IM Board Review

A 48-year-old man with gout, multiple sclerosis, and previously treated methicillin-resistant Staphylococcus aureus (MRSA) infection presented to the emergency room with pain and significant swelling at the site of a dog bite on his left forearm. He had been bitten 2 weeks earlier by a friend’s dog, and the bite had punctured the skin. He also had red streaking on the skin of the left arm from the wrist to the elbow, and he reported feeling “feverish” and having night sweats.

At first, the bite had seemed to improve, then swelling and pain had developed and increased. He reported this to his primary care physician, along with the information that he had previously had an anaphylactic reaction to penicillin and a cephalosporin. His physician, considering a penicillin allergy, started him on ciprofloxacin (Cipro) plus clindamycin (Cleocin). The patient took this for 5 days, but without improvement. The appearance of the red streaking on his left forearm prompted his presentation to our emergency room.

ORGANISMS IN DOG BITES

1. Which is the most common cause of infected dog bite?

• Pasteurella canis
• Streptococci and S aureus
• Erysipelothrix rhusiopathiae
• Capnocytophaga canimorsus
• Eikenella corrodens

Streptococci (50%) and S aureus (20% to 40%) are the organisms most commonly responsible for infected dog bites, as they are for other skin and soft-tissue infections.¹P canis is unique to dog bite infections but accounts for only 18%.²E rhusiopathiae is an unusual isolate from cat and dog bites and is more commonly isolated from the mouths of fish and aquatic mammals. C canimorsus is a normal inhabitant of the oral cavity of dogs and cats but an unusual cause of wound infection from a dog bite. It is notable for sepsis and central nervous system infections uniquely associated with veterinarians, dog owners, kennel workers, and mail carriers.³E corrodens infection is more common with human bites.⁴

THE EVALUATION BEGINS

On examination, the patient had marked edema of the left forearm and pain in the joints of the left hand. His temperature was 100.2°F (37.9°C). Because of the duration and severity of symptoms, the examining physician was concerned about septic arthritis of the wrist, and the patient was admitted to the hospital.

In the hospital, our patient was thermodynamically stable without documented fever or chills. There was no open wound to culture, and blood cultures were negative. Marked edema and joint involvement raised suspicion of erysipeloid. This “cousin” of erysipelas often involves the underlying joint, is associated with edema, and produces systemic manifestations of fever and arthralgia.

Radiography of the left forearm and hand demonstrated multiple foci of demineralization within the carpal bones and proximal radius, attributed to disuse. Magnetic resonance imaging (MRI) the next day showed multiple bone infarcts in the carpal bones and the distal radius, with synovitis and fluid in the carpal joints and without adjacent osteomyelitis. Fluid was also seen in the soft tissues in the ulnar aspect of the left wrist, and tenosynovitis involving the flexor carpi radialis tendon was noted.

Arthrocentesis of his left radiocarpal joint produced synovial fluid negative for crystals and negative on Gram stain; the fluid was also sent for culture. The patient’s tetanus immunization was current, and the dog was known to have been immunized against rabies.

ANTIBIOTICS FOR INFECTED DOG BITES

2. Which antibiotic regimen would you choose for this patient?

• Oral amoxicillin and clavulanate
• Meropenem
• Vancomycin, clindamycin, aztreonam
• Clindamycin and levofloxacin
• Clindamycin and trimethoprim-sulfamethoxazole

Oral amoxicillin and clavulanate (Augmentin) is a judicious choice for prophylactic treatment of deep bites in the early stages of infection. However, our patient’s wound was no longer in the early stages of infection, and he had a history of an adverse reaction to penicillin.

Meropenem (Merrem IV) cross-reacts minimally with penicillin allergy and is reported to be safe in patients with a history of anaphylactic reactions to penicillin,⁵ but overuse of carbapenems has led to the development of carbapenem-resistant strains of Klebsiella, Stenotrophomonas, and Acinetobacter organisms.

Given the rise of MRSA infections and the common involvement of staphylococci, streptococci, and anaerobic bacteria in complicated dog bites, the combination of vancomycin and clindamycin is a good choice, and aztreonam (Azactam) would add empiric coverage of gram-negative enteric organisms.

Levofloxacin (Levaquin) also covers gramnegative enteric organisms, but Fusobacterium canifelinum, a common anaerobe in the oral flora of dogs and cats, is intrinsically resistant to fluoroquinolones.

Clindamycin and levofloxacin would be a good step-down oral regimen. Pasteurella multocida has variable sensitivity to the commonly used agents dicloxacillin (Dynapen), cephalexin (Keflex), macrolides, and clindamycin, but it is a less likely pathogen at this late stage and could be covered with levofloxacin alone.

C canimorsus is resistant to trimethoprim-sulfamethoxazole (Bactrim) and cephalexin, but is well covered by clindamycin.⁶

CASE CONTINUED

Our patient was started on intravenous vancomycin, clindamycin, and aztreonam for coverage of dog-mouth flora. Blood cultures and cultures of synovial fluid of the left wrist were negative. Vancomycin was discontinued after 48 hours when blood cultures did not grow staphylococcal organisms, but clindamycin and aztreonam were continued for a total of 8 days to treat possible infection with anaerobic and gram-negative enteric pathogens.

To test for autonomic dysfunction, a plastic pen case drawn lightly across each forearm revealed a loss of tactile adherence (ie, areas where moist, sweaty skin impeded the movement of the pen case) on the affected forearm, a sign of underlying nerve injury. The affected forearm was sensitive to light touch, with pain out of proportion to the stimulus.

ARRIVING AT THE DIAGNOSIS

Based on the wide distribution of inflammation, autonomic dysfunction (shown by differences in temperature and sweating), radiographic evidence of demineralization, hyperesthesia, and lack of improvement in pain and swelling after two courses of antibiotics, the patient’s clinical course was determined to be consistent with complex regional pain syndrome type 1, previously referred to as reflex sympathetic dystrophy.

Symptoms of complex regional pain syndrome traditionally include pain, regional edema, joint stiffness, muscular atrophy, vasomotor disturbances (causing temperature variability and erythema), regional diaphoresis, and localized skeletal demineralization on radiography.

Complex regional pain syndrome type 1 occurs as regional pain and inflammation as an excessive sympathetic reaction to an often minor insult, without nerve injury. When the syndrome occurs in a patient with obvious partial nerve injury, it is categorized as type 2 (formerly known as causalgia). The two types are clinically indistinguishable and are not uncommon. About 10% of all patients with complex regional pain syndrome have obvious nerve injury (complex regional pain syndrome type 2). In a study of 109 patients with Colles fracture, 25% developed symptoms of complex regional pain syndrome.⁷

Complex regional pain syndrome is difficult to diagnose, as it resembles many other ailments, such as gout, infection, bone tumor, stress fracture, and arthritis. Its pathophysiology is poorly understood, but it is believed to result from a “short circuit” in the reflex arc between somatic afferent sensory fibers and autonomic sympathetic efferent fibers, and this is thought to explain the increased sympathetic stimulation.

Although the pathophysiology is likely the same in type 1 and type 2, electromyography with a nerve conduction study is a reliable way to detect nerve damage and thus distinguish between the two types of complex regional pain syndrome.⁸

Our understanding of this syndrome is evolving. A recent study using sensory testing showed that 33% of patients with type 1 had combinations of increased and decreased thresholds for the detection of thermal, vibratory, and mechanical stimuli in the distribution of discrete peripheral nerves, suggesting that the patients actually had type 2.⁹

CONFIRMING COMPLEX REGIONAL PAIN SYNDROME TYPE 1

3. Which of the following is the best way to confirm complex regional pain syndrome type 1?

• Erythrocyte sedimentation rate, C-reactive protein, and complete blood cell count
• Plain radiography of the hand and forearm
• Three-phase technetium bone scan
• The Budapest diagnostic criteria
• MRI
• Autonomic testing

Complex regional pain syndrome type 1 is a clinical diagnosis. Diagnostic studies lack sensitivity and specificity but may confirm complex regional pain syndrome type 1 or rule out other diagnoses. The Budapest diagnostic criteria¹⁰ (Table 1) may be the best way to confirm this diagnosis. The criteria are as follows: continuing pain disproportionate to an inciting event, coupled with three of four symptoms plus at least one sign from sensory, vasomotor, sudomotor, and motor-trophic categories.

Laboratory tests are not helpful because acute-phase reactants and blood counts remain normal in these patients.

Plain radiography is not sensitive in early diagnosis, but at 2 weeks it may show patchy areas of osteopenia in adjacent bones throughout the region, as well as subsequent diffuse demineralization.

Three-phase bone scanning is more sensitive than plain radiography, with 75% of patients showing regional disparities in blood flow in early sequences and increased bone uptake in the later sequences.

MRI is a sensitive early test, as it better defines focal areas of bone loss and increased T2 bone signal in adjacent bone, as well as early soft-tissue changes. Computed tomography does not show early specific changes in muscle, tendon, or bone and so is not recommended.

THE EVALUATION CONTINUES

The admitting diagnosis was septic arthritis, and our patient underwent computed tomography, which showed focal demineralization that could have represented bone infarcts or infection, confounding the diagnosis of complex regional pain syndrome.

Autonomic nerve testing can help distinguish complex regional pain syndrome from other disorders. Complex regional pain syndrome is characterized by increased sympathetic activity and results in increased sweat output. Autonomic testing includes resting sweat output, resting skin temperature, and quantitative sudomotor axon reflex testing. In one study, an increase in resting sweat output used in conjunction with quantitative sudomotor axon reflex testing predicted the diagnosis of complex regional pain syndrome with a specificity of 98%.¹¹ However, autonomic testing is limited to academic centers and is not readily available.

TREATING COMPLEX REGIONAL PAIN SYNDROME TYPE 1

4. Which is the best first-line therapy for complex regional pain syndrome type 1?

• Stellate ganglion nerve block
• Occupational therapy to splint the wrist and forearm
• Oral corticosteroids
• Physical therapy to prevent loss of joint motion
• Tricyclic antidepressant drugs (eg, amitriptyline), pregabalin, and bisphosphonates

Physical therapy should be started early in all patients, with range-of-motion exercises to prevent contracture and enhance mobility.

Stellate ganglion nerve block has been used to counter severe sympathetic hyperactivity, but it also may aggravate symptoms of complex regional pain syndrome and so remains a controversial treatment.

Immobilization and splinting should be avoided, as this will augment edema, pain, and contracture of joints.

Corticosteroids do not shorten the course or assuage symptoms and may increase edema.

Amitriptyline (Elavil) and pregabalin (Lyrica) have been used successfully to counter extended courses of allodynia and hyperalgesia. Bisphosphonates may decrease bone loss and pain and may be needed should the course be complicated by myositis ossificans, a form of dystrophic bone formation in juxtaposed tendon and muscle related to neuroactivation of fibroblasts and osteoblasts.

THE COURSE OF COMPLEX REGIONAL PAIN SYNDROME

Traditionally, type 1 was divided into three stages—an early inflammatory stage, a dystrophic stage, and a late atrophic stage.¹² Although there is no evidence to support a consistent three-stage evolution, the severity of symptoms may help determine the best approach to management.¹³

Patients initially exhibit burning or throbbing pain, diffuse aching, sensitivity to touch or cold (allodynia), localized edema, and vasomotor disturbances of variable intensity that may produce altered color and temperature. Topical capsaicin cream; a tricyclic antidepressant; an anticonvulsant such as gabapentin (Neurontin), pregabalin, or lamotrigine (Lamictal); or a nonsteroidal anti-inflammatory drug should be tried first. Some of these treatments are poorly tolerated in elderly patients. If pain persists, nasal calcitonin may be added. Trigger-point injections with an anesthetic or glucocorticoid may be tried.

The management of early complex regional pain syndrome is sometimes supplemented with systemic corticosteroids, but reviews of randomized controlled trials have failed to show efficacy.¹⁴

Later in the course, patients may suffer persistent soft-tissue edema, accompanied by thickening of the skin and periarticular soft tissues, muscle wasting, and the skin changes of brawny edema. Regional blockade of sympathetic ganglions, epidural administration of clonidine, implantable peripheral nerve stimulators, and spinal cord stimulators have all been applied by experts in pain management and may provide benefit. Progression of the syndrome may include cyanosis, mottling, increased sweating, abnormal hair growth, and diffuse swelling in nonarticular tissue.

It is always acceptable to refer to an experienced pain management specialist, and a multidisciplinary approach is recommended at the outset.¹²

OUR PATIENT’S CARE CONTINUED

Our patient’s forearm and wrist were placed in a sling to keep his left arm elevated when active. This helped control sympathetic vascular edema and throbbing pain. Physical therapy with range-of-motion exercises prevented contracture.

He was discharged home on limited oxycodone as needed, with close follow-up by his primary care physician to monitor his pain symptoms. The pain and swelling slowly improved over the next 2 months, but he suffered a fall, twisting his left wrist. This minor injury was followed by more intense pain and swelling of the forearm, hand, and wrist.

COMORBIDITIES

5. Which of the following statements about conditions associated with complex regional pain syndrome most likely applies to our patient?

• Gout is likely following minor trauma
• Minor trauma or surgical bone biopsy may reactivate complex regional pain syndrome
• Septic hip arthritis due to MRSA may have reemerged and seeded the wrist
• Patients with multiple sclerosis have a propensity for complex regional pain syndrome
• Complex regional pain syndrome type 1 begets type 2

Gout does follow minor injury, but our patient’s uric acid was well controlled on allopurinol (Zyloprim), and gout is unlikely to be causing polyarticular swelling of the hand, wrist, and forearm.

Minor trauma, sometimes inconsequential enough to have been completely forgotten, may either initiate complex regional pain syndrome or, as seen here, reactivate it. Bone changes seen on MRI sometimes trigger surgical bone biopsy, only to reactivate the dysesthesia and sympathetic vascular reaction. Surgery should be avoided. Trauma and surgery are causative rather than associative comorbidities.

Sepsis due to MRSA after total hip arthroplasty may be reactivated, especially in the setting of immunosuppressive treatment. But the diffuse bone changes seen in multiple carpal, radial, and ulnar bones suggest generalized vascular and sympathetic disarray, most consistent with complex regional pain syndrome type 1.

AN ASSOCIATION WITH MULTIPLE SCLEROSIS?

Multiple sclerosis and other central neuropathic conditions such as stroke are associated with complex regional pain syndrome type 1.^15,16

A hypothetical cause for the higher prevalence of complex regional pain syndrome in patients with multiple sclerosis may be demyelination resulting in aberrant signaling and overreaction to distal pain receptors. Demyelination of neurons within the autonomic or spinothalamic tracts potentially increases susceptibility to development of the pain syndrome.

Our patient had an apparent stimulus for the development of the syndrome, ie, the initial dog bite, and the wrist injury later may have caused peripheral nerve injury. Such injury may lead to release of vasodilatory neuropeptides including substance P from stimulated cutaneous nerves with cell bodies in the dorsal root ganglia. Excessive vasodilation and increased vascular permeability result in the affected limb becoming edematous and causing cutaneous nerves to be further activated. Stimulated cutaneous neurons normally have an inhibitory influence on sympathetic activity at the level of entry of the dorsal root ganglia in the cord. In complex regional pain syndrome, this inhibition is lost, resulting in a hyperactive somatosympathetic reflex.¹⁷ Underlying multiple sclerosis may have contributed to the loss of inhibition by the cutaneous nerves on the sympathetic system.

CASE CONCLUDED

We continued to closely follow this patient, who was on a self-directed program of physical therapy. One year after the original dog bite, the complex regional pain syndrome had completely resolved.

A 48-year-old man with gout, multiple sclerosis, and previously treated methicillin-resistant Staphylococcus aureus (MRSA) infection presented to the emergency room with pain and significant swelling at the site of a dog bite on his left forearm. He had been bitten 2 weeks earlier by a friend’s dog, and the bite had punctured the skin. He also had red streaking on the skin of the left arm from the wrist to the elbow, and he reported feeling “feverish” and having night sweats.

At first, the bite had seemed to improve, then swelling and pain had developed and increased. He reported this to his primary care physician, along with the information that he had previously had an anaphylactic reaction to penicillin and a cephalosporin. His physician, considering a penicillin allergy, started him on ciprofloxacin (Cipro) plus clindamycin (Cleocin). The patient took this for 5 days, but without improvement. The appearance of the red streaking on his left forearm prompted his presentation to our emergency room.

ORGANISMS IN DOG BITES

1. Which is the most common cause of infected dog bite?

• Pasteurella canis
• Streptococci and S aureus
• Erysipelothrix rhusiopathiae
• Capnocytophaga canimorsus
• Eikenella corrodens

Streptococci (50%) and S aureus (20% to 40%) are the organisms most commonly responsible for infected dog bites, as they are for other skin and soft-tissue infections.¹P canis is unique to dog bite infections but accounts for only 18%.²E rhusiopathiae is an unusual isolate from cat and dog bites and is more commonly isolated from the mouths of fish and aquatic mammals. C canimorsus is a normal inhabitant of the oral cavity of dogs and cats but an unusual cause of wound infection from a dog bite. It is notable for sepsis and central nervous system infections uniquely associated with veterinarians, dog owners, kennel workers, and mail carriers.³E corrodens infection is more common with human bites.⁴

THE EVALUATION BEGINS

On examination, the patient had marked edema of the left forearm and pain in the joints of the left hand. His temperature was 100.2°F (37.9°C). Because of the duration and severity of symptoms, the examining physician was concerned about septic arthritis of the wrist, and the patient was admitted to the hospital.

In the hospital, our patient was thermodynamically stable without documented fever or chills. There was no open wound to culture, and blood cultures were negative. Marked edema and joint involvement raised suspicion of erysipeloid. This “cousin” of erysipelas often involves the underlying joint, is associated with edema, and produces systemic manifestations of fever and arthralgia.

Radiography of the left forearm and hand demonstrated multiple foci of demineralization within the carpal bones and proximal radius, attributed to disuse. Magnetic resonance imaging (MRI) the next day showed multiple bone infarcts in the carpal bones and the distal radius, with synovitis and fluid in the carpal joints and without adjacent osteomyelitis. Fluid was also seen in the soft tissues in the ulnar aspect of the left wrist, and tenosynovitis involving the flexor carpi radialis tendon was noted.

Arthrocentesis of his left radiocarpal joint produced synovial fluid negative for crystals and negative on Gram stain; the fluid was also sent for culture. The patient’s tetanus immunization was current, and the dog was known to have been immunized against rabies.

ANTIBIOTICS FOR INFECTED DOG BITES

2. Which antibiotic regimen would you choose for this patient?

• Oral amoxicillin and clavulanate
• Meropenem
• Vancomycin, clindamycin, aztreonam
• Clindamycin and levofloxacin
• Clindamycin and trimethoprim-sulfamethoxazole

Oral amoxicillin and clavulanate (Augmentin) is a judicious choice for prophylactic treatment of deep bites in the early stages of infection. However, our patient’s wound was no longer in the early stages of infection, and he had a history of an adverse reaction to penicillin.

Meropenem (Merrem IV) cross-reacts minimally with penicillin allergy and is reported to be safe in patients with a history of anaphylactic reactions to penicillin,⁵ but overuse of carbapenems has led to the development of carbapenem-resistant strains of Klebsiella, Stenotrophomonas, and Acinetobacter organisms.

Given the rise of MRSA infections and the common involvement of staphylococci, streptococci, and anaerobic bacteria in complicated dog bites, the combination of vancomycin and clindamycin is a good choice, and aztreonam (Azactam) would add empiric coverage of gram-negative enteric organisms.

Levofloxacin (Levaquin) also covers gramnegative enteric organisms, but Fusobacterium canifelinum, a common anaerobe in the oral flora of dogs and cats, is intrinsically resistant to fluoroquinolones.

Clindamycin and levofloxacin would be a good step-down oral regimen. Pasteurella multocida has variable sensitivity to the commonly used agents dicloxacillin (Dynapen), cephalexin (Keflex), macrolides, and clindamycin, but it is a less likely pathogen at this late stage and could be covered with levofloxacin alone.

C canimorsus is resistant to trimethoprim-sulfamethoxazole (Bactrim) and cephalexin, but is well covered by clindamycin.⁶

CASE CONTINUED

Our patient was started on intravenous vancomycin, clindamycin, and aztreonam for coverage of dog-mouth flora. Blood cultures and cultures of synovial fluid of the left wrist were negative. Vancomycin was discontinued after 48 hours when blood cultures did not grow staphylococcal organisms, but clindamycin and aztreonam were continued for a total of 8 days to treat possible infection with anaerobic and gram-negative enteric pathogens.

To test for autonomic dysfunction, a plastic pen case drawn lightly across each forearm revealed a loss of tactile adherence (ie, areas where moist, sweaty skin impeded the movement of the pen case) on the affected forearm, a sign of underlying nerve injury. The affected forearm was sensitive to light touch, with pain out of proportion to the stimulus.

ARRIVING AT THE DIAGNOSIS

Based on the wide distribution of inflammation, autonomic dysfunction (shown by differences in temperature and sweating), radiographic evidence of demineralization, hyperesthesia, and lack of improvement in pain and swelling after two courses of antibiotics, the patient’s clinical course was determined to be consistent with complex regional pain syndrome type 1, previously referred to as reflex sympathetic dystrophy.

Symptoms of complex regional pain syndrome traditionally include pain, regional edema, joint stiffness, muscular atrophy, vasomotor disturbances (causing temperature variability and erythema), regional diaphoresis, and localized skeletal demineralization on radiography.

Complex regional pain syndrome type 1 occurs as regional pain and inflammation as an excessive sympathetic reaction to an often minor insult, without nerve injury. When the syndrome occurs in a patient with obvious partial nerve injury, it is categorized as type 2 (formerly known as causalgia). The two types are clinically indistinguishable and are not uncommon. About 10% of all patients with complex regional pain syndrome have obvious nerve injury (complex regional pain syndrome type 2). In a study of 109 patients with Colles fracture, 25% developed symptoms of complex regional pain syndrome.⁷

Complex regional pain syndrome is difficult to diagnose, as it resembles many other ailments, such as gout, infection, bone tumor, stress fracture, and arthritis. Its pathophysiology is poorly understood, but it is believed to result from a “short circuit” in the reflex arc between somatic afferent sensory fibers and autonomic sympathetic efferent fibers, and this is thought to explain the increased sympathetic stimulation.

Although the pathophysiology is likely the same in type 1 and type 2, electromyography with a nerve conduction study is a reliable way to detect nerve damage and thus distinguish between the two types of complex regional pain syndrome.⁸

Our understanding of this syndrome is evolving. A recent study using sensory testing showed that 33% of patients with type 1 had combinations of increased and decreased thresholds for the detection of thermal, vibratory, and mechanical stimuli in the distribution of discrete peripheral nerves, suggesting that the patients actually had type 2.⁹

CONFIRMING COMPLEX REGIONAL PAIN SYNDROME TYPE 1

3. Which of the following is the best way to confirm complex regional pain syndrome type 1?

• Erythrocyte sedimentation rate, C-reactive protein, and complete blood cell count
• Plain radiography of the hand and forearm
• Three-phase technetium bone scan
• The Budapest diagnostic criteria
• MRI
• Autonomic testing

Complex regional pain syndrome type 1 is a clinical diagnosis. Diagnostic studies lack sensitivity and specificity but may confirm complex regional pain syndrome type 1 or rule out other diagnoses. The Budapest diagnostic criteria¹⁰ (Table 1) may be the best way to confirm this diagnosis. The criteria are as follows: continuing pain disproportionate to an inciting event, coupled with three of four symptoms plus at least one sign from sensory, vasomotor, sudomotor, and motor-trophic categories.

Laboratory tests are not helpful because acute-phase reactants and blood counts remain normal in these patients.

Plain radiography is not sensitive in early diagnosis, but at 2 weeks it may show patchy areas of osteopenia in adjacent bones throughout the region, as well as subsequent diffuse demineralization.

Three-phase bone scanning is more sensitive than plain radiography, with 75% of patients showing regional disparities in blood flow in early sequences and increased bone uptake in the later sequences.

MRI is a sensitive early test, as it better defines focal areas of bone loss and increased T2 bone signal in adjacent bone, as well as early soft-tissue changes. Computed tomography does not show early specific changes in muscle, tendon, or bone and so is not recommended.

THE EVALUATION CONTINUES

The admitting diagnosis was septic arthritis, and our patient underwent computed tomography, which showed focal demineralization that could have represented bone infarcts or infection, confounding the diagnosis of complex regional pain syndrome.

Autonomic nerve testing can help distinguish complex regional pain syndrome from other disorders. Complex regional pain syndrome is characterized by increased sympathetic activity and results in increased sweat output. Autonomic testing includes resting sweat output, resting skin temperature, and quantitative sudomotor axon reflex testing. In one study, an increase in resting sweat output used in conjunction with quantitative sudomotor axon reflex testing predicted the diagnosis of complex regional pain syndrome with a specificity of 98%.¹¹ However, autonomic testing is limited to academic centers and is not readily available.

TREATING COMPLEX REGIONAL PAIN SYNDROME TYPE 1

4. Which is the best first-line therapy for complex regional pain syndrome type 1?

• Stellate ganglion nerve block
• Occupational therapy to splint the wrist and forearm
• Oral corticosteroids
• Physical therapy to prevent loss of joint motion
• Tricyclic antidepressant drugs (eg, amitriptyline), pregabalin, and bisphosphonates

Physical therapy should be started early in all patients, with range-of-motion exercises to prevent contracture and enhance mobility.

Stellate ganglion nerve block has been used to counter severe sympathetic hyperactivity, but it also may aggravate symptoms of complex regional pain syndrome and so remains a controversial treatment.

Immobilization and splinting should be avoided, as this will augment edema, pain, and contracture of joints.

Corticosteroids do not shorten the course or assuage symptoms and may increase edema.

Amitriptyline (Elavil) and pregabalin (Lyrica) have been used successfully to counter extended courses of allodynia and hyperalgesia. Bisphosphonates may decrease bone loss and pain and may be needed should the course be complicated by myositis ossificans, a form of dystrophic bone formation in juxtaposed tendon and muscle related to neuroactivation of fibroblasts and osteoblasts.

THE COURSE OF COMPLEX REGIONAL PAIN SYNDROME

Traditionally, type 1 was divided into three stages—an early inflammatory stage, a dystrophic stage, and a late atrophic stage.¹² Although there is no evidence to support a consistent three-stage evolution, the severity of symptoms may help determine the best approach to management.¹³

Patients initially exhibit burning or throbbing pain, diffuse aching, sensitivity to touch or cold (allodynia), localized edema, and vasomotor disturbances of variable intensity that may produce altered color and temperature. Topical capsaicin cream; a tricyclic antidepressant; an anticonvulsant such as gabapentin (Neurontin), pregabalin, or lamotrigine (Lamictal); or a nonsteroidal anti-inflammatory drug should be tried first. Some of these treatments are poorly tolerated in elderly patients. If pain persists, nasal calcitonin may be added. Trigger-point injections with an anesthetic or glucocorticoid may be tried.

The management of early complex regional pain syndrome is sometimes supplemented with systemic corticosteroids, but reviews of randomized controlled trials have failed to show efficacy.¹⁴

Later in the course, patients may suffer persistent soft-tissue edema, accompanied by thickening of the skin and periarticular soft tissues, muscle wasting, and the skin changes of brawny edema. Regional blockade of sympathetic ganglions, epidural administration of clonidine, implantable peripheral nerve stimulators, and spinal cord stimulators have all been applied by experts in pain management and may provide benefit. Progression of the syndrome may include cyanosis, mottling, increased sweating, abnormal hair growth, and diffuse swelling in nonarticular tissue.

It is always acceptable to refer to an experienced pain management specialist, and a multidisciplinary approach is recommended at the outset.¹²

OUR PATIENT’S CARE CONTINUED

Our patient’s forearm and wrist were placed in a sling to keep his left arm elevated when active. This helped control sympathetic vascular edema and throbbing pain. Physical therapy with range-of-motion exercises prevented contracture.

He was discharged home on limited oxycodone as needed, with close follow-up by his primary care physician to monitor his pain symptoms. The pain and swelling slowly improved over the next 2 months, but he suffered a fall, twisting his left wrist. This minor injury was followed by more intense pain and swelling of the forearm, hand, and wrist.

COMORBIDITIES

5. Which of the following statements about conditions associated with complex regional pain syndrome most likely applies to our patient?

• Gout is likely following minor trauma
• Minor trauma or surgical bone biopsy may reactivate complex regional pain syndrome
• Septic hip arthritis due to MRSA may have reemerged and seeded the wrist
• Patients with multiple sclerosis have a propensity for complex regional pain syndrome
• Complex regional pain syndrome type 1 begets type 2

Gout does follow minor injury, but our patient’s uric acid was well controlled on allopurinol (Zyloprim), and gout is unlikely to be causing polyarticular swelling of the hand, wrist, and forearm.

Minor trauma, sometimes inconsequential enough to have been completely forgotten, may either initiate complex regional pain syndrome or, as seen here, reactivate it. Bone changes seen on MRI sometimes trigger surgical bone biopsy, only to reactivate the dysesthesia and sympathetic vascular reaction. Surgery should be avoided. Trauma and surgery are causative rather than associative comorbidities.

Sepsis due to MRSA after total hip arthroplasty may be reactivated, especially in the setting of immunosuppressive treatment. But the diffuse bone changes seen in multiple carpal, radial, and ulnar bones suggest generalized vascular and sympathetic disarray, most consistent with complex regional pain syndrome type 1.

AN ASSOCIATION WITH MULTIPLE SCLEROSIS?

Multiple sclerosis and other central neuropathic conditions such as stroke are associated with complex regional pain syndrome type 1.^15,16

A hypothetical cause for the higher prevalence of complex regional pain syndrome in patients with multiple sclerosis may be demyelination resulting in aberrant signaling and overreaction to distal pain receptors. Demyelination of neurons within the autonomic or spinothalamic tracts potentially increases susceptibility to development of the pain syndrome.

Our patient had an apparent stimulus for the development of the syndrome, ie, the initial dog bite, and the wrist injury later may have caused peripheral nerve injury. Such injury may lead to release of vasodilatory neuropeptides including substance P from stimulated cutaneous nerves with cell bodies in the dorsal root ganglia. Excessive vasodilation and increased vascular permeability result in the affected limb becoming edematous and causing cutaneous nerves to be further activated. Stimulated cutaneous neurons normally have an inhibitory influence on sympathetic activity at the level of entry of the dorsal root ganglia in the cord. In complex regional pain syndrome, this inhibition is lost, resulting in a hyperactive somatosympathetic reflex.¹⁷ Underlying multiple sclerosis may have contributed to the loss of inhibition by the cutaneous nerves on the sympathetic system.

CASE CONCLUDED

We continued to closely follow this patient, who was on a self-directed program of physical therapy. One year after the original dog bite, the complex regional pain syndrome had completely resolved.

A 48-year-old man with gout, multiple sclerosis, and previously treated methicillin-resistant Staphylococcus aureus (MRSA) infection presented to the emergency room with pain and significant swelling at the site of a dog bite on his left forearm. He had been bitten 2 weeks earlier by a friend’s dog, and the bite had punctured the skin. He also had red streaking on the skin of the left arm from the wrist to the elbow, and he reported feeling “feverish” and having night sweats.

At first, the bite had seemed to improve, then swelling and pain had developed and increased. He reported this to his primary care physician, along with the information that he had previously had an anaphylactic reaction to penicillin and a cephalosporin. His physician, considering a penicillin allergy, started him on ciprofloxacin (Cipro) plus clindamycin (Cleocin). The patient took this for 5 days, but without improvement. The appearance of the red streaking on his left forearm prompted his presentation to our emergency room.

ORGANISMS IN DOG BITES

1. Which is the most common cause of infected dog bite?

• Pasteurella canis
• Streptococci and S aureus
• Erysipelothrix rhusiopathiae
• Capnocytophaga canimorsus
• Eikenella corrodens

Streptococci (50%) and S aureus (20% to 40%) are the organisms most commonly responsible for infected dog bites, as they are for other skin and soft-tissue infections.¹P canis is unique to dog bite infections but accounts for only 18%.²E rhusiopathiae is an unusual isolate from cat and dog bites and is more commonly isolated from the mouths of fish and aquatic mammals. C canimorsus is a normal inhabitant of the oral cavity of dogs and cats but an unusual cause of wound infection from a dog bite. It is notable for sepsis and central nervous system infections uniquely associated with veterinarians, dog owners, kennel workers, and mail carriers.³E corrodens infection is more common with human bites.⁴

THE EVALUATION BEGINS

On examination, the patient had marked edema of the left forearm and pain in the joints of the left hand. His temperature was 100.2°F (37.9°C). Because of the duration and severity of symptoms, the examining physician was concerned about septic arthritis of the wrist, and the patient was admitted to the hospital.

In the hospital, our patient was thermodynamically stable without documented fever or chills. There was no open wound to culture, and blood cultures were negative. Marked edema and joint involvement raised suspicion of erysipeloid. This “cousin” of erysipelas often involves the underlying joint, is associated with edema, and produces systemic manifestations of fever and arthralgia.

Radiography of the left forearm and hand demonstrated multiple foci of demineralization within the carpal bones and proximal radius, attributed to disuse. Magnetic resonance imaging (MRI) the next day showed multiple bone infarcts in the carpal bones and the distal radius, with synovitis and fluid in the carpal joints and without adjacent osteomyelitis. Fluid was also seen in the soft tissues in the ulnar aspect of the left wrist, and tenosynovitis involving the flexor carpi radialis tendon was noted.

Arthrocentesis of his left radiocarpal joint produced synovial fluid negative for crystals and negative on Gram stain; the fluid was also sent for culture. The patient’s tetanus immunization was current, and the dog was known to have been immunized against rabies.

ANTIBIOTICS FOR INFECTED DOG BITES

2. Which antibiotic regimen would you choose for this patient?

• Oral amoxicillin and clavulanate
• Meropenem
• Vancomycin, clindamycin, aztreonam
• Clindamycin and levofloxacin
• Clindamycin and trimethoprim-sulfamethoxazole

Oral amoxicillin and clavulanate (Augmentin) is a judicious choice for prophylactic treatment of deep bites in the early stages of infection. However, our patient’s wound was no longer in the early stages of infection, and he had a history of an adverse reaction to penicillin.

Meropenem (Merrem IV) cross-reacts minimally with penicillin allergy and is reported to be safe in patients with a history of anaphylactic reactions to penicillin,⁵ but overuse of carbapenems has led to the development of carbapenem-resistant strains of Klebsiella, Stenotrophomonas, and Acinetobacter organisms.

Given the rise of MRSA infections and the common involvement of staphylococci, streptococci, and anaerobic bacteria in complicated dog bites, the combination of vancomycin and clindamycin is a good choice, and aztreonam (Azactam) would add empiric coverage of gram-negative enteric organisms.

Levofloxacin (Levaquin) also covers gramnegative enteric organisms, but Fusobacterium canifelinum, a common anaerobe in the oral flora of dogs and cats, is intrinsically resistant to fluoroquinolones.

Clindamycin and levofloxacin would be a good step-down oral regimen. Pasteurella multocida has variable sensitivity to the commonly used agents dicloxacillin (Dynapen), cephalexin (Keflex), macrolides, and clindamycin, but it is a less likely pathogen at this late stage and could be covered with levofloxacin alone.

C canimorsus is resistant to trimethoprim-sulfamethoxazole (Bactrim) and cephalexin, but is well covered by clindamycin.⁶

CASE CONTINUED

Our patient was started on intravenous vancomycin, clindamycin, and aztreonam for coverage of dog-mouth flora. Blood cultures and cultures of synovial fluid of the left wrist were negative. Vancomycin was discontinued after 48 hours when blood cultures did not grow staphylococcal organisms, but clindamycin and aztreonam were continued for a total of 8 days to treat possible infection with anaerobic and gram-negative enteric pathogens.

To test for autonomic dysfunction, a plastic pen case drawn lightly across each forearm revealed a loss of tactile adherence (ie, areas where moist, sweaty skin impeded the movement of the pen case) on the affected forearm, a sign of underlying nerve injury. The affected forearm was sensitive to light touch, with pain out of proportion to the stimulus.

ARRIVING AT THE DIAGNOSIS

Based on the wide distribution of inflammation, autonomic dysfunction (shown by differences in temperature and sweating), radiographic evidence of demineralization, hyperesthesia, and lack of improvement in pain and swelling after two courses of antibiotics, the patient’s clinical course was determined to be consistent with complex regional pain syndrome type 1, previously referred to as reflex sympathetic dystrophy.

Symptoms of complex regional pain syndrome traditionally include pain, regional edema, joint stiffness, muscular atrophy, vasomotor disturbances (causing temperature variability and erythema), regional diaphoresis, and localized skeletal demineralization on radiography.

Complex regional pain syndrome type 1 occurs as regional pain and inflammation as an excessive sympathetic reaction to an often minor insult, without nerve injury. When the syndrome occurs in a patient with obvious partial nerve injury, it is categorized as type 2 (formerly known as causalgia). The two types are clinically indistinguishable and are not uncommon. About 10% of all patients with complex regional pain syndrome have obvious nerve injury (complex regional pain syndrome type 2). In a study of 109 patients with Colles fracture, 25% developed symptoms of complex regional pain syndrome.⁷

Complex regional pain syndrome is difficult to diagnose, as it resembles many other ailments, such as gout, infection, bone tumor, stress fracture, and arthritis. Its pathophysiology is poorly understood, but it is believed to result from a “short circuit” in the reflex arc between somatic afferent sensory fibers and autonomic sympathetic efferent fibers, and this is thought to explain the increased sympathetic stimulation.

Although the pathophysiology is likely the same in type 1 and type 2, electromyography with a nerve conduction study is a reliable way to detect nerve damage and thus distinguish between the two types of complex regional pain syndrome.⁸

Our understanding of this syndrome is evolving. A recent study using sensory testing showed that 33% of patients with type 1 had combinations of increased and decreased thresholds for the detection of thermal, vibratory, and mechanical stimuli in the distribution of discrete peripheral nerves, suggesting that the patients actually had type 2.⁹

CONFIRMING COMPLEX REGIONAL PAIN SYNDROME TYPE 1

3. Which of the following is the best way to confirm complex regional pain syndrome type 1?

• Erythrocyte sedimentation rate, C-reactive protein, and complete blood cell count
• Plain radiography of the hand and forearm
• Three-phase technetium bone scan
• The Budapest diagnostic criteria
• MRI
• Autonomic testing

Complex regional pain syndrome type 1 is a clinical diagnosis. Diagnostic studies lack sensitivity and specificity but may confirm complex regional pain syndrome type 1 or rule out other diagnoses. The Budapest diagnostic criteria¹⁰ (Table 1) may be the best way to confirm this diagnosis. The criteria are as follows: continuing pain disproportionate to an inciting event, coupled with three of four symptoms plus at least one sign from sensory, vasomotor, sudomotor, and motor-trophic categories.

Laboratory tests are not helpful because acute-phase reactants and blood counts remain normal in these patients.

Plain radiography is not sensitive in early diagnosis, but at 2 weeks it may show patchy areas of osteopenia in adjacent bones throughout the region, as well as subsequent diffuse demineralization.

Three-phase bone scanning is more sensitive than plain radiography, with 75% of patients showing regional disparities in blood flow in early sequences and increased bone uptake in the later sequences.

MRI is a sensitive early test, as it better defines focal areas of bone loss and increased T2 bone signal in adjacent bone, as well as early soft-tissue changes. Computed tomography does not show early specific changes in muscle, tendon, or bone and so is not recommended.

THE EVALUATION CONTINUES

The admitting diagnosis was septic arthritis, and our patient underwent computed tomography, which showed focal demineralization that could have represented bone infarcts or infection, confounding the diagnosis of complex regional pain syndrome.

Autonomic nerve testing can help distinguish complex regional pain syndrome from other disorders. Complex regional pain syndrome is characterized by increased sympathetic activity and results in increased sweat output. Autonomic testing includes resting sweat output, resting skin temperature, and quantitative sudomotor axon reflex testing. In one study, an increase in resting sweat output used in conjunction with quantitative sudomotor axon reflex testing predicted the diagnosis of complex regional pain syndrome with a specificity of 98%.¹¹ However, autonomic testing is limited to academic centers and is not readily available.

TREATING COMPLEX REGIONAL PAIN SYNDROME TYPE 1

4. Which is the best first-line therapy for complex regional pain syndrome type 1?

• Stellate ganglion nerve block
• Occupational therapy to splint the wrist and forearm
• Oral corticosteroids
• Physical therapy to prevent loss of joint motion
• Tricyclic antidepressant drugs (eg, amitriptyline), pregabalin, and bisphosphonates

Physical therapy should be started early in all patients, with range-of-motion exercises to prevent contracture and enhance mobility.

Stellate ganglion nerve block has been used to counter severe sympathetic hyperactivity, but it also may aggravate symptoms of complex regional pain syndrome and so remains a controversial treatment.

Immobilization and splinting should be avoided, as this will augment edema, pain, and contracture of joints.

Corticosteroids do not shorten the course or assuage symptoms and may increase edema.

Amitriptyline (Elavil) and pregabalin (Lyrica) have been used successfully to counter extended courses of allodynia and hyperalgesia. Bisphosphonates may decrease bone loss and pain and may be needed should the course be complicated by myositis ossificans, a form of dystrophic bone formation in juxtaposed tendon and muscle related to neuroactivation of fibroblasts and osteoblasts.

THE COURSE OF COMPLEX REGIONAL PAIN SYNDROME

Traditionally, type 1 was divided into three stages—an early inflammatory stage, a dystrophic stage, and a late atrophic stage.¹² Although there is no evidence to support a consistent three-stage evolution, the severity of symptoms may help determine the best approach to management.¹³

Patients initially exhibit burning or throbbing pain, diffuse aching, sensitivity to touch or cold (allodynia), localized edema, and vasomotor disturbances of variable intensity that may produce altered color and temperature. Topical capsaicin cream; a tricyclic antidepressant; an anticonvulsant such as gabapentin (Neurontin), pregabalin, or lamotrigine (Lamictal); or a nonsteroidal anti-inflammatory drug should be tried first. Some of these treatments are poorly tolerated in elderly patients. If pain persists, nasal calcitonin may be added. Trigger-point injections with an anesthetic or glucocorticoid may be tried.

The management of early complex regional pain syndrome is sometimes supplemented with systemic corticosteroids, but reviews of randomized controlled trials have failed to show efficacy.¹⁴

Later in the course, patients may suffer persistent soft-tissue edema, accompanied by thickening of the skin and periarticular soft tissues, muscle wasting, and the skin changes of brawny edema. Regional blockade of sympathetic ganglions, epidural administration of clonidine, implantable peripheral nerve stimulators, and spinal cord stimulators have all been applied by experts in pain management and may provide benefit. Progression of the syndrome may include cyanosis, mottling, increased sweating, abnormal hair growth, and diffuse swelling in nonarticular tissue.

It is always acceptable to refer to an experienced pain management specialist, and a multidisciplinary approach is recommended at the outset.¹²

OUR PATIENT’S CARE CONTINUED

Our patient’s forearm and wrist were placed in a sling to keep his left arm elevated when active. This helped control sympathetic vascular edema and throbbing pain. Physical therapy with range-of-motion exercises prevented contracture.

He was discharged home on limited oxycodone as needed, with close follow-up by his primary care physician to monitor his pain symptoms. The pain and swelling slowly improved over the next 2 months, but he suffered a fall, twisting his left wrist. This minor injury was followed by more intense pain and swelling of the forearm, hand, and wrist.

COMORBIDITIES

5. Which of the following statements about conditions associated with complex regional pain syndrome most likely applies to our patient?

• Gout is likely following minor trauma
• Minor trauma or surgical bone biopsy may reactivate complex regional pain syndrome
• Septic hip arthritis due to MRSA may have reemerged and seeded the wrist
• Patients with multiple sclerosis have a propensity for complex regional pain syndrome
• Complex regional pain syndrome type 1 begets type 2

Gout does follow minor injury, but our patient’s uric acid was well controlled on allopurinol (Zyloprim), and gout is unlikely to be causing polyarticular swelling of the hand, wrist, and forearm.

Minor trauma, sometimes inconsequential enough to have been completely forgotten, may either initiate complex regional pain syndrome or, as seen here, reactivate it. Bone changes seen on MRI sometimes trigger surgical bone biopsy, only to reactivate the dysesthesia and sympathetic vascular reaction. Surgery should be avoided. Trauma and surgery are causative rather than associative comorbidities.

Sepsis due to MRSA after total hip arthroplasty may be reactivated, especially in the setting of immunosuppressive treatment. But the diffuse bone changes seen in multiple carpal, radial, and ulnar bones suggest generalized vascular and sympathetic disarray, most consistent with complex regional pain syndrome type 1.

AN ASSOCIATION WITH MULTIPLE SCLEROSIS?

Multiple sclerosis and other central neuropathic conditions such as stroke are associated with complex regional pain syndrome type 1.^15,16

A hypothetical cause for the higher prevalence of complex regional pain syndrome in patients with multiple sclerosis may be demyelination resulting in aberrant signaling and overreaction to distal pain receptors. Demyelination of neurons within the autonomic or spinothalamic tracts potentially increases susceptibility to development of the pain syndrome.

Our patient had an apparent stimulus for the development of the syndrome, ie, the initial dog bite, and the wrist injury later may have caused peripheral nerve injury. Such injury may lead to release of vasodilatory neuropeptides including substance P from stimulated cutaneous nerves with cell bodies in the dorsal root ganglia. Excessive vasodilation and increased vascular permeability result in the affected limb becoming edematous and causing cutaneous nerves to be further activated. Stimulated cutaneous neurons normally have an inhibitory influence on sympathetic activity at the level of entry of the dorsal root ganglia in the cord. In complex regional pain syndrome, this inhibition is lost, resulting in a hyperactive somatosympathetic reflex.¹⁷ Underlying multiple sclerosis may have contributed to the loss of inhibition by the cutaneous nerves on the sympathetic system.

CASE CONCLUDED

We continued to closely follow this patient, who was on a self-directed program of physical therapy. One year after the original dog bite, the complex regional pain syndrome had completely resolved.

A 20-year-old woman presents to the emergency department with fatigue and the sudden onset of palpitations. She reports no history of significant illness or surgery. She says she is not currently taking prescription or over-the-counter medications. She does not smoke, drink alcohol, or use illicit drugs.

Her weight is 52 kg (115 lb), her height is 170 cm (67 in), and her body mass index (BMI) is 18 kg/m². Vital signs: temperature 35.7°C (96.4°F), blood pressure 92/48 mm Hg, heart rate 73 bpm, respiratory rate 5 breaths per minute, and oxygen saturation 98% on room air.

She appears tired but is alert, conversant, and cooperative. Her skin is normal, and dentition is fair. Her pulse is regular, and respirations are slow. The abdomen is soft, non-tender, and flat. Strength is 4 on a scale of 5 in all extremities. Deep-tendon reflexes are 2+ and symmetric.

Electrocardiography (Figure 1) in the emergency department shows ST-segment depression, a prolonged corrected QT interval of 665 msec, T-wave inversion, PR prolongation, increased P-wave amplitude, and U waves.

1. Which electrolyte abnormality is associated with this electrocardiographic picture?

• Hypercalcemia
• Hyperkalemia
• Hypocalcemia
• Hypokalemia

Hypokalemia is the likely cause of these findings. The finding of U waves is considered significant when they are inverted, merged with the T wave, or have an amplitude greater than the T wave.¹ U waves are best seen in the precordial leads. When severe, hypokalemia can lead to potentially fatal arrhythmias such as high-grade atrioventricular block, ventricular tachycardia, and ventricular fibrillation.²

Hyperkalemia is associated with peaked T waves, a prolonged PR interval, decreased P wave amplitude, and a widened QRS complex.² When acute and severe, hyperkalemia is associated with ventricular arrhythmia.

Hypocalcemia is associated with a prolonged QT interval and ventricular dysrhythmia, but not U waves.²

Hypercalcemia is associated with bradydysrhythmia, as well as with a shortened QT interval.²

LABORATORY TESTING

Laboratory testing shows the following:

• Sodium 126 mmol/L (reference range 135–145)
• Potassium 1.5 mmol/L (3.5–5.1)
• Chloride 58 mmol/L (100–110)
• Bicarbonate 62 mmol/L (20–30)
• Blood urea nitrogen 16 mg/dL (7–18)
• Creatinine 0.8 mg/dL (0.5–1.0)
• Glucose 106 mg/dL (70–110)
• Ionized calcium 4.4 mg/dL (4.5–5.3)
• Magnesium 1.8 mg/dL (1.7–2.3)
• Phosphorus 4.1 mg/dL (2.5–4.5)
• Venous blood gases pH 7.56 (7.35–7.45), Pco₂ 69 mm Hg (35–45).

POTASSIUM HOMEOSTASIS

Ninety-eight percent of potassium is intracellular and only 2% is extracellular.³ The main cellular stores are myocytes and hepatocytes. Patients with decreased muscle mass may be at a higher risk of hypokalemia as a result of decreased skeletal muscle stores.⁴

The acute development of hypokalemia occurs from transcellular shifts. Alkalosis, insulin secretion, and beta-adrenergic stimulation promote the intracellular uptake of potassium. The major hormonal regulator of potassium excretion is aldosterone, which is stimulated by renal hypoperfusion and promotes potassium-ion secretion in the distal convoluted tubule.

Chronic hypokalemia develops in patients with ongoing renal or gastrointestinal potassium loss. If the cause of potassium loss is not elucidated by the history, the physical, and a review of medications, then one of two things is possible: either the patient has renal tubular disease affecting acid-base and potassium regulation, causing excessive mineralocorticoid secretion, which is associated with an abnormal response to aldosterone; or the patient is not being forthcoming in the history.

2. Which is the most likely cause of hypokalemia in this patient?

• Vomiting
• Liddle syndrome
• Bartter syndrome
• Gitelman syndrome
• Diuretic use

Her laboratory tests reveal hypokalemia and hyponatremic-hypochloremic metabolic alkalosis with compensatory respiratory acidosis. In metabolic alkalosis, the expected respiratory compensation is an increase of 0.7 mm Hg in Pco₂ for each 1-mEq/L increase in bicarbonate. Therefore, the expected Pco₂ is 67, close to the patient’s actual value of 69.

Protracted vomiting with loss of gastric acid juices could be a cause of the metabolic disturbances in this young woman, although she did not mention vomiting during the history.

Liddle syndrome, or pseudoaldosteronism, is a rare autosomal dominant disorder characterized by altered renal epithelial sodium channels, excessive sodium retention, and resultant hypertension. Hypokalemia and alkalosis are seen in Liddle syndrome, but the absence of hypertension in our patient makes Liddle syndrome unlikely.

Bartter syndrome is an inherited autosomal recessive disorder of the sodium-potassium-chloride cotransporter in the thick ascending loop of Henle, resulting in impaired reabsorption of chloride and sodium. Bartter syndrome mimics chronic loop-diuretic use and is associated with hypercalciuria. Bartter syndrome is possible in this patient; however, patients with Bartter syndrome are usually diagnosed in infancy or childhood and have evidence of growth impairment.

Gitelman syndrome is an autosomal recessive disorder of the thiazide-sensitive sodium-chloride cotransporter. Although Gitelman syndrome is more common than Bartter syndrome and presents at older ages, it is not usually associated with such profound metabolic alkalosis. Gitelman syndrome mimics chronic use of thiazide diuretics and is associated with hypocalciuria.

Diuretic use could also cause the metabolic disturbances described; however, the patient denied taking diuretics.

The most common cause of hypokalemia in clinical practice is diuretic use.⁴ In this young woman with unexplained hypokalemia, the most likely cause is either undisclosed self-induced vomiting or diuretic abuse. The degree of metabolic alkalosis suggests vomiting, since metabolic alkalosis this severe is usually seen only with protracted vomiting. Bartter and Gitelman syndromes are included in the differential diagnosis, but they are much less common than hypokalemia associated with diuretics or self-induced vomiting.⁵

3. Which test could help elucidate the cause of hypokalemia in this patient?

• Ratio of plasma aldosterone to rennin
• Urine chloride
• Ratio of urinary potassium to creatinine
• Urinary anion gap and urinary pH

APPROACH TO HYPOKALEMIA

Determining the cause of hypokalemia starts with a thorough history and physical examination. The history should focus on drugs such as diuretics and laxatives. Women should be asked about their menstrual history since irregular periods may suggest an eating disorder. The physical examination should focus on signs that suggest self-induced vomiting, such as dry skin, dental erosions, enlarged parotid glands, and calluses or scars on the knuckles.

Patients with an unclear cause of hypokalemia after a thorough history and physical examination can be categorized into one of three groups based on blood pressure and acid-base status:

• Hypokalemia, hypertension, metabolic alkalosis
• Hypokalemia, normal blood pressure, metabolic acidosis
• Hypokalemia, normal blood pressure, metabolic alkalosis.

Hypokalemia, hypertension, metabolic alkalosis

The blood pressure provides an important clue in the evaluation of hypokalemia. The combination of hypertension, hypokalemia, and alkalosis should raise concern for hyperaldosteronism or pseudoaldosteronism. Primary hyperaldosteronism from an adrenal adenoma (Conn syndrome) is characterized by a plasma aldosterone-renin ratio of greater than 20.^6,7 In contrast, patients with secondary hyperaldosteronism due to renovascular disease have a plasma aldosterone-renin ratio of less than 10. Patients with pseudoaldosteronism have low aldosterone and renin levels and hypertension. Since our patient has a normal blood pressure, testing the plasma aldosterone and renin levels would not help determine the cause of her hypokalemia.

Hypokalemia, normal blood pressure, metabolic acidosis

Patients with normal blood pressure, hypokalemia, and normal plasma anion gap acidosis either have renal tubular acidosis or have lost potassium because of diarrhea or laxative abuse. In a patient who denies taking laxatives or denies a history of diarrhea, checking the urinary anion gap and urinary pH may help differentiate the cause of acidosis and hypokalemia.

The urinary anion gap, calculated by the equation sodium + potassium − chloride, is an indirect estimate of hydrogen excretion in the form of ammonium ion⁸; the normal value is 0 to 10 mEq/L. A negative value represents increased hydrogen excretion in response to systemic acidosis from gastrointestinal or renal loss of bicarbonate (proximal renal tubular acidosis). A urinary pH greater than 5.5 in the setting of systemic acidosis suggests impaired ability of the kidneys to acidify urine and raises the possibility of renal tubular acidosis.

This patient has metabolic alkalosis, so calculation of the urinary anion gap would not be helpful.

Hypokalemia, normal blood pressure, metabolic alkalosis

Patients such as ours, with normal blood pressure, hypokalemia, and alkalosis, have been vomiting, have used diuretics, or have an inherited renal tubulopathy such as Bartter or Gitelman syndrome. Usually, differentiating Bartter and Gitelman syndromes from chronic vomiting or diuretic use is done with the history and physical examination. However, in patients with a questionable history and a lack of findings on physical examination, checking the urinary chloride, potassium, calcium, and creatinine may be helpful.

A urinary potassium-creatinine ratio greater than 15 suggests renal loss, whereas a ratio less than 15 suggests extrarenal loss.⁹

Patients who are taking a diuretic or who have Bartter or Gitelman syndrome have a high urinary chloride concentration, ie, greater than 20 mmol/L, whereas patients with hypokalemia and alkalosis from chronic vomiting tend to have a concentration less than 10 mmol/L.¹⁰

Table 1 summarizes an approach to the evaluation of unexplained hypokalemia based on blood pressure and acid-base status.

A HIDDEN HISTORY

On further questioning, the patient admits to an 8-year history of daily self-induced vomiting in an attempt to lose weight, in addition to multiple hospitalizations for hypokalemia and a previous diagnosis of an eating disorder.

INITIAL MANAGEMENT OF HYPOKALEMIA

The initial management of hypokalemia should focus on life-threatening emergencies. While patients with potassium levels greater than 3 mmol/L are usually asymptomatic, those with levels below 3 mmol/L present with muscle weakness and rhabdomyolysis.⁴ An acute drop in serum potassium to less than 2 mmol/L is associated with respiratory muscle weakness and ventricular arrhythmias.⁴ If the patient has cardiac symptoms or hypoventilation due to respiratory muscle weakness, continuous monitoring in the intensive care unit and aggressive therapy are warranted.

4. Which potassium formulation is most appropriate for the treatment of hypokalemia in this patient?

• Potassium chloride
• Potassium phosphate
• Potassium acetate

Oral potassium is preferable in patients with a serum potassium above 2.5 mmol/L.^4,11 Potassium phosphate should be used when supplementation with both potassium and phosphorus is needed. Potassium acetate should be reserved for patients with acidosis and hypokalemia. Otherwise, potassium chloride is typically preferred.^4,12 It comes in liquid and tablet forms. Liquid forms have an unpleasant taste, whereas tablets are usually well tolerated. No more than 20 to 40 mEq of potassium chloride tablets should be given at a time, since higher doses are associated with gastrointestinal mucosal injury.¹²

Potassium chloride is particularly preferred in patients with metabolic alkalosis, since increased chloride intake and delivery to the distal tubule increases the expression of pendrin, a luminal chloride and bicarbonate exchanger in the cortical collecting duct.¹³ With metabolic alkalosis, increased excretion of bicarbonate occurs through up-regulation of pendrin. Potassium depletion down-regulates pendrin.¹³ Additionally, correction of metabolic alkalosis increases serum potassium by movement of potassium from the intracellular to the extracellular space.

Intravenous potassium should be reserved for patients with severe hypokalemia (< 2.5 mmol/L) or significant arrhythmias.¹¹ Oral and intravenous potassium can safely be given simultaneously.¹¹ The intravenous rate should not exceed more than 10 to 20 mEq of potassium chloride per hour unless the patient has a life-threatening arrhythmia, respiratory failure, or severe hypokalemia.^14,15 In life-threatening situations, a femoral line should be placed, and potassium should be given as rapidly as 20 mEq over 15 to 20 minutes.¹⁴ Cannulation of the subclavian and internal jugular veins should be avoided in severe hypokalemia since mechanical irritation from guidewire placement can provoke ventricular arrhythmias.¹⁴

During intravenous administration of potassium, laboratory monitoring after every 20 mEq of potassium chloride is advised because of the possibility of rebound hyperkalemia. In patients with severe hypokalemia, avoidance of factors that can worsen intracellular shift of potassium is also important. Avoid dextrose-containing fluids to prevent insulin-induced shifting of potassium into cells. Restore intravascular volume to blunt hypovolemia-induced renin and aldosterone secretion. If a patient presents with severe hypokalemia and acidosis, correct the hypokalemia before the acidosis to avoid intracellular shift of potassium.

OUR PATIENT’S MANAGEMENT AND FOLLOW-UP PLAN

Given the severity of our patient’s hypokalemia and her complaint of palpitations, she was admitted to the hospital for monitoring. She required 180 mEq of intravenous potassium chloride and 140 mEq of oral potassium chloride during the first 24 hours in order to achieve a serum potassium level above 3 mmol/L. Electrocardiographic U waves resolved once the level was above 2 mmol/L, and ST depressions resolved once it was above 3 mmol/L. The QT interval normalized after 24 hours of hospitalization.

On discharge, she was prescribed oral potassium chloride 40 mEq daily and magnesium sulfate 400 mg twice daily, with plans for a followup visit with her outpatient therapy team, which includes a psychiatrist, a social worker, and her primary care provider. She declined a referral for inpatient therapy but agreed to a goal of decreasing the frequency of induced vomiting and outpatient visits. She was also educated on how and when to access emergency medical care.¹⁶

A 20-year-old woman presents to the emergency department with fatigue and the sudden onset of palpitations. She reports no history of significant illness or surgery. She says she is not currently taking prescription or over-the-counter medications. She does not smoke, drink alcohol, or use illicit drugs.

Her weight is 52 kg (115 lb), her height is 170 cm (67 in), and her body mass index (BMI) is 18 kg/m². Vital signs: temperature 35.7°C (96.4°F), blood pressure 92/48 mm Hg, heart rate 73 bpm, respiratory rate 5 breaths per minute, and oxygen saturation 98% on room air.

She appears tired but is alert, conversant, and cooperative. Her skin is normal, and dentition is fair. Her pulse is regular, and respirations are slow. The abdomen is soft, non-tender, and flat. Strength is 4 on a scale of 5 in all extremities. Deep-tendon reflexes are 2+ and symmetric.

Electrocardiography (Figure 1) in the emergency department shows ST-segment depression, a prolonged corrected QT interval of 665 msec, T-wave inversion, PR prolongation, increased P-wave amplitude, and U waves.

1. Which electrolyte abnormality is associated with this electrocardiographic picture?

• Hypercalcemia
• Hyperkalemia
• Hypocalcemia
• Hypokalemia

Hypokalemia is the likely cause of these findings. The finding of U waves is considered significant when they are inverted, merged with the T wave, or have an amplitude greater than the T wave.¹ U waves are best seen in the precordial leads. When severe, hypokalemia can lead to potentially fatal arrhythmias such as high-grade atrioventricular block, ventricular tachycardia, and ventricular fibrillation.²

Hyperkalemia is associated with peaked T waves, a prolonged PR interval, decreased P wave amplitude, and a widened QRS complex.² When acute and severe, hyperkalemia is associated with ventricular arrhythmia.

Hypocalcemia is associated with a prolonged QT interval and ventricular dysrhythmia, but not U waves.²

Hypercalcemia is associated with bradydysrhythmia, as well as with a shortened QT interval.²

LABORATORY TESTING

Laboratory testing shows the following:

• Sodium 126 mmol/L (reference range 135–145)
• Potassium 1.5 mmol/L (3.5–5.1)
• Chloride 58 mmol/L (100–110)
• Bicarbonate 62 mmol/L (20–30)
• Blood urea nitrogen 16 mg/dL (7–18)
• Creatinine 0.8 mg/dL (0.5–1.0)
• Glucose 106 mg/dL (70–110)
• Ionized calcium 4.4 mg/dL (4.5–5.3)
• Magnesium 1.8 mg/dL (1.7–2.3)
• Phosphorus 4.1 mg/dL (2.5–4.5)
• Venous blood gases pH 7.56 (7.35–7.45), Pco₂ 69 mm Hg (35–45).

POTASSIUM HOMEOSTASIS

Ninety-eight percent of potassium is intracellular and only 2% is extracellular.³ The main cellular stores are myocytes and hepatocytes. Patients with decreased muscle mass may be at a higher risk of hypokalemia as a result of decreased skeletal muscle stores.⁴

The acute development of hypokalemia occurs from transcellular shifts. Alkalosis, insulin secretion, and beta-adrenergic stimulation promote the intracellular uptake of potassium. The major hormonal regulator of potassium excretion is aldosterone, which is stimulated by renal hypoperfusion and promotes potassium-ion secretion in the distal convoluted tubule.

Chronic hypokalemia develops in patients with ongoing renal or gastrointestinal potassium loss. If the cause of potassium loss is not elucidated by the history, the physical, and a review of medications, then one of two things is possible: either the patient has renal tubular disease affecting acid-base and potassium regulation, causing excessive mineralocorticoid secretion, which is associated with an abnormal response to aldosterone; or the patient is not being forthcoming in the history.

2. Which is the most likely cause of hypokalemia in this patient?

• Vomiting
• Liddle syndrome
• Bartter syndrome
• Gitelman syndrome
• Diuretic use

Her laboratory tests reveal hypokalemia and hyponatremic-hypochloremic metabolic alkalosis with compensatory respiratory acidosis. In metabolic alkalosis, the expected respiratory compensation is an increase of 0.7 mm Hg in Pco₂ for each 1-mEq/L increase in bicarbonate. Therefore, the expected Pco₂ is 67, close to the patient’s actual value of 69.

Protracted vomiting with loss of gastric acid juices could be a cause of the metabolic disturbances in this young woman, although she did not mention vomiting during the history.

Liddle syndrome, or pseudoaldosteronism, is a rare autosomal dominant disorder characterized by altered renal epithelial sodium channels, excessive sodium retention, and resultant hypertension. Hypokalemia and alkalosis are seen in Liddle syndrome, but the absence of hypertension in our patient makes Liddle syndrome unlikely.

Bartter syndrome is an inherited autosomal recessive disorder of the sodium-potassium-chloride cotransporter in the thick ascending loop of Henle, resulting in impaired reabsorption of chloride and sodium. Bartter syndrome mimics chronic loop-diuretic use and is associated with hypercalciuria. Bartter syndrome is possible in this patient; however, patients with Bartter syndrome are usually diagnosed in infancy or childhood and have evidence of growth impairment.

Gitelman syndrome is an autosomal recessive disorder of the thiazide-sensitive sodium-chloride cotransporter. Although Gitelman syndrome is more common than Bartter syndrome and presents at older ages, it is not usually associated with such profound metabolic alkalosis. Gitelman syndrome mimics chronic use of thiazide diuretics and is associated with hypocalciuria.

Diuretic use could also cause the metabolic disturbances described; however, the patient denied taking diuretics.

The most common cause of hypokalemia in clinical practice is diuretic use.⁴ In this young woman with unexplained hypokalemia, the most likely cause is either undisclosed self-induced vomiting or diuretic abuse. The degree of metabolic alkalosis suggests vomiting, since metabolic alkalosis this severe is usually seen only with protracted vomiting. Bartter and Gitelman syndromes are included in the differential diagnosis, but they are much less common than hypokalemia associated with diuretics or self-induced vomiting.⁵

3. Which test could help elucidate the cause of hypokalemia in this patient?

• Ratio of plasma aldosterone to rennin
• Urine chloride
• Ratio of urinary potassium to creatinine
• Urinary anion gap and urinary pH

APPROACH TO HYPOKALEMIA

Determining the cause of hypokalemia starts with a thorough history and physical examination. The history should focus on drugs such as diuretics and laxatives. Women should be asked about their menstrual history since irregular periods may suggest an eating disorder. The physical examination should focus on signs that suggest self-induced vomiting, such as dry skin, dental erosions, enlarged parotid glands, and calluses or scars on the knuckles.

Patients with an unclear cause of hypokalemia after a thorough history and physical examination can be categorized into one of three groups based on blood pressure and acid-base status:

• Hypokalemia, hypertension, metabolic alkalosis
• Hypokalemia, normal blood pressure, metabolic acidosis
• Hypokalemia, normal blood pressure, metabolic alkalosis.

Hypokalemia, hypertension, metabolic alkalosis

The blood pressure provides an important clue in the evaluation of hypokalemia. The combination of hypertension, hypokalemia, and alkalosis should raise concern for hyperaldosteronism or pseudoaldosteronism. Primary hyperaldosteronism from an adrenal adenoma (Conn syndrome) is characterized by a plasma aldosterone-renin ratio of greater than 20.^6,7 In contrast, patients with secondary hyperaldosteronism due to renovascular disease have a plasma aldosterone-renin ratio of less than 10. Patients with pseudoaldosteronism have low aldosterone and renin levels and hypertension. Since our patient has a normal blood pressure, testing the plasma aldosterone and renin levels would not help determine the cause of her hypokalemia.

Hypokalemia, normal blood pressure, metabolic acidosis

Patients with normal blood pressure, hypokalemia, and normal plasma anion gap acidosis either have renal tubular acidosis or have lost potassium because of diarrhea or laxative abuse. In a patient who denies taking laxatives or denies a history of diarrhea, checking the urinary anion gap and urinary pH may help differentiate the cause of acidosis and hypokalemia.

The urinary anion gap, calculated by the equation sodium + potassium − chloride, is an indirect estimate of hydrogen excretion in the form of ammonium ion⁸; the normal value is 0 to 10 mEq/L. A negative value represents increased hydrogen excretion in response to systemic acidosis from gastrointestinal or renal loss of bicarbonate (proximal renal tubular acidosis). A urinary pH greater than 5.5 in the setting of systemic acidosis suggests impaired ability of the kidneys to acidify urine and raises the possibility of renal tubular acidosis.

This patient has metabolic alkalosis, so calculation of the urinary anion gap would not be helpful.

Hypokalemia, normal blood pressure, metabolic alkalosis

Patients such as ours, with normal blood pressure, hypokalemia, and alkalosis, have been vomiting, have used diuretics, or have an inherited renal tubulopathy such as Bartter or Gitelman syndrome. Usually, differentiating Bartter and Gitelman syndromes from chronic vomiting or diuretic use is done with the history and physical examination. However, in patients with a questionable history and a lack of findings on physical examination, checking the urinary chloride, potassium, calcium, and creatinine may be helpful.

A urinary potassium-creatinine ratio greater than 15 suggests renal loss, whereas a ratio less than 15 suggests extrarenal loss.⁹

Patients who are taking a diuretic or who have Bartter or Gitelman syndrome have a high urinary chloride concentration, ie, greater than 20 mmol/L, whereas patients with hypokalemia and alkalosis from chronic vomiting tend to have a concentration less than 10 mmol/L.¹⁰

Table 1 summarizes an approach to the evaluation of unexplained hypokalemia based on blood pressure and acid-base status.

A HIDDEN HISTORY

On further questioning, the patient admits to an 8-year history of daily self-induced vomiting in an attempt to lose weight, in addition to multiple hospitalizations for hypokalemia and a previous diagnosis of an eating disorder.

INITIAL MANAGEMENT OF HYPOKALEMIA

The initial management of hypokalemia should focus on life-threatening emergencies. While patients with potassium levels greater than 3 mmol/L are usually asymptomatic, those with levels below 3 mmol/L present with muscle weakness and rhabdomyolysis.⁴ An acute drop in serum potassium to less than 2 mmol/L is associated with respiratory muscle weakness and ventricular arrhythmias.⁴ If the patient has cardiac symptoms or hypoventilation due to respiratory muscle weakness, continuous monitoring in the intensive care unit and aggressive therapy are warranted.

4. Which potassium formulation is most appropriate for the treatment of hypokalemia in this patient?

• Potassium chloride
• Potassium phosphate
• Potassium acetate

Oral potassium is preferable in patients with a serum potassium above 2.5 mmol/L.^4,11 Potassium phosphate should be used when supplementation with both potassium and phosphorus is needed. Potassium acetate should be reserved for patients with acidosis and hypokalemia. Otherwise, potassium chloride is typically preferred.^4,12 It comes in liquid and tablet forms. Liquid forms have an unpleasant taste, whereas tablets are usually well tolerated. No more than 20 to 40 mEq of potassium chloride tablets should be given at a time, since higher doses are associated with gastrointestinal mucosal injury.¹²

Potassium chloride is particularly preferred in patients with metabolic alkalosis, since increased chloride intake and delivery to the distal tubule increases the expression of pendrin, a luminal chloride and bicarbonate exchanger in the cortical collecting duct.¹³ With metabolic alkalosis, increased excretion of bicarbonate occurs through up-regulation of pendrin. Potassium depletion down-regulates pendrin.¹³ Additionally, correction of metabolic alkalosis increases serum potassium by movement of potassium from the intracellular to the extracellular space.

Intravenous potassium should be reserved for patients with severe hypokalemia (< 2.5 mmol/L) or significant arrhythmias.¹¹ Oral and intravenous potassium can safely be given simultaneously.¹¹ The intravenous rate should not exceed more than 10 to 20 mEq of potassium chloride per hour unless the patient has a life-threatening arrhythmia, respiratory failure, or severe hypokalemia.^14,15 In life-threatening situations, a femoral line should be placed, and potassium should be given as rapidly as 20 mEq over 15 to 20 minutes.¹⁴ Cannulation of the subclavian and internal jugular veins should be avoided in severe hypokalemia since mechanical irritation from guidewire placement can provoke ventricular arrhythmias.¹⁴

During intravenous administration of potassium, laboratory monitoring after every 20 mEq of potassium chloride is advised because of the possibility of rebound hyperkalemia. In patients with severe hypokalemia, avoidance of factors that can worsen intracellular shift of potassium is also important. Avoid dextrose-containing fluids to prevent insulin-induced shifting of potassium into cells. Restore intravascular volume to blunt hypovolemia-induced renin and aldosterone secretion. If a patient presents with severe hypokalemia and acidosis, correct the hypokalemia before the acidosis to avoid intracellular shift of potassium.

OUR PATIENT’S MANAGEMENT AND FOLLOW-UP PLAN

Given the severity of our patient’s hypokalemia and her complaint of palpitations, she was admitted to the hospital for monitoring. She required 180 mEq of intravenous potassium chloride and 140 mEq of oral potassium chloride during the first 24 hours in order to achieve a serum potassium level above 3 mmol/L. Electrocardiographic U waves resolved once the level was above 2 mmol/L, and ST depressions resolved once it was above 3 mmol/L. The QT interval normalized after 24 hours of hospitalization.

On discharge, she was prescribed oral potassium chloride 40 mEq daily and magnesium sulfate 400 mg twice daily, with plans for a followup visit with her outpatient therapy team, which includes a psychiatrist, a social worker, and her primary care provider. She declined a referral for inpatient therapy but agreed to a goal of decreasing the frequency of induced vomiting and outpatient visits. She was also educated on how and when to access emergency medical care.¹⁶

A 20-year-old woman presents to the emergency department with fatigue and the sudden onset of palpitations. She reports no history of significant illness or surgery. She says she is not currently taking prescription or over-the-counter medications. She does not smoke, drink alcohol, or use illicit drugs.

Her weight is 52 kg (115 lb), her height is 170 cm (67 in), and her body mass index (BMI) is 18 kg/m². Vital signs: temperature 35.7°C (96.4°F), blood pressure 92/48 mm Hg, heart rate 73 bpm, respiratory rate 5 breaths per minute, and oxygen saturation 98% on room air.

She appears tired but is alert, conversant, and cooperative. Her skin is normal, and dentition is fair. Her pulse is regular, and respirations are slow. The abdomen is soft, non-tender, and flat. Strength is 4 on a scale of 5 in all extremities. Deep-tendon reflexes are 2+ and symmetric.

Electrocardiography (Figure 1) in the emergency department shows ST-segment depression, a prolonged corrected QT interval of 665 msec, T-wave inversion, PR prolongation, increased P-wave amplitude, and U waves.

1. Which electrolyte abnormality is associated with this electrocardiographic picture?

• Hypercalcemia
• Hyperkalemia
• Hypocalcemia
• Hypokalemia

Hypokalemia is the likely cause of these findings. The finding of U waves is considered significant when they are inverted, merged with the T wave, or have an amplitude greater than the T wave.¹ U waves are best seen in the precordial leads. When severe, hypokalemia can lead to potentially fatal arrhythmias such as high-grade atrioventricular block, ventricular tachycardia, and ventricular fibrillation.²

Hyperkalemia is associated with peaked T waves, a prolonged PR interval, decreased P wave amplitude, and a widened QRS complex.² When acute and severe, hyperkalemia is associated with ventricular arrhythmia.

Hypocalcemia is associated with a prolonged QT interval and ventricular dysrhythmia, but not U waves.²

Hypercalcemia is associated with bradydysrhythmia, as well as with a shortened QT interval.²

LABORATORY TESTING

Laboratory testing shows the following:

• Sodium 126 mmol/L (reference range 135–145)
• Potassium 1.5 mmol/L (3.5–5.1)
• Chloride 58 mmol/L (100–110)
• Bicarbonate 62 mmol/L (20–30)
• Blood urea nitrogen 16 mg/dL (7–18)
• Creatinine 0.8 mg/dL (0.5–1.0)
• Glucose 106 mg/dL (70–110)
• Ionized calcium 4.4 mg/dL (4.5–5.3)
• Magnesium 1.8 mg/dL (1.7–2.3)
• Phosphorus 4.1 mg/dL (2.5–4.5)
• Venous blood gases pH 7.56 (7.35–7.45), Pco₂ 69 mm Hg (35–45).

POTASSIUM HOMEOSTASIS

Ninety-eight percent of potassium is intracellular and only 2% is extracellular.³ The main cellular stores are myocytes and hepatocytes. Patients with decreased muscle mass may be at a higher risk of hypokalemia as a result of decreased skeletal muscle stores.⁴

The acute development of hypokalemia occurs from transcellular shifts. Alkalosis, insulin secretion, and beta-adrenergic stimulation promote the intracellular uptake of potassium. The major hormonal regulator of potassium excretion is aldosterone, which is stimulated by renal hypoperfusion and promotes potassium-ion secretion in the distal convoluted tubule.

Chronic hypokalemia develops in patients with ongoing renal or gastrointestinal potassium loss. If the cause of potassium loss is not elucidated by the history, the physical, and a review of medications, then one of two things is possible: either the patient has renal tubular disease affecting acid-base and potassium regulation, causing excessive mineralocorticoid secretion, which is associated with an abnormal response to aldosterone; or the patient is not being forthcoming in the history.

2. Which is the most likely cause of hypokalemia in this patient?

• Vomiting
• Liddle syndrome
• Bartter syndrome
• Gitelman syndrome
• Diuretic use

Her laboratory tests reveal hypokalemia and hyponatremic-hypochloremic metabolic alkalosis with compensatory respiratory acidosis. In metabolic alkalosis, the expected respiratory compensation is an increase of 0.7 mm Hg in Pco₂ for each 1-mEq/L increase in bicarbonate. Therefore, the expected Pco₂ is 67, close to the patient’s actual value of 69.

Protracted vomiting with loss of gastric acid juices could be a cause of the metabolic disturbances in this young woman, although she did not mention vomiting during the history.

Liddle syndrome, or pseudoaldosteronism, is a rare autosomal dominant disorder characterized by altered renal epithelial sodium channels, excessive sodium retention, and resultant hypertension. Hypokalemia and alkalosis are seen in Liddle syndrome, but the absence of hypertension in our patient makes Liddle syndrome unlikely.

Bartter syndrome is an inherited autosomal recessive disorder of the sodium-potassium-chloride cotransporter in the thick ascending loop of Henle, resulting in impaired reabsorption of chloride and sodium. Bartter syndrome mimics chronic loop-diuretic use and is associated with hypercalciuria. Bartter syndrome is possible in this patient; however, patients with Bartter syndrome are usually diagnosed in infancy or childhood and have evidence of growth impairment.

Gitelman syndrome is an autosomal recessive disorder of the thiazide-sensitive sodium-chloride cotransporter. Although Gitelman syndrome is more common than Bartter syndrome and presents at older ages, it is not usually associated with such profound metabolic alkalosis. Gitelman syndrome mimics chronic use of thiazide diuretics and is associated with hypocalciuria.

Diuretic use could also cause the metabolic disturbances described; however, the patient denied taking diuretics.

The most common cause of hypokalemia in clinical practice is diuretic use.⁴ In this young woman with unexplained hypokalemia, the most likely cause is either undisclosed self-induced vomiting or diuretic abuse. The degree of metabolic alkalosis suggests vomiting, since metabolic alkalosis this severe is usually seen only with protracted vomiting. Bartter and Gitelman syndromes are included in the differential diagnosis, but they are much less common than hypokalemia associated with diuretics or self-induced vomiting.⁵

3. Which test could help elucidate the cause of hypokalemia in this patient?

• Ratio of plasma aldosterone to rennin
• Urine chloride
• Ratio of urinary potassium to creatinine
• Urinary anion gap and urinary pH

APPROACH TO HYPOKALEMIA

Determining the cause of hypokalemia starts with a thorough history and physical examination. The history should focus on drugs such as diuretics and laxatives. Women should be asked about their menstrual history since irregular periods may suggest an eating disorder. The physical examination should focus on signs that suggest self-induced vomiting, such as dry skin, dental erosions, enlarged parotid glands, and calluses or scars on the knuckles.

Patients with an unclear cause of hypokalemia after a thorough history and physical examination can be categorized into one of three groups based on blood pressure and acid-base status:

• Hypokalemia, hypertension, metabolic alkalosis
• Hypokalemia, normal blood pressure, metabolic acidosis
• Hypokalemia, normal blood pressure, metabolic alkalosis.

Hypokalemia, hypertension, metabolic alkalosis

The blood pressure provides an important clue in the evaluation of hypokalemia. The combination of hypertension, hypokalemia, and alkalosis should raise concern for hyperaldosteronism or pseudoaldosteronism. Primary hyperaldosteronism from an adrenal adenoma (Conn syndrome) is characterized by a plasma aldosterone-renin ratio of greater than 20.^6,7 In contrast, patients with secondary hyperaldosteronism due to renovascular disease have a plasma aldosterone-renin ratio of less than 10. Patients with pseudoaldosteronism have low aldosterone and renin levels and hypertension. Since our patient has a normal blood pressure, testing the plasma aldosterone and renin levels would not help determine the cause of her hypokalemia.

Hypokalemia, normal blood pressure, metabolic acidosis

Patients with normal blood pressure, hypokalemia, and normal plasma anion gap acidosis either have renal tubular acidosis or have lost potassium because of diarrhea or laxative abuse. In a patient who denies taking laxatives or denies a history of diarrhea, checking the urinary anion gap and urinary pH may help differentiate the cause of acidosis and hypokalemia.

The urinary anion gap, calculated by the equation sodium + potassium − chloride, is an indirect estimate of hydrogen excretion in the form of ammonium ion⁸; the normal value is 0 to 10 mEq/L. A negative value represents increased hydrogen excretion in response to systemic acidosis from gastrointestinal or renal loss of bicarbonate (proximal renal tubular acidosis). A urinary pH greater than 5.5 in the setting of systemic acidosis suggests impaired ability of the kidneys to acidify urine and raises the possibility of renal tubular acidosis.

This patient has metabolic alkalosis, so calculation of the urinary anion gap would not be helpful.

Hypokalemia, normal blood pressure, metabolic alkalosis

Patients such as ours, with normal blood pressure, hypokalemia, and alkalosis, have been vomiting, have used diuretics, or have an inherited renal tubulopathy such as Bartter or Gitelman syndrome. Usually, differentiating Bartter and Gitelman syndromes from chronic vomiting or diuretic use is done with the history and physical examination. However, in patients with a questionable history and a lack of findings on physical examination, checking the urinary chloride, potassium, calcium, and creatinine may be helpful.

A urinary potassium-creatinine ratio greater than 15 suggests renal loss, whereas a ratio less than 15 suggests extrarenal loss.⁹

Patients who are taking a diuretic or who have Bartter or Gitelman syndrome have a high urinary chloride concentration, ie, greater than 20 mmol/L, whereas patients with hypokalemia and alkalosis from chronic vomiting tend to have a concentration less than 10 mmol/L.¹⁰

Table 1 summarizes an approach to the evaluation of unexplained hypokalemia based on blood pressure and acid-base status.

A HIDDEN HISTORY

On further questioning, the patient admits to an 8-year history of daily self-induced vomiting in an attempt to lose weight, in addition to multiple hospitalizations for hypokalemia and a previous diagnosis of an eating disorder.

INITIAL MANAGEMENT OF HYPOKALEMIA

The initial management of hypokalemia should focus on life-threatening emergencies. While patients with potassium levels greater than 3 mmol/L are usually asymptomatic, those with levels below 3 mmol/L present with muscle weakness and rhabdomyolysis.⁴ An acute drop in serum potassium to less than 2 mmol/L is associated with respiratory muscle weakness and ventricular arrhythmias.⁴ If the patient has cardiac symptoms or hypoventilation due to respiratory muscle weakness, continuous monitoring in the intensive care unit and aggressive therapy are warranted.

4. Which potassium formulation is most appropriate for the treatment of hypokalemia in this patient?

• Potassium chloride
• Potassium phosphate
• Potassium acetate

Oral potassium is preferable in patients with a serum potassium above 2.5 mmol/L.^4,11 Potassium phosphate should be used when supplementation with both potassium and phosphorus is needed. Potassium acetate should be reserved for patients with acidosis and hypokalemia. Otherwise, potassium chloride is typically preferred.^4,12 It comes in liquid and tablet forms. Liquid forms have an unpleasant taste, whereas tablets are usually well tolerated. No more than 20 to 40 mEq of potassium chloride tablets should be given at a time, since higher doses are associated with gastrointestinal mucosal injury.¹²

Potassium chloride is particularly preferred in patients with metabolic alkalosis, since increased chloride intake and delivery to the distal tubule increases the expression of pendrin, a luminal chloride and bicarbonate exchanger in the cortical collecting duct.¹³ With metabolic alkalosis, increased excretion of bicarbonate occurs through up-regulation of pendrin. Potassium depletion down-regulates pendrin.¹³ Additionally, correction of metabolic alkalosis increases serum potassium by movement of potassium from the intracellular to the extracellular space.

Intravenous potassium should be reserved for patients with severe hypokalemia (< 2.5 mmol/L) or significant arrhythmias.¹¹ Oral and intravenous potassium can safely be given simultaneously.¹¹ The intravenous rate should not exceed more than 10 to 20 mEq of potassium chloride per hour unless the patient has a life-threatening arrhythmia, respiratory failure, or severe hypokalemia.^14,15 In life-threatening situations, a femoral line should be placed, and potassium should be given as rapidly as 20 mEq over 15 to 20 minutes.¹⁴ Cannulation of the subclavian and internal jugular veins should be avoided in severe hypokalemia since mechanical irritation from guidewire placement can provoke ventricular arrhythmias.¹⁴

During intravenous administration of potassium, laboratory monitoring after every 20 mEq of potassium chloride is advised because of the possibility of rebound hyperkalemia. In patients with severe hypokalemia, avoidance of factors that can worsen intracellular shift of potassium is also important. Avoid dextrose-containing fluids to prevent insulin-induced shifting of potassium into cells. Restore intravascular volume to blunt hypovolemia-induced renin and aldosterone secretion. If a patient presents with severe hypokalemia and acidosis, correct the hypokalemia before the acidosis to avoid intracellular shift of potassium.

OUR PATIENT’S MANAGEMENT AND FOLLOW-UP PLAN

Given the severity of our patient’s hypokalemia and her complaint of palpitations, she was admitted to the hospital for monitoring. She required 180 mEq of intravenous potassium chloride and 140 mEq of oral potassium chloride during the first 24 hours in order to achieve a serum potassium level above 3 mmol/L. Electrocardiographic U waves resolved once the level was above 2 mmol/L, and ST depressions resolved once it was above 3 mmol/L. The QT interval normalized after 24 hours of hospitalization.

On discharge, she was prescribed oral potassium chloride 40 mEq daily and magnesium sulfate 400 mg twice daily, with plans for a followup visit with her outpatient therapy team, which includes a psychiatrist, a social worker, and her primary care provider. She declined a referral for inpatient therapy but agreed to a goal of decreasing the frequency of induced vomiting and outpatient visits. She was also educated on how and when to access emergency medical care.¹⁶

An 85-year-old man with hypertension, hyperlipidemia, and coronary artery disease presented to our clinic with diffuse muscle pain. The pain had been present for about 3 months, but it had become noticeably worse over the past few weeks.

He was not aware of any trauma. He described the muscle pain as dull and particularly severe in his lower extremities (his thighs and calves). The pain did not limit his daily activities, nor did physical exertion or the time of day have any effect on the level of the pain.

His medications at that time included metoprolol, aspirin, hydrochlorothiazide, simvastatin, and a daily multivitamin.

He was not in acute distress. On neurologic and musculoskeletal examinations, all deep-tendon reflexes were intact, with no tenderness to palpation of the upper and lower extremities. No abnormalities were noted on the joint examination. He had full range of motion, with 5/5 muscle strength in the upper and lower extremities bilaterally and normal muscle tone. He was able to walk with ease. Results of initial laboratory testing, including creatine kinase and erythrocyte sedimentation rate, were normal.

1. What should be the next best step in the evaluation of this patient’s muscle pain?

• Order tests for cyclic citrullinated peptide (CCP) antibody and rheumatoid factor
• Advise him to refrain from physical activity until his symptoms resolve
• Take a more detailed history, including a review of medications and supplements
• Recommend a trial of a nonsteroidal anti-inflammatory drug (NSAID)
• Send him for radiographic imaging

Since his muscle pain has persisted for several months without improvement, a more detailed history should be taken, including a review of current medications and supplements.

Testing CCP antibody and rheumatoid factor would be useful if rheumatoid arthritis were suspected, but in the absence of demonstrable arthritis on examination, these tests would have low specificity even if the results were positive.

An NSAID may temporarily alleviate his pain, but it will not help establish a diagnosis. And in elderly patients, NSAIDs are not without complications and so should be prescribed only in appropriate situations.

Imaging would be appropriate at this point only if there was clinical suspicion of a specific disease. However, our patient has no focal deficits, and the suspicion of fracture or malignancy is low.

The medical history should include asking about current drug regimens, recent medication changes, and the use of herbal supplements, since polypharmacy is common in elderly patients with multiple comorbidities.

On further questioning, our patient said that his dose of simvastatin had been increased from 40 mg daily to 80 mg daily about 1 month before his symptoms appeared. He was taking a daily multivitamin but was not using herbal supplements or other over-the-counter products. He did not recall any constitutional symptoms before the onset of his current symptoms, and he had never had similar muscle pain in the past.

2. Based on the additional information from the history, what is the most likely cause of his muscle pain?

• Limited myositis secondary to recent viral infection
• Rhabdomyolysis
• Hypothyroidism
• Drug-drug interaction
• Statin-induced myalgia

Our patient’s history provided nothing to suggest viral myositis. Hypothyroidism should always be considered in patients with myalgia, but this is not likely in our patient, as he does not display other characteristics, such as diminished reflexes, hypotonia, cold intolerance, and mood instability. Even though calcium channel blockers have been known to cause myalgia in patients on statins, a drug-drug reaction is not likely, as he had not started taking a calcium channel blocker before his symptoms began. This patient did not show signs or symptoms of rhabdomyolysis, a type of myopathy in which necrosis of the muscle tissue occurs, generally causing profound weakness and pain.¹

Therefore, statin-induced myopathy is the most likely cause of his diffuse muscle pain, particularly since his simvastatin had been increased 1 month before the onset of symptoms.

3. What should be the next step in his management?

• Decrease the dose of simvastatin to the last known dose he was able to tolerate
• Continue simvastatin at the same dose and then monitor
• Switch to another statin
• Add coenzyme Q10
• Stop simvastatin

Decreasing the statin dosage to the last well-tolerated dose would not be appropriate in a patient with myopathy, as the symptoms would probably not improve.^2–4 Also, one should not switch to a different statin while a patient is experiencing symptoms. Rather, the statin should be stopped for at least 6 weeks or until the symptoms have fully resolved.¹

Adding coenzyme Q10 is another option, especially in a patient with previously diagnosed coronary artery disease,⁵ when continued statin therapy is thought necessary to reduce the likelihood of repeat coronary events.

We discontinued his simvastatin. Followup 3 weeks later in the outpatient clinic showed that his symptoms were slowly improving. The symptoms had resolved completely 4 months later.

4. How should we manage our patient’s hyperlipidemia once his symptoms have resolved?

• Restart simvastatin at the 80-mg dose
• Restart simvastatin at the 40-mg dose
• Start a hydrophilic statin at full dose
• Use a drug from another class of lipid-lowering drugs
• Wait another 3 months before prescribing any lipid-lowering drug

His treatment for hyperlipidemia should be continued, considering his comorbidities. However, restarting the same statin, even at a lower dose, will likely cause his symptoms to recur. Thus, a different statin should be tried once his muscle pain has resolved.

Other classes of lipid-lowering drugs are usually less efficacious than statins, particularly when trying to control low-density lipoprotein (LDL) cholesterol, so a drug from another class should not be used until other statin options have been attempted.^2,6,7

Simvastatin is lipophilic. Trying a statin with hydrophilic properties (eg, pravastatin, rosuvastatin, fluvastatin) has been shown to convey similar cardioprotective effects with a lower propensity for myalgia, as lipophilic statins have a higher propensity to penetrate muscle tissue than do hydrophilic statins.^3,4,8

Once his symptoms resolved, our patient was started on a hydrophilic statin, fluvastatin 20 mg daily. Unfortunately, his pain recurred 3 weeks later. The statin was stopped, and his symptoms again resolved.

5. Since our patient was unable to tolerate a second statin, what should be the next step in his management?

• Restart simvastatin 
• Use a drug from another class to control the hyperlipidemia
• Wait at least 6 months after symptoms resolve before trying any lipid-lowering drug
• Initiate therapy with coenzyme Q10 and fish oil
• Wait for symptoms to resolve, then restart a hydrophilic statin at a lower dose and lower frequency

Restarting simvastatin will likely cause a recurrence of the myalgia. Other lipid-lowering drugs such as nicotinic acid, bile acid resins, and fibrates are not as efficacious as statins. Coenzyme Q10 and fish oil can reduce lipid levels, but they are not as efficacious as statins.

In view of our patient’s lipid profile—LDL cholesterol elevated at 167 mg/dL, high-density lipoprotein cholesterol 31 mg/dL, triglycerides 47 mg/dL—it is important to treat his hyperlipidemia. Therefore, another attempt at statin therapy should be made once his symptoms have resolved.

Studies have shown that restarting a statin at a low dose and low frequency is effective in patients who have experienced intolerance to a statin.^3,4 Our patient was treated with low-dose pravastatin (20 mg), resulting in a moderate improvement in his LDL cholesterol to 123 mg/dL.

STATIN-INDUCED MYOPATHY: ADDRESSING THE DILEMMA

Treating hyperlipidemia is important to prevent vascular events in patients with or without coronary artery disease. Statins are the most effective agents available for controlling hypercholesterolemia, specifically LDL levels, as well as for preventing myocardial infarction.

Unfortunately, significant side effects have been reported, and myopathy is the most prevalent. Statin-induced myopathy includes a combination of muscle tenderness, myalgia, and weakness.^2–11 In randomized controlled trials, the risk of myopathy was estimated to be between 1.5% and 5%.⁶ In unselected clinic patients on high-dose statins, the rate of muscle complaints may be as high as 20%.¹²

The cause of statin-induced myopathy is not known, although studies have linked it to genetic defects.⁷ Risk factors have been identified and include personal and family history of myalgia, Asian ethnicity, hypothyroidism, and type 1 diabetes. The incidence of statin-induced myalgia is two to three times higher in patients on corticosteroid therapy. Other risk factors include female sex, liver disease, and renal dysfunction.^7,8

A less common etiology is anti-HMG coenzyme A reductase antibodies. Studies have shown that these antibody levels correlate well with the amount of myositis as measured by creatine kinase levels. However, there is no consensus yet on screening for these antibodies.¹³

Statin therapy poses a dilemma, as there is a thin line between the benefits and the risks of side effects, especially statin-induced myopathy.^3,4 Current recommendations include discontinuing the statin until symptoms fully resolve. Creatine kinase levels may be useful in assessing for potential muscle breakdown, especially in patients with reduced renal function, as this predisposes them to statin-induced myopathy, yet normal values do not preclude the diagnosis of statin-induced myopathy.^3,4,7,8

Once symptoms resolve and laboratory test results normalize, a trial of a different statin is recommended. If patients become symptomatic, a trial of a low-dose hydrophilic statin at a once- or twice-weekly interval has been recommended. Several studies have assessed the efficacy of a low-dose statin with decreased frequency of administration and have consistently shown significant improvement in lipid levels.^3,4 For instance, once-weekly rosuvastatin at a dose between 5 mg and 20 mg resulted in a 29% reduction in LDL cholesterol levels, and 80% of patients did not experience a recurrence of myalgia.³ Furthermore, a study of patients treated with 5 mg to 10 mg of rosuvastatin twice a week resulted in a 26% decrease in LDL cholesterol levels.⁴ This study also showed that when an additional non-statin lipid-lowering drug was prescribed (eg, ezetimibe, bile acid resin, nicotinic acid), more than half of the patients reached their goal lipid level.⁴

The addition of coenzyme Q10 and fish oil has also been suggested. Although, the evidence to support this is inconclusive, the potential benefit outweighs the risk, since the side effects are minimal.¹ However, no study yet has evaluated the risks vs the benefits in patients with elevated creatine kinase.

Statin-induced myopathy is a commonly encountered adverse effect. Currently, there are no guidelines on restarting statin therapy after statin-induced myopathy; however, data suggest that statin therapy should be restarted once symptoms resolve, and that variations in dose and frequency may be necessary.^1–8,14

An 85-year-old man with hypertension, hyperlipidemia, and coronary artery disease presented to our clinic with diffuse muscle pain. The pain had been present for about 3 months, but it had become noticeably worse over the past few weeks.

He was not aware of any trauma. He described the muscle pain as dull and particularly severe in his lower extremities (his thighs and calves). The pain did not limit his daily activities, nor did physical exertion or the time of day have any effect on the level of the pain.

His medications at that time included metoprolol, aspirin, hydrochlorothiazide, simvastatin, and a daily multivitamin.

He was not in acute distress. On neurologic and musculoskeletal examinations, all deep-tendon reflexes were intact, with no tenderness to palpation of the upper and lower extremities. No abnormalities were noted on the joint examination. He had full range of motion, with 5/5 muscle strength in the upper and lower extremities bilaterally and normal muscle tone. He was able to walk with ease. Results of initial laboratory testing, including creatine kinase and erythrocyte sedimentation rate, were normal.

1. What should be the next best step in the evaluation of this patient’s muscle pain?

• Order tests for cyclic citrullinated peptide (CCP) antibody and rheumatoid factor
• Advise him to refrain from physical activity until his symptoms resolve
• Take a more detailed history, including a review of medications and supplements
• Recommend a trial of a nonsteroidal anti-inflammatory drug (NSAID)
• Send him for radiographic imaging

Since his muscle pain has persisted for several months without improvement, a more detailed history should be taken, including a review of current medications and supplements.

Testing CCP antibody and rheumatoid factor would be useful if rheumatoid arthritis were suspected, but in the absence of demonstrable arthritis on examination, these tests would have low specificity even if the results were positive.

An NSAID may temporarily alleviate his pain, but it will not help establish a diagnosis. And in elderly patients, NSAIDs are not without complications and so should be prescribed only in appropriate situations.

Imaging would be appropriate at this point only if there was clinical suspicion of a specific disease. However, our patient has no focal deficits, and the suspicion of fracture or malignancy is low.

The medical history should include asking about current drug regimens, recent medication changes, and the use of herbal supplements, since polypharmacy is common in elderly patients with multiple comorbidities.

On further questioning, our patient said that his dose of simvastatin had been increased from 40 mg daily to 80 mg daily about 1 month before his symptoms appeared. He was taking a daily multivitamin but was not using herbal supplements or other over-the-counter products. He did not recall any constitutional symptoms before the onset of his current symptoms, and he had never had similar muscle pain in the past.

2. Based on the additional information from the history, what is the most likely cause of his muscle pain?

• Limited myositis secondary to recent viral infection
• Rhabdomyolysis
• Hypothyroidism
• Drug-drug interaction
• Statin-induced myalgia

Our patient’s history provided nothing to suggest viral myositis. Hypothyroidism should always be considered in patients with myalgia, but this is not likely in our patient, as he does not display other characteristics, such as diminished reflexes, hypotonia, cold intolerance, and mood instability. Even though calcium channel blockers have been known to cause myalgia in patients on statins, a drug-drug reaction is not likely, as he had not started taking a calcium channel blocker before his symptoms began. This patient did not show signs or symptoms of rhabdomyolysis, a type of myopathy in which necrosis of the muscle tissue occurs, generally causing profound weakness and pain.¹

Therefore, statin-induced myopathy is the most likely cause of his diffuse muscle pain, particularly since his simvastatin had been increased 1 month before the onset of symptoms.

3. What should be the next step in his management?

• Decrease the dose of simvastatin to the last known dose he was able to tolerate
• Continue simvastatin at the same dose and then monitor
• Switch to another statin
• Add coenzyme Q10
• Stop simvastatin

Decreasing the statin dosage to the last well-tolerated dose would not be appropriate in a patient with myopathy, as the symptoms would probably not improve.^2–4 Also, one should not switch to a different statin while a patient is experiencing symptoms. Rather, the statin should be stopped for at least 6 weeks or until the symptoms have fully resolved.¹

Adding coenzyme Q10 is another option, especially in a patient with previously diagnosed coronary artery disease,⁵ when continued statin therapy is thought necessary to reduce the likelihood of repeat coronary events.

We discontinued his simvastatin. Followup 3 weeks later in the outpatient clinic showed that his symptoms were slowly improving. The symptoms had resolved completely 4 months later.

4. How should we manage our patient’s hyperlipidemia once his symptoms have resolved?

• Restart simvastatin at the 80-mg dose
• Restart simvastatin at the 40-mg dose
• Start a hydrophilic statin at full dose
• Use a drug from another class of lipid-lowering drugs
• Wait another 3 months before prescribing any lipid-lowering drug

His treatment for hyperlipidemia should be continued, considering his comorbidities. However, restarting the same statin, even at a lower dose, will likely cause his symptoms to recur. Thus, a different statin should be tried once his muscle pain has resolved.

Other classes of lipid-lowering drugs are usually less efficacious than statins, particularly when trying to control low-density lipoprotein (LDL) cholesterol, so a drug from another class should not be used until other statin options have been attempted.^2,6,7

Simvastatin is lipophilic. Trying a statin with hydrophilic properties (eg, pravastatin, rosuvastatin, fluvastatin) has been shown to convey similar cardioprotective effects with a lower propensity for myalgia, as lipophilic statins have a higher propensity to penetrate muscle tissue than do hydrophilic statins.^3,4,8

Once his symptoms resolved, our patient was started on a hydrophilic statin, fluvastatin 20 mg daily. Unfortunately, his pain recurred 3 weeks later. The statin was stopped, and his symptoms again resolved.

5. Since our patient was unable to tolerate a second statin, what should be the next step in his management?

• Restart simvastatin 
• Use a drug from another class to control the hyperlipidemia
• Wait at least 6 months after symptoms resolve before trying any lipid-lowering drug
• Initiate therapy with coenzyme Q10 and fish oil
• Wait for symptoms to resolve, then restart a hydrophilic statin at a lower dose and lower frequency

Restarting simvastatin will likely cause a recurrence of the myalgia. Other lipid-lowering drugs such as nicotinic acid, bile acid resins, and fibrates are not as efficacious as statins. Coenzyme Q10 and fish oil can reduce lipid levels, but they are not as efficacious as statins.

In view of our patient’s lipid profile—LDL cholesterol elevated at 167 mg/dL, high-density lipoprotein cholesterol 31 mg/dL, triglycerides 47 mg/dL—it is important to treat his hyperlipidemia. Therefore, another attempt at statin therapy should be made once his symptoms have resolved.

Studies have shown that restarting a statin at a low dose and low frequency is effective in patients who have experienced intolerance to a statin.^3,4 Our patient was treated with low-dose pravastatin (20 mg), resulting in a moderate improvement in his LDL cholesterol to 123 mg/dL.

STATIN-INDUCED MYOPATHY: ADDRESSING THE DILEMMA

Treating hyperlipidemia is important to prevent vascular events in patients with or without coronary artery disease. Statins are the most effective agents available for controlling hypercholesterolemia, specifically LDL levels, as well as for preventing myocardial infarction.

Unfortunately, significant side effects have been reported, and myopathy is the most prevalent. Statin-induced myopathy includes a combination of muscle tenderness, myalgia, and weakness.^2–11 In randomized controlled trials, the risk of myopathy was estimated to be between 1.5% and 5%.⁶ In unselected clinic patients on high-dose statins, the rate of muscle complaints may be as high as 20%.¹²

The cause of statin-induced myopathy is not known, although studies have linked it to genetic defects.⁷ Risk factors have been identified and include personal and family history of myalgia, Asian ethnicity, hypothyroidism, and type 1 diabetes. The incidence of statin-induced myalgia is two to three times higher in patients on corticosteroid therapy. Other risk factors include female sex, liver disease, and renal dysfunction.^7,8

A less common etiology is anti-HMG coenzyme A reductase antibodies. Studies have shown that these antibody levels correlate well with the amount of myositis as measured by creatine kinase levels. However, there is no consensus yet on screening for these antibodies.¹³

Statin therapy poses a dilemma, as there is a thin line between the benefits and the risks of side effects, especially statin-induced myopathy.^3,4 Current recommendations include discontinuing the statin until symptoms fully resolve. Creatine kinase levels may be useful in assessing for potential muscle breakdown, especially in patients with reduced renal function, as this predisposes them to statin-induced myopathy, yet normal values do not preclude the diagnosis of statin-induced myopathy.^3,4,7,8

Once symptoms resolve and laboratory test results normalize, a trial of a different statin is recommended. If patients become symptomatic, a trial of a low-dose hydrophilic statin at a once- or twice-weekly interval has been recommended. Several studies have assessed the efficacy of a low-dose statin with decreased frequency of administration and have consistently shown significant improvement in lipid levels.^3,4 For instance, once-weekly rosuvastatin at a dose between 5 mg and 20 mg resulted in a 29% reduction in LDL cholesterol levels, and 80% of patients did not experience a recurrence of myalgia.³ Furthermore, a study of patients treated with 5 mg to 10 mg of rosuvastatin twice a week resulted in a 26% decrease in LDL cholesterol levels.⁴ This study also showed that when an additional non-statin lipid-lowering drug was prescribed (eg, ezetimibe, bile acid resin, nicotinic acid), more than half of the patients reached their goal lipid level.⁴

The addition of coenzyme Q10 and fish oil has also been suggested. Although, the evidence to support this is inconclusive, the potential benefit outweighs the risk, since the side effects are minimal.¹ However, no study yet has evaluated the risks vs the benefits in patients with elevated creatine kinase.

Statin-induced myopathy is a commonly encountered adverse effect. Currently, there are no guidelines on restarting statin therapy after statin-induced myopathy; however, data suggest that statin therapy should be restarted once symptoms resolve, and that variations in dose and frequency may be necessary.^1–8,14

An 85-year-old man with hypertension, hyperlipidemia, and coronary artery disease presented to our clinic with diffuse muscle pain. The pain had been present for about 3 months, but it had become noticeably worse over the past few weeks.

He was not aware of any trauma. He described the muscle pain as dull and particularly severe in his lower extremities (his thighs and calves). The pain did not limit his daily activities, nor did physical exertion or the time of day have any effect on the level of the pain.

His medications at that time included metoprolol, aspirin, hydrochlorothiazide, simvastatin, and a daily multivitamin.

He was not in acute distress. On neurologic and musculoskeletal examinations, all deep-tendon reflexes were intact, with no tenderness to palpation of the upper and lower extremities. No abnormalities were noted on the joint examination. He had full range of motion, with 5/5 muscle strength in the upper and lower extremities bilaterally and normal muscle tone. He was able to walk with ease. Results of initial laboratory testing, including creatine kinase and erythrocyte sedimentation rate, were normal.

1. What should be the next best step in the evaluation of this patient’s muscle pain?

• Order tests for cyclic citrullinated peptide (CCP) antibody and rheumatoid factor
• Advise him to refrain from physical activity until his symptoms resolve
• Take a more detailed history, including a review of medications and supplements
• Recommend a trial of a nonsteroidal anti-inflammatory drug (NSAID)
• Send him for radiographic imaging

Since his muscle pain has persisted for several months without improvement, a more detailed history should be taken, including a review of current medications and supplements.

Testing CCP antibody and rheumatoid factor would be useful if rheumatoid arthritis were suspected, but in the absence of demonstrable arthritis on examination, these tests would have low specificity even if the results were positive.

An NSAID may temporarily alleviate his pain, but it will not help establish a diagnosis. And in elderly patients, NSAIDs are not without complications and so should be prescribed only in appropriate situations.

Imaging would be appropriate at this point only if there was clinical suspicion of a specific disease. However, our patient has no focal deficits, and the suspicion of fracture or malignancy is low.

The medical history should include asking about current drug regimens, recent medication changes, and the use of herbal supplements, since polypharmacy is common in elderly patients with multiple comorbidities.

On further questioning, our patient said that his dose of simvastatin had been increased from 40 mg daily to 80 mg daily about 1 month before his symptoms appeared. He was taking a daily multivitamin but was not using herbal supplements or other over-the-counter products. He did not recall any constitutional symptoms before the onset of his current symptoms, and he had never had similar muscle pain in the past.

2. Based on the additional information from the history, what is the most likely cause of his muscle pain?

• Limited myositis secondary to recent viral infection
• Rhabdomyolysis
• Hypothyroidism
• Drug-drug interaction
• Statin-induced myalgia

Our patient’s history provided nothing to suggest viral myositis. Hypothyroidism should always be considered in patients with myalgia, but this is not likely in our patient, as he does not display other characteristics, such as diminished reflexes, hypotonia, cold intolerance, and mood instability. Even though calcium channel blockers have been known to cause myalgia in patients on statins, a drug-drug reaction is not likely, as he had not started taking a calcium channel blocker before his symptoms began. This patient did not show signs or symptoms of rhabdomyolysis, a type of myopathy in which necrosis of the muscle tissue occurs, generally causing profound weakness and pain.¹

Therefore, statin-induced myopathy is the most likely cause of his diffuse muscle pain, particularly since his simvastatin had been increased 1 month before the onset of symptoms.

3. What should be the next step in his management?

• Decrease the dose of simvastatin to the last known dose he was able to tolerate
• Continue simvastatin at the same dose and then monitor
• Switch to another statin
• Add coenzyme Q10
• Stop simvastatin

Decreasing the statin dosage to the last well-tolerated dose would not be appropriate in a patient with myopathy, as the symptoms would probably not improve.^2–4 Also, one should not switch to a different statin while a patient is experiencing symptoms. Rather, the statin should be stopped for at least 6 weeks or until the symptoms have fully resolved.¹

Adding coenzyme Q10 is another option, especially in a patient with previously diagnosed coronary artery disease,⁵ when continued statin therapy is thought necessary to reduce the likelihood of repeat coronary events.

We discontinued his simvastatin. Followup 3 weeks later in the outpatient clinic showed that his symptoms were slowly improving. The symptoms had resolved completely 4 months later.

4. How should we manage our patient’s hyperlipidemia once his symptoms have resolved?

• Restart simvastatin at the 80-mg dose
• Restart simvastatin at the 40-mg dose
• Start a hydrophilic statin at full dose
• Use a drug from another class of lipid-lowering drugs
• Wait another 3 months before prescribing any lipid-lowering drug

His treatment for hyperlipidemia should be continued, considering his comorbidities. However, restarting the same statin, even at a lower dose, will likely cause his symptoms to recur. Thus, a different statin should be tried once his muscle pain has resolved.

Other classes of lipid-lowering drugs are usually less efficacious than statins, particularly when trying to control low-density lipoprotein (LDL) cholesterol, so a drug from another class should not be used until other statin options have been attempted.^2,6,7

Simvastatin is lipophilic. Trying a statin with hydrophilic properties (eg, pravastatin, rosuvastatin, fluvastatin) has been shown to convey similar cardioprotective effects with a lower propensity for myalgia, as lipophilic statins have a higher propensity to penetrate muscle tissue than do hydrophilic statins.^3,4,8

Once his symptoms resolved, our patient was started on a hydrophilic statin, fluvastatin 20 mg daily. Unfortunately, his pain recurred 3 weeks later. The statin was stopped, and his symptoms again resolved.

5. Since our patient was unable to tolerate a second statin, what should be the next step in his management?

• Restart simvastatin 
• Use a drug from another class to control the hyperlipidemia
• Wait at least 6 months after symptoms resolve before trying any lipid-lowering drug
• Initiate therapy with coenzyme Q10 and fish oil
• Wait for symptoms to resolve, then restart a hydrophilic statin at a lower dose and lower frequency

Restarting simvastatin will likely cause a recurrence of the myalgia. Other lipid-lowering drugs such as nicotinic acid, bile acid resins, and fibrates are not as efficacious as statins. Coenzyme Q10 and fish oil can reduce lipid levels, but they are not as efficacious as statins.

In view of our patient’s lipid profile—LDL cholesterol elevated at 167 mg/dL, high-density lipoprotein cholesterol 31 mg/dL, triglycerides 47 mg/dL—it is important to treat his hyperlipidemia. Therefore, another attempt at statin therapy should be made once his symptoms have resolved.

Studies have shown that restarting a statin at a low dose and low frequency is effective in patients who have experienced intolerance to a statin.^3,4 Our patient was treated with low-dose pravastatin (20 mg), resulting in a moderate improvement in his LDL cholesterol to 123 mg/dL.

STATIN-INDUCED MYOPATHY: ADDRESSING THE DILEMMA

Treating hyperlipidemia is important to prevent vascular events in patients with or without coronary artery disease. Statins are the most effective agents available for controlling hypercholesterolemia, specifically LDL levels, as well as for preventing myocardial infarction.

Unfortunately, significant side effects have been reported, and myopathy is the most prevalent. Statin-induced myopathy includes a combination of muscle tenderness, myalgia, and weakness.^2–11 In randomized controlled trials, the risk of myopathy was estimated to be between 1.5% and 5%.⁶ In unselected clinic patients on high-dose statins, the rate of muscle complaints may be as high as 20%.¹²

The cause of statin-induced myopathy is not known, although studies have linked it to genetic defects.⁷ Risk factors have been identified and include personal and family history of myalgia, Asian ethnicity, hypothyroidism, and type 1 diabetes. The incidence of statin-induced myalgia is two to three times higher in patients on corticosteroid therapy. Other risk factors include female sex, liver disease, and renal dysfunction.^7,8

A less common etiology is anti-HMG coenzyme A reductase antibodies. Studies have shown that these antibody levels correlate well with the amount of myositis as measured by creatine kinase levels. However, there is no consensus yet on screening for these antibodies.¹³

Statin therapy poses a dilemma, as there is a thin line between the benefits and the risks of side effects, especially statin-induced myopathy.^3,4 Current recommendations include discontinuing the statin until symptoms fully resolve. Creatine kinase levels may be useful in assessing for potential muscle breakdown, especially in patients with reduced renal function, as this predisposes them to statin-induced myopathy, yet normal values do not preclude the diagnosis of statin-induced myopathy.^3,4,7,8

Once symptoms resolve and laboratory test results normalize, a trial of a different statin is recommended. If patients become symptomatic, a trial of a low-dose hydrophilic statin at a once- or twice-weekly interval has been recommended. Several studies have assessed the efficacy of a low-dose statin with decreased frequency of administration and have consistently shown significant improvement in lipid levels.^3,4 For instance, once-weekly rosuvastatin at a dose between 5 mg and 20 mg resulted in a 29% reduction in LDL cholesterol levels, and 80% of patients did not experience a recurrence of myalgia.³ Furthermore, a study of patients treated with 5 mg to 10 mg of rosuvastatin twice a week resulted in a 26% decrease in LDL cholesterol levels.⁴ This study also showed that when an additional non-statin lipid-lowering drug was prescribed (eg, ezetimibe, bile acid resin, nicotinic acid), more than half of the patients reached their goal lipid level.⁴

The addition of coenzyme Q10 and fish oil has also been suggested. Although, the evidence to support this is inconclusive, the potential benefit outweighs the risk, since the side effects are minimal.¹ However, no study yet has evaluated the risks vs the benefits in patients with elevated creatine kinase.

Statin-induced myopathy is a commonly encountered adverse effect. Currently, there are no guidelines on restarting statin therapy after statin-induced myopathy; however, data suggest that statin therapy should be restarted once symptoms resolve, and that variations in dose and frequency may be necessary.^1–8,14

A 42-year-old woman is admitted to the hospital with worsening shortness of breath on exertion, poor exercise tolerance, leg edema, and swelling of the abdomen. Her symptoms have been getting worse over the last 4 months. She reports no history of fever, chills, night sweats, bleeding disorder, joint pain, weight loss, or loss of appetite.

She has type 2 diabetes mellitus and hypothyroidism. She had rheumatoid arthritis but said it was “inactive,” not requiring treatment for the last 18 years. Three months ago, she underwent a total hysterectomy and salpingo-oophorectomy for a complex adnexal mass, biopsy of which revealed a benign mucinous ovarian cyst.

Her current medications include furosemide, levothyroxine, and metformin. She is an ex-smoker with a 7 pack-year history. She drinks a glass of wine on social occasions only. Her family history is unremarkable.

On examination, she is not in distress and she has no fever. She has jugular venous distention of 5 cm, tense ascites, and marked edema of the legs, as well as hyperpigmented patches and erythematous plaques over both shins. Neck palpation reveals no lymphadenopathy or thyromegaly.

Her liver and the tip of the spleen are palpable following paracentesis, once ascitic fluid is removed.

The cardiovascular examination is normal. Chest auscultation reveals decreased breath sounds at the right lung base with bibasilar crackles. No focal neurologic deficit is noted on clinical examination.

Laboratory testing at the time of hospital admission (Table 1) includes a hepatitis panel (negative for exposure to hepatitis A, B, and C) and ascitic fluid studies. Chest radiography shows a right pleural effusion. Echocardiography demonstrates moderate pericardial effusion without tamponade; left and right ventricular function is normal. Cardiac magnetic resonance imaging finds no evidence of pericardial constriction or restrictive cardiomyopathy. Pressures are normal on pulmonary artery catheterization.

FINDING THE CAUSE OF ASCITES

1. What is the most likely cause of ascites in this patient?

• Cirrhosis
• Recent abdominal surgery
• Congestive heart failure
• Abdominal malignancy
• Nephrotic syndrome

The serum-ascites albumin gradient—ie, the serum albumin concentration minus the ascitic fluid albumin concentration—helps determine whether ascites is related to portal hypertension.¹ A high gradient (ie, above 1.1 g/dL) is seen in cirrhosis, alcoholic hepatitis, congestive heart failure, vascular occlusion syndromes (eg, Budd-Chiari syndrome), and metastatic liver disease.

From the values in Table 1, our patient’s gradient is 0.8 g/dL, which is considered low. However, we cannot completely rule out cirrhosis as the cause of her ascites because she was taking a diuretic, and diuretics can falsely decrease the gradient. Heart failure is unlikely, based on the results of echocardiography and catheterization. In addition, the 24-hour urinary protein concentration is normal, as is alpha-1 antitrypsin secretion in the stool, ruling out protein-losing nephropathy or enteropathy as the cause of her low albumin and ascites.

A high triglyceride content in her ascitic fluid (> 150 mg/dL) is consistent with chylous ascites, which is seen in patients with previous abdominal surgery or with lymphatic obstruction due to malignancy. A high neutrophil count in the ascitic fluid and a negative culture are also consistent with chylous ascites. However, in this patient, recent surgery as the cause of chylous ascites does not explain the systemic features of hepatosplenomegaly, anemia, thrombocytosis, and low albumin. Moreover, her high C-reactive protein value suggests an ongoing inflammatory process, although her erythrocyte sedimentation rate is not significantly elevated.

Therefore, the most likely cause of ascites in this patient is abdominal malignancy.

WHAT SHOULD BE DONE NEXT?

2. Which of the following studies is reasonable in this patient at this point?

• Serum protein electrophoresis
• Computed tomography (CT) of the chest, abdomen, and pelvis
• Liver biopsy
• Cytologic study of the ascitic fluid

All of these studies would be reasonable and in fact were done in this patient.

Serum protein electrophoresis (Table 2) identified a monoclonal protein band in the immunoglobulin G (IgG) kappa region.

Cytologic study of the ascitic fluid was negative for malignant cells.

Chest CT revealed bilateral pleural effusions, pericardial effusion, and bilateral axillary lymphadenopathy. CT of the abdomen and pelvis was normal, except for ascites, and no pelvic tumor was noted.

Liver biopsy was done to look for the source of her unexplained ascites with elevated alkaline phosphatase, as all other investigations so far were normal. It revealed mild centrilobular scarring, but the rest of the parenchymal architecture was normal, with no evidence of bridging fibrosis or nodular regenerative hyperplasia (Figure 1).

Transjugular measurement of the hepatic vein pressure revealed a hepatic vein pressure gradient of 9 mm Hg, indicating mild portal hypertension. Venography showed widely patent hepatic and portal veins. Her high inflammatory marker levels could have been caused by smoldering rheumatoid arthritis; however, since the patient has had no joint symptoms for 18 years, this is very unlikely. It is more likely to be caused by a plasma cell disorder, as suggested by a monoclonal protein on electrophoresis.

WHAT IS THE DIAGNOSIS?

3. What is the most likely diagnosis in our patient?

• Rheumatoid arthritis
• Cryoglobulinemia
• Capillary leak syndrome
• Hematologic malignancy
• Syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS syndrome)

Rheumatoid arthritis can present with hepatosplenomegaly, lymphadenopathy, ascites, and skin rash, particularly if antinuclear antibody and rheumatoid factor are elevated. Ascites is known to occur in association with rheumatoid arthritis in the setting of Felty syndrome or nodular regenerative hyperplasia of the liver.² However, our patient did not have leukopenia or evidence of regenerative hyperplasia on liver biopsy. Moreover, her rheumatoid arthritis had remained clinically inactive for a long time.

Cryoglobulinemia was possible, given her ascites, neuropathy, and splenomegaly, but her serum hepatic antibody and C4 complement values were normal.³ Also, the appearance of her rash was not typical of cryoglobulinemia.

Capillary leak syndrome was ruled out by the absence of hypotensive episodes, edema of the face or upper extremities, or renal failure.⁴

Lymphoma was excluded by flow cytometry.

A monoclonal protein on serum electrophoresis may suggest multiple myeloma, but this patient had multisystem involvement including organomegaly, endocrinopathy, and skin abnormalities. Thus, POEMS syndrome is the most likely diagnosis.

4. Which test should be done at this time to confirm the diagnosis of POEMS syndrome?

• Bone marrow biopsy
• Vascular endothelial growth factor testing
• Nerve conduction study
• Complete x-ray bone survey

A test for vascular endothelial growth factor should be done. This growth factor is almost always elevated in POEMS, and a positive test helps confirm the diagnosis of POEMS. Our patient’s level was elevated at 1,664 pg/mL (reference range 31–86).

POEMS is thought to be a variant of plasma cell dyscrasia, and all patients with POEMS have a monoclonal protein on electrophoresis. On this background, multiple myeloma is an important consideration.

Our patient underwent bone marrow biopsy, which revealed mild plasmacytosis (< 10%) (Figure 2). A complete bone survey showed generalized osteopenia without blastic or lytic lesions. To complete the workup for POEMS syndrome, a nerve conduction study was done to look for neuropathy; it showed bilateral sensory motor neuropathy with features of both a demyelinating process and axonal loss.

POEMS SYNDROME

POEMS syndrome is a constellation of features such as organomegaly and endocrine and skin abnormalities in association with neuropathy and a monoclonal protein on electrophoresis.⁵ In 2003, Dispenzieri et al⁶ described the major and minor diagnostic criteria based on a retrospective analysis of 99 patients with POEMS syndrome.⁶ Later, elevated vascular endothelial growth factor was added as a confirmatory diagnostic criterion.⁷ This growth factor is also an indicator of prognosis in POEMS syndrome, and its level can be used to monitor the response to treatment.⁷

Our patient met both major criteria for POEMS syndrome, ie, polyneuropathy (based on nerve conduction studies) and a monoclonal protein. Polyneuropathy in POEMS syndrome usually occurs as sensorimotor peripheral neuropathy of insidious onset and is seldom painful. Nerve biopsy study reveals demyelination with features of axonal loss. Interestingly, although our patient had neuropathy as diagnosed by electromyography, she remained clinically asymptomatic.

The monoclonal protein in POEMS syndrome is commonly IgA or IgG. Light chains are always present and are mainly the lambda type; kappa light chains are also reported in rare cases. Our patient had IgG kappa light chains.

Our patient met a number of the minor criteria for POEMS syndrome: ie, organomegaly (hepatosplenomegaly, lymphadenopathy), endocrinopathy (hypothyroidism, diabetes), skin changes (hyperpigmentation and plaques of the lower extremities), edema, pleural effusion, and ascites.

Endocrine disorders in POEMS syndrome

The endocrine abnormalities most often described in POEMS syndrome are hypogonadism, hypothyroidism, and diabetes mellitus. But because hypothyroidism and diabetes are common in the general population, it is debatable whether either of these could constitute the endocrine component of POEMS syndrome. Nevertheless, in three large series,^6,7 occurrences of these two disorders were common, although less specific than adrenal or pituitary involvement.

In the analysis by Dispenzieri et al,⁶ 67% of patients had at least one endocrine abnormality. Our patient had no evidence of an adrenal disorder.

Skin, skeletal, and other changes

The skin changes in POEMS syndrome are often nonspecific and include hyperpigmentation, sclerodema-like thickening, and plaques.

Skeletal changes are noted in up to 97% of patients. A skeletal survey in our patient revealed generalized osteopenia as opposed to osteosclerotic lesions, which are common in POEMS syndrome.

Anemia and thrombocytosis (as in our patient) are usually seen in POEMS syndrome and are induced by cytokines.⁶ POEMS syndrome also leads to increased thrombotic complications from the release of inflammatory cytokines.

Hypoalbuminemia and anasarca including ascites are often seen in POEMS syndrome (prevalence 29% to 89%) and are attributed to cytokine-induced increased vascular permeability. In POEMS syndrome, the serum-ascites albumin gradient is usually less than 1.1 g/dL, as in our patient.

Stepani et al⁸ reported one case of culture-negative neutrocytic ascites with portal hypertension in POEMS syndrome.⁸ (Culture-negative neutrocytic ascites is defined as an ascitic fluid polymorphonuclear count greater than 250/mm³ and a negative ascitic fluid culture in the absence of previous antibiotic therapy.) Chylous ascites has not yet been described in POEMS syndrome. However, chylous ascites is predominantly lymphocytic, whereas our patient had neutrocytic ascites.

We concluded that the cause of our patient’s ascites was multifactorial and included previous surgery and POEMS syndrome.

Nonclassic presentation

In addition to its classic presentation, POEMS syndrome is often reported in association with other “unusual features” such as cardiomyopathy, pulmonary hypertension, and cryoglobulinemia.⁶

So far, very few cases of portal hypertension in POEMS syndrome have been reported. Stepani et al⁸ described a patient who had POEMS syndrome and portal hypertension with extensive portal fibrosis without cirrhosis on liver biopsy. Inoue et al⁹ reported a liver biopsy feature consistent with idiopathic portal hypertension, also noting a case with mild fibrosis and few lymphocytic infiltrates in the portal tract.⁹

The etiopathogenesis of POEMS syndrome is attributed to proangiogenic vascular endothelial growth factor, and other inflammatory cytokines (interleukin 6, interleukin 1 beta, tumor necrosis factor alpha) also play a key role in pulmonary hypertension.^10,11 A similar pathogenesis could also contribute to the development of portal hypertension (Figure 3).

CASE CONCLUDED

We started our patient on oral prednisone 60 mg daily for a month, tapered to a maintenance dose of 15 mg to suppress clonal proliferation of plasma cells. Her symptoms improved. Her vascular endothelial growth factor level decreased from 1,664 to 624 pg/mL. She was enrolled in a National Institutes of Health study to evaluate the effect of a potential new immunomodulator treatment for POEMS syndrome.

In conclusion, POEMS syndrome is rare and can present with many atypical features. A high index of suspicion is needed to detect it in a patient who has noncirrhotic portal hypertension with ascites and multisystem involvement.

A 42-year-old woman is admitted to the hospital with worsening shortness of breath on exertion, poor exercise tolerance, leg edema, and swelling of the abdomen. Her symptoms have been getting worse over the last 4 months. She reports no history of fever, chills, night sweats, bleeding disorder, joint pain, weight loss, or loss of appetite.

She has type 2 diabetes mellitus and hypothyroidism. She had rheumatoid arthritis but said it was “inactive,” not requiring treatment for the last 18 years. Three months ago, she underwent a total hysterectomy and salpingo-oophorectomy for a complex adnexal mass, biopsy of which revealed a benign mucinous ovarian cyst.

Her current medications include furosemide, levothyroxine, and metformin. She is an ex-smoker with a 7 pack-year history. She drinks a glass of wine on social occasions only. Her family history is unremarkable.

On examination, she is not in distress and she has no fever. She has jugular venous distention of 5 cm, tense ascites, and marked edema of the legs, as well as hyperpigmented patches and erythematous plaques over both shins. Neck palpation reveals no lymphadenopathy or thyromegaly.

Her liver and the tip of the spleen are palpable following paracentesis, once ascitic fluid is removed.

The cardiovascular examination is normal. Chest auscultation reveals decreased breath sounds at the right lung base with bibasilar crackles. No focal neurologic deficit is noted on clinical examination.

Laboratory testing at the time of hospital admission (Table 1) includes a hepatitis panel (negative for exposure to hepatitis A, B, and C) and ascitic fluid studies. Chest radiography shows a right pleural effusion. Echocardiography demonstrates moderate pericardial effusion without tamponade; left and right ventricular function is normal. Cardiac magnetic resonance imaging finds no evidence of pericardial constriction or restrictive cardiomyopathy. Pressures are normal on pulmonary artery catheterization.

FINDING THE CAUSE OF ASCITES

1. What is the most likely cause of ascites in this patient?

• Cirrhosis
• Recent abdominal surgery
• Congestive heart failure
• Abdominal malignancy
• Nephrotic syndrome

The serum-ascites albumin gradient—ie, the serum albumin concentration minus the ascitic fluid albumin concentration—helps determine whether ascites is related to portal hypertension.¹ A high gradient (ie, above 1.1 g/dL) is seen in cirrhosis, alcoholic hepatitis, congestive heart failure, vascular occlusion syndromes (eg, Budd-Chiari syndrome), and metastatic liver disease.

From the values in Table 1, our patient’s gradient is 0.8 g/dL, which is considered low. However, we cannot completely rule out cirrhosis as the cause of her ascites because she was taking a diuretic, and diuretics can falsely decrease the gradient. Heart failure is unlikely, based on the results of echocardiography and catheterization. In addition, the 24-hour urinary protein concentration is normal, as is alpha-1 antitrypsin secretion in the stool, ruling out protein-losing nephropathy or enteropathy as the cause of her low albumin and ascites.

A high triglyceride content in her ascitic fluid (> 150 mg/dL) is consistent with chylous ascites, which is seen in patients with previous abdominal surgery or with lymphatic obstruction due to malignancy. A high neutrophil count in the ascitic fluid and a negative culture are also consistent with chylous ascites. However, in this patient, recent surgery as the cause of chylous ascites does not explain the systemic features of hepatosplenomegaly, anemia, thrombocytosis, and low albumin. Moreover, her high C-reactive protein value suggests an ongoing inflammatory process, although her erythrocyte sedimentation rate is not significantly elevated.

Therefore, the most likely cause of ascites in this patient is abdominal malignancy.

WHAT SHOULD BE DONE NEXT?

2. Which of the following studies is reasonable in this patient at this point?

• Serum protein electrophoresis
• Computed tomography (CT) of the chest, abdomen, and pelvis
• Liver biopsy
• Cytologic study of the ascitic fluid

All of these studies would be reasonable and in fact were done in this patient.

Serum protein electrophoresis (Table 2) identified a monoclonal protein band in the immunoglobulin G (IgG) kappa region.

Cytologic study of the ascitic fluid was negative for malignant cells.

Chest CT revealed bilateral pleural effusions, pericardial effusion, and bilateral axillary lymphadenopathy. CT of the abdomen and pelvis was normal, except for ascites, and no pelvic tumor was noted.

Liver biopsy was done to look for the source of her unexplained ascites with elevated alkaline phosphatase, as all other investigations so far were normal. It revealed mild centrilobular scarring, but the rest of the parenchymal architecture was normal, with no evidence of bridging fibrosis or nodular regenerative hyperplasia (Figure 1).

Transjugular measurement of the hepatic vein pressure revealed a hepatic vein pressure gradient of 9 mm Hg, indicating mild portal hypertension. Venography showed widely patent hepatic and portal veins. Her high inflammatory marker levels could have been caused by smoldering rheumatoid arthritis; however, since the patient has had no joint symptoms for 18 years, this is very unlikely. It is more likely to be caused by a plasma cell disorder, as suggested by a monoclonal protein on electrophoresis.

WHAT IS THE DIAGNOSIS?

3. What is the most likely diagnosis in our patient?

• Rheumatoid arthritis
• Cryoglobulinemia
• Capillary leak syndrome
• Hematologic malignancy
• Syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS syndrome)

Rheumatoid arthritis can present with hepatosplenomegaly, lymphadenopathy, ascites, and skin rash, particularly if antinuclear antibody and rheumatoid factor are elevated. Ascites is known to occur in association with rheumatoid arthritis in the setting of Felty syndrome or nodular regenerative hyperplasia of the liver.² However, our patient did not have leukopenia or evidence of regenerative hyperplasia on liver biopsy. Moreover, her rheumatoid arthritis had remained clinically inactive for a long time.

Cryoglobulinemia was possible, given her ascites, neuropathy, and splenomegaly, but her serum hepatic antibody and C4 complement values were normal.³ Also, the appearance of her rash was not typical of cryoglobulinemia.

Capillary leak syndrome was ruled out by the absence of hypotensive episodes, edema of the face or upper extremities, or renal failure.⁴

Lymphoma was excluded by flow cytometry.

A monoclonal protein on serum electrophoresis may suggest multiple myeloma, but this patient had multisystem involvement including organomegaly, endocrinopathy, and skin abnormalities. Thus, POEMS syndrome is the most likely diagnosis.

4. Which test should be done at this time to confirm the diagnosis of POEMS syndrome?

• Bone marrow biopsy
• Vascular endothelial growth factor testing
• Nerve conduction study
• Complete x-ray bone survey

A test for vascular endothelial growth factor should be done. This growth factor is almost always elevated in POEMS, and a positive test helps confirm the diagnosis of POEMS. Our patient’s level was elevated at 1,664 pg/mL (reference range 31–86).

POEMS is thought to be a variant of plasma cell dyscrasia, and all patients with POEMS have a monoclonal protein on electrophoresis. On this background, multiple myeloma is an important consideration.

Our patient underwent bone marrow biopsy, which revealed mild plasmacytosis (< 10%) (Figure 2). A complete bone survey showed generalized osteopenia without blastic or lytic lesions. To complete the workup for POEMS syndrome, a nerve conduction study was done to look for neuropathy; it showed bilateral sensory motor neuropathy with features of both a demyelinating process and axonal loss.

POEMS SYNDROME

POEMS syndrome is a constellation of features such as organomegaly and endocrine and skin abnormalities in association with neuropathy and a monoclonal protein on electrophoresis.⁵ In 2003, Dispenzieri et al⁶ described the major and minor diagnostic criteria based on a retrospective analysis of 99 patients with POEMS syndrome.⁶ Later, elevated vascular endothelial growth factor was added as a confirmatory diagnostic criterion.⁷ This growth factor is also an indicator of prognosis in POEMS syndrome, and its level can be used to monitor the response to treatment.⁷

Our patient met both major criteria for POEMS syndrome, ie, polyneuropathy (based on nerve conduction studies) and a monoclonal protein. Polyneuropathy in POEMS syndrome usually occurs as sensorimotor peripheral neuropathy of insidious onset and is seldom painful. Nerve biopsy study reveals demyelination with features of axonal loss. Interestingly, although our patient had neuropathy as diagnosed by electromyography, she remained clinically asymptomatic.

The monoclonal protein in POEMS syndrome is commonly IgA or IgG. Light chains are always present and are mainly the lambda type; kappa light chains are also reported in rare cases. Our patient had IgG kappa light chains.

Our patient met a number of the minor criteria for POEMS syndrome: ie, organomegaly (hepatosplenomegaly, lymphadenopathy), endocrinopathy (hypothyroidism, diabetes), skin changes (hyperpigmentation and plaques of the lower extremities), edema, pleural effusion, and ascites.

Endocrine disorders in POEMS syndrome

The endocrine abnormalities most often described in POEMS syndrome are hypogonadism, hypothyroidism, and diabetes mellitus. But because hypothyroidism and diabetes are common in the general population, it is debatable whether either of these could constitute the endocrine component of POEMS syndrome. Nevertheless, in three large series,^6,7 occurrences of these two disorders were common, although less specific than adrenal or pituitary involvement.

In the analysis by Dispenzieri et al,⁶ 67% of patients had at least one endocrine abnormality. Our patient had no evidence of an adrenal disorder.

Skin, skeletal, and other changes

The skin changes in POEMS syndrome are often nonspecific and include hyperpigmentation, sclerodema-like thickening, and plaques.

Skeletal changes are noted in up to 97% of patients. A skeletal survey in our patient revealed generalized osteopenia as opposed to osteosclerotic lesions, which are common in POEMS syndrome.

Anemia and thrombocytosis (as in our patient) are usually seen in POEMS syndrome and are induced by cytokines.⁶ POEMS syndrome also leads to increased thrombotic complications from the release of inflammatory cytokines.

Hypoalbuminemia and anasarca including ascites are often seen in POEMS syndrome (prevalence 29% to 89%) and are attributed to cytokine-induced increased vascular permeability. In POEMS syndrome, the serum-ascites albumin gradient is usually less than 1.1 g/dL, as in our patient.

Stepani et al⁸ reported one case of culture-negative neutrocytic ascites with portal hypertension in POEMS syndrome.⁸ (Culture-negative neutrocytic ascites is defined as an ascitic fluid polymorphonuclear count greater than 250/mm³ and a negative ascitic fluid culture in the absence of previous antibiotic therapy.) Chylous ascites has not yet been described in POEMS syndrome. However, chylous ascites is predominantly lymphocytic, whereas our patient had neutrocytic ascites.

We concluded that the cause of our patient’s ascites was multifactorial and included previous surgery and POEMS syndrome.

Nonclassic presentation

In addition to its classic presentation, POEMS syndrome is often reported in association with other “unusual features” such as cardiomyopathy, pulmonary hypertension, and cryoglobulinemia.⁶

So far, very few cases of portal hypertension in POEMS syndrome have been reported. Stepani et al⁸ described a patient who had POEMS syndrome and portal hypertension with extensive portal fibrosis without cirrhosis on liver biopsy. Inoue et al⁹ reported a liver biopsy feature consistent with idiopathic portal hypertension, also noting a case with mild fibrosis and few lymphocytic infiltrates in the portal tract.⁹

The etiopathogenesis of POEMS syndrome is attributed to proangiogenic vascular endothelial growth factor, and other inflammatory cytokines (interleukin 6, interleukin 1 beta, tumor necrosis factor alpha) also play a key role in pulmonary hypertension.^10,11 A similar pathogenesis could also contribute to the development of portal hypertension (Figure 3).

CASE CONCLUDED

We started our patient on oral prednisone 60 mg daily for a month, tapered to a maintenance dose of 15 mg to suppress clonal proliferation of plasma cells. Her symptoms improved. Her vascular endothelial growth factor level decreased from 1,664 to 624 pg/mL. She was enrolled in a National Institutes of Health study to evaluate the effect of a potential new immunomodulator treatment for POEMS syndrome.

In conclusion, POEMS syndrome is rare and can present with many atypical features. A high index of suspicion is needed to detect it in a patient who has noncirrhotic portal hypertension with ascites and multisystem involvement.

A 42-year-old woman is admitted to the hospital with worsening shortness of breath on exertion, poor exercise tolerance, leg edema, and swelling of the abdomen. Her symptoms have been getting worse over the last 4 months. She reports no history of fever, chills, night sweats, bleeding disorder, joint pain, weight loss, or loss of appetite.

She has type 2 diabetes mellitus and hypothyroidism. She had rheumatoid arthritis but said it was “inactive,” not requiring treatment for the last 18 years. Three months ago, she underwent a total hysterectomy and salpingo-oophorectomy for a complex adnexal mass, biopsy of which revealed a benign mucinous ovarian cyst.

Her current medications include furosemide, levothyroxine, and metformin. She is an ex-smoker with a 7 pack-year history. She drinks a glass of wine on social occasions only. Her family history is unremarkable.

On examination, she is not in distress and she has no fever. She has jugular venous distention of 5 cm, tense ascites, and marked edema of the legs, as well as hyperpigmented patches and erythematous plaques over both shins. Neck palpation reveals no lymphadenopathy or thyromegaly.

Her liver and the tip of the spleen are palpable following paracentesis, once ascitic fluid is removed.

The cardiovascular examination is normal. Chest auscultation reveals decreased breath sounds at the right lung base with bibasilar crackles. No focal neurologic deficit is noted on clinical examination.

Laboratory testing at the time of hospital admission (Table 1) includes a hepatitis panel (negative for exposure to hepatitis A, B, and C) and ascitic fluid studies. Chest radiography shows a right pleural effusion. Echocardiography demonstrates moderate pericardial effusion without tamponade; left and right ventricular function is normal. Cardiac magnetic resonance imaging finds no evidence of pericardial constriction or restrictive cardiomyopathy. Pressures are normal on pulmonary artery catheterization.

FINDING THE CAUSE OF ASCITES

1. What is the most likely cause of ascites in this patient?

• Cirrhosis
• Recent abdominal surgery
• Congestive heart failure
• Abdominal malignancy
• Nephrotic syndrome

The serum-ascites albumin gradient—ie, the serum albumin concentration minus the ascitic fluid albumin concentration—helps determine whether ascites is related to portal hypertension.¹ A high gradient (ie, above 1.1 g/dL) is seen in cirrhosis, alcoholic hepatitis, congestive heart failure, vascular occlusion syndromes (eg, Budd-Chiari syndrome), and metastatic liver disease.

From the values in Table 1, our patient’s gradient is 0.8 g/dL, which is considered low. However, we cannot completely rule out cirrhosis as the cause of her ascites because she was taking a diuretic, and diuretics can falsely decrease the gradient. Heart failure is unlikely, based on the results of echocardiography and catheterization. In addition, the 24-hour urinary protein concentration is normal, as is alpha-1 antitrypsin secretion in the stool, ruling out protein-losing nephropathy or enteropathy as the cause of her low albumin and ascites.

A high triglyceride content in her ascitic fluid (> 150 mg/dL) is consistent with chylous ascites, which is seen in patients with previous abdominal surgery or with lymphatic obstruction due to malignancy. A high neutrophil count in the ascitic fluid and a negative culture are also consistent with chylous ascites. However, in this patient, recent surgery as the cause of chylous ascites does not explain the systemic features of hepatosplenomegaly, anemia, thrombocytosis, and low albumin. Moreover, her high C-reactive protein value suggests an ongoing inflammatory process, although her erythrocyte sedimentation rate is not significantly elevated.

Therefore, the most likely cause of ascites in this patient is abdominal malignancy.

WHAT SHOULD BE DONE NEXT?

2. Which of the following studies is reasonable in this patient at this point?

• Serum protein electrophoresis
• Computed tomography (CT) of the chest, abdomen, and pelvis
• Liver biopsy
• Cytologic study of the ascitic fluid

All of these studies would be reasonable and in fact were done in this patient.

Serum protein electrophoresis (Table 2) identified a monoclonal protein band in the immunoglobulin G (IgG) kappa region.

Cytologic study of the ascitic fluid was negative for malignant cells.

Chest CT revealed bilateral pleural effusions, pericardial effusion, and bilateral axillary lymphadenopathy. CT of the abdomen and pelvis was normal, except for ascites, and no pelvic tumor was noted.

Liver biopsy was done to look for the source of her unexplained ascites with elevated alkaline phosphatase, as all other investigations so far were normal. It revealed mild centrilobular scarring, but the rest of the parenchymal architecture was normal, with no evidence of bridging fibrosis or nodular regenerative hyperplasia (Figure 1).

Transjugular measurement of the hepatic vein pressure revealed a hepatic vein pressure gradient of 9 mm Hg, indicating mild portal hypertension. Venography showed widely patent hepatic and portal veins. Her high inflammatory marker levels could have been caused by smoldering rheumatoid arthritis; however, since the patient has had no joint symptoms for 18 years, this is very unlikely. It is more likely to be caused by a plasma cell disorder, as suggested by a monoclonal protein on electrophoresis.

WHAT IS THE DIAGNOSIS?

3. What is the most likely diagnosis in our patient?

• Rheumatoid arthritis
• Cryoglobulinemia
• Capillary leak syndrome
• Hematologic malignancy
• Syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS syndrome)

Rheumatoid arthritis can present with hepatosplenomegaly, lymphadenopathy, ascites, and skin rash, particularly if antinuclear antibody and rheumatoid factor are elevated. Ascites is known to occur in association with rheumatoid arthritis in the setting of Felty syndrome or nodular regenerative hyperplasia of the liver.² However, our patient did not have leukopenia or evidence of regenerative hyperplasia on liver biopsy. Moreover, her rheumatoid arthritis had remained clinically inactive for a long time.

Cryoglobulinemia was possible, given her ascites, neuropathy, and splenomegaly, but her serum hepatic antibody and C4 complement values were normal.³ Also, the appearance of her rash was not typical of cryoglobulinemia.

Capillary leak syndrome was ruled out by the absence of hypotensive episodes, edema of the face or upper extremities, or renal failure.⁴

Lymphoma was excluded by flow cytometry.

A monoclonal protein on serum electrophoresis may suggest multiple myeloma, but this patient had multisystem involvement including organomegaly, endocrinopathy, and skin abnormalities. Thus, POEMS syndrome is the most likely diagnosis.

4. Which test should be done at this time to confirm the diagnosis of POEMS syndrome?

• Bone marrow biopsy
• Vascular endothelial growth factor testing
• Nerve conduction study
• Complete x-ray bone survey

A test for vascular endothelial growth factor should be done. This growth factor is almost always elevated in POEMS, and a positive test helps confirm the diagnosis of POEMS. Our patient’s level was elevated at 1,664 pg/mL (reference range 31–86).

POEMS is thought to be a variant of plasma cell dyscrasia, and all patients with POEMS have a monoclonal protein on electrophoresis. On this background, multiple myeloma is an important consideration.

Our patient underwent bone marrow biopsy, which revealed mild plasmacytosis (< 10%) (Figure 2). A complete bone survey showed generalized osteopenia without blastic or lytic lesions. To complete the workup for POEMS syndrome, a nerve conduction study was done to look for neuropathy; it showed bilateral sensory motor neuropathy with features of both a demyelinating process and axonal loss.

POEMS SYNDROME

POEMS syndrome is a constellation of features such as organomegaly and endocrine and skin abnormalities in association with neuropathy and a monoclonal protein on electrophoresis.⁵ In 2003, Dispenzieri et al⁶ described the major and minor diagnostic criteria based on a retrospective analysis of 99 patients with POEMS syndrome.⁶ Later, elevated vascular endothelial growth factor was added as a confirmatory diagnostic criterion.⁷ This growth factor is also an indicator of prognosis in POEMS syndrome, and its level can be used to monitor the response to treatment.⁷

Our patient met both major criteria for POEMS syndrome, ie, polyneuropathy (based on nerve conduction studies) and a monoclonal protein. Polyneuropathy in POEMS syndrome usually occurs as sensorimotor peripheral neuropathy of insidious onset and is seldom painful. Nerve biopsy study reveals demyelination with features of axonal loss. Interestingly, although our patient had neuropathy as diagnosed by electromyography, she remained clinically asymptomatic.

The monoclonal protein in POEMS syndrome is commonly IgA or IgG. Light chains are always present and are mainly the lambda type; kappa light chains are also reported in rare cases. Our patient had IgG kappa light chains.

Our patient met a number of the minor criteria for POEMS syndrome: ie, organomegaly (hepatosplenomegaly, lymphadenopathy), endocrinopathy (hypothyroidism, diabetes), skin changes (hyperpigmentation and plaques of the lower extremities), edema, pleural effusion, and ascites.

Endocrine disorders in POEMS syndrome

The endocrine abnormalities most often described in POEMS syndrome are hypogonadism, hypothyroidism, and diabetes mellitus. But because hypothyroidism and diabetes are common in the general population, it is debatable whether either of these could constitute the endocrine component of POEMS syndrome. Nevertheless, in three large series,^6,7 occurrences of these two disorders were common, although less specific than adrenal or pituitary involvement.

In the analysis by Dispenzieri et al,⁶ 67% of patients had at least one endocrine abnormality. Our patient had no evidence of an adrenal disorder.

Skin, skeletal, and other changes

The skin changes in POEMS syndrome are often nonspecific and include hyperpigmentation, sclerodema-like thickening, and plaques.

Skeletal changes are noted in up to 97% of patients. A skeletal survey in our patient revealed generalized osteopenia as opposed to osteosclerotic lesions, which are common in POEMS syndrome.

Anemia and thrombocytosis (as in our patient) are usually seen in POEMS syndrome and are induced by cytokines.⁶ POEMS syndrome also leads to increased thrombotic complications from the release of inflammatory cytokines.

Hypoalbuminemia and anasarca including ascites are often seen in POEMS syndrome (prevalence 29% to 89%) and are attributed to cytokine-induced increased vascular permeability. In POEMS syndrome, the serum-ascites albumin gradient is usually less than 1.1 g/dL, as in our patient.

Stepani et al⁸ reported one case of culture-negative neutrocytic ascites with portal hypertension in POEMS syndrome.⁸ (Culture-negative neutrocytic ascites is defined as an ascitic fluid polymorphonuclear count greater than 250/mm³ and a negative ascitic fluid culture in the absence of previous antibiotic therapy.) Chylous ascites has not yet been described in POEMS syndrome. However, chylous ascites is predominantly lymphocytic, whereas our patient had neutrocytic ascites.

We concluded that the cause of our patient’s ascites was multifactorial and included previous surgery and POEMS syndrome.

Nonclassic presentation

In addition to its classic presentation, POEMS syndrome is often reported in association with other “unusual features” such as cardiomyopathy, pulmonary hypertension, and cryoglobulinemia.⁶

So far, very few cases of portal hypertension in POEMS syndrome have been reported. Stepani et al⁸ described a patient who had POEMS syndrome and portal hypertension with extensive portal fibrosis without cirrhosis on liver biopsy. Inoue et al⁹ reported a liver biopsy feature consistent with idiopathic portal hypertension, also noting a case with mild fibrosis and few lymphocytic infiltrates in the portal tract.⁹

The etiopathogenesis of POEMS syndrome is attributed to proangiogenic vascular endothelial growth factor, and other inflammatory cytokines (interleukin 6, interleukin 1 beta, tumor necrosis factor alpha) also play a key role in pulmonary hypertension.^10,11 A similar pathogenesis could also contribute to the development of portal hypertension (Figure 3).

CASE CONCLUDED

We started our patient on oral prednisone 60 mg daily for a month, tapered to a maintenance dose of 15 mg to suppress clonal proliferation of plasma cells. Her symptoms improved. Her vascular endothelial growth factor level decreased from 1,664 to 624 pg/mL. She was enrolled in a National Institutes of Health study to evaluate the effect of a potential new immunomodulator treatment for POEMS syndrome.

In conclusion, POEMS syndrome is rare and can present with many atypical features. A high index of suspicion is needed to detect it in a patient who has noncirrhotic portal hypertension with ascites and multisystem involvement.

A 51-year-old woman presents to the emergency department with dyspnea, which began 4 days ago. She reports no chest pain, palpitations, hemoptysis, fevers, chills, weight loss, recent travel, immobility, or surgery. One week ago she noticed cramping in her right calf, but that has since resolved.

Her history includes hypertension, hypothyroidism, and immune-mediated glomerulonephritis with proteinuria. She is premenopausal. She takes losartan and levothyroxine; she is not taking oral contraceptives or herbal supplements. She is up to date with her cancer screening and has had negative findings on colonoscopy and mammography within the past year.

She has never smoked and she does not drink alcohol or use illicit drugs. Her mother has a history of provoked deep vein thrombosis and colon cancer.

Her temperature is 36.2°C (97.2°F), heart rate 163 beats per minute, blood pressure 158/102 mm Hg, respiratory rate 40 breaths per minute, and oxygen saturation by pulse oximetry 80% while breathing room air, corrected to 94% with oxygen 6 L/min via nasal cannula.

On physical examination, she is sitting upright on a stretcher and appears uncomfortable and anxious. She is awake and able to communicate clearly. Examination of the head, ears, eyes, nose, and throat is unremarkable, with moist mucous membranes. Her lungs are clear to auscultation. Her heart beat is very rapid, with a regular rhythm and an accentuated P2 heart sound. A right parasternal heave can be palpated in addition to a rightwardly displaced point of maximal impulse. The abdomen is normal, with no tenderness or organomegaly. She has no pain, edema, or erythema in the legs or feet, and she has strong, symmetric pulses (2+) in all extremities. The neurologic examination is nonfocal.

Electrocardiography (ECG) done on arrival (Figure 1) reveals supraventricular tachycardia, a normal axis, and nonspecific ST-segment and T-wave abnormalities, findings commonly seen in pulmonary embolism.^1,2 On the other hand, her ECG does not show some of the other signs of right ventricular strain due to pulmonary embolism such as atrial arrhythmias, complete right bundle branch block, or inferior Q-waves.^3,4

In view of her ECG findings and her symptoms of dyspnea, calf pain, tachypnea, tachycardia, and a pronounced P2 heart sound, her physician concludes that she very likely has a pulmonary embolism1 and orders an intravenous infusion of unfractionated heparin to be started immediately.

TESTING FOR PULMONARY EMBOLISM

1. Which of the following would be the best initial diagnostic imaging study to perform in this patient, who has a high pretest probability of pulmonary embolism?

• Multidetector computed tomographic (CT) pulmonary angiography
• Transthoracic echocardiography
• Magnetic resonance imaging
• Lower-extremity duplex ultrasonography
• Pulmonary angiography
• Ventilation-perfusion scintigraphy

Multidetector CT angiography is rapid, noninvasive, and highly sensitive (83%–90%) and specific (96%) for pulmonary embolism.^5,6 In patients such as ours who have a high pretest probability of having the disease, its positive predictive value is 96%.⁵ Therefore, it would be the initial diagnostic study to perform in our patient.

Although transthoracic echocardiography is noninvasive and can detect right ventricular strain in the setting of pulmonary embolism, it may miss half of all pulmonary emboli detected by angiography.^7,8

When technically adequate images are obtained, the combination of magnetic resonance angiography and magnetic resonance venography is very sensitive (92%) and specific (96%) for pulmonary embolism.⁹ However, one-fourth of patients undergoing these studies may have technically inadequate results, so this is not the best choice for diagnosis.⁹

As our patient complained of recent cramping in the right calf, lower-extremity duplex ultrasonography would be a reasonable test to screen for acute deep vein thrombosis as the source of pulmonary embolism. However, given her worrisome vital signs and impending hemodynamic collapse, CT pulmonary angiography would be a better initial test as it may guide more aggressive therapy. Furthermore, even if ultrasonography showed no evidence of deep vein thrombosis, clinical suspicion for pulmonary embolism would remain high enough that therapeutic anticoagulation would be continued until further testing ruled out this diagnosis.

Pulmonary angiography is the gold-standard test for pulmonary embolism. However, it is time-consuming, expensive, and invasive and so is not usually done unless the diagnosis cannot be made with other imaging studies.

Ventilation-perfusion scintigraphy is an established and safe diagnostic test for pulmonary embolism. It is particularly helpful in patients who have renal dysfunction or contrast allergy. The sensitivity of a high-probability scan is 78%, while the specificity of a very-low-probability scan is 97%.10 However, this study is often nondiagnostic (in 26.5% of cases),10 and further imaging may be required.

RESULTS OF CT ANGIOGRAPHY

Our patient undergoes CT angiography, which reveals multiple bilateral pulmonary emboli and right ventricular enlargement (Figure 2). Transthoracic echocardiography shows dilation of the right ventricle, with severely reduced systolic function, an underfilled and hyperdynamic left ventricle (ejection fraction 75%), and moderate tricuspid valve regurgitation. Her right ventricular systolic pressure is estimated to be 47 mm Hg.

Doppler ultrasonography of the legs reveals an occlusive thrombus within the right small saphenous vein that bulges and extends into the right popliteal vein. Also noted is a nonocclusive thrombus in the upper right popliteal vein that likely originated from the thrombus in the small saphenous vein.

Initial laboratory testing (Table 1) shows elevations of the cardiac enzymes troponin T and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP).

ESTIMATING PROGNOSIS IN PULMONARY EMBOLISM

2. Which of the following laboratory results at presentation is independently associated with a worse outcome in patients with pulmonary embolism?

• Elevated NT-pro-BNP
• Hypercalcemia
• Thrombocytosis
• Hypernatremia
• Elevated procalcitonin

The Pulmonary Embolism Severity Index¹¹ and the Simplified Pulmonary Embolism Severity Index¹² (Table 2) are clinical calculators that help predict 30-day risk of death in patients with pulmonary embolism. Our patient’s Pulmonary Embolism Severity Index score is 60, indicating a very low risk, but her simplified severity index score is 2, indicating a high risk.

A shock index score (the heart rate divided by the systolic blood pressure) greater than 1 is also a sensitive measure of risk.¹³ (Our patient’s shock index score is 1.03.) Although the simplified version is more accurate,¹⁴ the shock index is also helpful when deciding whether patients with suspected pulmonary embolism should receive early fibrinolysis.¹⁵

In a large registry of patients with confirmed pulmonary embolism, risk factors for death were age greater than 70, cancer, clinical congestive heart failure, chronic obstructive pulmonary disease, systolic blood pressure lower than 90 mm Hg, respiratory rate less than 20 per minute, and right ventricular hypokinesis.¹⁶ Right ventricular dysfunction progressing to right ventricular failure and cardiogenic shock is the most common cause of death in patients with pulmonary embolism.^16–18

Post hoc analysis has also shown that elevations of the biomarkers BNP, NT-pro-BNP, and cardiac troponins I and T are associated with a prolonged hospital course and a higher risk of death within 30 days.¹⁹ Interestingly, a recent retrospective analysis found hyponatremia to be an independent risk factor for death in the short term.²⁰

Thrombocytopenia, not thrombocytosis, is associated with worse outcomes in patients with pulmonary embolism.¹⁶ Procalcitonin is elevated in bacterial pneumonia but is normal in pulmonary embolism and so may be helpful in differentiating between the two.^21,22 Hypernatremia, hypercalcemia, and elevated procalcitonin have not been shown to be independently associated with worse outcomes in acute pulmonary embolism.

Thus, of the answer choices shown above, elevated NT-pro-BNP is the correct answer.

Pulmonary embolism is often stratified as massive, submassive, or low-risk, reflecting the severity and the degree of cardiovascular collapse. The treatment depends on the classification.

Pulmonary embolism is classified as massive if the patient has a cardiac arrest or a systolic blood pressure lower than 90 mm Hg for more than 15 minutes.²³ Nearly half of patients in this category die.²⁴

Pulmonary embolism is submassive if the patient has systolic pressure greater than 90 mm Hg but has right ventricular dysfunction, as evidenced by physical examination, elevated cardiac biomarkers, electrocardiography, transthoracic echocardiography, or computed tomography. The death rate is as high as 15%.²⁴

Pulmonary embolism in a normotensive patient with no right ventricular dysfunction is defined as low-risk.

Our patient so far

Our patient has bilateral pulmonary emboli, most likely originating from a deep vein thrombosis in her right lower leg. Her pulmonary embolism would be classified as submassive, as her systolic pressure is greater than 90 mm Hg and right ventricular dysfunction—significant right ventricular strain—was noted on both transthoracic echocardiography and computed tomography. Also, cardiac biomarkers are elevated, and the physical examination revealed a prominent P2 sound and right parasternal heave, also suggestive of right ventricular dysfunction.

Now, 6 hours have passed, and even though she has been receiving intravenous heparin during this time, her shock index remains greater than 1, indicating hemodynamic instability. Her pulse rate is still markedly high—over 160 bpm—and she still appears quite anxious and uncomfortable.

HOW SHOULD THIS PATIENT BE TREATED?

3. Which of the following is the most appropriate treatment for this patient?

• Start warfarin immediately while bridging with unfractionated heparin, low-molecular-weight heparin, or fondaparinux
• Start fibrinolysis with alteplase
• Give metoprolol intravenously to control her heart rate
• Start dabigatran immediately while bridging with unfractionated heparin
• Place an inferior vena cava filter
• Consult cardiothoracic surgery for emergency pulmonary embolectomy

All patients with confirmed pulmonary embolism and no contraindications to anticoagulation should begin treatment with low-molecular-weight heparin, unfractionated heparin, or fondaparinux.²³ In addition, this therapy should be started empirically while the patient is still undergoing diagnostic testing if the pretest probability of pulmonary embolism is intermediate or high.²³

Warfarin is indicated for all patients with pulmonary embolism who do not have contraindications to it (Table 3). If unfractionated heparin, low-molecular-weight heparin, or fondaparinux has not already been started, it should be started at the same time as warfarin and should be continued until the international normalized ratio (INR) is within the therapeutic range.

Fibrinolysis. Treatment with a fibrinolytic agent in addition to heparin results in faster improvement of right ventricular function and pulmonary perfusion than with heparin alone.²⁵ It may also decrease the incidence of pulmonary hypertension secondary to chronic thromboembolic disease.²⁶ It should be considered in patients with massive pulmonary embolism.²³

Whether fibrinolysis is appropriate for all patients with submassive pulmonary embolism remains controversial. Currently, it is not recommended for minor right ventricular dysfunction or myocardial necrosis if the patient has no signs of overt clinical decline.²³ The Pulmonary Embolism Thrombolysis trial²⁷ is an ongoing prospective randomized comparison of tenecteplase in a single bolus plus heparin vs heparin alone in normotensive patients with submassive pulmonary embolism, such as our patient. This trial may elucidate the benefit of fibrinolytic therapy in patients with submassive pulmonary embolism.

Patients at low risk are generally treated with heparin and warfarin anticoagulation alone. Fibrinolysis is not recommended in these patients, as the risk of bleeding outweighs the potential benefits.²³

Metoprolol may not be advisable for our patient, as her tachycardia is likely compensatory, and beta-blocker therapy could blunt this compensatory response, leading to inadequate systemic perfusion.

Dabigatran is an oral direct thrombin inhibitor that does not require laboratory monitoring. It is currently approved for the prevention of stroke in patients with atrial fibrillation. It has been shown to be as effective as warfarin in the treatment of acute venous thromboembolism²⁸ and may be a viable option in the future, but as of this writing it has not yet been approved in the United States for this indication. Furthermore, dabigatran inhibits thrombin immediately, so continued heparin bridging would not be necessary.

An inferior vena cava filter may prevent recurrent pulmonary embolism for patients who have absolute contraindications to anticoagulation, most significantly in the short term, ie, in the first few weeks after placement. However, these devices have not yet been shown to improve long-term mortality rates.

Embolectomy, percutaneous or surgical, is also an option. For patients in whom thrombolytic therapy is not effective, “rescue” surgical embolectomy has been associated with better outcomes compared with secondary thrombolysis and so should be considered.²⁹

Back to our patient

An intravenous infusion of alteplase is started, and the patient’s tachycardia improves. Her oxygen requirements normalize, and she is transferred to the general medical floor the next day. She receives subcutaneous dalteparin as a bridge therapy, and warfarin is titrated to a goal INR of 2.0 to 3.0. Because of the acute deep vein thrombosis in her right lower leg, she is instructed to wear knee-high fitted compression hose for primary prevention of postphlebitic syndrome.

HOW LONG TO TREAT? IS GENETIC TESTING INDICATED?

Patients with a first episode of unprovoked venous thromboembolism should receive oral anticoagulants for 6 months, while those with recurrent unprovoked venous thromboembolism require lifelong oral anticoagulation.²³

Whether to test for inherited thrombophilia after a first episode of venous thromboembolism to guide the duration of anticoagulation is controversial.³⁰ Indiscriminate testing has not been recommended in these patients,³¹ but the American College of Medical Genetics recommends genetic screening for factor V Leiden in patients who have an unprovoked incident of venous thromboembolism before age 50.³²

No randomized controlled trial has assessed whether thrombophilia testing decreases the recurrence rate of venous thromboembolism.³³ One uncontrolled study suggested that testing for inherited thrombophilias in patients with a first episode does not affect the risk of recurrence.³⁴ Testing is costly and may cause psychological distress for patients and family members.

Our patient is discharged home on warfarin for 6 months with subsequent follow-up evaluation in the thrombophilia clinic.

WHEN SHOULD WARFARIN BE RESTARTED?

4. If our patient were to discontinue oral anticoagulation in 6 months, which of the following, if present 1 month afterwards, would be a reason to restart oral anticoagulation?

• Elevated serum cotinine
• Positive pregnancy test
• Elevated follicle-stimulating hormone and luteinizing hormone and low estradiol levels
• Elevated D-dimer

Cotinine is a nicotine metabolite, and serum levels are elevated in smokers. Smoking and pregnancy both increase the risk of venous thromboembolism. However, smoking or pregnancy alone would not be a reason to increase the duration of anticoagulation.

Warfarin is contraindicated in pregnancy because of its teratogenic effects, particularly in the first trimester. Follicle-stimulating hormone and luteinizing hormone levels increase in response to decreased estradiol at menopause. Postmenopausal women are not at increased risk of venous thromboembolism unless they are taking oral estrogen hormone replacement therapy.

An elevated D-dimer level 1 month after stopping of oral anticoagulation has been associated with a higher rate of recurrence of venous thromboembolism, which is reduced by a resumption of anticoagulation.³⁵ Therefore, consideration should be given to resuming anticoagulation in patients who have an elevated D-dimer level.

TAKE-HOME POINTS

It is important to distinguish between massive, submassive, and low-risk pulmonary embolism, since each type has a different treatment and prognosis.

Fibrinolytic therapy is indicated in patients with massive pulmonary embolism when no contraindication is present, whereas it is not indicated in those with low-risk pulmonary embolism.

Management of submassive pulmonary embolism continues to be an area of considerable debate. Current American Heart Association guidelines recommend consideration of fibrinolysis initially in patients with submassive acute pulmonary embolism if there is concurrent clinical evidence of adverse prognosis—eg, new hemodynamic instability, worsening respiratory insufficiency, severe right ventricular dysfunction, or major myocardial necrosis.²³ On the other hand, the American College of Chest Physicians recommends against initial systemic fibrinolysis in submassive acute pulmonary embolism based on biomarkers or findings on ECG, transthoracic echocardiography, or CT, recommending it only in therapeutically anticoagulated patients deemed to be at high risk of hypotension.³⁶

Since the optimal treatment of submassive pulmonary embolism is still not known, it is important that clinicians remain up to date on the evidence and guidelines.

A 51-year-old woman presents to the emergency department with dyspnea, which began 4 days ago. She reports no chest pain, palpitations, hemoptysis, fevers, chills, weight loss, recent travel, immobility, or surgery. One week ago she noticed cramping in her right calf, but that has since resolved.

Her history includes hypertension, hypothyroidism, and immune-mediated glomerulonephritis with proteinuria. She is premenopausal. She takes losartan and levothyroxine; she is not taking oral contraceptives or herbal supplements. She is up to date with her cancer screening and has had negative findings on colonoscopy and mammography within the past year.

She has never smoked and she does not drink alcohol or use illicit drugs. Her mother has a history of provoked deep vein thrombosis and colon cancer.

Her temperature is 36.2°C (97.2°F), heart rate 163 beats per minute, blood pressure 158/102 mm Hg, respiratory rate 40 breaths per minute, and oxygen saturation by pulse oximetry 80% while breathing room air, corrected to 94% with oxygen 6 L/min via nasal cannula.

On physical examination, she is sitting upright on a stretcher and appears uncomfortable and anxious. She is awake and able to communicate clearly. Examination of the head, ears, eyes, nose, and throat is unremarkable, with moist mucous membranes. Her lungs are clear to auscultation. Her heart beat is very rapid, with a regular rhythm and an accentuated P2 heart sound. A right parasternal heave can be palpated in addition to a rightwardly displaced point of maximal impulse. The abdomen is normal, with no tenderness or organomegaly. She has no pain, edema, or erythema in the legs or feet, and she has strong, symmetric pulses (2+) in all extremities. The neurologic examination is nonfocal.

Electrocardiography (ECG) done on arrival (Figure 1) reveals supraventricular tachycardia, a normal axis, and nonspecific ST-segment and T-wave abnormalities, findings commonly seen in pulmonary embolism.^1,2 On the other hand, her ECG does not show some of the other signs of right ventricular strain due to pulmonary embolism such as atrial arrhythmias, complete right bundle branch block, or inferior Q-waves.^3,4

In view of her ECG findings and her symptoms of dyspnea, calf pain, tachypnea, tachycardia, and a pronounced P2 heart sound, her physician concludes that she very likely has a pulmonary embolism1 and orders an intravenous infusion of unfractionated heparin to be started immediately.

TESTING FOR PULMONARY EMBOLISM

1. Which of the following would be the best initial diagnostic imaging study to perform in this patient, who has a high pretest probability of pulmonary embolism?

• Multidetector computed tomographic (CT) pulmonary angiography
• Transthoracic echocardiography
• Magnetic resonance imaging
• Lower-extremity duplex ultrasonography
• Pulmonary angiography
• Ventilation-perfusion scintigraphy

Multidetector CT angiography is rapid, noninvasive, and highly sensitive (83%–90%) and specific (96%) for pulmonary embolism.^5,6 In patients such as ours who have a high pretest probability of having the disease, its positive predictive value is 96%.⁵ Therefore, it would be the initial diagnostic study to perform in our patient.

Although transthoracic echocardiography is noninvasive and can detect right ventricular strain in the setting of pulmonary embolism, it may miss half of all pulmonary emboli detected by angiography.^7,8

When technically adequate images are obtained, the combination of magnetic resonance angiography and magnetic resonance venography is very sensitive (92%) and specific (96%) for pulmonary embolism.⁹ However, one-fourth of patients undergoing these studies may have technically inadequate results, so this is not the best choice for diagnosis.⁹

As our patient complained of recent cramping in the right calf, lower-extremity duplex ultrasonography would be a reasonable test to screen for acute deep vein thrombosis as the source of pulmonary embolism. However, given her worrisome vital signs and impending hemodynamic collapse, CT pulmonary angiography would be a better initial test as it may guide more aggressive therapy. Furthermore, even if ultrasonography showed no evidence of deep vein thrombosis, clinical suspicion for pulmonary embolism would remain high enough that therapeutic anticoagulation would be continued until further testing ruled out this diagnosis.

Pulmonary angiography is the gold-standard test for pulmonary embolism. However, it is time-consuming, expensive, and invasive and so is not usually done unless the diagnosis cannot be made with other imaging studies.

Ventilation-perfusion scintigraphy is an established and safe diagnostic test for pulmonary embolism. It is particularly helpful in patients who have renal dysfunction or contrast allergy. The sensitivity of a high-probability scan is 78%, while the specificity of a very-low-probability scan is 97%.10 However, this study is often nondiagnostic (in 26.5% of cases),10 and further imaging may be required.

RESULTS OF CT ANGIOGRAPHY

Our patient undergoes CT angiography, which reveals multiple bilateral pulmonary emboli and right ventricular enlargement (Figure 2). Transthoracic echocardiography shows dilation of the right ventricle, with severely reduced systolic function, an underfilled and hyperdynamic left ventricle (ejection fraction 75%), and moderate tricuspid valve regurgitation. Her right ventricular systolic pressure is estimated to be 47 mm Hg.

Doppler ultrasonography of the legs reveals an occlusive thrombus within the right small saphenous vein that bulges and extends into the right popliteal vein. Also noted is a nonocclusive thrombus in the upper right popliteal vein that likely originated from the thrombus in the small saphenous vein.

Initial laboratory testing (Table 1) shows elevations of the cardiac enzymes troponin T and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP).

ESTIMATING PROGNOSIS IN PULMONARY EMBOLISM

2. Which of the following laboratory results at presentation is independently associated with a worse outcome in patients with pulmonary embolism?

• Elevated NT-pro-BNP
• Hypercalcemia
• Thrombocytosis
• Hypernatremia
• Elevated procalcitonin

The Pulmonary Embolism Severity Index¹¹ and the Simplified Pulmonary Embolism Severity Index¹² (Table 2) are clinical calculators that help predict 30-day risk of death in patients with pulmonary embolism. Our patient’s Pulmonary Embolism Severity Index score is 60, indicating a very low risk, but her simplified severity index score is 2, indicating a high risk.

A shock index score (the heart rate divided by the systolic blood pressure) greater than 1 is also a sensitive measure of risk.¹³ (Our patient’s shock index score is 1.03.) Although the simplified version is more accurate,¹⁴ the shock index is also helpful when deciding whether patients with suspected pulmonary embolism should receive early fibrinolysis.¹⁵

In a large registry of patients with confirmed pulmonary embolism, risk factors for death were age greater than 70, cancer, clinical congestive heart failure, chronic obstructive pulmonary disease, systolic blood pressure lower than 90 mm Hg, respiratory rate less than 20 per minute, and right ventricular hypokinesis.¹⁶ Right ventricular dysfunction progressing to right ventricular failure and cardiogenic shock is the most common cause of death in patients with pulmonary embolism.^16–18

Post hoc analysis has also shown that elevations of the biomarkers BNP, NT-pro-BNP, and cardiac troponins I and T are associated with a prolonged hospital course and a higher risk of death within 30 days.¹⁹ Interestingly, a recent retrospective analysis found hyponatremia to be an independent risk factor for death in the short term.²⁰

Thrombocytopenia, not thrombocytosis, is associated with worse outcomes in patients with pulmonary embolism.¹⁶ Procalcitonin is elevated in bacterial pneumonia but is normal in pulmonary embolism and so may be helpful in differentiating between the two.^21,22 Hypernatremia, hypercalcemia, and elevated procalcitonin have not been shown to be independently associated with worse outcomes in acute pulmonary embolism.

Thus, of the answer choices shown above, elevated NT-pro-BNP is the correct answer.

Pulmonary embolism is often stratified as massive, submassive, or low-risk, reflecting the severity and the degree of cardiovascular collapse. The treatment depends on the classification.

Pulmonary embolism is classified as massive if the patient has a cardiac arrest or a systolic blood pressure lower than 90 mm Hg for more than 15 minutes.²³ Nearly half of patients in this category die.²⁴

Pulmonary embolism is submassive if the patient has systolic pressure greater than 90 mm Hg but has right ventricular dysfunction, as evidenced by physical examination, elevated cardiac biomarkers, electrocardiography, transthoracic echocardiography, or computed tomography. The death rate is as high as 15%.²⁴

Pulmonary embolism in a normotensive patient with no right ventricular dysfunction is defined as low-risk.

Our patient so far

Our patient has bilateral pulmonary emboli, most likely originating from a deep vein thrombosis in her right lower leg. Her pulmonary embolism would be classified as submassive, as her systolic pressure is greater than 90 mm Hg and right ventricular dysfunction—significant right ventricular strain—was noted on both transthoracic echocardiography and computed tomography. Also, cardiac biomarkers are elevated, and the physical examination revealed a prominent P2 sound and right parasternal heave, also suggestive of right ventricular dysfunction.

Now, 6 hours have passed, and even though she has been receiving intravenous heparin during this time, her shock index remains greater than 1, indicating hemodynamic instability. Her pulse rate is still markedly high—over 160 bpm—and she still appears quite anxious and uncomfortable.

HOW SHOULD THIS PATIENT BE TREATED?

3. Which of the following is the most appropriate treatment for this patient?

• Start warfarin immediately while bridging with unfractionated heparin, low-molecular-weight heparin, or fondaparinux
• Start fibrinolysis with alteplase
• Give metoprolol intravenously to control her heart rate
• Start dabigatran immediately while bridging with unfractionated heparin
• Place an inferior vena cava filter
• Consult cardiothoracic surgery for emergency pulmonary embolectomy

All patients with confirmed pulmonary embolism and no contraindications to anticoagulation should begin treatment with low-molecular-weight heparin, unfractionated heparin, or fondaparinux.²³ In addition, this therapy should be started empirically while the patient is still undergoing diagnostic testing if the pretest probability of pulmonary embolism is intermediate or high.²³

Warfarin is indicated for all patients with pulmonary embolism who do not have contraindications to it (Table 3). If unfractionated heparin, low-molecular-weight heparin, or fondaparinux has not already been started, it should be started at the same time as warfarin and should be continued until the international normalized ratio (INR) is within the therapeutic range.

Fibrinolysis. Treatment with a fibrinolytic agent in addition to heparin results in faster improvement of right ventricular function and pulmonary perfusion than with heparin alone.²⁵ It may also decrease the incidence of pulmonary hypertension secondary to chronic thromboembolic disease.²⁶ It should be considered in patients with massive pulmonary embolism.²³

Whether fibrinolysis is appropriate for all patients with submassive pulmonary embolism remains controversial. Currently, it is not recommended for minor right ventricular dysfunction or myocardial necrosis if the patient has no signs of overt clinical decline.²³ The Pulmonary Embolism Thrombolysis trial²⁷ is an ongoing prospective randomized comparison of tenecteplase in a single bolus plus heparin vs heparin alone in normotensive patients with submassive pulmonary embolism, such as our patient. This trial may elucidate the benefit of fibrinolytic therapy in patients with submassive pulmonary embolism.

Patients at low risk are generally treated with heparin and warfarin anticoagulation alone. Fibrinolysis is not recommended in these patients, as the risk of bleeding outweighs the potential benefits.²³

Metoprolol may not be advisable for our patient, as her tachycardia is likely compensatory, and beta-blocker therapy could blunt this compensatory response, leading to inadequate systemic perfusion.

Dabigatran is an oral direct thrombin inhibitor that does not require laboratory monitoring. It is currently approved for the prevention of stroke in patients with atrial fibrillation. It has been shown to be as effective as warfarin in the treatment of acute venous thromboembolism²⁸ and may be a viable option in the future, but as of this writing it has not yet been approved in the United States for this indication. Furthermore, dabigatran inhibits thrombin immediately, so continued heparin bridging would not be necessary.

An inferior vena cava filter may prevent recurrent pulmonary embolism for patients who have absolute contraindications to anticoagulation, most significantly in the short term, ie, in the first few weeks after placement. However, these devices have not yet been shown to improve long-term mortality rates.

Embolectomy, percutaneous or surgical, is also an option. For patients in whom thrombolytic therapy is not effective, “rescue” surgical embolectomy has been associated with better outcomes compared with secondary thrombolysis and so should be considered.²⁹

Back to our patient

An intravenous infusion of alteplase is started, and the patient’s tachycardia improves. Her oxygen requirements normalize, and she is transferred to the general medical floor the next day. She receives subcutaneous dalteparin as a bridge therapy, and warfarin is titrated to a goal INR of 2.0 to 3.0. Because of the acute deep vein thrombosis in her right lower leg, she is instructed to wear knee-high fitted compression hose for primary prevention of postphlebitic syndrome.

HOW LONG TO TREAT? IS GENETIC TESTING INDICATED?

Patients with a first episode of unprovoked venous thromboembolism should receive oral anticoagulants for 6 months, while those with recurrent unprovoked venous thromboembolism require lifelong oral anticoagulation.²³

Whether to test for inherited thrombophilia after a first episode of venous thromboembolism to guide the duration of anticoagulation is controversial.³⁰ Indiscriminate testing has not been recommended in these patients,³¹ but the American College of Medical Genetics recommends genetic screening for factor V Leiden in patients who have an unprovoked incident of venous thromboembolism before age 50.³²

No randomized controlled trial has assessed whether thrombophilia testing decreases the recurrence rate of venous thromboembolism.³³ One uncontrolled study suggested that testing for inherited thrombophilias in patients with a first episode does not affect the risk of recurrence.³⁴ Testing is costly and may cause psychological distress for patients and family members.

Our patient is discharged home on warfarin for 6 months with subsequent follow-up evaluation in the thrombophilia clinic.

WHEN SHOULD WARFARIN BE RESTARTED?

4. If our patient were to discontinue oral anticoagulation in 6 months, which of the following, if present 1 month afterwards, would be a reason to restart oral anticoagulation?

• Elevated serum cotinine
• Positive pregnancy test
• Elevated follicle-stimulating hormone and luteinizing hormone and low estradiol levels
• Elevated D-dimer

Cotinine is a nicotine metabolite, and serum levels are elevated in smokers. Smoking and pregnancy both increase the risk of venous thromboembolism. However, smoking or pregnancy alone would not be a reason to increase the duration of anticoagulation.

Warfarin is contraindicated in pregnancy because of its teratogenic effects, particularly in the first trimester. Follicle-stimulating hormone and luteinizing hormone levels increase in response to decreased estradiol at menopause. Postmenopausal women are not at increased risk of venous thromboembolism unless they are taking oral estrogen hormone replacement therapy.

An elevated D-dimer level 1 month after stopping of oral anticoagulation has been associated with a higher rate of recurrence of venous thromboembolism, which is reduced by a resumption of anticoagulation.³⁵ Therefore, consideration should be given to resuming anticoagulation in patients who have an elevated D-dimer level.

TAKE-HOME POINTS

It is important to distinguish between massive, submassive, and low-risk pulmonary embolism, since each type has a different treatment and prognosis.

Fibrinolytic therapy is indicated in patients with massive pulmonary embolism when no contraindication is present, whereas it is not indicated in those with low-risk pulmonary embolism.

Management of submassive pulmonary embolism continues to be an area of considerable debate. Current American Heart Association guidelines recommend consideration of fibrinolysis initially in patients with submassive acute pulmonary embolism if there is concurrent clinical evidence of adverse prognosis—eg, new hemodynamic instability, worsening respiratory insufficiency, severe right ventricular dysfunction, or major myocardial necrosis.²³ On the other hand, the American College of Chest Physicians recommends against initial systemic fibrinolysis in submassive acute pulmonary embolism based on biomarkers or findings on ECG, transthoracic echocardiography, or CT, recommending it only in therapeutically anticoagulated patients deemed to be at high risk of hypotension.³⁶

Since the optimal treatment of submassive pulmonary embolism is still not known, it is important that clinicians remain up to date on the evidence and guidelines.

A 51-year-old woman presents to the emergency department with dyspnea, which began 4 days ago. She reports no chest pain, palpitations, hemoptysis, fevers, chills, weight loss, recent travel, immobility, or surgery. One week ago she noticed cramping in her right calf, but that has since resolved.

Her history includes hypertension, hypothyroidism, and immune-mediated glomerulonephritis with proteinuria. She is premenopausal. She takes losartan and levothyroxine; she is not taking oral contraceptives or herbal supplements. She is up to date with her cancer screening and has had negative findings on colonoscopy and mammography within the past year.

She has never smoked and she does not drink alcohol or use illicit drugs. Her mother has a history of provoked deep vein thrombosis and colon cancer.

Her temperature is 36.2°C (97.2°F), heart rate 163 beats per minute, blood pressure 158/102 mm Hg, respiratory rate 40 breaths per minute, and oxygen saturation by pulse oximetry 80% while breathing room air, corrected to 94% with oxygen 6 L/min via nasal cannula.

On physical examination, she is sitting upright on a stretcher and appears uncomfortable and anxious. She is awake and able to communicate clearly. Examination of the head, ears, eyes, nose, and throat is unremarkable, with moist mucous membranes. Her lungs are clear to auscultation. Her heart beat is very rapid, with a regular rhythm and an accentuated P2 heart sound. A right parasternal heave can be palpated in addition to a rightwardly displaced point of maximal impulse. The abdomen is normal, with no tenderness or organomegaly. She has no pain, edema, or erythema in the legs or feet, and she has strong, symmetric pulses (2+) in all extremities. The neurologic examination is nonfocal.

Electrocardiography (ECG) done on arrival (Figure 1) reveals supraventricular tachycardia, a normal axis, and nonspecific ST-segment and T-wave abnormalities, findings commonly seen in pulmonary embolism.^1,2 On the other hand, her ECG does not show some of the other signs of right ventricular strain due to pulmonary embolism such as atrial arrhythmias, complete right bundle branch block, or inferior Q-waves.^3,4

In view of her ECG findings and her symptoms of dyspnea, calf pain, tachypnea, tachycardia, and a pronounced P2 heart sound, her physician concludes that she very likely has a pulmonary embolism1 and orders an intravenous infusion of unfractionated heparin to be started immediately.

TESTING FOR PULMONARY EMBOLISM

1. Which of the following would be the best initial diagnostic imaging study to perform in this patient, who has a high pretest probability of pulmonary embolism?

• Multidetector computed tomographic (CT) pulmonary angiography
• Transthoracic echocardiography
• Magnetic resonance imaging
• Lower-extremity duplex ultrasonography
• Pulmonary angiography
• Ventilation-perfusion scintigraphy

Multidetector CT angiography is rapid, noninvasive, and highly sensitive (83%–90%) and specific (96%) for pulmonary embolism.^5,6 In patients such as ours who have a high pretest probability of having the disease, its positive predictive value is 96%.⁵ Therefore, it would be the initial diagnostic study to perform in our patient.

Although transthoracic echocardiography is noninvasive and can detect right ventricular strain in the setting of pulmonary embolism, it may miss half of all pulmonary emboli detected by angiography.^7,8

When technically adequate images are obtained, the combination of magnetic resonance angiography and magnetic resonance venography is very sensitive (92%) and specific (96%) for pulmonary embolism.⁹ However, one-fourth of patients undergoing these studies may have technically inadequate results, so this is not the best choice for diagnosis.⁹

As our patient complained of recent cramping in the right calf, lower-extremity duplex ultrasonography would be a reasonable test to screen for acute deep vein thrombosis as the source of pulmonary embolism. However, given her worrisome vital signs and impending hemodynamic collapse, CT pulmonary angiography would be a better initial test as it may guide more aggressive therapy. Furthermore, even if ultrasonography showed no evidence of deep vein thrombosis, clinical suspicion for pulmonary embolism would remain high enough that therapeutic anticoagulation would be continued until further testing ruled out this diagnosis.

Pulmonary angiography is the gold-standard test for pulmonary embolism. However, it is time-consuming, expensive, and invasive and so is not usually done unless the diagnosis cannot be made with other imaging studies.

Ventilation-perfusion scintigraphy is an established and safe diagnostic test for pulmonary embolism. It is particularly helpful in patients who have renal dysfunction or contrast allergy. The sensitivity of a high-probability scan is 78%, while the specificity of a very-low-probability scan is 97%.10 However, this study is often nondiagnostic (in 26.5% of cases),10 and further imaging may be required.

RESULTS OF CT ANGIOGRAPHY

Our patient undergoes CT angiography, which reveals multiple bilateral pulmonary emboli and right ventricular enlargement (Figure 2). Transthoracic echocardiography shows dilation of the right ventricle, with severely reduced systolic function, an underfilled and hyperdynamic left ventricle (ejection fraction 75%), and moderate tricuspid valve regurgitation. Her right ventricular systolic pressure is estimated to be 47 mm Hg.

Doppler ultrasonography of the legs reveals an occlusive thrombus within the right small saphenous vein that bulges and extends into the right popliteal vein. Also noted is a nonocclusive thrombus in the upper right popliteal vein that likely originated from the thrombus in the small saphenous vein.

Initial laboratory testing (Table 1) shows elevations of the cardiac enzymes troponin T and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP).

ESTIMATING PROGNOSIS IN PULMONARY EMBOLISM

2. Which of the following laboratory results at presentation is independently associated with a worse outcome in patients with pulmonary embolism?

• Elevated NT-pro-BNP
• Hypercalcemia
• Thrombocytosis
• Hypernatremia
• Elevated procalcitonin

The Pulmonary Embolism Severity Index¹¹ and the Simplified Pulmonary Embolism Severity Index¹² (Table 2) are clinical calculators that help predict 30-day risk of death in patients with pulmonary embolism. Our patient’s Pulmonary Embolism Severity Index score is 60, indicating a very low risk, but her simplified severity index score is 2, indicating a high risk.

A shock index score (the heart rate divided by the systolic blood pressure) greater than 1 is also a sensitive measure of risk.¹³ (Our patient’s shock index score is 1.03.) Although the simplified version is more accurate,¹⁴ the shock index is also helpful when deciding whether patients with suspected pulmonary embolism should receive early fibrinolysis.¹⁵

In a large registry of patients with confirmed pulmonary embolism, risk factors for death were age greater than 70, cancer, clinical congestive heart failure, chronic obstructive pulmonary disease, systolic blood pressure lower than 90 mm Hg, respiratory rate less than 20 per minute, and right ventricular hypokinesis.¹⁶ Right ventricular dysfunction progressing to right ventricular failure and cardiogenic shock is the most common cause of death in patients with pulmonary embolism.^16–18

Post hoc analysis has also shown that elevations of the biomarkers BNP, NT-pro-BNP, and cardiac troponins I and T are associated with a prolonged hospital course and a higher risk of death within 30 days.¹⁹ Interestingly, a recent retrospective analysis found hyponatremia to be an independent risk factor for death in the short term.²⁰

Thrombocytopenia, not thrombocytosis, is associated with worse outcomes in patients with pulmonary embolism.¹⁶ Procalcitonin is elevated in bacterial pneumonia but is normal in pulmonary embolism and so may be helpful in differentiating between the two.^21,22 Hypernatremia, hypercalcemia, and elevated procalcitonin have not been shown to be independently associated with worse outcomes in acute pulmonary embolism.

Thus, of the answer choices shown above, elevated NT-pro-BNP is the correct answer.

Pulmonary embolism is often stratified as massive, submassive, or low-risk, reflecting the severity and the degree of cardiovascular collapse. The treatment depends on the classification.

Pulmonary embolism is classified as massive if the patient has a cardiac arrest or a systolic blood pressure lower than 90 mm Hg for more than 15 minutes.²³ Nearly half of patients in this category die.²⁴

Pulmonary embolism is submassive if the patient has systolic pressure greater than 90 mm Hg but has right ventricular dysfunction, as evidenced by physical examination, elevated cardiac biomarkers, electrocardiography, transthoracic echocardiography, or computed tomography. The death rate is as high as 15%.²⁴

Pulmonary embolism in a normotensive patient with no right ventricular dysfunction is defined as low-risk.

Our patient so far

Our patient has bilateral pulmonary emboli, most likely originating from a deep vein thrombosis in her right lower leg. Her pulmonary embolism would be classified as submassive, as her systolic pressure is greater than 90 mm Hg and right ventricular dysfunction—significant right ventricular strain—was noted on both transthoracic echocardiography and computed tomography. Also, cardiac biomarkers are elevated, and the physical examination revealed a prominent P2 sound and right parasternal heave, also suggestive of right ventricular dysfunction.

Now, 6 hours have passed, and even though she has been receiving intravenous heparin during this time, her shock index remains greater than 1, indicating hemodynamic instability. Her pulse rate is still markedly high—over 160 bpm—and she still appears quite anxious and uncomfortable.

HOW SHOULD THIS PATIENT BE TREATED?

3. Which of the following is the most appropriate treatment for this patient?

• Start warfarin immediately while bridging with unfractionated heparin, low-molecular-weight heparin, or fondaparinux
• Start fibrinolysis with alteplase
• Give metoprolol intravenously to control her heart rate
• Start dabigatran immediately while bridging with unfractionated heparin
• Place an inferior vena cava filter
• Consult cardiothoracic surgery for emergency pulmonary embolectomy

All patients with confirmed pulmonary embolism and no contraindications to anticoagulation should begin treatment with low-molecular-weight heparin, unfractionated heparin, or fondaparinux.²³ In addition, this therapy should be started empirically while the patient is still undergoing diagnostic testing if the pretest probability of pulmonary embolism is intermediate or high.²³

Warfarin is indicated for all patients with pulmonary embolism who do not have contraindications to it (Table 3). If unfractionated heparin, low-molecular-weight heparin, or fondaparinux has not already been started, it should be started at the same time as warfarin and should be continued until the international normalized ratio (INR) is within the therapeutic range.

Fibrinolysis. Treatment with a fibrinolytic agent in addition to heparin results in faster improvement of right ventricular function and pulmonary perfusion than with heparin alone.²⁵ It may also decrease the incidence of pulmonary hypertension secondary to chronic thromboembolic disease.²⁶ It should be considered in patients with massive pulmonary embolism.²³

Whether fibrinolysis is appropriate for all patients with submassive pulmonary embolism remains controversial. Currently, it is not recommended for minor right ventricular dysfunction or myocardial necrosis if the patient has no signs of overt clinical decline.²³ The Pulmonary Embolism Thrombolysis trial²⁷ is an ongoing prospective randomized comparison of tenecteplase in a single bolus plus heparin vs heparin alone in normotensive patients with submassive pulmonary embolism, such as our patient. This trial may elucidate the benefit of fibrinolytic therapy in patients with submassive pulmonary embolism.

Patients at low risk are generally treated with heparin and warfarin anticoagulation alone. Fibrinolysis is not recommended in these patients, as the risk of bleeding outweighs the potential benefits.²³

Metoprolol may not be advisable for our patient, as her tachycardia is likely compensatory, and beta-blocker therapy could blunt this compensatory response, leading to inadequate systemic perfusion.

Dabigatran is an oral direct thrombin inhibitor that does not require laboratory monitoring. It is currently approved for the prevention of stroke in patients with atrial fibrillation. It has been shown to be as effective as warfarin in the treatment of acute venous thromboembolism²⁸ and may be a viable option in the future, but as of this writing it has not yet been approved in the United States for this indication. Furthermore, dabigatran inhibits thrombin immediately, so continued heparin bridging would not be necessary.

An inferior vena cava filter may prevent recurrent pulmonary embolism for patients who have absolute contraindications to anticoagulation, most significantly in the short term, ie, in the first few weeks after placement. However, these devices have not yet been shown to improve long-term mortality rates.

Embolectomy, percutaneous or surgical, is also an option. For patients in whom thrombolytic therapy is not effective, “rescue” surgical embolectomy has been associated with better outcomes compared with secondary thrombolysis and so should be considered.²⁹

Back to our patient

An intravenous infusion of alteplase is started, and the patient’s tachycardia improves. Her oxygen requirements normalize, and she is transferred to the general medical floor the next day. She receives subcutaneous dalteparin as a bridge therapy, and warfarin is titrated to a goal INR of 2.0 to 3.0. Because of the acute deep vein thrombosis in her right lower leg, she is instructed to wear knee-high fitted compression hose for primary prevention of postphlebitic syndrome.

HOW LONG TO TREAT? IS GENETIC TESTING INDICATED?

Patients with a first episode of unprovoked venous thromboembolism should receive oral anticoagulants for 6 months, while those with recurrent unprovoked venous thromboembolism require lifelong oral anticoagulation.²³

Whether to test for inherited thrombophilia after a first episode of venous thromboembolism to guide the duration of anticoagulation is controversial.³⁰ Indiscriminate testing has not been recommended in these patients,³¹ but the American College of Medical Genetics recommends genetic screening for factor V Leiden in patients who have an unprovoked incident of venous thromboembolism before age 50.³²

No randomized controlled trial has assessed whether thrombophilia testing decreases the recurrence rate of venous thromboembolism.³³ One uncontrolled study suggested that testing for inherited thrombophilias in patients with a first episode does not affect the risk of recurrence.³⁴ Testing is costly and may cause psychological distress for patients and family members.

Our patient is discharged home on warfarin for 6 months with subsequent follow-up evaluation in the thrombophilia clinic.

WHEN SHOULD WARFARIN BE RESTARTED?

4. If our patient were to discontinue oral anticoagulation in 6 months, which of the following, if present 1 month afterwards, would be a reason to restart oral anticoagulation?

• Elevated serum cotinine
• Positive pregnancy test
• Elevated follicle-stimulating hormone and luteinizing hormone and low estradiol levels
• Elevated D-dimer

Cotinine is a nicotine metabolite, and serum levels are elevated in smokers. Smoking and pregnancy both increase the risk of venous thromboembolism. However, smoking or pregnancy alone would not be a reason to increase the duration of anticoagulation.

Warfarin is contraindicated in pregnancy because of its teratogenic effects, particularly in the first trimester. Follicle-stimulating hormone and luteinizing hormone levels increase in response to decreased estradiol at menopause. Postmenopausal women are not at increased risk of venous thromboembolism unless they are taking oral estrogen hormone replacement therapy.

An elevated D-dimer level 1 month after stopping of oral anticoagulation has been associated with a higher rate of recurrence of venous thromboembolism, which is reduced by a resumption of anticoagulation.³⁵ Therefore, consideration should be given to resuming anticoagulation in patients who have an elevated D-dimer level.

TAKE-HOME POINTS

It is important to distinguish between massive, submassive, and low-risk pulmonary embolism, since each type has a different treatment and prognosis.

Fibrinolytic therapy is indicated in patients with massive pulmonary embolism when no contraindication is present, whereas it is not indicated in those with low-risk pulmonary embolism.

Management of submassive pulmonary embolism continues to be an area of considerable debate. Current American Heart Association guidelines recommend consideration of fibrinolysis initially in patients with submassive acute pulmonary embolism if there is concurrent clinical evidence of adverse prognosis—eg, new hemodynamic instability, worsening respiratory insufficiency, severe right ventricular dysfunction, or major myocardial necrosis.²³ On the other hand, the American College of Chest Physicians recommends against initial systemic fibrinolysis in submassive acute pulmonary embolism based on biomarkers or findings on ECG, transthoracic echocardiography, or CT, recommending it only in therapeutically anticoagulated patients deemed to be at high risk of hypotension.³⁶

Since the optimal treatment of submassive pulmonary embolism is still not known, it is important that clinicians remain up to date on the evidence and guidelines.

A 32-year-old man presents to the emergency department with excruciating abdominal pain associated with multiple episodes of vomiting for the past 2 days. He reports no fevers, headaches, diarrhea, constipation, hematochezia, melena, musculoskeletal symptoms, or weight loss. His abdominal pain is generalized and crampy. It does not radiate and has no precipitating factors. The pain is relieved only with intravenous narcotics.

See related editorial

He does not smoke, drink alcohol, or use illicit drugs. He has no known drug or food allergies. He says that his current condition causes him emotional stress that affects his performance at work.

About a year ago, after a complicated surgical procedure, he needed chronic high-dose narcotics. A few months later, he developed multiple bouts of abdominal pain and vomiting that required hospital visits. He now takes oral oxycodone 10–15 mg every 4–6 hours.

On admission, his vital signs are stable, but he is in excruciating pain. He is alert and oriented to person, place, and time. His sclera are anicteric, and the pupils are equal, round, and reactive to light. Lung and heart examinations are normal. The abdomen is soft and nondistended but tender in all four quadrants without guarding; the liver and spleen are not palpable, and no abdominal masses are detected. He has no skin rash, joint swelling or tenderness, or peripheral edema. The neurologic examination is normal. Computed tomography (CT) of the abdomen with contrast shows no signs of bowel obstruction, pancreatic calcifications or edema, cholecystitis, or hepatobiliary disease. Results of initial laboratory testing are shown in Table 1.

1. Based on the information available, which is the least likely cause of his symptoms?

• Acute pancreatitis
• Cyclic vomiting syndrome
• Acute intermittent porphyria
• Gastroparesis

Acute pancreatitis

Acute pancreatitis is the least likely cause of his symptoms. It is commonly caused by gallstones, alcohol, hypertriglyceridemia, and certain drugs.¹ The associated abdominal pain is usually epigastric, radiates to the back, and is accompanied by nausea or vomiting, or both. The onset of pain is sudden and rapidly increases in severity within 30 minutes. CT shows enlargement of the pancreas with diffuse edema, heterogeneity of pancreatic parenchyma, peripancreatic stranding, and peripancreatic fluid collections.¹ The diagnosis is based on two of the following three criteria: abdominal pain characteristic of acute pancreatitis; a serum amylase or lipase concentration three or more times the upper limit of normal; and characteristic findings of acute pancreatitis on CT.¹

Cyclic vomiting syndrome

Cyclic vomiting syndrome is thought to be caused by episodic dysautonomia, mitochondrial DNA mutations, and hypothalamic emetic response oversensitivity,^2–4 but the exact pathogenesis is unknown. The syndrome has been strongly linked to migraine and to the chronic excessive use of cannabinoids.^5–9 The Rome III diagnostic criteria¹⁰ are the following: the vomiting episodes are stereotypical, ie, they are acute and last for less than 1 week; the patient has had three or more episodes in the previous year; and the patient has no nausea or vomiting between episodes. The patient must meet all three criteria. A history of migraine or a family history of migraine further supports the diagnosis.

Acute intermittent porphyria

Acute intermittent porphyria is characterized by neurovisceral symptoms such as convulsions, paresis, autonomic dysfunction, constipation, and diarrhea that result from the overproduction of porphyrin precursors and deficiency of porphobilinogen deaminase.¹¹

Most patients have poorly localized, severe, steady abdominal pain that develops over hours to days and that may persist for days to weeks.¹¹ Since the pain is neuropathic, abdominal tenderness is usually minimal during an acute attack. Other clues include signs of ileus, such as constipation, nausea, abdominal distention, or decreased bowel sounds; bladder dysfunction, eg, urinary retention, incontinence, or dysuria; reddish-brown urine; and sensory neuropathy of the chest, back, and extremities.¹¹ Blistering skin lesions are usually not seen. The presence of porphobilinogen in the urine confirms the diagnosis.¹¹

Gastroparesis

Gastroparesis is a result of discoordination between the sympathetic and parasympathetic nervous systems, neurons, and smooth muscles within the stomach, causing a decrease in gastric motility. Common causes are diabetes,¹² scleroderma,¹³ and neurologic disorders.¹⁴ It can also be iatrogenic,¹⁵ resulting from visceral nerve injury and drug treatment with narcotics, calcium channel blockers, muscarinic cholinergic antagonists, or certain antidepressants. Symptoms are related to gastric stasis, ie, abdominal pain from gastric distention, bloating, vomiting, and early satiety.¹⁵ Abdominal pain may worsen after eating, and vomitus usually consists of recently ingested food. These patients may have abdominal distension or tenderness and succussion splash. After excluding possible mechanical obstruction, a gastric-emptying study may be necessary to make the diagnosis.¹⁵

CASE CONTINUED

A serum and urine drug screen in our patient is positive only for opioids. Urine measures of delta-aminolevulinic acid and porphobilinogen are normal. CT angiography of the abdomen shows no signs of mesenteric vascular occlusion. Esophagogastroduodenoscopy shows antral gastritis, but the esophagus and duodenum appear normal, and colonoscopy is normal as well. Histologic study of biopsy specimens obtained during endoscopy is unrevealing. A gastric-emptying study shows delayed emptying. The patient’s abdominal pain and vomiting persist with the initial dose of intravenous narcotic but resolve with escalating doses. When asked, the patient denies an excessive need for hot baths.

2. Which is the most likely diagnosis at this point?

• Narcotic bowel syndrome
• Opioid withdrawal
• Crohn disease
• Chronic pancreatitis
• Chronic mesenteric ischemia
• Cannabinoid hyperemesis

Narcotic bowel syndrome

Narcotic bowel syndrome is the most likely diagnosis. Grunkemeier et al¹⁶ described it as chronic or frequently recurring abdominal pain that is treated with narcotics, either chronically or acutely with high doses, and that includes all the following features¹⁶:

• The pain worsens or resolves incompletely with continued or increasing doses of narcotics
• The pain markedly worsens when the narcotic dose is decreased, and decreases when the drug is reinstituted (the “soarand-crash” effect)
• The frequency, duration, and intensity of the pain episodes gradually increase
• The nature of the pain and its intensity are not explained by a current or previous gastrointestinal diagnosis.¹⁶

This syndrome is common in patients who receive high doses of narcotics for postoperative pain or for other, nonmalignant causes of pain. Patients eventually become dependent on the drugs but are not aware that chronic use activates and facilitates areas in the brain that enhance the perception of pain.¹⁶ A study of a rat model of narcotic bowel syndrome¹⁷ showed that morphine-induced hyperalgesia depends on central sensitization involving the activation of spinal microglia. This eventually results in concomitant peripheral sensitization involving the colonic mucosal neuroimmune system, and also in central or peripheral activation of opioid kappa-receptors by dynorphin release.¹⁷

Patients tend to present with chronic or intermittent colicky abdominal pain that requires escalating doses of narcotics. Eventually, they develop tachyphylaxis and shortened pain-free periods and will require even higher doses of narcotics. This ultimately enhances the perception of pain and worsens opioid bowel symptoms, causing a vicious circle of pain and more narcotic use.¹⁶

Laboratory tests are usually normal, and imaging may show only ileus. Gastric emptying may be delayed in patients who have either narcotic bowel syndrome or gastroparesis, but since abdominal pain from narcotic bowel syndrome is a result of central and visceral hypersensitivity, these patients perceive more severe abdominal pain than patients with gastroparesis alone.

Opioid withdrawal

Symptoms of opioid withdrawal may appear as soon as 6 to 24 hours after cessation of the opioid in patients known to be dependent on opioids. These patients present with crampy abdominal pain with nausea.¹⁸ Other symptoms include agitation, rhinorrhea, lacrimation, excessive yawning, arthralgias, papillary dilation, and piloerection.¹⁸

Our patient did not have the typical signs of opioid withdrawal.

Crohn disease

Crohn disease is a multisystem disorder with specific clinical and pathologic features. It is characterized by focal, asymmetric, transmural, and occasionally granulomatous inflammation primarily affecting the gastrointestinal tract.¹⁹ Characteristic symptoms include abdominal pain, chronic diarrhea with or without rectal bleeding, and weight loss. Extraintestinal signs may include anemia and inflammatory changes in the eyes, skin, and joints. The diagnosis is based on endoscopic, radiographic, and pathologic findings.¹⁹

Our patient did not have diarrhea or signs of Crohn disease on CT, endoscopy, or histology.

Chronic pancreatitis

Chronic pancreatitis involves progressive inflammatory changes resulting in permanent structural damage to the pancreas and subsequent exocrine and endocrine dysfunction.²⁰ Patients have epigastric abdominal pain that often radiates to the back²⁰; it is associated with eating and is partly relieved with leaning forward. Symptoms of pancreatic insufficiency such as fat malabsorption (resulting in steatorrhea and fat-soluble vitamin deficiency) and diabetes are common. Calcifications within the pancreas on CT suggest chronic pancreatitis.²⁰ Serum lipase and amylase levels may be normal or slightly elevated.²⁰

Our patient’s abdominal pain was not typical of pancreatitis. He had no signs or symptoms of pancreatic insufficiency and no calcifications within the pancreas.

Chronic mesenteric ischemia

Chronic mesenteric ischemia (“intestinal angina”) is caused by a reduction in intestinal blood flow as a result of occlusion, vasospasm, or hypoperfusion of the mesenteric vasculature.²¹ It is commonly seen in patients who smoke or who have atherosclerotic vascular disease. These patients have chronic dull or crampy abdominal pain that usually occurs within 1 hour after eating.²¹ To avoid pain, patients avoid eating, resulting in weight loss.²¹ CT angiography with multi-detector CT is as effective as angiography (the gold standard) in depicting splanchnic arterial anatomy.²²

Our patient is young and has no known risk factors for atherosclerosis such as smoking. His abdominal pain is more intermittent than chronic and is not associated with eating.

Cannabinoid hyperemesis

Cannabinoid hyperemesis should be considered in patients with long-term cannabis use presenting with cyclic vomiting, abdominal pain, compulsive use of hot showers, and improvement of symptoms with cannabis cessation.²³ Although cannabinoids have been recognized for their antiemetic effects, long-term use may eventually cause autonomic instability and disturbances in the hypothalamic-pituitary-adrenal axis, resulting in cyclic vomiting and thermoregulatory impairment.²³

Although our patient presented with multiple episodes of vomiting and abdominal pain, he denied using marijuana, he tested negative for tetrahydrocannabinol, and he did not associate any relief of his symptoms with hot baths.

CASE CONTINUED

Our patient receives intravenous hydration, antiemetics, and a narcotic in tapering intravenous doses, and his symptoms gradually improve. He is discharged from the hospital. However, a few weeks later he is readmitted with the same symptoms of abdominal pain and nausea.

3. What is the cornerstone of treatment for narcotic bowel syndrome?

• Establishing a therapeutic relationship
• Detoxification
• Supportive management with intravenous fluids, antiemetics, and stool-softeners
• Medical management with a short-acting narcotic, clonidine, lorazepam, and desipramine

MANAGEMENT OF NARCOTIC BOWEL SYNDROME

An effective therapeutic relationship with the patient is the cornerstone of treatment and should be established before starting detoxification.¹⁷ The physician must first learn to accept that the patient’s condition is real and must show genuine empathy as well as provide information about the pathophysiologic basis of the condition, the rationale for withholding narcotics, and the detrimental role narcotics play in the vicious circle of pain.

Detoxification involves gradually withdrawing the narcotic and substituting a nonnarcotic such as an antidepressant for pain control, as well as prescribing a drug such as a benzodiazepine or clonidine to prevent withdrawal symptoms and a laxative to prevent constipation.^17,24 The physician must reassure the patient that he or she will not be abandoned in pain and that all medications will be continuously adjusted as needed to keep him or her comfortable throughout the detoxification process.^17,24 The physician must continuously gauge the patient’s willingness to continue with treatment and must also be readily available to address the patient’s concerns in a timely manner.^17,24 Involving family members and friends may provide additional support to the patient. Referral to a functional gastrointestinal motility program, a pain specialist, and a psychologist may also be considered.^17,24 Follow-up care is essential, even after the withdrawal program has ended.^17,24

BACK TO THE PATIENT

After successfully establishing a therapeutic relationship and discussing the treatment plan with our patient, we started him on the same dosage of narcotic that he had been receiving, calculated in intravenous morphine equivalents to achieve maximal comfort, and then decreased the dosage by 10% to 33% daily until he was completely off narcotics. An antidepressant and a benzodiazepine were given simultaneously with narcotic tapering. Oral clonidine (0.1–0.4 mg/day) was given after the narcotic dosage was reduced to about half, and polyethylene glycol was given as needed for constipation. The total duration of detoxification was 7 days.

The patient was referred to a psychologist for cognitive-behavioral and relaxation therapy, as well as for encouragement and support. At 6 months, he had had no recurrence of symptoms.

TAKE-HOME MESSAGE

In the United States, the number of patients taking a narcotic for nonmalignant pain is increasing, ²⁵ and physicians should be more aware of complications such as narcotic bowel syndrome.

Narcotic bowel syndrome should be suspected in any patient with prolonged narcotic use presenting with multiple recurrent episodes of abdominal pain after other causes are ruled out.

Establishing a good therapeutic relationship with the patient is the cornerstone of successful treatment. Patients who understand their condition and are willing to be treated tend to have better outcomes.

Supportive treatment, symptom relief, and emotional support during detoxification increase compliance.

A 32-year-old man presents to the emergency department with excruciating abdominal pain associated with multiple episodes of vomiting for the past 2 days. He reports no fevers, headaches, diarrhea, constipation, hematochezia, melena, musculoskeletal symptoms, or weight loss. His abdominal pain is generalized and crampy. It does not radiate and has no precipitating factors. The pain is relieved only with intravenous narcotics.

See related editorial

He does not smoke, drink alcohol, or use illicit drugs. He has no known drug or food allergies. He says that his current condition causes him emotional stress that affects his performance at work.

About a year ago, after a complicated surgical procedure, he needed chronic high-dose narcotics. A few months later, he developed multiple bouts of abdominal pain and vomiting that required hospital visits. He now takes oral oxycodone 10–15 mg every 4–6 hours.

On admission, his vital signs are stable, but he is in excruciating pain. He is alert and oriented to person, place, and time. His sclera are anicteric, and the pupils are equal, round, and reactive to light. Lung and heart examinations are normal. The abdomen is soft and nondistended but tender in all four quadrants without guarding; the liver and spleen are not palpable, and no abdominal masses are detected. He has no skin rash, joint swelling or tenderness, or peripheral edema. The neurologic examination is normal. Computed tomography (CT) of the abdomen with contrast shows no signs of bowel obstruction, pancreatic calcifications or edema, cholecystitis, or hepatobiliary disease. Results of initial laboratory testing are shown in Table 1.

1. Based on the information available, which is the least likely cause of his symptoms?

• Acute pancreatitis
• Cyclic vomiting syndrome
• Acute intermittent porphyria
• Gastroparesis

Acute pancreatitis

Acute pancreatitis is the least likely cause of his symptoms. It is commonly caused by gallstones, alcohol, hypertriglyceridemia, and certain drugs.¹ The associated abdominal pain is usually epigastric, radiates to the back, and is accompanied by nausea or vomiting, or both. The onset of pain is sudden and rapidly increases in severity within 30 minutes. CT shows enlargement of the pancreas with diffuse edema, heterogeneity of pancreatic parenchyma, peripancreatic stranding, and peripancreatic fluid collections.¹ The diagnosis is based on two of the following three criteria: abdominal pain characteristic of acute pancreatitis; a serum amylase or lipase concentration three or more times the upper limit of normal; and characteristic findings of acute pancreatitis on CT.¹

Cyclic vomiting syndrome

Cyclic vomiting syndrome is thought to be caused by episodic dysautonomia, mitochondrial DNA mutations, and hypothalamic emetic response oversensitivity,^2–4 but the exact pathogenesis is unknown. The syndrome has been strongly linked to migraine and to the chronic excessive use of cannabinoids.^5–9 The Rome III diagnostic criteria¹⁰ are the following: the vomiting episodes are stereotypical, ie, they are acute and last for less than 1 week; the patient has had three or more episodes in the previous year; and the patient has no nausea or vomiting between episodes. The patient must meet all three criteria. A history of migraine or a family history of migraine further supports the diagnosis.

Acute intermittent porphyria

Acute intermittent porphyria is characterized by neurovisceral symptoms such as convulsions, paresis, autonomic dysfunction, constipation, and diarrhea that result from the overproduction of porphyrin precursors and deficiency of porphobilinogen deaminase.¹¹

Most patients have poorly localized, severe, steady abdominal pain that develops over hours to days and that may persist for days to weeks.¹¹ Since the pain is neuropathic, abdominal tenderness is usually minimal during an acute attack. Other clues include signs of ileus, such as constipation, nausea, abdominal distention, or decreased bowel sounds; bladder dysfunction, eg, urinary retention, incontinence, or dysuria; reddish-brown urine; and sensory neuropathy of the chest, back, and extremities.¹¹ Blistering skin lesions are usually not seen. The presence of porphobilinogen in the urine confirms the diagnosis.¹¹

Gastroparesis

Gastroparesis is a result of discoordination between the sympathetic and parasympathetic nervous systems, neurons, and smooth muscles within the stomach, causing a decrease in gastric motility. Common causes are diabetes,¹² scleroderma,¹³ and neurologic disorders.¹⁴ It can also be iatrogenic,¹⁵ resulting from visceral nerve injury and drug treatment with narcotics, calcium channel blockers, muscarinic cholinergic antagonists, or certain antidepressants. Symptoms are related to gastric stasis, ie, abdominal pain from gastric distention, bloating, vomiting, and early satiety.¹⁵ Abdominal pain may worsen after eating, and vomitus usually consists of recently ingested food. These patients may have abdominal distension or tenderness and succussion splash. After excluding possible mechanical obstruction, a gastric-emptying study may be necessary to make the diagnosis.¹⁵

CASE CONTINUED

A serum and urine drug screen in our patient is positive only for opioids. Urine measures of delta-aminolevulinic acid and porphobilinogen are normal. CT angiography of the abdomen shows no signs of mesenteric vascular occlusion. Esophagogastroduodenoscopy shows antral gastritis, but the esophagus and duodenum appear normal, and colonoscopy is normal as well. Histologic study of biopsy specimens obtained during endoscopy is unrevealing. A gastric-emptying study shows delayed emptying. The patient’s abdominal pain and vomiting persist with the initial dose of intravenous narcotic but resolve with escalating doses. When asked, the patient denies an excessive need for hot baths.

2. Which is the most likely diagnosis at this point?

• Narcotic bowel syndrome
• Opioid withdrawal
• Crohn disease
• Chronic pancreatitis
• Chronic mesenteric ischemia
• Cannabinoid hyperemesis

Narcotic bowel syndrome

Narcotic bowel syndrome is the most likely diagnosis. Grunkemeier et al¹⁶ described it as chronic or frequently recurring abdominal pain that is treated with narcotics, either chronically or acutely with high doses, and that includes all the following features¹⁶:

• The pain worsens or resolves incompletely with continued or increasing doses of narcotics
• The pain markedly worsens when the narcotic dose is decreased, and decreases when the drug is reinstituted (the “soarand-crash” effect)
• The frequency, duration, and intensity of the pain episodes gradually increase
• The nature of the pain and its intensity are not explained by a current or previous gastrointestinal diagnosis.¹⁶

This syndrome is common in patients who receive high doses of narcotics for postoperative pain or for other, nonmalignant causes of pain. Patients eventually become dependent on the drugs but are not aware that chronic use activates and facilitates areas in the brain that enhance the perception of pain.¹⁶ A study of a rat model of narcotic bowel syndrome¹⁷ showed that morphine-induced hyperalgesia depends on central sensitization involving the activation of spinal microglia. This eventually results in concomitant peripheral sensitization involving the colonic mucosal neuroimmune system, and also in central or peripheral activation of opioid kappa-receptors by dynorphin release.¹⁷

Patients tend to present with chronic or intermittent colicky abdominal pain that requires escalating doses of narcotics. Eventually, they develop tachyphylaxis and shortened pain-free periods and will require even higher doses of narcotics. This ultimately enhances the perception of pain and worsens opioid bowel symptoms, causing a vicious circle of pain and more narcotic use.¹⁶

Laboratory tests are usually normal, and imaging may show only ileus. Gastric emptying may be delayed in patients who have either narcotic bowel syndrome or gastroparesis, but since abdominal pain from narcotic bowel syndrome is a result of central and visceral hypersensitivity, these patients perceive more severe abdominal pain than patients with gastroparesis alone.

Opioid withdrawal

Symptoms of opioid withdrawal may appear as soon as 6 to 24 hours after cessation of the opioid in patients known to be dependent on opioids. These patients present with crampy abdominal pain with nausea.¹⁸ Other symptoms include agitation, rhinorrhea, lacrimation, excessive yawning, arthralgias, papillary dilation, and piloerection.¹⁸

Our patient did not have the typical signs of opioid withdrawal.

Crohn disease

Crohn disease is a multisystem disorder with specific clinical and pathologic features. It is characterized by focal, asymmetric, transmural, and occasionally granulomatous inflammation primarily affecting the gastrointestinal tract.¹⁹ Characteristic symptoms include abdominal pain, chronic diarrhea with or without rectal bleeding, and weight loss. Extraintestinal signs may include anemia and inflammatory changes in the eyes, skin, and joints. The diagnosis is based on endoscopic, radiographic, and pathologic findings.¹⁹

Our patient did not have diarrhea or signs of Crohn disease on CT, endoscopy, or histology.

Chronic pancreatitis

Chronic pancreatitis involves progressive inflammatory changes resulting in permanent structural damage to the pancreas and subsequent exocrine and endocrine dysfunction.²⁰ Patients have epigastric abdominal pain that often radiates to the back²⁰; it is associated with eating and is partly relieved with leaning forward. Symptoms of pancreatic insufficiency such as fat malabsorption (resulting in steatorrhea and fat-soluble vitamin deficiency) and diabetes are common. Calcifications within the pancreas on CT suggest chronic pancreatitis.²⁰ Serum lipase and amylase levels may be normal or slightly elevated.²⁰

Our patient’s abdominal pain was not typical of pancreatitis. He had no signs or symptoms of pancreatic insufficiency and no calcifications within the pancreas.

Chronic mesenteric ischemia

Chronic mesenteric ischemia (“intestinal angina”) is caused by a reduction in intestinal blood flow as a result of occlusion, vasospasm, or hypoperfusion of the mesenteric vasculature.²¹ It is commonly seen in patients who smoke or who have atherosclerotic vascular disease. These patients have chronic dull or crampy abdominal pain that usually occurs within 1 hour after eating.²¹ To avoid pain, patients avoid eating, resulting in weight loss.²¹ CT angiography with multi-detector CT is as effective as angiography (the gold standard) in depicting splanchnic arterial anatomy.²²

Our patient is young and has no known risk factors for atherosclerosis such as smoking. His abdominal pain is more intermittent than chronic and is not associated with eating.

Cannabinoid hyperemesis

Cannabinoid hyperemesis should be considered in patients with long-term cannabis use presenting with cyclic vomiting, abdominal pain, compulsive use of hot showers, and improvement of symptoms with cannabis cessation.²³ Although cannabinoids have been recognized for their antiemetic effects, long-term use may eventually cause autonomic instability and disturbances in the hypothalamic-pituitary-adrenal axis, resulting in cyclic vomiting and thermoregulatory impairment.²³

Although our patient presented with multiple episodes of vomiting and abdominal pain, he denied using marijuana, he tested negative for tetrahydrocannabinol, and he did not associate any relief of his symptoms with hot baths.

CASE CONTINUED

Our patient receives intravenous hydration, antiemetics, and a narcotic in tapering intravenous doses, and his symptoms gradually improve. He is discharged from the hospital. However, a few weeks later he is readmitted with the same symptoms of abdominal pain and nausea.

3. What is the cornerstone of treatment for narcotic bowel syndrome?

• Establishing a therapeutic relationship
• Detoxification
• Supportive management with intravenous fluids, antiemetics, and stool-softeners
• Medical management with a short-acting narcotic, clonidine, lorazepam, and desipramine

MANAGEMENT OF NARCOTIC BOWEL SYNDROME

An effective therapeutic relationship with the patient is the cornerstone of treatment and should be established before starting detoxification.¹⁷ The physician must first learn to accept that the patient’s condition is real and must show genuine empathy as well as provide information about the pathophysiologic basis of the condition, the rationale for withholding narcotics, and the detrimental role narcotics play in the vicious circle of pain.

Detoxification involves gradually withdrawing the narcotic and substituting a nonnarcotic such as an antidepressant for pain control, as well as prescribing a drug such as a benzodiazepine or clonidine to prevent withdrawal symptoms and a laxative to prevent constipation.^17,24 The physician must reassure the patient that he or she will not be abandoned in pain and that all medications will be continuously adjusted as needed to keep him or her comfortable throughout the detoxification process.^17,24 The physician must continuously gauge the patient’s willingness to continue with treatment and must also be readily available to address the patient’s concerns in a timely manner.^17,24 Involving family members and friends may provide additional support to the patient. Referral to a functional gastrointestinal motility program, a pain specialist, and a psychologist may also be considered.^17,24 Follow-up care is essential, even after the withdrawal program has ended.^17,24

BACK TO THE PATIENT

After successfully establishing a therapeutic relationship and discussing the treatment plan with our patient, we started him on the same dosage of narcotic that he had been receiving, calculated in intravenous morphine equivalents to achieve maximal comfort, and then decreased the dosage by 10% to 33% daily until he was completely off narcotics. An antidepressant and a benzodiazepine were given simultaneously with narcotic tapering. Oral clonidine (0.1–0.4 mg/day) was given after the narcotic dosage was reduced to about half, and polyethylene glycol was given as needed for constipation. The total duration of detoxification was 7 days.

The patient was referred to a psychologist for cognitive-behavioral and relaxation therapy, as well as for encouragement and support. At 6 months, he had had no recurrence of symptoms.

TAKE-HOME MESSAGE

In the United States, the number of patients taking a narcotic for nonmalignant pain is increasing, ²⁵ and physicians should be more aware of complications such as narcotic bowel syndrome.

Narcotic bowel syndrome should be suspected in any patient with prolonged narcotic use presenting with multiple recurrent episodes of abdominal pain after other causes are ruled out.

Establishing a good therapeutic relationship with the patient is the cornerstone of successful treatment. Patients who understand their condition and are willing to be treated tend to have better outcomes.

Supportive treatment, symptom relief, and emotional support during detoxification increase compliance.

A 32-year-old man presents to the emergency department with excruciating abdominal pain associated with multiple episodes of vomiting for the past 2 days. He reports no fevers, headaches, diarrhea, constipation, hematochezia, melena, musculoskeletal symptoms, or weight loss. His abdominal pain is generalized and crampy. It does not radiate and has no precipitating factors. The pain is relieved only with intravenous narcotics.

See related editorial

He does not smoke, drink alcohol, or use illicit drugs. He has no known drug or food allergies. He says that his current condition causes him emotional stress that affects his performance at work.

About a year ago, after a complicated surgical procedure, he needed chronic high-dose narcotics. A few months later, he developed multiple bouts of abdominal pain and vomiting that required hospital visits. He now takes oral oxycodone 10–15 mg every 4–6 hours.

On admission, his vital signs are stable, but he is in excruciating pain. He is alert and oriented to person, place, and time. His sclera are anicteric, and the pupils are equal, round, and reactive to light. Lung and heart examinations are normal. The abdomen is soft and nondistended but tender in all four quadrants without guarding; the liver and spleen are not palpable, and no abdominal masses are detected. He has no skin rash, joint swelling or tenderness, or peripheral edema. The neurologic examination is normal. Computed tomography (CT) of the abdomen with contrast shows no signs of bowel obstruction, pancreatic calcifications or edema, cholecystitis, or hepatobiliary disease. Results of initial laboratory testing are shown in Table 1.

1. Based on the information available, which is the least likely cause of his symptoms?

• Acute pancreatitis
• Cyclic vomiting syndrome
• Acute intermittent porphyria
• Gastroparesis

Acute pancreatitis

Acute pancreatitis is the least likely cause of his symptoms. It is commonly caused by gallstones, alcohol, hypertriglyceridemia, and certain drugs.¹ The associated abdominal pain is usually epigastric, radiates to the back, and is accompanied by nausea or vomiting, or both. The onset of pain is sudden and rapidly increases in severity within 30 minutes. CT shows enlargement of the pancreas with diffuse edema, heterogeneity of pancreatic parenchyma, peripancreatic stranding, and peripancreatic fluid collections.¹ The diagnosis is based on two of the following three criteria: abdominal pain characteristic of acute pancreatitis; a serum amylase or lipase concentration three or more times the upper limit of normal; and characteristic findings of acute pancreatitis on CT.¹

Cyclic vomiting syndrome

Cyclic vomiting syndrome is thought to be caused by episodic dysautonomia, mitochondrial DNA mutations, and hypothalamic emetic response oversensitivity,^2–4 but the exact pathogenesis is unknown. The syndrome has been strongly linked to migraine and to the chronic excessive use of cannabinoids.^5–9 The Rome III diagnostic criteria¹⁰ are the following: the vomiting episodes are stereotypical, ie, they are acute and last for less than 1 week; the patient has had three or more episodes in the previous year; and the patient has no nausea or vomiting between episodes. The patient must meet all three criteria. A history of migraine or a family history of migraine further supports the diagnosis.

Acute intermittent porphyria

Acute intermittent porphyria is characterized by neurovisceral symptoms such as convulsions, paresis, autonomic dysfunction, constipation, and diarrhea that result from the overproduction of porphyrin precursors and deficiency of porphobilinogen deaminase.¹¹

Most patients have poorly localized, severe, steady abdominal pain that develops over hours to days and that may persist for days to weeks.¹¹ Since the pain is neuropathic, abdominal tenderness is usually minimal during an acute attack. Other clues include signs of ileus, such as constipation, nausea, abdominal distention, or decreased bowel sounds; bladder dysfunction, eg, urinary retention, incontinence, or dysuria; reddish-brown urine; and sensory neuropathy of the chest, back, and extremities.¹¹ Blistering skin lesions are usually not seen. The presence of porphobilinogen in the urine confirms the diagnosis.¹¹

Gastroparesis

Gastroparesis is a result of discoordination between the sympathetic and parasympathetic nervous systems, neurons, and smooth muscles within the stomach, causing a decrease in gastric motility. Common causes are diabetes,¹² scleroderma,¹³ and neurologic disorders.¹⁴ It can also be iatrogenic,¹⁵ resulting from visceral nerve injury and drug treatment with narcotics, calcium channel blockers, muscarinic cholinergic antagonists, or certain antidepressants. Symptoms are related to gastric stasis, ie, abdominal pain from gastric distention, bloating, vomiting, and early satiety.¹⁵ Abdominal pain may worsen after eating, and vomitus usually consists of recently ingested food. These patients may have abdominal distension or tenderness and succussion splash. After excluding possible mechanical obstruction, a gastric-emptying study may be necessary to make the diagnosis.¹⁵

CASE CONTINUED

A serum and urine drug screen in our patient is positive only for opioids. Urine measures of delta-aminolevulinic acid and porphobilinogen are normal. CT angiography of the abdomen shows no signs of mesenteric vascular occlusion. Esophagogastroduodenoscopy shows antral gastritis, but the esophagus and duodenum appear normal, and colonoscopy is normal as well. Histologic study of biopsy specimens obtained during endoscopy is unrevealing. A gastric-emptying study shows delayed emptying. The patient’s abdominal pain and vomiting persist with the initial dose of intravenous narcotic but resolve with escalating doses. When asked, the patient denies an excessive need for hot baths.

2. Which is the most likely diagnosis at this point?

• Narcotic bowel syndrome
• Opioid withdrawal
• Crohn disease
• Chronic pancreatitis
• Chronic mesenteric ischemia
• Cannabinoid hyperemesis

Narcotic bowel syndrome

Narcotic bowel syndrome is the most likely diagnosis. Grunkemeier et al¹⁶ described it as chronic or frequently recurring abdominal pain that is treated with narcotics, either chronically or acutely with high doses, and that includes all the following features¹⁶:

• The pain worsens or resolves incompletely with continued or increasing doses of narcotics
• The pain markedly worsens when the narcotic dose is decreased, and decreases when the drug is reinstituted (the “soarand-crash” effect)
• The frequency, duration, and intensity of the pain episodes gradually increase
• The nature of the pain and its intensity are not explained by a current or previous gastrointestinal diagnosis.¹⁶

This syndrome is common in patients who receive high doses of narcotics for postoperative pain or for other, nonmalignant causes of pain. Patients eventually become dependent on the drugs but are not aware that chronic use activates and facilitates areas in the brain that enhance the perception of pain.¹⁶ A study of a rat model of narcotic bowel syndrome¹⁷ showed that morphine-induced hyperalgesia depends on central sensitization involving the activation of spinal microglia. This eventually results in concomitant peripheral sensitization involving the colonic mucosal neuroimmune system, and also in central or peripheral activation of opioid kappa-receptors by dynorphin release.¹⁷

Patients tend to present with chronic or intermittent colicky abdominal pain that requires escalating doses of narcotics. Eventually, they develop tachyphylaxis and shortened pain-free periods and will require even higher doses of narcotics. This ultimately enhances the perception of pain and worsens opioid bowel symptoms, causing a vicious circle of pain and more narcotic use.¹⁶

Laboratory tests are usually normal, and imaging may show only ileus. Gastric emptying may be delayed in patients who have either narcotic bowel syndrome or gastroparesis, but since abdominal pain from narcotic bowel syndrome is a result of central and visceral hypersensitivity, these patients perceive more severe abdominal pain than patients with gastroparesis alone.

Opioid withdrawal

Symptoms of opioid withdrawal may appear as soon as 6 to 24 hours after cessation of the opioid in patients known to be dependent on opioids. These patients present with crampy abdominal pain with nausea.¹⁸ Other symptoms include agitation, rhinorrhea, lacrimation, excessive yawning, arthralgias, papillary dilation, and piloerection.¹⁸

Our patient did not have the typical signs of opioid withdrawal.

Crohn disease

Crohn disease is a multisystem disorder with specific clinical and pathologic features. It is characterized by focal, asymmetric, transmural, and occasionally granulomatous inflammation primarily affecting the gastrointestinal tract.¹⁹ Characteristic symptoms include abdominal pain, chronic diarrhea with or without rectal bleeding, and weight loss. Extraintestinal signs may include anemia and inflammatory changes in the eyes, skin, and joints. The diagnosis is based on endoscopic, radiographic, and pathologic findings.¹⁹

Our patient did not have diarrhea or signs of Crohn disease on CT, endoscopy, or histology.

Chronic pancreatitis

Chronic pancreatitis involves progressive inflammatory changes resulting in permanent structural damage to the pancreas and subsequent exocrine and endocrine dysfunction.²⁰ Patients have epigastric abdominal pain that often radiates to the back²⁰; it is associated with eating and is partly relieved with leaning forward. Symptoms of pancreatic insufficiency such as fat malabsorption (resulting in steatorrhea and fat-soluble vitamin deficiency) and diabetes are common. Calcifications within the pancreas on CT suggest chronic pancreatitis.²⁰ Serum lipase and amylase levels may be normal or slightly elevated.²⁰

Our patient’s abdominal pain was not typical of pancreatitis. He had no signs or symptoms of pancreatic insufficiency and no calcifications within the pancreas.

Chronic mesenteric ischemia

Chronic mesenteric ischemia (“intestinal angina”) is caused by a reduction in intestinal blood flow as a result of occlusion, vasospasm, or hypoperfusion of the mesenteric vasculature.²¹ It is commonly seen in patients who smoke or who have atherosclerotic vascular disease. These patients have chronic dull or crampy abdominal pain that usually occurs within 1 hour after eating.²¹ To avoid pain, patients avoid eating, resulting in weight loss.²¹ CT angiography with multi-detector CT is as effective as angiography (the gold standard) in depicting splanchnic arterial anatomy.²²

Our patient is young and has no known risk factors for atherosclerosis such as smoking. His abdominal pain is more intermittent than chronic and is not associated with eating.

Cannabinoid hyperemesis

Cannabinoid hyperemesis should be considered in patients with long-term cannabis use presenting with cyclic vomiting, abdominal pain, compulsive use of hot showers, and improvement of symptoms with cannabis cessation.²³ Although cannabinoids have been recognized for their antiemetic effects, long-term use may eventually cause autonomic instability and disturbances in the hypothalamic-pituitary-adrenal axis, resulting in cyclic vomiting and thermoregulatory impairment.²³

Although our patient presented with multiple episodes of vomiting and abdominal pain, he denied using marijuana, he tested negative for tetrahydrocannabinol, and he did not associate any relief of his symptoms with hot baths.

CASE CONTINUED

Our patient receives intravenous hydration, antiemetics, and a narcotic in tapering intravenous doses, and his symptoms gradually improve. He is discharged from the hospital. However, a few weeks later he is readmitted with the same symptoms of abdominal pain and nausea.

3. What is the cornerstone of treatment for narcotic bowel syndrome?

• Establishing a therapeutic relationship
• Detoxification
• Supportive management with intravenous fluids, antiemetics, and stool-softeners
• Medical management with a short-acting narcotic, clonidine, lorazepam, and desipramine

MANAGEMENT OF NARCOTIC BOWEL SYNDROME

An effective therapeutic relationship with the patient is the cornerstone of treatment and should be established before starting detoxification.¹⁷ The physician must first learn to accept that the patient’s condition is real and must show genuine empathy as well as provide information about the pathophysiologic basis of the condition, the rationale for withholding narcotics, and the detrimental role narcotics play in the vicious circle of pain.

Detoxification involves gradually withdrawing the narcotic and substituting a nonnarcotic such as an antidepressant for pain control, as well as prescribing a drug such as a benzodiazepine or clonidine to prevent withdrawal symptoms and a laxative to prevent constipation.^17,24 The physician must reassure the patient that he or she will not be abandoned in pain and that all medications will be continuously adjusted as needed to keep him or her comfortable throughout the detoxification process.^17,24 The physician must continuously gauge the patient’s willingness to continue with treatment and must also be readily available to address the patient’s concerns in a timely manner.^17,24 Involving family members and friends may provide additional support to the patient. Referral to a functional gastrointestinal motility program, a pain specialist, and a psychologist may also be considered.^17,24 Follow-up care is essential, even after the withdrawal program has ended.^17,24

BACK TO THE PATIENT

After successfully establishing a therapeutic relationship and discussing the treatment plan with our patient, we started him on the same dosage of narcotic that he had been receiving, calculated in intravenous morphine equivalents to achieve maximal comfort, and then decreased the dosage by 10% to 33% daily until he was completely off narcotics. An antidepressant and a benzodiazepine were given simultaneously with narcotic tapering. Oral clonidine (0.1–0.4 mg/day) was given after the narcotic dosage was reduced to about half, and polyethylene glycol was given as needed for constipation. The total duration of detoxification was 7 days.

The patient was referred to a psychologist for cognitive-behavioral and relaxation therapy, as well as for encouragement and support. At 6 months, he had had no recurrence of symptoms.

TAKE-HOME MESSAGE

In the United States, the number of patients taking a narcotic for nonmalignant pain is increasing, ²⁵ and physicians should be more aware of complications such as narcotic bowel syndrome.

Narcotic bowel syndrome should be suspected in any patient with prolonged narcotic use presenting with multiple recurrent episodes of abdominal pain after other causes are ruled out.

Establishing a good therapeutic relationship with the patient is the cornerstone of successful treatment. Patients who understand their condition and are willing to be treated tend to have better outcomes.

Supportive treatment, symptom relief, and emotional support during detoxification increase compliance.