Cleveland Clinic Journal of Medicine

With a substantial increase in antidepressant use in the United States over the last 2 decades, serotonin syndrome has become an increasingly common and significant clinical concern. In 1999, 6.5% of adults age 18 and older were taking antidepressants; by 2010, the percentage had increased to 10.4%.¹ Though the true incidence of serotonin syndrome is difficult to determine, the number of ingestions of selective serotonin reuptake inhibitors (SSRIs) associated with moderate to major effects reported to US poison control centers increased from 7,349 in 2002² to 8,585 in 2005.³

Though the clinical manifestations are often mild to moderate, patients with serotonin syndrome can deteriorate rapidly and require intensive care. Unlike neuroleptic malignant syndrome, serotonin syndrome should not be considered an extremely rare idiosyncratic reaction to medication, but rather a progression of serotonergic toxicity based on increasing concentration levels that can occur in any patient regardless of age.⁴

Because it has a nonspecific prodrome and protean manifestations, serotonin syndrome can easily be overlooked, misdiagnosed, or exacerbated if not carefully assessed. Diagnosis requires a low threshold for suspicion and a meticulous history and physical examination. In the syndrome’s mildest stage, symptoms are often misattributed to other causes, and in its most severe form, it can easily be mistaken for neuroleptic malignant syndrome.

WHAT IS SEROTONIN SYNDROME?

Serotonin syndrome classically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. These symptoms are a result of increased serotonin levels affecting the central and peripheral nervous systems. Serotonin affects a family of receptors that has seven members, of which 5-HT1A and 5-HT2A are most often responsible for serotonin syndrome.⁵

Conditions that can alter the regulation of serotonin include therapeutic doses, drug interactions, intentional or unintentional overdoses, and overlapping transitions between medications. As a result, drugs that have been associated with serotonin syndrome can be classified into the following five categories as shown below and in Table 1:

Drugs that decrease serotonin breakdown include monoamine oxidase inhibitors (MAOIs), linezolid,⁶ methylene blue, procarbazine, and Syrian rue.

Drugs that decrease serotonin reuptake include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, opioids (meperidine, buprenorphine, tramadol, tapentadol, dextromethorphan), antiepileptics (carbamazepine, valproate), and antiemetics (ondansetron, granisetron, metoclopramide), and the herbal preparation St. John’s wort.

Drugs that increase serotonin precursors or agonists include tryptophan, lithium, fentanyl, and lysergic acid diethylamide (LSD).

Drugs that increase serotonin release include fenfluramine, amphetamines, and methylenedioxymethamphetamine (ecstasy).

Drugs that prevent breakdown of the agents listed above are CYP2D6 and CYP3A4 inhibitors, eg, erythromycin,⁷ ciprofloxacin, fluconazole, ritonavir, and grapefruit juice.

However, the only drugs that have been reliably confirmed to precipitate serotonin syndrome are MAOIs, SSRIs, SNRIs, and serotonin releasers. Other listed drug interactions are based on case reports and have not been thoroughly evaluated.^6–9

Currently, SSRIs are the most commonly prescribed antidepressant medications and, consequently, they are the ones most often implicated in serotonergic toxicity.^1,10 An estimated 15% of SSRI overdoses lead to mild or moderate serotonin toxicity.¹¹ Serotonergic agents used in conjunction can increase the risk for severe serotonin syndrome; an SSRI and an MAOI in combination poses the greatest risk.⁵

Ultimately, the incidence of serotonin syndrome is difficult to assess, but it is believed to be underreported because it is easy to misdiagnose and mild symptoms may be dismissed.

WHO IS AT RISK OF SEROTONIN SYNDROME?

Long-term antidepressant use has disproportionately increased in middle-aged and older adults and non-Hispanic whites.^1,12,13 Intuitively, as the risk for depression increases dramatically in patients with chronic medical conditions, serotonin syndrome should be more prevalent among the elderly. In addition, patients with multiple comorbidities take more medications, increasing the risk of polypharmacy and adverse drug reactions.¹⁴

Although the epidemiology of serotonin syndrome has yet to be extensively studied, the combination of age and comorbidities may increase the risk for this condition.

HOW DOES IT PRESENT?

Serotonin syndrome characteristically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. However, these symptoms may not occur simultaneously: autonomic dysfunction is present in 40% of patients, neuromuscular excitation in 50%, and altered mental status in 40%.¹⁵ The symptoms can range from mild to life-threatening (Table 2).¹⁶

Autonomic dysfunction. Diaphoresis is present in 48.8% of cases, tachycardia in 44%, nausea and vomiting in 26.8%, and mydriasis in 19.5%. Other signs are hyperactive bowel sounds, diarrhea, and flushing.¹⁶

Neuromuscular excitation. Myoclonus is present in 48.8%, hyperreflexia in 41%, hyperthermia in 26.8%, and hypertonicity and rigidity in 19.5%. Other signs are spontaneous or inducible clonus, ocular clonus (continuous rhythmic oscillations of gaze), and tremor.

Altered mental status. Confusion is present in 41.2% and agitation in 36.5%. Other signs are anxiety, lethargy, and coma.

Symptoms of serotonin toxicity arise within an hour of a precipitating event (eg, ingestion) in approximately 28% of patients, and within 6 hours in 61%.¹⁶ Highly diagnostic features include hyperreflexia and induced or spontaneous clonus that are generally more pronounced in the lower limbs.¹¹ Clonus can be elicited with ankle dorsiflexion.

In mild toxicity, patients may present with tremor or twitching and anxiety, as well as with hyperreflexia, tachycardia, diaphoresis, and mydriasis. Further investigation may uncover a recently initiated antidepressant or a cold-and-cough medication that contains dextromethorphan.^15,17

In moderate toxicity, patients present in significant distress, with agitation and restlessness. Features may include hyperreflexia and clonus of the lower extremities, opsoclonus, hyperactive bowel sounds, diarrhea, nausea, vomiting, tachycardia, hypertension, diaphoresis, mydriasis, and hyperthermia (< 40°C, 104°F). The patient’s history may reveal use of ecstasy or combined treatment with serotonin-potentiating agents such as an antidepressant with a proserotonergic opioid, antiepileptic, or CYP2D6 or CYP3A4 inhibitor.¹⁵

Severe serotonin toxicity is a life-threatening condition that can lead to multiorgan failure within hours. It can be characterized by muscle rigidity, which can cause the body temperature to elevate rapidly to over 40°C. This hypertonicity can mask the classic and diagnostic signs of hyperreflexia and clonus. Patients may have unstable and dynamic vital signs with confusion or delirium and can experience tonic-clonic seizures.

If the muscle rigidity and resulting hyperthermia are not managed properly, patients can develop cellular damage and enzyme dysfunction leading to rhabdomyolysis, myoglobinuria, renal failure, metabolic acidosis, acute respiratory distress syndrome, and disseminated intravascular coagulation.^16,18

Serotonin crisis is usually caused by the co-ingestion of multiple serotonergic agents, such as an antidepressant with an aforementioned opioid and antiemetic¹⁹; combining an SSRI and an MAOI poses the greatest risk. Alternatively, patients may have recently switched antidepressants without observing a safe washout period, leading to an overlap of serotonin levels.¹⁶

HOW DO WE DIAGNOSE SEROTONIN SYNDROME?

Serotonin syndrome is a clinical diagnosis and therefore requires a thorough review of medications and physical examination. Serum serotonin levels are an unreliable indicator of toxicity and do not correlate well with the clinical presentation.¹⁶

Currently, there are two clinical tools for diagnosing serotonin syndrome: the Hunter serotonin toxicity criteria (Figure 1) and the Sternbach criteria.

The Hunter criteria are based more heavily on physical findings. The patient must have taken a serotonergic agent and have one of the following:

• Spontaneous clonus
• Inducible clonus plus agitation or diaphoresis
• Ocular clonus plus agitation or diaphoresis
• Inducible clonus or ocular clonus, plus hypertonia and hyperthermia
• Tremor plus hyperreflexia.

The Sternbach criteria. The patient must be using a serotonergic agent, must have no other causes of symptoms, must not have recently used a neuroleptic agent, and must have three of the following:

• Mental status changes
• Agitation
• Hyperreflexia
• Myoclonus
• Diaphoresis
• Shivering
• Tremor
• Diarrhea
• Incoordination
• Fever

The Hunter criteria are recommended and are more specific (97% vs 96%) and more sensitive (84% vs 75%) than the Sternbach criteria when compared with the gold standard of diagnosis by a clinical toxicologist.¹ The Hunter criteria are also less likely to yield false-positive results.¹¹

Differential diagnosis

The differential diagnosis for serotonin syndrome includes neuroleptic malignant syndrome, anticholinergic poisoning (Table 3), metastatic carcinoma, central nervous system infection, gastroenteritis, and sepsis.

Neuroleptic malignant syndrome, the disorder most often misdiagnosed as serotonin syndrome, is an idiosyncratic reaction to a dopamine antagonist (eg, haloperidol, fluphenazine) that develops over days to weeks.²⁰ In 70% of patients, agitated delirium with confusion appears first, followed by lead pipe rigidity and cogwheel tremor, then hyperthermia with body temperature greater than 40°C, and finally, profuse diaphoresis, tachycardia, hypertension, and tachypnea.²¹

Key elements that distinguish neuroleptic malignant syndrome are the timeline of the clinical course, bradyreflexia, and the absence of clonus. Prodromal symptoms of nausea, vomiting, and diarrhea are also rare in neuroleptic malignant syndrome. Neuroleptic malignant syndrome typically requires an average of 9 days to resolve.

Anticholinergic poisoning usually develops within 1 to 2 hours of oral ingestion. Symptoms include flushing, anhidrosis, anhidrotic hyperthermia, mydriasis, urinary retention, decreased bowel sounds, agitated delirium, and visual hallucinations. In contrast to serotonin syndrome, reflexes and muscle tone are normal with anticholinergic poisoning.

HOW CAN WE TREAT SEROTONIN SYNDROME?

The two mainstays of serotonin syndrome management are to discontinue the serotonergic agent and to give supportive care. Most patients improve within 24 hours of stopping the precipitating drug and starting therapy.¹⁶

For mild serotonin syndrome, treatment involves discontinuing the offending agent and supportive therapy with intravenous fluids, correction of vital signs, and symptomatic treatment with a benzodiazepine. Patients should be admitted and observed for 12 to 24 hours to prevent exacerbation.

For moderate serotonin syndrome, treatment also involves stopping the serotonergic agent and giving supportive care. Symptomatic treatment with a benzodiazepine and nonserotonergic antiemetics is recommended, and standard cooling measures should be implemented for hyperthermia. Patients should be admitted and observed for 12 to 24 hours to prevent exacerbation.

For severe serotonin toxicity, treatment should focus on management of airway, breathing, and circulation—ie, the “ABCs.” The two primary life-threatening concerns are hyperthermia (temperature > 40°C or 104°F) and rigidity, which can lead to hypoventilation.^1,22 Controlling hyperthermia and rigidity can prevent other grave complications. Patients with severe serotonin toxicity should be sedated, paralyzed, and intubated.²¹ This will reverse ventilatory hypertonia and allow for mechanical ventilation. Paralysis will also prevent the exacerbation of hyperthermia, which is caused by muscle rigidity. Antipyretics have no role in the treatment of serotonin syndrome since the hyperthermia is not caused by a change in the hypothalamic temperature set point.²¹ Standard cooling measures should be used to manage hyperthermia.

Serotonin antagonists

Serotonin antagonists have had some success in case reports, but further studies are needed to confirm this.^4,23,24

Cyproheptadine is a potent 5-HT2A antagonist; patients usually respond within 1 to 2 hours of administration. Signs and symptoms have resolved completely within times ranging from 20 minutes to 48 hours, depending on the severity of toxicity.

The recommended initial dose of cyproheptadine is 12 mg, followed by 2 mg every 2 hours if symptoms continue.¹⁶ Maintenance dosing with 8 mg every 6 hours should be prescribed once stabilization is achieved. The total daily dose for adults should not exceed 0.5 mg/kg/day. Cyproheptadine is available only in oral form but can be crushed and administered via a nasogastric tube.²¹

Chlorpromazine is a 5-HT1A and 5-HT2A antagonist and can be given intramuscularly. Despite case reports citing its effectiveness, the risk of hypotension, dystonic reactions, and neuroleptic malignant syndrome may make it a less desirable option.^4,25

Cyproheptadine, chlorpromazine, and other serotonin receptor antagonists require further investigation beyond individual case reports to determine their effectiveness and reliability in treating serotonin syndrome.

Other agents

Benzodiazepines are considered a mainstay for symptomatic relief because of their anxiolytic and muscle relaxant effects.²⁶ However, animal studies showed that treatment with benzodiazepines attenuated hyperthermia but had no effect on time to recovery or outcome.²⁷

Neuromuscular blocking agents. The suggested neuromuscular blocking agent for severe toxicity is a nondepolarizing agent such as vecuronium. Succinylcholine should be avoided, as it can exacerbate rhabdomyolysis and hyperkalemia.²¹

Dantrolene has also been suggested for its muscle-relaxing effects and use in malignant hyperthermia. However, this treatment has not been successful in isolated case reports and has been ineffective in animal models.^4,28

Physical restraints are ill-advised, since isometric muscle contractions can exacerbate hyperthermia and lactic acidosis in agitated patients.²¹ If physical restraints are necessary to deliver medications, they should be removed as soon as possible.

HOW CAN WE PREVENT SEROTONIN SYNDROME?

Prevention of serotonin syndrome begins with improving education and awareness in patients and healthcare providers. Patients should be primarily concerned with taking their medications carefully as prescribed and recognizing early signs and symptoms of serotonin toxicity.

As use of antidepressants among an aging population continues to increase, and as physicians in multiple disciplines prescribe them for evolving indications (eg, duloxetine to treat osteoarthritis, diabetic neuropathy, fibromyalgia, and chemotherapy-induced peripheral neuropathy), healthcare providers need to be prepared to see more cases of serotonin syndrome and its deleterious effects.^29–31 Physicians should be vigilant in minimizing unnecessary use of serotonergic agents and reviewing drug regimens regularly to limit polypharmacy.

Electronic ordering systems should be designed to detect and alert the prescriber to possible interactions that can potentiate serotonin syndrome, and to not place the order until the prescriber overrides the alert. Combinations of SSRIs and MAOIs have the highest risk for inducing severe serotonin syndrome and should always be avoided.

If a patient is transitioning between serotonergic agents, physicians should observe a safe washout period to prevent overlap.^16,32 Washout periods may differ among medications depending on their half-lives. For example, sertraline has a washout period of 2 weeks, while fluoxetine requires a washout period of 5 to 6 weeks.³³ Consulting a pharmacist may be helpful when considering half-lives and washout periods.

We believe that educating both patients and physicians regarding prevention will help minimize the risk for serotonergic syndrome and will improve efficiency in assessment and management should toxicity develop.

With a substantial increase in antidepressant use in the United States over the last 2 decades, serotonin syndrome has become an increasingly common and significant clinical concern. In 1999, 6.5% of adults age 18 and older were taking antidepressants; by 2010, the percentage had increased to 10.4%.¹ Though the true incidence of serotonin syndrome is difficult to determine, the number of ingestions of selective serotonin reuptake inhibitors (SSRIs) associated with moderate to major effects reported to US poison control centers increased from 7,349 in 2002² to 8,585 in 2005.³

Though the clinical manifestations are often mild to moderate, patients with serotonin syndrome can deteriorate rapidly and require intensive care. Unlike neuroleptic malignant syndrome, serotonin syndrome should not be considered an extremely rare idiosyncratic reaction to medication, but rather a progression of serotonergic toxicity based on increasing concentration levels that can occur in any patient regardless of age.⁴

Because it has a nonspecific prodrome and protean manifestations, serotonin syndrome can easily be overlooked, misdiagnosed, or exacerbated if not carefully assessed. Diagnosis requires a low threshold for suspicion and a meticulous history and physical examination. In the syndrome’s mildest stage, symptoms are often misattributed to other causes, and in its most severe form, it can easily be mistaken for neuroleptic malignant syndrome.

WHAT IS SEROTONIN SYNDROME?

Serotonin syndrome classically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. These symptoms are a result of increased serotonin levels affecting the central and peripheral nervous systems. Serotonin affects a family of receptors that has seven members, of which 5-HT1A and 5-HT2A are most often responsible for serotonin syndrome.⁵

Conditions that can alter the regulation of serotonin include therapeutic doses, drug interactions, intentional or unintentional overdoses, and overlapping transitions between medications. As a result, drugs that have been associated with serotonin syndrome can be classified into the following five categories as shown below and in Table 1:

Drugs that decrease serotonin breakdown include monoamine oxidase inhibitors (MAOIs), linezolid,⁶ methylene blue, procarbazine, and Syrian rue.

Drugs that decrease serotonin reuptake include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, opioids (meperidine, buprenorphine, tramadol, tapentadol, dextromethorphan), antiepileptics (carbamazepine, valproate), and antiemetics (ondansetron, granisetron, metoclopramide), and the herbal preparation St. John’s wort.

Drugs that increase serotonin precursors or agonists include tryptophan, lithium, fentanyl, and lysergic acid diethylamide (LSD).

Drugs that increase serotonin release include fenfluramine, amphetamines, and methylenedioxymethamphetamine (ecstasy).

Drugs that prevent breakdown of the agents listed above are CYP2D6 and CYP3A4 inhibitors, eg, erythromycin,⁷ ciprofloxacin, fluconazole, ritonavir, and grapefruit juice.

However, the only drugs that have been reliably confirmed to precipitate serotonin syndrome are MAOIs, SSRIs, SNRIs, and serotonin releasers. Other listed drug interactions are based on case reports and have not been thoroughly evaluated.^6–9

Currently, SSRIs are the most commonly prescribed antidepressant medications and, consequently, they are the ones most often implicated in serotonergic toxicity.^1,10 An estimated 15% of SSRI overdoses lead to mild or moderate serotonin toxicity.¹¹ Serotonergic agents used in conjunction can increase the risk for severe serotonin syndrome; an SSRI and an MAOI in combination poses the greatest risk.⁵

Ultimately, the incidence of serotonin syndrome is difficult to assess, but it is believed to be underreported because it is easy to misdiagnose and mild symptoms may be dismissed.

WHO IS AT RISK OF SEROTONIN SYNDROME?

Long-term antidepressant use has disproportionately increased in middle-aged and older adults and non-Hispanic whites.^1,12,13 Intuitively, as the risk for depression increases dramatically in patients with chronic medical conditions, serotonin syndrome should be more prevalent among the elderly. In addition, patients with multiple comorbidities take more medications, increasing the risk of polypharmacy and adverse drug reactions.¹⁴

Although the epidemiology of serotonin syndrome has yet to be extensively studied, the combination of age and comorbidities may increase the risk for this condition.

HOW DOES IT PRESENT?

Serotonin syndrome characteristically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. However, these symptoms may not occur simultaneously: autonomic dysfunction is present in 40% of patients, neuromuscular excitation in 50%, and altered mental status in 40%.¹⁵ The symptoms can range from mild to life-threatening (Table 2).¹⁶

Autonomic dysfunction. Diaphoresis is present in 48.8% of cases, tachycardia in 44%, nausea and vomiting in 26.8%, and mydriasis in 19.5%. Other signs are hyperactive bowel sounds, diarrhea, and flushing.¹⁶

Neuromuscular excitation. Myoclonus is present in 48.8%, hyperreflexia in 41%, hyperthermia in 26.8%, and hypertonicity and rigidity in 19.5%. Other signs are spontaneous or inducible clonus, ocular clonus (continuous rhythmic oscillations of gaze), and tremor.

Altered mental status. Confusion is present in 41.2% and agitation in 36.5%. Other signs are anxiety, lethargy, and coma.

Symptoms of serotonin toxicity arise within an hour of a precipitating event (eg, ingestion) in approximately 28% of patients, and within 6 hours in 61%.¹⁶ Highly diagnostic features include hyperreflexia and induced or spontaneous clonus that are generally more pronounced in the lower limbs.¹¹ Clonus can be elicited with ankle dorsiflexion.

In mild toxicity, patients may present with tremor or twitching and anxiety, as well as with hyperreflexia, tachycardia, diaphoresis, and mydriasis. Further investigation may uncover a recently initiated antidepressant or a cold-and-cough medication that contains dextromethorphan.^15,17

In moderate toxicity, patients present in significant distress, with agitation and restlessness. Features may include hyperreflexia and clonus of the lower extremities, opsoclonus, hyperactive bowel sounds, diarrhea, nausea, vomiting, tachycardia, hypertension, diaphoresis, mydriasis, and hyperthermia (< 40°C, 104°F). The patient’s history may reveal use of ecstasy or combined treatment with serotonin-potentiating agents such as an antidepressant with a proserotonergic opioid, antiepileptic, or CYP2D6 or CYP3A4 inhibitor.¹⁵

Severe serotonin toxicity is a life-threatening condition that can lead to multiorgan failure within hours. It can be characterized by muscle rigidity, which can cause the body temperature to elevate rapidly to over 40°C. This hypertonicity can mask the classic and diagnostic signs of hyperreflexia and clonus. Patients may have unstable and dynamic vital signs with confusion or delirium and can experience tonic-clonic seizures.

If the muscle rigidity and resulting hyperthermia are not managed properly, patients can develop cellular damage and enzyme dysfunction leading to rhabdomyolysis, myoglobinuria, renal failure, metabolic acidosis, acute respiratory distress syndrome, and disseminated intravascular coagulation.^16,18

Serotonin crisis is usually caused by the co-ingestion of multiple serotonergic agents, such as an antidepressant with an aforementioned opioid and antiemetic¹⁹; combining an SSRI and an MAOI poses the greatest risk. Alternatively, patients may have recently switched antidepressants without observing a safe washout period, leading to an overlap of serotonin levels.¹⁶

HOW DO WE DIAGNOSE SEROTONIN SYNDROME?

Serotonin syndrome is a clinical diagnosis and therefore requires a thorough review of medications and physical examination. Serum serotonin levels are an unreliable indicator of toxicity and do not correlate well with the clinical presentation.¹⁶

Currently, there are two clinical tools for diagnosing serotonin syndrome: the Hunter serotonin toxicity criteria (Figure 1) and the Sternbach criteria.

The Hunter criteria are based more heavily on physical findings. The patient must have taken a serotonergic agent and have one of the following:

• Spontaneous clonus
• Inducible clonus plus agitation or diaphoresis
• Ocular clonus plus agitation or diaphoresis
• Inducible clonus or ocular clonus, plus hypertonia and hyperthermia
• Tremor plus hyperreflexia.

The Sternbach criteria. The patient must be using a serotonergic agent, must have no other causes of symptoms, must not have recently used a neuroleptic agent, and must have three of the following:

• Mental status changes
• Agitation
• Hyperreflexia
• Myoclonus
• Diaphoresis
• Shivering
• Tremor
• Diarrhea
• Incoordination
• Fever

The Hunter criteria are recommended and are more specific (97% vs 96%) and more sensitive (84% vs 75%) than the Sternbach criteria when compared with the gold standard of diagnosis by a clinical toxicologist.¹ The Hunter criteria are also less likely to yield false-positive results.¹¹

Differential diagnosis

The differential diagnosis for serotonin syndrome includes neuroleptic malignant syndrome, anticholinergic poisoning (Table 3), metastatic carcinoma, central nervous system infection, gastroenteritis, and sepsis.

Neuroleptic malignant syndrome, the disorder most often misdiagnosed as serotonin syndrome, is an idiosyncratic reaction to a dopamine antagonist (eg, haloperidol, fluphenazine) that develops over days to weeks.²⁰ In 70% of patients, agitated delirium with confusion appears first, followed by lead pipe rigidity and cogwheel tremor, then hyperthermia with body temperature greater than 40°C, and finally, profuse diaphoresis, tachycardia, hypertension, and tachypnea.²¹

Key elements that distinguish neuroleptic malignant syndrome are the timeline of the clinical course, bradyreflexia, and the absence of clonus. Prodromal symptoms of nausea, vomiting, and diarrhea are also rare in neuroleptic malignant syndrome. Neuroleptic malignant syndrome typically requires an average of 9 days to resolve.

Anticholinergic poisoning usually develops within 1 to 2 hours of oral ingestion. Symptoms include flushing, anhidrosis, anhidrotic hyperthermia, mydriasis, urinary retention, decreased bowel sounds, agitated delirium, and visual hallucinations. In contrast to serotonin syndrome, reflexes and muscle tone are normal with anticholinergic poisoning.

HOW CAN WE TREAT SEROTONIN SYNDROME?

The two mainstays of serotonin syndrome management are to discontinue the serotonergic agent and to give supportive care. Most patients improve within 24 hours of stopping the precipitating drug and starting therapy.¹⁶

For mild serotonin syndrome, treatment involves discontinuing the offending agent and supportive therapy with intravenous fluids, correction of vital signs, and symptomatic treatment with a benzodiazepine. Patients should be admitted and observed for 12 to 24 hours to prevent exacerbation.

For moderate serotonin syndrome, treatment also involves stopping the serotonergic agent and giving supportive care. Symptomatic treatment with a benzodiazepine and nonserotonergic antiemetics is recommended, and standard cooling measures should be implemented for hyperthermia. Patients should be admitted and observed for 12 to 24 hours to prevent exacerbation.

For severe serotonin toxicity, treatment should focus on management of airway, breathing, and circulation—ie, the “ABCs.” The two primary life-threatening concerns are hyperthermia (temperature > 40°C or 104°F) and rigidity, which can lead to hypoventilation.^1,22 Controlling hyperthermia and rigidity can prevent other grave complications. Patients with severe serotonin toxicity should be sedated, paralyzed, and intubated.²¹ This will reverse ventilatory hypertonia and allow for mechanical ventilation. Paralysis will also prevent the exacerbation of hyperthermia, which is caused by muscle rigidity. Antipyretics have no role in the treatment of serotonin syndrome since the hyperthermia is not caused by a change in the hypothalamic temperature set point.²¹ Standard cooling measures should be used to manage hyperthermia.

Serotonin antagonists

Serotonin antagonists have had some success in case reports, but further studies are needed to confirm this.^4,23,24

Cyproheptadine is a potent 5-HT2A antagonist; patients usually respond within 1 to 2 hours of administration. Signs and symptoms have resolved completely within times ranging from 20 minutes to 48 hours, depending on the severity of toxicity.

The recommended initial dose of cyproheptadine is 12 mg, followed by 2 mg every 2 hours if symptoms continue.¹⁶ Maintenance dosing with 8 mg every 6 hours should be prescribed once stabilization is achieved. The total daily dose for adults should not exceed 0.5 mg/kg/day. Cyproheptadine is available only in oral form but can be crushed and administered via a nasogastric tube.²¹

Chlorpromazine is a 5-HT1A and 5-HT2A antagonist and can be given intramuscularly. Despite case reports citing its effectiveness, the risk of hypotension, dystonic reactions, and neuroleptic malignant syndrome may make it a less desirable option.^4,25

Cyproheptadine, chlorpromazine, and other serotonin receptor antagonists require further investigation beyond individual case reports to determine their effectiveness and reliability in treating serotonin syndrome.

Other agents

Benzodiazepines are considered a mainstay for symptomatic relief because of their anxiolytic and muscle relaxant effects.²⁶ However, animal studies showed that treatment with benzodiazepines attenuated hyperthermia but had no effect on time to recovery or outcome.²⁷

Neuromuscular blocking agents. The suggested neuromuscular blocking agent for severe toxicity is a nondepolarizing agent such as vecuronium. Succinylcholine should be avoided, as it can exacerbate rhabdomyolysis and hyperkalemia.²¹

Dantrolene has also been suggested for its muscle-relaxing effects and use in malignant hyperthermia. However, this treatment has not been successful in isolated case reports and has been ineffective in animal models.^4,28

Physical restraints are ill-advised, since isometric muscle contractions can exacerbate hyperthermia and lactic acidosis in agitated patients.²¹ If physical restraints are necessary to deliver medications, they should be removed as soon as possible.

HOW CAN WE PREVENT SEROTONIN SYNDROME?

Prevention of serotonin syndrome begins with improving education and awareness in patients and healthcare providers. Patients should be primarily concerned with taking their medications carefully as prescribed and recognizing early signs and symptoms of serotonin toxicity.

As use of antidepressants among an aging population continues to increase, and as physicians in multiple disciplines prescribe them for evolving indications (eg, duloxetine to treat osteoarthritis, diabetic neuropathy, fibromyalgia, and chemotherapy-induced peripheral neuropathy), healthcare providers need to be prepared to see more cases of serotonin syndrome and its deleterious effects.^29–31 Physicians should be vigilant in minimizing unnecessary use of serotonergic agents and reviewing drug regimens regularly to limit polypharmacy.

Electronic ordering systems should be designed to detect and alert the prescriber to possible interactions that can potentiate serotonin syndrome, and to not place the order until the prescriber overrides the alert. Combinations of SSRIs and MAOIs have the highest risk for inducing severe serotonin syndrome and should always be avoided.

If a patient is transitioning between serotonergic agents, physicians should observe a safe washout period to prevent overlap.^16,32 Washout periods may differ among medications depending on their half-lives. For example, sertraline has a washout period of 2 weeks, while fluoxetine requires a washout period of 5 to 6 weeks.³³ Consulting a pharmacist may be helpful when considering half-lives and washout periods.

We believe that educating both patients and physicians regarding prevention will help minimize the risk for serotonergic syndrome and will improve efficiency in assessment and management should toxicity develop.

With a substantial increase in antidepressant use in the United States over the last 2 decades, serotonin syndrome has become an increasingly common and significant clinical concern. In 1999, 6.5% of adults age 18 and older were taking antidepressants; by 2010, the percentage had increased to 10.4%.¹ Though the true incidence of serotonin syndrome is difficult to determine, the number of ingestions of selective serotonin reuptake inhibitors (SSRIs) associated with moderate to major effects reported to US poison control centers increased from 7,349 in 2002² to 8,585 in 2005.³

Though the clinical manifestations are often mild to moderate, patients with serotonin syndrome can deteriorate rapidly and require intensive care. Unlike neuroleptic malignant syndrome, serotonin syndrome should not be considered an extremely rare idiosyncratic reaction to medication, but rather a progression of serotonergic toxicity based on increasing concentration levels that can occur in any patient regardless of age.⁴

Because it has a nonspecific prodrome and protean manifestations, serotonin syndrome can easily be overlooked, misdiagnosed, or exacerbated if not carefully assessed. Diagnosis requires a low threshold for suspicion and a meticulous history and physical examination. In the syndrome’s mildest stage, symptoms are often misattributed to other causes, and in its most severe form, it can easily be mistaken for neuroleptic malignant syndrome.

WHAT IS SEROTONIN SYNDROME?

Serotonin syndrome classically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. These symptoms are a result of increased serotonin levels affecting the central and peripheral nervous systems. Serotonin affects a family of receptors that has seven members, of which 5-HT1A and 5-HT2A are most often responsible for serotonin syndrome.⁵

Conditions that can alter the regulation of serotonin include therapeutic doses, drug interactions, intentional or unintentional overdoses, and overlapping transitions between medications. As a result, drugs that have been associated with serotonin syndrome can be classified into the following five categories as shown below and in Table 1:

Drugs that decrease serotonin breakdown include monoamine oxidase inhibitors (MAOIs), linezolid,⁶ methylene blue, procarbazine, and Syrian rue.

Drugs that decrease serotonin reuptake include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, opioids (meperidine, buprenorphine, tramadol, tapentadol, dextromethorphan), antiepileptics (carbamazepine, valproate), and antiemetics (ondansetron, granisetron, metoclopramide), and the herbal preparation St. John’s wort.

Drugs that increase serotonin precursors or agonists include tryptophan, lithium, fentanyl, and lysergic acid diethylamide (LSD).

Drugs that increase serotonin release include fenfluramine, amphetamines, and methylenedioxymethamphetamine (ecstasy).

Drugs that prevent breakdown of the agents listed above are CYP2D6 and CYP3A4 inhibitors, eg, erythromycin,⁷ ciprofloxacin, fluconazole, ritonavir, and grapefruit juice.

However, the only drugs that have been reliably confirmed to precipitate serotonin syndrome are MAOIs, SSRIs, SNRIs, and serotonin releasers. Other listed drug interactions are based on case reports and have not been thoroughly evaluated.^6–9

Currently, SSRIs are the most commonly prescribed antidepressant medications and, consequently, they are the ones most often implicated in serotonergic toxicity.^1,10 An estimated 15% of SSRI overdoses lead to mild or moderate serotonin toxicity.¹¹ Serotonergic agents used in conjunction can increase the risk for severe serotonin syndrome; an SSRI and an MAOI in combination poses the greatest risk.⁵

Ultimately, the incidence of serotonin syndrome is difficult to assess, but it is believed to be underreported because it is easy to misdiagnose and mild symptoms may be dismissed.

WHO IS AT RISK OF SEROTONIN SYNDROME?

Long-term antidepressant use has disproportionately increased in middle-aged and older adults and non-Hispanic whites.^1,12,13 Intuitively, as the risk for depression increases dramatically in patients with chronic medical conditions, serotonin syndrome should be more prevalent among the elderly. In addition, patients with multiple comorbidities take more medications, increasing the risk of polypharmacy and adverse drug reactions.¹⁴

Although the epidemiology of serotonin syndrome has yet to be extensively studied, the combination of age and comorbidities may increase the risk for this condition.

HOW DOES IT PRESENT?

Serotonin syndrome characteristically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. However, these symptoms may not occur simultaneously: autonomic dysfunction is present in 40% of patients, neuromuscular excitation in 50%, and altered mental status in 40%.¹⁵ The symptoms can range from mild to life-threatening (Table 2).¹⁶

Autonomic dysfunction. Diaphoresis is present in 48.8% of cases, tachycardia in 44%, nausea and vomiting in 26.8%, and mydriasis in 19.5%. Other signs are hyperactive bowel sounds, diarrhea, and flushing.¹⁶

Neuromuscular excitation. Myoclonus is present in 48.8%, hyperreflexia in 41%, hyperthermia in 26.8%, and hypertonicity and rigidity in 19.5%. Other signs are spontaneous or inducible clonus, ocular clonus (continuous rhythmic oscillations of gaze), and tremor.

Altered mental status. Confusion is present in 41.2% and agitation in 36.5%. Other signs are anxiety, lethargy, and coma.

Symptoms of serotonin toxicity arise within an hour of a precipitating event (eg, ingestion) in approximately 28% of patients, and within 6 hours in 61%.¹⁶ Highly diagnostic features include hyperreflexia and induced or spontaneous clonus that are generally more pronounced in the lower limbs.¹¹ Clonus can be elicited with ankle dorsiflexion.

In mild toxicity, patients may present with tremor or twitching and anxiety, as well as with hyperreflexia, tachycardia, diaphoresis, and mydriasis. Further investigation may uncover a recently initiated antidepressant or a cold-and-cough medication that contains dextromethorphan.^15,17

In moderate toxicity, patients present in significant distress, with agitation and restlessness. Features may include hyperreflexia and clonus of the lower extremities, opsoclonus, hyperactive bowel sounds, diarrhea, nausea, vomiting, tachycardia, hypertension, diaphoresis, mydriasis, and hyperthermia (< 40°C, 104°F). The patient’s history may reveal use of ecstasy or combined treatment with serotonin-potentiating agents such as an antidepressant with a proserotonergic opioid, antiepileptic, or CYP2D6 or CYP3A4 inhibitor.¹⁵

Severe serotonin toxicity is a life-threatening condition that can lead to multiorgan failure within hours. It can be characterized by muscle rigidity, which can cause the body temperature to elevate rapidly to over 40°C. This hypertonicity can mask the classic and diagnostic signs of hyperreflexia and clonus. Patients may have unstable and dynamic vital signs with confusion or delirium and can experience tonic-clonic seizures.

If the muscle rigidity and resulting hyperthermia are not managed properly, patients can develop cellular damage and enzyme dysfunction leading to rhabdomyolysis, myoglobinuria, renal failure, metabolic acidosis, acute respiratory distress syndrome, and disseminated intravascular coagulation.^16,18

Serotonin crisis is usually caused by the co-ingestion of multiple serotonergic agents, such as an antidepressant with an aforementioned opioid and antiemetic¹⁹; combining an SSRI and an MAOI poses the greatest risk. Alternatively, patients may have recently switched antidepressants without observing a safe washout period, leading to an overlap of serotonin levels.¹⁶

HOW DO WE DIAGNOSE SEROTONIN SYNDROME?

Serotonin syndrome is a clinical diagnosis and therefore requires a thorough review of medications and physical examination. Serum serotonin levels are an unreliable indicator of toxicity and do not correlate well with the clinical presentation.¹⁶

Currently, there are two clinical tools for diagnosing serotonin syndrome: the Hunter serotonin toxicity criteria (Figure 1) and the Sternbach criteria.

The Hunter criteria are based more heavily on physical findings. The patient must have taken a serotonergic agent and have one of the following:

• Spontaneous clonus
• Inducible clonus plus agitation or diaphoresis
• Ocular clonus plus agitation or diaphoresis
• Inducible clonus or ocular clonus, plus hypertonia and hyperthermia
• Tremor plus hyperreflexia.

The Sternbach criteria. The patient must be using a serotonergic agent, must have no other causes of symptoms, must not have recently used a neuroleptic agent, and must have three of the following:

• Mental status changes
• Agitation
• Hyperreflexia
• Myoclonus
• Diaphoresis
• Shivering
• Tremor
• Diarrhea
• Incoordination
• Fever

The Hunter criteria are recommended and are more specific (97% vs 96%) and more sensitive (84% vs 75%) than the Sternbach criteria when compared with the gold standard of diagnosis by a clinical toxicologist.¹ The Hunter criteria are also less likely to yield false-positive results.¹¹

Differential diagnosis

The differential diagnosis for serotonin syndrome includes neuroleptic malignant syndrome, anticholinergic poisoning (Table 3), metastatic carcinoma, central nervous system infection, gastroenteritis, and sepsis.

Neuroleptic malignant syndrome, the disorder most often misdiagnosed as serotonin syndrome, is an idiosyncratic reaction to a dopamine antagonist (eg, haloperidol, fluphenazine) that develops over days to weeks.²⁰ In 70% of patients, agitated delirium with confusion appears first, followed by lead pipe rigidity and cogwheel tremor, then hyperthermia with body temperature greater than 40°C, and finally, profuse diaphoresis, tachycardia, hypertension, and tachypnea.²¹

Key elements that distinguish neuroleptic malignant syndrome are the timeline of the clinical course, bradyreflexia, and the absence of clonus. Prodromal symptoms of nausea, vomiting, and diarrhea are also rare in neuroleptic malignant syndrome. Neuroleptic malignant syndrome typically requires an average of 9 days to resolve.

Anticholinergic poisoning usually develops within 1 to 2 hours of oral ingestion. Symptoms include flushing, anhidrosis, anhidrotic hyperthermia, mydriasis, urinary retention, decreased bowel sounds, agitated delirium, and visual hallucinations. In contrast to serotonin syndrome, reflexes and muscle tone are normal with anticholinergic poisoning.

HOW CAN WE TREAT SEROTONIN SYNDROME?

The two mainstays of serotonin syndrome management are to discontinue the serotonergic agent and to give supportive care. Most patients improve within 24 hours of stopping the precipitating drug and starting therapy.¹⁶

For mild serotonin syndrome, treatment involves discontinuing the offending agent and supportive therapy with intravenous fluids, correction of vital signs, and symptomatic treatment with a benzodiazepine. Patients should be admitted and observed for 12 to 24 hours to prevent exacerbation.

For moderate serotonin syndrome, treatment also involves stopping the serotonergic agent and giving supportive care. Symptomatic treatment with a benzodiazepine and nonserotonergic antiemetics is recommended, and standard cooling measures should be implemented for hyperthermia. Patients should be admitted and observed for 12 to 24 hours to prevent exacerbation.

For severe serotonin toxicity, treatment should focus on management of airway, breathing, and circulation—ie, the “ABCs.” The two primary life-threatening concerns are hyperthermia (temperature > 40°C or 104°F) and rigidity, which can lead to hypoventilation.^1,22 Controlling hyperthermia and rigidity can prevent other grave complications. Patients with severe serotonin toxicity should be sedated, paralyzed, and intubated.²¹ This will reverse ventilatory hypertonia and allow for mechanical ventilation. Paralysis will also prevent the exacerbation of hyperthermia, which is caused by muscle rigidity. Antipyretics have no role in the treatment of serotonin syndrome since the hyperthermia is not caused by a change in the hypothalamic temperature set point.²¹ Standard cooling measures should be used to manage hyperthermia.

Serotonin antagonists

Serotonin antagonists have had some success in case reports, but further studies are needed to confirm this.^4,23,24

Cyproheptadine is a potent 5-HT2A antagonist; patients usually respond within 1 to 2 hours of administration. Signs and symptoms have resolved completely within times ranging from 20 minutes to 48 hours, depending on the severity of toxicity.

The recommended initial dose of cyproheptadine is 12 mg, followed by 2 mg every 2 hours if symptoms continue.¹⁶ Maintenance dosing with 8 mg every 6 hours should be prescribed once stabilization is achieved. The total daily dose for adults should not exceed 0.5 mg/kg/day. Cyproheptadine is available only in oral form but can be crushed and administered via a nasogastric tube.²¹

Chlorpromazine is a 5-HT1A and 5-HT2A antagonist and can be given intramuscularly. Despite case reports citing its effectiveness, the risk of hypotension, dystonic reactions, and neuroleptic malignant syndrome may make it a less desirable option.^4,25

Cyproheptadine, chlorpromazine, and other serotonin receptor antagonists require further investigation beyond individual case reports to determine their effectiveness and reliability in treating serotonin syndrome.

Other agents

Benzodiazepines are considered a mainstay for symptomatic relief because of their anxiolytic and muscle relaxant effects.²⁶ However, animal studies showed that treatment with benzodiazepines attenuated hyperthermia but had no effect on time to recovery or outcome.²⁷

Neuromuscular blocking agents. The suggested neuromuscular blocking agent for severe toxicity is a nondepolarizing agent such as vecuronium. Succinylcholine should be avoided, as it can exacerbate rhabdomyolysis and hyperkalemia.²¹

Dantrolene has also been suggested for its muscle-relaxing effects and use in malignant hyperthermia. However, this treatment has not been successful in isolated case reports and has been ineffective in animal models.^4,28

Physical restraints are ill-advised, since isometric muscle contractions can exacerbate hyperthermia and lactic acidosis in agitated patients.²¹ If physical restraints are necessary to deliver medications, they should be removed as soon as possible.

HOW CAN WE PREVENT SEROTONIN SYNDROME?

Prevention of serotonin syndrome begins with improving education and awareness in patients and healthcare providers. Patients should be primarily concerned with taking their medications carefully as prescribed and recognizing early signs and symptoms of serotonin toxicity.

As use of antidepressants among an aging population continues to increase, and as physicians in multiple disciplines prescribe them for evolving indications (eg, duloxetine to treat osteoarthritis, diabetic neuropathy, fibromyalgia, and chemotherapy-induced peripheral neuropathy), healthcare providers need to be prepared to see more cases of serotonin syndrome and its deleterious effects.^29–31 Physicians should be vigilant in minimizing unnecessary use of serotonergic agents and reviewing drug regimens regularly to limit polypharmacy.

Electronic ordering systems should be designed to detect and alert the prescriber to possible interactions that can potentiate serotonin syndrome, and to not place the order until the prescriber overrides the alert. Combinations of SSRIs and MAOIs have the highest risk for inducing severe serotonin syndrome and should always be avoided.

If a patient is transitioning between serotonergic agents, physicians should observe a safe washout period to prevent overlap.^16,32 Washout periods may differ among medications depending on their half-lives. For example, sertraline has a washout period of 2 weeks, while fluoxetine requires a washout period of 5 to 6 weeks.³³ Consulting a pharmacist may be helpful when considering half-lives and washout periods.

We believe that educating both patients and physicians regarding prevention will help minimize the risk for serotonergic syndrome and will improve efficiency in assessment and management should toxicity develop.

Intestinal failure, the inability of the gut to maintain nutritional homeostasis,¹ is a complication of vascular thrombosis, inflammatory bowel disease, radiation enteritis, obstruction, and other conditions, and of removing segments of the small and large intestines in response to these diseases.^1,2 Imbalances of fluids and electrolytes, dehydration, malabsorption, vitamin and mineral deficiencies, chronic diarrhea, and increased ostomy output contribute to a decline in the quality of life and in the survival rate in these patients.^2,3

Referral to an intestinal rehabilitation program that combines gastroenterology, nutrition, pharmacy, nursing, and social work can improve nutritional status and quality of life.⁴ Whenever possible, the goal of rehabilitation is nutritional autonomy, helping the patient make the transition to an independent oral diet.⁴ In selected patients in whom rehabilitation is not effective, intestinal transplant may be an option.

In this article, we review the intestinal adaptations that follow surgical resection and provide an update on intestinal rehabilitation techniques such as dietary modification, drug therapy, and parenteral nutrition. We also review experience with intestinal transplant in patients with intestinal failure.

INTESTINAL FAILURE

Intestinal failure results from reduction in enterocyte cell mass, obstruction, dysmotility, surgical resection, congenital defects, or disease-associated loss of absorption with suboptimal nutritional autonomy.⁵ Patients often suffer from extensive nutrient, electrolyte, and fluid abnormalities proportional to the remnant length and part of the intestine removed.⁵

Epidemiologic studies have demonstrated that short-bowel syndrome is the most common cause of intestinal failure in adults and children.^6,7 Short-bowel syndrome is defined as a small-bowel length less than 200 cm, most commonly from extensive resections for inflammatory bowel disease.⁶ In children, the syndrome is also defined by a residual small-bowel length of less than 25% expected for gestational age.⁷

Table 1 lists the frequencies of the underlying disorders leading to intestinal failure or short-bowel syndrome in one series.⁸

INTESTINAL ADAPTATION

The gastrointestinal tract is the only organ for nutrient, fluid, and electrolyte absorption.⁹ Every day, 8 to 9 L of fluids and secretions reach the small intestine, comprising about 2 to 3 L of oral fluids, 1 L of saliva, 2 L of gastric juices, 1 L of bile, and 2 L of pancreatic juices.⁹ Approximately 7 to 8 L are reabsorbed by the small intestine and 1 to 2 L by the colon.⁹

Although carbohydrates, lipids, and proteins are absorbed through the entire small intestine and colon, site-specific digestion and absorption of different nutrients occur in different parts of the gastrointestinal tract.¹⁰ Also, certain nutrients may need site-specific receptors or transporters for their absorption,¹⁰  for example:

• Iron in the duodenum and proximal jejunum¹
• Lactose in the brush border membrane of the jejunum and proximal ileum, where most of the enzyme lactase is present
• Vitamin B₁₂ and bile salts in the distal ileum.

Hence, resection of a specific part of the intestine may predict deficiencies the patient may encounter after surgery.

The diarrhea that occurs in short-bowel syndrome may be due partly to loss of neurohumoral mediators that govern gastrointestinal transit time, most importantly cholecystokinin, peptide YY, and glucagon-like peptide 1.¹¹ After contact with lipid- or protein-rich nutrients, cholecystokinin is released from the proximal small intestine, which decreases the gastric emptying to maximize nutrient digestion.¹² Additionally, release of peptide YY and glucagon-like peptide 1 from the ileal L cells decreases gastric and intestinal motility. These mediators prolong gastrointestinal transit, increase nutrient processing time, and enhance absorption.¹²

After massive intestinal resection, the remnant bowel undergoes physiologic and functional adaptation to maintain nutritional homeostasis.¹³ Enterocytes express membrane-bound transporters and undergo accelerated cell division to enhance the absorptive surface area.¹³ Intestinal hypertrophy, which includes an increase in villous diameter and crypt height, continues for 2 years or more after intestinal resection, leading to greater absorptive surface area.¹⁴ It is estimated that villous height may increase by as much as 80%, illustrating a dynamic process in response to intestinal stress.¹⁵

Luminal nutrients are essential to the stimulation of enterocyte cells through paracrine mechanisms as well as through the up-regulation of colonic peptide transporter PepT1.¹⁵ Furthermore, gut motility is initially decreased in order to increase the concentration of local luminal growth factors.¹⁶

Other factors that may affect intestinal adaptation are the length of the residual colon and small intestine, enteral growth, and enterotropic factors.¹⁶ And especially in patients with short-bowel syndrome, complications such as malabsorption secondary to pancreatic insufficiency or rapid transit, excessive gastric acid secretion, bile acid wasting due to terminal ileum resection, and bacterial overgrowth in the small intestine result in worsened nutritional status and poor quality of life.¹⁶ 

Key factors that affect the degree of nutritional deficiencies

The degree of nutritional deficiencies and fluid and electrolyte imbalances depends on the length and location of resection and whether the colon is still continuous with the small intestine.¹⁷ Normal small-bowel length in adults is highly variable and can be up to 600 cm. Malnutrition after surgical resection usually occurs when more than three-fourths of intestinal tissue is removed.¹⁷ However, because of intestinal adaptation, patients with 50% of remnant small bowel may be able to achieve nutritional autonomy.¹⁸ Furthermore, because absorption of nutrients occurs primarily in the first 150 cm of the small intestine, resections of this anatomic region have the highest probability of resulting in malnutrition.¹⁸

After extensive intestinal resection, absorption of water and electrolytes is better and intestinal transit time is longer if the colon is still continuous with the rest of the gastrointestinal system.¹⁹ Approximately 100 cm of remnant intestinal tissue without colonic continuity or 60 cm with colonic continuity is needed to ensure the possibility of nutritional autonomy and independence from parenteral nutrition.¹⁹ Severe malnutrition and fluid and electrolyte imbalances can be prevented by appropriate and timely multidisciplinary care and early referral for intestinal rehabilitation.

INTESTINAL REHABILITATION AND NUTRITIONAL AUTONOMY

The aim of intestinal rehabilitation is to improve quality of life by reversing malnutrition and promoting nutritional autonomy, ie, independence from parenteral nutrition (Table 2).²⁰ The complex nature of intestinal failure necessitates collaboration of multiple specialists—gastroenterologists, surgeons, dietitians, nurses, psychiatrists or psychologists, pharmacists, and social workers.²⁰

Although most patients with intestinal failure initially require parenteral nutrition to maintain nutritional homeostasis, progressive adaptation of the remnant intestine enables a transition to enteral nutrition.²¹ Stimulation of the remnant intestine by enteral feeding reduces the complications of parenteral nutrition and encourages intestinal adaptation.²¹

Outpatient participation in an intestinal rehabilitation program can facilitate weaning from parenteral nutrition. Patients are monitored and supported during dietary modification, pharmacologic interventions, and reconstructive surgeries.²¹ A study of 61 patients with short-bowel syndrome undergoing a 3-week program of intestinal rehabilitation (recombinant human growth hormone, glutamine, enteral nutrition, and parenteral nutrition) reported an overall survival rate of 95% with an 85% success rate in weaning from parenteral nutrition during a mean follow-up of 50 (± 24) months.²² Permanent dependence on parenteral nutrition despite rehabilitation was predicted by length of the small bowel less than 100 cm and by the absence of terminal ileum and colon.²²

Permanent intestinal failure, defined by the inability to wean from parenteral nutrition and restore nutrition autonomy, may require early referral for evaluation for intestinal and multivisceral transplant. Early referral improves survival rates, possibly because of fewer complications from parenteral nutrition.⁴

DIETARY MODIFICATION

Dietary modification is the single most effective means of weaning patients safely from parenteral nutrition (Table 3).^23,24 Small, frequent feedings help reduce symptoms associated with rapid intestinal transit and increase the activity of luminal growth factors.²³ Likewise, limits on intake of simple sugars, stimulants such as caffeine or insoluble fiber, and hypo- or hypertonic fluids decrease intestinal losses and the risk of dehydration.²³ Low sugar loads also aim to reduce the occurrence of d-lactic acidosis and bacterial overgrowth in the small intestine.²³ Patients who cannot maintain positive fluid balance may require standardized oral rehydration (Table 4) to improve absorption by way of the sodium-glucose coupled transporters at the brush border membrane, or they may require intravenous fluid supplementation.²⁵

Colonic continuity

Other dietary recommendations depend on colonic continuity. In 1994, Nordgaard et al²⁶ compared the effects of high-carbohydrate and high-fat diets in eight patients with colonic continuity and six patients with jejunostomies. The authors noted that a high-carbohydrate diet (60% carbohydrate, 20% fat) reduced fecal loss of energy and increased energy absorption in patients with colonic continuity. However, patients with an end-jejunostomy experienced equal fecal losses of carbohydrates and fat proportional to the amount consumed. The authors concluded that the presence of colonic bacteria promoted carbohydrate salvage, ie, the fermentation of malabsorbed carbohydrates to easily absorbed short-chain fatty acids.²⁶

The colon can salvage as much as 1,000 kcal/day in patients with less than 200 cm of small bowel, and the presence of at least 50% of colon in continuity has been shown to reduce parenteral nutrition requirements by half in patients with less than 100 cm of small bowel.²⁷ As a result, a diet high in complex carbohydrates and soluble fiber supplements is recommended in cases of preserved colon to promote adaptation and nutritional autonomy.²⁷

Another aim of a high-carbohydrate, low- fat diet is to prevent calcium oxalate-related nephrolithiasis and choleretic diarrhea.²⁶

In summary, patients with short-bowel syndrome with or without colonic continuity need different dietary regimens to attain nutritional autonomy.

DRUG THERAPY

In addition to diet therapy, most patients with intestinal failure require pharmacologic therapy.²⁸ High stool or stoma effluent is most commonly treated with an antidiarrheal to increase transit time; diphenoxylate-atropine, loperamide, codeine sulfate, paregoric, and opium tincture are commonly prescribed (Table 5).²⁷ In severe high-output states, a somatostatin analogue (eg, octreotide) may be added.²⁹

Postoperative increases in gastric secretion may be countered by histamine 2 receptor antagonists and proton pump inhibitors, but long-term use of these drugs may lead to nutritional deficiencies and bacterial overgrowth in the small intestine.²⁹ Bile acid sequestrants (in cases of distal ileal resection) and pancreatic enzymes target fat malabsorption, resultant cases of choleretic diarrhea, deficiency of essential fatty acids, kidney stones, and deficiency of fat-soluble vitamins.²⁹ Probiotics and antibiotics can also be given for prevention and treatment of small-intestinal bacterial overgrowth.²⁹

When traditional dietary modification and medical therapy fail to achieve nutritional homeostasis, another option to consider is a glucagon-like peptide-2 analogue to enhance intestinal adaptation.³⁰ Produced in the native distal ileum and colon, glucagon-like peptide 2 moderates the rate of gastric emptying and small-bowel transit and enhances epithelial cell proliferation, thereby promoting intestinal adaptation.³⁰ Further, a randomized controlled trial of 83 patients reported efficacy of these agents in reducing parenteral nutrition requirements in patients with intestinal failure.³¹

Hence, in patients with intestinal failure who have increased stoma effluent, drug therapy may play an important role in maintaining fluid and nutritional homeostasis.

THE ROLE OF PARENTERAL NUTRITION IN INTESTINAL FAILURE

Despite the best efforts of an intestinal rehabilitation program, not all patients gain nutritional autonomy.³² Physiologic, psychological, social, and economic factors may contribute to dependence on parenteral nutrition.³² Currently, more than 40,000 US patients depend on it for survival.³³

The need for short-term or long-term parenteral nutrition is determined by the patient’s medical needs.³³ Patients requiring short-term parenteral nutrition (2–6 weeks) include those whose bowel function has not returned to normal postoperatively, and those who were severely malnourished preoperatively.³⁴ Patients needing it long-term (from months to years to lifelong) are those with gastrointestinal dysmotility and short-bowel syndrome due to extensive bowel resections.³³

Complications of parenteral nutrition

Catheter-related bloodstream infection is the most common complication and cause of hospitalization. Infection can be localized to the exit site or tunnel or can be systemic (eg, line sepsis).³⁵Staphylococcus aureus and coagulase-negative staphylococci are most often implicated in catheter infection.³⁵ When possible, catheter salvage is desirable, but the central venous catheter must be removed in cases of tunnel infection, port abscess, septic shock, paired blood cultures positive for fungi or highly virulent bacteria, endocarditis, septic thrombosis, and other conditions.^35,36

Liver disease is a serious complication of long-term parenteral nutrition and may occur in up to 55% of patients on therapy for more than 2 years; it carries a mortality rate of 15%.³⁷

Risk factors include younger age and use of excessive carbohydrate and fat compositions, mainly soybean-oil–based lipid emulsions.³⁷ However, fish-oil–based lipid emulsions have recently shown promise in preventing and reversing parenteral nutrition-associated liver failure and cholestasis, especially in a pediatric population.³⁸

Catheter thrombosis may occur in up to 30% of patients on long-term parenteral nutrition.³⁹ However, this risk is reduced with appropriate positioning of the catheter tip in the mid or lower superior vena cava.³⁷ Treatment of thrombosis of the central access includes either anticoagulation or thrombolysis.³⁷

Hence, appropriate and timely follow-up of patients on parenteral nutrition is essential in reducing associated complications. Monitoring weight, fluid status, serum glucose, and patency of central access are critical to ensure that the patient maintains nutritional status effectively.⁴⁰ To prevent complications, a specialized nutritional support team should monitor the patient’s parenteral nutrition both in the hospital and at home.

RECONSTRUCTIVE SURGERY

Patients with intestinal failure due to short- bowel syndrome should be considered for reconstructive surgery during different phases of the adaptation process. Options include reversed-segment procedures, stricturoplasty, bowel-lengthening procedures (eg, the Bianchi procedure), and serial transverse enteroplasty.^41,42 If reconstructive surgery is ineffective, referral to an intestinal transplant program should be considered.

INTESTINAL AND MULTIVISCERAL TRANSPLANT

For patients who develop permanent intestinal failure and require lifelong parenteral nutrition, and for patients who experience significant complications of parenteral nutrition, such as infections and liver disease,⁴³ intestinal transplant has emerged as a way to restore clinical nutritional autonomy.⁴⁴ In one study, the 1-year survival rate after intestinal transplant was approximately 90%.⁴⁴

There are currently three transplant procedures: isolated intestine transplant, combined liver-intestine transplant, and multivisceral transplant with or without a liver, depending on the presence of parenteral nutrition-associated liver disease.^42,45 Close postoperative care is required to help the patient transition from parenteral to enteral nutrition.⁴² An intestinal rehabilitation team is equipped to provide this level of postoperative care.⁴²

Intestinal and multivisceral transplant gained momentum in the early 1960s in preclinical and clinical studies.^46,47 Since that time, the field has experienced remarkable advances due to standardization of surgical techniques, novel immunosuppressive therapies and induction protocols, and improved postoperative care.⁴⁸ With the advent of tacrolimus in 1989, the rates of allograft rejection improved significantly, and the field of transplant emerged as a potentially lifesaving therapy for patients with permanent intestinal failure.⁴⁸

Since 1990, more than 2,300 intestinal transplant procedures have been performed for various etiologies of intestinal failure, with short-bowel syndrome being the most common.⁴⁹

The indications for intestinal transplant approved by the US Centers for Medicare and Medicaid services are detailed in Table 6.⁵⁰ Despite ongoing challenges of graft rejection and maintenance immunosuppression, posttransplant quality-of-life questionnaires have indicated a significant improvement in functional status and a decrease in depressive symptoms.⁵¹ As such, it is evident that intestinal and multivisceral transplant offers substantial promise in restoring a patient’s quality of life and nutritional status.

Intestinal failure, the inability of the gut to maintain nutritional homeostasis,¹ is a complication of vascular thrombosis, inflammatory bowel disease, radiation enteritis, obstruction, and other conditions, and of removing segments of the small and large intestines in response to these diseases.^1,2 Imbalances of fluids and electrolytes, dehydration, malabsorption, vitamin and mineral deficiencies, chronic diarrhea, and increased ostomy output contribute to a decline in the quality of life and in the survival rate in these patients.^2,3

Referral to an intestinal rehabilitation program that combines gastroenterology, nutrition, pharmacy, nursing, and social work can improve nutritional status and quality of life.⁴ Whenever possible, the goal of rehabilitation is nutritional autonomy, helping the patient make the transition to an independent oral diet.⁴ In selected patients in whom rehabilitation is not effective, intestinal transplant may be an option.

In this article, we review the intestinal adaptations that follow surgical resection and provide an update on intestinal rehabilitation techniques such as dietary modification, drug therapy, and parenteral nutrition. We also review experience with intestinal transplant in patients with intestinal failure.

INTESTINAL FAILURE

Intestinal failure results from reduction in enterocyte cell mass, obstruction, dysmotility, surgical resection, congenital defects, or disease-associated loss of absorption with suboptimal nutritional autonomy.⁵ Patients often suffer from extensive nutrient, electrolyte, and fluid abnormalities proportional to the remnant length and part of the intestine removed.⁵

Epidemiologic studies have demonstrated that short-bowel syndrome is the most common cause of intestinal failure in adults and children.^6,7 Short-bowel syndrome is defined as a small-bowel length less than 200 cm, most commonly from extensive resections for inflammatory bowel disease.⁶ In children, the syndrome is also defined by a residual small-bowel length of less than 25% expected for gestational age.⁷

Table 1 lists the frequencies of the underlying disorders leading to intestinal failure or short-bowel syndrome in one series.⁸

INTESTINAL ADAPTATION

The gastrointestinal tract is the only organ for nutrient, fluid, and electrolyte absorption.⁹ Every day, 8 to 9 L of fluids and secretions reach the small intestine, comprising about 2 to 3 L of oral fluids, 1 L of saliva, 2 L of gastric juices, 1 L of bile, and 2 L of pancreatic juices.⁹ Approximately 7 to 8 L are reabsorbed by the small intestine and 1 to 2 L by the colon.⁹

Although carbohydrates, lipids, and proteins are absorbed through the entire small intestine and colon, site-specific digestion and absorption of different nutrients occur in different parts of the gastrointestinal tract.¹⁰ Also, certain nutrients may need site-specific receptors or transporters for their absorption,¹⁰  for example:

• Iron in the duodenum and proximal jejunum¹
• Lactose in the brush border membrane of the jejunum and proximal ileum, where most of the enzyme lactase is present
• Vitamin B₁₂ and bile salts in the distal ileum.

Hence, resection of a specific part of the intestine may predict deficiencies the patient may encounter after surgery.

The diarrhea that occurs in short-bowel syndrome may be due partly to loss of neurohumoral mediators that govern gastrointestinal transit time, most importantly cholecystokinin, peptide YY, and glucagon-like peptide 1.¹¹ After contact with lipid- or protein-rich nutrients, cholecystokinin is released from the proximal small intestine, which decreases the gastric emptying to maximize nutrient digestion.¹² Additionally, release of peptide YY and glucagon-like peptide 1 from the ileal L cells decreases gastric and intestinal motility. These mediators prolong gastrointestinal transit, increase nutrient processing time, and enhance absorption.¹²

After massive intestinal resection, the remnant bowel undergoes physiologic and functional adaptation to maintain nutritional homeostasis.¹³ Enterocytes express membrane-bound transporters and undergo accelerated cell division to enhance the absorptive surface area.¹³ Intestinal hypertrophy, which includes an increase in villous diameter and crypt height, continues for 2 years or more after intestinal resection, leading to greater absorptive surface area.¹⁴ It is estimated that villous height may increase by as much as 80%, illustrating a dynamic process in response to intestinal stress.¹⁵

Luminal nutrients are essential to the stimulation of enterocyte cells through paracrine mechanisms as well as through the up-regulation of colonic peptide transporter PepT1.¹⁵ Furthermore, gut motility is initially decreased in order to increase the concentration of local luminal growth factors.¹⁶

Other factors that may affect intestinal adaptation are the length of the residual colon and small intestine, enteral growth, and enterotropic factors.¹⁶ And especially in patients with short-bowel syndrome, complications such as malabsorption secondary to pancreatic insufficiency or rapid transit, excessive gastric acid secretion, bile acid wasting due to terminal ileum resection, and bacterial overgrowth in the small intestine result in worsened nutritional status and poor quality of life.¹⁶ 

Key factors that affect the degree of nutritional deficiencies

The degree of nutritional deficiencies and fluid and electrolyte imbalances depends on the length and location of resection and whether the colon is still continuous with the small intestine.¹⁷ Normal small-bowel length in adults is highly variable and can be up to 600 cm. Malnutrition after surgical resection usually occurs when more than three-fourths of intestinal tissue is removed.¹⁷ However, because of intestinal adaptation, patients with 50% of remnant small bowel may be able to achieve nutritional autonomy.¹⁸ Furthermore, because absorption of nutrients occurs primarily in the first 150 cm of the small intestine, resections of this anatomic region have the highest probability of resulting in malnutrition.¹⁸

After extensive intestinal resection, absorption of water and electrolytes is better and intestinal transit time is longer if the colon is still continuous with the rest of the gastrointestinal system.¹⁹ Approximately 100 cm of remnant intestinal tissue without colonic continuity or 60 cm with colonic continuity is needed to ensure the possibility of nutritional autonomy and independence from parenteral nutrition.¹⁹ Severe malnutrition and fluid and electrolyte imbalances can be prevented by appropriate and timely multidisciplinary care and early referral for intestinal rehabilitation.

INTESTINAL REHABILITATION AND NUTRITIONAL AUTONOMY

The aim of intestinal rehabilitation is to improve quality of life by reversing malnutrition and promoting nutritional autonomy, ie, independence from parenteral nutrition (Table 2).²⁰ The complex nature of intestinal failure necessitates collaboration of multiple specialists—gastroenterologists, surgeons, dietitians, nurses, psychiatrists or psychologists, pharmacists, and social workers.²⁰

Although most patients with intestinal failure initially require parenteral nutrition to maintain nutritional homeostasis, progressive adaptation of the remnant intestine enables a transition to enteral nutrition.²¹ Stimulation of the remnant intestine by enteral feeding reduces the complications of parenteral nutrition and encourages intestinal adaptation.²¹

Outpatient participation in an intestinal rehabilitation program can facilitate weaning from parenteral nutrition. Patients are monitored and supported during dietary modification, pharmacologic interventions, and reconstructive surgeries.²¹ A study of 61 patients with short-bowel syndrome undergoing a 3-week program of intestinal rehabilitation (recombinant human growth hormone, glutamine, enteral nutrition, and parenteral nutrition) reported an overall survival rate of 95% with an 85% success rate in weaning from parenteral nutrition during a mean follow-up of 50 (± 24) months.²² Permanent dependence on parenteral nutrition despite rehabilitation was predicted by length of the small bowel less than 100 cm and by the absence of terminal ileum and colon.²²

Permanent intestinal failure, defined by the inability to wean from parenteral nutrition and restore nutrition autonomy, may require early referral for evaluation for intestinal and multivisceral transplant. Early referral improves survival rates, possibly because of fewer complications from parenteral nutrition.⁴

DIETARY MODIFICATION

Dietary modification is the single most effective means of weaning patients safely from parenteral nutrition (Table 3).^23,24 Small, frequent feedings help reduce symptoms associated with rapid intestinal transit and increase the activity of luminal growth factors.²³ Likewise, limits on intake of simple sugars, stimulants such as caffeine or insoluble fiber, and hypo- or hypertonic fluids decrease intestinal losses and the risk of dehydration.²³ Low sugar loads also aim to reduce the occurrence of d-lactic acidosis and bacterial overgrowth in the small intestine.²³ Patients who cannot maintain positive fluid balance may require standardized oral rehydration (Table 4) to improve absorption by way of the sodium-glucose coupled transporters at the brush border membrane, or they may require intravenous fluid supplementation.²⁵

Colonic continuity

Other dietary recommendations depend on colonic continuity. In 1994, Nordgaard et al²⁶ compared the effects of high-carbohydrate and high-fat diets in eight patients with colonic continuity and six patients with jejunostomies. The authors noted that a high-carbohydrate diet (60% carbohydrate, 20% fat) reduced fecal loss of energy and increased energy absorption in patients with colonic continuity. However, patients with an end-jejunostomy experienced equal fecal losses of carbohydrates and fat proportional to the amount consumed. The authors concluded that the presence of colonic bacteria promoted carbohydrate salvage, ie, the fermentation of malabsorbed carbohydrates to easily absorbed short-chain fatty acids.²⁶

The colon can salvage as much as 1,000 kcal/day in patients with less than 200 cm of small bowel, and the presence of at least 50% of colon in continuity has been shown to reduce parenteral nutrition requirements by half in patients with less than 100 cm of small bowel.²⁷ As a result, a diet high in complex carbohydrates and soluble fiber supplements is recommended in cases of preserved colon to promote adaptation and nutritional autonomy.²⁷

Another aim of a high-carbohydrate, low- fat diet is to prevent calcium oxalate-related nephrolithiasis and choleretic diarrhea.²⁶

In summary, patients with short-bowel syndrome with or without colonic continuity need different dietary regimens to attain nutritional autonomy.

DRUG THERAPY

In addition to diet therapy, most patients with intestinal failure require pharmacologic therapy.²⁸ High stool or stoma effluent is most commonly treated with an antidiarrheal to increase transit time; diphenoxylate-atropine, loperamide, codeine sulfate, paregoric, and opium tincture are commonly prescribed (Table 5).²⁷ In severe high-output states, a somatostatin analogue (eg, octreotide) may be added.²⁹

Postoperative increases in gastric secretion may be countered by histamine 2 receptor antagonists and proton pump inhibitors, but long-term use of these drugs may lead to nutritional deficiencies and bacterial overgrowth in the small intestine.²⁹ Bile acid sequestrants (in cases of distal ileal resection) and pancreatic enzymes target fat malabsorption, resultant cases of choleretic diarrhea, deficiency of essential fatty acids, kidney stones, and deficiency of fat-soluble vitamins.²⁹ Probiotics and antibiotics can also be given for prevention and treatment of small-intestinal bacterial overgrowth.²⁹

When traditional dietary modification and medical therapy fail to achieve nutritional homeostasis, another option to consider is a glucagon-like peptide-2 analogue to enhance intestinal adaptation.³⁰ Produced in the native distal ileum and colon, glucagon-like peptide 2 moderates the rate of gastric emptying and small-bowel transit and enhances epithelial cell proliferation, thereby promoting intestinal adaptation.³⁰ Further, a randomized controlled trial of 83 patients reported efficacy of these agents in reducing parenteral nutrition requirements in patients with intestinal failure.³¹

Hence, in patients with intestinal failure who have increased stoma effluent, drug therapy may play an important role in maintaining fluid and nutritional homeostasis.

THE ROLE OF PARENTERAL NUTRITION IN INTESTINAL FAILURE

Despite the best efforts of an intestinal rehabilitation program, not all patients gain nutritional autonomy.³² Physiologic, psychological, social, and economic factors may contribute to dependence on parenteral nutrition.³² Currently, more than 40,000 US patients depend on it for survival.³³

The need for short-term or long-term parenteral nutrition is determined by the patient’s medical needs.³³ Patients requiring short-term parenteral nutrition (2–6 weeks) include those whose bowel function has not returned to normal postoperatively, and those who were severely malnourished preoperatively.³⁴ Patients needing it long-term (from months to years to lifelong) are those with gastrointestinal dysmotility and short-bowel syndrome due to extensive bowel resections.³³

Complications of parenteral nutrition

Catheter-related bloodstream infection is the most common complication and cause of hospitalization. Infection can be localized to the exit site or tunnel or can be systemic (eg, line sepsis).³⁵Staphylococcus aureus and coagulase-negative staphylococci are most often implicated in catheter infection.³⁵ When possible, catheter salvage is desirable, but the central venous catheter must be removed in cases of tunnel infection, port abscess, septic shock, paired blood cultures positive for fungi or highly virulent bacteria, endocarditis, septic thrombosis, and other conditions.^35,36

Liver disease is a serious complication of long-term parenteral nutrition and may occur in up to 55% of patients on therapy for more than 2 years; it carries a mortality rate of 15%.³⁷

Risk factors include younger age and use of excessive carbohydrate and fat compositions, mainly soybean-oil–based lipid emulsions.³⁷ However, fish-oil–based lipid emulsions have recently shown promise in preventing and reversing parenteral nutrition-associated liver failure and cholestasis, especially in a pediatric population.³⁸

Catheter thrombosis may occur in up to 30% of patients on long-term parenteral nutrition.³⁹ However, this risk is reduced with appropriate positioning of the catheter tip in the mid or lower superior vena cava.³⁷ Treatment of thrombosis of the central access includes either anticoagulation or thrombolysis.³⁷

Hence, appropriate and timely follow-up of patients on parenteral nutrition is essential in reducing associated complications. Monitoring weight, fluid status, serum glucose, and patency of central access are critical to ensure that the patient maintains nutritional status effectively.⁴⁰ To prevent complications, a specialized nutritional support team should monitor the patient’s parenteral nutrition both in the hospital and at home.

RECONSTRUCTIVE SURGERY

Patients with intestinal failure due to short- bowel syndrome should be considered for reconstructive surgery during different phases of the adaptation process. Options include reversed-segment procedures, stricturoplasty, bowel-lengthening procedures (eg, the Bianchi procedure), and serial transverse enteroplasty.^41,42 If reconstructive surgery is ineffective, referral to an intestinal transplant program should be considered.

INTESTINAL AND MULTIVISCERAL TRANSPLANT

For patients who develop permanent intestinal failure and require lifelong parenteral nutrition, and for patients who experience significant complications of parenteral nutrition, such as infections and liver disease,⁴³ intestinal transplant has emerged as a way to restore clinical nutritional autonomy.⁴⁴ In one study, the 1-year survival rate after intestinal transplant was approximately 90%.⁴⁴

There are currently three transplant procedures: isolated intestine transplant, combined liver-intestine transplant, and multivisceral transplant with or without a liver, depending on the presence of parenteral nutrition-associated liver disease.^42,45 Close postoperative care is required to help the patient transition from parenteral to enteral nutrition.⁴² An intestinal rehabilitation team is equipped to provide this level of postoperative care.⁴²

Intestinal and multivisceral transplant gained momentum in the early 1960s in preclinical and clinical studies.^46,47 Since that time, the field has experienced remarkable advances due to standardization of surgical techniques, novel immunosuppressive therapies and induction protocols, and improved postoperative care.⁴⁸ With the advent of tacrolimus in 1989, the rates of allograft rejection improved significantly, and the field of transplant emerged as a potentially lifesaving therapy for patients with permanent intestinal failure.⁴⁸

Since 1990, more than 2,300 intestinal transplant procedures have been performed for various etiologies of intestinal failure, with short-bowel syndrome being the most common.⁴⁹

The indications for intestinal transplant approved by the US Centers for Medicare and Medicaid services are detailed in Table 6.⁵⁰ Despite ongoing challenges of graft rejection and maintenance immunosuppression, posttransplant quality-of-life questionnaires have indicated a significant improvement in functional status and a decrease in depressive symptoms.⁵¹ As such, it is evident that intestinal and multivisceral transplant offers substantial promise in restoring a patient’s quality of life and nutritional status.

Intestinal failure, the inability of the gut to maintain nutritional homeostasis,¹ is a complication of vascular thrombosis, inflammatory bowel disease, radiation enteritis, obstruction, and other conditions, and of removing segments of the small and large intestines in response to these diseases.^1,2 Imbalances of fluids and electrolytes, dehydration, malabsorption, vitamin and mineral deficiencies, chronic diarrhea, and increased ostomy output contribute to a decline in the quality of life and in the survival rate in these patients.^2,3

Referral to an intestinal rehabilitation program that combines gastroenterology, nutrition, pharmacy, nursing, and social work can improve nutritional status and quality of life.⁴ Whenever possible, the goal of rehabilitation is nutritional autonomy, helping the patient make the transition to an independent oral diet.⁴ In selected patients in whom rehabilitation is not effective, intestinal transplant may be an option.

In this article, we review the intestinal adaptations that follow surgical resection and provide an update on intestinal rehabilitation techniques such as dietary modification, drug therapy, and parenteral nutrition. We also review experience with intestinal transplant in patients with intestinal failure.

INTESTINAL FAILURE

Intestinal failure results from reduction in enterocyte cell mass, obstruction, dysmotility, surgical resection, congenital defects, or disease-associated loss of absorption with suboptimal nutritional autonomy.⁵ Patients often suffer from extensive nutrient, electrolyte, and fluid abnormalities proportional to the remnant length and part of the intestine removed.⁵

Epidemiologic studies have demonstrated that short-bowel syndrome is the most common cause of intestinal failure in adults and children.^6,7 Short-bowel syndrome is defined as a small-bowel length less than 200 cm, most commonly from extensive resections for inflammatory bowel disease.⁶ In children, the syndrome is also defined by a residual small-bowel length of less than 25% expected for gestational age.⁷

Table 1 lists the frequencies of the underlying disorders leading to intestinal failure or short-bowel syndrome in one series.⁸

INTESTINAL ADAPTATION

The gastrointestinal tract is the only organ for nutrient, fluid, and electrolyte absorption.⁹ Every day, 8 to 9 L of fluids and secretions reach the small intestine, comprising about 2 to 3 L of oral fluids, 1 L of saliva, 2 L of gastric juices, 1 L of bile, and 2 L of pancreatic juices.⁹ Approximately 7 to 8 L are reabsorbed by the small intestine and 1 to 2 L by the colon.⁹

Although carbohydrates, lipids, and proteins are absorbed through the entire small intestine and colon, site-specific digestion and absorption of different nutrients occur in different parts of the gastrointestinal tract.¹⁰ Also, certain nutrients may need site-specific receptors or transporters for their absorption,¹⁰  for example:

• Iron in the duodenum and proximal jejunum¹
• Lactose in the brush border membrane of the jejunum and proximal ileum, where most of the enzyme lactase is present
• Vitamin B₁₂ and bile salts in the distal ileum.

Hence, resection of a specific part of the intestine may predict deficiencies the patient may encounter after surgery.

The diarrhea that occurs in short-bowel syndrome may be due partly to loss of neurohumoral mediators that govern gastrointestinal transit time, most importantly cholecystokinin, peptide YY, and glucagon-like peptide 1.¹¹ After contact with lipid- or protein-rich nutrients, cholecystokinin is released from the proximal small intestine, which decreases the gastric emptying to maximize nutrient digestion.¹² Additionally, release of peptide YY and glucagon-like peptide 1 from the ileal L cells decreases gastric and intestinal motility. These mediators prolong gastrointestinal transit, increase nutrient processing time, and enhance absorption.¹²

After massive intestinal resection, the remnant bowel undergoes physiologic and functional adaptation to maintain nutritional homeostasis.¹³ Enterocytes express membrane-bound transporters and undergo accelerated cell division to enhance the absorptive surface area.¹³ Intestinal hypertrophy, which includes an increase in villous diameter and crypt height, continues for 2 years or more after intestinal resection, leading to greater absorptive surface area.¹⁴ It is estimated that villous height may increase by as much as 80%, illustrating a dynamic process in response to intestinal stress.¹⁵

Luminal nutrients are essential to the stimulation of enterocyte cells through paracrine mechanisms as well as through the up-regulation of colonic peptide transporter PepT1.¹⁵ Furthermore, gut motility is initially decreased in order to increase the concentration of local luminal growth factors.¹⁶

Other factors that may affect intestinal adaptation are the length of the residual colon and small intestine, enteral growth, and enterotropic factors.¹⁶ And especially in patients with short-bowel syndrome, complications such as malabsorption secondary to pancreatic insufficiency or rapid transit, excessive gastric acid secretion, bile acid wasting due to terminal ileum resection, and bacterial overgrowth in the small intestine result in worsened nutritional status and poor quality of life.¹⁶ 

Key factors that affect the degree of nutritional deficiencies

The degree of nutritional deficiencies and fluid and electrolyte imbalances depends on the length and location of resection and whether the colon is still continuous with the small intestine.¹⁷ Normal small-bowel length in adults is highly variable and can be up to 600 cm. Malnutrition after surgical resection usually occurs when more than three-fourths of intestinal tissue is removed.¹⁷ However, because of intestinal adaptation, patients with 50% of remnant small bowel may be able to achieve nutritional autonomy.¹⁸ Furthermore, because absorption of nutrients occurs primarily in the first 150 cm of the small intestine, resections of this anatomic region have the highest probability of resulting in malnutrition.¹⁸

After extensive intestinal resection, absorption of water and electrolytes is better and intestinal transit time is longer if the colon is still continuous with the rest of the gastrointestinal system.¹⁹ Approximately 100 cm of remnant intestinal tissue without colonic continuity or 60 cm with colonic continuity is needed to ensure the possibility of nutritional autonomy and independence from parenteral nutrition.¹⁹ Severe malnutrition and fluid and electrolyte imbalances can be prevented by appropriate and timely multidisciplinary care and early referral for intestinal rehabilitation.

INTESTINAL REHABILITATION AND NUTRITIONAL AUTONOMY

The aim of intestinal rehabilitation is to improve quality of life by reversing malnutrition and promoting nutritional autonomy, ie, independence from parenteral nutrition (Table 2).²⁰ The complex nature of intestinal failure necessitates collaboration of multiple specialists—gastroenterologists, surgeons, dietitians, nurses, psychiatrists or psychologists, pharmacists, and social workers.²⁰

Although most patients with intestinal failure initially require parenteral nutrition to maintain nutritional homeostasis, progressive adaptation of the remnant intestine enables a transition to enteral nutrition.²¹ Stimulation of the remnant intestine by enteral feeding reduces the complications of parenteral nutrition and encourages intestinal adaptation.²¹

Outpatient participation in an intestinal rehabilitation program can facilitate weaning from parenteral nutrition. Patients are monitored and supported during dietary modification, pharmacologic interventions, and reconstructive surgeries.²¹ A study of 61 patients with short-bowel syndrome undergoing a 3-week program of intestinal rehabilitation (recombinant human growth hormone, glutamine, enteral nutrition, and parenteral nutrition) reported an overall survival rate of 95% with an 85% success rate in weaning from parenteral nutrition during a mean follow-up of 50 (± 24) months.²² Permanent dependence on parenteral nutrition despite rehabilitation was predicted by length of the small bowel less than 100 cm and by the absence of terminal ileum and colon.²²

Permanent intestinal failure, defined by the inability to wean from parenteral nutrition and restore nutrition autonomy, may require early referral for evaluation for intestinal and multivisceral transplant. Early referral improves survival rates, possibly because of fewer complications from parenteral nutrition.⁴

DIETARY MODIFICATION

Dietary modification is the single most effective means of weaning patients safely from parenteral nutrition (Table 3).^23,24 Small, frequent feedings help reduce symptoms associated with rapid intestinal transit and increase the activity of luminal growth factors.²³ Likewise, limits on intake of simple sugars, stimulants such as caffeine or insoluble fiber, and hypo- or hypertonic fluids decrease intestinal losses and the risk of dehydration.²³ Low sugar loads also aim to reduce the occurrence of d-lactic acidosis and bacterial overgrowth in the small intestine.²³ Patients who cannot maintain positive fluid balance may require standardized oral rehydration (Table 4) to improve absorption by way of the sodium-glucose coupled transporters at the brush border membrane, or they may require intravenous fluid supplementation.²⁵

Colonic continuity

Other dietary recommendations depend on colonic continuity. In 1994, Nordgaard et al²⁶ compared the effects of high-carbohydrate and high-fat diets in eight patients with colonic continuity and six patients with jejunostomies. The authors noted that a high-carbohydrate diet (60% carbohydrate, 20% fat) reduced fecal loss of energy and increased energy absorption in patients with colonic continuity. However, patients with an end-jejunostomy experienced equal fecal losses of carbohydrates and fat proportional to the amount consumed. The authors concluded that the presence of colonic bacteria promoted carbohydrate salvage, ie, the fermentation of malabsorbed carbohydrates to easily absorbed short-chain fatty acids.²⁶

The colon can salvage as much as 1,000 kcal/day in patients with less than 200 cm of small bowel, and the presence of at least 50% of colon in continuity has been shown to reduce parenteral nutrition requirements by half in patients with less than 100 cm of small bowel.²⁷ As a result, a diet high in complex carbohydrates and soluble fiber supplements is recommended in cases of preserved colon to promote adaptation and nutritional autonomy.²⁷

Another aim of a high-carbohydrate, low- fat diet is to prevent calcium oxalate-related nephrolithiasis and choleretic diarrhea.²⁶

In summary, patients with short-bowel syndrome with or without colonic continuity need different dietary regimens to attain nutritional autonomy.

DRUG THERAPY

In addition to diet therapy, most patients with intestinal failure require pharmacologic therapy.²⁸ High stool or stoma effluent is most commonly treated with an antidiarrheal to increase transit time; diphenoxylate-atropine, loperamide, codeine sulfate, paregoric, and opium tincture are commonly prescribed (Table 5).²⁷ In severe high-output states, a somatostatin analogue (eg, octreotide) may be added.²⁹

Postoperative increases in gastric secretion may be countered by histamine 2 receptor antagonists and proton pump inhibitors, but long-term use of these drugs may lead to nutritional deficiencies and bacterial overgrowth in the small intestine.²⁹ Bile acid sequestrants (in cases of distal ileal resection) and pancreatic enzymes target fat malabsorption, resultant cases of choleretic diarrhea, deficiency of essential fatty acids, kidney stones, and deficiency of fat-soluble vitamins.²⁹ Probiotics and antibiotics can also be given for prevention and treatment of small-intestinal bacterial overgrowth.²⁹

When traditional dietary modification and medical therapy fail to achieve nutritional homeostasis, another option to consider is a glucagon-like peptide-2 analogue to enhance intestinal adaptation.³⁰ Produced in the native distal ileum and colon, glucagon-like peptide 2 moderates the rate of gastric emptying and small-bowel transit and enhances epithelial cell proliferation, thereby promoting intestinal adaptation.³⁰ Further, a randomized controlled trial of 83 patients reported efficacy of these agents in reducing parenteral nutrition requirements in patients with intestinal failure.³¹

Hence, in patients with intestinal failure who have increased stoma effluent, drug therapy may play an important role in maintaining fluid and nutritional homeostasis.

THE ROLE OF PARENTERAL NUTRITION IN INTESTINAL FAILURE

Despite the best efforts of an intestinal rehabilitation program, not all patients gain nutritional autonomy.³² Physiologic, psychological, social, and economic factors may contribute to dependence on parenteral nutrition.³² Currently, more than 40,000 US patients depend on it for survival.³³

The need for short-term or long-term parenteral nutrition is determined by the patient’s medical needs.³³ Patients requiring short-term parenteral nutrition (2–6 weeks) include those whose bowel function has not returned to normal postoperatively, and those who were severely malnourished preoperatively.³⁴ Patients needing it long-term (from months to years to lifelong) are those with gastrointestinal dysmotility and short-bowel syndrome due to extensive bowel resections.³³

Complications of parenteral nutrition

Catheter-related bloodstream infection is the most common complication and cause of hospitalization. Infection can be localized to the exit site or tunnel or can be systemic (eg, line sepsis).³⁵Staphylococcus aureus and coagulase-negative staphylococci are most often implicated in catheter infection.³⁵ When possible, catheter salvage is desirable, but the central venous catheter must be removed in cases of tunnel infection, port abscess, septic shock, paired blood cultures positive for fungi or highly virulent bacteria, endocarditis, septic thrombosis, and other conditions.^35,36

Liver disease is a serious complication of long-term parenteral nutrition and may occur in up to 55% of patients on therapy for more than 2 years; it carries a mortality rate of 15%.³⁷

Risk factors include younger age and use of excessive carbohydrate and fat compositions, mainly soybean-oil–based lipid emulsions.³⁷ However, fish-oil–based lipid emulsions have recently shown promise in preventing and reversing parenteral nutrition-associated liver failure and cholestasis, especially in a pediatric population.³⁸

Catheter thrombosis may occur in up to 30% of patients on long-term parenteral nutrition.³⁹ However, this risk is reduced with appropriate positioning of the catheter tip in the mid or lower superior vena cava.³⁷ Treatment of thrombosis of the central access includes either anticoagulation or thrombolysis.³⁷

Hence, appropriate and timely follow-up of patients on parenteral nutrition is essential in reducing associated complications. Monitoring weight, fluid status, serum glucose, and patency of central access are critical to ensure that the patient maintains nutritional status effectively.⁴⁰ To prevent complications, a specialized nutritional support team should monitor the patient’s parenteral nutrition both in the hospital and at home.

RECONSTRUCTIVE SURGERY

Patients with intestinal failure due to short- bowel syndrome should be considered for reconstructive surgery during different phases of the adaptation process. Options include reversed-segment procedures, stricturoplasty, bowel-lengthening procedures (eg, the Bianchi procedure), and serial transverse enteroplasty.^41,42 If reconstructive surgery is ineffective, referral to an intestinal transplant program should be considered.

INTESTINAL AND MULTIVISCERAL TRANSPLANT

For patients who develop permanent intestinal failure and require lifelong parenteral nutrition, and for patients who experience significant complications of parenteral nutrition, such as infections and liver disease,⁴³ intestinal transplant has emerged as a way to restore clinical nutritional autonomy.⁴⁴ In one study, the 1-year survival rate after intestinal transplant was approximately 90%.⁴⁴

There are currently three transplant procedures: isolated intestine transplant, combined liver-intestine transplant, and multivisceral transplant with or without a liver, depending on the presence of parenteral nutrition-associated liver disease.^42,45 Close postoperative care is required to help the patient transition from parenteral to enteral nutrition.⁴² An intestinal rehabilitation team is equipped to provide this level of postoperative care.⁴²

Intestinal and multivisceral transplant gained momentum in the early 1960s in preclinical and clinical studies.^46,47 Since that time, the field has experienced remarkable advances due to standardization of surgical techniques, novel immunosuppressive therapies and induction protocols, and improved postoperative care.⁴⁸ With the advent of tacrolimus in 1989, the rates of allograft rejection improved significantly, and the field of transplant emerged as a potentially lifesaving therapy for patients with permanent intestinal failure.⁴⁸

Since 1990, more than 2,300 intestinal transplant procedures have been performed for various etiologies of intestinal failure, with short-bowel syndrome being the most common.⁴⁹

The indications for intestinal transplant approved by the US Centers for Medicare and Medicaid services are detailed in Table 6.⁵⁰ Despite ongoing challenges of graft rejection and maintenance immunosuppression, posttransplant quality-of-life questionnaires have indicated a significant improvement in functional status and a decrease in depressive symptoms.⁵¹ As such, it is evident that intestinal and multivisceral transplant offers substantial promise in restoring a patient’s quality of life and nutritional status.

The mass media and the medical literature have been saturated in the last few years by concerns about a variety of emerging viral epidemics such as Ebola and Zika. We must always remember that influenza will continue to affect many more patients worldwide.

The Cleveland Clinic Journal of Medicine periodically publishes updates on influenza, a topic befitting the large proportion of internists and internal medicine subspecialists who regularly read the Journal. This series began in 1975 with an article by Steven R. Mostow, MD,¹ which followed three pandemics that changed the world’s attitude about influenza.

A lot has changed since then, including another pandemic in 2009–2010. Here, I review recent information relevant to daily practice.

NO REASON FOR COMPLACENCY

The relatively mild 2015–2016 influenza season is no reason for complacency this season.

Influenza activity in 2015–2016 was milder than in most seasons in the last decade.² Activity peaked in mid-March and resulted in fewer outpatient visits, hospitalizations, and deaths than in previous seasons. Influenza A (H1N1)pdm09 has remained the predominant circulating virus since 2009. Although the overall rate of influenza-related hospitalization was less than half that in previous years, the hospitalization rate of middle-aged adults was relatively high (16.8 per 100,000 population). Importantly, 92% of adults with influenza illness that required hospitalization had at least one underlying medical condition, alerting us as healthcare providers that there is plenty of room for improvement in preventing such hospitalizations.

We should remain vigilant. We should put forth our best efforts in vaccinating all individuals above the age of 6 months and in diagnosing influenza early in the course of the illness in order to prescribe antiviral therapy within 48 hours of onset of symptoms. These actions not only shorten the illness and prevent hospitalization and secondary bacterial infection, but also reduce contagion and thus reduce overall healthcare costs.

School closure as a measure to halt epidemics has been lately called into question,³ since there are not enough data to support doing this routinely. School closure in Western Kentucky during the 2013 influenza epidemic did not reduce transmission but caused additional economic and social difficulties for certain households.⁴

STUDIES REINFORCE EARLIER DATA THAT INFLUENZA VACCINE WORKS

In the several decades since influenza vaccine became available, hundreds of studies have demonstrated the value of the “flu shot.” A few recent papers that support these well-established data:

• In adults who sought medical care for acute respiratory illness, influenza vaccine was 58.4% effective in preventing laboratory-confirmed influenza illness in adults age 50 and older.­⁵
• In the same age group, influenza vaccine was 56.8% effective in preventing laboratory-confirmed influenza hospitalizations.⁶
• Influenza vaccination in patients with heart failure reduced all-cause hospitalizations, particularly cardiovascular hospitalizations (30% reduction) and hospitalizations for respiratory infections (16% reduction).⁷ This effect lasted up to 4 months after influenza vaccination.
• Patients who were hospitalized with community-acquired, laboratory-confirmed influenza pneumonia were 43% less likely to have received the influenza vaccine than patients hospitalized with community-acquired pneumonia due to other pathogens.⁸

INFLUENZA VACCINE IS EVEN MORE VALUABLE DURING PREGNANCY

Influenza vaccination during pregnancy prevented one in five preterm deliveries in a developing country⁹ and reduced the risk of stillbirth by 50% in Australia.¹⁰

An interesting collateral benefit was demonstrated in a survey conducted in Minnesota, where children of mothers who self-reported prenatal influenza vaccination were more likely to complete their routine childhood vaccination series.¹¹

ADDITIONAL BENEFITS OF INFLUENZA VACCINATION

A recently appreciated benefit is that influenza vaccine induces cross-reactive protective immune responses (“heterologous immunity”) to viral strains not included in the vaccine, even in immunosuppressed individuals such as kidney transplant recipients.¹² Interestingly, patients were more likely to seroconvert for a cross-reactive “heterologous” antigen if they also seroconverted for the vaccine-specific “homologous” antigen.

In a study in mice, an influenza vaccine with an adjuvant protected mice not only from influenza virus challenge, but also from a Staphylococcus aureus superinfection challenge.¹³ This novel idea suggests that influenza vaccine protects not only against influenza virus infection, but also against a potentially fatal secondary bacterial infection. This has significant implications for curbing antibacterial use, with an expected reduction in antimicrobial resistance.

Another important benefit of influenza vaccination was recently demonstrated when ferrets were intranasally inoculated with the highly pathogenic influenza A(H5N1) strain and then received either influenza vaccine or prophylactic oseltamivir. Ferrets that received the vaccine were less likely to develop severe meningoencephalitis.¹⁴ Since influenza A(H5N1) is much more virulent than the current circulating influenza strains, and since it may be the cause of the next pandemic, preventing such a serious complication of influenza would be lifesaving.

SAFETY OF INFLUENZA VACCINATION

Hundreds of studies involving thousands of people have established the safety of influenza vaccination.

Issues related to Guillain-Barré syndrome have long been put to rest. A large retrospective study found no evidence of increased risk of Guillain-Barré syndrome following vaccination of any kind, including influenza vaccination.¹⁵

Local reactions after vaccination are transient and do not interfere with the ability to perform daily activities.

In this era of utilization review, it is reassuring to know that giving influenza vaccine to hospitalized surgical patients was not associated with an increased rate of postdischarge fever or other clinical concern for infection requiring emergency room visits or rehospitalization.¹⁶

WHY INFLUENZA VACCINE MAY NOT PREVENT ALL CASES OF INFLUENZA

Whether neutralizing antibodies to influenza virus hemagglutinin antigen should be the main immune correlate of protection for influenza vaccines remains in question. Although prepandemic avian influenza vaccines are poorly immunogenic in inducing neutralizing antibodies, they confer considerable protection. A recent study showed that antibody-dependent cell-mediated cytotoxicity to hemagglutinin antigen in an avian influenza vaccine was a better predictor of protective capacity than neutralizing antibodies.¹⁷

Patterns of immunity induced by the live-attenuated influenza vaccine and the inactivated influenza vaccine are different.¹⁸ In fact, no single cytokine or chemokine measurement predicts protection.

Even though adults age 50 and older mount statistically significant humoral and cell-mediated immune responses to the inactivated vaccine, two-thirds do not reach hemagglutination inhibition antibody titers of 40 or higher for influenza A(H1N1), and one-fifth do not reach hemagglutination inhibition antibody titers of 40 or higher for influenza A(H3N2).¹⁹ While age had some negative effect on vaccine responsiveness, prevaccination titers were much better at predicting postvaccination antibody levels.

ONGOING DEBATE OVER LIVE-ATTENUATED INFLUENZA VACCINE

Several studies had shown that the live-attenuated influenza vaccine, given intranasally, was not only more protective in vaccinated children, but also provided herd protection in unvaccinated contacts. However, a recently published study conducted in Canadian Hutterite children showed that the live-attenuated vaccine did not result in herd immunity when compared to the inactivated influenza vaccine.²⁰

On June 22, 2016, the US Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices recommended against the use of the live-attenuated vaccine for the 2016–2017 season,²¹ based on data showing negligible protection conferred by the live-attenuated influenza vaccine in the three preceding influenza seasons.

This decision created significant debate among experts in the field. It is unclear why the live-attenuated influenza vaccine was much less protective in the last three seasons than in prior seasons. Recommending against its use in the United States will essentially eliminate any possibility of reassessing its efficacy in this country. Of note, the quadrivalent live-attenuated influenza vaccine had recently replaced the previous trivalent live-attenuated vaccine, which may have introduced some “competition” among the vaccine strains to infect enough cells to allow viral replication and subsequent immune response. Another potential explanation is that consistent annual vaccination may have resulted in a cumulative immunity that could hamper response to subsequent doses.

COMPOSITION OF THE 2016–2017 INFLUENZA VACCINE

The 2016–2017 quadrivalent inactivated influenza vaccine will contain²²:

• A/California/7/2009 (H1N1)pdm09-like virus
• A/Hong Kong/4801/2014 (H3N2)-like virus
• B/Brisbane/60/2008-like virus (B/Victoria lineage)
• B/Phuket/3073/2013-like virus (B/Yamagata lineage).

This represents a change in the A (H3N2) component compared with the 2015–2016 vaccine.

Influenza vaccine manufacturers estimated they would produce 170 million doses for distribution in the United States for the upcoming influenza season. The previously mentioned recommendation against the use of the live-attenuated vaccine, which accounts for approximately 8% of the influenza vaccine supply, may affect vaccine uptake, particularly in children.

NEW ANTI-INFLUENZA AGENTS AND UPDATE ON EXISTING AGENTS

Neuraminidase inhibitors are the only class of antiviral drugs currently recommended for prevention and treatment of influenza. The three products currently available in the United States are oseltamivir, zanamivir, and peramivir. Oseltamivir is administered orally, and the first generic version was approved by the US Food and Drug Administration on August 3, 2016. Zanamivir is administered by oral inhalation. Both oseltamivir and zanamivir are approved for treatment and prevention of influenza. Peramivir is administered intravenously as a single dose and is approved only for the treatment of acute influenza, not prevention.

Unfortunately, the influenza vaccination rate during pregnancy in the United States remains only around 50%.²³ Physicians’ recommendations are strongly associated with vaccine uptake, particularly when they emphasize protective effect on the newborn. Influenza during pregnancy carries higher mortality than in the general population, with collateral fetal loss.

Early initiation of antiviral therapy is particularly imperative during pregnancy. A recent study showed that starting antiviral therapy within 2 days of onset of illness in pregnant women hospitalized with severe influenza reduced length of stay by 5.6 days compared with those in whom therapy was started more than 2 days after illness onset.²⁴

A single dose of laninamivir octanoate, a long-acting neuraminidase inhibitor currently approved in Japan for treating influenza, was recently shown to be effective as postexposure prophylaxis.²⁵ This option may be convenient for people who prefer not to take a daily medication for several days, or in an outbreak in a healthcare facility.

The mass media and the medical literature have been saturated in the last few years by concerns about a variety of emerging viral epidemics such as Ebola and Zika. We must always remember that influenza will continue to affect many more patients worldwide.

The Cleveland Clinic Journal of Medicine periodically publishes updates on influenza, a topic befitting the large proportion of internists and internal medicine subspecialists who regularly read the Journal. This series began in 1975 with an article by Steven R. Mostow, MD,¹ which followed three pandemics that changed the world’s attitude about influenza.

A lot has changed since then, including another pandemic in 2009–2010. Here, I review recent information relevant to daily practice.

NO REASON FOR COMPLACENCY

The relatively mild 2015–2016 influenza season is no reason for complacency this season.

Influenza activity in 2015–2016 was milder than in most seasons in the last decade.² Activity peaked in mid-March and resulted in fewer outpatient visits, hospitalizations, and deaths than in previous seasons. Influenza A (H1N1)pdm09 has remained the predominant circulating virus since 2009. Although the overall rate of influenza-related hospitalization was less than half that in previous years, the hospitalization rate of middle-aged adults was relatively high (16.8 per 100,000 population). Importantly, 92% of adults with influenza illness that required hospitalization had at least one underlying medical condition, alerting us as healthcare providers that there is plenty of room for improvement in preventing such hospitalizations.

We should remain vigilant. We should put forth our best efforts in vaccinating all individuals above the age of 6 months and in diagnosing influenza early in the course of the illness in order to prescribe antiviral therapy within 48 hours of onset of symptoms. These actions not only shorten the illness and prevent hospitalization and secondary bacterial infection, but also reduce contagion and thus reduce overall healthcare costs.

School closure as a measure to halt epidemics has been lately called into question,³ since there are not enough data to support doing this routinely. School closure in Western Kentucky during the 2013 influenza epidemic did not reduce transmission but caused additional economic and social difficulties for certain households.⁴

STUDIES REINFORCE EARLIER DATA THAT INFLUENZA VACCINE WORKS

In the several decades since influenza vaccine became available, hundreds of studies have demonstrated the value of the “flu shot.” A few recent papers that support these well-established data:

• In adults who sought medical care for acute respiratory illness, influenza vaccine was 58.4% effective in preventing laboratory-confirmed influenza illness in adults age 50 and older.­⁵
• In the same age group, influenza vaccine was 56.8% effective in preventing laboratory-confirmed influenza hospitalizations.⁶
• Influenza vaccination in patients with heart failure reduced all-cause hospitalizations, particularly cardiovascular hospitalizations (30% reduction) and hospitalizations for respiratory infections (16% reduction).⁷ This effect lasted up to 4 months after influenza vaccination.
• Patients who were hospitalized with community-acquired, laboratory-confirmed influenza pneumonia were 43% less likely to have received the influenza vaccine than patients hospitalized with community-acquired pneumonia due to other pathogens.⁸

INFLUENZA VACCINE IS EVEN MORE VALUABLE DURING PREGNANCY

Influenza vaccination during pregnancy prevented one in five preterm deliveries in a developing country⁹ and reduced the risk of stillbirth by 50% in Australia.¹⁰

An interesting collateral benefit was demonstrated in a survey conducted in Minnesota, where children of mothers who self-reported prenatal influenza vaccination were more likely to complete their routine childhood vaccination series.¹¹

ADDITIONAL BENEFITS OF INFLUENZA VACCINATION

A recently appreciated benefit is that influenza vaccine induces cross-reactive protective immune responses (“heterologous immunity”) to viral strains not included in the vaccine, even in immunosuppressed individuals such as kidney transplant recipients.¹² Interestingly, patients were more likely to seroconvert for a cross-reactive “heterologous” antigen if they also seroconverted for the vaccine-specific “homologous” antigen.

In a study in mice, an influenza vaccine with an adjuvant protected mice not only from influenza virus challenge, but also from a Staphylococcus aureus superinfection challenge.¹³ This novel idea suggests that influenza vaccine protects not only against influenza virus infection, but also against a potentially fatal secondary bacterial infection. This has significant implications for curbing antibacterial use, with an expected reduction in antimicrobial resistance.

Another important benefit of influenza vaccination was recently demonstrated when ferrets were intranasally inoculated with the highly pathogenic influenza A(H5N1) strain and then received either influenza vaccine or prophylactic oseltamivir. Ferrets that received the vaccine were less likely to develop severe meningoencephalitis.¹⁴ Since influenza A(H5N1) is much more virulent than the current circulating influenza strains, and since it may be the cause of the next pandemic, preventing such a serious complication of influenza would be lifesaving.

SAFETY OF INFLUENZA VACCINATION

Hundreds of studies involving thousands of people have established the safety of influenza vaccination.

Issues related to Guillain-Barré syndrome have long been put to rest. A large retrospective study found no evidence of increased risk of Guillain-Barré syndrome following vaccination of any kind, including influenza vaccination.¹⁵

Local reactions after vaccination are transient and do not interfere with the ability to perform daily activities.

In this era of utilization review, it is reassuring to know that giving influenza vaccine to hospitalized surgical patients was not associated with an increased rate of postdischarge fever or other clinical concern for infection requiring emergency room visits or rehospitalization.¹⁶

WHY INFLUENZA VACCINE MAY NOT PREVENT ALL CASES OF INFLUENZA

Whether neutralizing antibodies to influenza virus hemagglutinin antigen should be the main immune correlate of protection for influenza vaccines remains in question. Although prepandemic avian influenza vaccines are poorly immunogenic in inducing neutralizing antibodies, they confer considerable protection. A recent study showed that antibody-dependent cell-mediated cytotoxicity to hemagglutinin antigen in an avian influenza vaccine was a better predictor of protective capacity than neutralizing antibodies.¹⁷

Patterns of immunity induced by the live-attenuated influenza vaccine and the inactivated influenza vaccine are different.¹⁸ In fact, no single cytokine or chemokine measurement predicts protection.

Even though adults age 50 and older mount statistically significant humoral and cell-mediated immune responses to the inactivated vaccine, two-thirds do not reach hemagglutination inhibition antibody titers of 40 or higher for influenza A(H1N1), and one-fifth do not reach hemagglutination inhibition antibody titers of 40 or higher for influenza A(H3N2).¹⁹ While age had some negative effect on vaccine responsiveness, prevaccination titers were much better at predicting postvaccination antibody levels.

ONGOING DEBATE OVER LIVE-ATTENUATED INFLUENZA VACCINE

Several studies had shown that the live-attenuated influenza vaccine, given intranasally, was not only more protective in vaccinated children, but also provided herd protection in unvaccinated contacts. However, a recently published study conducted in Canadian Hutterite children showed that the live-attenuated vaccine did not result in herd immunity when compared to the inactivated influenza vaccine.²⁰

On June 22, 2016, the US Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices recommended against the use of the live-attenuated vaccine for the 2016–2017 season,²¹ based on data showing negligible protection conferred by the live-attenuated influenza vaccine in the three preceding influenza seasons.

This decision created significant debate among experts in the field. It is unclear why the live-attenuated influenza vaccine was much less protective in the last three seasons than in prior seasons. Recommending against its use in the United States will essentially eliminate any possibility of reassessing its efficacy in this country. Of note, the quadrivalent live-attenuated influenza vaccine had recently replaced the previous trivalent live-attenuated vaccine, which may have introduced some “competition” among the vaccine strains to infect enough cells to allow viral replication and subsequent immune response. Another potential explanation is that consistent annual vaccination may have resulted in a cumulative immunity that could hamper response to subsequent doses.

COMPOSITION OF THE 2016–2017 INFLUENZA VACCINE

The 2016–2017 quadrivalent inactivated influenza vaccine will contain²²:

• A/California/7/2009 (H1N1)pdm09-like virus
• A/Hong Kong/4801/2014 (H3N2)-like virus
• B/Brisbane/60/2008-like virus (B/Victoria lineage)
• B/Phuket/3073/2013-like virus (B/Yamagata lineage).

This represents a change in the A (H3N2) component compared with the 2015–2016 vaccine.

Influenza vaccine manufacturers estimated they would produce 170 million doses for distribution in the United States for the upcoming influenza season. The previously mentioned recommendation against the use of the live-attenuated vaccine, which accounts for approximately 8% of the influenza vaccine supply, may affect vaccine uptake, particularly in children.

NEW ANTI-INFLUENZA AGENTS AND UPDATE ON EXISTING AGENTS

Neuraminidase inhibitors are the only class of antiviral drugs currently recommended for prevention and treatment of influenza. The three products currently available in the United States are oseltamivir, zanamivir, and peramivir. Oseltamivir is administered orally, and the first generic version was approved by the US Food and Drug Administration on August 3, 2016. Zanamivir is administered by oral inhalation. Both oseltamivir and zanamivir are approved for treatment and prevention of influenza. Peramivir is administered intravenously as a single dose and is approved only for the treatment of acute influenza, not prevention.

Unfortunately, the influenza vaccination rate during pregnancy in the United States remains only around 50%.²³ Physicians’ recommendations are strongly associated with vaccine uptake, particularly when they emphasize protective effect on the newborn. Influenza during pregnancy carries higher mortality than in the general population, with collateral fetal loss.

Early initiation of antiviral therapy is particularly imperative during pregnancy. A recent study showed that starting antiviral therapy within 2 days of onset of illness in pregnant women hospitalized with severe influenza reduced length of stay by 5.6 days compared with those in whom therapy was started more than 2 days after illness onset.²⁴

A single dose of laninamivir octanoate, a long-acting neuraminidase inhibitor currently approved in Japan for treating influenza, was recently shown to be effective as postexposure prophylaxis.²⁵ This option may be convenient for people who prefer not to take a daily medication for several days, or in an outbreak in a healthcare facility.

The mass media and the medical literature have been saturated in the last few years by concerns about a variety of emerging viral epidemics such as Ebola and Zika. We must always remember that influenza will continue to affect many more patients worldwide.

The Cleveland Clinic Journal of Medicine periodically publishes updates on influenza, a topic befitting the large proportion of internists and internal medicine subspecialists who regularly read the Journal. This series began in 1975 with an article by Steven R. Mostow, MD,¹ which followed three pandemics that changed the world’s attitude about influenza.

A lot has changed since then, including another pandemic in 2009–2010. Here, I review recent information relevant to daily practice.

NO REASON FOR COMPLACENCY

The relatively mild 2015–2016 influenza season is no reason for complacency this season.

Influenza activity in 2015–2016 was milder than in most seasons in the last decade.² Activity peaked in mid-March and resulted in fewer outpatient visits, hospitalizations, and deaths than in previous seasons. Influenza A (H1N1)pdm09 has remained the predominant circulating virus since 2009. Although the overall rate of influenza-related hospitalization was less than half that in previous years, the hospitalization rate of middle-aged adults was relatively high (16.8 per 100,000 population). Importantly, 92% of adults with influenza illness that required hospitalization had at least one underlying medical condition, alerting us as healthcare providers that there is plenty of room for improvement in preventing such hospitalizations.

We should remain vigilant. We should put forth our best efforts in vaccinating all individuals above the age of 6 months and in diagnosing influenza early in the course of the illness in order to prescribe antiviral therapy within 48 hours of onset of symptoms. These actions not only shorten the illness and prevent hospitalization and secondary bacterial infection, but also reduce contagion and thus reduce overall healthcare costs.

School closure as a measure to halt epidemics has been lately called into question,³ since there are not enough data to support doing this routinely. School closure in Western Kentucky during the 2013 influenza epidemic did not reduce transmission but caused additional economic and social difficulties for certain households.⁴

STUDIES REINFORCE EARLIER DATA THAT INFLUENZA VACCINE WORKS

In the several decades since influenza vaccine became available, hundreds of studies have demonstrated the value of the “flu shot.” A few recent papers that support these well-established data:

• In adults who sought medical care for acute respiratory illness, influenza vaccine was 58.4% effective in preventing laboratory-confirmed influenza illness in adults age 50 and older.­⁵
• In the same age group, influenza vaccine was 56.8% effective in preventing laboratory-confirmed influenza hospitalizations.⁶
• Influenza vaccination in patients with heart failure reduced all-cause hospitalizations, particularly cardiovascular hospitalizations (30% reduction) and hospitalizations for respiratory infections (16% reduction).⁷ This effect lasted up to 4 months after influenza vaccination.
• Patients who were hospitalized with community-acquired, laboratory-confirmed influenza pneumonia were 43% less likely to have received the influenza vaccine than patients hospitalized with community-acquired pneumonia due to other pathogens.⁸

INFLUENZA VACCINE IS EVEN MORE VALUABLE DURING PREGNANCY

Influenza vaccination during pregnancy prevented one in five preterm deliveries in a developing country⁹ and reduced the risk of stillbirth by 50% in Australia.¹⁰

An interesting collateral benefit was demonstrated in a survey conducted in Minnesota, where children of mothers who self-reported prenatal influenza vaccination were more likely to complete their routine childhood vaccination series.¹¹

ADDITIONAL BENEFITS OF INFLUENZA VACCINATION

A recently appreciated benefit is that influenza vaccine induces cross-reactive protective immune responses (“heterologous immunity”) to viral strains not included in the vaccine, even in immunosuppressed individuals such as kidney transplant recipients.¹² Interestingly, patients were more likely to seroconvert for a cross-reactive “heterologous” antigen if they also seroconverted for the vaccine-specific “homologous” antigen.

In a study in mice, an influenza vaccine with an adjuvant protected mice not only from influenza virus challenge, but also from a Staphylococcus aureus superinfection challenge.¹³ This novel idea suggests that influenza vaccine protects not only against influenza virus infection, but also against a potentially fatal secondary bacterial infection. This has significant implications for curbing antibacterial use, with an expected reduction in antimicrobial resistance.

Another important benefit of influenza vaccination was recently demonstrated when ferrets were intranasally inoculated with the highly pathogenic influenza A(H5N1) strain and then received either influenza vaccine or prophylactic oseltamivir. Ferrets that received the vaccine were less likely to develop severe meningoencephalitis.¹⁴ Since influenza A(H5N1) is much more virulent than the current circulating influenza strains, and since it may be the cause of the next pandemic, preventing such a serious complication of influenza would be lifesaving.

SAFETY OF INFLUENZA VACCINATION

Hundreds of studies involving thousands of people have established the safety of influenza vaccination.

Issues related to Guillain-Barré syndrome have long been put to rest. A large retrospective study found no evidence of increased risk of Guillain-Barré syndrome following vaccination of any kind, including influenza vaccination.¹⁵

Local reactions after vaccination are transient and do not interfere with the ability to perform daily activities.

In this era of utilization review, it is reassuring to know that giving influenza vaccine to hospitalized surgical patients was not associated with an increased rate of postdischarge fever or other clinical concern for infection requiring emergency room visits or rehospitalization.¹⁶

WHY INFLUENZA VACCINE MAY NOT PREVENT ALL CASES OF INFLUENZA

Whether neutralizing antibodies to influenza virus hemagglutinin antigen should be the main immune correlate of protection for influenza vaccines remains in question. Although prepandemic avian influenza vaccines are poorly immunogenic in inducing neutralizing antibodies, they confer considerable protection. A recent study showed that antibody-dependent cell-mediated cytotoxicity to hemagglutinin antigen in an avian influenza vaccine was a better predictor of protective capacity than neutralizing antibodies.¹⁷

Patterns of immunity induced by the live-attenuated influenza vaccine and the inactivated influenza vaccine are different.¹⁸ In fact, no single cytokine or chemokine measurement predicts protection.

Even though adults age 50 and older mount statistically significant humoral and cell-mediated immune responses to the inactivated vaccine, two-thirds do not reach hemagglutination inhibition antibody titers of 40 or higher for influenza A(H1N1), and one-fifth do not reach hemagglutination inhibition antibody titers of 40 or higher for influenza A(H3N2).¹⁹ While age had some negative effect on vaccine responsiveness, prevaccination titers were much better at predicting postvaccination antibody levels.

ONGOING DEBATE OVER LIVE-ATTENUATED INFLUENZA VACCINE

Several studies had shown that the live-attenuated influenza vaccine, given intranasally, was not only more protective in vaccinated children, but also provided herd protection in unvaccinated contacts. However, a recently published study conducted in Canadian Hutterite children showed that the live-attenuated vaccine did not result in herd immunity when compared to the inactivated influenza vaccine.²⁰

On June 22, 2016, the US Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices recommended against the use of the live-attenuated vaccine for the 2016–2017 season,²¹ based on data showing negligible protection conferred by the live-attenuated influenza vaccine in the three preceding influenza seasons.

This decision created significant debate among experts in the field. It is unclear why the live-attenuated influenza vaccine was much less protective in the last three seasons than in prior seasons. Recommending against its use in the United States will essentially eliminate any possibility of reassessing its efficacy in this country. Of note, the quadrivalent live-attenuated influenza vaccine had recently replaced the previous trivalent live-attenuated vaccine, which may have introduced some “competition” among the vaccine strains to infect enough cells to allow viral replication and subsequent immune response. Another potential explanation is that consistent annual vaccination may have resulted in a cumulative immunity that could hamper response to subsequent doses.

COMPOSITION OF THE 2016–2017 INFLUENZA VACCINE

The 2016–2017 quadrivalent inactivated influenza vaccine will contain²²:

• A/California/7/2009 (H1N1)pdm09-like virus
• A/Hong Kong/4801/2014 (H3N2)-like virus
• B/Brisbane/60/2008-like virus (B/Victoria lineage)
• B/Phuket/3073/2013-like virus (B/Yamagata lineage).

This represents a change in the A (H3N2) component compared with the 2015–2016 vaccine.

Influenza vaccine manufacturers estimated they would produce 170 million doses for distribution in the United States for the upcoming influenza season. The previously mentioned recommendation against the use of the live-attenuated vaccine, which accounts for approximately 8% of the influenza vaccine supply, may affect vaccine uptake, particularly in children.

NEW ANTI-INFLUENZA AGENTS AND UPDATE ON EXISTING AGENTS

Neuraminidase inhibitors are the only class of antiviral drugs currently recommended for prevention and treatment of influenza. The three products currently available in the United States are oseltamivir, zanamivir, and peramivir. Oseltamivir is administered orally, and the first generic version was approved by the US Food and Drug Administration on August 3, 2016. Zanamivir is administered by oral inhalation. Both oseltamivir and zanamivir are approved for treatment and prevention of influenza. Peramivir is administered intravenously as a single dose and is approved only for the treatment of acute influenza, not prevention.

Unfortunately, the influenza vaccination rate during pregnancy in the United States remains only around 50%.²³ Physicians’ recommendations are strongly associated with vaccine uptake, particularly when they emphasize protective effect on the newborn. Influenza during pregnancy carries higher mortality than in the general population, with collateral fetal loss.

Early initiation of antiviral therapy is particularly imperative during pregnancy. A recent study showed that starting antiviral therapy within 2 days of onset of illness in pregnant women hospitalized with severe influenza reduced length of stay by 5.6 days compared with those in whom therapy was started more than 2 days after illness onset.²⁴

A single dose of laninamivir octanoate, a long-acting neuraminidase inhibitor currently approved in Japan for treating influenza, was recently shown to be effective as postexposure prophylaxis.²⁵ This option may be convenient for people who prefer not to take a daily medication for several days, or in an outbreak in a healthcare facility.

A 70-year-old man with hypertension and hypercholesterolemia presented to the emergency department after the acute onset of substernal, pressure-like chest pain while climbing a flight of stairs. His physical examination was normal, but he was noted to have bilateral diagonal earlobe creases (the Frank sign) (Figure 1), considered by some to indicate risk of coronary artery disease.^1–5

Electrocardiography showed atrial fibrillation with a ventricular rate of 149 beats per minute, ST-segment elevation in leads V₁ and aVR, and ST-segment depression in leads V₃ to V₆, II, III, and aVF.

Urgent coronary arteriography showed severe coronary artery disease (Figure 2). Left ventriculography showed an ejection fraction of 50% with mild anterior wall hypokinesis. A drug-eluting stent was placed in the mid-left anterior descending artery. The patient tolerated the procedure well, and his chest pain resolved afterward.

A STILL-UNCLEAR ASSOCIATION

Sanders T. Frank, in 1973, first described a diagonal wrinkle-like line on the earlobe as a sign of coronary artery disease.¹ Subsequently, autopsy studies suggested that deep bilateral earlobe creases could be an important sign of coronary atherosclerosis.² Diagonal earlobe creases have been shown to be independently associated with increased prevalence, extent, and severity of coronary artery disease.^3,4 They are also associated with major adverse cardiovascular events⁴ and ischemic stroke.⁵ The mechanism linking diagonal earlobe creases and atherosclerotic disease is not yet clear.

This patient’s presentation and evaluation remind us that bilateral earlobe creases may be useful to include in the clinical examination of patients with suspected coronary artery disease and may facilitate early recognition of disease in a patient at high risk.

A 70-year-old man with hypertension and hypercholesterolemia presented to the emergency department after the acute onset of substernal, pressure-like chest pain while climbing a flight of stairs. His physical examination was normal, but he was noted to have bilateral diagonal earlobe creases (the Frank sign) (Figure 1), considered by some to indicate risk of coronary artery disease.^1–5

Electrocardiography showed atrial fibrillation with a ventricular rate of 149 beats per minute, ST-segment elevation in leads V₁ and aVR, and ST-segment depression in leads V₃ to V₆, II, III, and aVF.

Urgent coronary arteriography showed severe coronary artery disease (Figure 2). Left ventriculography showed an ejection fraction of 50% with mild anterior wall hypokinesis. A drug-eluting stent was placed in the mid-left anterior descending artery. The patient tolerated the procedure well, and his chest pain resolved afterward.

A STILL-UNCLEAR ASSOCIATION

Sanders T. Frank, in 1973, first described a diagonal wrinkle-like line on the earlobe as a sign of coronary artery disease.¹ Subsequently, autopsy studies suggested that deep bilateral earlobe creases could be an important sign of coronary atherosclerosis.² Diagonal earlobe creases have been shown to be independently associated with increased prevalence, extent, and severity of coronary artery disease.^3,4 They are also associated with major adverse cardiovascular events⁴ and ischemic stroke.⁵ The mechanism linking diagonal earlobe creases and atherosclerotic disease is not yet clear.

This patient’s presentation and evaluation remind us that bilateral earlobe creases may be useful to include in the clinical examination of patients with suspected coronary artery disease and may facilitate early recognition of disease in a patient at high risk.

A 70-year-old man with hypertension and hypercholesterolemia presented to the emergency department after the acute onset of substernal, pressure-like chest pain while climbing a flight of stairs. His physical examination was normal, but he was noted to have bilateral diagonal earlobe creases (the Frank sign) (Figure 1), considered by some to indicate risk of coronary artery disease.^1–5

Electrocardiography showed atrial fibrillation with a ventricular rate of 149 beats per minute, ST-segment elevation in leads V₁ and aVR, and ST-segment depression in leads V₃ to V₆, II, III, and aVF.

Urgent coronary arteriography showed severe coronary artery disease (Figure 2). Left ventriculography showed an ejection fraction of 50% with mild anterior wall hypokinesis. A drug-eluting stent was placed in the mid-left anterior descending artery. The patient tolerated the procedure well, and his chest pain resolved afterward.

A STILL-UNCLEAR ASSOCIATION

Sanders T. Frank, in 1973, first described a diagonal wrinkle-like line on the earlobe as a sign of coronary artery disease.¹ Subsequently, autopsy studies suggested that deep bilateral earlobe creases could be an important sign of coronary atherosclerosis.² Diagonal earlobe creases have been shown to be independently associated with increased prevalence, extent, and severity of coronary artery disease.^3,4 They are also associated with major adverse cardiovascular events⁴ and ischemic stroke.⁵ The mechanism linking diagonal earlobe creases and atherosclerotic disease is not yet clear.

This patient’s presentation and evaluation remind us that bilateral earlobe creases may be useful to include in the clinical examination of patients with suspected coronary artery disease and may facilitate early recognition of disease in a patient at high risk.

On an otherwise pleasant evening during the first week of July 2016, a businessman who was a citizen of the United Arab Emirates visiting Cleveland for medical treatment was falsely accused of links to a terror organization. Officers stormed his hotel with assault rifles and handcuffed and arrested him—all this, apparently, because the man was dressed in traditional Emirati clothing.

See related article

This case highlights a level of complexity in providing medical care to foreigners far beyond language interpreting services and outside the borders of the institution where medical care is provided. In the current issue of the Journal, Cawcutt and Wilson¹ review their experiences in the care of international patients and the unique challenges associated with it.

FROM THE TEMPLE OF AESCULAPIUS TO CLEVELAND CLINIC

In 2015, patients from more than 100 countries traveled to Cleveland seeking care at Cleveland Clinic. But medical travel was part of the practice of medicine long before major US hospitals became destinations for international patients, and it has been refined over the years.

Ancient cultures had a thriving tradition of patients traveling long distances for the best and most advanced medical treatment.^2–4 In ancient Greece, people from all around the Mediterranean came to the city of Epidaurus to be cured in its famous temple of Aesculapius, built as a medical center.

Similarly, early Islamic cultures established a healthcare system that catered to foreigners. A noted example is the Mansuri hospital in Cairo, built in 1248 ce and considered the most advanced hospital of its time. Accommodating nearly 8,000 patients, the Mansuri hospital became a healthcare destination for foreigners regardless of race or religion.^2–4

Europe also had a great tradition of providing medical care to foreign patients. Between the 15th and 17th centuries, belief in the healing power of mineral water led to the establishment of spas and the rise of spa towns, particularly in the south of France near mineral springs. The poor sanitary conditions of Europe at the time may have prompted the interest in the healing effect of mineral spas, but wealthy individuals from all over the world traveled to these destinations, creating local prosperity due to medical tourism.^2–4

The city of Bath, in England, is a great example. In the 1720s, Bath was a popular destination for those traveling for healthcare. It became the first city in England to build a covered sewage system, ahead of London by several years. It also had paved roads, lights, hotels, and restaurants in much greater numbers than other cities in England, a likely result of prosperity associated with medical tourism.

ALL PATIENTS WANT TO BE TREATED WITH RESPECT AND KINDNESS

While medical knowledge and health delivery models have changed over the years, caring for foreign patients is perhaps as old as medicine itself. The central focus of restoring health is certainly not unique to international patients, but understanding their unique needs is important in order to achieve the best outcomes, something that Cawcutt and Wilson highlight well.¹

A number of studies have addressed the question of what patients really want. Responses were surprisingly consistent: they want to be treated with respect and kindness.^5,6 In other words, they want empathy, and this is true of all patients regardless of ethnicity or background. Empathy is a tremendous therapeutic force and can narrow what may look like an unbridgeable gap between patient and physician.^7,8

EMPATHY REQUIRES EFFECTIVE COMMUNICATION

Empathy, though sometimes innate, requires effective communication and shared experiences. Neither of these two requirements is easily achievable in the care of foreign patients.

Communication is hampered by language barriers, although it can be enhanced significantly by language translating services and the work of certified medical interpreters. These often-invisible heroes should be recognized as essential members of the medical team. Their work requires cultural sensitivity and formal training to avoid miscommunication and medical errors. Codes of ethics for medical interpreters include confidentiality, accuracy in conveying the content and spirit of the message, freedom from personal biases, cultural training, and professional boundaries.⁹

TOWARD CULTURAL COMPETENCY

Lack of shared experiences between the foreign patient and care provider is an even greater obstacle to overcome in eliminating any empathy deficit. Shared experiences, whether cultural, religious, or social, help us to see the world through the eyes of the patient.

International patients may differ from us in background, ethnicity, religion, dress, expectations, and other areas. Cultural and religious backgrounds often dictate certain behaviors in the event of critical illness or death. Even in routine and less acute medical care, the background of a foreign patient may lead to logistical quandaries such as the need for same-sex caregivers or a private room.

A paradox currently exists in our efforts to meet patients’ need and desire for empathy. While culturally empathic care is necessary to achieve the best medical outcomes, this topic is not yet part of the curriculum for physicians or other healthcare providers in training. A culturally sensitive institution has many business advantages.¹⁰ Thorough and focused cultural training of medical staff is essential. Shared experiences can potentially be fashioned through a well-designed cultural competency training program to enhance empathy for foreign patients.

A SERVICE-ORIENTED APPROACH

Besides cultural competency and language training, a service-oriented approach to accommodate the needs of medical travelers and their family members is of paramount importance. Many of the complaints and burdens of medical visitors concern services that are not medical in nature, such as daily living necessities. Transportation, religious services, banking, extended-stay facilities, cell phone service, legal services, shopping, dining, and entertainment are among many other living needs for those receiving medical care abroad. These services are inconsistently provided throughout medical institutions in the United States, which provide care to thousands of international patients annually.

Unique challenges of providing medical care to international patients have direct effects on medical outcomes. A population-based cohort study of US-born and foreign-born adults with lung or colorectal cancer suggested disparities in quality and type of care.¹¹ Foreign-born patients reported lower-quality care and were less likely to receive complex cancer treatments recommended by clinical guidelines. The authors proposed that quality of care and outcomes may be improved with greater emphasis on coordination of care and improving communication. Similar findings were reported in foreign-born patients with breast cancer.¹²

‘WHAT WOULD YOU THINK TO BE USED THUS?’

Four hundred years ago, in the play Sir Thomas More (a collaboration between several Elizabethan playwrights),¹³ the title character confronts a mob of anti-immigrant rioters, and in a speech believed to have been written by William Shakespeare (Act 2, Scene 4), asks them to imagine themselves banished to a foreign country and subjected to hostility such as they were meting out:

Empathy for foreigners seeking medical care is not merely an act of kindness; rather, it is a central piece of healing. Medical institutions interested in providing healthcare to this unique group of patients should take these principles into account and carefully examine their ability to deliver compassionate care collectively to local and foreign-born patients alike.

On an otherwise pleasant evening during the first week of July 2016, a businessman who was a citizen of the United Arab Emirates visiting Cleveland for medical treatment was falsely accused of links to a terror organization. Officers stormed his hotel with assault rifles and handcuffed and arrested him—all this, apparently, because the man was dressed in traditional Emirati clothing.

See related article

This case highlights a level of complexity in providing medical care to foreigners far beyond language interpreting services and outside the borders of the institution where medical care is provided. In the current issue of the Journal, Cawcutt and Wilson¹ review their experiences in the care of international patients and the unique challenges associated with it.

FROM THE TEMPLE OF AESCULAPIUS TO CLEVELAND CLINIC

In 2015, patients from more than 100 countries traveled to Cleveland seeking care at Cleveland Clinic. But medical travel was part of the practice of medicine long before major US hospitals became destinations for international patients, and it has been refined over the years.

Ancient cultures had a thriving tradition of patients traveling long distances for the best and most advanced medical treatment.^2–4 In ancient Greece, people from all around the Mediterranean came to the city of Epidaurus to be cured in its famous temple of Aesculapius, built as a medical center.

Similarly, early Islamic cultures established a healthcare system that catered to foreigners. A noted example is the Mansuri hospital in Cairo, built in 1248 ce and considered the most advanced hospital of its time. Accommodating nearly 8,000 patients, the Mansuri hospital became a healthcare destination for foreigners regardless of race or religion.^2–4

Europe also had a great tradition of providing medical care to foreign patients. Between the 15th and 17th centuries, belief in the healing power of mineral water led to the establishment of spas and the rise of spa towns, particularly in the south of France near mineral springs. The poor sanitary conditions of Europe at the time may have prompted the interest in the healing effect of mineral spas, but wealthy individuals from all over the world traveled to these destinations, creating local prosperity due to medical tourism.^2–4

The city of Bath, in England, is a great example. In the 1720s, Bath was a popular destination for those traveling for healthcare. It became the first city in England to build a covered sewage system, ahead of London by several years. It also had paved roads, lights, hotels, and restaurants in much greater numbers than other cities in England, a likely result of prosperity associated with medical tourism.

ALL PATIENTS WANT TO BE TREATED WITH RESPECT AND KINDNESS

While medical knowledge and health delivery models have changed over the years, caring for foreign patients is perhaps as old as medicine itself. The central focus of restoring health is certainly not unique to international patients, but understanding their unique needs is important in order to achieve the best outcomes, something that Cawcutt and Wilson highlight well.¹

A number of studies have addressed the question of what patients really want. Responses were surprisingly consistent: they want to be treated with respect and kindness.^5,6 In other words, they want empathy, and this is true of all patients regardless of ethnicity or background. Empathy is a tremendous therapeutic force and can narrow what may look like an unbridgeable gap between patient and physician.^7,8

EMPATHY REQUIRES EFFECTIVE COMMUNICATION

Empathy, though sometimes innate, requires effective communication and shared experiences. Neither of these two requirements is easily achievable in the care of foreign patients.

Communication is hampered by language barriers, although it can be enhanced significantly by language translating services and the work of certified medical interpreters. These often-invisible heroes should be recognized as essential members of the medical team. Their work requires cultural sensitivity and formal training to avoid miscommunication and medical errors. Codes of ethics for medical interpreters include confidentiality, accuracy in conveying the content and spirit of the message, freedom from personal biases, cultural training, and professional boundaries.⁹

TOWARD CULTURAL COMPETENCY

Lack of shared experiences between the foreign patient and care provider is an even greater obstacle to overcome in eliminating any empathy deficit. Shared experiences, whether cultural, religious, or social, help us to see the world through the eyes of the patient.

International patients may differ from us in background, ethnicity, religion, dress, expectations, and other areas. Cultural and religious backgrounds often dictate certain behaviors in the event of critical illness or death. Even in routine and less acute medical care, the background of a foreign patient may lead to logistical quandaries such as the need for same-sex caregivers or a private room.

A paradox currently exists in our efforts to meet patients’ need and desire for empathy. While culturally empathic care is necessary to achieve the best medical outcomes, this topic is not yet part of the curriculum for physicians or other healthcare providers in training. A culturally sensitive institution has many business advantages.¹⁰ Thorough and focused cultural training of medical staff is essential. Shared experiences can potentially be fashioned through a well-designed cultural competency training program to enhance empathy for foreign patients.

A SERVICE-ORIENTED APPROACH

Besides cultural competency and language training, a service-oriented approach to accommodate the needs of medical travelers and their family members is of paramount importance. Many of the complaints and burdens of medical visitors concern services that are not medical in nature, such as daily living necessities. Transportation, religious services, banking, extended-stay facilities, cell phone service, legal services, shopping, dining, and entertainment are among many other living needs for those receiving medical care abroad. These services are inconsistently provided throughout medical institutions in the United States, which provide care to thousands of international patients annually.

Unique challenges of providing medical care to international patients have direct effects on medical outcomes. A population-based cohort study of US-born and foreign-born adults with lung or colorectal cancer suggested disparities in quality and type of care.¹¹ Foreign-born patients reported lower-quality care and were less likely to receive complex cancer treatments recommended by clinical guidelines. The authors proposed that quality of care and outcomes may be improved with greater emphasis on coordination of care and improving communication. Similar findings were reported in foreign-born patients with breast cancer.¹²

‘WHAT WOULD YOU THINK TO BE USED THUS?’

Four hundred years ago, in the play Sir Thomas More (a collaboration between several Elizabethan playwrights),¹³ the title character confronts a mob of anti-immigrant rioters, and in a speech believed to have been written by William Shakespeare (Act 2, Scene 4), asks them to imagine themselves banished to a foreign country and subjected to hostility such as they were meting out:

Empathy for foreigners seeking medical care is not merely an act of kindness; rather, it is a central piece of healing. Medical institutions interested in providing healthcare to this unique group of patients should take these principles into account and carefully examine their ability to deliver compassionate care collectively to local and foreign-born patients alike.

On an otherwise pleasant evening during the first week of July 2016, a businessman who was a citizen of the United Arab Emirates visiting Cleveland for medical treatment was falsely accused of links to a terror organization. Officers stormed his hotel with assault rifles and handcuffed and arrested him—all this, apparently, because the man was dressed in traditional Emirati clothing.

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This case highlights a level of complexity in providing medical care to foreigners far beyond language interpreting services and outside the borders of the institution where medical care is provided. In the current issue of the Journal, Cawcutt and Wilson¹ review their experiences in the care of international patients and the unique challenges associated with it.

FROM THE TEMPLE OF AESCULAPIUS TO CLEVELAND CLINIC

In 2015, patients from more than 100 countries traveled to Cleveland seeking care at Cleveland Clinic. But medical travel was part of the practice of medicine long before major US hospitals became destinations for international patients, and it has been refined over the years.

Ancient cultures had a thriving tradition of patients traveling long distances for the best and most advanced medical treatment.^2–4 In ancient Greece, people from all around the Mediterranean came to the city of Epidaurus to be cured in its famous temple of Aesculapius, built as a medical center.

Similarly, early Islamic cultures established a healthcare system that catered to foreigners. A noted example is the Mansuri hospital in Cairo, built in 1248 ce and considered the most advanced hospital of its time. Accommodating nearly 8,000 patients, the Mansuri hospital became a healthcare destination for foreigners regardless of race or religion.^2–4

Europe also had a great tradition of providing medical care to foreign patients. Between the 15th and 17th centuries, belief in the healing power of mineral water led to the establishment of spas and the rise of spa towns, particularly in the south of France near mineral springs. The poor sanitary conditions of Europe at the time may have prompted the interest in the healing effect of mineral spas, but wealthy individuals from all over the world traveled to these destinations, creating local prosperity due to medical tourism.^2–4

The city of Bath, in England, is a great example. In the 1720s, Bath was a popular destination for those traveling for healthcare. It became the first city in England to build a covered sewage system, ahead of London by several years. It also had paved roads, lights, hotels, and restaurants in much greater numbers than other cities in England, a likely result of prosperity associated with medical tourism.

ALL PATIENTS WANT TO BE TREATED WITH RESPECT AND KINDNESS

While medical knowledge and health delivery models have changed over the years, caring for foreign patients is perhaps as old as medicine itself. The central focus of restoring health is certainly not unique to international patients, but understanding their unique needs is important in order to achieve the best outcomes, something that Cawcutt and Wilson highlight well.¹