in these cases.

Syncope is a transient loss of consciousness and postural tone with spontaneous, complete recovery. There are three major types: neurally mediated, orthostatic, and cardiac (Table 1).

NEURALLY MEDIATED SYNCOPE

Neurally mediated (reflex) syncope is the most common type, accounting for two-thirds of cases.^1–3 It results from autonomic reflexes that respond inappropriately, leading to vasodilation and bradycardia.

See related patient-education handout

Neurally mediated syncope is usually preceded by premonitory symptoms such as lightheadedness, diaphoresis, nausea, malaise, abdominal discomfort, and tunnel vision. However, this may not be the case in one-third of patients, especially in elderly patients, who may not recognize or remember the warning symptoms. Palpitations are frequently reported with neurally mediated syncope and do not necessarily imply that the syncope is due to an arrhythmia.^4,5 Neurally mediated syncope does not usually occur in the supine position^4,5 but can occur in the seated position.⁶

Subtypes of neurally mediated syncope are as follows:

Vasovagal syncope

Vasovagal syncope is usually triggered by sudden emotional stress, prolonged sitting or standing, dehydration, or a warm environment, but it can also occur without a trigger. It is the most common type of syncope in young patients (more so in females than in males), but contrary to a common misconception, it can also occur in the elderly.⁷ Usually, it is not only preceded by but also followed by nausea, malaise, fatigue, and diaphoresis^4,5,8; full recovery may be slow. If the syncope lasts longer than 30 to 60 seconds, clonic movements and loss of bladder control are common.⁹

Mechanism. Vasovagal syncope is initiated by anything that leads to strong myocardial contractions in an "empty" heart. Emotional stress, reduced venous return (from dehydration or prolonged standing), or vasodilation (caused by a hot environment) stimulates the sympathetic nervous system and reduces the left ventricular cavity size, which leads to strong hyperdynamic contractions in a relatively empty heart. This hyperdynamic cavity obliteration activates myocardial mechanoreceptors, initiating a paradoxical vagal reflex with vasodilation and relative bradycardia.¹⁰ Vasodilation is usually the predominant mechanism (vasodepressor response), particularly in older patients, but severe bradycardia is also possible (cardioinhibitory response), particularly in younger patients.⁷ Diuretic and vasodilator therapies increase the predisposition to vasovagal syncope, particularly in the elderly.

On tilt-table testing, vasovagal syncope is characterized by hypotension and relative bradycardia, sometimes severe (see Note on Tilt-Table Testing).^10–12

Situational syncope

Situational syncope is caused by a reflex triggered in specific circumstances such as micturition, defecation, coughing, weight-lifting, laughing, or deglutition. The reflex may be initiated by a receptor on the visceral wall (eg, the bladder wall) or by straining that reduces venous return.

Carotid sinus hypersensitivity

Carotid sinus hypersensitivity is an abnormal response to carotid massage, predominantly occurring in patients over the age of 50. In spontaneous carotid sinus syndrome, syncope clearly occurs in a situation that stimulates the carotid sinus, such as head rotation, head extension, shaving, or wearing a tight collar. It is a rare cause of syncope, responsible for about 1% of cases. Conversely, induced carotid sinus syndrome is much more common and represents carotid sinus hypersensitivity in a patient with unexplained syncope and without obvious triggers; the abnormal response is mainly induced during carotid massage rather than spontaneously. In the latter case, carotid sinus hypersensitivity is a marker of a diseased sinus node or atrioventricular node that cannot withstand any inhibition. This diseased node is the true cause of syncope rather than carotid sinus hypersensitivity per se, and carotid massage is a "stress test" that unveils conduction disease.

Palpitations do not necessarily imply that syncope is due to an arrhythmia

Thus, carotid massage is indicated in cases of unexplained syncope regardless of circumstantial triggers. This test consists of applying firm pressure over each carotid bifurcation (just below the angle of the jaw) consecutively for 10 seconds. It is performed at the bedside, and may be performed with the patient in both supine and erect positions during tilt-table testing; erect positioning of the patient increases the sensitivity of this test.

An abnormal response to carotid sinus massage is defined as any of the following^13–15:

• Vasodepressor response: the systolic blood pressure decreases by at least 50 mm Hg
• Cardioinhibitory response: sinus or atrioventricular block causes the heartbeat to pause for 3 or more seconds
• Mixed vasodepressor and cardioinhibitory response.

Overall, a cardioinhibitory component is present in about two-thirds of cases of carotid sinus hypersensitivity.

Carotid sinus hypersensitivity is found in 25% to 50% of patients over age 50 who have had unexplained syncope or a fall, and it is seen almost equally in men and women.¹³

One study correlated carotid sinus hypersensitivity with the later occurrence of asystolic syncope during prolonged internal loop monitoring; subsequent pacemaker therapy reduced the burden of syncope.¹⁴ Another study, in patients over 50 years old with unexplained falls, found that 16% had cardioinhibitory carotid sinus hypersensitivity. Pacemaker placement reduced falls and syncope by 70% compared with no pacemaker therapy in these patients.¹⁵

On the other hand, carotid sinus hypersensitivity can be found in 39% of elderly patients who do not have a history of fainting or falling, so it is important to rule out other causes of syncope before attributing it to carotid sinus hypersensitivity.

Postexertional syncope

While syncope on exertion raises the worrisome possibility of a cardiac cause, postexertional syncope is usually a form of vasovagal syncope. When exercise ceases, venous blood stops getting pumped back to the heart by peripheral muscular contraction. Yet the heart is still exposed to the catecholamine surge induced by exercising, and it hypercontracts on an empty cavity. This triggers a vagal reflex.

Postexertional syncope may also be seen in hypertrophic obstructive cardiomyopathy or aortic stenosis, in which the small left ventricular cavity is less likely to tolerate the reduced preload after exercise and is more likely to obliterate.

ORTHOSTATIC HYPOTENSION

Orthostatic hypotension accounts for about 10% of cases of syncope.^1–3

Normally, after the first few minutes of standing, about 25% to 30% of the blood pools in the veins of the pelvis and the lower extremities, strikingly reducing venous return and stroke volume. Upon more prolonged standing, more blood leaves the vascular space and collects in the extravascular space, further reducing venous return. This normally leads to a reflex increase in sympathetic tone, peripheral and splanchnic vasoconstriction, and an increase in heart rate of 10 to 15 beats per minute. Overall, cardiac output is reduced and vascular resistance is increased while blood pressure is maintained, blood pressure being equal to cardiac output times vascular resistance.

Vasovagal syncope is initiated by anything that leads to strong contractions in an 'empty' heart

Orthostatic hypotension is characterized by autonomic failure, with a lack of compensatory increase in vascular resistance or heart rate upon orthostasis, or by significant hypovolemia that cannot be overcome by sympathetic mechanisms. It is defined as a drop in systolic blood pressure of 20 mm Hg or more or a drop in diastolic pressure of 10 mm Hg or more after 30 seconds to 5 minutes of upright posture. Blood pressure is checked immediately upon standing and at 3 and 5 minutes. This may be done at the bedside or during tilt-table testing.^2,4

Some patients have an immediate drop in blood pressure of more than 40 mm Hg upon standing, with a quick return to normal within 30 seconds. This "initial orthostatic hypotension" may be common in elderly patients taking antihypertensive drugs and may elude detection during standard blood pressure measurement.² Other patients with milder orthostatic hypotension may develop a more delayed hypotension 10 to 15 minutes later, as more blood pools in the periphery.¹⁶

Along with the drop in blood pressure, a failure of the heart rate to increase identifies autonomic dysfunction. On the other hand, an increase in the heart rate of more than 20 to 30 beats per minute may signify a hypovolemic state even if blood pressure is maintained, the lack of blood pressure drop being related to the excessive heart rate increase.

Orthostatic hypotension is the most common cause of syncope in the elderly and may be due to autonomic dysfunction (related to age, diabetes, uremia, or Parkinson disease), volume depletion, or drugs that block autonomic effects or cause hypovolemia, such as vasodilators, beta-blockers, diuretics, neuropsychiatric medications, and alcohol.

Since digestion leads to peripheral vasodilation and splanchnic blood pooling, syncope that occurs within 1 hour after eating has a mechanism similar to that of orthostatic syncope.

Supine hypertension with orthostatic hypotension. Some patients with severe autonomic dysfunction and the inability to regulate vascular tone have severe hypertension when supine and significant hypotension when upright.

Postural orthostatic tachycardia syndrome, another form of orthostatic failure, occurs most frequently in young women (under the age of 50). In this syndrome, autonomic dysfunction affects peripheral vascular resistance, which fails to increase in response to orthostatic stress. This autonomic dysfunction does not affect the heart, which manifests a striking compensatory increase in rate of more than 30 beats per minute within the first 10 minutes of orthostasis, or an absolute heart rate greater than 120 beats per minute. Unlike in orthostatic hypotension, blood pressure and cardiac output are maintained through this increase in heart rate, although the patient still develops symptoms of severe fatigue or near-syncope, possibly because of flow maldistribution and reduced cerebral flow.²

While postural orthostatic tachycardia syndrome per se does not induce syncope,² it may be associated with a vasovagal form of syncope that occurs beyond the first 10 minutes of orthostasis in up to 38% of these patients.¹⁷

In a less common, hyperadrenergic form of postural orthostatic tachycardia syndrome, there is no autonomic failure but the sympathetic system is overly activated, with orthostasis leading to excessive tachycardia.^10,18

CARDIAC SYNCOPE

Accounting for 10% to 20% of cases of syncope, a cardiac cause is the main concern in patients presenting with syncope, as cardiac syncope predicts an increased risk of death and may herald sudden cardiac death.^1,2,8,19,20 It often occurs suddenly without any warning signs, in which case it is called malignant syncope. Unlike what occurs in neurally mediated syncope, the postrecovery period is not usually marked by lingering malaise.

There are three forms of cardiac syncope:

Syncope due to structural heart disease with cardiac obstruction

In cases of aortic stenosis, hypertrophic obstructive cardiomyopathy, or severe pulmonary arterial hypertension, peripheral vasodilation occurs during exercise, but cardiac output cannot increase because of the fixed or dynamic obstruction to the ventricular outflow. Since blood pressure is equal to cardiac output times peripheral vascular resistance, pressure drops with the reduction in peripheral vascular resistance. Exertional ventricular arrhythmias may also occur in these patients. Conversely, postexertional syncope is usually benign.

Syncope due to ventricular tachycardia

Ventricular tachycardia can be secondary to underlying structural heart disease, with or without reduced ejection fraction, such as coronary arterial disease, hypertrophic cardiomyopathy, hypertensive cardiomyopathy, or valvular disease. It can also be secondary to primary electrical disease (eg, long QT syndrome, Wolff-Parkinson-White syndrome, Brugada syndrome, arrhythmogenic right ventricular dysplasia, sarcoidosis).

Occasionally, fast supraventricular tachycardia causes syncope at its onset, before vascular compensation develops. This occurs in patients with underlying heart disease.^2,8,19

Syncope from bradyarrhythmias

Bradyarrhythmias can occur with or without underlying structural heart disease. They are most often related to degeneration of the conduction system or to medications rather than to cardiomyopathy.

Caveats

When a patient with a history of heart failure presents with syncope, the top considerations are ventricular tachycardia and bradyarrhythmia. Nevertheless, about half of cases of syncope in patients with cardiac disease have a noncardiac cause,¹⁹ including the hypotensive or bradycardiac side effect of drugs.

As noted above, most cases of syncope are neurally mediated. However, long asystolic pauses due to sinus or atrioventricular nodal block are the most frequent mechanism of unexplained syncope and are seen in more than 50% of syncope cases on prolonged rhythm monitoring.^1,21 These pauses may be related to intrinsic sinus or atrioventricular nodal disease or, more commonly, to extrinsic effects such as the vasovagal mechanism. Some experts favor classifying and treating syncope on the basis of the final mechanism rather than the initiating process, but this is not universally accepted.^1,22

OTHER CAUSES OF SYNCOPE

Acute medical or cardiovascular illnesses can cause syncope and are looked for in the appropriate clinical context: severe hypovolemia or gastrointestinal bleeding, large pulmonary embolus with hemodynamic compromise, tamponade, aortic dissection, or hypoglycemia.

Bilateral critical carotid disease or severe vertebrobasilar disease very rarely cause syncope, and, when they do, they are associated with focal neurologic deficits.² Vertebrobasilar disease may cause "drop attacks," ie, a loss of muscular tone with falling but without loss of consciousness.²³

Severe proximal subclavian disease leads to reversal of the flow in the ipsilateral vertebral artery as blood is shunted toward the upper extremity. It manifests as dizziness and syncope during the ipsilateral upper extremity activity, usually with focal neurologic signs (subclavian steal syndrome).²

Psychogenic pseudosyncope is characterized by frequent attacks that typically last longer than true syncope and occur multiple times per day or week, sometimes with a loss of motor tone.² It occurs in patients with anxiety or somatization disorders.

SEIZURE: A SYNCOPE MIMIC

Certain features differentiate seizure from syncope:

• In seizure, unconsciousness often lasts longer than 5 minutes
• After a seizure, the patient may experience postictal confusion or paralysis
• Seizure may include prolonged tonic-clonic movements; although these movements may be seen with any form of syncope lasting more than 30 seconds, the movements during syncope are more limited and brief, lasting less than 15 seconds
• Tongue biting strongly suggests seizure.

Urinary incontinence does not help distinguish the two, as it frequently occurs with syncope as well as seizure.

DIAGNOSTIC EVALUATION OF SYNCOPE

Table 2 lists clinical clues to the type of syncope.^2–5,8

Underlying structural heart disease is the most important predictor of ventricular arrhythmia and death.^20,24–26 Thus, the primary goal of the evaluation is to rule out structural heart disease by history, examination, electrocardiography, and echocardiography (Figure 1).

Initial strategy for finding the cause

The cause of syncope is diagnosed by history and physical examination alone in up to 50% of cases, mainly neurally mediated syncope, orthostatic syncope, or seizure.^2,3,19

Always check blood pressure with the patient both standing and sitting and in both arms, and obtain an electrocardiogram.

Perform carotid massage in all patients over age 50 if syncope is not clearly vasovagal or orthostatic and if cardiac syncope is not likely. Carotid massage is contraindicated if the patient has a carotid bruit or a history of stroke.

Electrocardiography establishes or suggests a diagnosis in 10% of patients (Table 3, Figure 2).^1,2,8,19 A normal electrocardiogram or a mild nonspecific ST-T abnormality suggests a low likelihood of cardiac syncope and is associated with an excellent prognosis. Abnormal electrocardiographic findings are seen in 90% of cases of cardiac syncope and in only 6% of cases of neurally mediated syncope.²⁷ In one study of syncope patients with normal electrocardiograms and negative cardiac histories, none had an abnormal echocardiogram.²⁸

If the heart is normal

If the history suggests neurally mediated syncope or orthostatic hypotension and the history, examination, and electrocardiogram do not suggest coronary artery disease or any other cardiac disease, the workup is stopped.

If the patient has signs or symptoms of heart disease

If the patient has signs or symptoms of heart disease (angina, exertional syncope, dyspnea, clinical signs of heart failure, murmur), a history of heart disease, or exertional, supine, or malignant features, heart disease should be looked for and the following performed:

• Echocardiography to assess left ventricular function, severe valvular disease, and left ventricular hypertrophy
• A stress test (possibly) in cases of exertional syncope or associated angina; however, the overall yield of stress testing in syncope is low (< 5%).²⁹

If electrocardiography and echocardiography do not suggest heart disease

Often, in this situation, the workup can be stopped and syncope can be considered neurally mediated. The likelihood of cardiac syncope is very low in patients with normal findings on electrocardiography and echocardiography, and several studies have shown that patients with syncope who have no structural heart disease have normal long-term survival rates.^20,26,30

The following workup may, however, be ordered if the presentation is atypical and syncope is malignant, recurrent, or associated with physical injury, or occurs in the supine position¹⁹:

Carotid sinus massage in patients over age 50, if not already performed. Up to 50% of these patients with unexplained syncope have carotid sinus hypersensitivity.¹³

24-hour Holter monitoring rarely detects significant arrhythmias, but if syncope or dizziness occurs without any arrhythmia, Holter monitoring rules out arrhythmia as the cause of the symptoms.³¹ The diagnostic yield of Holter monitoring is low (1% to 2%) in patients with infrequent symptoms^1,2 and is not improved with 72-hour monitoring.³⁰ The yield is higher in patients with very frequent daily symptoms, many of whom have psychogenic pseudosyncope.²

Tilt-table testing to diagnose vasovagal syncope. This test is positive for a vasovagal response in up to 66% of patients with unexplained syncope.^1,19 Patients with heart disease taking vasodilators or beta-blockers may have abnormal baroreflexes. Therefore, a positive tilt test is less specific in these patients and does not necessarily indicate vasovagal syncope.

Event monitoring. If the etiology remains unclear or there are some concerns about arrhythmia, an event monitor (4 weeks of external rhythm monitoring) or an implantable loop recorder (implanted subcutaneously in the prepectoral area for 1 to 2 years) is placed. These monitors record the rhythm when the rate is lower or higher than predefined cutoffs or when the rhythm is irregular, regardless of symptoms. The patient or an observer can also activate the event monitor during or after an event, which freezes the recording of the 2 to 5 minutes preceding the activation and the 1 minute after it.

In a patient who has had syncope, a pacemaker is indicated for episodes of high-grade atrioventricular block, pauses longer than 3 seconds while awake, or bradycardia (< 40 beats per minute) while awake, and an implantable cardioverter-defibrillator is indicated for sustained ventricular tachycardia, even if syncope does not occur concomitantly with these findings. The finding of nonsustained ventricular tachycardia on monitoring increases the suspicion of ventricular tachycardia as the cause of syncope but does not prove it, nor does it necessarily dictate implantation of a cardioverter-defibrillator device.

An electrophysiologic study has a low yield in patients with normal electrocardiographic and echocardiographic studies. Bradycardia is detected in 10%.³¹

If heart disease or a rhythm abnormality is found

If heart disease is diagnosed by echocardiography or if significant electrocardiographic abnormalities are found, perform the following:

Pacemaker placement for the following electrocardiographic abnormalities^1,2,19:

• Second-degree Mobitz II or third-degree atrioventricular block
• Sinus pause (> 3 seconds) or bradycardia (< 40 beats per minute) while awake
• Alternating left bundle branch block and right bundle branch block on the same electrocardiogram or separate ones.

Telemetric monitoring (inpatient).

An electrophysiologic study is valuable mainly for patients with structural heart disease, including an ejection fraction 36% to 49%, coronary artery disease, or left ventricular hypertrophy with a normal ejection fraction.³² Overall, in patients with structural heart disease and unexplained syncope, the yield is 55% (inducible ventricular tachycardia in 21%, abnormal indices of bradycardia in 34%).³¹

However, the yield of electrophysiologic testing is low in bradyarrhythmia and in patients with an ejection fraction of 35% or less.³³ In the latter case, the syncope is often arrhythmia-related and the patient often has an indication for an implantable cardioverter-defibrillator regardless of electrophysiologic study results, especially if the low ejection fraction has persisted despite medical therapy.³²

If the electrophysiologic study is negative

If the electrophysiologic study is negative, the differential diagnosis still includes arrhythmia, as the yield of electrophysiologic study is low for bradyarrhythmias and some ventricular tachycardias, and the differential diagnosis also includes, at this point, neurally mediated syncope.

The next step may be either prolonged rhythm monitoring or tilt-table testing. An event monitor or an implantable loop recorder can be placed for prolonged monitoring. The yield of the 30-day event monitor is highest in patients with frequently recurring syncope, in whom it reaches a yield of up to 40% (10% to 20% will have a positive diagnosis of arrhythmia, while 15% to 20% will have symptoms with a normal rhythm).^31,34 The implantable recorder has a high overall diagnostic yield and is used in patients with infrequent syncopal episodes (yield up to 50%).^1,35,36

In brief, there are two diagnostic approaches to unexplained syncope: the monitoring approach (loop recorder) and the testing approach (tilt-table testing). A combination of both strategies is frequently required in patients with unexplained syncope, and, according to some investigators, a loop recorder may be implanted early on.²¹

Heart disease with left ventricular dysfunction and low ejection fraction

Carotid massage is indicated in cases of unexplained syncope regardless of circumstantial triggers

In patients with heart disease with left ventricular dysfunction and an ejection fraction of 35% or less, an implantable cardioverter-defibrillator can be placed without the need for an electrophysiologic study. These patients need these devices anyway to prevent sudden death, even if the cause of syncope is not an arrhythmia. Patients with a low ejection fraction and a history of syncope are at a high risk of sudden cardiac death.³² Yet in some patients with newly diagnosed cardiomyopathy, left ventricular function may improve with medical therapy. Because the arrhythmic risk is essentially high during the period of ventricular dysfunction, a wearable external defibrillator may be placed while the decision about an implantable defibrillator is finalized within the ensuing months.

In patients with hypertrophic cardiomyopathy, place an implantable cardioverter-defibrillator after any unexplained syncopal episode.

Valvular heart disease needs surgical correction.

If ischemic heart disease is suspected, coronary angiography is indicated, with revascularization if appropriate. An implantable cardioverter-defibrillator should be placed if the ejection fraction is lower than 35%. Except in a large acute myocardial infarction, the substrate for ventricular tachycardia is not ameliorated with revascularization.^32,37 Consider an electrophysiologic study when syncope occurs with coronary artery disease and a higher ejection fraction.

A note on left or right bundle branch block

Patients with left or right bundle branch block and unexplained syncope (not clearly vasovagal or orthostatic) likely have syncope related to intermittent high-grade atrioventricular block.³⁸

One study monitored these patients with an implanted loop recorder and showed that about 40% had a recurrence of syncope within 48 days, often concomitantly with complete atrioventricular block. About 55% of these patients had a major event (syncope or high-grade atrioventricular block).³⁹ Many of the patients had had a positive tilt test; thus, tilt testing is not specific for vasovagal syncope in these patients and should not be used to exclude a bradyarrhythmic syncope. Also, patients selected for this study had undergone carotid sinus massage and an electrophysiology study with a negative result.

Underlying structural heart disease is the most important predictor of ventricular arrhythmia and death

In another analysis, an electrophysiologic study detected a proportion of the bradyarrhythmias but, more importantly, it induced ventricular tachycardia in 14% of patients with right or left bundle branch block. Although it is not sensitive enough for bradyarrhythmia, electrophysiologic study was highly specific and fairly sensitive for the occurrence of ventricular tachycardia on follow-up.³⁸ Thus, unexplained syncope in a patient with right or left bundle branch block may warrant carotid sinus massage, then an electrophysiologic study to rule out ventricular tachycardia, followed by placement of a dual-chamber pacemaker if the study is negative for ventricular tachycardia, or at least placement of a loop recorder.

INDICATIONS FOR HOSPITALIZATION

Patients should be hospitalized if they have severe hypovolemia or bleeding, or if there is any suspicion of heart disease by history, examination, or electrocardiography, including:

• History of heart failure, low ejection fraction, or coronary artery disease
• An electrocardiogram suggestive of arrhythmia (Table 3)
• Family history of sudden death
• Lack of prodromes; occurrence of physical injury, exertional syncope, syncope in a supine position, or syncope associated with dyspnea or chest pain.^2,40

In these situations, there is concern about arrhythmia, structural heart disease, or acute myocardial ischemia. The patient is admitted for immediate telemetric monitoring. Echocardiography and sometimes stress testing are performed. The patient is discharged if this initial workup does not suggest underlying heart disease. Alternatively, an electrophysiologic study is performed or a device is placed in patients found to have structural heart disease. Prolonged rhythm monitoring or tilt-table testing may be performed when syncope with underlying heart disease or worrisome features remains unexplained.

Several Web-based interactive algorithms have been used to determine the indication for hospitalization. They incorporate the above clinical, electrocardiographic, and sometimes echocardiographic features.^{2,24,25,40–42} A cardiology consultation is usually necessary in patients with the above features, as they frequently require specialized cardiac testing.

Among high-risk patients, the risk of sudden death, a major cardiovascular event, or significant arrhythmia is high in the first few days after the index syncopal episode, justifying the hospitalization and inpatient rhythm monitoring and workup in the presence of the above criteria.^24,40,42

SYNCOPE AND DRIVING

A study has shown that the most common cause of syncope while driving is vasovagal syncope.⁶ In all patients, the risk of another episode of syncope was relatively higher during the first 6 months after the event, with a 12% recurrence rate during this period. However, recurrences were often also seen more than 6 months later (12% recurrence between 6 months and the following few years).⁶ Fortunately, those episodes rarely occurred while the patient was driving. In a study in survivors of ventricular arrhythmia, the risk of recurrence of arrhythmic events was highest during the first 6 to 12 months after the event.⁴³

Thus, in general, patients with syncope should be prohibited from driving for at least the period of time (eg, 6 months) during which the risk of a recurrent episode of syncope is highest and during which serious cardiac disease or arrhythmia, if present, would emerge. Recurrence of syncope is more likely and more dangerous for commercial drivers who spend a significant proportion of their time driving; individualized decisions are made in these cases.

Guidelines jointly issued by the American College of Cardiology and American Heart Association (ACC/AHA)¹ provide a framework for evaluating and managing perioperative cardiac risk in noncardiac surgery. An overriding theme in successive documents from these organizations through the years has been that preoperative intervention, coronary artery bypass grafting, or percutaneous coronary intervention is rarely necessary just to get the patient through surgery, unless it is otherwise indicated independent of the need for surgery.

See related commentary

This article highlights some of the key recommendations in the 2014 updates to these guidelines,^1–3 how they differ from previous guidelines,⁴ and the ongoing challenges and unresolved issues facing physicians involved in perioperative care.

Of note, while these guidelines were being updated, Erasmus University⁵ expressed concern about the scientific integrity of some of the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE) trials. As a result, the evidence review committee included these trials in its analysis but not in a systematic review of beta-blockers.² These trials were not included in the clinical practice guideline supplements and tables but were cited in the text if relevant.

The European Society of Cardiology and European Society of Anesthesiology⁶ revised their guidelines concurrently with but independently of the ACC/AHA, and although they discussed and aligned some recommendations, many differences remain between the two sets of guidelines. Readers should consult the full guidelines for more detailed information.¹

THE ROLE OF THE PREOPERATIVE CARDIAC EVALUATION

The purpose of preoperative medical evaluation is not to "get medical clearance" but rather to evaluate the patient’s medical status and risk of complications. The process includes:

• Identifying risk factors and assessing their severity and stability
• Establishing a clinical risk profile for informed and shared decision-making
• Recommending needed changes in management, further testing, or specialty consultation.

The updated guidelines emphasize the importance of communication among the perioperative team and with the patient. They reiterate the focus on appropriateness of care and cost containment—one should order a test only if the result may change the patient’s management.

HOW URGENT IS SURGERY? HOW RISKY?

The new guidelines classify the urgency of surgery as follows:

• Emergency (necessary within 6 hours)
• Urgent (necessary within 6–24 hours)
• Time-sensitive (can delay 1–6 weeks)
• Elective (can delay up to 1 year).

One should order a test only if the result may change the patient's management

Surgical risk is now classified as either low (< 1% risk of major adverse cardiac events) or elevated (≥ 1%) on the basis of surgical and patient characteristics. Previous schemas included an intermediate-risk category. Low-risk procedures include endoscopic procedures, superficial procedures, cataract surgery, breast surgery, and ambulatory surgery. Elevated-risk procedures include vascular surgery, intraperitoneal and intrathoracic surgery, head and neck surgery, orthopedic surgery, and prostate surgery.

Risk calculators and biomarkers

To estimate the perioperative risk of major adverse cardiac events, the guidelines suggest incorporating the Revised Cardiac Risk Index (RCRI)⁷ with an estimation of surgical risk or using a newer surgical risk calculator derived from a database of the American College of Surgeons’ National Surgical Quality Improvement Project (ACS NSQIP).

The RCRI is based on six risk factors, each worth 1 point:

• High-risk surgery
• Ischemic heart disease
• Heart failure
• Stroke or transient ischemic attack
• Diabetes requiring insulin
• Renal insufficiency (serum creatinine > 2.0 mg/dL).⁷

MICA. The Myocardial Infarction or Cardiac Arrest (MICA) calculator⁸ has a narrower focus and was validated in only one center.

ACS NSQIP. The recommended newer ACS NSQIP surgical risk calculator⁹ provides an estimate of procedure-specific risk based on Current Procedural Terminology code and includes 21 patient-specific variables to predict death, major adverse cardiac events, and eight other outcomes. While more comprehensive, this risk calculator has yet to be validated outside of the ACS NSQIP database.

Reconstructed RCRI. The RCRI has been externally validated, but it underestimates risk in major vascular surgery and was outperformed by the MICA calculator. Although not discussed in the new guidelines, a recently published "reconstructed RCRI,"¹⁰ in which a serum creatinine level greater than 2 mg/dL in the original RCRI is replaced by a glomerular filtration rate less than 30 mL/min and diabetes is eliminated, may outperform the standard RCRI. A patient with either an RCRI score or a reconstructed RCRI score of 0 or 1 would be considered to be at low risk, whereas patients with two or more risk factors would have an elevated risk.

Cardiac biomarkers, primarily B-type natriuretic peptide (BNP) and N-terminal (NT) proBNP, are independent predictors of cardiac risk, and their addition to preoperative risk indices may provide incremental predictive value. However, how to use these biomarkers and whether any treatment aimed at them will reduce risk is unclear, and the new guidelines did not recommend their routine use.

CLINICAL RISK FACTORS

Coronary artery disease

Ischemic symptoms, a history of myocardial infarction, and elevated cardiac biomarkers are individually associated with perioperative risk of morbidity and death. The risk is modified by how long ago the infarction occurred, whether the patient underwent coronary revascularization, and if so, what type (bypass grafting or percutaneous coronary intervention). A patient with acute coronary syndrome (currently or in the recent past) is at higher risk, and should have elective surgery delayed and be referred for cardiac evaluation and management according to guidelines.

Heart failure

In terms of posing a risk for major adverse cardiac events, heart failure is at least equal to coronary artery disease, and is possibly worse. Its impact depends on its stability, its symptoms, and the patient’s left ventricular function. Symptomatic decompensated heart failure and depressed left ventricular function (ejection fraction < 30% or 40%) confer higher risk than asymptomatic heart failure and preserved left ventricular function. However, evidence is limited with respect to asymptomatic left ventricular dysfunction and diastolic dysfunction. Patients with stable heart failure treated according to guidelines may have better perioperative outcomes.

Valvular heart disease

Significant valvular heart disease is associated with increased risk of postoperative cardiac complications. This risk depends on the type and severity of the valvular lesion and type of noncardiac surgery, but can be minimized by clinical and echocardiographic assessment, choosing appropriate anesthesia, and closer perioperative monitoring. Aortic and mitral stenosis are associated with greater risk of perioperative adverse cardiac events than regurgitant valvular disease.

Echocardiography is recommended in patients suspected of having moderate to severe stenotic or regurgitant lesions if it has not been done within the past year or if the patient’s clinical condition has worsened.

The purpose is not to 'get clearance' but to evaluate the patient's medical status and risk of complications

If indicated, valvular intervention can reduce perioperative risk in these patients. Even if the planned noncardiac surgery is high-risk, it may be reasonable to proceed with it (using appropriate perioperative hemodynamic monitoring, which is not specified but typically would be with an arterial line, central line, and possibly a pulmonary arterial catheter) in patients who have asymptomatic severe aortic or mitral regurgitation or aortic stenosis. Surgery may also be reasonable in patients with asymptomatic severe mitral stenosis who are not candidates for repair.

Arrhythmias

Cardiac arrhythmias and conduction defects are often seen in the perioperative period, but there is only limited evidence as to how they affect surgical risk. In addition to their hemodynamic effects, certain arrhythmias (atrial fibrillation, ventricular tachycardia) often indicate underlying structural heart disease, which requires further evaluation before surgery.

The new guidelines refer the reader to previously published clinical practice guidelines for atrial fibrillation,¹¹ supraventricular arrhythmias,¹² and device-based therapy.¹³

ALGORITHM FOR PREOPERATIVE CARDIAC ASSESSMENT

The new algorithm for evaluating a patient who is known to have coronary artery disease or risk factors for it has seven steps (Figure 1).^{1,11,12,14–17} It differs from the previous algorithm in several details:

• Instead of listing the four active cardiac conditions for which elective surgery should be delayed while the patient is being evaluated and treated (unstable coronary syndrome, decompensated heart failure, significant arrhythmias, severe valvular heart disease), the new version specifically asks about acute coronary syndrome and recommends cardiac evaluation and treatment according to guidelines. A footnote directs readers to other clinical practice guidelines for symptomatic heart failure,¹⁴ valvular heart disease,¹⁵ and arrhythmias.^11,12
• Instead of asking if the procedure is low-risk, the guidelines recommend estimating risk of major adverse cardiac events on the basis of combined clinical and surgical risk and define only two categories: low or elevated. Patients at low risk proceed to surgery with no further testing, as in the earlier algorithm.
• "Excellent" exercise capacity (> 10 metabolic equivalents of task [METs]) is separated from "moderate/good" (4–10 METs), presumably to indicate a stronger recommendation, but patients in both categories proceed to surgery as before.
• If the patient cannot exercise to at least 4 METs, the new algorithm asks whether further testing will affect decision-making or perioperative care (an addition to the previous algorithm). This entails discussing with the patient and perioperative team whether the original surgery will be performed and whether the patient is willing to undergo revascularization if indicated. If so, pharmacologic stress testing is recommended. Previously, this decision also included the number of RCRI factors as well as the type of surgery (vascular or nonvascular).
• If testing will not affect the decision or if the stress test is normal, in addition to recommending proceeding to surgery according to guidelines the new algorithm also lists an option for alternative strategies, including palliation.
• If the stress test is abnormal, especially with left main disease, it recommends coronary revascularization according to the 2011 clinical practice guidelines.^18,19

TESTING FOR LEFT VENTRICULAR DYSFUNCTION OR ISCHEMIA

In patients with dyspnea of unexplained cause or worsening dyspnea, assessment of left ventricular function is reasonable, but this is not part of a routine preoperative evaluation.

Pharmacologic stress testing is reasonable for patients at elevated risk with poor functional capacity if the results will change their management, but it is not useful for patients undergoing low-risk surgery. Although dobutamine stress echocardiography may be slightly superior to pharmacologic myocardial perfusion imaging, there are no head-to-head randomized controlled trials, and the guidelines suggest considering local expertise in deciding which test to use.

The presence of moderate to large areas of ischemia (reversible perfusion defects or new wall-motion abnormalities) is associated with risk of perioperative myocardial infarction or death, whereas evidence of an old infarction is associated with long-term but not short-term risk. The negative predictive value of these tests in predicting postoperative cardiac events is high (> 90%), but the positive predictive value is low.

CORONARY REVASCULARIZATION

Coronary artery bypass grafting and percutaneous coronary intervention

The guidelines recommend coronary revascularization before noncardiac surgery only when it is indicated anyway, on the basis of existing clinical practice guidelines.

Whether performing percutaneous coronary intervention before surgery will reduce perioperative cardiac complications is uncertain, and coronary revascularization should not be routinely performed solely to reduce perioperative cardiac events. The only two randomized controlled trials, Coronary Artery Revascularization Prophylaxis (CARP)²⁰ and DECREASE V²¹ evaluating prophylactic coronary revascularization before noncardiac surgery found no difference in either short-term or long-term outcomes, although subgroup analysis found a survival benefit in patients with left main disease who underwent bypass grafting. Preoperative percutaneous coronary intervention should be limited to patients with left main disease in whom comorbidities preclude bypass surgery and those with unstable coronary disease who may benefit from early invasive management.

The urgency and timing of the noncardiac surgery needs to be taken into account if percutaneous coronary intervention is being considered because of the need for antiplatelet therapy after the procedure, and the potential risks of bleeding and stent thrombosis. If the planned surgery is deemed time-sensitive, then balloon angioplasty or bare-metal stenting is preferred over placement of a drug-eluting stent.

The new guidelines continue to recommend that elective noncardiac surgery be delayed at least 14 days after balloon angioplasty, 30 days after bare-metal stent implantation, and ideally 365 days after drug-eluting stent placement, and reiterate that it is potentially harmful to perform elective surgery within these time frames without any antiplatelet therapy. However, a new class IIb recommendation (benefit ≥ risk) states that "elective noncardiac surgery after [drug-eluting stent] implantation may be considered after 180 days if the risk of further delay is greater than the expected risks of ischemia and stent thrombosis."

This is an important addition to the guidelines because we are often faced with patients needing to undergo surgery in the 6 to 12 months after placement of a drug-eluting stent. Based on previous guidelines, whether it was safe to proceed in this setting created controversy among the perioperative team caring for the patient, and surgery was often delayed unnecessarily. Recent studies^22,23 suggest that the newer drug-eluting stents may require a shorter duration of dual antiplatelet therapy, at least in the nonsurgical setting.

MEDICAL THERAPY

Antiplatelet therapy: Stop or continue?

The risk of perioperative bleeding if antiplatelet drugs are continued must be weighed against the risk of stent thrombosis and ischemia if they are stopped before the recommended duration of therapy. Ideally, some antiplatelet therapy should be continued perioperatively in these situations, but the guidelines recommend that a consensus decision among the treating physicians should be made regarding the relative risks of surgery and discontinuation or continuation of antiplatelet therapy. Whenever possible, aspirin should be continued in these patients.

Although the Perioperative Ischemic Evaluation (POISE)-2 trial²⁴ found that perioperative aspirin use was not associated with lower rates of postoperative myocardial infarction or death, it increased bleeding. Patients with stents who had not completed the recommended duration of antiplatelet therapy were excluded from the trial. Additionally, only 5% of the study patients had undergone percutaneous coronary intervention.

According to the guidelines and package inserts, if antiplatelet agents need to be discontinued before surgery, aspirin can be stopped 3 to 7 days before, clopidogrel and ticagrelor 5 days before, and prasugrel 7 days before. In patients without stents, it may be reasonable to continue aspirin perioperatively if the risk of cardiac events outweighs the risk of bleeding, but starting aspirin is not beneficial for patients undergoing elective noncardiac noncarotid surgery unless the risk of ischemic events outweighs the risk of bleeding.

Beta-blockers

In view of the issue of scientific integrity of the DECREASE trials, a separately commissioned systematic review² of perioperative beta-blocker therapy was performed. This review suggested that giving beta-blockers before surgery was associated with fewer postoperative cardiac events, primarily ischemia and nonfatal myocardial infarction, but few data supported their use to reduce postoperative mortality. Beta-blocker use was associated with adverse outcomes that included bradycardia and stroke. These findings were similar with the inclusion or exclusion of the DECREASE trials in question or of the POISE trial.²⁵

In addition to recommending continuing beta-blockers in patients already on them (class I—the highest recommendation), the guidelines say that it may be reasonable to start them in patients with intermediate- or high-risk ischemia on stress tests as well as in patients with three or more RCRI risk factors (class IIb). In the absence of these indications, initiating beta-blockers preoperatively to reduce risk even in patients with long-term indications is of uncertain benefit. They also recommended starting beta-blockers more than 1 day preoperatively, preferably at least 2 to 7 days before, and note that it was harmful to start them on the day of surgery, particularly at high doses, and with long-acting formulations.

Additionally, there is evidence of differences in outcome within the class of beta-blockers, with the more cardioselective drugs bisoprolol and atenolol being associated with more favorable outcomes than metoprolol in observational studies.

Statins

Multiple observational trials have reported that statins are associated with decreased perioperative morbidity and mortality. Limited evidence from three randomized controlled trials (including two from the discredited DECREASE group) suggests that there is a benefit in patients undergoing vascular surgery, but it is unclear for nonvascular surgery.^26–30

The ACC/AHA guidelines again give a class I recommendation to continue statin therapy perioperatively in patients already taking statins and undergoing noncardiac surgery, as there is some evidence that statin withdrawal is associated with increased risk. The guidelines comment that starting statin therapy perioperatively is reasonable for patients undergoing vascular surgery (class IIa) and may be considered in patients with other clinical guideline indications who are undergoing elevated-risk surgery (class IIb).

The mechanism of this benefit is unclear and may relate to the pleotropic as well as the lipid-lowering effects of the statins. Statins may also have beneficial effects in reducing the incidence of acute kidney injury and postoperative atrial fibrillation.

Whether a particular statin, dose, or time of initiation before surgery affects risk is also unknown at this time. The European guidelines⁶ recommend starting a longer-acting statin ideally at least 2 weeks before surgery for maximal plaque-stabilizing effects.

The risk of statin-induced myopathy, rhabdomyolysis, and hepatic injury appears to be minimal.

Other medications

Of note, the new guidelines do not recommend starting alpha-2 agonists for preventing cardiac events in patients undergoing noncardiac surgery. Despite previous evidence from smaller studies suggesting a benefit, the POISE-2 trial³¹ demonstrated that perioperative use of clonidine did not reduce cardiac events and was associated with a significant increase in hypotension and nonfatal cardiac arrest. However, clonidine should be continued in patients already taking it.

A somewhat surprising recommendation is that it is reasonable to continue angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and if they are held before surgery, to restart them as soon as possible postoperatively (class IIa). The guidelines note reports of increased hypotension associated with induction of anesthesia in patients taking these drugs but also note that there was no change in important postoperative cardiac and other outcomes. Although evidence of harm if these drugs are temporarily discontinued before surgery is sparse, the guidelines advocate continuing them in patients with heart failure or hypertension.

ANESTHESIA AND INTRAOPERATIVE MANAGEMENT

The classes of anesthesia include local, regional (nerve block or neuraxial), monitored anesthesia care (ie, intravenous sedation), and general (volatile agent, total intravenous, or a combination). The guideline committee found no evidence to support the use of neuraxial over general anesthesia, volatile over total intravenous anesthesia, or monitored anesthesia care over general anesthesia. Neuraxial anesthesia for postoperative pain relief in patients undergoing abdominal aortic surgery did reduce the incidence of myocardial infarction.

Heart failure is at least equal to coronary artery disease in terms of risk

The guidelines do not recommend routinely using intraoperative transesophageal echocardiography during noncardiac surgery to screen for cardiac abnormalities or to monitor for myocardial ischemia in patients without risk factors or procedural risks for significant hemodynamic, pulmonary, or neurologic compromise. Only in emergency settings do they deem perioperative transesophageal echocardiography reasonable to determine the cause of hemodynamic instability when it persists despite attempted corrective therapy.

Maintenance of normothermia is reasonable, as studies evaluating hypothermia or use of warmed air did not find a lower rate of cardiac events.^32,33

POSTOPERATIVE SURVEILLANCE

In observational studies, elevated troponin levels, and even detectable levels within the normal range, have been associated with adverse outcomes and predict mortality after noncardiac surgery—the higher the level, the higher the mortality rate.³⁴ Elevated troponins have many potential causes, both cardiac and noncardiac.

An entity termed myocardial injury after noncardiac surgery (MINS)³⁵ was described as prognostically relevant myocardial injury with a troponin T level higher than 0.03 ng/mL in the absence of a nonischemic etiology but not requiring the presence of ischemic features. Patients who had MINS had a higher 30-day mortality rate (9.8% vs 1.1%) and were also at higher risk of nonfatal cardiac arrest, heart failure, and stroke compared with patients who did not.

The guidelines recommend obtaining an electrocardiogram and troponin levels if there are signs or symptoms suggesting myocardial ischemia or infarction. However, despite the association between troponin and mortality, the guidelines state that "the usefulness of postoperative screening with troponin levels (and electrocardiograms) in patients at high risk for perioperative myocardial infarction, but without signs or symptoms suggestive of myocardial ischemia or infarction, is uncertain in the absence of established risks and benefits of a defined management strategy." They also recommend against routinely measuring postoperative troponins in unselected patients without signs or symptoms suggestive of myocardial ischemia or infarction, stating it is not useful for guiding perioperative management.

Although there was a suggestion that patients in the POISE trial³⁶ who suffered postoperative myocardial infarction had better outcomes if they had received aspirin and statins, and another study³⁷ showed that intensification of cardiac therapy in patients with elevated postoperative troponin levels after vascular surgery led to better 1-year outcomes, there are no randomized controlled trials at this time to support any specific plan or intervention.

IMPACT ON CLINICAL PRACTICE: A PERIOPERATIVE HOSPITALIST'S VIEW

Regarding testing

Although the updated guidelines provide some novel concepts in risk stratification, the new algorithm still leaves many patients in a gray zone with respect to noninvasive testing. Patients with heart failure, valvular heart disease, and arrhythmias appear to be somewhat disconnected from the algorithm in this version, and management according to clinical practice guidelines is recommended.

Patients with acute coronary syndrome remain embedded in the algorithm, with recommendations for cardiology evaluation and management according to standard guidelines before proceeding to elective surgery.

The concept of a combined risk based on clinical factors along with the surgical procedure is important, and an alternative to the RCRI factors is offered. However, while this new NSQIP surgical risk calculator is more comprehensive, it may be too time-consuming for routine clinical use and still needs to be externally validated.

There is only limited evidence as to how arrhythmias affect surgical risk

The concept of shared decision-making and team communication is stressed, but the physician may still have difficulty deciding when further testing may influence management. The guidelines remain somewhat vague, and many physicians may be uncomfortable and will continue to look for further guidance in this area.

Without more specific recommendations, this uncertainty may result in more stress tests being ordered—often inappropriately, as they rarely change management. Future prospective studies using biomarkers in conjunction with risk calculators may shed some light on this decision.

The new perioperative guidelines incorporate other ACC/AHA guidelines for valvular heart disease¹⁵ and heart failure.¹⁴ Some of their recommendations, in my opinion, may lead to excessive testing (eg, repeat echocardiograms) that will not change perioperative management.

Regarding revascularization

The ACC/AHA guidelines continue to emphasize the important concept that coronary revascularization is rarely indicated just to get the patient through surgery.

The new guidelines give physicians some leeway in allowing patients with drug-eluting stents to undergo surgery after 6 rather than 12 months of dual antiplatelet therapy if they believe that delaying surgery would place the patient at more risk than that of stent thrombosis. There is evidence in the nonsurgical setting that the newer stents currently being used may require no more than 6 months of therapy. In my opinion it was never clear that there was a statistically significant benefit in delaying surgery more than 6 months after placement of a drug-eluting stent, so this is a welcome addition.

Regarding beta-blockers

The systematic review of beta-blockers reinforces the importance of continuing them preoperatively while downgrading recommendations for their prophylactic use in patients who are not at increased risk.

Although the debate continues, there is no doubt that beta-blockers are associated with a decrease in myocardial ischemia and infarction but an increase in bradycardia and hypotension. They probably are associated with some increased risk of stroke, although this may be related to the specific beta-blocker used as well as the time of initiation before surgery. Evidence of a possible effect on mortality depends on whether the DECREASE and POISE trials are included or excluded in the analysis.

In the absence of new large-scale randomized controlled trials, we are forced to rely on observational trials and expert opinion in the meantime. I think that if a beta-blocker is to be started preoperatively, it should be done at least 1 week before surgery, and a more cardioselective beta-blocker should be used.

Regarding other drugs and tests

I agree with the recommendation to continue ACE inhibitors and ARBs preoperatively in patients with heart failure and poorly controlled hypertension. Although somewhat contrary to current practice, continuance of these drugs has not been associated with an increase in myocardial infarction or death despite concern about intraoperative hypotension.

Data from randomized controlled trials of perioperative statins are limited, but the information from observational studies is favorable, and I see little downside to initiating statins preoperatively in patients who otherwise have indications for their use, particularly if undergoing vascular or other high-risk noncardiac surgery. It is not known whether the specific drug, dose, or timing of initiation of statins influences outcome.

Although multiple studies of biomarkers suggest that there is an association with outcome, there are no randomized controlled trials or specific interventions shown to improve outcome.

Some of the recommended interventions have included various cardiac medications, stress testing, possible coronary angiography, and revascularization, which are not without risk. In the absence of data and following the directive to "first do no harm," the ACC/AHA has been appropriately cautious in not recommending them for routine use at this time.

The updated guidelines have summarized the new evidence in perioperative cardiac evaluation and management. Many of their recommendations were reinforced by this information and remain essentially unchanged. Several new recommendations will lead to changes in management going forward. Unfortunately, we lack the evidence to answer many questions that arise in routine practice and are therefore forced to rely on expert opinion and our clinical judgment in these cases. The ACC/AHA guidelines do provide a framework for our evaluation and management and help keep clinicians up-to-date with the latest evidence.

Guidelines jointly issued by the American College of Cardiology and American Heart Association (ACC/AHA)¹ provide a framework for evaluating and managing perioperative cardiac risk in noncardiac surgery. An overriding theme in successive documents from these organizations through the years has been that preoperative intervention, coronary artery bypass grafting, or percutaneous coronary intervention is rarely necessary just to get the patient through surgery, unless it is otherwise indicated independent of the need for surgery.

See related commentary

This article highlights some of the key recommendations in the 2014 updates to these guidelines,^1–3 how they differ from previous guidelines,⁴ and the ongoing challenges and unresolved issues facing physicians involved in perioperative care.

Of note, while these guidelines were being updated, Erasmus University⁵ expressed concern about the scientific integrity of some of the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE) trials. As a result, the evidence review committee included these trials in its analysis but not in a systematic review of beta-blockers.² These trials were not included in the clinical practice guideline supplements and tables but were cited in the text if relevant.

The European Society of Cardiology and European Society of Anesthesiology⁶ revised their guidelines concurrently with but independently of the ACC/AHA, and although they discussed and aligned some recommendations, many differences remain between the two sets of guidelines. Readers should consult the full guidelines for more detailed information.¹

THE ROLE OF THE PREOPERATIVE CARDIAC EVALUATION

The purpose of preoperative medical evaluation is not to "get medical clearance" but rather to evaluate the patient’s medical status and risk of complications. The process includes:

• Identifying risk factors and assessing their severity and stability
• Establishing a clinical risk profile for informed and shared decision-making
• Recommending needed changes in management, further testing, or specialty consultation.

The updated guidelines emphasize the importance of communication among the perioperative team and with the patient. They reiterate the focus on appropriateness of care and cost containment—one should order a test only if the result may change the patient’s management.

HOW URGENT IS SURGERY? HOW RISKY?

The new guidelines classify the urgency of surgery as follows:

• Emergency (necessary within 6 hours)
• Urgent (necessary within 6–24 hours)
• Time-sensitive (can delay 1–6 weeks)
• Elective (can delay up to 1 year).

One should order a test only if the result may change the patient's management

Surgical risk is now classified as either low (< 1% risk of major adverse cardiac events) or elevated (≥ 1%) on the basis of surgical and patient characteristics. Previous schemas included an intermediate-risk category. Low-risk procedures include endoscopic procedures, superficial procedures, cataract surgery, breast surgery, and ambulatory surgery. Elevated-risk procedures include vascular surgery, intraperitoneal and intrathoracic surgery, head and neck surgery, orthopedic surgery, and prostate surgery.

Risk calculators and biomarkers

To estimate the perioperative risk of major adverse cardiac events, the guidelines suggest incorporating the Revised Cardiac Risk Index (RCRI)⁷ with an estimation of surgical risk or using a newer surgical risk calculator derived from a database of the American College of Surgeons’ National Surgical Quality Improvement Project (ACS NSQIP).

The RCRI is based on six risk factors, each worth 1 point:

• High-risk surgery
• Ischemic heart disease
• Heart failure
• Stroke or transient ischemic attack
• Diabetes requiring insulin
• Renal insufficiency (serum creatinine > 2.0 mg/dL).⁷

MICA. The Myocardial Infarction or Cardiac Arrest (MICA) calculator⁸ has a narrower focus and was validated in only one center.

ACS NSQIP. The recommended newer ACS NSQIP surgical risk calculator⁹ provides an estimate of procedure-specific risk based on Current Procedural Terminology code and includes 21 patient-specific variables to predict death, major adverse cardiac events, and eight other outcomes. While more comprehensive, this risk calculator has yet to be validated outside of the ACS NSQIP database.

Reconstructed RCRI. The RCRI has been externally validated, but it underestimates risk in major vascular surgery and was outperformed by the MICA calculator. Although not discussed in the new guidelines, a recently published "reconstructed RCRI,"¹⁰ in which a serum creatinine level greater than 2 mg/dL in the original RCRI is replaced by a glomerular filtration rate less than 30 mL/min and diabetes is eliminated, may outperform the standard RCRI. A patient with either an RCRI score or a reconstructed RCRI score of 0 or 1 would be considered to be at low risk, whereas patients with two or more risk factors would have an elevated risk.

Cardiac biomarkers, primarily B-type natriuretic peptide (BNP) and N-terminal (NT) proBNP, are independent predictors of cardiac risk, and their addition to preoperative risk indices may provide incremental predictive value. However, how to use these biomarkers and whether any treatment aimed at them will reduce risk is unclear, and the new guidelines did not recommend their routine use.

CLINICAL RISK FACTORS

Coronary artery disease

Ischemic symptoms, a history of myocardial infarction, and elevated cardiac biomarkers are individually associated with perioperative risk of morbidity and death. The risk is modified by how long ago the infarction occurred, whether the patient underwent coronary revascularization, and if so, what type (bypass grafting or percutaneous coronary intervention). A patient with acute coronary syndrome (currently or in the recent past) is at higher risk, and should have elective surgery delayed and be referred for cardiac evaluation and management according to guidelines.

Heart failure

In terms of posing a risk for major adverse cardiac events, heart failure is at least equal to coronary artery disease, and is possibly worse. Its impact depends on its stability, its symptoms, and the patient’s left ventricular function. Symptomatic decompensated heart failure and depressed left ventricular function (ejection fraction < 30% or 40%) confer higher risk than asymptomatic heart failure and preserved left ventricular function. However, evidence is limited with respect to asymptomatic left ventricular dysfunction and diastolic dysfunction. Patients with stable heart failure treated according to guidelines may have better perioperative outcomes.

Valvular heart disease

Significant valvular heart disease is associated with increased risk of postoperative cardiac complications. This risk depends on the type and severity of the valvular lesion and type of noncardiac surgery, but can be minimized by clinical and echocardiographic assessment, choosing appropriate anesthesia, and closer perioperative monitoring. Aortic and mitral stenosis are associated with greater risk of perioperative adverse cardiac events than regurgitant valvular disease.

Echocardiography is recommended in patients suspected of having moderate to severe stenotic or regurgitant lesions if it has not been done within the past year or if the patient’s clinical condition has worsened.

The purpose is not to 'get clearance' but to evaluate the patient's medical status and risk of complications

If indicated, valvular intervention can reduce perioperative risk in these patients. Even if the planned noncardiac surgery is high-risk, it may be reasonable to proceed with it (using appropriate perioperative hemodynamic monitoring, which is not specified but typically would be with an arterial line, central line, and possibly a pulmonary arterial catheter) in patients who have asymptomatic severe aortic or mitral regurgitation or aortic stenosis. Surgery may also be reasonable in patients with asymptomatic severe mitral stenosis who are not candidates for repair.

Arrhythmias

Cardiac arrhythmias and conduction defects are often seen in the perioperative period, but there is only limited evidence as to how they affect surgical risk. In addition to their hemodynamic effects, certain arrhythmias (atrial fibrillation, ventricular tachycardia) often indicate underlying structural heart disease, which requires further evaluation before surgery.

The new guidelines refer the reader to previously published clinical practice guidelines for atrial fibrillation,¹¹ supraventricular arrhythmias,¹² and device-based therapy.¹³

ALGORITHM FOR PREOPERATIVE CARDIAC ASSESSMENT

The new algorithm for evaluating a patient who is known to have coronary artery disease or risk factors for it has seven steps (Figure 1).^{1,11,12,14–17} It differs from the previous algorithm in several details:

• Instead of listing the four active cardiac conditions for which elective surgery should be delayed while the patient is being evaluated and treated (unstable coronary syndrome, decompensated heart failure, significant arrhythmias, severe valvular heart disease), the new version specifically asks about acute coronary syndrome and recommends cardiac evaluation and treatment according to guidelines. A footnote directs readers to other clinical practice guidelines for symptomatic heart failure,¹⁴ valvular heart disease,¹⁵ and arrhythmias.^11,12
• Instead of asking if the procedure is low-risk, the guidelines recommend estimating risk of major adverse cardiac events on the basis of combined clinical and surgical risk and define only two categories: low or elevated. Patients at low risk proceed to surgery with no further testing, as in the earlier algorithm.
• "Excellent" exercise capacity (> 10 metabolic equivalents of task [METs]) is separated from "moderate/good" (4–10 METs), presumably to indicate a stronger recommendation, but patients in both categories proceed to surgery as before.
• If the patient cannot exercise to at least 4 METs, the new algorithm asks whether further testing will affect decision-making or perioperative care (an addition to the previous algorithm). This entails discussing with the patient and perioperative team whether the original surgery will be performed and whether the patient is willing to undergo revascularization if indicated. If so, pharmacologic stress testing is recommended. Previously, this decision also included the number of RCRI factors as well as the type of surgery (vascular or nonvascular).
• If testing will not affect the decision or if the stress test is normal, in addition to recommending proceeding to surgery according to guidelines the new algorithm also lists an option for alternative strategies, including palliation.
• If the stress test is abnormal, especially with left main disease, it recommends coronary revascularization according to the 2011 clinical practice guidelines.^18,19

TESTING FOR LEFT VENTRICULAR DYSFUNCTION OR ISCHEMIA

In patients with dyspnea of unexplained cause or worsening dyspnea, assessment of left ventricular function is reasonable, but this is not part of a routine preoperative evaluation.

Pharmacologic stress testing is reasonable for patients at elevated risk with poor functional capacity if the results will change their management, but it is not useful for patients undergoing low-risk surgery. Although dobutamine stress echocardiography may be slightly superior to pharmacologic myocardial perfusion imaging, there are no head-to-head randomized controlled trials, and the guidelines suggest considering local expertise in deciding which test to use.

The presence of moderate to large areas of ischemia (reversible perfusion defects or new wall-motion abnormalities) is associated with risk of perioperative myocardial infarction or death, whereas evidence of an old infarction is associated with long-term but not short-term risk. The negative predictive value of these tests in predicting postoperative cardiac events is high (> 90%), but the positive predictive value is low.

CORONARY REVASCULARIZATION

Coronary artery bypass grafting and percutaneous coronary intervention

The guidelines recommend coronary revascularization before noncardiac surgery only when it is indicated anyway, on the basis of existing clinical practice guidelines.

Whether performing percutaneous coronary intervention before surgery will reduce perioperative cardiac complications is uncertain, and coronary revascularization should not be routinely performed solely to reduce perioperative cardiac events. The only two randomized controlled trials, Coronary Artery Revascularization Prophylaxis (CARP)²⁰ and DECREASE V²¹ evaluating prophylactic coronary revascularization before noncardiac surgery found no difference in either short-term or long-term outcomes, although subgroup analysis found a survival benefit in patients with left main disease who underwent bypass grafting. Preoperative percutaneous coronary intervention should be limited to patients with left main disease in whom comorbidities preclude bypass surgery and those with unstable coronary disease who may benefit from early invasive management.

The urgency and timing of the noncardiac surgery needs to be taken into account if percutaneous coronary intervention is being considered because of the need for antiplatelet therapy after the procedure, and the potential risks of bleeding and stent thrombosis. If the planned surgery is deemed time-sensitive, then balloon angioplasty or bare-metal stenting is preferred over placement of a drug-eluting stent.

The new guidelines continue to recommend that elective noncardiac surgery be delayed at least 14 days after balloon angioplasty, 30 days after bare-metal stent implantation, and ideally 365 days after drug-eluting stent placement, and reiterate that it is potentially harmful to perform elective surgery within these time frames without any antiplatelet therapy. However, a new class IIb recommendation (benefit ≥ risk) states that "elective noncardiac surgery after [drug-eluting stent] implantation may be considered after 180 days if the risk of further delay is greater than the expected risks of ischemia and stent thrombosis."

This is an important addition to the guidelines because we are often faced with patients needing to undergo surgery in the 6 to 12 months after placement of a drug-eluting stent. Based on previous guidelines, whether it was safe to proceed in this setting created controversy among the perioperative team caring for the patient, and surgery was often delayed unnecessarily. Recent studies^22,23 suggest that the newer drug-eluting stents may require a shorter duration of dual antiplatelet therapy, at least in the nonsurgical setting.

MEDICAL THERAPY

Antiplatelet therapy: Stop or continue?

The risk of perioperative bleeding if antiplatelet drugs are continued must be weighed against the risk of stent thrombosis and ischemia if they are stopped before the recommended duration of therapy. Ideally, some antiplatelet therapy should be continued perioperatively in these situations, but the guidelines recommend that a consensus decision among the treating physicians should be made regarding the relative risks of surgery and discontinuation or continuation of antiplatelet therapy. Whenever possible, aspirin should be continued in these patients.

Although the Perioperative Ischemic Evaluation (POISE)-2 trial²⁴ found that perioperative aspirin use was not associated with lower rates of postoperative myocardial infarction or death, it increased bleeding. Patients with stents who had not completed the recommended duration of antiplatelet therapy were excluded from the trial. Additionally, only 5% of the study patients had undergone percutaneous coronary intervention.

According to the guidelines and package inserts, if antiplatelet agents need to be discontinued before surgery, aspirin can be stopped 3 to 7 days before, clopidogrel and ticagrelor 5 days before, and prasugrel 7 days before. In patients without stents, it may be reasonable to continue aspirin perioperatively if the risk of cardiac events outweighs the risk of bleeding, but starting aspirin is not beneficial for patients undergoing elective noncardiac noncarotid surgery unless the risk of ischemic events outweighs the risk of bleeding.

Beta-blockers

In view of the issue of scientific integrity of the DECREASE trials, a separately commissioned systematic review² of perioperative beta-blocker therapy was performed. This review suggested that giving beta-blockers before surgery was associated with fewer postoperative cardiac events, primarily ischemia and nonfatal myocardial infarction, but few data supported their use to reduce postoperative mortality. Beta-blocker use was associated with adverse outcomes that included bradycardia and stroke. These findings were similar with the inclusion or exclusion of the DECREASE trials in question or of the POISE trial.²⁵

In addition to recommending continuing beta-blockers in patients already on them (class I—the highest recommendation), the guidelines say that it may be reasonable to start them in patients with intermediate- or high-risk ischemia on stress tests as well as in patients with three or more RCRI risk factors (class IIb). In the absence of these indications, initiating beta-blockers preoperatively to reduce risk even in patients with long-term indications is of uncertain benefit. They also recommended starting beta-blockers more than 1 day preoperatively, preferably at least 2 to 7 days before, and note that it was harmful to start them on the day of surgery, particularly at high doses, and with long-acting formulations.

Additionally, there is evidence of differences in outcome within the class of beta-blockers, with the more cardioselective drugs bisoprolol and atenolol being associated with more favorable outcomes than metoprolol in observational studies.

Statins

Multiple observational trials have reported that statins are associated with decreased perioperative morbidity and mortality. Limited evidence from three randomized controlled trials (including two from the discredited DECREASE group) suggests that there is a benefit in patients undergoing vascular surgery, but it is unclear for nonvascular surgery.^26–30

The ACC/AHA guidelines again give a class I recommendation to continue statin therapy perioperatively in patients already taking statins and undergoing noncardiac surgery, as there is some evidence that statin withdrawal is associated with increased risk. The guidelines comment that starting statin therapy perioperatively is reasonable for patients undergoing vascular surgery (class IIa) and may be considered in patients with other clinical guideline indications who are undergoing elevated-risk surgery (class IIb).

The mechanism of this benefit is unclear and may relate to the pleotropic as well as the lipid-lowering effects of the statins. Statins may also have beneficial effects in reducing the incidence of acute kidney injury and postoperative atrial fibrillation.

Whether a particular statin, dose, or time of initiation before surgery affects risk is also unknown at this time. The European guidelines⁶ recommend starting a longer-acting statin ideally at least 2 weeks before surgery for maximal plaque-stabilizing effects.

The risk of statin-induced myopathy, rhabdomyolysis, and hepatic injury appears to be minimal.

Other medications

Of note, the new guidelines do not recommend starting alpha-2 agonists for preventing cardiac events in patients undergoing noncardiac surgery. Despite previous evidence from smaller studies suggesting a benefit, the POISE-2 trial³¹ demonstrated that perioperative use of clonidine did not reduce cardiac events and was associated with a significant increase in hypotension and nonfatal cardiac arrest. However, clonidine should be continued in patients already taking it.

A somewhat surprising recommendation is that it is reasonable to continue angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and if they are held before surgery, to restart them as soon as possible postoperatively (class IIa). The guidelines note reports of increased hypotension associated with induction of anesthesia in patients taking these drugs but also note that there was no change in important postoperative cardiac and other outcomes. Although evidence of harm if these drugs are temporarily discontinued before surgery is sparse, the guidelines advocate continuing them in patients with heart failure or hypertension.

ANESTHESIA AND INTRAOPERATIVE MANAGEMENT

The classes of anesthesia include local, regional (nerve block or neuraxial), monitored anesthesia care (ie, intravenous sedation), and general (volatile agent, total intravenous, or a combination). The guideline committee found no evidence to support the use of neuraxial over general anesthesia, volatile over total intravenous anesthesia, or monitored anesthesia care over general anesthesia. Neuraxial anesthesia for postoperative pain relief in patients undergoing abdominal aortic surgery did reduce the incidence of myocardial infarction.

Heart failure is at least equal to coronary artery disease in terms of risk

The guidelines do not recommend routinely using intraoperative transesophageal echocardiography during noncardiac surgery to screen for cardiac abnormalities or to monitor for myocardial ischemia in patients without risk factors or procedural risks for significant hemodynamic, pulmonary, or neurologic compromise. Only in emergency settings do they deem perioperative transesophageal echocardiography reasonable to determine the cause of hemodynamic instability when it persists despite attempted corrective therapy.

Maintenance of normothermia is reasonable, as studies evaluating hypothermia or use of warmed air did not find a lower rate of cardiac events.^32,33

POSTOPERATIVE SURVEILLANCE

In observational studies, elevated troponin levels, and even detectable levels within the normal range, have been associated with adverse outcomes and predict mortality after noncardiac surgery—the higher the level, the higher the mortality rate.³⁴ Elevated troponins have many potential causes, both cardiac and noncardiac.

An entity termed myocardial injury after noncardiac surgery (MINS)³⁵ was described as prognostically relevant myocardial injury with a troponin T level higher than 0.03 ng/mL in the absence of a nonischemic etiology but not requiring the presence of ischemic features. Patients who had MINS had a higher 30-day mortality rate (9.8% vs 1.1%) and were also at higher risk of nonfatal cardiac arrest, heart failure, and stroke compared with patients who did not.

The guidelines recommend obtaining an electrocardiogram and troponin levels if there are signs or symptoms suggesting myocardial ischemia or infarction. However, despite the association between troponin and mortality, the guidelines state that "the usefulness of postoperative screening with troponin levels (and electrocardiograms) in patients at high risk for perioperative myocardial infarction, but without signs or symptoms suggestive of myocardial ischemia or infarction, is uncertain in the absence of established risks and benefits of a defined management strategy." They also recommend against routinely measuring postoperative troponins in unselected patients without signs or symptoms suggestive of myocardial ischemia or infarction, stating it is not useful for guiding perioperative management.

Although there was a suggestion that patients in the POISE trial³⁶ who suffered postoperative myocardial infarction had better outcomes if they had received aspirin and statins, and another study³⁷ showed that intensification of cardiac therapy in patients with elevated postoperative troponin levels after vascular surgery led to better 1-year outcomes, there are no randomized controlled trials at this time to support any specific plan or intervention.

IMPACT ON CLINICAL PRACTICE: A PERIOPERATIVE HOSPITALIST'S VIEW

Regarding testing

Although the updated guidelines provide some novel concepts in risk stratification, the new algorithm still leaves many patients in a gray zone with respect to noninvasive testing. Patients with heart failure, valvular heart disease, and arrhythmias appear to be somewhat disconnected from the algorithm in this version, and management according to clinical practice guidelines is recommended.

Patients with acute coronary syndrome remain embedded in the algorithm, with recommendations for cardiology evaluation and management according to standard guidelines before proceeding to elective surgery.

The concept of a combined risk based on clinical factors along with the surgical procedure is important, and an alternative to the RCRI factors is offered. However, while this new NSQIP surgical risk calculator is more comprehensive, it may be too time-consuming for routine clinical use and still needs to be externally validated.

There is only limited evidence as to how arrhythmias affect surgical risk

The concept of shared decision-making and team communication is stressed, but the physician may still have difficulty deciding when further testing may influence management. The guidelines remain somewhat vague, and many physicians may be uncomfortable and will continue to look for further guidance in this area.

Without more specific recommendations, this uncertainty may result in more stress tests being ordered—often inappropriately, as they rarely change management. Future prospective studies using biomarkers in conjunction with risk calculators may shed some light on this decision.

The new perioperative guidelines incorporate other ACC/AHA guidelines for valvular heart disease¹⁵ and heart failure.¹⁴ Some of their recommendations, in my opinion, may lead to excessive testing (eg, repeat echocardiograms) that will not change perioperative management.

Regarding revascularization

The ACC/AHA guidelines continue to emphasize the important concept that coronary revascularization is rarely indicated just to get the patient through surgery.

The new guidelines give physicians some leeway in allowing patients with drug-eluting stents to undergo surgery after 6 rather than 12 months of dual antiplatelet therapy if they believe that delaying surgery would place the patient at more risk than that of stent thrombosis. There is evidence in the nonsurgical setting that the newer stents currently being used may require no more than 6 months of therapy. In my opinion it was never clear that there was a statistically significant benefit in delaying surgery more than 6 months after placement of a drug-eluting stent, so this is a welcome addition.

Regarding beta-blockers

The systematic review of beta-blockers reinforces the importance of continuing them preoperatively while downgrading recommendations for their prophylactic use in patients who are not at increased risk.

Although the debate continues, there is no doubt that beta-blockers are associated with a decrease in myocardial ischemia and infarction but an increase in bradycardia and hypotension. They probably are associated with some increased risk of stroke, although this may be related to the specific beta-blocker used as well as the time of initiation before surgery. Evidence of a possible effect on mortality depends on whether the DECREASE and POISE trials are included or excluded in the analysis.

In the absence of new large-scale randomized controlled trials, we are forced to rely on observational trials and expert opinion in the meantime. I think that if a beta-blocker is to be started preoperatively, it should be done at least 1 week before surgery, and a more cardioselective beta-blocker should be used.

Regarding other drugs and tests

I agree with the recommendation to continue ACE inhibitors and ARBs preoperatively in patients with heart failure and poorly controlled hypertension. Although somewhat contrary to current practice, continuance of these drugs has not been associated with an increase in myocardial infarction or death despite concern about intraoperative hypotension.

Data from randomized controlled trials of perioperative statins are limited, but the information from observational studies is favorable, and I see little downside to initiating statins preoperatively in patients who otherwise have indications for their use, particularly if undergoing vascular or other high-risk noncardiac surgery. It is not known whether the specific drug, dose, or timing of initiation of statins influences outcome.

Although multiple studies of biomarkers suggest that there is an association with outcome, there are no randomized controlled trials or specific interventions shown to improve outcome.

Some of the recommended interventions have included various cardiac medications, stress testing, possible coronary angiography, and revascularization, which are not without risk. In the absence of data and following the directive to "first do no harm," the ACC/AHA has been appropriately cautious in not recommending them for routine use at this time.

The updated guidelines have summarized the new evidence in perioperative cardiac evaluation and management. Many of their recommendations were reinforced by this information and remain essentially unchanged. Several new recommendations will lead to changes in management going forward. Unfortunately, we lack the evidence to answer many questions that arise in routine practice and are therefore forced to rely on expert opinion and our clinical judgment in these cases. The ACC/AHA guidelines do provide a framework for our evaluation and management and help keep clinicians up-to-date with the latest evidence.

Guidelines jointly issued by the American College of Cardiology and American Heart Association (ACC/AHA)¹ provide a framework for evaluating and managing perioperative cardiac risk in noncardiac surgery. An overriding theme in successive documents from these organizations through the years has been that preoperative intervention, coronary artery bypass grafting, or percutaneous coronary intervention is rarely necessary just to get the patient through surgery, unless it is otherwise indicated independent of the need for surgery.

See related commentary

This article highlights some of the key recommendations in the 2014 updates to these guidelines,^1–3 how they differ from previous guidelines,⁴ and the ongoing challenges and unresolved issues facing physicians involved in perioperative care.

Of note, while these guidelines were being updated, Erasmus University⁵ expressed concern about the scientific integrity of some of the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE) trials. As a result, the evidence review committee included these trials in its analysis but not in a systematic review of beta-blockers.² These trials were not included in the clinical practice guideline supplements and tables but were cited in the text if relevant.

The European Society of Cardiology and European Society of Anesthesiology⁶ revised their guidelines concurrently with but independently of the ACC/AHA, and although they discussed and aligned some recommendations, many differences remain between the two sets of guidelines. Readers should consult the full guidelines for more detailed information.¹

THE ROLE OF THE PREOPERATIVE CARDIAC EVALUATION

The purpose of preoperative medical evaluation is not to "get medical clearance" but rather to evaluate the patient’s medical status and risk of complications. The process includes:

• Identifying risk factors and assessing their severity and stability
• Establishing a clinical risk profile for informed and shared decision-making
• Recommending needed changes in management, further testing, or specialty consultation.

The updated guidelines emphasize the importance of communication among the perioperative team and with the patient. They reiterate the focus on appropriateness of care and cost containment—one should order a test only if the result may change the patient’s management.

HOW URGENT IS SURGERY? HOW RISKY?

The new guidelines classify the urgency of surgery as follows:

• Emergency (necessary within 6 hours)
• Urgent (necessary within 6–24 hours)
• Time-sensitive (can delay 1–6 weeks)
• Elective (can delay up to 1 year).

One should order a test only if the result may change the patient's management

Surgical risk is now classified as either low (< 1% risk of major adverse cardiac events) or elevated (≥ 1%) on the basis of surgical and patient characteristics. Previous schemas included an intermediate-risk category. Low-risk procedures include endoscopic procedures, superficial procedures, cataract surgery, breast surgery, and ambulatory surgery. Elevated-risk procedures include vascular surgery, intraperitoneal and intrathoracic surgery, head and neck surgery, orthopedic surgery, and prostate surgery.

Risk calculators and biomarkers

To estimate the perioperative risk of major adverse cardiac events, the guidelines suggest incorporating the Revised Cardiac Risk Index (RCRI)⁷ with an estimation of surgical risk or using a newer surgical risk calculator derived from a database of the American College of Surgeons’ National Surgical Quality Improvement Project (ACS NSQIP).

The RCRI is based on six risk factors, each worth 1 point:

• High-risk surgery
• Ischemic heart disease
• Heart failure
• Stroke or transient ischemic attack
• Diabetes requiring insulin
• Renal insufficiency (serum creatinine > 2.0 mg/dL).⁷

MICA. The Myocardial Infarction or Cardiac Arrest (MICA) calculator⁸ has a narrower focus and was validated in only one center.

ACS NSQIP. The recommended newer ACS NSQIP surgical risk calculator⁹ provides an estimate of procedure-specific risk based on Current Procedural Terminology code and includes 21 patient-specific variables to predict death, major adverse cardiac events, and eight other outcomes. While more comprehensive, this risk calculator has yet to be validated outside of the ACS NSQIP database.

Reconstructed RCRI. The RCRI has been externally validated, but it underestimates risk in major vascular surgery and was outperformed by the MICA calculator. Although not discussed in the new guidelines, a recently published "reconstructed RCRI,"¹⁰ in which a serum creatinine level greater than 2 mg/dL in the original RCRI is replaced by a glomerular filtration rate less than 30 mL/min and diabetes is eliminated, may outperform the standard RCRI. A patient with either an RCRI score or a reconstructed RCRI score of 0 or 1 would be considered to be at low risk, whereas patients with two or more risk factors would have an elevated risk.

Cardiac biomarkers, primarily B-type natriuretic peptide (BNP) and N-terminal (NT) proBNP, are independent predictors of cardiac risk, and their addition to preoperative risk indices may provide incremental predictive value. However, how to use these biomarkers and whether any treatment aimed at them will reduce risk is unclear, and the new guidelines did not recommend their routine use.

CLINICAL RISK FACTORS

Coronary artery disease

Ischemic symptoms, a history of myocardial infarction, and elevated cardiac biomarkers are individually associated with perioperative risk of morbidity and death. The risk is modified by how long ago the infarction occurred, whether the patient underwent coronary revascularization, and if so, what type (bypass grafting or percutaneous coronary intervention). A patient with acute coronary syndrome (currently or in the recent past) is at higher risk, and should have elective surgery delayed and be referred for cardiac evaluation and management according to guidelines.

Heart failure

In terms of posing a risk for major adverse cardiac events, heart failure is at least equal to coronary artery disease, and is possibly worse. Its impact depends on its stability, its symptoms, and the patient’s left ventricular function. Symptomatic decompensated heart failure and depressed left ventricular function (ejection fraction < 30% or 40%) confer higher risk than asymptomatic heart failure and preserved left ventricular function. However, evidence is limited with respect to asymptomatic left ventricular dysfunction and diastolic dysfunction. Patients with stable heart failure treated according to guidelines may have better perioperative outcomes.

Valvular heart disease

Significant valvular heart disease is associated with increased risk of postoperative cardiac complications. This risk depends on the type and severity of the valvular lesion and type of noncardiac surgery, but can be minimized by clinical and echocardiographic assessment, choosing appropriate anesthesia, and closer perioperative monitoring. Aortic and mitral stenosis are associated with greater risk of perioperative adverse cardiac events than regurgitant valvular disease.

Echocardiography is recommended in patients suspected of having moderate to severe stenotic or regurgitant lesions if it has not been done within the past year or if the patient’s clinical condition has worsened.

The purpose is not to 'get clearance' but to evaluate the patient's medical status and risk of complications

If indicated, valvular intervention can reduce perioperative risk in these patients. Even if the planned noncardiac surgery is high-risk, it may be reasonable to proceed with it (using appropriate perioperative hemodynamic monitoring, which is not specified but typically would be with an arterial line, central line, and possibly a pulmonary arterial catheter) in patients who have asymptomatic severe aortic or mitral regurgitation or aortic stenosis. Surgery may also be reasonable in patients with asymptomatic severe mitral stenosis who are not candidates for repair.

Arrhythmias

Cardiac arrhythmias and conduction defects are often seen in the perioperative period, but there is only limited evidence as to how they affect surgical risk. In addition to their hemodynamic effects, certain arrhythmias (atrial fibrillation, ventricular tachycardia) often indicate underlying structural heart disease, which requires further evaluation before surgery.

The new guidelines refer the reader to previously published clinical practice guidelines for atrial fibrillation,¹¹ supraventricular arrhythmias,¹² and device-based therapy.¹³

ALGORITHM FOR PREOPERATIVE CARDIAC ASSESSMENT

The new algorithm for evaluating a patient who is known to have coronary artery disease or risk factors for it has seven steps (Figure 1).^{1,11,12,14–17} It differs from the previous algorithm in several details:

• Instead of listing the four active cardiac conditions for which elective surgery should be delayed while the patient is being evaluated and treated (unstable coronary syndrome, decompensated heart failure, significant arrhythmias, severe valvular heart disease), the new version specifically asks about acute coronary syndrome and recommends cardiac evaluation and treatment according to guidelines. A footnote directs readers to other clinical practice guidelines for symptomatic heart failure,¹⁴ valvular heart disease,¹⁵ and arrhythmias.^11,12
• Instead of asking if the procedure is low-risk, the guidelines recommend estimating risk of major adverse cardiac events on the basis of combined clinical and surgical risk and define only two categories: low or elevated. Patients at low risk proceed to surgery with no further testing, as in the earlier algorithm.
• "Excellent" exercise capacity (> 10 metabolic equivalents of task [METs]) is separated from "moderate/good" (4–10 METs), presumably to indicate a stronger recommendation, but patients in both categories proceed to surgery as before.
• If the patient cannot exercise to at least 4 METs, the new algorithm asks whether further testing will affect decision-making or perioperative care (an addition to the previous algorithm). This entails discussing with the patient and perioperative team whether the original surgery will be performed and whether the patient is willing to undergo revascularization if indicated. If so, pharmacologic stress testing is recommended. Previously, this decision also included the number of RCRI factors as well as the type of surgery (vascular or nonvascular).
• If testing will not affect the decision or if the stress test is normal, in addition to recommending proceeding to surgery according to guidelines the new algorithm also lists an option for alternative strategies, including palliation.
• If the stress test is abnormal, especially with left main disease, it recommends coronary revascularization according to the 2011 clinical practice guidelines.^18,19

TESTING FOR LEFT VENTRICULAR DYSFUNCTION OR ISCHEMIA

In patients with dyspnea of unexplained cause or worsening dyspnea, assessment of left ventricular function is reasonable, but this is not part of a routine preoperative evaluation.

Pharmacologic stress testing is reasonable for patients at elevated risk with poor functional capacity if the results will change their management, but it is not useful for patients undergoing low-risk surgery. Although dobutamine stress echocardiography may be slightly superior to pharmacologic myocardial perfusion imaging, there are no head-to-head randomized controlled trials, and the guidelines suggest considering local expertise in deciding which test to use.

The presence of moderate to large areas of ischemia (reversible perfusion defects or new wall-motion abnormalities) is associated with risk of perioperative myocardial infarction or death, whereas evidence of an old infarction is associated with long-term but not short-term risk. The negative predictive value of these tests in predicting postoperative cardiac events is high (> 90%), but the positive predictive value is low.

CORONARY REVASCULARIZATION

Coronary artery bypass grafting and percutaneous coronary intervention

The guidelines recommend coronary revascularization before noncardiac surgery only when it is indicated anyway, on the basis of existing clinical practice guidelines.

Whether performing percutaneous coronary intervention before surgery will reduce perioperative cardiac complications is uncertain, and coronary revascularization should not be routinely performed solely to reduce perioperative cardiac events. The only two randomized controlled trials, Coronary Artery Revascularization Prophylaxis (CARP)²⁰ and DECREASE V²¹ evaluating prophylactic coronary revascularization before noncardiac surgery found no difference in either short-term or long-term outcomes, although subgroup analysis found a survival benefit in patients with left main disease who underwent bypass grafting. Preoperative percutaneous coronary intervention should be limited to patients with left main disease in whom comorbidities preclude bypass surgery and those with unstable coronary disease who may benefit from early invasive management.

The urgency and timing of the noncardiac surgery needs to be taken into account if percutaneous coronary intervention is being considered because of the need for antiplatelet therapy after the procedure, and the potential risks of bleeding and stent thrombosis. If the planned surgery is deemed time-sensitive, then balloon angioplasty or bare-metal stenting is preferred over placement of a drug-eluting stent.

The new guidelines continue to recommend that elective noncardiac surgery be delayed at least 14 days after balloon angioplasty, 30 days after bare-metal stent implantation, and ideally 365 days after drug-eluting stent placement, and reiterate that it is potentially harmful to perform elective surgery within these time frames without any antiplatelet therapy. However, a new class IIb recommendation (benefit ≥ risk) states that "elective noncardiac surgery after [drug-eluting stent] implantation may be considered after 180 days if the risk of further delay is greater than the expected risks of ischemia and stent thrombosis."

This is an important addition to the guidelines because we are often faced with patients needing to undergo surgery in the 6 to 12 months after placement of a drug-eluting stent. Based on previous guidelines, whether it was safe to proceed in this setting created controversy among the perioperative team caring for the patient, and surgery was often delayed unnecessarily. Recent studies^22,23 suggest that the newer drug-eluting stents may require a shorter duration of dual antiplatelet therapy, at least in the nonsurgical setting.

MEDICAL THERAPY

Antiplatelet therapy: Stop or continue?

The risk of perioperative bleeding if antiplatelet drugs are continued must be weighed against the risk of stent thrombosis and ischemia if they are stopped before the recommended duration of therapy. Ideally, some antiplatelet therapy should be continued perioperatively in these situations, but the guidelines recommend that a consensus decision among the treating physicians should be made regarding the relative risks of surgery and discontinuation or continuation of antiplatelet therapy. Whenever possible, aspirin should be continued in these patients.

Although the Perioperative Ischemic Evaluation (POISE)-2 trial²⁴ found that perioperative aspirin use was not associated with lower rates of postoperative myocardial infarction or death, it increased bleeding. Patients with stents who had not completed the recommended duration of antiplatelet therapy were excluded from the trial. Additionally, only 5% of the study patients had undergone percutaneous coronary intervention.

According to the guidelines and package inserts, if antiplatelet agents need to be discontinued before surgery, aspirin can be stopped 3 to 7 days before, clopidogrel and ticagrelor 5 days before, and prasugrel 7 days before. In patients without stents, it may be reasonable to continue aspirin perioperatively if the risk of cardiac events outweighs the risk of bleeding, but starting aspirin is not beneficial for patients undergoing elective noncardiac noncarotid surgery unless the risk of ischemic events outweighs the risk of bleeding.

Beta-blockers

In view of the issue of scientific integrity of the DECREASE trials, a separately commissioned systematic review² of perioperative beta-blocker therapy was performed. This review suggested that giving beta-blockers before surgery was associated with fewer postoperative cardiac events, primarily ischemia and nonfatal myocardial infarction, but few data supported their use to reduce postoperative mortality. Beta-blocker use was associated with adverse outcomes that included bradycardia and stroke. These findings were similar with the inclusion or exclusion of the DECREASE trials in question or of the POISE trial.²⁵

In addition to recommending continuing beta-blockers in patients already on them (class I—the highest recommendation), the guidelines say that it may be reasonable to start them in patients with intermediate- or high-risk ischemia on stress tests as well as in patients with three or more RCRI risk factors (class IIb). In the absence of these indications, initiating beta-blockers preoperatively to reduce risk even in patients with long-term indications is of uncertain benefit. They also recommended starting beta-blockers more than 1 day preoperatively, preferably at least 2 to 7 days before, and note that it was harmful to start them on the day of surgery, particularly at high doses, and with long-acting formulations.

Additionally, there is evidence of differences in outcome within the class of beta-blockers, with the more cardioselective drugs bisoprolol and atenolol being associated with more favorable outcomes than metoprolol in observational studies.

Statins

Multiple observational trials have reported that statins are associated with decreased perioperative morbidity and mortality. Limited evidence from three randomized controlled trials (including two from the discredited DECREASE group) suggests that there is a benefit in patients undergoing vascular surgery, but it is unclear for nonvascular surgery.^26–30

The ACC/AHA guidelines again give a class I recommendation to continue statin therapy perioperatively in patients already taking statins and undergoing noncardiac surgery, as there is some evidence that statin withdrawal is associated with increased risk. The guidelines comment that starting statin therapy perioperatively is reasonable for patients undergoing vascular surgery (class IIa) and may be considered in patients with other clinical guideline indications who are undergoing elevated-risk surgery (class IIb).

The mechanism of this benefit is unclear and may relate to the pleotropic as well as the lipid-lowering effects of the statins. Statins may also have beneficial effects in reducing the incidence of acute kidney injury and postoperative atrial fibrillation.

Whether a particular statin, dose, or time of initiation before surgery affects risk is also unknown at this time. The European guidelines⁶ recommend starting a longer-acting statin ideally at least 2 weeks before surgery for maximal plaque-stabilizing effects.

The risk of statin-induced myopathy, rhabdomyolysis, and hepatic injury appears to be minimal.

Other medications

Of note, the new guidelines do not recommend starting alpha-2 agonists for preventing cardiac events in patients undergoing noncardiac surgery. Despite previous evidence from smaller studies suggesting a benefit, the POISE-2 trial³¹ demonstrated that perioperative use of clonidine did not reduce cardiac events and was associated with a significant increase in hypotension and nonfatal cardiac arrest. However, clonidine should be continued in patients already taking it.

A somewhat surprising recommendation is that it is reasonable to continue angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and if they are held before surgery, to restart them as soon as possible postoperatively (class IIa). The guidelines note reports of increased hypotension associated with induction of anesthesia in patients taking these drugs but also note that there was no change in important postoperative cardiac and other outcomes. Although evidence of harm if these drugs are temporarily discontinued before surgery is sparse, the guidelines advocate continuing them in patients with heart failure or hypertension.

ANESTHESIA AND INTRAOPERATIVE MANAGEMENT

The classes of anesthesia include local, regional (nerve block or neuraxial), monitored anesthesia care (ie, intravenous sedation), and general (volatile agent, total intravenous, or a combination). The guideline committee found no evidence to support the use of neuraxial over general anesthesia, volatile over total intravenous anesthesia, or monitored anesthesia care over general anesthesia. Neuraxial anesthesia for postoperative pain relief in patients undergoing abdominal aortic surgery did reduce the incidence of myocardial infarction.

Heart failure is at least equal to coronary artery disease in terms of risk

The guidelines do not recommend routinely using intraoperative transesophageal echocardiography during noncardiac surgery to screen for cardiac abnormalities or to monitor for myocardial ischemia in patients without risk factors or procedural risks for significant hemodynamic, pulmonary, or neurologic compromise. Only in emergency settings do they deem perioperative transesophageal echocardiography reasonable to determine the cause of hemodynamic instability when it persists despite attempted corrective therapy.

Maintenance of normothermia is reasonable, as studies evaluating hypothermia or use of warmed air did not find a lower rate of cardiac events.^32,33

POSTOPERATIVE SURVEILLANCE

In observational studies, elevated troponin levels, and even detectable levels within the normal range, have been associated with adverse outcomes and predict mortality after noncardiac surgery—the higher the level, the higher the mortality rate.³⁴ Elevated troponins have many potential causes, both cardiac and noncardiac.

An entity termed myocardial injury after noncardiac surgery (MINS)³⁵ was described as prognostically relevant myocardial injury with a troponin T level higher than 0.03 ng/mL in the absence of a nonischemic etiology but not requiring the presence of ischemic features. Patients who had MINS had a higher 30-day mortality rate (9.8% vs 1.1%) and were also at higher risk of nonfatal cardiac arrest, heart failure, and stroke compared with patients who did not.

The guidelines recommend obtaining an electrocardiogram and troponin levels if there are signs or symptoms suggesting myocardial ischemia or infarction. However, despite the association between troponin and mortality, the guidelines state that "the usefulness of postoperative screening with troponin levels (and electrocardiograms) in patients at high risk for perioperative myocardial infarction, but without signs or symptoms suggestive of myocardial ischemia or infarction, is uncertain in the absence of established risks and benefits of a defined management strategy." They also recommend against routinely measuring postoperative troponins in unselected patients without signs or symptoms suggestive of myocardial ischemia or infarction, stating it is not useful for guiding perioperative management.

Although there was a suggestion that patients in the POISE trial³⁶ who suffered postoperative myocardial infarction had better outcomes if they had received aspirin and statins, and another study³⁷ showed that intensification of cardiac therapy in patients with elevated postoperative troponin levels after vascular surgery led to better 1-year outcomes, there are no randomized controlled trials at this time to support any specific plan or intervention.

IMPACT ON CLINICAL PRACTICE: A PERIOPERATIVE HOSPITALIST'S VIEW

Regarding testing

Although the updated guidelines provide some novel concepts in risk stratification, the new algorithm still leaves many patients in a gray zone with respect to noninvasive testing. Patients with heart failure, valvular heart disease, and arrhythmias appear to be somewhat disconnected from the algorithm in this version, and management according to clinical practice guidelines is recommended.

Patients with acute coronary syndrome remain embedded in the algorithm, with recommendations for cardiology evaluation and management according to standard guidelines before proceeding to elective surgery.

The concept of a combined risk based on clinical factors along with the surgical procedure is important, and an alternative to the RCRI factors is offered. However, while this new NSQIP surgical risk calculator is more comprehensive, it may be too time-consuming for routine clinical use and still needs to be externally validated.

There is only limited evidence as to how arrhythmias affect surgical risk

The concept of shared decision-making and team communication is stressed, but the physician may still have difficulty deciding when further testing may influence management. The guidelines remain somewhat vague, and many physicians may be uncomfortable and will continue to look for further guidance in this area.

Without more specific recommendations, this uncertainty may result in more stress tests being ordered—often inappropriately, as they rarely change management. Future prospective studies using biomarkers in conjunction with risk calculators may shed some light on this decision.

The new perioperative guidelines incorporate other ACC/AHA guidelines for valvular heart disease¹⁵ and heart failure.¹⁴ Some of their recommendations, in my opinion, may lead to excessive testing (eg, repeat echocardiograms) that will not change perioperative management.

Regarding revascularization

The ACC/AHA guidelines continue to emphasize the important concept that coronary revascularization is rarely indicated just to get the patient through surgery.

The new guidelines give physicians some leeway in allowing patients with drug-eluting stents to undergo surgery after 6 rather than 12 months of dual antiplatelet therapy if they believe that delaying surgery would place the patient at more risk than that of stent thrombosis. There is evidence in the nonsurgical setting that the newer stents currently being used may require no more than 6 months of therapy. In my opinion it was never clear that there was a statistically significant benefit in delaying surgery more than 6 months after placement of a drug-eluting stent, so this is a welcome addition.

Regarding beta-blockers

The systematic review of beta-blockers reinforces the importance of continuing them preoperatively while downgrading recommendations for their prophylactic use in patients who are not at increased risk.

Although the debate continues, there is no doubt that beta-blockers are associated with a decrease in myocardial ischemia and infarction but an increase in bradycardia and hypotension. They probably are associated with some increased risk of stroke, although this may be related to the specific beta-blocker used as well as the time of initiation before surgery. Evidence of a possible effect on mortality depends on whether the DECREASE and POISE trials are included or excluded in the analysis.

In the absence of new large-scale randomized controlled trials, we are forced to rely on observational trials and expert opinion in the meantime. I think that if a beta-blocker is to be started preoperatively, it should be done at least 1 week before surgery, and a more cardioselective beta-blocker should be used.

Regarding other drugs and tests

I agree with the recommendation to continue ACE inhibitors and ARBs preoperatively in patients with heart failure and poorly controlled hypertension. Although somewhat contrary to current practice, continuance of these drugs has not been associated with an increase in myocardial infarction or death despite concern about intraoperative hypotension.

Data from randomized controlled trials of perioperative statins are limited, but the information from observational studies is favorable, and I see little downside to initiating statins preoperatively in patients who otherwise have indications for their use, particularly if undergoing vascular or other high-risk noncardiac surgery. It is not known whether the specific drug, dose, or timing of initiation of statins influences outcome.

Although multiple studies of biomarkers suggest that there is an association with outcome, there are no randomized controlled trials or specific interventions shown to improve outcome.

Some of the recommended interventions have included various cardiac medications, stress testing, possible coronary angiography, and revascularization, which are not without risk. In the absence of data and following the directive to "first do no harm," the ACC/AHA has been appropriately cautious in not recommending them for routine use at this time.

The updated guidelines have summarized the new evidence in perioperative cardiac evaluation and management. Many of their recommendations were reinforced by this information and remain essentially unchanged. Several new recommendations will lead to changes in management going forward. Unfortunately, we lack the evidence to answer many questions that arise in routine practice and are therefore forced to rely on expert opinion and our clinical judgment in these cases. The ACC/AHA guidelines do provide a framework for our evaluation and management and help keep clinicians up-to-date with the latest evidence.

Statins are among the most widely prescribed drugs, as they reduce cardiovascular risk very effectively. They work by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a key enzyme in cholesterol biosynthesis. Although most patients tolerate statins well, muscle-related toxicity can limit the use of these drugs.

Recently, progressive necrotizing myopathy leading to profound weakness has been directly linked to statin therapy. Proper recognition of this ominous complication is important to prevent further damage from statin use.

STATIN-ASSOCIATED MUSCLE EFFECTS: A SPECTRUM

Muscle symptoms are among the best known and most important side effects of statins, ranging from asymptomatic, mild elevation of creatine kinase and benign myalgias to life-threatening rhabdomyolysis. As the various terms are often used inconsistently in the literature, we will briefly review each entity to put immune-necrotizing myopathy in its proper context on the spectrum of statin-associated muscle symptoms.

Myalgia

Myalgia, ie, muscle pain without elevation of muscle enzymes, is the most common side effect of statins. The incidence is about 10% in observational studies^1,2; however, the incidence in the real world of clinical practice seems much higher. Myalgias can present as widespread pain or as localized pain, usually in the lower extremities. Muscle cramps and tendonitis-related pain are commonly reported.

Most patients tolerate statins well, but muscle toxicity can limit the use of these drugs

Several clinical predictors of increased risk of statin-associated muscle pain were noted in the Prediction of Muscular Risk in Observational Conditions (PRIMO) study,² assessing mild to moderate muscular symptoms in patients on high-dose statins. These included a history of muscle pain with another lipid-lowering agent, a history of cramps, a history of elevated creatine kinase levels, a personal or family history of muscle symptoms, untreated hypothyroidism, and a background of fibromyalgia-like symptoms. The incidence of muscle symptoms  increased with the level of physical activity, and the median time of symptom onset was 1 month after starting statin therapy or titrating to a high dose.

In patients with myalgia alone, symptoms often improve when the statin is stopped.

Myopathy, myositis

The general terms myopathy and myositis have been used to refer to elevated muscle enzymes together with the muscle symptoms of pain, cramps, soreness, or weakness. An analysis of 21 clinical trials of statin therapy found that myopathy (creatine kinase level more than 10 times the upper limit of normal) occurred in 5 patients per 100,000 person-years.³ The incidence of myopathy increases when statins are used in high doses.

In another cohort of patients seen for statin intolerance,¹ conventional risk factors for overt myositis included renal disease, diabetes, and thyroid disease. Electrolyte abnormalities did not differ between statin-tolerant and statin-intolerant patients.¹

The search for genetic indicators of risk

In 2008, the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group conducted a genome-wide association study to identify genetic variants associated with myopathy with high-dose statin therapy.⁴ Eighty-five patients who had developed definite myopathy (muscle symptoms with enzyme levels more than 10 times the upper limit of normal) or incipient myopathy (asymptomatic or symptomatic, but enzyme levels at least three times the upper limit of normal) while taking simvastatin 80 mg were compared with 90 controls taking the same daily dose. The study reported variants in the SLCO1B1 gene as “strongly associated with an increased risk of statin-associated myopathy.”⁴

The C variant of SLCO1B1 increases the risk of myopathy with statins

SLCO1B1 encodes the peptide responsible for hepatic uptake of statins, thus affecting the blood level of these drugs. Patients in the study who had the C variant, which predisposes to higher blood levels of statins, were at higher risk of myopathy than those with the T variant. The odds ratio for myopathy increased from 4.4 in heterozygotes for the C allele to 17.4 for homozygotes. This effect was similar even with lower doses of statins.⁴

We believe that these findings provide a strong basis for genetic testing of patients who may be at risk of statin-associated myopathy.

Rechallenging with a different statin

Often, patients with myopathy can be rechallenged with a different statin agent. In a study done in a lipid clinic, patients identified as having simvastatin-associated myopathy were given another statin.⁵ Between 15% and 42% tolerated the second statin, with no statistically significant difference between the tolerability rates with the different agents used (atorvastatin, rosuvastatin, pravastatin, and fluvastatin).

Rhabdomyolysis

Rhabdomyolysis, the most devastating complication of statin use, is marked by a creatine kinase level more than 10 times the upper limit of normal or greater than 10,000 IU/L, resulting from acute and massive destruction of muscle fibers and release of their contents into the bloodstream.

But rhabdomyolysis is a clinical syndrome, not solely an alarming increase in muscle enzyme levels. It can include renal failure and death. The rate of occurrence is low (1/100,000), but it can occur at any point in treatment.⁶ An analysis of Canadian and US case reports of statin-associated rhabdomyolysis showed an average of 824 cases each year.⁷ A dose-response relationship was observed with higher statin doses.

But statin-associated myopathy may not stop when the drug is stopped

The types of muscle toxicity discussed above stem from direct myotoxic effects of statins and are thought to be related to the blood concentration of the statin.^6,8 They may be limited by genetic susceptibility. Mechanisms may include a change in muscle membrane excitability caused by modulation in membrane cholesterol levels, impaired mitochondrial function and calcium signaling, induction of apoptosis, and increased lipid peroxidation. Stopping the offending drug can often halt these downstream effects—hence the dictum that statin myopathy is self-limiting and should resolve with cessation of the drug.

But as we discuss in the following sections, some patients on statin therapy develop an immune-mediated myopathy that does not resolve with discontinuation of the statin and that may only resolve with immunosuppressive therapy.

STATINS AND AUTOIMMUNE NECROTIZING MYOPATHY

At the Johns Hopkins Myositis Center, a group of patients was identified who had necrotizing myopathy on biopsy but no known underlying condition or associated autoantibodies. In an attempt to establish an autoimmune basis for their disease, the sera from 26 patients were screened for novel antibodies.⁹ Sera from 16 of the patients immunoprecipitated a pair of proteins (sizes 100 kd and 200 kd), indicating these patients had an antibody to these proteins. This finding was highly specific for necrotizing myopathy when compared with controls, ie, other patients with myositis. Patients who had this finding displayed proximal muscle weakness, elevated muscle enzyme levels, and myopathic findings on electromyography; 63% had been exposed to statins before the onset of weakness, and when only patients over age 50 were included, the number rose to 83%.

This association of statins with necrotizing myopathy had been previously noted by two other groups. Needham et al¹⁰ described eight patients who, while on statins, developed myopathy that continued to worsen despite cessation of the drugs. An analysis of their muscle pathology revealed myofiber necrosis with little inflammatory infiltrate, as well as widespread up-regulation of expression of major histocompatibility complex class 1. These patients required immunosuppressive treatment (prednisone and methotrexate) to control their disease.

Grable-Esposito et al¹¹ corroborated this finding by identifying 25 additional patients who developed a similar necrotizing myopathy while on statins.¹¹ They also noted a significantly higher frequency of statin use in patients with necrotizing myopathy than in age-matched controls with polymyositis or inclusion-body myositis.

Anti-HMGCR is highly specific for statin-associated autoimmune necrotizing myopathy

The researchers at the Johns Hopkins Myositis Center noted the similarity between these two patient groups and their own group of patients with necrotizing myopathy. Thus, a follow-up study was done to identify the 100-kg and 200-kd autoantigens observed in their earlier study. Exposure to a statin was found to up-regulate the expression of the two molecules.¹² HMGCR was hypothesized as being the 100-kd antigen, because of its 97-kd molecular weight, and also because statin treatment had already been shown to up-regulate the expression of HMGCR.¹³ The researchers concluded that HMGCR was indeed the 100-kd antigen, with no distinctive antibodies recognizing the 200-kd protein. Although the 200-kd protein was once postulated to be a dimer of the 100-kd protein, its identity remains unknown.

The anti-HMGCR antibody was then screened for in a cohort of 750 myositis patients. The 16 patients previously found to have anti-200/100 were all positive for anti-HMGCR antibody. An additional 45 patients from the cohort (6%) were anti-HMGCR-positive by enzyme-linked immunosorbent assay, and all had necrotizing myopathy. Patients with other types of myopathy, including inflammatory myopathy, do not possess this antibody.¹²

The HMGCR antibody was quite specific for immune-mediated necrotizing myopathy, and this suggested that statins were capable of triggering an immune-mediated myopathy that is then perpetuated even if the drug is discontinued. As it was also demonstrated that statins increase the expression of HMGCR in muscle as well as in regenerating cells, the process may be sustained through persistently increased HMGCR expression associated with muscle repair.¹²

The C allele of the SLCO1B1 gene, which has been associated with statin-associated myopathy, was not increased in this population of patients positive for anti-HMGCR. Follow-up studies of the prevalence of anti-HMGCR in statin users in the Atherosclerosis Risk in Communities (ARIC) cohort, including those with self-limited statin myotoxicity, have also shown the absence of this antibody.¹⁴ This shows that anti-HMGCR is not found in the majority of statin-exposed patients and is highly specific for autoimmune myopathy. This also suggests that statin-associated autoimmune myopathy represents a pathologic process that is distinct from self-limited statin intolerance.

HOW THE CONDITION PRESENTS

Immune-mediated statin myopathy presents similarly to other idiopathic inflammatory myopathies such as polymyositis (Table 1). Symptoms often develop in a subacute to chronic course and can occur at any time with statin treatment. In one study,¹⁰ the average duration of statin use before the onset of weakness was 3 years (range 2 months to 10 years). In some patients whose statin had been stopped because of abnormal creatine kinase levels, weakness developed later, at a range of 0.5 to 20 months. Even low doses of statins (such as 10 mg of simvastatin) have been found to trigger this condition.¹⁰

Patients uniformly develop symmetric proximal arm and leg weakness, and distal weakness can also occur.¹¹ Other features have included dysphagia, arthralgias, myalgias, and Raynaud phenomenon.⁹ Men and women are represented in roughly equal numbers.

The muscle enzymes are strikingly elevated in this disease, with a mean creatine kinase value of 10,333 IU/L at initial presentation.⁹ Although the creatine kinase level may be very elevated, patients often do not present with weakness until a certain threshold value is reached, in contrast with patients with anti-signal recognition particle necrotizing myopathy, who can present with profound weakness at a lower level. Hence, by the time patients are clinically symptomatic, the process may have been going on for some time. Despite the seemingly massive leak in muscle enzymes, the patients do not develop rhabdomyolysis. Inflammatory markers need not be elevated, and an association with other antibodies such as antinuclear antibody is not often seen.

Magnetic resonance imaging of the thigh has shown muscle edema in all patients.⁹ In decreasing order of frequency, other findings are atrophy, fatty replacement, and fascial edema.

Electromyography of involved muscle has shown irritable myopathy in most patients (88%) and nonirritable myopathy in a few.

Muscle biopsy studies have shown prominent necrotic and regenerating fibers without significant inflammatory infiltrate.¹¹ There is also myophagocytosis of necrotic fibers and diffuse or focal up-regulation of major histocompatability complex class I expression.¹⁰

PATIENTS WITH ANTI-HMGCR WHO HAVE AND WHO HAVE NEVER TAKEN STATINS

When the anti-HMGCR antibody was tested for in the Johns Hopkins cohort,¹² 33% of patients with a necrotizing myopathy associated with this antibody had never taken a statin. The two groups were clinically indistinguishable, save for a few aspects. Compared with patients who had taken a statin, those who had never taken a statin were younger (mean age 37 vs 59), had higher levels of creatine kinase (13,392 vs 7,881 IU/L), and had a different race distribution (46.7% vs 86.7% white). Initial HMGCR antibody levels were also noted to correlate with creatine kinase levels and strength in statin-exposed patients but not in those who had never taken a statin.¹⁵

We hypothesize that in patients who have never taken a statin, other genetic or environmental factors may be the cause of the increased HMGCR expression, which then triggers the autoimmune response. Until further data are gathered, we should probably treat these patients as we treat those who develop this disease after taking a statin, and avoid giving them statins altogether.

MANAGEMENT OF STATIN-ASSOCIATED AUTOIMMUNE NECROTIZING MYOPATHY

Treatment of statin-associated autoimmune necrotizing myopathy can be challenging and requires immunosuppressive drugs.

Statin therapy should be stopped once this condition is suspected. Patients who continue to have elevated muscle enzymes or weakness should undergo further testing with electromyography, magnetic resonance imaging, and muscle biopsy. Electromyography detects myopathy and shows chronicity, distribution, and degree of severity. Although not necessary for diagnosis, magnetic resonance imaging helps to evaluate the extent of muscle involvement and damage and provides guidance when choosing a site for muscle biopsy. Muscle biopsy is necessary to determine the actual pathology and to exclude mimics such as dystrophy or metabolic myopathies.

When an immune-mediated myopathy is confirmed, prompt referral to a rheumatologist or a neuromuscular specialist is recommended.

Steroids are usually the first-line treatment for this disease

Steroids are usually the first-line treatment for this disease. Other immunosuppressives, such as methotrexate, azathioprine, mycophenolate mofetil, and rituximab have been used with varying levels of success. In our experience, intravenous immunoglobulin has been particularly beneficial for refractory cases. With treatment, muscle enzyme levels and weakness improve, but relapses can occur. The ideal choice of immunosuppressive therapy and the duration of therapy are currently under investigation.

Rechallenge with another statin

At this time, the issue of rechallenging the patient with another statin has not been clarified. Given the autoimmune nature of the disease, we would avoid exposing the patient to a known trigger. However, this may be a difficult decision in patients with cardiovascular risk factors who require statins for primary or secondary prevention. We suggest using alternative cholesterol-lowering agents first and using them in combination if needed.

We have had some success in maintaining a handful of patients on a statin while treating them concurrently with immunosuppression. This is not ideal because they are constantly being exposed to the likely trigger for their disease, but it may be unavoidable if statins are deemed absolutely necessary. We have also had a patient with known statin-associated immune-mediated necrotizing myopathy who later became profoundly weak after another physician started her on a newer-generation agent, pitavastatin. This suggests to us that rechallenging patients, even with a different statin, can have deleterious effects.

IMPLICATIONS FOR CLINICAL PRACTICE

The true prevalence of statin-associated autoimmune myopathy in practice is unknown. In the Johns Hopkins Myositis Center cohort of patients with suspected myopathy, anti-HMGCR was found in 6% of the patients and was the second most frequent antibody found after anti-Jo1.¹²

Given the frequency of muscle-related complaints in patients on statins, we recommend obtaining baseline muscle enzyme measurements before starting statin therapy. As recommended by the National Lipid Association Statin Safety Assessment Task Force, the creatine kinase level should be measured when a patient develops muscular complaints, to help gauge the severity of the disease and to help decide whether to continue therapy.⁸ Random testing of the creatine kinase level in asymptomatic patients is not recommended.

At present, the diagnosis of statin-associated autoimmune necrotizing myopathy is based on a combination of findings—elevated muscle enzyme levels, muscle weakness, irritable findings on electromyography, and necrotizing myopathy on biopsy in a patient on a statin. The finding of the HMGCR antibody confirms the diagnosis. A test for this antibody is now commercially available in the United States. We suggest testing for the antibody in the following scenarios:

• A persistently elevated or rising creatine kinase, aspartate aminotransferase, alanine aminotransferase, or aldolase level after the statin is stopped; although no fixed creatine kinase level has been determined, a level above 1,000 U/L would be a reasonable cutoff at which to test
• Muscle symptoms (proximal or distal weakness) that persist 12 weeks after statin cessation regardless of the creatine kinase level, especially if the patient has dysphagia
• The finding of muscle irritability on electromyography or diffuse muscle edema on magnetic resonance imaging when testing for other myositis-specific antibodies is negative
• Muscle biopsy showing necrotizing myopathy with little or no inflammation.

In addition, since necrotizing myopathy is known to be associated with malignancy and since necrotizing myopathy is more common in older people, who are also more likely to be taking a statin, an age-appropriate malignancy evaluation is warranted as well.

Statins are among the most widely prescribed drugs, as they reduce cardiovascular risk very effectively. They work by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a key enzyme in cholesterol biosynthesis. Although most patients tolerate statins well, muscle-related toxicity can limit the use of these drugs.

Recently, progressive necrotizing myopathy leading to profound weakness has been directly linked to statin therapy. Proper recognition of this ominous complication is important to prevent further damage from statin use.

STATIN-ASSOCIATED MUSCLE EFFECTS: A SPECTRUM

Muscle symptoms are among the best known and most important side effects of statins, ranging from asymptomatic, mild elevation of creatine kinase and benign myalgias to life-threatening rhabdomyolysis. As the various terms are often used inconsistently in the literature, we will briefly review each entity to put immune-necrotizing myopathy in its proper context on the spectrum of statin-associated muscle symptoms.

Myalgia

Myalgia, ie, muscle pain without elevation of muscle enzymes, is the most common side effect of statins. The incidence is about 10% in observational studies^1,2; however, the incidence in the real world of clinical practice seems much higher. Myalgias can present as widespread pain or as localized pain, usually in the lower extremities. Muscle cramps and tendonitis-related pain are commonly reported.

Most patients tolerate statins well, but muscle toxicity can limit the use of these drugs

Several clinical predictors of increased risk of statin-associated muscle pain were noted in the Prediction of Muscular Risk in Observational Conditions (PRIMO) study,² assessing mild to moderate muscular symptoms in patients on high-dose statins. These included a history of muscle pain with another lipid-lowering agent, a history of cramps, a history of elevated creatine kinase levels, a personal or family history of muscle symptoms, untreated hypothyroidism, and a background of fibromyalgia-like symptoms. The incidence of muscle symptoms  increased with the level of physical activity, and the median time of symptom onset was 1 month after starting statin therapy or titrating to a high dose.

In patients with myalgia alone, symptoms often improve when the statin is stopped.

Myopathy, myositis

The general terms myopathy and myositis have been used to refer to elevated muscle enzymes together with the muscle symptoms of pain, cramps, soreness, or weakness. An analysis of 21 clinical trials of statin therapy found that myopathy (creatine kinase level more than 10 times the upper limit of normal) occurred in 5 patients per 100,000 person-years.³ The incidence of myopathy increases when statins are used in high doses.

In another cohort of patients seen for statin intolerance,¹ conventional risk factors for overt myositis included renal disease, diabetes, and thyroid disease. Electrolyte abnormalities did not differ between statin-tolerant and statin-intolerant patients.¹

The search for genetic indicators of risk

In 2008, the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group conducted a genome-wide association study to identify genetic variants associated with myopathy with high-dose statin therapy.⁴ Eighty-five patients who had developed definite myopathy (muscle symptoms with enzyme levels more than 10 times the upper limit of normal) or incipient myopathy (asymptomatic or symptomatic, but enzyme levels at least three times the upper limit of normal) while taking simvastatin 80 mg were compared with 90 controls taking the same daily dose. The study reported variants in the SLCO1B1 gene as “strongly associated with an increased risk of statin-associated myopathy.”⁴

The C variant of SLCO1B1 increases the risk of myopathy with statins

SLCO1B1 encodes the peptide responsible for hepatic uptake of statins, thus affecting the blood level of these drugs. Patients in the study who had the C variant, which predisposes to higher blood levels of statins, were at higher risk of myopathy than those with the T variant. The odds ratio for myopathy increased from 4.4 in heterozygotes for the C allele to 17.4 for homozygotes. This effect was similar even with lower doses of statins.⁴

We believe that these findings provide a strong basis for genetic testing of patients who may be at risk of statin-associated myopathy.

Rechallenging with a different statin

Often, patients with myopathy can be rechallenged with a different statin agent. In a study done in a lipid clinic, patients identified as having simvastatin-associated myopathy were given another statin.⁵ Between 15% and 42% tolerated the second statin, with no statistically significant difference between the tolerability rates with the different agents used (atorvastatin, rosuvastatin, pravastatin, and fluvastatin).

Rhabdomyolysis

Rhabdomyolysis, the most devastating complication of statin use, is marked by a creatine kinase level more than 10 times the upper limit of normal or greater than 10,000 IU/L, resulting from acute and massive destruction of muscle fibers and release of their contents into the bloodstream.

But rhabdomyolysis is a clinical syndrome, not solely an alarming increase in muscle enzyme levels. It can include renal failure and death. The rate of occurrence is low (1/100,000), but it can occur at any point in treatment.⁶ An analysis of Canadian and US case reports of statin-associated rhabdomyolysis showed an average of 824 cases each year.⁷ A dose-response relationship was observed with higher statin doses.

But statin-associated myopathy may not stop when the drug is stopped

The types of muscle toxicity discussed above stem from direct myotoxic effects of statins and are thought to be related to the blood concentration of the statin.^6,8 They may be limited by genetic susceptibility. Mechanisms may include a change in muscle membrane excitability caused by modulation in membrane cholesterol levels, impaired mitochondrial function and calcium signaling, induction of apoptosis, and increased lipid peroxidation. Stopping the offending drug can often halt these downstream effects—hence the dictum that statin myopathy is self-limiting and should resolve with cessation of the drug.

But as we discuss in the following sections, some patients on statin therapy develop an immune-mediated myopathy that does not resolve with discontinuation of the statin and that may only resolve with immunosuppressive therapy.

STATINS AND AUTOIMMUNE NECROTIZING MYOPATHY

At the Johns Hopkins Myositis Center, a group of patients was identified who had necrotizing myopathy on biopsy but no known underlying condition or associated autoantibodies. In an attempt to establish an autoimmune basis for their disease, the sera from 26 patients were screened for novel antibodies.⁹ Sera from 16 of the patients immunoprecipitated a pair of proteins (sizes 100 kd and 200 kd), indicating these patients had an antibody to these proteins. This finding was highly specific for necrotizing myopathy when compared with controls, ie, other patients with myositis. Patients who had this finding displayed proximal muscle weakness, elevated muscle enzyme levels, and myopathic findings on electromyography; 63% had been exposed to statins before the onset of weakness, and when only patients over age 50 were included, the number rose to 83%.

This association of statins with necrotizing myopathy had been previously noted by two other groups. Needham et al¹⁰ described eight patients who, while on statins, developed myopathy that continued to worsen despite cessation of the drugs. An analysis of their muscle pathology revealed myofiber necrosis with little inflammatory infiltrate, as well as widespread up-regulation of expression of major histocompatibility complex class 1. These patients required immunosuppressive treatment (prednisone and methotrexate) to control their disease.

Grable-Esposito et al¹¹ corroborated this finding by identifying 25 additional patients who developed a similar necrotizing myopathy while on statins.¹¹ They also noted a significantly higher frequency of statin use in patients with necrotizing myopathy than in age-matched controls with polymyositis or inclusion-body myositis.

Anti-HMGCR is highly specific for statin-associated autoimmune necrotizing myopathy

The researchers at the Johns Hopkins Myositis Center noted the similarity between these two patient groups and their own group of patients with necrotizing myopathy. Thus, a follow-up study was done to identify the 100-kg and 200-kd autoantigens observed in their earlier study. Exposure to a statin was found to up-regulate the expression of the two molecules.¹² HMGCR was hypothesized as being the 100-kd antigen, because of its 97-kd molecular weight, and also because statin treatment had already been shown to up-regulate the expression of HMGCR.¹³ The researchers concluded that HMGCR was indeed the 100-kd antigen, with no distinctive antibodies recognizing the 200-kd protein. Although the 200-kd protein was once postulated to be a dimer of the 100-kd protein, its identity remains unknown.

The anti-HMGCR antibody was then screened for in a cohort of 750 myositis patients. The 16 patients previously found to have anti-200/100 were all positive for anti-HMGCR antibody. An additional 45 patients from the cohort (6%) were anti-HMGCR-positive by enzyme-linked immunosorbent assay, and all had necrotizing myopathy. Patients with other types of myopathy, including inflammatory myopathy, do not possess this antibody.¹²

The HMGCR antibody was quite specific for immune-mediated necrotizing myopathy, and this suggested that statins were capable of triggering an immune-mediated myopathy that is then perpetuated even if the drug is discontinued. As it was also demonstrated that statins increase the expression of HMGCR in muscle as well as in regenerating cells, the process may be sustained through persistently increased HMGCR expression associated with muscle repair.¹²

The C allele of the SLCO1B1 gene, which has been associated with statin-associated myopathy, was not increased in this population of patients positive for anti-HMGCR. Follow-up studies of the prevalence of anti-HMGCR in statin users in the Atherosclerosis Risk in Communities (ARIC) cohort, including those with self-limited statin myotoxicity, have also shown the absence of this antibody.¹⁴ This shows that anti-HMGCR is not found in the majority of statin-exposed patients and is highly specific for autoimmune myopathy. This also suggests that statin-associated autoimmune myopathy represents a pathologic process that is distinct from self-limited statin intolerance.

HOW THE CONDITION PRESENTS

Immune-mediated statin myopathy presents similarly to other idiopathic inflammatory myopathies such as polymyositis (Table 1). Symptoms often develop in a subacute to chronic course and can occur at any time with statin treatment. In one study,¹⁰ the average duration of statin use before the onset of weakness was 3 years (range 2 months to 10 years). In some patients whose statin had been stopped because of abnormal creatine kinase levels, weakness developed later, at a range of 0.5 to 20 months. Even low doses of statins (such as 10 mg of simvastatin) have been found to trigger this condition.¹⁰

Patients uniformly develop symmetric proximal arm and leg weakness, and distal weakness can also occur.¹¹ Other features have included dysphagia, arthralgias, myalgias, and Raynaud phenomenon.⁹ Men and women are represented in roughly equal numbers.

The muscle enzymes are strikingly elevated in this disease, with a mean creatine kinase value of 10,333 IU/L at initial presentation.⁹ Although the creatine kinase level may be very elevated, patients often do not present with weakness until a certain threshold value is reached, in contrast with patients with anti-signal recognition particle necrotizing myopathy, who can present with profound weakness at a lower level. Hence, by the time patients are clinically symptomatic, the process may have been going on for some time. Despite the seemingly massive leak in muscle enzymes, the patients do not develop rhabdomyolysis. Inflammatory markers need not be elevated, and an association with other antibodies such as antinuclear antibody is not often seen.

Magnetic resonance imaging of the thigh has shown muscle edema in all patients.⁹ In decreasing order of frequency, other findings are atrophy, fatty replacement, and fascial edema.

Electromyography of involved muscle has shown irritable myopathy in most patients (88%) and nonirritable myopathy in a few.

Muscle biopsy studies have shown prominent necrotic and regenerating fibers without significant inflammatory infiltrate.¹¹ There is also myophagocytosis of necrotic fibers and diffuse or focal up-regulation of major histocompatability complex class I expression.¹⁰

PATIENTS WITH ANTI-HMGCR WHO HAVE AND WHO HAVE NEVER TAKEN STATINS

When the anti-HMGCR antibody was tested for in the Johns Hopkins cohort,¹² 33% of patients with a necrotizing myopathy associated with this antibody had never taken a statin. The two groups were clinically indistinguishable, save for a few aspects. Compared with patients who had taken a statin, those who had never taken a statin were younger (mean age 37 vs 59), had higher levels of creatine kinase (13,392 vs 7,881 IU/L), and had a different race distribution (46.7% vs 86.7% white). Initial HMGCR antibody levels were also noted to correlate with creatine kinase levels and strength in statin-exposed patients but not in those who had never taken a statin.¹⁵

We hypothesize that in patients who have never taken a statin, other genetic or environmental factors may be the cause of the increased HMGCR expression, which then triggers the autoimmune response. Until further data are gathered, we should probably treat these patients as we treat those who develop this disease after taking a statin, and avoid giving them statins altogether.

MANAGEMENT OF STATIN-ASSOCIATED AUTOIMMUNE NECROTIZING MYOPATHY

Treatment of statin-associated autoimmune necrotizing myopathy can be challenging and requires immunosuppressive drugs.

Statin therapy should be stopped once this condition is suspected. Patients who continue to have elevated muscle enzymes or weakness should undergo further testing with electromyography, magnetic resonance imaging, and muscle biopsy. Electromyography detects myopathy and shows chronicity, distribution, and degree of severity. Although not necessary for diagnosis, magnetic resonance imaging helps to evaluate the extent of muscle involvement and damage and provides guidance when choosing a site for muscle biopsy. Muscle biopsy is necessary to determine the actual pathology and to exclude mimics such as dystrophy or metabolic myopathies.

When an immune-mediated myopathy is confirmed, prompt referral to a rheumatologist or a neuromuscular specialist is recommended.

Steroids are usually the first-line treatment for this disease

Steroids are usually the first-line treatment for this disease. Other immunosuppressives, such as methotrexate, azathioprine, mycophenolate mofetil, and rituximab have been used with varying levels of success. In our experience, intravenous immunoglobulin has been particularly beneficial for refractory cases. With treatment, muscle enzyme levels and weakness improve, but relapses can occur. The ideal choice of immunosuppressive therapy and the duration of therapy are currently under investigation.

Rechallenge with another statin

At this time, the issue of rechallenging the patient with another statin has not been clarified. Given the autoimmune nature of the disease, we would avoid exposing the patient to a known trigger. However, this may be a difficult decision in patients with cardiovascular risk factors who require statins for primary or secondary prevention. We suggest using alternative cholesterol-lowering agents first and using them in combination if needed.

We have had some success in maintaining a handful of patients on a statin while treating them concurrently with immunosuppression. This is not ideal because they are constantly being exposed to the likely trigger for their disease, but it may be unavoidable if statins are deemed absolutely necessary. We have also had a patient with known statin-associated immune-mediated necrotizing myopathy who later became profoundly weak after another physician started her on a newer-generation agent, pitavastatin. This suggests to us that rechallenging patients, even with a different statin, can have deleterious effects.

IMPLICATIONS FOR CLINICAL PRACTICE

The true prevalence of statin-associated autoimmune myopathy in practice is unknown. In the Johns Hopkins Myositis Center cohort of patients with suspected myopathy, anti-HMGCR was found in 6% of the patients and was the second most frequent antibody found after anti-Jo1.¹²

Given the frequency of muscle-related complaints in patients on statins, we recommend obtaining baseline muscle enzyme measurements before starting statin therapy. As recommended by the National Lipid Association Statin Safety Assessment Task Force, the creatine kinase level should be measured when a patient develops muscular complaints, to help gauge the severity of the disease and to help decide whether to continue therapy.⁸ Random testing of the creatine kinase level in asymptomatic patients is not recommended.

At present, the diagnosis of statin-associated autoimmune necrotizing myopathy is based on a combination of findings—elevated muscle enzyme levels, muscle weakness, irritable findings on electromyography, and necrotizing myopathy on biopsy in a patient on a statin. The finding of the HMGCR antibody confirms the diagnosis. A test for this antibody is now commercially available in the United States. We suggest testing for the antibody in the following scenarios:

• A persistently elevated or rising creatine kinase, aspartate aminotransferase, alanine aminotransferase, or aldolase level after the statin is stopped; although no fixed creatine kinase level has been determined, a level above 1,000 U/L would be a reasonable cutoff at which to test
• Muscle symptoms (proximal or distal weakness) that persist 12 weeks after statin cessation regardless of the creatine kinase level, especially if the patient has dysphagia
• The finding of muscle irritability on electromyography or diffuse muscle edema on magnetic resonance imaging when testing for other myositis-specific antibodies is negative
• Muscle biopsy showing necrotizing myopathy with little or no inflammation.

In addition, since necrotizing myopathy is known to be associated with malignancy and since necrotizing myopathy is more common in older people, who are also more likely to be taking a statin, an age-appropriate malignancy evaluation is warranted as well.

Statins are among the most widely prescribed drugs, as they reduce cardiovascular risk very effectively. They work by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a key enzyme in cholesterol biosynthesis. Although most patients tolerate statins well, muscle-related toxicity can limit the use of these drugs.

Recently, progressive necrotizing myopathy leading to profound weakness has been directly linked to statin therapy. Proper recognition of this ominous complication is important to prevent further damage from statin use.

STATIN-ASSOCIATED MUSCLE EFFECTS: A SPECTRUM

Muscle symptoms are among the best known and most important side effects of statins, ranging from asymptomatic, mild elevation of creatine kinase and benign myalgias to life-threatening rhabdomyolysis. As the various terms are often used inconsistently in the literature, we will briefly review each entity to put immune-necrotizing myopathy in its proper context on the spectrum of statin-associated muscle symptoms.

Myalgia

Myalgia, ie, muscle pain without elevation of muscle enzymes, is the most common side effect of statins. The incidence is about 10% in observational studies^1,2; however, the incidence in the real world of clinical practice seems much higher. Myalgias can present as widespread pain or as localized pain, usually in the lower extremities. Muscle cramps and tendonitis-related pain are commonly reported.

Most patients tolerate statins well, but muscle toxicity can limit the use of these drugs

Several clinical predictors of increased risk of statin-associated muscle pain were noted in the Prediction of Muscular Risk in Observational Conditions (PRIMO) study,² assessing mild to moderate muscular symptoms in patients on high-dose statins. These included a history of muscle pain with another lipid-lowering agent, a history of cramps, a history of elevated creatine kinase levels, a personal or family history of muscle symptoms, untreated hypothyroidism, and a background of fibromyalgia-like symptoms. The incidence of muscle symptoms  increased with the level of physical activity, and the median time of symptom onset was 1 month after starting statin therapy or titrating to a high dose.

In patients with myalgia alone, symptoms often improve when the statin is stopped.

Myopathy, myositis

The general terms myopathy and myositis have been used to refer to elevated muscle enzymes together with the muscle symptoms of pain, cramps, soreness, or weakness. An analysis of 21 clinical trials of statin therapy found that myopathy (creatine kinase level more than 10 times the upper limit of normal) occurred in 5 patients per 100,000 person-years.³ The incidence of myopathy increases when statins are used in high doses.

In another cohort of patients seen for statin intolerance,¹ conventional risk factors for overt myositis included renal disease, diabetes, and thyroid disease. Electrolyte abnormalities did not differ between statin-tolerant and statin-intolerant patients.¹

The search for genetic indicators of risk

In 2008, the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group conducted a genome-wide association study to identify genetic variants associated with myopathy with high-dose statin therapy.⁴ Eighty-five patients who had developed definite myopathy (muscle symptoms with enzyme levels more than 10 times the upper limit of normal) or incipient myopathy (asymptomatic or symptomatic, but enzyme levels at least three times the upper limit of normal) while taking simvastatin 80 mg were compared with 90 controls taking the same daily dose. The study reported variants in the SLCO1B1 gene as “strongly associated with an increased risk of statin-associated myopathy.”⁴

The C variant of SLCO1B1 increases the risk of myopathy with statins

SLCO1B1 encodes the peptide responsible for hepatic uptake of statins, thus affecting the blood level of these drugs. Patients in the study who had the C variant, which predisposes to higher blood levels of statins, were at higher risk of myopathy than those with the T variant. The odds ratio for myopathy increased from 4.4 in heterozygotes for the C allele to 17.4 for homozygotes. This effect was similar even with lower doses of statins.⁴

We believe that these findings provide a strong basis for genetic testing of patients who may be at risk of statin-associated myopathy.

Rechallenging with a different statin

Often, patients with myopathy can be rechallenged with a different statin agent. In a study done in a lipid clinic, patients identified as having simvastatin-associated myopathy were given another statin.⁵ Between 15% and 42% tolerated the second statin, with no statistically significant difference between the tolerability rates with the different agents used (atorvastatin, rosuvastatin, pravastatin, and fluvastatin).

Rhabdomyolysis

Rhabdomyolysis, the most devastating complication of statin use, is marked by a creatine kinase level more than 10 times the upper limit of normal or greater than 10,000 IU/L, resulting from acute and massive destruction of muscle fibers and release of their contents into the bloodstream.

But rhabdomyolysis is a clinical syndrome, not solely an alarming increase in muscle enzyme levels. It can include renal failure and death. The rate of occurrence is low (1/100,000), but it can occur at any point in treatment.⁶ An analysis of Canadian and US case reports of statin-associated rhabdomyolysis showed an average of 824 cases each year.⁷ A dose-response relationship was observed with higher statin doses.

But statin-associated myopathy may not stop when the drug is stopped

The types of muscle toxicity discussed above stem from direct myotoxic effects of statins and are thought to be related to the blood concentration of the statin.^6,8 They may be limited by genetic susceptibility. Mechanisms may include a change in muscle membrane excitability caused by modulation in membrane cholesterol levels, impaired mitochondrial function and calcium signaling, induction of apoptosis, and increased lipid peroxidation. Stopping the offending drug can often halt these downstream effects—hence the dictum that statin myopathy is self-limiting and should resolve with cessation of the drug.

But as we discuss in the following sections, some patients on statin therapy develop an immune-mediated myopathy that does not resolve with discontinuation of the statin and that may only resolve with immunosuppressive therapy.

STATINS AND AUTOIMMUNE NECROTIZING MYOPATHY

At the Johns Hopkins Myositis Center, a group of patients was identified who had necrotizing myopathy on biopsy but no known underlying condition or associated autoantibodies. In an attempt to establish an autoimmune basis for their disease, the sera from 26 patients were screened for novel antibodies.⁹ Sera from 16 of the patients immunoprecipitated a pair of proteins (sizes 100 kd and 200 kd), indicating these patients had an antibody to these proteins. This finding was highly specific for necrotizing myopathy when compared with controls, ie, other patients with myositis. Patients who had this finding displayed proximal muscle weakness, elevated muscle enzyme levels, and myopathic findings on electromyography; 63% had been exposed to statins before the onset of weakness, and when only patients over age 50 were included, the number rose to 83%.

This association of statins with necrotizing myopathy had been previously noted by two other groups. Needham et al¹⁰ described eight patients who, while on statins, developed myopathy that continued to worsen despite cessation of the drugs. An analysis of their muscle pathology revealed myofiber necrosis with little inflammatory infiltrate, as well as widespread up-regulation of expression of major histocompatibility complex class 1. These patients required immunosuppressive treatment (prednisone and methotrexate) to control their disease.

Grable-Esposito et al¹¹ corroborated this finding by identifying 25 additional patients who developed a similar necrotizing myopathy while on statins.¹¹ They also noted a significantly higher frequency of statin use in patients with necrotizing myopathy than in age-matched controls with polymyositis or inclusion-body myositis.

Anti-HMGCR is highly specific for statin-associated autoimmune necrotizing myopathy

The researchers at the Johns Hopkins Myositis Center noted the similarity between these two patient groups and their own group of patients with necrotizing myopathy. Thus, a follow-up study was done to identify the 100-kg and 200-kd autoantigens observed in their earlier study. Exposure to a statin was found to up-regulate the expression of the two molecules.¹² HMGCR was hypothesized as being the 100-kd antigen, because of its 97-kd molecular weight, and also because statin treatment had already been shown to up-regulate the expression of HMGCR.¹³ The researchers concluded that HMGCR was indeed the 100-kd antigen, with no distinctive antibodies recognizing the 200-kd protein. Although the 200-kd protein was once postulated to be a dimer of the 100-kd protein, its identity remains unknown.

The anti-HMGCR antibody was then screened for in a cohort of 750 myositis patients. The 16 patients previously found to have anti-200/100 were all positive for anti-HMGCR antibody. An additional 45 patients from the cohort (6%) were anti-HMGCR-positive by enzyme-linked immunosorbent assay, and all had necrotizing myopathy. Patients with other types of myopathy, including inflammatory myopathy, do not possess this antibody.¹²

The HMGCR antibody was quite specific for immune-mediated necrotizing myopathy, and this suggested that statins were capable of triggering an immune-mediated myopathy that is then perpetuated even if the drug is discontinued. As it was also demonstrated that statins increase the expression of HMGCR in muscle as well as in regenerating cells, the process may be sustained through persistently increased HMGCR expression associated with muscle repair.¹²

The C allele of the SLCO1B1 gene, which has been associated with statin-associated myopathy, was not increased in this population of patients positive for anti-HMGCR. Follow-up studies of the prevalence of anti-HMGCR in statin users in the Atherosclerosis Risk in Communities (ARIC) cohort, including those with self-limited statin myotoxicity, have also shown the absence of this antibody.¹⁴ This shows that anti-HMGCR is not found in the majority of statin-exposed patients and is highly specific for autoimmune myopathy. This also suggests that statin-associated autoimmune myopathy represents a pathologic process that is distinct from self-limited statin intolerance.

HOW THE CONDITION PRESENTS

Immune-mediated statin myopathy presents similarly to other idiopathic inflammatory myopathies such as polymyositis (Table 1). Symptoms often develop in a subacute to chronic course and can occur at any time with statin treatment. In one study,¹⁰ the average duration of statin use before the onset of weakness was 3 years (range 2 months to 10 years). In some patients whose statin had been stopped because of abnormal creatine kinase levels, weakness developed later, at a range of 0.5 to 20 months. Even low doses of statins (such as 10 mg of simvastatin) have been found to trigger this condition.¹⁰

Patients uniformly develop symmetric proximal arm and leg weakness, and distal weakness can also occur.¹¹ Other features have included dysphagia, arthralgias, myalgias, and Raynaud phenomenon.⁹ Men and women are represented in roughly equal numbers.

The muscle enzymes are strikingly elevated in this disease, with a mean creatine kinase value of 10,333 IU/L at initial presentation.⁹ Although the creatine kinase level may be very elevated, patients often do not present with weakness until a certain threshold value is reached, in contrast with patients with anti-signal recognition particle necrotizing myopathy, who can present with profound weakness at a lower level. Hence, by the time patients are clinically symptomatic, the process may have been going on for some time. Despite the seemingly massive leak in muscle enzymes, the patients do not develop rhabdomyolysis. Inflammatory markers need not be elevated, and an association with other antibodies such as antinuclear antibody is not often seen.

Magnetic resonance imaging of the thigh has shown muscle edema in all patients.⁹ In decreasing order of frequency, other findings are atrophy, fatty replacement, and fascial edema.

Electromyography of involved muscle has shown irritable myopathy in most patients (88%) and nonirritable myopathy in a few.

Muscle biopsy studies have shown prominent necrotic and regenerating fibers without significant inflammatory infiltrate.¹¹ There is also myophagocytosis of necrotic fibers and diffuse or focal up-regulation of major histocompatability complex class I expression.¹⁰

PATIENTS WITH ANTI-HMGCR WHO HAVE AND WHO HAVE NEVER TAKEN STATINS

When the anti-HMGCR antibody was tested for in the Johns Hopkins cohort,¹² 33% of patients with a necrotizing myopathy associated with this antibody had never taken a statin. The two groups were clinically indistinguishable, save for a few aspects. Compared with patients who had taken a statin, those who had never taken a statin were younger (mean age 37 vs 59), had higher levels of creatine kinase (13,392 vs 7,881 IU/L), and had a different race distribution (46.7% vs 86.7% white). Initial HMGCR antibody levels were also noted to correlate with creatine kinase levels and strength in statin-exposed patients but not in those who had never taken a statin.¹⁵

We hypothesize that in patients who have never taken a statin, other genetic or environmental factors may be the cause of the increased HMGCR expression, which then triggers the autoimmune response. Until further data are gathered, we should probably treat these patients as we treat those who develop this disease after taking a statin, and avoid giving them statins altogether.

MANAGEMENT OF STATIN-ASSOCIATED AUTOIMMUNE NECROTIZING MYOPATHY

Treatment of statin-associated autoimmune necrotizing myopathy can be challenging and requires immunosuppressive drugs.

Statin therapy should be stopped once this condition is suspected. Patients who continue to have elevated muscle enzymes or weakness should undergo further testing with electromyography, magnetic resonance imaging, and muscle biopsy. Electromyography detects myopathy and shows chronicity, distribution, and degree of severity. Although not necessary for diagnosis, magnetic resonance imaging helps to evaluate the extent of muscle involvement and damage and provides guidance when choosing a site for muscle biopsy. Muscle biopsy is necessary to determine the actual pathology and to exclude mimics such as dystrophy or metabolic myopathies.

When an immune-mediated myopathy is confirmed, prompt referral to a rheumatologist or a neuromuscular specialist is recommended.

Steroids are usually the first-line treatment for this disease

Steroids are usually the first-line treatment for this disease. Other immunosuppressives, such as methotrexate, azathioprine, mycophenolate mofetil, and rituximab have been used with varying levels of success. In our experience, intravenous immunoglobulin has been particularly beneficial for refractory cases. With treatment, muscle enzyme levels and weakness improve, but relapses can occur. The ideal choice of immunosuppressive therapy and the duration of therapy are currently under investigation.

Rechallenge with another statin

At this time, the issue of rechallenging the patient with another statin has not been clarified. Given the autoimmune nature of the disease, we would avoid exposing the patient to a known trigger. However, this may be a difficult decision in patients with cardiovascular risk factors who require statins for primary or secondary prevention. We suggest using alternative cholesterol-lowering agents first and using them in combination if needed.

We have had some success in maintaining a handful of patients on a statin while treating them concurrently with immunosuppression. This is not ideal because they are constantly being exposed to the likely trigger for their disease, but it may be unavoidable if statins are deemed absolutely necessary. We have also had a patient with known statin-associated immune-mediated necrotizing myopathy who later became profoundly weak after another physician started her on a newer-generation agent, pitavastatin. This suggests to us that rechallenging patients, even with a different statin, can have deleterious effects.

IMPLICATIONS FOR CLINICAL PRACTICE

The true prevalence of statin-associated autoimmune myopathy in practice is unknown. In the Johns Hopkins Myositis Center cohort of patients with suspected myopathy, anti-HMGCR was found in 6% of the patients and was the second most frequent antibody found after anti-Jo1.¹²

Given the frequency of muscle-related complaints in patients on statins, we recommend obtaining baseline muscle enzyme measurements before starting statin therapy. As recommended by the National Lipid Association Statin Safety Assessment Task Force, the creatine kinase level should be measured when a patient develops muscular complaints, to help gauge the severity of the disease and to help decide whether to continue therapy.⁸ Random testing of the creatine kinase level in asymptomatic patients is not recommended.

At present, the diagnosis of statin-associated autoimmune necrotizing myopathy is based on a combination of findings—elevated muscle enzyme levels, muscle weakness, irritable findings on electromyography, and necrotizing myopathy on biopsy in a patient on a statin. The finding of the HMGCR antibody confirms the diagnosis. A test for this antibody is now commercially available in the United States. We suggest testing for the antibody in the following scenarios:

• A persistently elevated or rising creatine kinase, aspartate aminotransferase, alanine aminotransferase, or aldolase level after the statin is stopped; although no fixed creatine kinase level has been determined, a level above 1,000 U/L would be a reasonable cutoff at which to test
• Muscle symptoms (proximal or distal weakness) that persist 12 weeks after statin cessation regardless of the creatine kinase level, especially if the patient has dysphagia
• The finding of muscle irritability on electromyography or diffuse muscle edema on magnetic resonance imaging when testing for other myositis-specific antibodies is negative
• Muscle biopsy showing necrotizing myopathy with little or no inflammation.

In addition, since necrotizing myopathy is known to be associated with malignancy and since necrotizing myopathy is more common in older people, who are also more likely to be taking a statin, an age-appropriate malignancy evaluation is warranted as well.

Attention-deficit/hyperactivity disorder (ADHD) often persists beyond childhood into adulthood. One of the therapeutic challenges of treat­ing ADHD is identifying comorbidities, including underlying mood and anxiety disorders, and ongoing substance abuse. Effective treatment modalities tend to pri­oritize management of substance abuse, but the patient’s age may dictate the overall assessment plan.

So-called 'reward' center
Treating childhood ADHD with stimu­lants might reduce the risk for future drug abuse.¹ It is estimated that approximately 10 million people with ADHD are undiag­nosed in the United States²; characteristic ADHD symptoms—inattention, hyperac­tivity, impulsivity—can persist in adult­hood, and affected persons might not meet societal expectations. Previously uniden­tified attention difficulties may emerge during early adulthood because of increas­ingly complex tasks at school and work.

Persons with undiagnosed ADHD might turn to potentially self-destructive means of placating inner tension. Cocaine has phar­macological properties in common with stimulants such as methylphenidate, which often is prescribed for ADHD. Cocaine and methylphenidate both work on altering brain chemistry with a similar mechanism of action, allowing for increased dopamine in the nucleus accumbens, also known as the “reward center” of the brain.

Adults with ADHD have a 300% higher risk of developing a substance use disorder than adults without ADHD.³ An estimated 15% to 25% of adults with substance abuse have comorbid ADHD. Although these patients abuse of a variety of substances including Cannabis and alcohol, cocaine is one of the most commonly abused substances among this population. These observations could point to a self-medication hypothesis.
 

Why self-medicate?
The self-medication hypothesis, formu­lated by Khantzian in 1985, was based on several clinical observations. Khantzian stated that an abuser’s drug of choice is not selected at random but, rather, by an inherent desire to suppress the attri­butes of the condition that seems to oth­erwise wreak havoc on his (her) life. Almost a century earlier, Freud men­tioned that cocaine is an antidepressant. Among persons with ADHD who have not been given that diagnosis, or treated for the disorder, cocaine is a popular drug. Because of the antidepressant features of cocaine and its ability to produce a rapid increase of dopamine levels that exert a pro-euphoric effect, coupled with a seem­ingly paradoxical calming influence that leads to increased productivity, it is not surprising to find that cocaine is abused. Reportedly, persons who have not been treated because their ADHD is undiag­nosed turn to cocaine because it improves attention, raises self-esteem, and allows users to harness a level of focus that they could not otherwise achieve.⁴

Mechanism of action
Methylphenidate reduces ADHD symp­toms by increasing extracellular dopamine in the brain, acting by means of a mechanism that is similar to that of cocaine.⁵ By block­ing reuptake of dopamine and allowing an extracellular surplus, users continue to experience the pleasurable effect the neuro-transmitter produces. Methylphenidate has been shown to be an even more potent inhibitor of the same autoreceptors. Injecting methylphenidate has been shown to produce a rapid release of dopamine sim­ilar to that of cocaine.⁵

However, methylphenidate causes a much slower increase in dopamine; its effect on the brain has been shown to be similar to that of cocaine without the increased abuse potential. Cocaine use remodels the brain by reconfiguring con­nections that are essential for craving and self-control.⁵ Therefore, substituting meth­ylphenidate for cocaine could help ADHD patients by:
   • improving overall executive functioning
   • decreasing feelings of low self-worth
   • increasing daily functioning
   • minimizing craving and the risk of sub­sequent cocaine abuse.
 

Treatment recommendations
Carefully consider pharmacodynamics and pharmacokinetics when prescribing ADHD medication. In general, children and adolescents with ADHD respond more favorably to stimulants than adults do. In children, the mainstay of treatment is slow-dose stimulants such as methylphenidate; second-line treatments are immediate-release stimulants and atomoxetine, a selec­tive norepinephrine reuptake inhibitor.⁶ Adults with ADHD might benefit from a nonstimulant, in part because of the pres­ence of complex comorbidities.⁶ Modafinil often is prescribed for adults with ADHD.

Atomoxetine readily increases norepi­nephrine and dopamine in the prefrontal cortex as it bypasses the nucleus accum­bens. Although atomoxetine is not a stimu­lant, the efficacy of the drug is based on its ability to increase norepinephrine through selective inhibition of the norepineph­rine transporter. Norepinephrine modu­lates higher cortical functions—attention, executive function, arousal—that lead to a reduction in hyperactivity, inattention, and impulsivity.

Because dopamine is released in the prefrontal cortex—not in the nucleus accumbens—the addiction potential of atomoxetine is low.⁷ The drug might be an effective intervention for patients who are using cocaine to self-medicate. Stimulants such as methylphenidate have proven effective in safely mimicking the mecha­nism of action of cocaine. Nonstimulants, such as atomoxetine and modafinil, lack abuse potential and are excellent options for treating adults with ADHD.

Clinicians generally are advised to treat a patient’s underlying ADHD symptoms before addressing ongoing substance abuse. If a patient abruptly discontinues cocaine use before ADHD symptoms are properly controlled, her (his) condition might deterio­rate further and the treatment plan might fail to progress. Some patients have experienced a reduction in craving for cocaine after they began stimulant therapy; these people no longer felt a need to self-medicate because their symptoms were being addressed.⁴

Attention-deficit/hyperactivity disorder (ADHD) often persists beyond childhood into adulthood. One of the therapeutic challenges of treat­ing ADHD is identifying comorbidities, including underlying mood and anxiety disorders, and ongoing substance abuse. Effective treatment modalities tend to pri­oritize management of substance abuse, but the patient’s age may dictate the overall assessment plan.

So-called 'reward' center
Treating childhood ADHD with stimu­lants might reduce the risk for future drug abuse.¹ It is estimated that approximately 10 million people with ADHD are undiag­nosed in the United States²; characteristic ADHD symptoms—inattention, hyperac­tivity, impulsivity—can persist in adult­hood, and affected persons might not meet societal expectations. Previously uniden­tified attention difficulties may emerge during early adulthood because of increas­ingly complex tasks at school and work.

Persons with undiagnosed ADHD might turn to potentially self-destructive means of placating inner tension. Cocaine has phar­macological properties in common with stimulants such as methylphenidate, which often is prescribed for ADHD. Cocaine and methylphenidate both work on altering brain chemistry with a similar mechanism of action, allowing for increased dopamine in the nucleus accumbens, also known as the “reward center” of the brain.

Adults with ADHD have a 300% higher risk of developing a substance use disorder than adults without ADHD.³ An estimated 15% to 25% of adults with substance abuse have comorbid ADHD. Although these patients abuse of a variety of substances including Cannabis and alcohol, cocaine is one of the most commonly abused substances among this population. These observations could point to a self-medication hypothesis.
 

Why self-medicate?
The self-medication hypothesis, formu­lated by Khantzian in 1985, was based on several clinical observations. Khantzian stated that an abuser’s drug of choice is not selected at random but, rather, by an inherent desire to suppress the attri­butes of the condition that seems to oth­erwise wreak havoc on his (her) life. Almost a century earlier, Freud men­tioned that cocaine is an antidepressant. Among persons with ADHD who have not been given that diagnosis, or treated for the disorder, cocaine is a popular drug. Because of the antidepressant features of cocaine and its ability to produce a rapid increase of dopamine levels that exert a pro-euphoric effect, coupled with a seem­ingly paradoxical calming influence that leads to increased productivity, it is not surprising to find that cocaine is abused. Reportedly, persons who have not been treated because their ADHD is undiag­nosed turn to cocaine because it improves attention, raises self-esteem, and allows users to harness a level of focus that they could not otherwise achieve.⁴

Mechanism of action
Methylphenidate reduces ADHD symp­toms by increasing extracellular dopamine in the brain, acting by means of a mechanism that is similar to that of cocaine.⁵ By block­ing reuptake of dopamine and allowing an extracellular surplus, users continue to experience the pleasurable effect the neuro-transmitter produces. Methylphenidate has been shown to be an even more potent inhibitor of the same autoreceptors. Injecting methylphenidate has been shown to produce a rapid release of dopamine sim­ilar to that of cocaine.⁵

However, methylphenidate causes a much slower increase in dopamine; its effect on the brain has been shown to be similar to that of cocaine without the increased abuse potential. Cocaine use remodels the brain by reconfiguring con­nections that are essential for craving and self-control.⁵ Therefore, substituting meth­ylphenidate for cocaine could help ADHD patients by:
   • improving overall executive functioning
   • decreasing feelings of low self-worth
   • increasing daily functioning
   • minimizing craving and the risk of sub­sequent cocaine abuse.
 

Treatment recommendations
Carefully consider pharmacodynamics and pharmacokinetics when prescribing ADHD medication. In general, children and adolescents with ADHD respond more favorably to stimulants than adults do. In children, the mainstay of treatment is slow-dose stimulants such as methylphenidate; second-line treatments are immediate-release stimulants and atomoxetine, a selec­tive norepinephrine reuptake inhibitor.⁶ Adults with ADHD might benefit from a nonstimulant, in part because of the pres­ence of complex comorbidities.⁶ Modafinil often is prescribed for adults with ADHD.

Atomoxetine readily increases norepi­nephrine and dopamine in the prefrontal cortex as it bypasses the nucleus accum­bens. Although atomoxetine is not a stimu­lant, the efficacy of the drug is based on its ability to increase norepinephrine through selective inhibition of the norepineph­rine transporter. Norepinephrine modu­lates higher cortical functions—attention, executive function, arousal—that lead to a reduction in hyperactivity, inattention, and impulsivity.

Because dopamine is released in the prefrontal cortex—not in the nucleus accumbens—the addiction potential of atomoxetine is low.⁷ The drug might be an effective intervention for patients who are using cocaine to self-medicate. Stimulants such as methylphenidate have proven effective in safely mimicking the mecha­nism of action of cocaine. Nonstimulants, such as atomoxetine and modafinil, lack abuse potential and are excellent options for treating adults with ADHD.

Clinicians generally are advised to treat a patient’s underlying ADHD symptoms before addressing ongoing substance abuse. If a patient abruptly discontinues cocaine use before ADHD symptoms are properly controlled, her (his) condition might deterio­rate further and the treatment plan might fail to progress. Some patients have experienced a reduction in craving for cocaine after they began stimulant therapy; these people no longer felt a need to self-medicate because their symptoms were being addressed.⁴

Attention-deficit/hyperactivity disorder (ADHD) often persists beyond childhood into adulthood. One of the therapeutic challenges of treat­ing ADHD is identifying comorbidities, including underlying mood and anxiety disorders, and ongoing substance abuse. Effective treatment modalities tend to pri­oritize management of substance abuse, but the patient’s age may dictate the overall assessment plan.

So-called 'reward' center
Treating childhood ADHD with stimu­lants might reduce the risk for future drug abuse.¹ It is estimated that approximately 10 million people with ADHD are undiag­nosed in the United States²; characteristic ADHD symptoms—inattention, hyperac­tivity, impulsivity—can persist in adult­hood, and affected persons might not meet societal expectations. Previously uniden­tified attention difficulties may emerge during early adulthood because of increas­ingly complex tasks at school and work.

Persons with undiagnosed ADHD might turn to potentially self-destructive means of placating inner tension. Cocaine has phar­macological properties in common with stimulants such as methylphenidate, which often is prescribed for ADHD. Cocaine and methylphenidate both work on altering brain chemistry with a similar mechanism of action, allowing for increased dopamine in the nucleus accumbens, also known as the “reward center” of the brain.

Adults with ADHD have a 300% higher risk of developing a substance use disorder than adults without ADHD.³ An estimated 15% to 25% of adults with substance abuse have comorbid ADHD. Although these patients abuse of a variety of substances including Cannabis and alcohol, cocaine is one of the most commonly abused substances among this population. These observations could point to a self-medication hypothesis.
 

Why self-medicate?
The self-medication hypothesis, formu­lated by Khantzian in 1985, was based on several clinical observations. Khantzian stated that an abuser’s drug of choice is not selected at random but, rather, by an inherent desire to suppress the attri­butes of the condition that seems to oth­erwise wreak havoc on his (her) life. Almost a century earlier, Freud men­tioned that cocaine is an antidepressant. Among persons with ADHD who have not been given that diagnosis, or treated for the disorder, cocaine is a popular drug. Because of the antidepressant features of cocaine and its ability to produce a rapid increase of dopamine levels that exert a pro-euphoric effect, coupled with a seem­ingly paradoxical calming influence that leads to increased productivity, it is not surprising to find that cocaine is abused. Reportedly, persons who have not been treated because their ADHD is undiag­nosed turn to cocaine because it improves attention, raises self-esteem, and allows users to harness a level of focus that they could not otherwise achieve.⁴

Mechanism of action
Methylphenidate reduces ADHD symp­toms by increasing extracellular dopamine in the brain, acting by means of a mechanism that is similar to that of cocaine.⁵ By block­ing reuptake of dopamine and allowing an extracellular surplus, users continue to experience the pleasurable effect the neuro-transmitter produces. Methylphenidate has been shown to be an even more potent inhibitor of the same autoreceptors. Injecting methylphenidate has been shown to produce a rapid release of dopamine sim­ilar to that of cocaine.⁵

However, methylphenidate causes a much slower increase in dopamine; its effect on the brain has been shown to be similar to that of cocaine without the increased abuse potential. Cocaine use remodels the brain by reconfiguring con­nections that are essential for craving and self-control.⁵ Therefore, substituting meth­ylphenidate for cocaine could help ADHD patients by:
   • improving overall executive functioning
   • decreasing feelings of low self-worth
   • increasing daily functioning
   • minimizing craving and the risk of sub­sequent cocaine abuse.
 

Treatment recommendations
Carefully consider pharmacodynamics and pharmacokinetics when prescribing ADHD medication. In general, children and adolescents with ADHD respond more favorably to stimulants than adults do. In children, the mainstay of treatment is slow-dose stimulants such as methylphenidate; second-line treatments are immediate-release stimulants and atomoxetine, a selec­tive norepinephrine reuptake inhibitor.⁶ Adults with ADHD might benefit from a nonstimulant, in part because of the pres­ence of complex comorbidities.⁶ Modafinil often is prescribed for adults with ADHD.

Atomoxetine readily increases norepi­nephrine and dopamine in the prefrontal cortex as it bypasses the nucleus accum­bens. Although atomoxetine is not a stimu­lant, the efficacy of the drug is based on its ability to increase norepinephrine through selective inhibition of the norepineph­rine transporter. Norepinephrine modu­lates higher cortical functions—attention, executive function, arousal—that lead to a reduction in hyperactivity, inattention, and impulsivity.

Because dopamine is released in the prefrontal cortex—not in the nucleus accumbens—the addiction potential of atomoxetine is low.⁷ The drug might be an effective intervention for patients who are using cocaine to self-medicate. Stimulants such as methylphenidate have proven effective in safely mimicking the mecha­nism of action of cocaine. Nonstimulants, such as atomoxetine and modafinil, lack abuse potential and are excellent options for treating adults with ADHD.

Clinicians generally are advised to treat a patient’s underlying ADHD symptoms before addressing ongoing substance abuse. If a patient abruptly discontinues cocaine use before ADHD symptoms are properly controlled, her (his) condition might deterio­rate further and the treatment plan might fail to progress. Some patients have experienced a reduction in craving for cocaine after they began stimulant therapy; these people no longer felt a need to self-medicate because their symptoms were being addressed.⁴