To the Editor: We found the article by Drs. Lansang and Kramer¹ on glucocorticoid-induced diabetes and adrenal suppression in the November 2011 issue to be a useful and clinically oriented review. However, we strongly believe there is an issue that should be addressed.

It is well accepted that the short cosyntropin (Cortrosyn) stimulation test is the best screening maneuver for assessing adrenocortical insufficiency. The authors state, however, that 250 μg is preferable to lower doses (10 μg or 1 μg), since these are not yet widely accepted, and refer to an article by Axelrod from 1976.²

Based on studies showing that 250 μg of cosyntropin is a pharmacologic rather than a physiologic stimulus that may overstimulate partially atrophied or mildly dysfunctional adrenal glands, multiple studies in the last 20 years have shown that the low-dose test has an equal or better result than the classic 250-μg dose test.³ Dorin et al,⁴ in a meta-analysis of the diagnosis of adrenocortical insufficiency that included more than 30 studies, found similar sensitivity and specificity in primary and secondary adrenal insufficiency comparing the 250-μg dose vs the low dose. In cases of mild primary adrenal failure, the low-dose test has better performance. A previous investigation in our research center contrasting 250 μg vs 10 μg proved that 10 μg had a better sensitivity than the standard dose, with excellent reproducibility and interchangeability.⁵ Similar findings have been shown by other authors contrasting 1 μg vs 250 μg of cosyntropin.⁶

We believe that the limited use of the low-dose cosyntropin test is not a matter of acceptance or performance but a consequence of the lack of vials containing lower doses of cosyntropin (1 to 10 μg), which makes this test technically challenging.^2,4 The steps needed for one-dose testing and the preservation time of the preparation are strong limitations to its wide use in clinical practice and endocrine laboratories.

To the Editor: We found the article by Drs. Lansang and Kramer¹ on glucocorticoid-induced diabetes and adrenal suppression in the November 2011 issue to be a useful and clinically oriented review. However, we strongly believe there is an issue that should be addressed.

It is well accepted that the short cosyntropin (Cortrosyn) stimulation test is the best screening maneuver for assessing adrenocortical insufficiency. The authors state, however, that 250 μg is preferable to lower doses (10 μg or 1 μg), since these are not yet widely accepted, and refer to an article by Axelrod from 1976.²

Based on studies showing that 250 μg of cosyntropin is a pharmacologic rather than a physiologic stimulus that may overstimulate partially atrophied or mildly dysfunctional adrenal glands, multiple studies in the last 20 years have shown that the low-dose test has an equal or better result than the classic 250-μg dose test.³ Dorin et al,⁴ in a meta-analysis of the diagnosis of adrenocortical insufficiency that included more than 30 studies, found similar sensitivity and specificity in primary and secondary adrenal insufficiency comparing the 250-μg dose vs the low dose. In cases of mild primary adrenal failure, the low-dose test has better performance. A previous investigation in our research center contrasting 250 μg vs 10 μg proved that 10 μg had a better sensitivity than the standard dose, with excellent reproducibility and interchangeability.⁵ Similar findings have been shown by other authors contrasting 1 μg vs 250 μg of cosyntropin.⁶

We believe that the limited use of the low-dose cosyntropin test is not a matter of acceptance or performance but a consequence of the lack of vials containing lower doses of cosyntropin (1 to 10 μg), which makes this test technically challenging.^2,4 The steps needed for one-dose testing and the preservation time of the preparation are strong limitations to its wide use in clinical practice and endocrine laboratories.

To the Editor: We found the article by Drs. Lansang and Kramer¹ on glucocorticoid-induced diabetes and adrenal suppression in the November 2011 issue to be a useful and clinically oriented review. However, we strongly believe there is an issue that should be addressed.

It is well accepted that the short cosyntropin (Cortrosyn) stimulation test is the best screening maneuver for assessing adrenocortical insufficiency. The authors state, however, that 250 μg is preferable to lower doses (10 μg or 1 μg), since these are not yet widely accepted, and refer to an article by Axelrod from 1976.²

Based on studies showing that 250 μg of cosyntropin is a pharmacologic rather than a physiologic stimulus that may overstimulate partially atrophied or mildly dysfunctional adrenal glands, multiple studies in the last 20 years have shown that the low-dose test has an equal or better result than the classic 250-μg dose test.³ Dorin et al,⁴ in a meta-analysis of the diagnosis of adrenocortical insufficiency that included more than 30 studies, found similar sensitivity and specificity in primary and secondary adrenal insufficiency comparing the 250-μg dose vs the low dose. In cases of mild primary adrenal failure, the low-dose test has better performance. A previous investigation in our research center contrasting 250 μg vs 10 μg proved that 10 μg had a better sensitivity than the standard dose, with excellent reproducibility and interchangeability.⁵ Similar findings have been shown by other authors contrasting 1 μg vs 250 μg of cosyntropin.⁶

We believe that the limited use of the low-dose cosyntropin test is not a matter of acceptance or performance but a consequence of the lack of vials containing lower doses of cosyntropin (1 to 10 μg), which makes this test technically challenging.^2,4 The steps needed for one-dose testing and the preservation time of the preparation are strong limitations to its wide use in clinical practice and endocrine laboratories.

Over the past year, it has been hard to avoid news reports involving people getting high on “bath salts” and “incense” (also known as “Spice” or “K2”). Addiction treatment professionals have been overwhelmed by questions regarding why one would want to “snort bath salts” or “smoke incense.”

These substances are not what they appear to be. They are sold as bath salts and incense and are labeled “not for human consumption” simply to avoid regulation by the US Food and Drug Administration (FDA). In reality, they are powerful psychoactive drugs, with effects that mimic those of more commonly abused drugs such as amphetamines and marijuana. Until recently, they were legally available over the counter at quick-marts, head shops, and on the Internet. Because they are relatively new, they may not be detectable on routine urine drug screens, and users may be unaware of the specific chemicals contained in them.

These drugs, which we have collectively termed synthetic legal intoxicating drugs (SLIDs), are increasing dramatically in use.^1–3 A survey of youths at a rave party indicated that 21% had used one of them on at least one occasion.⁴ The general impression held by the drug-using public is that SLIDs are relatively cheap, are not detected on standard urine drug screens, can produce a powerful high, and, until recently, were readily available through legitimate sources.

Physicians need to be aware of SLIDs in order to recognize and manage the intoxication syndromes associated with these substances when encountered in clinical practice, and in order to educate patients about their potential dangers.

SYNTHETIC CANNABINOIDS MARKETED AS INCENSE

Herbal incense products that could be smoked as an alternative to marijuana started appearing on the Internet in Europe in 2004. By 2008, when such products first appeared in the United States, their use in Europe was already widespread.

Initially, consumers were led to believe that such herbal smoking blends were safe, legal alternatives to marijuana, and that it was the proprietary blend of herbs that was responsible for the “natural” high. Spice, a specific brand name, was originally trademarked in England as incense and also as an herbal smoking product.⁵

Legal authorities, however, suspected that these herbal blends were adulterated with synthetic substances. In December 2008, the first such substance was found when Austrian authorities isolated a synthetic cannabinoid, JWH-018, from an herbal incense product.⁶ By the end of 2009, five other synthetic cannabinoids—CP-47,497, HU-210, JWH-073, JWH-250, and JWH-398—had been isolated from various herbal incense samples around the world.⁷

The synthetic cannabinoids in herbal incense products are not derived from the hemp plant (Cannabis sativa), but are synthesized in laboratories and are formulated to interact with the endogenous cannabinoid receptors in the brain to produce psychoactive effects.

Synthetic cannabinoids are full agonists; natural THC is only a partial agonist

Two types of cannabinoid receptors have been discovered in humans: CB1 and CB2. Both types are found in the central nervous system, and CB2 is also found extensively in the periphery. CB1 is the receptor responsible for the psychoactive effects of cannabinoids, including altered consciousness, euphoria, relaxation, perceptual disturbances, intensified sensory experiences, cognitive impairment, and increased reaction time.⁶ The physiologic role of CB2 remains uncertain.

The major psychoactive cannabinoid in naturally occurring marijuana is delta-9-tetrahydrocannabinol (THC). The so-called classic cannabinoids, such as HU-210, are analogues of THC and are based on its chemical structure. The rest of the synthetic cannabinoids commonly found in incense products differ in chemical structure from naturally occurring cannabinoids such as THC, but have activity at the CB1 receptor and are thus psychoactive.

Of clinical relevance is that THC is only a partial agonist at the CB1 receptor, while all synthetic cannabinoids commonly found in incense products are full agonists at CB1.⁷ This difference is important because partial agonists bind to receptors but stimulate them only partially and therefore exhibit a plateau effect in terms of dose vs clinical response. In contrast, full agonists have no ceiling on the dose-response relationship and therefore have a greater potential for overdose and severe toxic effects.

Despite uncertainties, use is widespread

Most of the synthetic cannabinoids in herbal incense products were developed for research purposes, and there are almost no reliable scientific data on their effects in humans. Of additional concern is that no research has been conducted on their pyrolytic effects, ie, how these chemicals are transformed when they are burned, such as when consumers smoke them. Furthermore, herbal incense products often vary in their active substances and concentrations, so consumers really do not know what they are getting.

Despite the many uncertainties, the use of these products is widespread. Data submitted to the US Drug Enforcement Administration (DEA) from a major toxicology laboratory indicated that from July through November of 2010, 3,700 samples tested positive for either JWH-018 or JWH-073. This report also indicated that 30% to 35% of specimens submitted by juvenile probation departments were positive for synthetic cannabinoids.⁸

MEDICAL CONCERNS OVER SYNTHETIC CANNABINOIDS

Amid the mysteries surrounding synthetic cannabinoids, one thing is clear: users are increasingly seeking medical attention. In 2010, there were 2,906 calls to poison control centers across the United States pertaining to “synthetic marijuana”; in 2011 there were 6,959 calls, and in January 2012, 639 such calls had been placed.⁹

The duration of the intoxicating effects of synthetic cannabinoids is generally longer than that of THC, but this seems to be variable. JWH-018, for instance, seems to have a shorter duration of action, at around 1 to 2 hours, while a longer, 5- to 6-hour intoxicating effect has been observed with CP-47,497.^7,12

Serious adverse effects

Although the prevalence of serious adverse effects associated with the use of synthetic cannabinoids is not known, a number of serious complications have been recognized.

Seizures. One case of seizure has been reported in association with the use of synthetic cannabinoids, specifically JWH-018.¹² This case involved a previously healthy 48-year-old man who had ingested a powder that was subsequently confirmed to be JWH-018, which he mixed with alcohol. Of further concern in this case is that this individual developed a refractory supraventricular tachycardia that required cardioversion on the first hospital day.

The authors speculated that the seizure may have been due to a dose-response mechanism that resulted in either the release of presynaptic excitatory neurotransmitters or the decreased release of inhibitory neurotransmitters. They further postulated that the supraventricular tachycardia could have been caused by one of two mechanisms previously reported in association with CB1 agonists: an increase in circulating catecholamines or heightened oxidative demands on the myocardium.¹²

Psychosis. The occurrence of psychotic symptoms such as hallucinations and paranoid delusions in association with synthetic cannabinoids is not surprising, given the well-documented link between marijuana use and psychosis.^13,14

A case report of a 25-year-old patient with a 7-year history of recurrent psychosis that was initially triggered by cannabis use indicated that the use of 3 g of herbal incense on three occasions was associated with worsening of previous psychotic symptoms and the emergence of command and paranoid types of auditory hallucination.¹⁰

Semistructured interviews of 15 patients in a forensic rehabilitative service, all of whom had a history of psychotic illness, showed that 69% experienced symptoms consistent with psychotic relapse after smoking an herbal incense product containing JWH-018.¹⁵

It is possible that psychotic symptoms may be more prominent with synthetic cannabinoids than with natural marijuana because not only are synthetic cannabinoids more potent and work as full agonists, but, unlike marijuana, they do not contain cannabidiol, which is thought to have antipsychotic efficacy.^10,16 However, the risk of psychotic symptoms in association with synthetic cannabinoid usage in otherwise healthy people is unknown.

Regulation lags behind

Growing concern over the perceived dangers posed by synthetic cannabinoids has led to a ban on some of the more common ones contained in herbal incense preparations. On March 1, 2011, the US DEA temporarily placed five synthetic cannabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol) under schedule I (banned substances).

Such a ban, however, may be futile because there are an estimated 100 synthetic cannabinoids that have yet to enter the market, and when one is banned, a new one is likely to be introduced immediately as a replacement.⁸

SYNTHETIC STIMULANTS MARKETED AS BATH SALTS

Like the herbal incense products, “bath salts” may likewise not be what they appear to be. They too may be labeled “not for human consumption” in an effort to bypass laws governing mind-altering substances.

Several pharmacologically active substances have been marketed as bath salts. Two of the more common ingredients are 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylcathinone (mephedrone).

MDPV is a dopamine and norepineph-rine reuptake inhibitor that acts as a powerful stimulant. It has no FDA-approved medical use, but it is an analogue of the stimulant pyrovalerone, which was once used to treat chronic fatigue.¹⁷

MDPV seems to be the most common substance found in bath salt products in the United States. A sample of this substance was first seized on the streets by German authorities in 2007. A study in Finland conducted from August 2009 to September 2010 estimated that 5.7% of all arrests for driving under the influence (DUI) unrelated to alcohol consumption involved MDPV intoxication.¹⁷ In 2009, the National Forensic Laboratory Information System of the US DEA had seized only two samples of MDPV, but by 2010 that had increased to 161.¹⁸

Mephedrone is derived from phenethylamine and is closely related to cathinone, the active ingredient in the African khat plant (Catha edulis).¹⁹ Khat has a history of abuse, and the chemical structure of cathinone and its derivatives is similar to that of amphetamine.

Mephedrone, a powerful stimulant, is suspected of working as a monoamine reuptake inhibitor, and it may also directly induce the presynaptic release of monoamines.²⁰ The net effect is an increase in serotonin, norepineph-rine, and dopamine levels at neuronal synapses.

Mephedrone was first described in 1929 by chemist Saem de Burnaga Sanchez, and it remained an obscure research chemical for many years.²¹ It was formally recognized as a drug of abuse in Europe in 2007, and by 2009 it was the sixth most frequently used such drug in Europe.^8,22

Although MDPV and mephedrone are the most common psychoactive ingredients in bath salts, many other synthetic drugs have been found on the market.

A temporary ban

On September 7, 2011, the US government made it illegal to possess or sell any substance containing MDPV, mephedrone, or methy-lone. This temporary restriction was to remain in effect for 1 year to give the DEA time to collect data to support a move to permanently control these substances.³

Like synthetic cannabinoids, however, synthetic stimulants are very difficult to regulate because they are a large group of substances. As soon as one substance is outlawed, another synthetic stimulant will likely take its place.

MEDICAL CONCERNS REGARDING SYNTHETIC STIMULANTS

The medical and psychiatric sequelae that are associated with the use of bath salts have sent an increasing number of people to emergency rooms. The number of bath-salt-related calls to US poison control centers increased dramatically from 303 in 2010 to 4,720 by August 31, 2011. Most of these calls were related to tachycardia, agitation, hallucinations, extreme paranoia, delusions, and elevations in blood pressure.³

A report of 35 cases of people who had used bath salts and who had reported to Michigan emergency rooms between November 13, 2010, and March 31, 2011, indicated that agitation was present in 66%, tachycardia in 63%, delusions and hallucinations in 40%, seizure or tremor in 29%, hypertension in 23%, drowsiness in 23%, paranoia in 20%, and mydriasis in 20%; one patient was dead on arrival. Of the 34 patients who were alive on arrival, 17 (50%) were hospitalized, 15 were released, and 2 left against medical advice. In the patients in this study, 63% had injected the drug, 26% snorted it, and 11% ingested it orally.² Toxicology results obtained during an autopsy on the one person who died revealed a high level of MDPV, and the coroner ruled that MDPV toxicity was the primary cause of death.²

Though the pharmacokinetic properties of mephedrone are unknown, James et al²⁴ noted that an interesting feature is that its clinical effects seem to persist for more than 24 hours after the last exposure to the drug, which would not be expected based on the rapid elimination of other similar cathinones.

Sympathomimetic toxicity. Many of the symptoms listed in Table 2 are consistent with a sympathomimetic syndrome. In a case series reported by Regan et al,²⁶ most of the 57 patients exhibited cardiovascular findings consistent with sympathomimetic toxicity.

In the study by James et al,²⁴ one of the patients with chest pain had electrocardiographic changes consistent with acute myocardial infarction. Though it is not possible to conclude from a single case that mephedrone poses a risk of myocardial infarction, such a risk has been reported with khat.²⁸ More research is needed to determine whether mephedrone poses a risk of cardiac events when used by people with or without an underlying cardiac condition.

Seizure also seems to be a relatively common feature associated with mephedrone use in case series of emergency room presentations. The US Centers for Disease Control and Prevention l² reported that of 35 patients who had used bath salts, 40% experienced seizures or “tremors.” A recent case series²⁷ of 15 patients presenting to an emergency department after mephedrone use reported that 20% had experienced seizures. In the study by James et al,²⁴ four patients (3% of the total group) experienced seizures after using mephedrone. It should be noted that, aside from people presenting to emergency rooms, seizures are rarely reported in the wider population of mephedrone users.

Psychotic symptoms are also quite common in users of synthetic stimulants who present to emergency rooms, occurring, as previously stated, in 14% to 40% of cases.^2,24

In a small case series, Penders and Gestring²⁹ pointed out some common features in three patients who had used MDPV and had presented with psychosis: sleep problems, inattention, vivid hallucinations of intruders, fearfulness, and inability to remember many of the events surrounding their drug use. The authors concluded that the psychotic syndrome present in their three patients was indicative of a short-term delirium rather than a substance-induced psychosis based on the presence of attention deficits and memory problems. The patients in this series responded well to brief hospitalization and antipsychotic medications.

As with seizure, extreme presentations such as psychosis are infrequently mentioned except in people requiring treatment at a hospital. There are simply no data regarding the prevalence of psychotic symptoms in the larger group of all synthetic stimulant users.

SUSPECT SLID INTOXICATION IN ‘PSYCHIATRIC’ PATIENTS

Despite the temporary ban on the more common substances found in Spice and bath salts, it is premature for the medical community to breath a sigh of relief. Producers of these products are already likely bringing to market new ones containing similar but as yet nonbanned substances. Furthermore, such bans will do little to affect Internet commerce; rather than go to a head shop, consumers will order the products online.

Doctors in urgent care centers, emergency rooms, and on general medical floors should pay close attention to any patient without a known psychiatric history who is acting in a bizarre fashion. Most SLID-intoxicated patients will present with anxiety, agitation, and psychosis. Rather than assume that they are psychiatric patients, one should consider the possibility of SLID intoxication and pay close attention to the possible medical sequelae associated with SLID use, such as elevated blood pressure, tachycardia, and seizure.

Benzodiazepines, especially lorazepam (Ativan), have been the agents most commonly used to treat both agitation and seizures associated with SLID intoxication.

Antipsychotics should be used judiciously because of their propensity to lower the seizure threshold, and patients with synthetic stimulant toxicity are already at increased risk of seizure.

A psychiatric consult should be considered in the event of any suspected toxicity or for any patient whose behavior is difficult to manage.

Restraints may be needed in some circumstances when agitation cannot be controlled with benzodiazepines alone, to ensure safety for the patient as well as that of others in the emergency department.

Routine laboratory tests should be part of the workup of patients suspected of being under the influence of SLIDs. These include a complete blood cell count, complete metabolic panel, and urine toxicology (Table 3).^23,25 A routine urine toxicology study will likely be negative, but either the patient or collateral information may give you a general idea of what the patient used, in which case the sample could be sent out for special tests for the more common substances found in herbal incense or bath salt products.

Electroencephalography may be indicated if there is any question as to whether the patient may have suffered a seizure. There should be a low threshold to order electrocardiography, especially in the case of synthetic stimulant intoxication.

Serial cardiac enzymes may be warranted if a patient with synthetic-stimulant intoxicated has chest pain.

Education, addiction treatment. Much is unknown about the risk of SLIDs, but given the adverse events reported in the literature, it seems likely that those with underlying cardiac or psychiatric issues may be at higher risk for the most serious drug-related consequences. With regard to synthetic stimulants, Winstock et al²⁰ recommend a harm-reduction approach involving educating patients about avoiding the development of tolerance, not engaging in polydrug use, not injecting, and paying special attention to remaining cool and well hydrated.

Experience shows that once SLID patients get through their acute crisis and are no longer psychotic, they tend to be forthright in divulging what they used to get high. At that point, consideration should be given to consulting an addiction treatment specialist for further evaluation of the patient’s drug use history and for formulation of a treatment plan to help ensure that the patient doesn’t return to using these drugs.

SLIDs POSE A REAL CHALLENGE

SLIDs present a real challenge to law enforcement, governments, the public, and the addiction treatment community. There is currently no way to routinely test for these substances. Furthermore, any tests that are developed or laws that are enacted will be easily evaded, as there are many more synthetic substances waiting in the wings to be released.

Don’t be lulled into thinking that SLIDs are gone with the recent bans against some of the more common substances. More SLIDs are coming, and more morbidity should be expected in medical settings.

Doctors in emergency departments and other settings need to be prepared for the agitated and often psychotic presentation of SLID-intoxicated patients and should be ready with benzodiazepines, restraints, and a calm and reassuring manner. And for patients who present with psychotic symptoms, medical staff should also be ready to consider involuntary short-term commitment to an inpatient psychiatric unit.

Once they recover, patients need to be educated about the dangers of substances such as SLIDs that, because of their novelty, may be perceived as less dangerous alternatives to traditional illicit drugs.

Over the past year, it has been hard to avoid news reports involving people getting high on “bath salts” and “incense” (also known as “Spice” or “K2”). Addiction treatment professionals have been overwhelmed by questions regarding why one would want to “snort bath salts” or “smoke incense.”

These substances are not what they appear to be. They are sold as bath salts and incense and are labeled “not for human consumption” simply to avoid regulation by the US Food and Drug Administration (FDA). In reality, they are powerful psychoactive drugs, with effects that mimic those of more commonly abused drugs such as amphetamines and marijuana. Until recently, they were legally available over the counter at quick-marts, head shops, and on the Internet. Because they are relatively new, they may not be detectable on routine urine drug screens, and users may be unaware of the specific chemicals contained in them.

These drugs, which we have collectively termed synthetic legal intoxicating drugs (SLIDs), are increasing dramatically in use.^1–3 A survey of youths at a rave party indicated that 21% had used one of them on at least one occasion.⁴ The general impression held by the drug-using public is that SLIDs are relatively cheap, are not detected on standard urine drug screens, can produce a powerful high, and, until recently, were readily available through legitimate sources.

Physicians need to be aware of SLIDs in order to recognize and manage the intoxication syndromes associated with these substances when encountered in clinical practice, and in order to educate patients about their potential dangers.

SYNTHETIC CANNABINOIDS MARKETED AS INCENSE

Herbal incense products that could be smoked as an alternative to marijuana started appearing on the Internet in Europe in 2004. By 2008, when such products first appeared in the United States, their use in Europe was already widespread.

Initially, consumers were led to believe that such herbal smoking blends were safe, legal alternatives to marijuana, and that it was the proprietary blend of herbs that was responsible for the “natural” high. Spice, a specific brand name, was originally trademarked in England as incense and also as an herbal smoking product.⁵

Legal authorities, however, suspected that these herbal blends were adulterated with synthetic substances. In December 2008, the first such substance was found when Austrian authorities isolated a synthetic cannabinoid, JWH-018, from an herbal incense product.⁶ By the end of 2009, five other synthetic cannabinoids—CP-47,497, HU-210, JWH-073, JWH-250, and JWH-398—had been isolated from various herbal incense samples around the world.⁷

The synthetic cannabinoids in herbal incense products are not derived from the hemp plant (Cannabis sativa), but are synthesized in laboratories and are formulated to interact with the endogenous cannabinoid receptors in the brain to produce psychoactive effects.

Synthetic cannabinoids are full agonists; natural THC is only a partial agonist

Two types of cannabinoid receptors have been discovered in humans: CB1 and CB2. Both types are found in the central nervous system, and CB2 is also found extensively in the periphery. CB1 is the receptor responsible for the psychoactive effects of cannabinoids, including altered consciousness, euphoria, relaxation, perceptual disturbances, intensified sensory experiences, cognitive impairment, and increased reaction time.⁶ The physiologic role of CB2 remains uncertain.

The major psychoactive cannabinoid in naturally occurring marijuana is delta-9-tetrahydrocannabinol (THC). The so-called classic cannabinoids, such as HU-210, are analogues of THC and are based on its chemical structure. The rest of the synthetic cannabinoids commonly found in incense products differ in chemical structure from naturally occurring cannabinoids such as THC, but have activity at the CB1 receptor and are thus psychoactive.

Of clinical relevance is that THC is only a partial agonist at the CB1 receptor, while all synthetic cannabinoids commonly found in incense products are full agonists at CB1.⁷ This difference is important because partial agonists bind to receptors but stimulate them only partially and therefore exhibit a plateau effect in terms of dose vs clinical response. In contrast, full agonists have no ceiling on the dose-response relationship and therefore have a greater potential for overdose and severe toxic effects.

Despite uncertainties, use is widespread

Most of the synthetic cannabinoids in herbal incense products were developed for research purposes, and there are almost no reliable scientific data on their effects in humans. Of additional concern is that no research has been conducted on their pyrolytic effects, ie, how these chemicals are transformed when they are burned, such as when consumers smoke them. Furthermore, herbal incense products often vary in their active substances and concentrations, so consumers really do not know what they are getting.

Despite the many uncertainties, the use of these products is widespread. Data submitted to the US Drug Enforcement Administration (DEA) from a major toxicology laboratory indicated that from July through November of 2010, 3,700 samples tested positive for either JWH-018 or JWH-073. This report also indicated that 30% to 35% of specimens submitted by juvenile probation departments were positive for synthetic cannabinoids.⁸

MEDICAL CONCERNS OVER SYNTHETIC CANNABINOIDS

Amid the mysteries surrounding synthetic cannabinoids, one thing is clear: users are increasingly seeking medical attention. In 2010, there were 2,906 calls to poison control centers across the United States pertaining to “synthetic marijuana”; in 2011 there were 6,959 calls, and in January 2012, 639 such calls had been placed.⁹

The duration of the intoxicating effects of synthetic cannabinoids is generally longer than that of THC, but this seems to be variable. JWH-018, for instance, seems to have a shorter duration of action, at around 1 to 2 hours, while a longer, 5- to 6-hour intoxicating effect has been observed with CP-47,497.^7,12

Serious adverse effects

Although the prevalence of serious adverse effects associated with the use of synthetic cannabinoids is not known, a number of serious complications have been recognized.

Seizures. One case of seizure has been reported in association with the use of synthetic cannabinoids, specifically JWH-018.¹² This case involved a previously healthy 48-year-old man who had ingested a powder that was subsequently confirmed to be JWH-018, which he mixed with alcohol. Of further concern in this case is that this individual developed a refractory supraventricular tachycardia that required cardioversion on the first hospital day.

The authors speculated that the seizure may have been due to a dose-response mechanism that resulted in either the release of presynaptic excitatory neurotransmitters or the decreased release of inhibitory neurotransmitters. They further postulated that the supraventricular tachycardia could have been caused by one of two mechanisms previously reported in association with CB1 agonists: an increase in circulating catecholamines or heightened oxidative demands on the myocardium.¹²

Psychosis. The occurrence of psychotic symptoms such as hallucinations and paranoid delusions in association with synthetic cannabinoids is not surprising, given the well-documented link between marijuana use and psychosis.^13,14

A case report of a 25-year-old patient with a 7-year history of recurrent psychosis that was initially triggered by cannabis use indicated that the use of 3 g of herbal incense on three occasions was associated with worsening of previous psychotic symptoms and the emergence of command and paranoid types of auditory hallucination.¹⁰

Semistructured interviews of 15 patients in a forensic rehabilitative service, all of whom had a history of psychotic illness, showed that 69% experienced symptoms consistent with psychotic relapse after smoking an herbal incense product containing JWH-018.¹⁵

It is possible that psychotic symptoms may be more prominent with synthetic cannabinoids than with natural marijuana because not only are synthetic cannabinoids more potent and work as full agonists, but, unlike marijuana, they do not contain cannabidiol, which is thought to have antipsychotic efficacy.^10,16 However, the risk of psychotic symptoms in association with synthetic cannabinoid usage in otherwise healthy people is unknown.

Regulation lags behind

Growing concern over the perceived dangers posed by synthetic cannabinoids has led to a ban on some of the more common ones contained in herbal incense preparations. On March 1, 2011, the US DEA temporarily placed five synthetic cannabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol) under schedule I (banned substances).

Such a ban, however, may be futile because there are an estimated 100 synthetic cannabinoids that have yet to enter the market, and when one is banned, a new one is likely to be introduced immediately as a replacement.⁸

SYNTHETIC STIMULANTS MARKETED AS BATH SALTS

Like the herbal incense products, “bath salts” may likewise not be what they appear to be. They too may be labeled “not for human consumption” in an effort to bypass laws governing mind-altering substances.

Several pharmacologically active substances have been marketed as bath salts. Two of the more common ingredients are 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylcathinone (mephedrone).

MDPV is a dopamine and norepineph-rine reuptake inhibitor that acts as a powerful stimulant. It has no FDA-approved medical use, but it is an analogue of the stimulant pyrovalerone, which was once used to treat chronic fatigue.¹⁷

MDPV seems to be the most common substance found in bath salt products in the United States. A sample of this substance was first seized on the streets by German authorities in 2007. A study in Finland conducted from August 2009 to September 2010 estimated that 5.7% of all arrests for driving under the influence (DUI) unrelated to alcohol consumption involved MDPV intoxication.¹⁷ In 2009, the National Forensic Laboratory Information System of the US DEA had seized only two samples of MDPV, but by 2010 that had increased to 161.¹⁸

Mephedrone is derived from phenethylamine and is closely related to cathinone, the active ingredient in the African khat plant (Catha edulis).¹⁹ Khat has a history of abuse, and the chemical structure of cathinone and its derivatives is similar to that of amphetamine.

Mephedrone, a powerful stimulant, is suspected of working as a monoamine reuptake inhibitor, and it may also directly induce the presynaptic release of monoamines.²⁰ The net effect is an increase in serotonin, norepineph-rine, and dopamine levels at neuronal synapses.

Mephedrone was first described in 1929 by chemist Saem de Burnaga Sanchez, and it remained an obscure research chemical for many years.²¹ It was formally recognized as a drug of abuse in Europe in 2007, and by 2009 it was the sixth most frequently used such drug in Europe.^8,22

Although MDPV and mephedrone are the most common psychoactive ingredients in bath salts, many other synthetic drugs have been found on the market.

A temporary ban

On September 7, 2011, the US government made it illegal to possess or sell any substance containing MDPV, mephedrone, or methy-lone. This temporary restriction was to remain in effect for 1 year to give the DEA time to collect data to support a move to permanently control these substances.³

Like synthetic cannabinoids, however, synthetic stimulants are very difficult to regulate because they are a large group of substances. As soon as one substance is outlawed, another synthetic stimulant will likely take its place.

MEDICAL CONCERNS REGARDING SYNTHETIC STIMULANTS

The medical and psychiatric sequelae that are associated with the use of bath salts have sent an increasing number of people to emergency rooms. The number of bath-salt-related calls to US poison control centers increased dramatically from 303 in 2010 to 4,720 by August 31, 2011. Most of these calls were related to tachycardia, agitation, hallucinations, extreme paranoia, delusions, and elevations in blood pressure.³

A report of 35 cases of people who had used bath salts and who had reported to Michigan emergency rooms between November 13, 2010, and March 31, 2011, indicated that agitation was present in 66%, tachycardia in 63%, delusions and hallucinations in 40%, seizure or tremor in 29%, hypertension in 23%, drowsiness in 23%, paranoia in 20%, and mydriasis in 20%; one patient was dead on arrival. Of the 34 patients who were alive on arrival, 17 (50%) were hospitalized, 15 were released, and 2 left against medical advice. In the patients in this study, 63% had injected the drug, 26% snorted it, and 11% ingested it orally.² Toxicology results obtained during an autopsy on the one person who died revealed a high level of MDPV, and the coroner ruled that MDPV toxicity was the primary cause of death.²

Though the pharmacokinetic properties of mephedrone are unknown, James et al²⁴ noted that an interesting feature is that its clinical effects seem to persist for more than 24 hours after the last exposure to the drug, which would not be expected based on the rapid elimination of other similar cathinones.

Sympathomimetic toxicity. Many of the symptoms listed in Table 2 are consistent with a sympathomimetic syndrome. In a case series reported by Regan et al,²⁶ most of the 57 patients exhibited cardiovascular findings consistent with sympathomimetic toxicity.

In the study by James et al,²⁴ one of the patients with chest pain had electrocardiographic changes consistent with acute myocardial infarction. Though it is not possible to conclude from a single case that mephedrone poses a risk of myocardial infarction, such a risk has been reported with khat.²⁸ More research is needed to determine whether mephedrone poses a risk of cardiac events when used by people with or without an underlying cardiac condition.

Seizure also seems to be a relatively common feature associated with mephedrone use in case series of emergency room presentations. The US Centers for Disease Control and Prevention l² reported that of 35 patients who had used bath salts, 40% experienced seizures or “tremors.” A recent case series²⁷ of 15 patients presenting to an emergency department after mephedrone use reported that 20% had experienced seizures. In the study by James et al,²⁴ four patients (3% of the total group) experienced seizures after using mephedrone. It should be noted that, aside from people presenting to emergency rooms, seizures are rarely reported in the wider population of mephedrone users.

Psychotic symptoms are also quite common in users of synthetic stimulants who present to emergency rooms, occurring, as previously stated, in 14% to 40% of cases.^2,24

In a small case series, Penders and Gestring²⁹ pointed out some common features in three patients who had used MDPV and had presented with psychosis: sleep problems, inattention, vivid hallucinations of intruders, fearfulness, and inability to remember many of the events surrounding their drug use. The authors concluded that the psychotic syndrome present in their three patients was indicative of a short-term delirium rather than a substance-induced psychosis based on the presence of attention deficits and memory problems. The patients in this series responded well to brief hospitalization and antipsychotic medications.

As with seizure, extreme presentations such as psychosis are infrequently mentioned except in people requiring treatment at a hospital. There are simply no data regarding the prevalence of psychotic symptoms in the larger group of all synthetic stimulant users.

SUSPECT SLID INTOXICATION IN ‘PSYCHIATRIC’ PATIENTS

Despite the temporary ban on the more common substances found in Spice and bath salts, it is premature for the medical community to breath a sigh of relief. Producers of these products are already likely bringing to market new ones containing similar but as yet nonbanned substances. Furthermore, such bans will do little to affect Internet commerce; rather than go to a head shop, consumers will order the products online.

Doctors in urgent care centers, emergency rooms, and on general medical floors should pay close attention to any patient without a known psychiatric history who is acting in a bizarre fashion. Most SLID-intoxicated patients will present with anxiety, agitation, and psychosis. Rather than assume that they are psychiatric patients, one should consider the possibility of SLID intoxication and pay close attention to the possible medical sequelae associated with SLID use, such as elevated blood pressure, tachycardia, and seizure.

Benzodiazepines, especially lorazepam (Ativan), have been the agents most commonly used to treat both agitation and seizures associated with SLID intoxication.

Antipsychotics should be used judiciously because of their propensity to lower the seizure threshold, and patients with synthetic stimulant toxicity are already at increased risk of seizure.

A psychiatric consult should be considered in the event of any suspected toxicity or for any patient whose behavior is difficult to manage.

Restraints may be needed in some circumstances when agitation cannot be controlled with benzodiazepines alone, to ensure safety for the patient as well as that of others in the emergency department.

Routine laboratory tests should be part of the workup of patients suspected of being under the influence of SLIDs. These include a complete blood cell count, complete metabolic panel, and urine toxicology (Table 3).^23,25 A routine urine toxicology study will likely be negative, but either the patient or collateral information may give you a general idea of what the patient used, in which case the sample could be sent out for special tests for the more common substances found in herbal incense or bath salt products.

Electroencephalography may be indicated if there is any question as to whether the patient may have suffered a seizure. There should be a low threshold to order electrocardiography, especially in the case of synthetic stimulant intoxication.

Serial cardiac enzymes may be warranted if a patient with synthetic-stimulant intoxicated has chest pain.

Education, addiction treatment. Much is unknown about the risk of SLIDs, but given the adverse events reported in the literature, it seems likely that those with underlying cardiac or psychiatric issues may be at higher risk for the most serious drug-related consequences. With regard to synthetic stimulants, Winstock et al²⁰ recommend a harm-reduction approach involving educating patients about avoiding the development of tolerance, not engaging in polydrug use, not injecting, and paying special attention to remaining cool and well hydrated.

Experience shows that once SLID patients get through their acute crisis and are no longer psychotic, they tend to be forthright in divulging what they used to get high. At that point, consideration should be given to consulting an addiction treatment specialist for further evaluation of the patient’s drug use history and for formulation of a treatment plan to help ensure that the patient doesn’t return to using these drugs.

SLIDs POSE A REAL CHALLENGE

SLIDs present a real challenge to law enforcement, governments, the public, and the addiction treatment community. There is currently no way to routinely test for these substances. Furthermore, any tests that are developed or laws that are enacted will be easily evaded, as there are many more synthetic substances waiting in the wings to be released.

Don’t be lulled into thinking that SLIDs are gone with the recent bans against some of the more common substances. More SLIDs are coming, and more morbidity should be expected in medical settings.

Doctors in emergency departments and other settings need to be prepared for the agitated and often psychotic presentation of SLID-intoxicated patients and should be ready with benzodiazepines, restraints, and a calm and reassuring manner. And for patients who present with psychotic symptoms, medical staff should also be ready to consider involuntary short-term commitment to an inpatient psychiatric unit.

Once they recover, patients need to be educated about the dangers of substances such as SLIDs that, because of their novelty, may be perceived as less dangerous alternatives to traditional illicit drugs.

Over the past year, it has been hard to avoid news reports involving people getting high on “bath salts” and “incense” (also known as “Spice” or “K2”). Addiction treatment professionals have been overwhelmed by questions regarding why one would want to “snort bath salts” or “smoke incense.”

These substances are not what they appear to be. They are sold as bath salts and incense and are labeled “not for human consumption” simply to avoid regulation by the US Food and Drug Administration (FDA). In reality, they are powerful psychoactive drugs, with effects that mimic those of more commonly abused drugs such as amphetamines and marijuana. Until recently, they were legally available over the counter at quick-marts, head shops, and on the Internet. Because they are relatively new, they may not be detectable on routine urine drug screens, and users may be unaware of the specific chemicals contained in them.

These drugs, which we have collectively termed synthetic legal intoxicating drugs (SLIDs), are increasing dramatically in use.^1–3 A survey of youths at a rave party indicated that 21% had used one of them on at least one occasion.⁴ The general impression held by the drug-using public is that SLIDs are relatively cheap, are not detected on standard urine drug screens, can produce a powerful high, and, until recently, were readily available through legitimate sources.

Physicians need to be aware of SLIDs in order to recognize and manage the intoxication syndromes associated with these substances when encountered in clinical practice, and in order to educate patients about their potential dangers.

SYNTHETIC CANNABINOIDS MARKETED AS INCENSE

Herbal incense products that could be smoked as an alternative to marijuana started appearing on the Internet in Europe in 2004. By 2008, when such products first appeared in the United States, their use in Europe was already widespread.

Initially, consumers were led to believe that such herbal smoking blends were safe, legal alternatives to marijuana, and that it was the proprietary blend of herbs that was responsible for the “natural” high. Spice, a specific brand name, was originally trademarked in England as incense and also as an herbal smoking product.⁵

Legal authorities, however, suspected that these herbal blends were adulterated with synthetic substances. In December 2008, the first such substance was found when Austrian authorities isolated a synthetic cannabinoid, JWH-018, from an herbal incense product.⁶ By the end of 2009, five other synthetic cannabinoids—CP-47,497, HU-210, JWH-073, JWH-250, and JWH-398—had been isolated from various herbal incense samples around the world.⁷

The synthetic cannabinoids in herbal incense products are not derived from the hemp plant (Cannabis sativa), but are synthesized in laboratories and are formulated to interact with the endogenous cannabinoid receptors in the brain to produce psychoactive effects.

Synthetic cannabinoids are full agonists; natural THC is only a partial agonist

Two types of cannabinoid receptors have been discovered in humans: CB1 and CB2. Both types are found in the central nervous system, and CB2 is also found extensively in the periphery. CB1 is the receptor responsible for the psychoactive effects of cannabinoids, including altered consciousness, euphoria, relaxation, perceptual disturbances, intensified sensory experiences, cognitive impairment, and increased reaction time.⁶ The physiologic role of CB2 remains uncertain.

The major psychoactive cannabinoid in naturally occurring marijuana is delta-9-tetrahydrocannabinol (THC). The so-called classic cannabinoids, such as HU-210, are analogues of THC and are based on its chemical structure. The rest of the synthetic cannabinoids commonly found in incense products differ in chemical structure from naturally occurring cannabinoids such as THC, but have activity at the CB1 receptor and are thus psychoactive.

Of clinical relevance is that THC is only a partial agonist at the CB1 receptor, while all synthetic cannabinoids commonly found in incense products are full agonists at CB1.⁷ This difference is important because partial agonists bind to receptors but stimulate them only partially and therefore exhibit a plateau effect in terms of dose vs clinical response. In contrast, full agonists have no ceiling on the dose-response relationship and therefore have a greater potential for overdose and severe toxic effects.

Despite uncertainties, use is widespread

Most of the synthetic cannabinoids in herbal incense products were developed for research purposes, and there are almost no reliable scientific data on their effects in humans. Of additional concern is that no research has been conducted on their pyrolytic effects, ie, how these chemicals are transformed when they are burned, such as when consumers smoke them. Furthermore, herbal incense products often vary in their active substances and concentrations, so consumers really do not know what they are getting.

Despite the many uncertainties, the use of these products is widespread. Data submitted to the US Drug Enforcement Administration (DEA) from a major toxicology laboratory indicated that from July through November of 2010, 3,700 samples tested positive for either JWH-018 or JWH-073. This report also indicated that 30% to 35% of specimens submitted by juvenile probation departments were positive for synthetic cannabinoids.⁸

MEDICAL CONCERNS OVER SYNTHETIC CANNABINOIDS

Amid the mysteries surrounding synthetic cannabinoids, one thing is clear: users are increasingly seeking medical attention. In 2010, there were 2,906 calls to poison control centers across the United States pertaining to “synthetic marijuana”; in 2011 there were 6,959 calls, and in January 2012, 639 such calls had been placed.⁹

The duration of the intoxicating effects of synthetic cannabinoids is generally longer than that of THC, but this seems to be variable. JWH-018, for instance, seems to have a shorter duration of action, at around 1 to 2 hours, while a longer, 5- to 6-hour intoxicating effect has been observed with CP-47,497.^7,12

Serious adverse effects

Although the prevalence of serious adverse effects associated with the use of synthetic cannabinoids is not known, a number of serious complications have been recognized.

Seizures. One case of seizure has been reported in association with the use of synthetic cannabinoids, specifically JWH-018.¹² This case involved a previously healthy 48-year-old man who had ingested a powder that was subsequently confirmed to be JWH-018, which he mixed with alcohol. Of further concern in this case is that this individual developed a refractory supraventricular tachycardia that required cardioversion on the first hospital day.

The authors speculated that the seizure may have been due to a dose-response mechanism that resulted in either the release of presynaptic excitatory neurotransmitters or the decreased release of inhibitory neurotransmitters. They further postulated that the supraventricular tachycardia could have been caused by one of two mechanisms previously reported in association with CB1 agonists: an increase in circulating catecholamines or heightened oxidative demands on the myocardium.¹²

Psychosis. The occurrence of psychotic symptoms such as hallucinations and paranoid delusions in association with synthetic cannabinoids is not surprising, given the well-documented link between marijuana use and psychosis.^13,14

A case report of a 25-year-old patient with a 7-year history of recurrent psychosis that was initially triggered by cannabis use indicated that the use of 3 g of herbal incense on three occasions was associated with worsening of previous psychotic symptoms and the emergence of command and paranoid types of auditory hallucination.¹⁰

Semistructured interviews of 15 patients in a forensic rehabilitative service, all of whom had a history of psychotic illness, showed that 69% experienced symptoms consistent with psychotic relapse after smoking an herbal incense product containing JWH-018.¹⁵

It is possible that psychotic symptoms may be more prominent with synthetic cannabinoids than with natural marijuana because not only are synthetic cannabinoids more potent and work as full agonists, but, unlike marijuana, they do not contain cannabidiol, which is thought to have antipsychotic efficacy.^10,16 However, the risk of psychotic symptoms in association with synthetic cannabinoid usage in otherwise healthy people is unknown.

Regulation lags behind

Growing concern over the perceived dangers posed by synthetic cannabinoids has led to a ban on some of the more common ones contained in herbal incense preparations. On March 1, 2011, the US DEA temporarily placed five synthetic cannabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol) under schedule I (banned substances).

Such a ban, however, may be futile because there are an estimated 100 synthetic cannabinoids that have yet to enter the market, and when one is banned, a new one is likely to be introduced immediately as a replacement.⁸

SYNTHETIC STIMULANTS MARKETED AS BATH SALTS

Like the herbal incense products, “bath salts” may likewise not be what they appear to be. They too may be labeled “not for human consumption” in an effort to bypass laws governing mind-altering substances.

Several pharmacologically active substances have been marketed as bath salts. Two of the more common ingredients are 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylcathinone (mephedrone).

MDPV is a dopamine and norepineph-rine reuptake inhibitor that acts as a powerful stimulant. It has no FDA-approved medical use, but it is an analogue of the stimulant pyrovalerone, which was once used to treat chronic fatigue.¹⁷

MDPV seems to be the most common substance found in bath salt products in the United States. A sample of this substance was first seized on the streets by German authorities in 2007. A study in Finland conducted from August 2009 to September 2010 estimated that 5.7% of all arrests for driving under the influence (DUI) unrelated to alcohol consumption involved MDPV intoxication.¹⁷ In 2009, the National Forensic Laboratory Information System of the US DEA had seized only two samples of MDPV, but by 2010 that had increased to 161.¹⁸

Mephedrone is derived from phenethylamine and is closely related to cathinone, the active ingredient in the African khat plant (Catha edulis).¹⁹ Khat has a history of abuse, and the chemical structure of cathinone and its derivatives is similar to that of amphetamine.

Mephedrone, a powerful stimulant, is suspected of working as a monoamine reuptake inhibitor, and it may also directly induce the presynaptic release of monoamines.²⁰ The net effect is an increase in serotonin, norepineph-rine, and dopamine levels at neuronal synapses.

Mephedrone was first described in 1929 by chemist Saem de Burnaga Sanchez, and it remained an obscure research chemical for many years.²¹ It was formally recognized as a drug of abuse in Europe in 2007, and by 2009 it was the sixth most frequently used such drug in Europe.^8,22

Although MDPV and mephedrone are the most common psychoactive ingredients in bath salts, many other synthetic drugs have been found on the market.

A temporary ban

On September 7, 2011, the US government made it illegal to possess or sell any substance containing MDPV, mephedrone, or methy-lone. This temporary restriction was to remain in effect for 1 year to give the DEA time to collect data to support a move to permanently control these substances.³

Like synthetic cannabinoids, however, synthetic stimulants are very difficult to regulate because they are a large group of substances. As soon as one substance is outlawed, another synthetic stimulant will likely take its place.

MEDICAL CONCERNS REGARDING SYNTHETIC STIMULANTS

The medical and psychiatric sequelae that are associated with the use of bath salts have sent an increasing number of people to emergency rooms. The number of bath-salt-related calls to US poison control centers increased dramatically from 303 in 2010 to 4,720 by August 31, 2011. Most of these calls were related to tachycardia, agitation, hallucinations, extreme paranoia, delusions, and elevations in blood pressure.³

A report of 35 cases of people who had used bath salts and who had reported to Michigan emergency rooms between November 13, 2010, and March 31, 2011, indicated that agitation was present in 66%, tachycardia in 63%, delusions and hallucinations in 40%, seizure or tremor in 29%, hypertension in 23%, drowsiness in 23%, paranoia in 20%, and mydriasis in 20%; one patient was dead on arrival. Of the 34 patients who were alive on arrival, 17 (50%) were hospitalized, 15 were released, and 2 left against medical advice. In the patients in this study, 63% had injected the drug, 26% snorted it, and 11% ingested it orally.² Toxicology results obtained during an autopsy on the one person who died revealed a high level of MDPV, and the coroner ruled that MDPV toxicity was the primary cause of death.²

Though the pharmacokinetic properties of mephedrone are unknown, James et al²⁴ noted that an interesting feature is that its clinical effects seem to persist for more than 24 hours after the last exposure to the drug, which would not be expected based on the rapid elimination of other similar cathinones.

Sympathomimetic toxicity. Many of the symptoms listed in Table 2 are consistent with a sympathomimetic syndrome. In a case series reported by Regan et al,²⁶ most of the 57 patients exhibited cardiovascular findings consistent with sympathomimetic toxicity.

In the study by James et al,²⁴ one of the patients with chest pain had electrocardiographic changes consistent with acute myocardial infarction. Though it is not possible to conclude from a single case that mephedrone poses a risk of myocardial infarction, such a risk has been reported with khat.²⁸ More research is needed to determine whether mephedrone poses a risk of cardiac events when used by people with or without an underlying cardiac condition.

Seizure also seems to be a relatively common feature associated with mephedrone use in case series of emergency room presentations. The US Centers for Disease Control and Prevention l² reported that of 35 patients who had used bath salts, 40% experienced seizures or “tremors.” A recent case series²⁷ of 15 patients presenting to an emergency department after mephedrone use reported that 20% had experienced seizures. In the study by James et al,²⁴ four patients (3% of the total group) experienced seizures after using mephedrone. It should be noted that, aside from people presenting to emergency rooms, seizures are rarely reported in the wider population of mephedrone users.

Psychotic symptoms are also quite common in users of synthetic stimulants who present to emergency rooms, occurring, as previously stated, in 14% to 40% of cases.^2,24

In a small case series, Penders and Gestring²⁹ pointed out some common features in three patients who had used MDPV and had presented with psychosis: sleep problems, inattention, vivid hallucinations of intruders, fearfulness, and inability to remember many of the events surrounding their drug use. The authors concluded that the psychotic syndrome present in their three patients was indicative of a short-term delirium rather than a substance-induced psychosis based on the presence of attention deficits and memory problems. The patients in this series responded well to brief hospitalization and antipsychotic medications.

As with seizure, extreme presentations such as psychosis are infrequently mentioned except in people requiring treatment at a hospital. There are simply no data regarding the prevalence of psychotic symptoms in the larger group of all synthetic stimulant users.

SUSPECT SLID INTOXICATION IN ‘PSYCHIATRIC’ PATIENTS

Despite the temporary ban on the more common substances found in Spice and bath salts, it is premature for the medical community to breath a sigh of relief. Producers of these products are already likely bringing to market new ones containing similar but as yet nonbanned substances. Furthermore, such bans will do little to affect Internet commerce; rather than go to a head shop, consumers will order the products online.

Doctors in urgent care centers, emergency rooms, and on general medical floors should pay close attention to any patient without a known psychiatric history who is acting in a bizarre fashion. Most SLID-intoxicated patients will present with anxiety, agitation, and psychosis. Rather than assume that they are psychiatric patients, one should consider the possibility of SLID intoxication and pay close attention to the possible medical sequelae associated with SLID use, such as elevated blood pressure, tachycardia, and seizure.

Benzodiazepines, especially lorazepam (Ativan), have been the agents most commonly used to treat both agitation and seizures associated with SLID intoxication.

Antipsychotics should be used judiciously because of their propensity to lower the seizure threshold, and patients with synthetic stimulant toxicity are already at increased risk of seizure.

A psychiatric consult should be considered in the event of any suspected toxicity or for any patient whose behavior is difficult to manage.

Restraints may be needed in some circumstances when agitation cannot be controlled with benzodiazepines alone, to ensure safety for the patient as well as that of others in the emergency department.

Routine laboratory tests should be part of the workup of patients suspected of being under the influence of SLIDs. These include a complete blood cell count, complete metabolic panel, and urine toxicology (Table 3).^23,25 A routine urine toxicology study will likely be negative, but either the patient or collateral information may give you a general idea of what the patient used, in which case the sample could be sent out for special tests for the more common substances found in herbal incense or bath salt products.

Electroencephalography may be indicated if there is any question as to whether the patient may have suffered a seizure. There should be a low threshold to order electrocardiography, especially in the case of synthetic stimulant intoxication.

Serial cardiac enzymes may be warranted if a patient with synthetic-stimulant intoxicated has chest pain.

Education, addiction treatment. Much is unknown about the risk of SLIDs, but given the adverse events reported in the literature, it seems likely that those with underlying cardiac or psychiatric issues may be at higher risk for the most serious drug-related consequences. With regard to synthetic stimulants, Winstock et al²⁰ recommend a harm-reduction approach involving educating patients about avoiding the development of tolerance, not engaging in polydrug use, not injecting, and paying special attention to remaining cool and well hydrated.

Experience shows that once SLID patients get through their acute crisis and are no longer psychotic, they tend to be forthright in divulging what they used to get high. At that point, consideration should be given to consulting an addiction treatment specialist for further evaluation of the patient’s drug use history and for formulation of a treatment plan to help ensure that the patient doesn’t return to using these drugs.

SLIDs POSE A REAL CHALLENGE

SLIDs present a real challenge to law enforcement, governments, the public, and the addiction treatment community. There is currently no way to routinely test for these substances. Furthermore, any tests that are developed or laws that are enacted will be easily evaded, as there are many more synthetic substances waiting in the wings to be released.

Don’t be lulled into thinking that SLIDs are gone with the recent bans against some of the more common substances. More SLIDs are coming, and more morbidity should be expected in medical settings.

Doctors in emergency departments and other settings need to be prepared for the agitated and often psychotic presentation of SLID-intoxicated patients and should be ready with benzodiazepines, restraints, and a calm and reassuring manner. And for patients who present with psychotic symptoms, medical staff should also be ready to consider involuntary short-term commitment to an inpatient psychiatric unit.

Once they recover, patients need to be educated about the dangers of substances such as SLIDs that, because of their novelty, may be perceived as less dangerous alternatives to traditional illicit drugs.

A 30-year-old man sustained traumatic amputations of three of his left fingers while at work. A heavy object fell when a supporting chain snapped; although he moved quickly, three of his left distal fingers were caught under the object. He was flown to a hospital for definitive hand care.

During the preadmission history and physical, it was noted that the patient had mild right knee pain in addition to his finger injuries. He had experienced no head injury and no loss of consciousness or other complaints. He did not remember injuring his leg, although he said it might have been struck by the falling object; all he could remember was the injury to his fingers.

On physical exam, the only abnormality other than the man’s traumatic finger amputations was mild right knee edema and a small bruised area medially. Initially, he complained of mild pain on palpation and moderate pain with passive range of motion, but range of motion was intact. His pain was worse at the proximal, medial tibial area, and he had mild lateral mid-calf tenderness though no bruising. Distally, his right lower extremity motor and sensory function were intact, and he had no open wounds or skin breakdown. He had 2+ dorsalis pedis pulse and 1+ posterior tibial pulse. The toes were pink and warm with brisk capillary refill. All compartments were soft and compressible.

Upon review of his plain radiographs (three views of the right knee), the patient was noted to have a severely comminuted medial tibial plateau fracture that extended to the midline in the region of the tibial spine, with mild depression of the fracture fragments measuring about 6 mm (see Figures 1a, 1b, and 1c). This would translate into a Schatzker IV classification type¹ fracture (see Figure 2^2,3).

The man was admitted and underwent emergent surgery on his injured left fingers that night. Further diagnostic knee testing was performed, including CT and MRI (see Figures 3 and 4). Three days after admission, the patient underwent open reduction and internal fixation (plating) of the right medial, proximal tibia (see Figure 5). He has done very well since without issue.

DISCUSSION
Fractures of the tibial plateau occur along the articular, or joint, surface of the proximal tibia. The plateau consists of lateral and medial condylar surfaces. These concave structures function as an articulation point for the cartilaginous menisci and the femoral condyles.⁴ The medial plateau and condyle are stronger than those of the lateral side, and therefore are less commonly fractured. An elevated intercondylar eminence divides the lateral and medial plateaus, providing an attachment site for the cruciate ligaments.³

The Schatzker classification system¹ is most commonly used to describe the types of tibial plateau fractures (as seen in Figure 2^2,3). Schatzker et al¹ divided these injuries into six categories, according to the impact of increased energy exerted onto the bone; the rising classification numbers indicate an increase in complexity and severity and usually a worsening prognosis.

The type I fracture represents a split fracture of the lateral plateau. Typically, a fracture of this type has depression or displacement measuring less than 4 mm.

Type II tibial plateau fractures, the most common Schatzker injury, are lateral plateau fractures with depression noted at the split. Not always evident on plain radiographs, this depression can often be overlooked, and the injury mistaken for a type I fracture. The depression is measured vertically from the lower edge of the medial plateau to the lowest depression point of the lateral plateau.⁵

Type III fractures, the least common among the Schatzker injuries, are described as pure depression fractures of the lateral plateau. These fractures do not have an appreciable “split” along the plateau and are usually found in older patients with osteopenia.²

The Schatzker type IV injury is a medial fracture with displacement or depression to a portion of the plateau. The fracture may be split or comminuted and may originate in the intercondylar area.

Type V fractures, also known as “bicondylar fractures,” affect both the lateral and medial plateau. An inverted “Y” pattern is frequently seen, and there may be additional involvement of the intercondylar eminence. Type V fractures differ from type VI injuries in that there is no disturbance of the metaphyseal-diaphyseal connection. Thus, type VI fractures also include a transverse component that separates the condyles (metaphysis) of the bone from the shaft (diaphysis). Wide variation is seen among type VI fractures.⁵

Assessment and Diagnosis
Originally termed “fender fractures” due to their frequent association with automobile injuries, fractures of the tibial plateau account for 1% of all fractures and 8% of fractures in elderly patients.⁶ Tibial plateau fractures occur when varus or valgus force is combined with axial loading. The fracture itself occurs when the femoral condyle is driven into the lateral or medial plateau. Bicondylar injuries occur when rigorous axial force is sustained in a fully extended knee.

Injuries may also include those of the ligaments or menisci, resulting in joint instability. Patients may present with generalized knee pain or difficulty bearing weight after sustaining injuries, such as being struck in a motor vehicle accident, being tackled, or falling from some height.⁴

Evaluation of a patient with a suspected tibial plateau fracture begins with a detailed history and thorough physical examination. Details regarding the mechanism of injury help to predict the pattern of the fracture and may indicate whether a more focused neurovascular exam is warranted. Low-energy injuries (often seen with Schatzker types I to III) or twisting injuries yield low suspicion for neurovascular injury or compartment syndrome. However, high-energy injuries (seen often with Schatzker types IV through VI) have a greater likelihood of resulting in complicated injuries that must be urgently or emergently treated.⁵

The popliteal artery is bound posteriorly and distally to the tibial plateau, and the peroneal nerve is located laterally and positioned around the fibular head. It is essential to assess for the popliteal pulse, as well as lateral lower-extremity sensation and the patient’s ability to dorsiflex. Along with motor and neurovascular injuries, presentation with a painful, strikingly swollen knee and difficulty bearing weight may indicate a hemarthrosis. Soft tissue injuries over the knee resulting from direct trauma may require a saline arthrogram to rule out communication into the joint. Furthermore, a thorough ligamentous exam of the knee is helpful in determining the extent of the injuries.³

Compartment syndrome is a serious, emergent complication that can occur with tibial plateau fractures, especially those sustained during high-energy trauma.⁷ The health care provider must perform serial exams of the lower extremity to assess for classic signs of compartment syndrome. Are the compartments tense or noncompressible? Does the patient have pain with passive stretch or with range of motion of the lower extremity? Is there pallor or paresthesia to the affected limb? Is the pulse weak or absent? Presence of any of the aforementioned symptoms should prompt a high suspicion for compartment syndrome, and the patient must be sent to an emergency department for urgent evaluation.⁵

Treatment/Rehabilitation
For Schatzker types I through III, intervention focuses on the articular cartilage examination and repair. Type IV injuries often include corresponding damage to the popliteal artery and/or peroneal nerve, and types V and VI often have such overlying soft tissue damage that temporary placement of an external fixation device is required before definitive surgical intervention can be performed.⁸

However, it should be noted that conservative versus surgical treatment is often debated among surgeons for treatment of Schatzker fractures. The management of a tibial plateau fracture depends on the physical demands and health of the patient, the severity of the fracture, the stability of the joint, and the surgeon’s skill set and preferences.⁴ Operative intervention is generally indicated for fractures with depressions greater than 2 mm (although some surgeons allow up to 1 cm of depression), fractures with joint instability, or open fractures. Injuries with concern for vascular injury or compartment syndrome are also treated both operatively and emergently. Postoperatively, patients will remain non–weight-bearing for eight to 12 weeks after surgery, and in the interim, depending on the surgeon’s preference, may or may not engage in active or passive range of motion of the knee.

Advocates of open reduction and internal fixation (ORIF) argue that this method allows for the fracture reduction and anatomic alignment to be directly examined, but they also acknowledge that this approach compromises a great deal of soft tissue surrounding the proximal tibia.^9,10

In order to reduce soft tissue damage, some surgeons favor external fixation. Initial use of this surgical technique results in minimal soft tissue swelling and allows early range of motion. While the external fixation device is in place, there is a risk for pin site infection, and proper site care must be provided.^6,11

Generally, the treatment of tibial plateau fractures is considered successful when the fracture reduction is sustained, the patient’s functional capacity and axial loading are restored, and the articular surface is reconstructed. As a rule, nonoperative treatment is reserved for tibial plateau fractures that are minimally depressed or nondisplaced, or for patients with advanced osteoporosis. Under these circumstances, after a non–weight-bearing period of four to eight weeks, patients will begin to perform protected and partial weight bearing using a hinged knee brace.² Early active range of motion, along with isometric exercises to strengthen the quadriceps, is recommended.

Whether surgical or conservative treatment is chosen, complications of tibial plateau fractures include knee stiffness, wound breakdown and infection, malunion or nonunion, vascular or neurologic injury, prominent or painful hardware, or avascular necrosis of fragmented bone pieces.⁴

CONCLUSION
The primary care practitioner must never overlook patients’ complaints of knee pain, especially after varus or valgus stress injuries or axial loading injuries to the knee. The patient may be able to ambulate; however, ordering a radiograph is an easy method for evaluation and for ruling out tibial plateau injuries. If there is any question regarding the presence of fracture with plain radiographs and/or the clinical exam warrants it, CT is an appropriate second diagnostic intervention.

Should a tibial plateau fracture present in a primary care or urgent care setting, thorough examination of neurovascular status and risk for compartment syndrome must be done urgently, followed by a referral to an orthopedic surgeon or emergency department.

REFERENCES
1. Schatzker J, McBroom R, Bruce D. The tibial plateau fracture: the Toronto experience, 1968–1975. Clin Orthop Relat Res. 1979;(138): 94-104.

2. Marsh JL. Tibial plateau fractures. In: Bucholz RW, Court-Brown CM, Heckman HD, Tornetta P. Rockwood and Green’s Fractures in Adults. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:1780-1831.

3. Egol K, Koval KJ, Zuckerman JD. Tibial plateau. In: Egol K, Koval KJ, Zuckerman JD.  Handbook of Fractures. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:455-463.

4. Fenton PP, Porter KK. Tibial plateau fractures: a review. Trauma. 2011;13(3):181-187.

5. Markhardt BK, Gross JM, Monu JU. Schatzker classification of tibial plateau fractures: use of CT and MR imaging improves assessment. Radiographics. 2009;29(2):585-597.

6. Lewis C. Does the mode of fixation of tibial plateau fractures, i.e. external fixation versus internal fixation, influence the time to union? A systematic review of the literature. Eur J Orthopaed Surg Traumatol. 2008;18(5):365-370.

7. Weinlein J, Schmidt A. Acute compartment syndrome in tibial plateau fractures—beware! J Knee Surg. 2010;31(1):9-16.

8. te Stroet MA, Holla M, Biert J, van Kampen A. The value of CT scan compared to plain radiographs for the classification and treatment plan in tibial plateau fractures. Emerg Radiol. 2011;18(4):279-283.

9. Musahl V, Tarkin I, Kobbe P, et al. New trends and techniques in open reduction and internal fixation of fractures of the tibial plateau. J Bone Joint Surg Br. 2009;91(4):426-433.

10. Toro-Arbelaez JB, Gardner MJ, Shindle MK, et al. Open reduction and internal fixation of intraarticular tibial plateau nonunions. Injury. 2007;38(3):378-383.

11. Marsh JL, Smith ST, Do TT. External fixation and limited internal fixation for complex fractures of the tibial plateau. J Bone Joint Surg Am. 1995;77(5):661-673.

A 30-year-old man sustained traumatic amputations of three of his left fingers while at work. A heavy object fell when a supporting chain snapped; although he moved quickly, three of his left distal fingers were caught under the object. He was flown to a hospital for definitive hand care.

During the preadmission history and physical, it was noted that the patient had mild right knee pain in addition to his finger injuries. He had experienced no head injury and no loss of consciousness or other complaints. He did not remember injuring his leg, although he said it might have been struck by the falling object; all he could remember was the injury to his fingers.

On physical exam, the only abnormality other than the man’s traumatic finger amputations was mild right knee edema and a small bruised area medially. Initially, he complained of mild pain on palpation and moderate pain with passive range of motion, but range of motion was intact. His pain was worse at the proximal, medial tibial area, and he had mild lateral mid-calf tenderness though no bruising. Distally, his right lower extremity motor and sensory function were intact, and he had no open wounds or skin breakdown. He had 2+ dorsalis pedis pulse and 1+ posterior tibial pulse. The toes were pink and warm with brisk capillary refill. All compartments were soft and compressible.

Upon review of his plain radiographs (three views of the right knee), the patient was noted to have a severely comminuted medial tibial plateau fracture that extended to the midline in the region of the tibial spine, with mild depression of the fracture fragments measuring about 6 mm (see Figures 1a, 1b, and 1c). This would translate into a Schatzker IV classification type¹ fracture (see Figure 2^2,3).

The man was admitted and underwent emergent surgery on his injured left fingers that night. Further diagnostic knee testing was performed, including CT and MRI (see Figures 3 and 4). Three days after admission, the patient underwent open reduction and internal fixation (plating) of the right medial, proximal tibia (see Figure 5). He has done very well since without issue.

DISCUSSION
Fractures of the tibial plateau occur along the articular, or joint, surface of the proximal tibia. The plateau consists of lateral and medial condylar surfaces. These concave structures function as an articulation point for the cartilaginous menisci and the femoral condyles.⁴ The medial plateau and condyle are stronger than those of the lateral side, and therefore are less commonly fractured. An elevated intercondylar eminence divides the lateral and medial plateaus, providing an attachment site for the cruciate ligaments.³

The Schatzker classification system¹ is most commonly used to describe the types of tibial plateau fractures (as seen in Figure 2^2,3). Schatzker et al¹ divided these injuries into six categories, according to the impact of increased energy exerted onto the bone; the rising classification numbers indicate an increase in complexity and severity and usually a worsening prognosis.

The type I fracture represents a split fracture of the lateral plateau. Typically, a fracture of this type has depression or displacement measuring less than 4 mm.

Type II tibial plateau fractures, the most common Schatzker injury, are lateral plateau fractures with depression noted at the split. Not always evident on plain radiographs, this depression can often be overlooked, and the injury mistaken for a type I fracture. The depression is measured vertically from the lower edge of the medial plateau to the lowest depression point of the lateral plateau.⁵

Type III fractures, the least common among the Schatzker injuries, are described as pure depression fractures of the lateral plateau. These fractures do not have an appreciable “split” along the plateau and are usually found in older patients with osteopenia.²

The Schatzker type IV injury is a medial fracture with displacement or depression to a portion of the plateau. The fracture may be split or comminuted and may originate in the intercondylar area.

Type V fractures, also known as “bicondylar fractures,” affect both the lateral and medial plateau. An inverted “Y” pattern is frequently seen, and there may be additional involvement of the intercondylar eminence. Type V fractures differ from type VI injuries in that there is no disturbance of the metaphyseal-diaphyseal connection. Thus, type VI fractures also include a transverse component that separates the condyles (metaphysis) of the bone from the shaft (diaphysis). Wide variation is seen among type VI fractures.⁵

Assessment and Diagnosis
Originally termed “fender fractures” due to their frequent association with automobile injuries, fractures of the tibial plateau account for 1% of all fractures and 8% of fractures in elderly patients.⁶ Tibial plateau fractures occur when varus or valgus force is combined with axial loading. The fracture itself occurs when the femoral condyle is driven into the lateral or medial plateau. Bicondylar injuries occur when rigorous axial force is sustained in a fully extended knee.

Injuries may also include those of the ligaments or menisci, resulting in joint instability. Patients may present with generalized knee pain or difficulty bearing weight after sustaining injuries, such as being struck in a motor vehicle accident, being tackled, or falling from some height.⁴

Evaluation of a patient with a suspected tibial plateau fracture begins with a detailed history and thorough physical examination. Details regarding the mechanism of injury help to predict the pattern of the fracture and may indicate whether a more focused neurovascular exam is warranted. Low-energy injuries (often seen with Schatzker types I to III) or twisting injuries yield low suspicion for neurovascular injury or compartment syndrome. However, high-energy injuries (seen often with Schatzker types IV through VI) have a greater likelihood of resulting in complicated injuries that must be urgently or emergently treated.⁵

The popliteal artery is bound posteriorly and distally to the tibial plateau, and the peroneal nerve is located laterally and positioned around the fibular head. It is essential to assess for the popliteal pulse, as well as lateral lower-extremity sensation and the patient’s ability to dorsiflex. Along with motor and neurovascular injuries, presentation with a painful, strikingly swollen knee and difficulty bearing weight may indicate a hemarthrosis. Soft tissue injuries over the knee resulting from direct trauma may require a saline arthrogram to rule out communication into the joint. Furthermore, a thorough ligamentous exam of the knee is helpful in determining the extent of the injuries.³

Compartment syndrome is a serious, emergent complication that can occur with tibial plateau fractures, especially those sustained during high-energy trauma.⁷ The health care provider must perform serial exams of the lower extremity to assess for classic signs of compartment syndrome. Are the compartments tense or noncompressible? Does the patient have pain with passive stretch or with range of motion of the lower extremity? Is there pallor or paresthesia to the affected limb? Is the pulse weak or absent? Presence of any of the aforementioned symptoms should prompt a high suspicion for compartment syndrome, and the patient must be sent to an emergency department for urgent evaluation.⁵

Treatment/Rehabilitation
For Schatzker types I through III, intervention focuses on the articular cartilage examination and repair. Type IV injuries often include corresponding damage to the popliteal artery and/or peroneal nerve, and types V and VI often have such overlying soft tissue damage that temporary placement of an external fixation device is required before definitive surgical intervention can be performed.⁸

However, it should be noted that conservative versus surgical treatment is often debated among surgeons for treatment of Schatzker fractures. The management of a tibial plateau fracture depends on the physical demands and health of the patient, the severity of the fracture, the stability of the joint, and the surgeon’s skill set and preferences.⁴ Operative intervention is generally indicated for fractures with depressions greater than 2 mm (although some surgeons allow up to 1 cm of depression), fractures with joint instability, or open fractures. Injuries with concern for vascular injury or compartment syndrome are also treated both operatively and emergently. Postoperatively, patients will remain non–weight-bearing for eight to 12 weeks after surgery, and in the interim, depending on the surgeon’s preference, may or may not engage in active or passive range of motion of the knee.

Advocates of open reduction and internal fixation (ORIF) argue that this method allows for the fracture reduction and anatomic alignment to be directly examined, but they also acknowledge that this approach compromises a great deal of soft tissue surrounding the proximal tibia.^9,10

In order to reduce soft tissue damage, some surgeons favor external fixation. Initial use of this surgical technique results in minimal soft tissue swelling and allows early range of motion. While the external fixation device is in place, there is a risk for pin site infection, and proper site care must be provided.^6,11

Generally, the treatment of tibial plateau fractures is considered successful when the fracture reduction is sustained, the patient’s functional capacity and axial loading are restored, and the articular surface is reconstructed. As a rule, nonoperative treatment is reserved for tibial plateau fractures that are minimally depressed or nondisplaced, or for patients with advanced osteoporosis. Under these circumstances, after a non–weight-bearing period of four to eight weeks, patients will begin to perform protected and partial weight bearing using a hinged knee brace.² Early active range of motion, along with isometric exercises to strengthen the quadriceps, is recommended.

Whether surgical or conservative treatment is chosen, complications of tibial plateau fractures include knee stiffness, wound breakdown and infection, malunion or nonunion, vascular or neurologic injury, prominent or painful hardware, or avascular necrosis of fragmented bone pieces.⁴

CONCLUSION
The primary care practitioner must never overlook patients’ complaints of knee pain, especially after varus or valgus stress injuries or axial loading injuries to the knee. The patient may be able to ambulate; however, ordering a radiograph is an easy method for evaluation and for ruling out tibial plateau injuries. If there is any question regarding the presence of fracture with plain radiographs and/or the clinical exam warrants it, CT is an appropriate second diagnostic intervention.

Should a tibial plateau fracture present in a primary care or urgent care setting, thorough examination of neurovascular status and risk for compartment syndrome must be done urgently, followed by a referral to an orthopedic surgeon or emergency department.

REFERENCES
1. Schatzker J, McBroom R, Bruce D. The tibial plateau fracture: the Toronto experience, 1968–1975. Clin Orthop Relat Res. 1979;(138): 94-104.

2. Marsh JL. Tibial plateau fractures. In: Bucholz RW, Court-Brown CM, Heckman HD, Tornetta P. Rockwood and Green’s Fractures in Adults. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:1780-1831.

3. Egol K, Koval KJ, Zuckerman JD. Tibial plateau. In: Egol K, Koval KJ, Zuckerman JD.  Handbook of Fractures. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:455-463.

4. Fenton PP, Porter KK. Tibial plateau fractures: a review. Trauma. 2011;13(3):181-187.

5. Markhardt BK, Gross JM, Monu JU. Schatzker classification of tibial plateau fractures: use of CT and MR imaging improves assessment. Radiographics. 2009;29(2):585-597.

6. Lewis C. Does the mode of fixation of tibial plateau fractures, i.e. external fixation versus internal fixation, influence the time to union? A systematic review of the literature. Eur J Orthopaed Surg Traumatol. 2008;18(5):365-370.

7. Weinlein J, Schmidt A. Acute compartment syndrome in tibial plateau fractures—beware! J Knee Surg. 2010;31(1):9-16.

8. te Stroet MA, Holla M, Biert J, van Kampen A. The value of CT scan compared to plain radiographs for the classification and treatment plan in tibial plateau fractures. Emerg Radiol. 2011;18(4):279-283.

9. Musahl V, Tarkin I, Kobbe P, et al. New trends and techniques in open reduction and internal fixation of fractures of the tibial plateau. J Bone Joint Surg Br. 2009;91(4):426-433.

10. Toro-Arbelaez JB, Gardner MJ, Shindle MK, et al. Open reduction and internal fixation of intraarticular tibial plateau nonunions. Injury. 2007;38(3):378-383.

11. Marsh JL, Smith ST, Do TT. External fixation and limited internal fixation for complex fractures of the tibial plateau. J Bone Joint Surg Am. 1995;77(5):661-673.

A 30-year-old man sustained traumatic amputations of three of his left fingers while at work. A heavy object fell when a supporting chain snapped; although he moved quickly, three of his left distal fingers were caught under the object. He was flown to a hospital for definitive hand care.

During the preadmission history and physical, it was noted that the patient had mild right knee pain in addition to his finger injuries. He had experienced no head injury and no loss of consciousness or other complaints. He did not remember injuring his leg, although he said it might have been struck by the falling object; all he could remember was the injury to his fingers.

On physical exam, the only abnormality other than the man’s traumatic finger amputations was mild right knee edema and a small bruised area medially. Initially, he complained of mild pain on palpation and moderate pain with passive range of motion, but range of motion was intact. His pain was worse at the proximal, medial tibial area, and he had mild lateral mid-calf tenderness though no bruising. Distally, his right lower extremity motor and sensory function were intact, and he had no open wounds or skin breakdown. He had 2+ dorsalis pedis pulse and 1+ posterior tibial pulse. The toes were pink and warm with brisk capillary refill. All compartments were soft and compressible.

Upon review of his plain radiographs (three views of the right knee), the patient was noted to have a severely comminuted medial tibial plateau fracture that extended to the midline in the region of the tibial spine, with mild depression of the fracture fragments measuring about 6 mm (see Figures 1a, 1b, and 1c). This would translate into a Schatzker IV classification type¹ fracture (see Figure 2^2,3).

The man was admitted and underwent emergent surgery on his injured left fingers that night. Further diagnostic knee testing was performed, including CT and MRI (see Figures 3 and 4). Three days after admission, the patient underwent open reduction and internal fixation (plating) of the right medial, proximal tibia (see Figure 5). He has done very well since without issue.

DISCUSSION
Fractures of the tibial plateau occur along the articular, or joint, surface of the proximal tibia. The plateau consists of lateral and medial condylar surfaces. These concave structures function as an articulation point for the cartilaginous menisci and the femoral condyles.⁴ The medial plateau and condyle are stronger than those of the lateral side, and therefore are less commonly fractured. An elevated intercondylar eminence divides the lateral and medial plateaus, providing an attachment site for the cruciate ligaments.³

The Schatzker classification system¹ is most commonly used to describe the types of tibial plateau fractures (as seen in Figure 2^2,3). Schatzker et al¹ divided these injuries into six categories, according to the impact of increased energy exerted onto the bone; the rising classification numbers indicate an increase in complexity and severity and usually a worsening prognosis.

The type I fracture represents a split fracture of the lateral plateau. Typically, a fracture of this type has depression or displacement measuring less than 4 mm.

Type II tibial plateau fractures, the most common Schatzker injury, are lateral plateau fractures with depression noted at the split. Not always evident on plain radiographs, this depression can often be overlooked, and the injury mistaken for a type I fracture. The depression is measured vertically from the lower edge of the medial plateau to the lowest depression point of the lateral plateau.⁵

Type III fractures, the least common among the Schatzker injuries, are described as pure depression fractures of the lateral plateau. These fractures do not have an appreciable “split” along the plateau and are usually found in older patients with osteopenia.²

The Schatzker type IV injury is a medial fracture with displacement or depression to a portion of the plateau. The fracture may be split or comminuted and may originate in the intercondylar area.

Type V fractures, also known as “bicondylar fractures,” affect both the lateral and medial plateau. An inverted “Y” pattern is frequently seen, and there may be additional involvement of the intercondylar eminence. Type V fractures differ from type VI injuries in that there is no disturbance of the metaphyseal-diaphyseal connection. Thus, type VI fractures also include a transverse component that separates the condyles (metaphysis) of the bone from the shaft (diaphysis). Wide variation is seen among type VI fractures.⁵

Assessment and Diagnosis
Originally termed “fender fractures” due to their frequent association with automobile injuries, fractures of the tibial plateau account for 1% of all fractures and 8% of fractures in elderly patients.⁶ Tibial plateau fractures occur when varus or valgus force is combined with axial loading. The fracture itself occurs when the femoral condyle is driven into the lateral or medial plateau. Bicondylar injuries occur when rigorous axial force is sustained in a fully extended knee.

Injuries may also include those of the ligaments or menisci, resulting in joint instability. Patients may present with generalized knee pain or difficulty bearing weight after sustaining injuries, such as being struck in a motor vehicle accident, being tackled, or falling from some height.⁴

Evaluation of a patient with a suspected tibial plateau fracture begins with a detailed history and thorough physical examination. Details regarding the mechanism of injury help to predict the pattern of the fracture and may indicate whether a more focused neurovascular exam is warranted. Low-energy injuries (often seen with Schatzker types I to III) or twisting injuries yield low suspicion for neurovascular injury or compartment syndrome. However, high-energy injuries (seen often with Schatzker types IV through VI) have a greater likelihood of resulting in complicated injuries that must be urgently or emergently treated.⁵

The popliteal artery is bound posteriorly and distally to the tibial plateau, and the peroneal nerve is located laterally and positioned around the fibular head. It is essential to assess for the popliteal pulse, as well as lateral lower-extremity sensation and the patient’s ability to dorsiflex. Along with motor and neurovascular injuries, presentation with a painful, strikingly swollen knee and difficulty bearing weight may indicate a hemarthrosis. Soft tissue injuries over the knee resulting from direct trauma may require a saline arthrogram to rule out communication into the joint. Furthermore, a thorough ligamentous exam of the knee is helpful in determining the extent of the injuries.³

Compartment syndrome is a serious, emergent complication that can occur with tibial plateau fractures, especially those sustained during high-energy trauma.⁷ The health care provider must perform serial exams of the lower extremity to assess for classic signs of compartment syndrome. Are the compartments tense or noncompressible? Does the patient have pain with passive stretch or with range of motion of the lower extremity? Is there pallor or paresthesia to the affected limb? Is the pulse weak or absent? Presence of any of the aforementioned symptoms should prompt a high suspicion for compartment syndrome, and the patient must be sent to an emergency department for urgent evaluation.⁵

Treatment/Rehabilitation
For Schatzker types I through III, intervention focuses on the articular cartilage examination and repair. Type IV injuries often include corresponding damage to the popliteal artery and/or peroneal nerve, and types V and VI often have such overlying soft tissue damage that temporary placement of an external fixation device is required before definitive surgical intervention can be performed.⁸

However, it should be noted that conservative versus surgical treatment is often debated among surgeons for treatment of Schatzker fractures. The management of a tibial plateau fracture depends on the physical demands and health of the patient, the severity of the fracture, the stability of the joint, and the surgeon’s skill set and preferences.⁴ Operative intervention is generally indicated for fractures with depressions greater than 2 mm (although some surgeons allow up to 1 cm of depression), fractures with joint instability, or open fractures. Injuries with concern for vascular injury or compartment syndrome are also treated both operatively and emergently. Postoperatively, patients will remain non–weight-bearing for eight to 12 weeks after surgery, and in the interim, depending on the surgeon’s preference, may or may not engage in active or passive range of motion of the knee.

Advocates of open reduction and internal fixation (ORIF) argue that this method allows for the fracture reduction and anatomic alignment to be directly examined, but they also acknowledge that this approach compromises a great deal of soft tissue surrounding the proximal tibia.^9,10

In order to reduce soft tissue damage, some surgeons favor external fixation. Initial use of this surgical technique results in minimal soft tissue swelling and allows early range of motion. While the external fixation device is in place, there is a risk for pin site infection, and proper site care must be provided.^6,11

Generally, the treatment of tibial plateau fractures is considered successful when the fracture reduction is sustained, the patient’s functional capacity and axial loading are restored, and the articular surface is reconstructed. As a rule, nonoperative treatment is reserved for tibial plateau fractures that are minimally depressed or nondisplaced, or for patients with advanced osteoporosis. Under these circumstances, after a non–weight-bearing period of four to eight weeks, patients will begin to perform protected and partial weight bearing using a hinged knee brace.² Early active range of motion, along with isometric exercises to strengthen the quadriceps, is recommended.

Whether surgical or conservative treatment is chosen, complications of tibial plateau fractures include knee stiffness, wound breakdown and infection, malunion or nonunion, vascular or neurologic injury, prominent or painful hardware, or avascular necrosis of fragmented bone pieces.⁴

CONCLUSION
The primary care practitioner must never overlook patients’ complaints of knee pain, especially after varus or valgus stress injuries or axial loading injuries to the knee. The patient may be able to ambulate; however, ordering a radiograph is an easy method for evaluation and for ruling out tibial plateau injuries. If there is any question regarding the presence of fracture with plain radiographs and/or the clinical exam warrants it, CT is an appropriate second diagnostic intervention.

Should a tibial plateau fracture present in a primary care or urgent care setting, thorough examination of neurovascular status and risk for compartment syndrome must be done urgently, followed by a referral to an orthopedic surgeon or emergency department.

REFERENCES
1. Schatzker J, McBroom R, Bruce D. The tibial plateau fracture: the Toronto experience, 1968–1975. Clin Orthop Relat Res. 1979;(138): 94-104.

2. Marsh JL. Tibial plateau fractures. In: Bucholz RW, Court-Brown CM, Heckman HD, Tornetta P. Rockwood and Green’s Fractures in Adults. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:1780-1831.

3. Egol K, Koval KJ, Zuckerman JD. Tibial plateau. In: Egol K, Koval KJ, Zuckerman JD.  Handbook of Fractures. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:455-463.

4. Fenton PP, Porter KK. Tibial plateau fractures: a review. Trauma. 2011;13(3):181-187.

5. Markhardt BK, Gross JM, Monu JU. Schatzker classification of tibial plateau fractures: use of CT and MR imaging improves assessment. Radiographics. 2009;29(2):585-597.

6. Lewis C. Does the mode of fixation of tibial plateau fractures, i.e. external fixation versus internal fixation, influence the time to union? A systematic review of the literature. Eur J Orthopaed Surg Traumatol. 2008;18(5):365-370.

7. Weinlein J, Schmidt A. Acute compartment syndrome in tibial plateau fractures—beware! J Knee Surg. 2010;31(1):9-16.

8. te Stroet MA, Holla M, Biert J, van Kampen A. The value of CT scan compared to plain radiographs for the classification and treatment plan in tibial plateau fractures. Emerg Radiol. 2011;18(4):279-283.

9. Musahl V, Tarkin I, Kobbe P, et al. New trends and techniques in open reduction and internal fixation of fractures of the tibial plateau. J Bone Joint Surg Br. 2009;91(4):426-433.

10. Toro-Arbelaez JB, Gardner MJ, Shindle MK, et al. Open reduction and internal fixation of intraarticular tibial plateau nonunions. Injury. 2007;38(3):378-383.

11. Marsh JL, Smith ST, Do TT. External fixation and limited internal fixation for complex fractures of the tibial plateau. J Bone Joint Surg Am. 1995;77(5):661-673.

Q: I have a patient with premature ovarian failure (diagnosed when she was 32) who is now in her late 40s. She is fatigued, and a blood test revealed a thyroid peroxidase antibodies level of 587 IU/mL. Would you supplement with thyroid replacement hormone, even though she has a TSH of 1.004?

The short answer is: No. Thyroid peroxidase (TPO) antibodies are a marker for the presence of autoimmune thyroid disease. Blood test results for TPO antibodies are positive in 95% of patients with chronic lymphocytic thyroiditis, also known as Hashimoto’s disease, and in 50% to 80% of patients with Graves’ disease. 

Patients with high levels of TPO antibodies are at risk for future thyroid dysfunction. Not all patients with Hashimoto’s develop hypothyroidism, and if present, it may not persist. Patients with Hashimoto’s, although rarely, can experience a change from a hypothyroid to a euthyroid or even a hyperthyroid state, because of the development of coexisting TSH-receptor antibodies (TRAb), which include thyroid-stimulating immunoglobulin (TSI) and thyrotropin-binding inhibitory immunoglobulin (TBII), as seen in Graves’ disease.

Thyroid nodules are common with Hashimoto’s and are associated with a small risk (5% to 7%) for thyroid cancer. Sudden enlargement of the thyroid gland in a patient with Hashimoto’s should raise concern about thyroid lymphoma. Some endocrinologists will give supplemental thyroid hormone to a patient with Hashimoto’s, even if the TSH is normal, in an attempt to shrink the size of the gland. However, the closer the TSH is to < 1, the less room there is to further suppress it without making the patient overtly hyperthyroid, and the less likely it is that you will achieve much shrinkage of the gland. 

Therefore, in the absence of a symptomatic goiter, there is no clinical reason to initiate any therapy. Even with mildly elevated TSH levels (5 to 10 mIU/L; ie, subclinical hypothyroidism) in an asymptomatic patient, there is considerable controversy about thyroid hormone initiation when the free T4 and T3 levels are normal. Most authorities agree that treatment should be initiated in most patients when the TSH rises above 10 mIU/L, regardless of symptoms. However, there are clearer indications to start thyroid hormone in women who want to become, or who are, pregnant, to maintain a TSH of < 2.5 mIU/L. Also, individuals with depression or hyperlipidemia warrant extra consideration for the use of thyroid hormone.

Since this particular patient had premature ovarian failure, which is often autoimmune in nature, she must be considered at risk for future development of hypothyroidism. This patient should be followed annually to ensure that her TSH does not rise. Should she develop symptoms suggestive of hypothyroidism and her TSH rises above 3, some endocrinologists would initiate a brief empiric trial of thyroid replacement to see if her symptoms respond when the TSH lowers again. If they do not, the thyroid hormone might be stopped, and the patient should continue to be followed.

Note: The definition of a “normal” TSH is evolving. Levels above 3.0 (suggested normal therapeutic range: 0.5 to 3.0) are considered possibly suspicious in symptomatic young people, while levels slightly above the normal reference range (5 to 7 mIU/L) may be deemed normal for the asymptomatic geriatric population.

The other point to remember is that when a clinician initiates any thyroid therapy, some patients fixate on the thyroid as the only source of their symptoms, such as fatigue, weight gain, and obesity, to the exclusion of any other etiologies. For example, sleep deprivation is a far more common cause of fatigue in our “open 24 hours” society, and lifestyle remains the major cause of obesity. Thus, there can be unintended consequences of a diagnosis of thyroid “disease.”

SUGGESTED READING
American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. www.aace.com/publications/guidelines. Accessed March 5, 2012.

Bremner AP, Feddema P, Leedman PJ, et al. Age-related changes in thyroid function: a longitudinal study of a community-based cohort. J Clin Endocrinol Metab. 2012 Feb 16; [Epub ahead of print].

Hutfless S, Matos P, Talor MV, et al. Significance of prediagnostic thyroid antibodies in women with autoimmune thyroid disease. J Clin Endocrinol Metab. 2011;96(9):E1466-E1471.

Kauffman RP, Castracane VD. Premature ovarian failure associated with autoimmune polyglandular syndrome: pathophysiological mechanisms and future fertility. J Womens Health (Larchmt). 2003;12(5):513-520.

Q: I have a patient with premature ovarian failure (diagnosed when she was 32) who is now in her late 40s. She is fatigued, and a blood test revealed a thyroid peroxidase antibodies level of 587 IU/mL. Would you supplement with thyroid replacement hormone, even though she has a TSH of 1.004?

The short answer is: No. Thyroid peroxidase (TPO) antibodies are a marker for the presence of autoimmune thyroid disease. Blood test results for TPO antibodies are positive in 95% of patients with chronic lymphocytic thyroiditis, also known as Hashimoto’s disease, and in 50% to 80% of patients with Graves’ disease. 

Patients with high levels of TPO antibodies are at risk for future thyroid dysfunction. Not all patients with Hashimoto’s develop hypothyroidism, and if present, it may not persist. Patients with Hashimoto’s, although rarely, can experience a change from a hypothyroid to a euthyroid or even a hyperthyroid state, because of the development of coexisting TSH-receptor antibodies (TRAb), which include thyroid-stimulating immunoglobulin (TSI) and thyrotropin-binding inhibitory immunoglobulin (TBII), as seen in Graves’ disease.

Thyroid nodules are common with Hashimoto’s and are associated with a small risk (5% to 7%) for thyroid cancer. Sudden enlargement of the thyroid gland in a patient with Hashimoto’s should raise concern about thyroid lymphoma. Some endocrinologists will give supplemental thyroid hormone to a patient with Hashimoto’s, even if the TSH is normal, in an attempt to shrink the size of the gland. However, the closer the TSH is to < 1, the less room there is to further suppress it without making the patient overtly hyperthyroid, and the less likely it is that you will achieve much shrinkage of the gland. 

Therefore, in the absence of a symptomatic goiter, there is no clinical reason to initiate any therapy. Even with mildly elevated TSH levels (5 to 10 mIU/L; ie, subclinical hypothyroidism) in an asymptomatic patient, there is considerable controversy about thyroid hormone initiation when the free T4 and T3 levels are normal. Most authorities agree that treatment should be initiated in most patients when the TSH rises above 10 mIU/L, regardless of symptoms. However, there are clearer indications to start thyroid hormone in women who want to become, or who are, pregnant, to maintain a TSH of < 2.5 mIU/L. Also, individuals with depression or hyperlipidemia warrant extra consideration for the use of thyroid hormone.

Since this particular patient had premature ovarian failure, which is often autoimmune in nature, she must be considered at risk for future development of hypothyroidism. This patient should be followed annually to ensure that her TSH does not rise. Should she develop symptoms suggestive of hypothyroidism and her TSH rises above 3, some endocrinologists would initiate a brief empiric trial of thyroid replacement to see if her symptoms respond when the TSH lowers again. If they do not, the thyroid hormone might be stopped, and the patient should continue to be followed.

Note: The definition of a “normal” TSH is evolving. Levels above 3.0 (suggested normal therapeutic range: 0.5 to 3.0) are considered possibly suspicious in symptomatic young people, while levels slightly above the normal reference range (5 to 7 mIU/L) may be deemed normal for the asymptomatic geriatric population.

The other point to remember is that when a clinician initiates any thyroid therapy, some patients fixate on the thyroid as the only source of their symptoms, such as fatigue, weight gain, and obesity, to the exclusion of any other etiologies. For example, sleep deprivation is a far more common cause of fatigue in our “open 24 hours” society, and lifestyle remains the major cause of obesity. Thus, there can be unintended consequences of a diagnosis of thyroid “disease.”

SUGGESTED READING
American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. www.aace.com/publications/guidelines. Accessed March 5, 2012.

Bremner AP, Feddema P, Leedman PJ, et al. Age-related changes in thyroid function: a longitudinal study of a community-based cohort. J Clin Endocrinol Metab. 2012 Feb 16; [Epub ahead of print].

Hutfless S, Matos P, Talor MV, et al. Significance of prediagnostic thyroid antibodies in women with autoimmune thyroid disease. J Clin Endocrinol Metab. 2011;96(9):E1466-E1471.

Kauffman RP, Castracane VD. Premature ovarian failure associated with autoimmune polyglandular syndrome: pathophysiological mechanisms and future fertility. J Womens Health (Larchmt). 2003;12(5):513-520.

Q: I have a patient with premature ovarian failure (diagnosed when she was 32) who is now in her late 40s. She is fatigued, and a blood test revealed a thyroid peroxidase antibodies level of 587 IU/mL. Would you supplement with thyroid replacement hormone, even though she has a TSH of 1.004?

The short answer is: No. Thyroid peroxidase (TPO) antibodies are a marker for the presence of autoimmune thyroid disease. Blood test results for TPO antibodies are positive in 95% of patients with chronic lymphocytic thyroiditis, also known as Hashimoto’s disease, and in 50% to 80% of patients with Graves’ disease. 

Patients with high levels of TPO antibodies are at risk for future thyroid dysfunction. Not all patients with Hashimoto’s develop hypothyroidism, and if present, it may not persist. Patients with Hashimoto’s, although rarely, can experience a change from a hypothyroid to a euthyroid or even a hyperthyroid state, because of the development of coexisting TSH-receptor antibodies (TRAb), which include thyroid-stimulating immunoglobulin (TSI) and thyrotropin-binding inhibitory immunoglobulin (TBII), as seen in Graves’ disease.

Thyroid nodules are common with Hashimoto’s and are associated with a small risk (5% to 7%) for thyroid cancer. Sudden enlargement of the thyroid gland in a patient with Hashimoto’s should raise concern about thyroid lymphoma. Some endocrinologists will give supplemental thyroid hormone to a patient with Hashimoto’s, even if the TSH is normal, in an attempt to shrink the size of the gland. However, the closer the TSH is to < 1, the less room there is to further suppress it without making the patient overtly hyperthyroid, and the less likely it is that you will achieve much shrinkage of the gland. 

Therefore, in the absence of a symptomatic goiter, there is no clinical reason to initiate any therapy. Even with mildly elevated TSH levels (5 to 10 mIU/L; ie, subclinical hypothyroidism) in an asymptomatic patient, there is considerable controversy about thyroid hormone initiation when the free T4 and T3 levels are normal. Most authorities agree that treatment should be initiated in most patients when the TSH rises above 10 mIU/L, regardless of symptoms. However, there are clearer indications to start thyroid hormone in women who want to become, or who are, pregnant, to maintain a TSH of < 2.5 mIU/L. Also, individuals with depression or hyperlipidemia warrant extra consideration for the use of thyroid hormone.

Since this particular patient had premature ovarian failure, which is often autoimmune in nature, she must be considered at risk for future development of hypothyroidism. This patient should be followed annually to ensure that her TSH does not rise. Should she develop symptoms suggestive of hypothyroidism and her TSH rises above 3, some endocrinologists would initiate a brief empiric trial of thyroid replacement to see if her symptoms respond when the TSH lowers again. If they do not, the thyroid hormone might be stopped, and the patient should continue to be followed.

Note: The definition of a “normal” TSH is evolving. Levels above 3.0 (suggested normal therapeutic range: 0.5 to 3.0) are considered possibly suspicious in symptomatic young people, while levels slightly above the normal reference range (5 to 7 mIU/L) may be deemed normal for the asymptomatic geriatric population.

The other point to remember is that when a clinician initiates any thyroid therapy, some patients fixate on the thyroid as the only source of their symptoms, such as fatigue, weight gain, and obesity, to the exclusion of any other etiologies. For example, sleep deprivation is a far more common cause of fatigue in our “open 24 hours” society, and lifestyle remains the major cause of obesity. Thus, there can be unintended consequences of a diagnosis of thyroid “disease.”

SUGGESTED READING
American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. www.aace.com/publications/guidelines. Accessed March 5, 2012.

Bremner AP, Feddema P, Leedman PJ, et al. Age-related changes in thyroid function: a longitudinal study of a community-based cohort. J Clin Endocrinol Metab. 2012 Feb 16; [Epub ahead of print].

Hutfless S, Matos P, Talor MV, et al. Significance of prediagnostic thyroid antibodies in women with autoimmune thyroid disease. J Clin Endocrinol Metab. 2011;96(9):E1466-E1471.

Kauffman RP, Castracane VD. Premature ovarian failure associated with autoimmune polyglandular syndrome: pathophysiological mechanisms and future fertility. J Womens Health (Larchmt). 2003;12(5):513-520.

Dr. Scott Freeman’s useful discussion of targeting acute risk factors in suicidal patients (“Suicide assessment: Targeting acute risk factors,” Current Psychiatry, January 2012, p. 52-57) ends by resolving the clinical vignette with a summary of hospital treatment. Apart from failing to indicate any psychotherapeutic inroads, Dr. Freeman seems to support prescribing clonazepam, 0.5 mg twice daily and 1 mg at bedtime. Clonazepam apparently “worked” by alleviating the patient’s anxiety and insomnia, but defied any pharmacologic rationale insofar as clonazepam has a slow onset and long half-life, making 3 doses per day irrational. This treatment strategy also risks problems of cumulative excess in the long run after discharge.

Aggressive pharmacotherapy may be the hallmark of modern acute hospital treatment, but surely it should incorporate careful understanding of specific medications’ pharmacodynamics, especially when relying on benzodiazepines. Needless to say, beginning a psychological process in the hospital also appears to have been shortchanged.

Sara Hartley, MD
Lecturer, Clinical Skills Program
University of California,
Berkeley-University of California,
San Francisco Joint Medical Program
Berkeley, CA

Dr. Freeman responds

I appreciate Dr. Hartley’s interest in my article. Although I agree with her that psychotherapy is an integral part of any treatment plan, the clinical vignette was used only to emphasize the need to aggressively and quickly start antidepressant and, more importantly, anxiolytic pharmacologic treatment in acutely suicidal patients with severe anxiety and depression.

With regard to clonazepam’s pharmacokinetics, although it does have a long half-life, it is only weakly lipophilic compared with other long-acting benzodiazepines such as diazepam. In fact, clonazepam has been shown to be less lipophilic than lorazepam,¹ meaning it has a much smaller volume of distribution and less accumulation in peripheral adipose tissue. Therefore, one would not be concerned about significant drug accumulation leading to unexpected toxicity with a less lipophilic agent such as clonazepam.

I do not agree that dosing clonazepam 3 times a day, especially in an acute crisis, is “irrational,” as Dr. Hartley suggests. According to the package insert, although clonazepam is recommended to be administered twice daily for panic disorder, it can be given 3 times a day for seizure disorders.²

Scott A. Freeman, MD
Medical Director
Schizophrenia and Bipolar Disorder Inpatient Unit
McLean Hospital
Belmont, MA

Dr. Scott Freeman’s useful discussion of targeting acute risk factors in suicidal patients (“Suicide assessment: Targeting acute risk factors,” Current Psychiatry, January 2012, p. 52-57) ends by resolving the clinical vignette with a summary of hospital treatment. Apart from failing to indicate any psychotherapeutic inroads, Dr. Freeman seems to support prescribing clonazepam, 0.5 mg twice daily and 1 mg at bedtime. Clonazepam apparently “worked” by alleviating the patient’s anxiety and insomnia, but defied any pharmacologic rationale insofar as clonazepam has a slow onset and long half-life, making 3 doses per day irrational. This treatment strategy also risks problems of cumulative excess in the long run after discharge.

Aggressive pharmacotherapy may be the hallmark of modern acute hospital treatment, but surely it should incorporate careful understanding of specific medications’ pharmacodynamics, especially when relying on benzodiazepines. Needless to say, beginning a psychological process in the hospital also appears to have been shortchanged.

Sara Hartley, MD
Lecturer, Clinical Skills Program
University of California,
Berkeley-University of California,
San Francisco Joint Medical Program
Berkeley, CA

Dr. Freeman responds

I appreciate Dr. Hartley’s interest in my article. Although I agree with her that psychotherapy is an integral part of any treatment plan, the clinical vignette was used only to emphasize the need to aggressively and quickly start antidepressant and, more importantly, anxiolytic pharmacologic treatment in acutely suicidal patients with severe anxiety and depression.

With regard to clonazepam’s pharmacokinetics, although it does have a long half-life, it is only weakly lipophilic compared with other long-acting benzodiazepines such as diazepam. In fact, clonazepam has been shown to be less lipophilic than lorazepam,¹ meaning it has a much smaller volume of distribution and less accumulation in peripheral adipose tissue. Therefore, one would not be concerned about significant drug accumulation leading to unexpected toxicity with a less lipophilic agent such as clonazepam.

I do not agree that dosing clonazepam 3 times a day, especially in an acute crisis, is “irrational,” as Dr. Hartley suggests. According to the package insert, although clonazepam is recommended to be administered twice daily for panic disorder, it can be given 3 times a day for seizure disorders.²

Scott A. Freeman, MD
Medical Director
Schizophrenia and Bipolar Disorder Inpatient Unit
McLean Hospital
Belmont, MA

Dr. Scott Freeman’s useful discussion of targeting acute risk factors in suicidal patients (“Suicide assessment: Targeting acute risk factors,” Current Psychiatry, January 2012, p. 52-57) ends by resolving the clinical vignette with a summary of hospital treatment. Apart from failing to indicate any psychotherapeutic inroads, Dr. Freeman seems to support prescribing clonazepam, 0.5 mg twice daily and 1 mg at bedtime. Clonazepam apparently “worked” by alleviating the patient’s anxiety and insomnia, but defied any pharmacologic rationale insofar as clonazepam has a slow onset and long half-life, making 3 doses per day irrational. This treatment strategy also risks problems of cumulative excess in the long run after discharge.

Aggressive pharmacotherapy may be the hallmark of modern acute hospital treatment, but surely it should incorporate careful understanding of specific medications’ pharmacodynamics, especially when relying on benzodiazepines. Needless to say, beginning a psychological process in the hospital also appears to have been shortchanged.

Sara Hartley, MD
Lecturer, Clinical Skills Program
University of California,
Berkeley-University of California,
San Francisco Joint Medical Program
Berkeley, CA

Dr. Freeman responds

I appreciate Dr. Hartley’s interest in my article. Although I agree with her that psychotherapy is an integral part of any treatment plan, the clinical vignette was used only to emphasize the need to aggressively and quickly start antidepressant and, more importantly, anxiolytic pharmacologic treatment in acutely suicidal patients with severe anxiety and depression.

With regard to clonazepam’s pharmacokinetics, although it does have a long half-life, it is only weakly lipophilic compared with other long-acting benzodiazepines such as diazepam. In fact, clonazepam has been shown to be less lipophilic than lorazepam,¹ meaning it has a much smaller volume of distribution and less accumulation in peripheral adipose tissue. Therefore, one would not be concerned about significant drug accumulation leading to unexpected toxicity with a less lipophilic agent such as clonazepam.

I do not agree that dosing clonazepam 3 times a day, especially in an acute crisis, is “irrational,” as Dr. Hartley suggests. According to the package insert, although clonazepam is recommended to be administered twice daily for panic disorder, it can be given 3 times a day for seizure disorders.²

Scott A. Freeman, MD
Medical Director
Schizophrenia and Bipolar Disorder Inpatient Unit
McLean Hospital
Belmont, MA

Vessel-sealing devices and hemostatic adjuvants are expanding the surgical armamentarium. These products provide a spectrum of alternatives that can serve you and your surgical patient well when traditional techniques for obtaining hemostasis fail to provide a satisfactory result. (Keep in mind, however, that technology is no substitute for excellent technique!)

In this article, we highlight three common scenarios in which topical hemostatic agents may be useful during gynecologic surgery. In addition, in the sidebar, five surgeons describe the hemostatic products they rely on most often—and tell why.

Following hysterectomy, persistent oozing along the anterior vaginal margin, distal to the cuff and adjacent to the site of bladder mobilization, may be managed with the aid of a topical hemostatic agent—in this case, a fibrin sealant.

When the site of bleeding is difficult to reach

CASE 1: Oozing at the site of bladder mobilization

You perform total hysterectomy in a 44-year-old woman who has uterine fibroids. After the procedure, you notice persistent oozing along the anterior vaginal margin, distal to the cuff and adjacent to where the bladder was mobilized.

How do you manage the oozing?

Wide mobilization of the bladder is a vital step in the safe performance of hysterectomy. Adhesions may complicate the process if the patient has had previous abdominal surgery, infection, or inflammation. Following mobilization of the bladder and removal of the uterus, bleeding may be visible along the adventitia of the posterior bladder wall or along the anterior surface of the vagina, distal to the cuff, as it is in this case (see the illustration).

Judicious application of an energy source is an option, but thermal injury to the bladder is a concern. A good alternative is proper placement of a hemostatic suture, but it can sometimes be difficult to avoid incorporating the bladder or injuring or obstructing the nearby ureter.

In this case, the location of the bleeding deep in the operative field poses a challenge, because of limited exposure and the proximity of the bladder and ureters. Virtually any hemostatic agent would work well in this circumstance (TABLE). For example, a flowable agent or fibrin sealant could be thoroughly applied to the area during a minimally invasive or open procedure and would naturally conform to the irregularities in the tissue, particularly the junction between the vagina and bladder flap.

A pliable product such as Surgicel Nu-Knit or Fibrillar would also work well in these circumstances, although successful application during laparoscopy may depend on the size of the trocar. For example, Nu-Knit would require trimming to a size suitable for passage through a trocar, made easier by moistening with saline. The weave of Fibrillar makes it more challenging to pass, intact, through a trocar; rolling the material into a cylindrical shape may reduce its diameter and allow it to pass more easily.

CASE 1: Resolved

You apply a fibrin sealant to the site of bleeding, and the oozing abates. Once complete hemostasis is ensured, you conclude the surgery and transfer the patient to recovery, where she does well.

Profiles in hemostasis: Strengths and weaknesses of topical agent

Controlling bleeding without injuring underlying tissue

CASE 2: After adhesiolysis, bleeding at multiple sites

You perform adnexectomy on a 47-year-old woman who has a large (7 to 8 cm), benign ovarian mass. As you operate, you discover that the lesion is adherent to the sigmoid mesentery and the posterior aspect of the uterus; it is also adherent to the pelvic sidewall, directly along the course of the ureter. Although you are able to release the various adhesive attachments, persistent bleeding is noted at multiple pinpoint areas along the mesentery, uterine serosa, and pelvic sidewall, even after the application of direct pressure.

What do you do next?

Although cautery can be used liberally on the uterus, its application to mesentery carries a risk of injury to the mesenteric vessels and bowel wall. Caution is advised when you are attempting to control bleeding on the peritoneum overlying the ureter, whether you are using suture ligature or an energy source. Ideally, you should identify the ureter using a retroperitoneal approach and mobilize it laterally before employing any of these techniques.

There are several potential approaches to the bleeding described in Case 2, all of them involving hemostatic adjuvants. The first decision you need to make, however, is whether to address each region separately or all sites in unison. If you opt to address them together—either during an open procedure or laparoscopy—a fibrin sealant (e.g., Evicel, Tisseel) is one option. It can be applied using a dripping technique or aerosolization, either of which allows for broad application of a thin film of the agent. The limitation of this approach is the volume of agent required to resolve the bleeding, with a potential need for multiple doses to completely coat the area.

Because fibrin sealants function independently of the patient’s coagulation cascade, they are particularly useful in the presence of disseminated intravascular coagulation (DIC) and other coagulopathies that might limit the effectiveness of preparations that require the patient’s own serum.

An alternative approach to Case 2 is to apply an oxidized regenerated cellulose (ORC) derivative directly to the affected areas. Various forms are available (e.g., Surgicel Fibrillar, Surgicel Nu-Knit). These ORC products can be cut and customized to the area in need of hemostasis, allowing each site to be addressed individually. These agents typically remain adherent after they are applied due to the nature of the interaction between the product, blood, and tissue.

A liquid or foam hemostatic agent (e.g., Surgiflo, Floseal, topical thrombin) could also be employed in this case, but application can be a challenge on a large area with a heterogeneous topography because of the tendency of such agents to migrate under the force of gravity, pooling away from the source of bleeding.

Is combining agents a good idea?

Although they are not typically approved for use in combination, sequential application of hemostatic agents may be considered when bleeding persists.

All hemostatic agents work best in combination with the application of pressure. It usually is advisable to use moist gauze for this purpose because it can be lifted away without significant adherence to the underlying hemostatic complex, avoiding clot

disruption.

CASE 2: Resolved

You opt to use an ORC product, customizing it to fit each bleeding site, and apply direct pressure. When hemostasis has been achieved at all sites, you complete the operation. The patient has an uneventful postoperative course.

Protect structures along the pelvic sidewall

CASE 3: When the application of pressure isn’t enough

While performing a left salpingo-oophorectomy for a 12-cm ovarian lesion, you use a retroperitoneal approach to identify the structures along the pelvic sidewall. During identification of the ureter, you encounter bleeding from a small vessel in the adjacent fatty areolar tissue. After a period of observation, during which you apply pressure to the area of concern, bleeding persists.

What hemostatic agent do you employ to stop it?

The careful application of steady pressure is often enough to safely control bleeding in the area of the pelvic sidewall. In the event that pressure alone fails to resolve the bleeding, however, it is critical to choose a remedy that avoids injuring the ureter, iliac vessels, and infundibulopelvic ligament. Wide exposure of the space may allow for direct identification of the point of bleeding and precise application of cautery, a hemoclip, or a tie. When this approach is not feasible, other solutions must be sought.

When traditional hemostatic techniques fail in delicate anatomic sites, such as the periureteral area, hemostatic agents are an effective option that can minimize the risk of injury to surrounding vital structures. The contour of the space calls for a product that can intercalate, such as a foam, sealant, or Surgicel Fibrillar. Direct, precise application to the point of bleeding is critical, and the “bunching up” of a more rigid and bulky agent may limit its application to the area of concern. Use of a moist gauze to apply direct pressure after application of the agent will increase the likelihood of success.

CASE 3: Resolved

You decide to apply a foam hemostatic agent because of its ability to conform to the irregular space. You also continue to apply gentle pressure to the point of bleeding, using a moist gauze. Within minutes, hemostasis is achieved. You are then able to finish the operation.

Other variables to consider

As these three cases illustrate, the use of hemostatic agents to control surgical bleeding requires an individualized approach. The site and amount of bleeding, as well as the patient’s hemodynamic and coagulation status, are key variables to be considered when selecting an agent.

For instance, because of their components, fibrin sealants can function independently of the patient’s coagulation status. ORC products provide a matrix that facilitates platelet aggregration and may be less effective when anti-platelet agents have been used.

It is also appropriate for the surgeon to be familiar with the relative cost of the agents available at his or her institution. In particular, when several agents may be equally effective in a particular set of circumstances, cost may be the determining factor.

Availability of these agents varies from one institution to the next; as a result, it can be challenging to maintain familiarity with all of the products in the marketplace. Having access to a diverse, readily available set of “go to” agents is critical to ensure rapid application in a clinical setting.

The surgeon’s preference also is important, particularly in regard to the ease of preparation and handling. Some agents may not be as suitable for minimally invasive procedures (see TABLE). For others, special laparoscopic applicators are available.

When using a hemostatic agent, it pays to consider the duration of its effect in the surgical site. Both the quantity of the agent that is applied and characteristics of the local operative site influence how quickly the agent degrades. Keep this in mind when imaging studies are planned for the early postoperative period. An ORC preparation, for example, may appear with small pockets of air that resemble an abscess. Effective communication with the radiology team is critical to avoid the misinterpretation of findings.

Choosing a topical agent? First, consider surgical technique.

Curious to discover the preferences and practices of surgeons likely to utilize topical hemostatic agents, OBG Management polled several experienced and expert surgeons, including members of the journal’s Board of Editors and Virtual Board of Editors. Their diverse responses offer a snapshot of gynecologic surgical practice in 2012—but all agree that hemostatic products are no substitute for sound surgical technique.
JANELLE YATES, SENIOR EDITOR

We want to hear from you! Tell us what you think.

Vessel-sealing devices and hemostatic adjuvants are expanding the surgical armamentarium. These products provide a spectrum of alternatives that can serve you and your surgical patient well when traditional techniques for obtaining hemostasis fail to provide a satisfactory result. (Keep in mind, however, that technology is no substitute for excellent technique!)

In this article, we highlight three common scenarios in which topical hemostatic agents may be useful during gynecologic surgery. In addition, in the sidebar, five surgeons describe the hemostatic products they rely on most often—and tell why.

Following hysterectomy, persistent oozing along the anterior vaginal margin, distal to the cuff and adjacent to the site of bladder mobilization, may be managed with the aid of a topical hemostatic agent—in this case, a fibrin sealant.

When the site of bleeding is difficult to reach

CASE 1: Oozing at the site of bladder mobilization

You perform total hysterectomy in a 44-year-old woman who has uterine fibroids. After the procedure, you notice persistent oozing along the anterior vaginal margin, distal to the cuff and adjacent to where the bladder was mobilized.

How do you manage the oozing?

Wide mobilization of the bladder is a vital step in the safe performance of hysterectomy. Adhesions may complicate the process if the patient has had previous abdominal surgery, infection, or inflammation. Following mobilization of the bladder and removal of the uterus, bleeding may be visible along the adventitia of the posterior bladder wall or along the anterior surface of the vagina, distal to the cuff, as it is in this case (see the illustration).

Judicious application of an energy source is an option, but thermal injury to the bladder is a concern. A good alternative is proper placement of a hemostatic suture, but it can sometimes be difficult to avoid incorporating the bladder or injuring or obstructing the nearby ureter.

In this case, the location of the bleeding deep in the operative field poses a challenge, because of limited exposure and the proximity of the bladder and ureters. Virtually any hemostatic agent would work well in this circumstance (TABLE). For example, a flowable agent or fibrin sealant could be thoroughly applied to the area during a minimally invasive or open procedure and would naturally conform to the irregularities in the tissue, particularly the junction between the vagina and bladder flap.

A pliable product such as Surgicel Nu-Knit or Fibrillar would also work well in these circumstances, although successful application during laparoscopy may depend on the size of the trocar. For example, Nu-Knit would require trimming to a size suitable for passage through a trocar, made easier by moistening with saline. The weave of Fibrillar makes it more challenging to pass, intact, through a trocar; rolling the material into a cylindrical shape may reduce its diameter and allow it to pass more easily.

CASE 1: Resolved

You apply a fibrin sealant to the site of bleeding, and the oozing abates. Once complete hemostasis is ensured, you conclude the surgery and transfer the patient to recovery, where she does well.

Profiles in hemostasis: Strengths and weaknesses of topical agent

Controlling bleeding without injuring underlying tissue

CASE 2: After adhesiolysis, bleeding at multiple sites

You perform adnexectomy on a 47-year-old woman who has a large (7 to 8 cm), benign ovarian mass. As you operate, you discover that the lesion is adherent to the sigmoid mesentery and the posterior aspect of the uterus; it is also adherent to the pelvic sidewall, directly along the course of the ureter. Although you are able to release the various adhesive attachments, persistent bleeding is noted at multiple pinpoint areas along the mesentery, uterine serosa, and pelvic sidewall, even after the application of direct pressure.

What do you do next?

Although cautery can be used liberally on the uterus, its application to mesentery carries a risk of injury to the mesenteric vessels and bowel wall. Caution is advised when you are attempting to control bleeding on the peritoneum overlying the ureter, whether you are using suture ligature or an energy source. Ideally, you should identify the ureter using a retroperitoneal approach and mobilize it laterally before employing any of these techniques.

There are several potential approaches to the bleeding described in Case 2, all of them involving hemostatic adjuvants. The first decision you need to make, however, is whether to address each region separately or all sites in unison. If you opt to address them together—either during an open procedure or laparoscopy—a fibrin sealant (e.g., Evicel, Tisseel) is one option. It can be applied using a dripping technique or aerosolization, either of which allows for broad application of a thin film of the agent. The limitation of this approach is the volume of agent required to resolve the bleeding, with a potential need for multiple doses to completely coat the area.

Because fibrin sealants function independently of the patient’s coagulation cascade, they are particularly useful in the presence of disseminated intravascular coagulation (DIC) and other coagulopathies that might limit the effectiveness of preparations that require the patient’s own serum.

An alternative approach to Case 2 is to apply an oxidized regenerated cellulose (ORC) derivative directly to the affected areas. Various forms are available (e.g., Surgicel Fibrillar, Surgicel Nu-Knit). These ORC products can be cut and customized to the area in need of hemostasis, allowing each site to be addressed individually. These agents typically remain adherent after they are applied due to the nature of the interaction between the product, blood, and tissue.

A liquid or foam hemostatic agent (e.g., Surgiflo, Floseal, topical thrombin) could also be employed in this case, but application can be a challenge on a large area with a heterogeneous topography because of the tendency of such agents to migrate under the force of gravity, pooling away from the source of bleeding.

Is combining agents a good idea?

Although they are not typically approved for use in combination, sequential application of hemostatic agents may be considered when bleeding persists.

All hemostatic agents work best in combination with the application of pressure. It usually is advisable to use moist gauze for this purpose because it can be lifted away without significant adherence to the underlying hemostatic complex, avoiding clot

disruption.

CASE 2: Resolved

You opt to use an ORC product, customizing it to fit each bleeding site, and apply direct pressure. When hemostasis has been achieved at all sites, you complete the operation. The patient has an uneventful postoperative course.

Protect structures along the pelvic sidewall

CASE 3: When the application of pressure isn’t enough

While performing a left salpingo-oophorectomy for a 12-cm ovarian lesion, you use a retroperitoneal approach to identify the structures along the pelvic sidewall. During identification of the ureter, you encounter bleeding from a small vessel in the adjacent fatty areolar tissue. After a period of observation, during which you apply pressure to the area of concern, bleeding persists.

What hemostatic agent do you employ to stop it?

The careful application of steady pressure is often enough to safely control bleeding in the area of the pelvic sidewall. In the event that pressure alone fails to resolve the bleeding, however, it is critical to choose a remedy that avoids injuring the ureter, iliac vessels, and infundibulopelvic ligament. Wide exposure of the space may allow for direct identification of the point of bleeding and precise application of cautery, a hemoclip, or a tie. When this approach is not feasible, other solutions must be sought.

When traditional hemostatic techniques fail in delicate anatomic sites, such as the periureteral area, hemostatic agents are an effective option that can minimize the risk of injury to surrounding vital structures. The contour of the space calls for a product that can intercalate, such as a foam, sealant, or Surgicel Fibrillar. Direct, precise application to the point of bleeding is critical, and the “bunching up” of a more rigid and bulky agent may limit its application to the area of concern. Use of a moist gauze to apply direct pressure after application of the agent will increase the likelihood of success.

CASE 3: Resolved

You decide to apply a foam hemostatic agent because of its ability to conform to the irregular space. You also continue to apply gentle pressure to the point of bleeding, using a moist gauze. Within minutes, hemostasis is achieved. You are then able to finish the operation.

Other variables to consider

As these three cases illustrate, the use of hemostatic agents to control surgical bleeding requires an individualized approach. The site and amount of bleeding, as well as the patient’s hemodynamic and coagulation status, are key variables to be considered when selecting an agent.

For instance, because of their components, fibrin sealants can function independently of the patient’s coagulation status. ORC products provide a matrix that facilitates platelet aggregration and may be less effective when anti-platelet agents have been used.

It is also appropriate for the surgeon to be familiar with the relative cost of the agents available at his or her institution. In particular, when several agents may be equally effective in a particular set of circumstances, cost may be the determining factor.

Availability of these agents varies from one institution to the next; as a result, it can be challenging to maintain familiarity with all of the products in the marketplace. Having access to a diverse, readily available set of “go to” agents is critical to ensure rapid application in a clinical setting.

The surgeon’s preference also is important, particularly in regard to the ease of preparation and handling. Some agents may not be as suitable for minimally invasive procedures (see TABLE). For others, special laparoscopic applicators are available.

When using a hemostatic agent, it pays to consider the duration of its effect in the surgical site. Both the quantity of the agent that is applied and characteristics of the local operative site influence how quickly the agent degrades. Keep this in mind when imaging studies are planned for the early postoperative period. An ORC preparation, for example, may appear with small pockets of air that resemble an abscess. Effective communication with the radiology team is critical to avoid the misinterpretation of findings.

Choosing a topical agent? First, consider surgical technique.

Curious to discover the preferences and practices of surgeons likely to utilize topical hemostatic agents, OBG Management polled several experienced and expert surgeons, including members of the journal’s Board of Editors and Virtual Board of Editors. Their diverse responses offer a snapshot of gynecologic surgical practice in 2012—but all agree that hemostatic products are no substitute for sound surgical technique.
JANELLE YATES, SENIOR EDITOR

We want to hear from you! Tell us what you think.

Vessel-sealing devices and hemostatic adjuvants are expanding the surgical armamentarium. These products provide a spectrum of alternatives that can serve you and your surgical patient well when traditional techniques for obtaining hemostasis fail to provide a satisfactory result. (Keep in mind, however, that technology is no substitute for excellent technique!)

In this article, we highlight three common scenarios in which topical hemostatic agents may be useful during gynecologic surgery. In addition, in the sidebar, five surgeons describe the hemostatic products they rely on most often—and tell why.

Following hysterectomy, persistent oozing along the anterior vaginal margin, distal to the cuff and adjacent to the site of bladder mobilization, may be managed with the aid of a topical hemostatic agent—in this case, a fibrin sealant.

When the site of bleeding is difficult to reach

CASE 1: Oozing at the site of bladder mobilization

You perform total hysterectomy in a 44-year-old woman who has uterine fibroids. After the procedure, you notice persistent oozing along the anterior vaginal margin, distal to the cuff and adjacent to where the bladder was mobilized.

How do you manage the oozing?

Wide mobilization of the bladder is a vital step in the safe performance of hysterectomy. Adhesions may complicate the process if the patient has had previous abdominal surgery, infection, or inflammation. Following mobilization of the bladder and removal of the uterus, bleeding may be visible along the adventitia of the posterior bladder wall or along the anterior surface of the vagina, distal to the cuff, as it is in this case (see the illustration).

Judicious application of an energy source is an option, but thermal injury to the bladder is a concern. A good alternative is proper placement of a hemostatic suture, but it can sometimes be difficult to avoid incorporating the bladder or injuring or obstructing the nearby ureter.

In this case, the location of the bleeding deep in the operative field poses a challenge, because of limited exposure and the proximity of the bladder and ureters. Virtually any hemostatic agent would work well in this circumstance (TABLE). For example, a flowable agent or fibrin sealant could be thoroughly applied to the area during a minimally invasive or open procedure and would naturally conform to the irregularities in the tissue, particularly the junction between the vagina and bladder flap.

A pliable product such as Surgicel Nu-Knit or Fibrillar would also work well in these circumstances, although successful application during laparoscopy may depend on the size of the trocar. For example, Nu-Knit would require trimming to a size suitable for passage through a trocar, made easier by moistening with saline. The weave of Fibrillar makes it more challenging to pass, intact, through a trocar; rolling the material into a cylindrical shape may reduce its diameter and allow it to pass more easily.

CASE 1: Resolved

You apply a fibrin sealant to the site of bleeding, and the oozing abates. Once complete hemostasis is ensured, you conclude the surgery and transfer the patient to recovery, where she does well.

Profiles in hemostasis: Strengths and weaknesses of topical agent

Controlling bleeding without injuring underlying tissue

CASE 2: After adhesiolysis, bleeding at multiple sites

You perform adnexectomy on a 47-year-old woman who has a large (7 to 8 cm), benign ovarian mass. As you operate, you discover that the lesion is adherent to the sigmoid mesentery and the posterior aspect of the uterus; it is also adherent to the pelvic sidewall, directly along the course of the ureter. Although you are able to release the various adhesive attachments, persistent bleeding is noted at multiple pinpoint areas along the mesentery, uterine serosa, and pelvic sidewall, even after the application of direct pressure.

What do you do next?

Although cautery can be used liberally on the uterus, its application to mesentery carries a risk of injury to the mesenteric vessels and bowel wall. Caution is advised when you are attempting to control bleeding on the peritoneum overlying the ureter, whether you are using suture ligature or an energy source. Ideally, you should identify the ureter using a retroperitoneal approach and mobilize it laterally before employing any of these techniques.

There are several potential approaches to the bleeding described in Case 2, all of them involving hemostatic adjuvants. The first decision you need to make, however, is whether to address each region separately or all sites in unison. If you opt to address them together—either during an open procedure or laparoscopy—a fibrin sealant (e.g., Evicel, Tisseel) is one option. It can be applied using a dripping technique or aerosolization, either of which allows for broad application of a thin film of the agent. The limitation of this approach is the volume of agent required to resolve the bleeding, with a potential need for multiple doses to completely coat the area.

Because fibrin sealants function independently of the patient’s coagulation cascade, they are particularly useful in the presence of disseminated intravascular coagulation (DIC) and other coagulopathies that might limit the effectiveness of preparations that require the patient’s own serum.

An alternative approach to Case 2 is to apply an oxidized regenerated cellulose (ORC) derivative directly to the affected areas. Various forms are available (e.g., Surgicel Fibrillar, Surgicel Nu-Knit). These ORC products can be cut and customized to the area in need of hemostasis, allowing each site to be addressed individually. These agents typically remain adherent after they are applied due to the nature of the interaction between the product, blood, and tissue.

A liquid or foam hemostatic agent (e.g., Surgiflo, Floseal, topical thrombin) could also be employed in this case, but application can be a challenge on a large area with a heterogeneous topography because of the tendency of such agents to migrate under the force of gravity, pooling away from the source of bleeding.

Is combining agents a good idea?

Although they are not typically approved for use in combination, sequential application of hemostatic agents may be considered when bleeding persists.

All hemostatic agents work best in combination with the application of pressure. It usually is advisable to use moist gauze for this purpose because it can be lifted away without significant adherence to the underlying hemostatic complex, avoiding clot

disruption.

CASE 2: Resolved

You opt to use an ORC product, customizing it to fit each bleeding site, and apply direct pressure. When hemostasis has been achieved at all sites, you complete the operation. The patient has an uneventful postoperative course.

Protect structures along the pelvic sidewall

CASE 3: When the application of pressure isn’t enough

While performing a left salpingo-oophorectomy for a 12-cm ovarian lesion, you use a retroperitoneal approach to identify the structures along the pelvic sidewall. During identification of the ureter, you encounter bleeding from a small vessel in the adjacent fatty areolar tissue. After a period of observation, during which you apply pressure to the area of concern, bleeding persists.

What hemostatic agent do you employ to stop it?

The careful application of steady pressure is often enough to safely control bleeding in the area of the pelvic sidewall. In the event that pressure alone fails to resolve the bleeding, however, it is critical to choose a remedy that avoids injuring the ureter, iliac vessels, and infundibulopelvic ligament. Wide exposure of the space may allow for direct identification of the point of bleeding and precise application of cautery, a hemoclip, or a tie. When this approach is not feasible, other solutions must be sought.

When traditional hemostatic techniques fail in delicate anatomic sites, such as the periureteral area, hemostatic agents are an effective option that can minimize the risk of injury to surrounding vital structures. The contour of the space calls for a product that can intercalate, such as a foam, sealant, or Surgicel Fibrillar. Direct, precise application to the point of bleeding is critical, and the “bunching up” of a more rigid and bulky agent may limit its application to the area of concern. Use of a moist gauze to apply direct pressure after application of the agent will increase the likelihood of success.

CASE 3: Resolved

You decide to apply a foam hemostatic agent because of its ability to conform to the irregular space. You also continue to apply gentle pressure to the point of bleeding, using a moist gauze. Within minutes, hemostasis is achieved. You are then able to finish the operation.

Other variables to consider

As these three cases illustrate, the use of hemostatic agents to control surgical bleeding requires an individualized approach. The site and amount of bleeding, as well as the patient’s hemodynamic and coagulation status, are key variables to be considered when selecting an agent.

For instance, because of their components, fibrin sealants can function independently of the patient’s coagulation status. ORC products provide a matrix that facilitates platelet aggregration and may be less effective when anti-platelet agents have been used.

It is also appropriate for the surgeon to be familiar with the relative cost of the agents available at his or her institution. In particular, when several agents may be equally effective in a particular set of circumstances, cost may be the determining factor.

Availability of these agents varies from one institution to the next; as a result, it can be challenging to maintain familiarity with all of the products in the marketplace. Having access to a diverse, readily available set of “go to” agents is critical to ensure rapid application in a clinical setting.

The surgeon’s preference also is important, particularly in regard to the ease of preparation and handling. Some agents may not be as suitable for minimally invasive procedures (see TABLE). For others, special laparoscopic applicators are available.

When using a hemostatic agent, it pays to consider the duration of its effect in the surgical site. Both the quantity of the agent that is applied and characteristics of the local operative site influence how quickly the agent degrades. Keep this in mind when imaging studies are planned for the early postoperative period. An ORC preparation, for example, may appear with small pockets of air that resemble an abscess. Effective communication with the radiology team is critical to avoid the misinterpretation of findings.

Choosing a topical agent? First, consider surgical technique.

Curious to discover the preferences and practices of surgeons likely to utilize topical hemostatic agents, OBG Management polled several experienced and expert surgeons, including members of the journal’s Board of Editors and Virtual Board of Editors. Their diverse responses offer a snapshot of gynecologic surgical practice in 2012—but all agree that hemostatic products are no substitute for sound surgical technique.
JANELLE YATES, SENIOR EDITOR

We want to hear from you! Tell us what you think.

Dr. Scott Freeman’s useful discussion of targeting acute risk factors in suicidal patients (“Suicide assessment: Targeting acute risk factors,” Current Psychiatry, January 2012, p. 52-57) ends by resolving the clinical vignette with a summary of hospital treatment. Apart from failing to indicate any psychotherapeutic inroads, Dr. Freeman seems to support prescribing clonazepam, 0.5 mg twice daily and 1 mg at bedtime. Clonazepam apparently “worked” by alleviating the patient’s anxiety and insomnia, but defied any pharmacologic rationale insofar as clonazepam has a slow onset and long half-life, making 3 doses per day irrational. This treatment strategy also risks problems of cumulative excess in the long run after discharge.

Aggressive pharmacotherapy may be the hallmark of modern acute hospital treatment, but surely it should incorporate careful understanding of specific medications’ pharmacodynamics, especially when relying on benzodiazepines. Needless to say, beginning a psychological process in the hospital also appears to have been shortchanged.

Sara Hartley, MD
Lecturer, Clinical Skills Program
University of California,
Berkeley-University of California,
San Francisco Joint Medical Program
Berkeley, CA

Dr. Freeman responds

I appreciate Dr. Hartley’s interest in my article. Although I agree with her that psychotherapy is an integral part of any treatment plan, the clinical vignette was used only to emphasize the need to aggressively and quickly start antidepressant and, more importantly, anxiolytic pharmacologic treatment in acutely suicidal patients with severe anxiety and depression.

With regard to clonazepam’s pharmacokinetics, although it does have a long half-life, it is only weakly lipophilic compared with other long-acting benzodiazepines such as diazepam. In fact, clonazepam has been shown to be less lipophilic than lorazepam,¹ meaning it has a much smaller volume of distribution and less accumulation in peripheral adipose tissue. Therefore, one would not be concerned about significant drug accumulation leading to unexpected toxicity with a less lipophilic agent such as clonazepam.

I do not agree that dosing clonazepam 3 times a day, especially in an acute crisis, is “irrational,” as Dr. Hartley suggests. According to the package insert, although clonazepam is recommended to be administered twice daily for panic disorder, it can be given 3 times a day for seizure disorders.²

Scott A. Freeman, MD
Medical Director
Schizophrenia and Bipolar Disorder Inpatient Unit
McLean Hospital
Belmont, MA

Dr. Scott Freeman’s useful discussion of targeting acute risk factors in suicidal patients (“Suicide assessment: Targeting acute risk factors,” Current Psychiatry, January 2012, p. 52-57) ends by resolving the clinical vignette with a summary of hospital treatment. Apart from failing to indicate any psychotherapeutic inroads, Dr. Freeman seems to support prescribing clonazepam, 0.5 mg twice daily and 1 mg at bedtime. Clonazepam apparently “worked” by alleviating the patient’s anxiety and insomnia, but defied any pharmacologic rationale insofar as clonazepam has a slow onset and long half-life, making 3 doses per day irrational. This treatment strategy also risks problems of cumulative excess in the long run after discharge.

Aggressive pharmacotherapy may be the hallmark of modern acute hospital treatment, but surely it should incorporate careful understanding of specific medications’ pharmacodynamics, especially when relying on benzodiazepines. Needless to say, beginning a psychological process in the hospital also appears to have been shortchanged.

Sara Hartley, MD
Lecturer, Clinical Skills Program
University of California,
Berkeley-University of California,
San Francisco Joint Medical Program
Berkeley, CA

Dr. Freeman responds

I appreciate Dr. Hartley’s interest in my article. Although I agree with her that psychotherapy is an integral part of any treatment plan, the clinical vignette was used only to emphasize the need to aggressively and quickly start antidepressant and, more importantly, anxiolytic pharmacologic treatment in acutely suicidal patients with severe anxiety and depression.

With regard to clonazepam’s pharmacokinetics, although it does have a long half-life, it is only weakly lipophilic compared with other long-acting benzodiazepines such as diazepam. In fact, clonazepam has been shown to be less lipophilic than lorazepam,¹ meaning it has a much smaller volume of distribution and less accumulation in peripheral adipose tissue. Therefore, one would not be concerned about significant drug accumulation leading to unexpected toxicity with a less lipophilic agent such as clonazepam.

I do not agree that dosing clonazepam 3 times a day, especially in an acute crisis, is “irrational,” as Dr. Hartley suggests. According to the package insert, although clonazepam is recommended to be administered twice daily for panic disorder, it can be given 3 times a day for seizure disorders.²

Scott A. Freeman, MD
Medical Director
Schizophrenia and Bipolar Disorder Inpatient Unit
McLean Hospital
Belmont, MA

Dr. Scott Freeman’s useful discussion of targeting acute risk factors in suicidal patients (“Suicide assessment: Targeting acute risk factors,” Current Psychiatry, January 2012, p. 52-57) ends by resolving the clinical vignette with a summary of hospital treatment. Apart from failing to indicate any psychotherapeutic inroads, Dr. Freeman seems to support prescribing clonazepam, 0.5 mg twice daily and 1 mg at bedtime. Clonazepam apparently “worked” by alleviating the patient’s anxiety and insomnia, but defied any pharmacologic rationale insofar as clonazepam has a slow onset and long half-life, making 3 doses per day irrational. This treatment strategy also risks problems of cumulative excess in the long run after discharge.

Aggressive pharmacotherapy may be the hallmark of modern acute hospital treatment, but surely it should incorporate careful understanding of specific medications’ pharmacodynamics, especially when relying on benzodiazepines. Needless to say, beginning a psychological process in the hospital also appears to have been shortchanged.

Sara Hartley, MD
Lecturer, Clinical Skills Program
University of California,
Berkeley-University of California,
San Francisco Joint Medical Program
Berkeley, CA

Dr. Freeman responds

I appreciate Dr. Hartley’s interest in my article. Although I agree with her that psychotherapy is an integral part of any treatment plan, the clinical vignette was used only to emphasize the need to aggressively and quickly start antidepressant and, more importantly, anxiolytic pharmacologic treatment in acutely suicidal patients with severe anxiety and depression.

With regard to clonazepam’s pharmacokinetics, although it does have a long half-life, it is only weakly lipophilic compared with other long-acting benzodiazepines such as diazepam. In fact, clonazepam has been shown to be less lipophilic than lorazepam,¹ meaning it has a much smaller volume of distribution and less accumulation in peripheral adipose tissue. Therefore, one would not be concerned about significant drug accumulation leading to unexpected toxicity with a less lipophilic agent such as clonazepam.

I do not agree that dosing clonazepam 3 times a day, especially in an acute crisis, is “irrational,” as Dr. Hartley suggests. According to the package insert, although clonazepam is recommended to be administered twice daily for panic disorder, it can be given 3 times a day for seizure disorders.²

Scott A. Freeman, MD
Medical Director
Schizophrenia and Bipolar Disorder Inpatient Unit
McLean Hospital
Belmont, MA

Helping hospitalized geriatric patients maintain an appropriate sleep-wake cycle can be a challenge. Older patients’ circadian rhythm may be affected by several factors—eg, obstructive sleep apnea and restless leg syndrome—that contribute to disrupted sleep and daytime fatigue. Some patients may have dementing illnesses that could dysregulate sleep. Many older patients experience delirium during hospitalization, of which sleep-wake cycle disturbances are a hallmark. Finally, geriatric patients’ natural sleep pattern often does not mimic a hospital’s typical schedule.

Sleep medication side effects

Medications used to promote sleep can cause side effects in geriatric patients. Benzodiazepine use by older adults is discouraged because these medications could cause falls or contribute to delirium. Non-benzodiazepine hypnotics such as zolpidem, zaleplon, and eszopiclone pose a similar risk. Medications containing diphenhydramine predispose patients to deliriogenic effects via their anticholinergic properties. Tricyclic antidepressants carry risks, such as delirium secondary to anticholinergic effects, orthostatic hypotension, falls from α-1 blockade, and cardiac arrythmias.

Atypical antipsychotics sometimes are used off-label to help initiate sleep, but they carry a “black-box” warning regarding sudden death from cardiovascular events in geriatric patients with dementia. Hydroxyzine and trazodone also are associated with side effects such as orthostatic hypotension and daytime sedation, and are not always effective.

Melatonin is a hormone secreted by the pineal gland in response to darkness, under the control of the suprachiasmatic nucleus (SCN), and is thought to promote sleep via synchronizing effects on the SCN.¹ Melatonin is available as an over-the-counter dietary supplement and via prescription in dosages of 1 or 3 mg. The typical effective dose is 3 to 9 mg.¹ Patients should take melatonin in the mid-evening, ideally between 7 pm and 8 pm, and effects become evident after a few days. Side effects are rare; the most common are headache and nausea. Daytime sedation and vivid dreams also have been reported. Melatonin can be used safely in conjunction with other sleep aids and its major drug-drug interactions involve enhancing the effects of other sedatives.²

We have found melatonin to be effective for treating sleep disturbances in older hospitalized patients. Its effectiveness may stem from the high incidence of dysregulated or calcified pineal glands in geriatric patients, which leads to a marked reduction in melatonin secretion.³ Recent evidence also suggests melatonin may reduce the incidence of delirium in older adults, and it has been proposed as a delirium treatment in post-operative and intensive care unit settings.⁴

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Helping hospitalized geriatric patients maintain an appropriate sleep-wake cycle can be a challenge. Older patients’ circadian rhythm may be affected by several factors—eg, obstructive sleep apnea and restless leg syndrome—that contribute to disrupted sleep and daytime fatigue. Some patients may have dementing illnesses that could dysregulate sleep. Many older patients experience delirium during hospitalization, of which sleep-wake cycle disturbances are a hallmark. Finally, geriatric patients’ natural sleep pattern often does not mimic a hospital’s typical schedule.

Sleep medication side effects

Medications used to promote sleep can cause side effects in geriatric patients. Benzodiazepine use by older adults is discouraged because these medications could cause falls or contribute to delirium. Non-benzodiazepine hypnotics such as zolpidem, zaleplon, and eszopiclone pose a similar risk. Medications containing diphenhydramine predispose patients to deliriogenic effects via their anticholinergic properties. Tricyclic antidepressants carry risks, such as delirium secondary to anticholinergic effects, orthostatic hypotension, falls from α-1 blockade, and cardiac arrythmias.

Atypical antipsychotics sometimes are used off-label to help initiate sleep, but they carry a “black-box” warning regarding sudden death from cardiovascular events in geriatric patients with dementia. Hydroxyzine and trazodone also are associated with side effects such as orthostatic hypotension and daytime sedation, and are not always effective.

Melatonin is a hormone secreted by the pineal gland in response to darkness, under the control of the suprachiasmatic nucleus (SCN), and is thought to promote sleep via synchronizing effects on the SCN.¹ Melatonin is available as an over-the-counter dietary supplement and via prescription in dosages of 1 or 3 mg. The typical effective dose is 3 to 9 mg.¹ Patients should take melatonin in the mid-evening, ideally between 7 pm and 8 pm, and effects become evident after a few days. Side effects are rare; the most common are headache and nausea. Daytime sedation and vivid dreams also have been reported. Melatonin can be used safely in conjunction with other sleep aids and its major drug-drug interactions involve enhancing the effects of other sedatives.²

We have found melatonin to be effective for treating sleep disturbances in older hospitalized patients. Its effectiveness may stem from the high incidence of dysregulated or calcified pineal glands in geriatric patients, which leads to a marked reduction in melatonin secretion.³ Recent evidence also suggests melatonin may reduce the incidence of delirium in older adults, and it has been proposed as a delirium treatment in post-operative and intensive care unit settings.⁴

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Helping hospitalized geriatric patients maintain an appropriate sleep-wake cycle can be a challenge. Older patients’ circadian rhythm may be affected by several factors—eg, obstructive sleep apnea and restless leg syndrome—that contribute to disrupted sleep and daytime fatigue. Some patients may have dementing illnesses that could dysregulate sleep. Many older patients experience delirium during hospitalization, of which sleep-wake cycle disturbances are a hallmark. Finally, geriatric patients’ natural sleep pattern often does not mimic a hospital’s typical schedule.

Sleep medication side effects

Medications used to promote sleep can cause side effects in geriatric patients. Benzodiazepine use by older adults is discouraged because these medications could cause falls or contribute to delirium. Non-benzodiazepine hypnotics such as zolpidem, zaleplon, and eszopiclone pose a similar risk. Medications containing diphenhydramine predispose patients to deliriogenic effects via their anticholinergic properties. Tricyclic antidepressants carry risks, such as delirium secondary to anticholinergic effects, orthostatic hypotension, falls from α-1 blockade, and cardiac arrythmias.

Atypical antipsychotics sometimes are used off-label to help initiate sleep, but they carry a “black-box” warning regarding sudden death from cardiovascular events in geriatric patients with dementia. Hydroxyzine and trazodone also are associated with side effects such as orthostatic hypotension and daytime sedation, and are not always effective.

Melatonin is a hormone secreted by the pineal gland in response to darkness, under the control of the suprachiasmatic nucleus (SCN), and is thought to promote sleep via synchronizing effects on the SCN.¹ Melatonin is available as an over-the-counter dietary supplement and via prescription in dosages of 1 or 3 mg. The typical effective dose is 3 to 9 mg.¹ Patients should take melatonin in the mid-evening, ideally between 7 pm and 8 pm, and effects become evident after a few days. Side effects are rare; the most common are headache and nausea. Daytime sedation and vivid dreams also have been reported. Melatonin can be used safely in conjunction with other sleep aids and its major drug-drug interactions involve enhancing the effects of other sedatives.²

We have found melatonin to be effective for treating sleep disturbances in older hospitalized patients. Its effectiveness may stem from the high incidence of dysregulated or calcified pineal glands in geriatric patients, which leads to a marked reduction in melatonin secretion.³ Recent evidence also suggests melatonin may reduce the incidence of delirium in older adults, and it has been proposed as a delirium treatment in post-operative and intensive care unit settings.⁴

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.