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Man, 56, With Wrist Pain After a Fall
A white man, age 56, presented to his primary care clinician with wrist pain and swelling. Two days earlier, he had fallen from a step stool and landed on his right wrist. He treated the pain by resting, elevating his arm, applying ice, and taking ibuprofen 800 mg tid. He said he had lost strength in his hand and arm and was experiencing numbness and tingling in his right hand and fingers.
The patient’s medical history included hypertension, type 2 diabetes mellitus, morbid obesity, obstructive sleep apnea, asthma, carpel tunnel syndrome, and peripheral neuropathy. His surgical history was significant for duodenal switch gastric bypass surgery, performed eight years earlier, and his weight at the time of presentation was 200 lb; before his gastric bypass, he weighed 385 lb. Since the surgery, his hypertension, diabetes, asthma, and sleep apnea had all resolved. Table 1 shows a list of medications he was taking at the time of presentation.
The patient, a registered nurse, had been married for 30 years and had one child. He had quit smoking 15 years earlier, with a 43–pack-year smoking history. He reported social drinking but denied any recreational drug use. He was unaware of having any allergies to food or medication.
His vital signs on presentation were blood pressure, 110/75 mm Hg; heart rate, 53 beats/min; respiration, 18 breaths/min; O2 saturation, 97% on room air; and temperature, 97.5°F.
Physical exam revealed that the patient’s right wrist was ecchymotic and swollen with +1 pitting edema. The skin was warm and dry to the touch. Decreased range of motion was noted in the right wrist, compared with the left. Pain with point tenderness was noted at the right lateral wrist. Pulses were +3 with capillary refill of less than 3 seconds. The rest of the exam was unremarkable.
The differential diagnosis included fracture secondary to the fall, osteoporosis, osteopenia, osteomalacia, Paget’s disease, tumor, infection, and sprain or strain of the wrist. A wrist x-ray was ordered, as were the following baseline labs: complete blood count with differential (CBC), vitamin B12 and folate levels, blood chemistry, lipid profile, liver profile, total vitamin D, and sensitive thyroid-stimulating hormone. Test results are shown in Table 2.
X-ray of the wrist showed fracture only, making it possible to rule out Paget’s disease (ie, no patchy white areas noted in the bone) and tumor (no masses seen) as the immediate cause of fracture. Normal body temperature and normal white blood cell count eliminated the possibility of infection.
Because the patient was only 56 and had a history of bariatric surgery, further testing was pursued to investigate a cause for the weakened bone. Bone mineral density (BMD) testing revealed the following results:
• The lumbar spine in frontal projection measured 0.968 g/cm2 with a T-score of –2.2 and a Z-score of –2.2.
• Total BMD of the left hip was 0.863 g/cm2 with a T-score of –1.7 and a Z-score of –1.4.
• Total BMD of the left femoral neck was 0.863 g/cm2 with a T-score of 1.7 and a Z-score of –1.1.
These findings suggested osteopenia1,2 (not osteoporosis) in all sites, with a 12% decrease of BMD in the spine (suggesting increased risk for spinal fracture) and a 16.3% decrease of BMD in the hip since the patient’s most recent bone scan five years earlier (radiologist’s report). Other abnormal findings were elevated parathyroid hormone (PTH) serum, 95.7 pg/mL (reference range, 10 to 65 pg/mL); low total calcium serum, 8.7 mg/dL (reference range, 8.9 to 10.2 mg/dL), and low 25-hydroxyvitamin D total, 12.3 ng/mL (reference range, 25 to 80 ng/mL).
A 2010 clinical practice guideline from the Endocrine Society3 specifies that after malabsorptive surgery, vitamin D and calcium supplementation should be adjusted by a qualified medical professional, based on serum markers and measures of bone density. An endocrinologist who was consulted at the patient’s initial visit prescribed the following medications: vitamin D2, 50,000 U/wk PO; combined calcium citrate (vitamin D3) 500 IU with calcium 630 mg, 1 tab bid; and calcitriol 0.5 μg bid.
The patient’s final diagnosis was osteomalacia secondary to gastric bypass surgery. (See “Making the Diagnosis of Osteomalacia.”4-6)
DISCUSSION
According to 2008 data from the World Health Organization (WHO),7 1.4 billion persons older than 20 worldwide were overweight, and 200 million men and 300 million women were considered obese—meaning that one in every 10 adults worldwide is overweight or obese. In 2010, the WHO reports, 40 million children younger than 5 worldwide were considered overweight.7 Health care providers need to be prepared to care for the increasing number of patients who will undergo bariatric surgeries to treat obesity and its related comorbidities.8
Postoperative follow-up for the malabsorption deficiencies related to bariatric procedures should be performed every six months, including obtaining levels of alkaline phosphatase and others previously discussed. In addition, the Endocrine Society guideline3 recommends measuring levels of vitamin B12, albumin, pre-albumin, iron, and ferritin, and obtaining a CBC, a liver profile, glucose reading, creatinine measurement, and a metabolic profile at one month and two months after surgery, then every six months until two years after surgery, then annually if findings are stable.
Furthermore, the Endocrine Society3 recommends obtaining zinc levels every six months for the first year, then annually. An annual vitamin A level is optional.9 Yearly bone density testing is recommended until the patient’s BMD is deemed stable.3
Additionally, Koch and Finelli10 recommend performing the following labs postoperatively: hemoglobin A1C every three months; copper, magnesium, whole blood thiamine, vitamin B12, and a 24-hour urinary calcium every six months for the first three years, then once a year if findings remain stable.
Use of alcohol should be discouraged among patients who have undergone bariatric surgery, as its use alters micronutrient requirements and metabolism. Alcohol consumption may also contribute to dumping syndrome (ie, rapid gastric emptying).11
Any patient with a history of malabsorptive bypass surgery who complains of neurologic, visual, or skin disorders, anemia, or edema may require a further workup to rule out other absorptive deficiencies. These include vitamins A, E, and B12, zinc, folate, thiamine, niacin, selenium, and ferritin.10
Osteomalacia
Metabolic bone diseases can result from genetics, dietary factors, medication use, surgery, or hormonal irregularities. They alter the normal biochemical reactions in bone structure.
The three most common forms of metabolic bone disease are osteoporosis, osteopenia, and osteomalacia. The WHO diagnostic classifications and associated T-scores for bone mineral density1,2 indicate a T-score above –1.0 as normal. A score between –1.0 and –2.5 is indicative of osteopenia, and a score below –2.5 indicates osteoporosis. A T-score below –2.5 in the patient with a history of fragility fracture indicates severe osteoporosis.1,2
In osteomalacia, bone volume remains unchanged, but mineralization of osteoid in the mature compact and spongy bone is either delayed or inadequate. The remolding cycle continues unchanged in the formation of osteoid, but mineral calcification and deposition do not occur.3-5
Osteomalacia is normally considered a rare disorder, but it may become more common as increasing numbers of patients undergo gastric bypass operations.12,13 Primary care practitioners should monitor for this condition in such patients before serious bone loss or other problems develop.9,13,14
Vitamin D deficiency (see “Vitamin D Metabolism,”4,15-19 below), whether or not the result of gastric bypass surgery, is a major risk factor for osteomalacia. Disorders of the small bowel, the hepatobiliary system, and the pancreas are all common causes of vitamin D deficiency. Liver disease interferes with the metabolism of vitamin D. Diseases of the pancreas may cause a deficiency of bile salts, which are vital for the intestinal absorption of vitamin D.17
Restriction and Malabsorption
The case patient had undergone a gastric bypass (duodenal switch), in which a large portion of the stomach is removed and a large part of the small bowel rerouted—with both parts of the procedure causing malabsorption.11 It is in the small bowel that absorption of vitamin D and calcium takes place.
The duodenal switch gastric bypass surgery causes both restriction and malabsorption. Though similar to a biliopancreatic diversion, the duodenal switch preserves the distal stomach and the pylorus20 by way of a sleeve gastrectomy that is performed to reduce the gastric reservoir; the common channel length after revision is 100 cm, not 50 cm (as in conventional biliopancreatic diversion).13 The sleeve gastrectomy involves removal of parietal cells, reducing production of hydrochloric acid (which is necessary to break down food), and hindering the absorption of certain nutrients, including the fat-soluble vitamins, vitamin B12, and iron.12 Patients who take H2-blockers or proton pump inhibitors experience an additional decrease in the production and availability of HCl and may have an increased risk for fracture.14,20,21
In addition to its biliopancreatic diversion component, the duodenal switch diverts a large portion of the small bowel, with food restricted from moving through it. Vitamin D and protein are normally absorbed at the jejunum and ileum, but only when bile salts are present; after a duodenal switch, bile and pancreatic enzymes are not introduced into the small intestines until 75 to 100 cm before they reach the large intestine. Thus, absorption of vitamin D, protein, calcium, and other nutrients is impaired.20,22
Since phosphorus and magnesium are also absorbed at the sites of the duodenum and jejunum, malabsorption of these nutrients may occur in a patient who has undergone a duodenal switch. Although vitamin B12 is absorbed at the site of the distal ileum, it also requires gastric acid to free it from the food. Zinc absorption, which normally occurs at the site of the jejunum, may be impaired after duodenal switch surgery, and calcium supplementation, though essential, may further reduce zinc absorption.9 Iron absorption requires HCl, facilitated by the presence of vitamin C. Use of H2-blockers and proton pump inhibitors may impair iron metabolism, resulting in anemia.20
In a randomized controlled trial, Aasheim et al23 compared the effects of Roux-en-Y gastric bypass with those of duodenal switch gastric bypass on patients’ vitamin metabolism. The researchers concluded that patients who undergo a duodenal switch are at greater risk for vitamin A and D deficiencies in the first year after surgery; and for thiamine deficiency in the months following surgery as a result of malabsorption, compared with patients who undergo Roux-en-Y gastric bypass.20,23
Patient Management
The case patient’s care necessitated consultations with endocrinology, dermatology, and gastroenterology (GI). Table 3 (below) shows the laboratory findings and the medication changes prompted by the patient’s physical exam and lab results. Table 4 lists the findings from other lab studies ordered throughout the patient’s course of treatment.
The endocrinologist was consulted at the first sign of osteopenia, and a workup was soon initiated, followed by treatment. GI was consulted six months after the beginning of treatment, when the patient began to complain of reflux while sleeping and frequent diarrhea throughout the day.
Results of esophagogastroduodenoscopy with biopsy ruled out celiac disease and mucosal ulceration, but a small hiatal hernia that was detected (< 3 cm) was determined to be an aggravating factor for the patient’s reflux. The patient was instructed in lifestyle modifications for hiatal hernia, including the need to remain upright one to two hours after eating before going to sleep to prevent aspiration. The patient was instructed to avoid taking iron and calcium within two hours of each other and to limit his alcohol intake. He was also educated in precautions against falls.
Dermatology was consulted nine months into treatment so that light therapy could be initiated, allowing the patient to take advantage of the body’s natural pathway to manufacture vitamin D3.
CONCLUSION
For post–bariatric surgery patients, primary care practitioners are in a position to coordinate care recommendations from multiple specialists, including those in nutrition, to determine the best course of action.
This case illustrates complications of bariatric surgery (malabsorption of key vitamins and minerals, wrist fracture, osteopenia, osteomalacia) that require diagnosis and treatment. The specialists and the primary care practitioner, along with the patient, had to weigh the risks and benefits of continued proton pump inhibitor use, as such medications can increase the risk for fracture. They also addressed the patient’s anemia and remained attentive to his preventive health care needs.
REFERENCES
1. Brusin JH. Update on bone densitometry. Radiol Technol. 2009;81(2):153BD-170BD.
2. Wilson CR. Essentials of bone densitometry for the medical physicist. Presented at: The American Association of Physicists in Medicine 2003 Annual Meeting; July 22-26, 2003; San Diego, CA.
3. Heber D, Greenway FL, Kaplan LM. et al. Endocrine and nutritional management of the post-bariatric surgery patient: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(11):4825-4843.
4. Osteomalacia: step-by-step diagnostic approach (2011). http://bestpractice.bmj.com/best-practice/monograph/517/diagnosis/step-by-step.html. Accessed December 18, 2012.
5. Gifre L, Peris P, Monegal A, et al. Osteomalacia revisited : a report on 28 cases. Clin Rheumatol. 2011;30(5):639-645.
6. Bingham CT, Fitzpatrick LA. Noninvasive testing in the diagnosis of osteomalacia. Am J Med. 1993;95(5):519-523.
7. World Health Organization. Obesity and overweight (May 2012). Fact Sheet No 311. www.who.int/mediacentre/factsheets/fs311/en/index.html. Accessed December 18, 2012.
8. Tanner BD, Allen JW. Complications of bariatric surgery: implications for the covering physician. Am Surg. 2009;75(2):103-112.
9. Soleymani T, Tejavanija S, Morgan S. Obesity, bariatric surgery, and bone. Curr Opin Rheumatol. 2011;23(4):396-405.
10. Koch TR, Finelli FC. Postoperative metabolic and nutritional complications of bariatric surgery. Gastroenterol Clin North Am. 2010;39(1):109-124.
11. Manchester S, Roye GD. Bariatric surgery: an overview for dietetics professionals. Nutr Today. 2011;46(6):264-275.
12. Bal BS, Finelli FC, Shope TR, Koch TR. Nutritional deficiencies after bariatric surgery. Nat Rev Endocrinol. 2012;8(9):544-546.
13. Iannelli A, Schneck AS, Dahman M, et al. Two-step laparoscopic duodenal switch for superobesity: a feasibility study. Surg Endosc. 2009;23(10):2385-2389.
14. Lalmohamed A, de Vries F, Bazelier MT, et al. Risk of fracture after bariatric surgery in the United Kingdom: population based, retrospective cohort study. BMJ. 2012;345:e5085.
15. Holrick MF. Vitamin D: important for prevention of osteoporosis, cardiovascular heart disease, type 1 diabetes, autoimmune diseases, and some cancers. South Med J. 2005;98 (10):1024-1027.
16. Kalro BN. Vitamin D and the skeleton. Alt Ther Womens Health. 2009;2(4):25-32.
17. Crowther-Radulewicz CL, McCance KL. Alterations of musculoskeletal function. In: McCance KL, Huether SE, Brashers VL, Rote NS, eds. Pathophysiology: The Biologic Basis for Disease in Adults and Children. 6th ed. Maryland Heights, MO: Mosby Elsevier; 2010:1568-1617.
18. Huether SE. Structure and function of the renal and urologic systems. In: McCance KL, Huether SE, Brashers VL, Rote NS, eds. Pathophysiology: The Biologic Basis for Disease in Adults and Children. 6th ed. Maryland Heights, MO: Mosby Elsevier; 2010:1344-1364.
19. Bhan A, Rao AD, Rao DS. Osteomalacia as a result of vitamin D deficiency. Endocrinol Metab Clin North Am. 2010;39(2):321-331.
20. Decker GA, Swain JM, Crowell MD. Gastrointestinal and nutritional complications after bariatric surgery. Am J Gastroenterol. 2007;102(11):2571-2580.
21. Targownik LE, Lix LM, Metge C, et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ. 2008;179(4):319-326.
22. Ybarra J, Sánchez-Hernández J, Pérez A. Hypovitaminosis D and morbid obesity. Nurs Clin North Am. 2007;42(1):19-27.
23. Aasheim ET, Björkman S, Søvik TT, et al. Vitamin status after bariatric surgery: a randomized study of gastric bypass and duodenal switch. Am J Clin Nutr. 2009;90(1):15-22.
A white man, age 56, presented to his primary care clinician with wrist pain and swelling. Two days earlier, he had fallen from a step stool and landed on his right wrist. He treated the pain by resting, elevating his arm, applying ice, and taking ibuprofen 800 mg tid. He said he had lost strength in his hand and arm and was experiencing numbness and tingling in his right hand and fingers.
The patient’s medical history included hypertension, type 2 diabetes mellitus, morbid obesity, obstructive sleep apnea, asthma, carpel tunnel syndrome, and peripheral neuropathy. His surgical history was significant for duodenal switch gastric bypass surgery, performed eight years earlier, and his weight at the time of presentation was 200 lb; before his gastric bypass, he weighed 385 lb. Since the surgery, his hypertension, diabetes, asthma, and sleep apnea had all resolved. Table 1 shows a list of medications he was taking at the time of presentation.
The patient, a registered nurse, had been married for 30 years and had one child. He had quit smoking 15 years earlier, with a 43–pack-year smoking history. He reported social drinking but denied any recreational drug use. He was unaware of having any allergies to food or medication.
His vital signs on presentation were blood pressure, 110/75 mm Hg; heart rate, 53 beats/min; respiration, 18 breaths/min; O2 saturation, 97% on room air; and temperature, 97.5°F.
Physical exam revealed that the patient’s right wrist was ecchymotic and swollen with +1 pitting edema. The skin was warm and dry to the touch. Decreased range of motion was noted in the right wrist, compared with the left. Pain with point tenderness was noted at the right lateral wrist. Pulses were +3 with capillary refill of less than 3 seconds. The rest of the exam was unremarkable.
The differential diagnosis included fracture secondary to the fall, osteoporosis, osteopenia, osteomalacia, Paget’s disease, tumor, infection, and sprain or strain of the wrist. A wrist x-ray was ordered, as were the following baseline labs: complete blood count with differential (CBC), vitamin B12 and folate levels, blood chemistry, lipid profile, liver profile, total vitamin D, and sensitive thyroid-stimulating hormone. Test results are shown in Table 2.
X-ray of the wrist showed fracture only, making it possible to rule out Paget’s disease (ie, no patchy white areas noted in the bone) and tumor (no masses seen) as the immediate cause of fracture. Normal body temperature and normal white blood cell count eliminated the possibility of infection.
Because the patient was only 56 and had a history of bariatric surgery, further testing was pursued to investigate a cause for the weakened bone. Bone mineral density (BMD) testing revealed the following results:
• The lumbar spine in frontal projection measured 0.968 g/cm2 with a T-score of –2.2 and a Z-score of –2.2.
• Total BMD of the left hip was 0.863 g/cm2 with a T-score of –1.7 and a Z-score of –1.4.
• Total BMD of the left femoral neck was 0.863 g/cm2 with a T-score of 1.7 and a Z-score of –1.1.
These findings suggested osteopenia1,2 (not osteoporosis) in all sites, with a 12% decrease of BMD in the spine (suggesting increased risk for spinal fracture) and a 16.3% decrease of BMD in the hip since the patient’s most recent bone scan five years earlier (radiologist’s report). Other abnormal findings were elevated parathyroid hormone (PTH) serum, 95.7 pg/mL (reference range, 10 to 65 pg/mL); low total calcium serum, 8.7 mg/dL (reference range, 8.9 to 10.2 mg/dL), and low 25-hydroxyvitamin D total, 12.3 ng/mL (reference range, 25 to 80 ng/mL).
A 2010 clinical practice guideline from the Endocrine Society3 specifies that after malabsorptive surgery, vitamin D and calcium supplementation should be adjusted by a qualified medical professional, based on serum markers and measures of bone density. An endocrinologist who was consulted at the patient’s initial visit prescribed the following medications: vitamin D2, 50,000 U/wk PO; combined calcium citrate (vitamin D3) 500 IU with calcium 630 mg, 1 tab bid; and calcitriol 0.5 μg bid.
The patient’s final diagnosis was osteomalacia secondary to gastric bypass surgery. (See “Making the Diagnosis of Osteomalacia.”4-6)
DISCUSSION
According to 2008 data from the World Health Organization (WHO),7 1.4 billion persons older than 20 worldwide were overweight, and 200 million men and 300 million women were considered obese—meaning that one in every 10 adults worldwide is overweight or obese. In 2010, the WHO reports, 40 million children younger than 5 worldwide were considered overweight.7 Health care providers need to be prepared to care for the increasing number of patients who will undergo bariatric surgeries to treat obesity and its related comorbidities.8
Postoperative follow-up for the malabsorption deficiencies related to bariatric procedures should be performed every six months, including obtaining levels of alkaline phosphatase and others previously discussed. In addition, the Endocrine Society guideline3 recommends measuring levels of vitamin B12, albumin, pre-albumin, iron, and ferritin, and obtaining a CBC, a liver profile, glucose reading, creatinine measurement, and a metabolic profile at one month and two months after surgery, then every six months until two years after surgery, then annually if findings are stable.
Furthermore, the Endocrine Society3 recommends obtaining zinc levels every six months for the first year, then annually. An annual vitamin A level is optional.9 Yearly bone density testing is recommended until the patient’s BMD is deemed stable.3
Additionally, Koch and Finelli10 recommend performing the following labs postoperatively: hemoglobin A1C every three months; copper, magnesium, whole blood thiamine, vitamin B12, and a 24-hour urinary calcium every six months for the first three years, then once a year if findings remain stable.
Use of alcohol should be discouraged among patients who have undergone bariatric surgery, as its use alters micronutrient requirements and metabolism. Alcohol consumption may also contribute to dumping syndrome (ie, rapid gastric emptying).11
Any patient with a history of malabsorptive bypass surgery who complains of neurologic, visual, or skin disorders, anemia, or edema may require a further workup to rule out other absorptive deficiencies. These include vitamins A, E, and B12, zinc, folate, thiamine, niacin, selenium, and ferritin.10
Osteomalacia
Metabolic bone diseases can result from genetics, dietary factors, medication use, surgery, or hormonal irregularities. They alter the normal biochemical reactions in bone structure.
The three most common forms of metabolic bone disease are osteoporosis, osteopenia, and osteomalacia. The WHO diagnostic classifications and associated T-scores for bone mineral density1,2 indicate a T-score above –1.0 as normal. A score between –1.0 and –2.5 is indicative of osteopenia, and a score below –2.5 indicates osteoporosis. A T-score below –2.5 in the patient with a history of fragility fracture indicates severe osteoporosis.1,2
In osteomalacia, bone volume remains unchanged, but mineralization of osteoid in the mature compact and spongy bone is either delayed or inadequate. The remolding cycle continues unchanged in the formation of osteoid, but mineral calcification and deposition do not occur.3-5
Osteomalacia is normally considered a rare disorder, but it may become more common as increasing numbers of patients undergo gastric bypass operations.12,13 Primary care practitioners should monitor for this condition in such patients before serious bone loss or other problems develop.9,13,14
Vitamin D deficiency (see “Vitamin D Metabolism,”4,15-19 below), whether or not the result of gastric bypass surgery, is a major risk factor for osteomalacia. Disorders of the small bowel, the hepatobiliary system, and the pancreas are all common causes of vitamin D deficiency. Liver disease interferes with the metabolism of vitamin D. Diseases of the pancreas may cause a deficiency of bile salts, which are vital for the intestinal absorption of vitamin D.17
Restriction and Malabsorption
The case patient had undergone a gastric bypass (duodenal switch), in which a large portion of the stomach is removed and a large part of the small bowel rerouted—with both parts of the procedure causing malabsorption.11 It is in the small bowel that absorption of vitamin D and calcium takes place.
The duodenal switch gastric bypass surgery causes both restriction and malabsorption. Though similar to a biliopancreatic diversion, the duodenal switch preserves the distal stomach and the pylorus20 by way of a sleeve gastrectomy that is performed to reduce the gastric reservoir; the common channel length after revision is 100 cm, not 50 cm (as in conventional biliopancreatic diversion).13 The sleeve gastrectomy involves removal of parietal cells, reducing production of hydrochloric acid (which is necessary to break down food), and hindering the absorption of certain nutrients, including the fat-soluble vitamins, vitamin B12, and iron.12 Patients who take H2-blockers or proton pump inhibitors experience an additional decrease in the production and availability of HCl and may have an increased risk for fracture.14,20,21
In addition to its biliopancreatic diversion component, the duodenal switch diverts a large portion of the small bowel, with food restricted from moving through it. Vitamin D and protein are normally absorbed at the jejunum and ileum, but only when bile salts are present; after a duodenal switch, bile and pancreatic enzymes are not introduced into the small intestines until 75 to 100 cm before they reach the large intestine. Thus, absorption of vitamin D, protein, calcium, and other nutrients is impaired.20,22
Since phosphorus and magnesium are also absorbed at the sites of the duodenum and jejunum, malabsorption of these nutrients may occur in a patient who has undergone a duodenal switch. Although vitamin B12 is absorbed at the site of the distal ileum, it also requires gastric acid to free it from the food. Zinc absorption, which normally occurs at the site of the jejunum, may be impaired after duodenal switch surgery, and calcium supplementation, though essential, may further reduce zinc absorption.9 Iron absorption requires HCl, facilitated by the presence of vitamin C. Use of H2-blockers and proton pump inhibitors may impair iron metabolism, resulting in anemia.20
In a randomized controlled trial, Aasheim et al23 compared the effects of Roux-en-Y gastric bypass with those of duodenal switch gastric bypass on patients’ vitamin metabolism. The researchers concluded that patients who undergo a duodenal switch are at greater risk for vitamin A and D deficiencies in the first year after surgery; and for thiamine deficiency in the months following surgery as a result of malabsorption, compared with patients who undergo Roux-en-Y gastric bypass.20,23
Patient Management
The case patient’s care necessitated consultations with endocrinology, dermatology, and gastroenterology (GI). Table 3 (below) shows the laboratory findings and the medication changes prompted by the patient’s physical exam and lab results. Table 4 lists the findings from other lab studies ordered throughout the patient’s course of treatment.
The endocrinologist was consulted at the first sign of osteopenia, and a workup was soon initiated, followed by treatment. GI was consulted six months after the beginning of treatment, when the patient began to complain of reflux while sleeping and frequent diarrhea throughout the day.
Results of esophagogastroduodenoscopy with biopsy ruled out celiac disease and mucosal ulceration, but a small hiatal hernia that was detected (< 3 cm) was determined to be an aggravating factor for the patient’s reflux. The patient was instructed in lifestyle modifications for hiatal hernia, including the need to remain upright one to two hours after eating before going to sleep to prevent aspiration. The patient was instructed to avoid taking iron and calcium within two hours of each other and to limit his alcohol intake. He was also educated in precautions against falls.
Dermatology was consulted nine months into treatment so that light therapy could be initiated, allowing the patient to take advantage of the body’s natural pathway to manufacture vitamin D3.
CONCLUSION
For post–bariatric surgery patients, primary care practitioners are in a position to coordinate care recommendations from multiple specialists, including those in nutrition, to determine the best course of action.
This case illustrates complications of bariatric surgery (malabsorption of key vitamins and minerals, wrist fracture, osteopenia, osteomalacia) that require diagnosis and treatment. The specialists and the primary care practitioner, along with the patient, had to weigh the risks and benefits of continued proton pump inhibitor use, as such medications can increase the risk for fracture. They also addressed the patient’s anemia and remained attentive to his preventive health care needs.
REFERENCES
1. Brusin JH. Update on bone densitometry. Radiol Technol. 2009;81(2):153BD-170BD.
2. Wilson CR. Essentials of bone densitometry for the medical physicist. Presented at: The American Association of Physicists in Medicine 2003 Annual Meeting; July 22-26, 2003; San Diego, CA.
3. Heber D, Greenway FL, Kaplan LM. et al. Endocrine and nutritional management of the post-bariatric surgery patient: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(11):4825-4843.
4. Osteomalacia: step-by-step diagnostic approach (2011). http://bestpractice.bmj.com/best-practice/monograph/517/diagnosis/step-by-step.html. Accessed December 18, 2012.
5. Gifre L, Peris P, Monegal A, et al. Osteomalacia revisited : a report on 28 cases. Clin Rheumatol. 2011;30(5):639-645.
6. Bingham CT, Fitzpatrick LA. Noninvasive testing in the diagnosis of osteomalacia. Am J Med. 1993;95(5):519-523.
7. World Health Organization. Obesity and overweight (May 2012). Fact Sheet No 311. www.who.int/mediacentre/factsheets/fs311/en/index.html. Accessed December 18, 2012.
8. Tanner BD, Allen JW. Complications of bariatric surgery: implications for the covering physician. Am Surg. 2009;75(2):103-112.
9. Soleymani T, Tejavanija S, Morgan S. Obesity, bariatric surgery, and bone. Curr Opin Rheumatol. 2011;23(4):396-405.
10. Koch TR, Finelli FC. Postoperative metabolic and nutritional complications of bariatric surgery. Gastroenterol Clin North Am. 2010;39(1):109-124.
11. Manchester S, Roye GD. Bariatric surgery: an overview for dietetics professionals. Nutr Today. 2011;46(6):264-275.
12. Bal BS, Finelli FC, Shope TR, Koch TR. Nutritional deficiencies after bariatric surgery. Nat Rev Endocrinol. 2012;8(9):544-546.
13. Iannelli A, Schneck AS, Dahman M, et al. Two-step laparoscopic duodenal switch for superobesity: a feasibility study. Surg Endosc. 2009;23(10):2385-2389.
14. Lalmohamed A, de Vries F, Bazelier MT, et al. Risk of fracture after bariatric surgery in the United Kingdom: population based, retrospective cohort study. BMJ. 2012;345:e5085.
15. Holrick MF. Vitamin D: important for prevention of osteoporosis, cardiovascular heart disease, type 1 diabetes, autoimmune diseases, and some cancers. South Med J. 2005;98 (10):1024-1027.
16. Kalro BN. Vitamin D and the skeleton. Alt Ther Womens Health. 2009;2(4):25-32.
17. Crowther-Radulewicz CL, McCance KL. Alterations of musculoskeletal function. In: McCance KL, Huether SE, Brashers VL, Rote NS, eds. Pathophysiology: The Biologic Basis for Disease in Adults and Children. 6th ed. Maryland Heights, MO: Mosby Elsevier; 2010:1568-1617.
18. Huether SE. Structure and function of the renal and urologic systems. In: McCance KL, Huether SE, Brashers VL, Rote NS, eds. Pathophysiology: The Biologic Basis for Disease in Adults and Children. 6th ed. Maryland Heights, MO: Mosby Elsevier; 2010:1344-1364.
19. Bhan A, Rao AD, Rao DS. Osteomalacia as a result of vitamin D deficiency. Endocrinol Metab Clin North Am. 2010;39(2):321-331.
20. Decker GA, Swain JM, Crowell MD. Gastrointestinal and nutritional complications after bariatric surgery. Am J Gastroenterol. 2007;102(11):2571-2580.
21. Targownik LE, Lix LM, Metge C, et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ. 2008;179(4):319-326.
22. Ybarra J, Sánchez-Hernández J, Pérez A. Hypovitaminosis D and morbid obesity. Nurs Clin North Am. 2007;42(1):19-27.
23. Aasheim ET, Björkman S, Søvik TT, et al. Vitamin status after bariatric surgery: a randomized study of gastric bypass and duodenal switch. Am J Clin Nutr. 2009;90(1):15-22.
A white man, age 56, presented to his primary care clinician with wrist pain and swelling. Two days earlier, he had fallen from a step stool and landed on his right wrist. He treated the pain by resting, elevating his arm, applying ice, and taking ibuprofen 800 mg tid. He said he had lost strength in his hand and arm and was experiencing numbness and tingling in his right hand and fingers.
The patient’s medical history included hypertension, type 2 diabetes mellitus, morbid obesity, obstructive sleep apnea, asthma, carpel tunnel syndrome, and peripheral neuropathy. His surgical history was significant for duodenal switch gastric bypass surgery, performed eight years earlier, and his weight at the time of presentation was 200 lb; before his gastric bypass, he weighed 385 lb. Since the surgery, his hypertension, diabetes, asthma, and sleep apnea had all resolved. Table 1 shows a list of medications he was taking at the time of presentation.
The patient, a registered nurse, had been married for 30 years and had one child. He had quit smoking 15 years earlier, with a 43–pack-year smoking history. He reported social drinking but denied any recreational drug use. He was unaware of having any allergies to food or medication.
His vital signs on presentation were blood pressure, 110/75 mm Hg; heart rate, 53 beats/min; respiration, 18 breaths/min; O2 saturation, 97% on room air; and temperature, 97.5°F.
Physical exam revealed that the patient’s right wrist was ecchymotic and swollen with +1 pitting edema. The skin was warm and dry to the touch. Decreased range of motion was noted in the right wrist, compared with the left. Pain with point tenderness was noted at the right lateral wrist. Pulses were +3 with capillary refill of less than 3 seconds. The rest of the exam was unremarkable.
The differential diagnosis included fracture secondary to the fall, osteoporosis, osteopenia, osteomalacia, Paget’s disease, tumor, infection, and sprain or strain of the wrist. A wrist x-ray was ordered, as were the following baseline labs: complete blood count with differential (CBC), vitamin B12 and folate levels, blood chemistry, lipid profile, liver profile, total vitamin D, and sensitive thyroid-stimulating hormone. Test results are shown in Table 2.
X-ray of the wrist showed fracture only, making it possible to rule out Paget’s disease (ie, no patchy white areas noted in the bone) and tumor (no masses seen) as the immediate cause of fracture. Normal body temperature and normal white blood cell count eliminated the possibility of infection.
Because the patient was only 56 and had a history of bariatric surgery, further testing was pursued to investigate a cause for the weakened bone. Bone mineral density (BMD) testing revealed the following results:
• The lumbar spine in frontal projection measured 0.968 g/cm2 with a T-score of –2.2 and a Z-score of –2.2.
• Total BMD of the left hip was 0.863 g/cm2 with a T-score of –1.7 and a Z-score of –1.4.
• Total BMD of the left femoral neck was 0.863 g/cm2 with a T-score of 1.7 and a Z-score of –1.1.
These findings suggested osteopenia1,2 (not osteoporosis) in all sites, with a 12% decrease of BMD in the spine (suggesting increased risk for spinal fracture) and a 16.3% decrease of BMD in the hip since the patient’s most recent bone scan five years earlier (radiologist’s report). Other abnormal findings were elevated parathyroid hormone (PTH) serum, 95.7 pg/mL (reference range, 10 to 65 pg/mL); low total calcium serum, 8.7 mg/dL (reference range, 8.9 to 10.2 mg/dL), and low 25-hydroxyvitamin D total, 12.3 ng/mL (reference range, 25 to 80 ng/mL).
A 2010 clinical practice guideline from the Endocrine Society3 specifies that after malabsorptive surgery, vitamin D and calcium supplementation should be adjusted by a qualified medical professional, based on serum markers and measures of bone density. An endocrinologist who was consulted at the patient’s initial visit prescribed the following medications: vitamin D2, 50,000 U/wk PO; combined calcium citrate (vitamin D3) 500 IU with calcium 630 mg, 1 tab bid; and calcitriol 0.5 μg bid.
The patient’s final diagnosis was osteomalacia secondary to gastric bypass surgery. (See “Making the Diagnosis of Osteomalacia.”4-6)
DISCUSSION
According to 2008 data from the World Health Organization (WHO),7 1.4 billion persons older than 20 worldwide were overweight, and 200 million men and 300 million women were considered obese—meaning that one in every 10 adults worldwide is overweight or obese. In 2010, the WHO reports, 40 million children younger than 5 worldwide were considered overweight.7 Health care providers need to be prepared to care for the increasing number of patients who will undergo bariatric surgeries to treat obesity and its related comorbidities.8
Postoperative follow-up for the malabsorption deficiencies related to bariatric procedures should be performed every six months, including obtaining levels of alkaline phosphatase and others previously discussed. In addition, the Endocrine Society guideline3 recommends measuring levels of vitamin B12, albumin, pre-albumin, iron, and ferritin, and obtaining a CBC, a liver profile, glucose reading, creatinine measurement, and a metabolic profile at one month and two months after surgery, then every six months until two years after surgery, then annually if findings are stable.
Furthermore, the Endocrine Society3 recommends obtaining zinc levels every six months for the first year, then annually. An annual vitamin A level is optional.9 Yearly bone density testing is recommended until the patient’s BMD is deemed stable.3
Additionally, Koch and Finelli10 recommend performing the following labs postoperatively: hemoglobin A1C every three months; copper, magnesium, whole blood thiamine, vitamin B12, and a 24-hour urinary calcium every six months for the first three years, then once a year if findings remain stable.
Use of alcohol should be discouraged among patients who have undergone bariatric surgery, as its use alters micronutrient requirements and metabolism. Alcohol consumption may also contribute to dumping syndrome (ie, rapid gastric emptying).11
Any patient with a history of malabsorptive bypass surgery who complains of neurologic, visual, or skin disorders, anemia, or edema may require a further workup to rule out other absorptive deficiencies. These include vitamins A, E, and B12, zinc, folate, thiamine, niacin, selenium, and ferritin.10
Osteomalacia
Metabolic bone diseases can result from genetics, dietary factors, medication use, surgery, or hormonal irregularities. They alter the normal biochemical reactions in bone structure.
The three most common forms of metabolic bone disease are osteoporosis, osteopenia, and osteomalacia. The WHO diagnostic classifications and associated T-scores for bone mineral density1,2 indicate a T-score above –1.0 as normal. A score between –1.0 and –2.5 is indicative of osteopenia, and a score below –2.5 indicates osteoporosis. A T-score below –2.5 in the patient with a history of fragility fracture indicates severe osteoporosis.1,2
In osteomalacia, bone volume remains unchanged, but mineralization of osteoid in the mature compact and spongy bone is either delayed or inadequate. The remolding cycle continues unchanged in the formation of osteoid, but mineral calcification and deposition do not occur.3-5
Osteomalacia is normally considered a rare disorder, but it may become more common as increasing numbers of patients undergo gastric bypass operations.12,13 Primary care practitioners should monitor for this condition in such patients before serious bone loss or other problems develop.9,13,14
Vitamin D deficiency (see “Vitamin D Metabolism,”4,15-19 below), whether or not the result of gastric bypass surgery, is a major risk factor for osteomalacia. Disorders of the small bowel, the hepatobiliary system, and the pancreas are all common causes of vitamin D deficiency. Liver disease interferes with the metabolism of vitamin D. Diseases of the pancreas may cause a deficiency of bile salts, which are vital for the intestinal absorption of vitamin D.17
Restriction and Malabsorption
The case patient had undergone a gastric bypass (duodenal switch), in which a large portion of the stomach is removed and a large part of the small bowel rerouted—with both parts of the procedure causing malabsorption.11 It is in the small bowel that absorption of vitamin D and calcium takes place.
The duodenal switch gastric bypass surgery causes both restriction and malabsorption. Though similar to a biliopancreatic diversion, the duodenal switch preserves the distal stomach and the pylorus20 by way of a sleeve gastrectomy that is performed to reduce the gastric reservoir; the common channel length after revision is 100 cm, not 50 cm (as in conventional biliopancreatic diversion).13 The sleeve gastrectomy involves removal of parietal cells, reducing production of hydrochloric acid (which is necessary to break down food), and hindering the absorption of certain nutrients, including the fat-soluble vitamins, vitamin B12, and iron.12 Patients who take H2-blockers or proton pump inhibitors experience an additional decrease in the production and availability of HCl and may have an increased risk for fracture.14,20,21
In addition to its biliopancreatic diversion component, the duodenal switch diverts a large portion of the small bowel, with food restricted from moving through it. Vitamin D and protein are normally absorbed at the jejunum and ileum, but only when bile salts are present; after a duodenal switch, bile and pancreatic enzymes are not introduced into the small intestines until 75 to 100 cm before they reach the large intestine. Thus, absorption of vitamin D, protein, calcium, and other nutrients is impaired.20,22
Since phosphorus and magnesium are also absorbed at the sites of the duodenum and jejunum, malabsorption of these nutrients may occur in a patient who has undergone a duodenal switch. Although vitamin B12 is absorbed at the site of the distal ileum, it also requires gastric acid to free it from the food. Zinc absorption, which normally occurs at the site of the jejunum, may be impaired after duodenal switch surgery, and calcium supplementation, though essential, may further reduce zinc absorption.9 Iron absorption requires HCl, facilitated by the presence of vitamin C. Use of H2-blockers and proton pump inhibitors may impair iron metabolism, resulting in anemia.20
In a randomized controlled trial, Aasheim et al23 compared the effects of Roux-en-Y gastric bypass with those of duodenal switch gastric bypass on patients’ vitamin metabolism. The researchers concluded that patients who undergo a duodenal switch are at greater risk for vitamin A and D deficiencies in the first year after surgery; and for thiamine deficiency in the months following surgery as a result of malabsorption, compared with patients who undergo Roux-en-Y gastric bypass.20,23
Patient Management
The case patient’s care necessitated consultations with endocrinology, dermatology, and gastroenterology (GI). Table 3 (below) shows the laboratory findings and the medication changes prompted by the patient’s physical exam and lab results. Table 4 lists the findings from other lab studies ordered throughout the patient’s course of treatment.
The endocrinologist was consulted at the first sign of osteopenia, and a workup was soon initiated, followed by treatment. GI was consulted six months after the beginning of treatment, when the patient began to complain of reflux while sleeping and frequent diarrhea throughout the day.
Results of esophagogastroduodenoscopy with biopsy ruled out celiac disease and mucosal ulceration, but a small hiatal hernia that was detected (< 3 cm) was determined to be an aggravating factor for the patient’s reflux. The patient was instructed in lifestyle modifications for hiatal hernia, including the need to remain upright one to two hours after eating before going to sleep to prevent aspiration. The patient was instructed to avoid taking iron and calcium within two hours of each other and to limit his alcohol intake. He was also educated in precautions against falls.
Dermatology was consulted nine months into treatment so that light therapy could be initiated, allowing the patient to take advantage of the body’s natural pathway to manufacture vitamin D3.
CONCLUSION
For post–bariatric surgery patients, primary care practitioners are in a position to coordinate care recommendations from multiple specialists, including those in nutrition, to determine the best course of action.
This case illustrates complications of bariatric surgery (malabsorption of key vitamins and minerals, wrist fracture, osteopenia, osteomalacia) that require diagnosis and treatment. The specialists and the primary care practitioner, along with the patient, had to weigh the risks and benefits of continued proton pump inhibitor use, as such medications can increase the risk for fracture. They also addressed the patient’s anemia and remained attentive to his preventive health care needs.
REFERENCES
1. Brusin JH. Update on bone densitometry. Radiol Technol. 2009;81(2):153BD-170BD.
2. Wilson CR. Essentials of bone densitometry for the medical physicist. Presented at: The American Association of Physicists in Medicine 2003 Annual Meeting; July 22-26, 2003; San Diego, CA.
3. Heber D, Greenway FL, Kaplan LM. et al. Endocrine and nutritional management of the post-bariatric surgery patient: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(11):4825-4843.
4. Osteomalacia: step-by-step diagnostic approach (2011). http://bestpractice.bmj.com/best-practice/monograph/517/diagnosis/step-by-step.html. Accessed December 18, 2012.
5. Gifre L, Peris P, Monegal A, et al. Osteomalacia revisited : a report on 28 cases. Clin Rheumatol. 2011;30(5):639-645.
6. Bingham CT, Fitzpatrick LA. Noninvasive testing in the diagnosis of osteomalacia. Am J Med. 1993;95(5):519-523.
7. World Health Organization. Obesity and overweight (May 2012). Fact Sheet No 311. www.who.int/mediacentre/factsheets/fs311/en/index.html. Accessed December 18, 2012.
8. Tanner BD, Allen JW. Complications of bariatric surgery: implications for the covering physician. Am Surg. 2009;75(2):103-112.
9. Soleymani T, Tejavanija S, Morgan S. Obesity, bariatric surgery, and bone. Curr Opin Rheumatol. 2011;23(4):396-405.
10. Koch TR, Finelli FC. Postoperative metabolic and nutritional complications of bariatric surgery. Gastroenterol Clin North Am. 2010;39(1):109-124.
11. Manchester S, Roye GD. Bariatric surgery: an overview for dietetics professionals. Nutr Today. 2011;46(6):264-275.
12. Bal BS, Finelli FC, Shope TR, Koch TR. Nutritional deficiencies after bariatric surgery. Nat Rev Endocrinol. 2012;8(9):544-546.
13. Iannelli A, Schneck AS, Dahman M, et al. Two-step laparoscopic duodenal switch for superobesity: a feasibility study. Surg Endosc. 2009;23(10):2385-2389.
14. Lalmohamed A, de Vries F, Bazelier MT, et al. Risk of fracture after bariatric surgery in the United Kingdom: population based, retrospective cohort study. BMJ. 2012;345:e5085.
15. Holrick MF. Vitamin D: important for prevention of osteoporosis, cardiovascular heart disease, type 1 diabetes, autoimmune diseases, and some cancers. South Med J. 2005;98 (10):1024-1027.
16. Kalro BN. Vitamin D and the skeleton. Alt Ther Womens Health. 2009;2(4):25-32.
17. Crowther-Radulewicz CL, McCance KL. Alterations of musculoskeletal function. In: McCance KL, Huether SE, Brashers VL, Rote NS, eds. Pathophysiology: The Biologic Basis for Disease in Adults and Children. 6th ed. Maryland Heights, MO: Mosby Elsevier; 2010:1568-1617.
18. Huether SE. Structure and function of the renal and urologic systems. In: McCance KL, Huether SE, Brashers VL, Rote NS, eds. Pathophysiology: The Biologic Basis for Disease in Adults and Children. 6th ed. Maryland Heights, MO: Mosby Elsevier; 2010:1344-1364.
19. Bhan A, Rao AD, Rao DS. Osteomalacia as a result of vitamin D deficiency. Endocrinol Metab Clin North Am. 2010;39(2):321-331.
20. Decker GA, Swain JM, Crowell MD. Gastrointestinal and nutritional complications after bariatric surgery. Am J Gastroenterol. 2007;102(11):2571-2580.
21. Targownik LE, Lix LM, Metge C, et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ. 2008;179(4):319-326.
22. Ybarra J, Sánchez-Hernández J, Pérez A. Hypovitaminosis D and morbid obesity. Nurs Clin North Am. 2007;42(1):19-27.
23. Aasheim ET, Björkman S, Søvik TT, et al. Vitamin status after bariatric surgery: a randomized study of gastric bypass and duodenal switch. Am J Clin Nutr. 2009;90(1):15-22.
Underlying Factors Influence Insulin's Effect
Q: Help! How do you proceed if, after you’ve continually increased a patient’s insulin dose, his/her blood glucose levels do not improve?
This is a common scenario in diabetes management. Here are nine things to consider when a patient’s situation just doesn’t make sense clinically:
1. Noncompliance with the prescribed dose. This is the most common scenario. Ask the patient, “How many injections do you miss in a typical week?” Assure that he or she is actually taking the currently prescribed amount of insulin before you further increase the dose.
2. Inaccurate insulin dosing. This problem can be due to impaired vision, poor technique, dexterity issues, or dementia. Ask the patient to demonstrate for you how he/she draws up and takes the insulin at home. You might just be surprised at what you see, even in patients who have been giving themselves insulin for years. Consider prescribing an insulin pen or having a family member or significant other dose the insulin if the patient is no longer reliable to accurately dose it for him- or herself.
3. “Bad insulin.” What this actually means is loss of potency. This can be caused by improper storage, exposure to heat or cold, or use of an insulin delivery device (ie, vial or pen) past the 28- to 45-day period recommended, depending on the type of insulin. Replace the vial or pen and re-assess for improvement in diabetes control.
4. Lipohypertrophy of injection sites due to overuse. Palpate and visually inspect injection sites to look for firm or hypertrophied tissue. Advise the patient to avoid these areas for future injection, as absorption from these sites can be poor and unpredictable.
5. Dietary issues. The patient may be increasing his/her food intake along with the increased insulin doses. One clue that should raise suspicion for this occurrence is rapidly increasing body weight. Consider referring the patient to a dietitian for nutrition counseling.
6. New medication. Sometimes a new treatment is added to a patient’s regimen by another provider, and the medication might have an adverse effect on blood glucose control. Common examples include steroids (typically a cortisone injection) or methylprednisolone dose-packs taken during an asthma flare.
7. Occult infection. Urinary tract infections, pneumonia, and the like can impact blood glucose control. Consider ordering a urinalysis and complete blood count if infection seems a likely cause.
8. Major life stressors. Inquire as to what is happening in the patient’s life that might impact his/her body’s response to insulin. They might be in the middle of a divorce or other family crisis or experiencing severe stress at work.
9. Technique and equipment issues. Inaccurate glucose monitoring technique or use of expired strips can lead to “false high” readings. Also, patients with a continuous glucose monitor may record false high results when they are taking acetaminophen. If this is the case, increasing the insulin dose will often result in hypoglycemia.
It may be helpful to keep this clinical checklist handy and add to it any other issues that you come across when the clinical picture doesn’t make sense. You may also want to consider referral to a diabetes educator; patients will often confide what is really going on to an educator in a longer visit, rather than in the typically shorter visits with their health care provider.
SUGGESTED READING
Sadler C, Einhorn D. Tailoring insulin regimens for type 2 diabetes mellitus. JAAPA. 1998;11(4):55-71.
Q: Help! How do you proceed if, after you’ve continually increased a patient’s insulin dose, his/her blood glucose levels do not improve?
This is a common scenario in diabetes management. Here are nine things to consider when a patient’s situation just doesn’t make sense clinically:
1. Noncompliance with the prescribed dose. This is the most common scenario. Ask the patient, “How many injections do you miss in a typical week?” Assure that he or she is actually taking the currently prescribed amount of insulin before you further increase the dose.
2. Inaccurate insulin dosing. This problem can be due to impaired vision, poor technique, dexterity issues, or dementia. Ask the patient to demonstrate for you how he/she draws up and takes the insulin at home. You might just be surprised at what you see, even in patients who have been giving themselves insulin for years. Consider prescribing an insulin pen or having a family member or significant other dose the insulin if the patient is no longer reliable to accurately dose it for him- or herself.
3. “Bad insulin.” What this actually means is loss of potency. This can be caused by improper storage, exposure to heat or cold, or use of an insulin delivery device (ie, vial or pen) past the 28- to 45-day period recommended, depending on the type of insulin. Replace the vial or pen and re-assess for improvement in diabetes control.
4. Lipohypertrophy of injection sites due to overuse. Palpate and visually inspect injection sites to look for firm or hypertrophied tissue. Advise the patient to avoid these areas for future injection, as absorption from these sites can be poor and unpredictable.
5. Dietary issues. The patient may be increasing his/her food intake along with the increased insulin doses. One clue that should raise suspicion for this occurrence is rapidly increasing body weight. Consider referring the patient to a dietitian for nutrition counseling.
6. New medication. Sometimes a new treatment is added to a patient’s regimen by another provider, and the medication might have an adverse effect on blood glucose control. Common examples include steroids (typically a cortisone injection) or methylprednisolone dose-packs taken during an asthma flare.
7. Occult infection. Urinary tract infections, pneumonia, and the like can impact blood glucose control. Consider ordering a urinalysis and complete blood count if infection seems a likely cause.
8. Major life stressors. Inquire as to what is happening in the patient’s life that might impact his/her body’s response to insulin. They might be in the middle of a divorce or other family crisis or experiencing severe stress at work.
9. Technique and equipment issues. Inaccurate glucose monitoring technique or use of expired strips can lead to “false high” readings. Also, patients with a continuous glucose monitor may record false high results when they are taking acetaminophen. If this is the case, increasing the insulin dose will often result in hypoglycemia.
It may be helpful to keep this clinical checklist handy and add to it any other issues that you come across when the clinical picture doesn’t make sense. You may also want to consider referral to a diabetes educator; patients will often confide what is really going on to an educator in a longer visit, rather than in the typically shorter visits with their health care provider.
SUGGESTED READING
Sadler C, Einhorn D. Tailoring insulin regimens for type 2 diabetes mellitus. JAAPA. 1998;11(4):55-71.
Q: Help! How do you proceed if, after you’ve continually increased a patient’s insulin dose, his/her blood glucose levels do not improve?
This is a common scenario in diabetes management. Here are nine things to consider when a patient’s situation just doesn’t make sense clinically:
1. Noncompliance with the prescribed dose. This is the most common scenario. Ask the patient, “How many injections do you miss in a typical week?” Assure that he or she is actually taking the currently prescribed amount of insulin before you further increase the dose.
2. Inaccurate insulin dosing. This problem can be due to impaired vision, poor technique, dexterity issues, or dementia. Ask the patient to demonstrate for you how he/she draws up and takes the insulin at home. You might just be surprised at what you see, even in patients who have been giving themselves insulin for years. Consider prescribing an insulin pen or having a family member or significant other dose the insulin if the patient is no longer reliable to accurately dose it for him- or herself.
3. “Bad insulin.” What this actually means is loss of potency. This can be caused by improper storage, exposure to heat or cold, or use of an insulin delivery device (ie, vial or pen) past the 28- to 45-day period recommended, depending on the type of insulin. Replace the vial or pen and re-assess for improvement in diabetes control.
4. Lipohypertrophy of injection sites due to overuse. Palpate and visually inspect injection sites to look for firm or hypertrophied tissue. Advise the patient to avoid these areas for future injection, as absorption from these sites can be poor and unpredictable.
5. Dietary issues. The patient may be increasing his/her food intake along with the increased insulin doses. One clue that should raise suspicion for this occurrence is rapidly increasing body weight. Consider referring the patient to a dietitian for nutrition counseling.
6. New medication. Sometimes a new treatment is added to a patient’s regimen by another provider, and the medication might have an adverse effect on blood glucose control. Common examples include steroids (typically a cortisone injection) or methylprednisolone dose-packs taken during an asthma flare.
7. Occult infection. Urinary tract infections, pneumonia, and the like can impact blood glucose control. Consider ordering a urinalysis and complete blood count if infection seems a likely cause.
8. Major life stressors. Inquire as to what is happening in the patient’s life that might impact his/her body’s response to insulin. They might be in the middle of a divorce or other family crisis or experiencing severe stress at work.
9. Technique and equipment issues. Inaccurate glucose monitoring technique or use of expired strips can lead to “false high” readings. Also, patients with a continuous glucose monitor may record false high results when they are taking acetaminophen. If this is the case, increasing the insulin dose will often result in hypoglycemia.
It may be helpful to keep this clinical checklist handy and add to it any other issues that you come across when the clinical picture doesn’t make sense. You may also want to consider referral to a diabetes educator; patients will often confide what is really going on to an educator in a longer visit, rather than in the typically shorter visits with their health care provider.
SUGGESTED READING
Sadler C, Einhorn D. Tailoring insulin regimens for type 2 diabetes mellitus. JAAPA. 1998;11(4):55-71.
New-Generation Radiofrequency Technology
Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema
Cutis Tricolor
Circumscribed Acral Hypokeratosis
Paranoid, agitated, and manipulative
CASE: Agitation
Mrs. M, age 39, presents to the emergency department (ED) with altered mental status. She is escorted by her husband and the police. She has a history of severe alcohol dependence, bipolar disorder (BD), anxiety, borderline personality disorder (BPD), hypothyroidism, and bulimia, and had gastric bypass surgery 4 years ago. Her husband called 911 when he could no longer manage Mrs. M’s agitated state. The police found her to be extremely paranoid, restless, and disoriented. Her husband reports that she shouted “the world is going to end” before she escaped naked into her neighborhood streets.
On several occasions Mrs. M had been admitted to the same hospital for alcohol withdrawal and dependence with subsequent liver failure, leading to jaundice, coagulopathy, and ascites. During these hospitalizations, she exhibited poor behavioral tendencies, unhealthy psychological defenses, and chronic maladaptive coping and defense mechanisms congruent with her BPD diagnosis. Specifically, she engaged in splitting of hospital staff, ranging from extreme flattery to overt devaluation and hostility. Other defense mechanisms included denial, distortion, acting out, and passive-aggressive behavior. During these admissions, Mrs. M often displayed deficits in recall and attention on Mini-Mental State Examination (MMSE), but these deficits were associated with concurrent alcohol use and improved rapidly during her stay.
In her current presentation, Mrs. M’s mental status change is more pronounced and atypical compared with earlier admissions. Her outpatient medication regimen includes lamotrigine, 100 mg/d, levothyroxine, 88 mcg/d, venlafaxine extended release (XR), 75 mg/d, clonazepam, 3 mg/d, docusate as needed for constipation, and a daily multivitamin.
The authors’ observations
Delirium is a disturbance of consciousness manifested by a reduced clarity of awareness (impairment in attention) and change in cognition (impairment in orientation, memory, and language).1,2 The disturbance develops over a short time and tends to fluctuate during the day. Delirium is a direct physiological consequence of a general medical condition, substance use (intoxication or withdrawal), or both (Table).3
Delirium generally is a reversible mental disorder but can progress to irreversible brain damage. Prompt and accurate diagnosis of delirium is essential,4 although the condition often is underdiagnosed or misdiagnosed because of lack of recognition.
Table
DSM-IV-TR diagnostic criteria for delirium
|
| Source: Reference 3 |
Patients who have convoluted histories, such as Mrs. M, are common and difficult to manage and treat. These patients become substantially more complex when they are admitted to inpatient medical or surgical services. The need to clarify between delirium (primarily medical) and depression (primarily psychiatric) becomes paramount when administering treatment and evaluating decision-making capacity.5 In Mrs. M’s case, internal medicine, neurology, and psychiatry teams each had a different approach to altered mental status. Each team’s different terminology, assessment, and objectives further complicated an already challenging case.6
EVALUATION: Confounding results
The ED physicians offer a working diagnosis of acute mental status change, administer IV lorazepam, 4 mg, and order restraints for Mrs. M’s severe agitation. Her initial vital signs reveal slightly elevated blood pressure (140/90 mm Hg) and tachycardia (115 beats per minute). Internal medicine clinicians note that Mrs. M is not in acute distress, although she refuses to speak and has a small amount of dried blood on her lips, presumably from a struggle with the police before coming to the hospital, but this is not certain. Her abdomen is not tender; she has normal bowel sounds, and no asterixis is noted on neurologic exam. Physical exam is otherwise normal. A noncontrast head CT scan shows no acute process. Initial lab values show elevations in ammonia (277 μg/dL) and γ-glutamyl transpeptidase (68 U/L). Thyroid-stimulating hormone is 1.45 mlU/L, prothrombin time is 19.5 s, partial thromboplastin time is 40.3 s, and international normalized ratio is 1.67. The internal medicine team admits Mrs. M to the intensive care unit (ICU) for further management of her mental status change with alcohol withdrawal or hepatic encephalopathy as the most likely etiologies.
Mrs. M’s husband says that his wife has not consumed alcohol in the last 4 months in preparation for a possible liver transplant; however, past interactions with Mrs. M’s family suggest they are unreliable. The Clinical Institute Withdrawal Assessment (CIWA) protocol is implemented in case her symptoms are caused by alcohol withdrawal. Her vital signs are stable and IV lorazepam, 4 mg, is administered once for agitation. Mrs. M’s husband also reports that 1 month ago his wife underwent a transjugular intrahepatic portosystemic shunt (TIPS) procedure for portal hypertension. Outpatient psychotropics (lamotrigine, 100 mg/d, and venlafaxine XR, 75 mg/d) are restarted because withdrawal from these drugs may exacerbate her symptoms. In the ICU Mrs. M experiences a tonic-clonic seizure with fecal incontinence and bitten tongue, which results in a consultation from neurology and the psychiatry consultation-liaison service.
Psychiatry recommends withholding psychotropics, stopping CIWA, and using vital sign parameters along with objective signs of diaphoresis and tremors as indicators of alcohol withdrawal for lorazepam administration. Mrs. M receives IV haloperidol, 1 mg, once during her second day in the hospital for severe agitation, but this medication is discontinued because of concern about lowering her seizure threshold.7 After treatment with lactulose, her ammonia levels trend down to 33 μg/dL, but her altered mental state persists with significant deficits in attention and orientation.
The neurology service performs an EEG that shows no slow-wave, triphasic waves, or epileptiform activity, which likely would be present in delirium or seizures. See Figure 1 for an example of triphasic waves on an EEG and Figure 2 for Mrs. M's EEG results. Subsequent lumbar puncture, MRI, and a second EEG are unremarkable. By the fifth hospital day, Mrs. M is calm and her paranoia has subsided, but she still is confused and disoriented. Psychiatry orders a third EEG while she is in this confused state; it shows no pathologic process. Based on these examinations, neurology posits that Mrs. M is not encephalopathic.
Figure 1: Representative sample of triphasic waves
This EEG tracing is from a 54-year-old woman who underwent prolonged abdominal surgery for lysis of adhesions during which she suffered an intraoperative left subinsular stroke followed by nonconvulsive status epilepticus. The tracing demonstrates typical morphology with the positive sharp transient preceded and followed by smaller amplitude negative deflections. Symmetric, frontal predominance of findings seen is this tracing is common
Figure 2: Mrs. M’s EEG results
This is a representative tracing of Mrs. M’s 3 EEGs revealing an 8.5 to 9 Hz dominant alpha rhythm. There is superimposed frontally dominant beta fast activity, which is consistent with known administration of benzodiazepines
The authors’ observations
Mrs. M had repeated admissions for alcohol dependence and subsequent liver failure. Her recent hospitalization was complicated by a TIPS procedure done 1 month ago. The incidence of hepatic encephalopathy in patients undergoing TIPS is >30%, especially in the first month post-procedure, which raised suspicion that hepatic encephalopathy played a significant role in Mrs. M’s delirium.8
Because of frequent hospitalization, Mrs. M was well known to the internal medicine, neurology, and psychiatry teams, and each used different terms to describe her mental state. Internal medicine used the phrase “acute mental status change,” which covers a broad differential. Neurology used “encephalopathy,” which also is a general term. Psychiatry used “delirium,” which has narrower and more specific diagnostic criteria. Engel et al9 described the delirious patient as having “cerebral insufficiency” with universally abnormal EEG. Regardless of terminology, based on Mrs. M’s acute confusion, one would expect an abnormal EEG, but repeat EEGs were unremarkable.
Interpreting EEG
EEG is one of the few tools available for measuring acute changes in cerebral function, and an EEG slowing remains a hallmark in encephalopathic processes.10,11 Initially, the 3 specialties agreed that Mrs. M’s presentation likely was caused by underlying medical issues or substances (alcohol or others). EEG can help recognize delirium, and, in some cases, elucidate the underlying cause.10,12 It was surprising that Mrs. M’s EEGs were normal despite a clinical presentation of delirium. Because of the normal EEG findings, neurology leaned toward a primary psychiatric (“functional”) etiology as the cause of her delirium vs a general medical condition or alcohol withdrawal (“organic”).
A literature search in regards to sensitivity of EEG in delirium revealed conflicting statements and data. A standard textbook in neurology and psychiatry states that “a normal EEG virtually excludes a toxic-metabolic encephalopathy.”13 The American Psychiatric Association’s (APA) practice guidelines for delirium states: “The presence of EEG abnormalities has fairly good sensitivities for delirium (in one study, the sensitivity was found to be 75%), but the absence does not rule out the diagnosis; thus the EEG is no substitute for careful clinical observation.”6
At the beginning of Mrs. M’s care, in discussion with the neurology and internal medicine teams, we argued that Mrs. M was experiencing delirium despite her initial normal EEG. We did not expect that 2 subsequent EEGs would be normal, especially because the teams witnessed the final EEG being performed while Mrs. M was clinically evaluated and observed to be in a state of delirium.
OUTCOME: Cause still unknown
By the 6th day of hospitalization, Mrs. M’s vitals are normal and she remains hemodynamically stable. Differential diagnosis remains wide and unclear. The psychiatry team feels she could have atypical catatonia due to an underlying mood disorder. One hour after a trial of IV lorazepam, 1 mg, Mrs. M is more lucid and fully oriented, with MMSE of 28/30 (recall was 1/3), indicating normal cognition. During the exam, a psychiatry resident notes Mrs. M winks and feigns a yawn at the medical students and nurses in the room, displaying her boredom with the interview and simplicity of the mental status exam questions. Later that evening, Mrs. M exhibits bizarre sexual gestures toward male hospital staff, including licking a male nursing staff member’s hand.
Although Mrs. M’s initial confusion resolved, the severity of her comorbid psychiatric history warrants inpatient psychiatric hospitalization. She agrees to transfer to the psychiatric ward after she confesses anxiety regarding death, intense demoralization, and guilt related to her condition and her relationship with her 12-year-old daughter. She tearfully reports that she discontinued her psychotropic medications shortly after stopping alcohol 4 months ago. Shortly before her transfer, psychiatry is called back to the medicine floor because of Mrs. M’s disruptive behavior.
The team finds Mrs. M in her hospital gown, pursuing her husband in the hallway as he is leaving, yelling profanities and blaming him for her horrible experience in the hospital. Based on her demeanor, the team determines that she is back to her baseline mental state despite her mood disorder, and that her upcoming inpatient psychiatric stay likely would be too short to address her comorbid personality disorder. The next day she signs out of the hospital against medical advice.
The authors’ observations
We never clearly identified the specific etiology responsible for Mrs. M’s delirium. We assume at the initial presentation she had toxic-metabolic encephalopathy that rapidly resolved with lactulose treatment and lowering her ammonia. She then had a single tonic-clonic seizure, perhaps related to stopping and then restarting her psychotropics. Her subsequent confusion, bizarre sexual behavior, and demeanor on her final hospital days were more indicative of her psychiatric diagnoses. We now suspect that Mrs. M’s delirium was briefer than presumed and she returned to her baseline borderline personality, resulting in some factitious staging of delirium to confuse her 3 treating teams (a psychoanalyst may say this was a form of projective identification).
We felt that if Mrs. M truly was delirious due to metabolic or hepatic dysfunction or alcohol withdrawal, she would have had abnormal EEG findings. We discovered that the notion of “75% sensitivity” of EEG abnormalities cited in the APA guidelines comes from studies that include patients with “psychogenic” and “organic” delirium. Acute manias and agitated psychoses were termed “psychogenic delirium” and acute confusion due to medical conditions or substance issues was termed “organic delirium.”9,12,14-16
This poses a circular reasoning in the diagnostic criteria and clinical approach to delirium. The fallacy is that, according to DSM-IV-TR, delirium is supposed to be the result of a direct physiological consequence of a general medical condition or substance use (criterion D), and cannot be due to psychosis (eg, schizophrenia) or mania (eg, BD). We question the presumptive 75% sensitivity of EEG abnormalities in patients with delirium because it is possible that when some of these studies were conducted the definition of delirium was not solidified or fully understood. We suspect the sensitivity would be much higher if the correct definition of delirium according to DSM-IV-TR is used in future studies. To improve interdisciplinary communication and future research, it would be constructive if all disciplines could agree on a single term, with the same diagnostic criteria, when evaluating a patient with acute confusion.
Related Resources
- Meagher D. Delirium: the role of psychiatry. Advances in Psychiatric Treatment. 2001;7:433-442.
- Casey DA, DeFazio JV Jr, Vansickle K, et al. Delirium. Quick recognition, careful evaluation, and appropriate treatment. Postgrad Med. 1996;100(1):121-4, 128, 133-134.
Drug Brand Names
- Clonazepam • Klonopin
- Docusate • Surfak
- Haloperidol • Haldol
- Lamotrigine • Lamictal
- Lorazepam • Ativan
- Levothyroxine • Levoxyl, Synthtoid
- Venlafaxine XR • Effexor XR
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Acknowledgment
The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government. The authors are employees of the U.S. Government. This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the U.S. Government.” Title 17 U.S.C. 101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties.
1. Katz IR, Mossey J, Sussman N, et al. Bedside clinical and electrophysiological assessment: assessment of change in vulnerable patients. Int Psychogeriatr. 1991;3(2):289-300.
2. Inouye SK. Delirium in older persons. N Engl J Med. 2006;354(11):1157-1165.
3. Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington DC: American Psychiatric Association; 2000.
4. McPhee SJ, Papadakis M, Rabow MW. CURRENT medical diagnosis and treatment. New York NY: McGraw Hill Medical; 2012.
5. Brody B. Who has capacity? N Engl J Med. 2009;361(3):232-233.
6. Practice guideline for the treatment of patients with delirium. American Psychiatric Association. Am J Psychiatry. 1999;156(5 suppl):1-20.
7. Fricchione GL, Nejad SH, Esses JA, et al. Postoperative delirium. Am J Psychiatry. 2008;165(7):803-812.
8. Sanyal AJ, Freedman AM, Shiffman ML, et al. Portosystemic encephalopathy after transjugular intrahepatic portosystemic shunt: results of a prospective controlled study. Hepatology. 1994;20(1 pt 1):46-55.
9. Engel GL, Romano J. Delirium a syndrome of cerebral insufficiency. 1959. J Neuropsychiatry Clin Neurosci. 2004;16(4):526-538.
10. Pro JD, Wells CE. The use of the electroencephalogram in the diagnosis of delirium. Dis Nerv Syst. 1977;38(10):804-808.
11. Sidhu KS, Balon R, Ajluni V, et al. Standard EEG and the difficult-to-assess mental status. Ann Clin Psychiatry. 2009;21(2):103-108.
12. Brenner RP. Utility of EEG in delirium: past views and current practice. Int Psychogeriatr. 1991;3(2):211-229.
13. Kaufman DM. Clinical neurology for psychiatrists. 5th ed. Philadelphia PA: Saunders; 2001: 230-232.
14. Bond TC. Recognition of acute delirious mania. Arch Gen Psychiatry. 1980;37(5):553-554.
15. Krauthammer C, Klerman GL. Secondary mania: manic syndromes associated with antecedent physical illness or drugs. Arch Gen Psychiatry. 1978;35(11):1333-1339.
16. Larson EW, Richelson E. Organic causes of mania. Mayo Clin Proc. 1988;63(9):906-912.
CASE: Agitation
Mrs. M, age 39, presents to the emergency department (ED) with altered mental status. She is escorted by her husband and the police. She has a history of severe alcohol dependence, bipolar disorder (BD), anxiety, borderline personality disorder (BPD), hypothyroidism, and bulimia, and had gastric bypass surgery 4 years ago. Her husband called 911 when he could no longer manage Mrs. M’s agitated state. The police found her to be extremely paranoid, restless, and disoriented. Her husband reports that she shouted “the world is going to end” before she escaped naked into her neighborhood streets.
On several occasions Mrs. M had been admitted to the same hospital for alcohol withdrawal and dependence with subsequent liver failure, leading to jaundice, coagulopathy, and ascites. During these hospitalizations, she exhibited poor behavioral tendencies, unhealthy psychological defenses, and chronic maladaptive coping and defense mechanisms congruent with her BPD diagnosis. Specifically, she engaged in splitting of hospital staff, ranging from extreme flattery to overt devaluation and hostility. Other defense mechanisms included denial, distortion, acting out, and passive-aggressive behavior. During these admissions, Mrs. M often displayed deficits in recall and attention on Mini-Mental State Examination (MMSE), but these deficits were associated with concurrent alcohol use and improved rapidly during her stay.
In her current presentation, Mrs. M’s mental status change is more pronounced and atypical compared with earlier admissions. Her outpatient medication regimen includes lamotrigine, 100 mg/d, levothyroxine, 88 mcg/d, venlafaxine extended release (XR), 75 mg/d, clonazepam, 3 mg/d, docusate as needed for constipation, and a daily multivitamin.
The authors’ observations
Delirium is a disturbance of consciousness manifested by a reduced clarity of awareness (impairment in attention) and change in cognition (impairment in orientation, memory, and language).1,2 The disturbance develops over a short time and tends to fluctuate during the day. Delirium is a direct physiological consequence of a general medical condition, substance use (intoxication or withdrawal), or both (Table).3
Delirium generally is a reversible mental disorder but can progress to irreversible brain damage. Prompt and accurate diagnosis of delirium is essential,4 although the condition often is underdiagnosed or misdiagnosed because of lack of recognition.
Table
DSM-IV-TR diagnostic criteria for delirium
|
| Source: Reference 3 |
Patients who have convoluted histories, such as Mrs. M, are common and difficult to manage and treat. These patients become substantially more complex when they are admitted to inpatient medical or surgical services. The need to clarify between delirium (primarily medical) and depression (primarily psychiatric) becomes paramount when administering treatment and evaluating decision-making capacity.5 In Mrs. M’s case, internal medicine, neurology, and psychiatry teams each had a different approach to altered mental status. Each team’s different terminology, assessment, and objectives further complicated an already challenging case.6
EVALUATION: Confounding results
The ED physicians offer a working diagnosis of acute mental status change, administer IV lorazepam, 4 mg, and order restraints for Mrs. M’s severe agitation. Her initial vital signs reveal slightly elevated blood pressure (140/90 mm Hg) and tachycardia (115 beats per minute). Internal medicine clinicians note that Mrs. M is not in acute distress, although she refuses to speak and has a small amount of dried blood on her lips, presumably from a struggle with the police before coming to the hospital, but this is not certain. Her abdomen is not tender; she has normal bowel sounds, and no asterixis is noted on neurologic exam. Physical exam is otherwise normal. A noncontrast head CT scan shows no acute process. Initial lab values show elevations in ammonia (277 μg/dL) and γ-glutamyl transpeptidase (68 U/L). Thyroid-stimulating hormone is 1.45 mlU/L, prothrombin time is 19.5 s, partial thromboplastin time is 40.3 s, and international normalized ratio is 1.67. The internal medicine team admits Mrs. M to the intensive care unit (ICU) for further management of her mental status change with alcohol withdrawal or hepatic encephalopathy as the most likely etiologies.
Mrs. M’s husband says that his wife has not consumed alcohol in the last 4 months in preparation for a possible liver transplant; however, past interactions with Mrs. M’s family suggest they are unreliable. The Clinical Institute Withdrawal Assessment (CIWA) protocol is implemented in case her symptoms are caused by alcohol withdrawal. Her vital signs are stable and IV lorazepam, 4 mg, is administered once for agitation. Mrs. M’s husband also reports that 1 month ago his wife underwent a transjugular intrahepatic portosystemic shunt (TIPS) procedure for portal hypertension. Outpatient psychotropics (lamotrigine, 100 mg/d, and venlafaxine XR, 75 mg/d) are restarted because withdrawal from these drugs may exacerbate her symptoms. In the ICU Mrs. M experiences a tonic-clonic seizure with fecal incontinence and bitten tongue, which results in a consultation from neurology and the psychiatry consultation-liaison service.
Psychiatry recommends withholding psychotropics, stopping CIWA, and using vital sign parameters along with objective signs of diaphoresis and tremors as indicators of alcohol withdrawal for lorazepam administration. Mrs. M receives IV haloperidol, 1 mg, once during her second day in the hospital for severe agitation, but this medication is discontinued because of concern about lowering her seizure threshold.7 After treatment with lactulose, her ammonia levels trend down to 33 μg/dL, but her altered mental state persists with significant deficits in attention and orientation.
The neurology service performs an EEG that shows no slow-wave, triphasic waves, or epileptiform activity, which likely would be present in delirium or seizures. See Figure 1 for an example of triphasic waves on an EEG and Figure 2 for Mrs. M's EEG results. Subsequent lumbar puncture, MRI, and a second EEG are unremarkable. By the fifth hospital day, Mrs. M is calm and her paranoia has subsided, but she still is confused and disoriented. Psychiatry orders a third EEG while she is in this confused state; it shows no pathologic process. Based on these examinations, neurology posits that Mrs. M is not encephalopathic.
Figure 1: Representative sample of triphasic waves
This EEG tracing is from a 54-year-old woman who underwent prolonged abdominal surgery for lysis of adhesions during which she suffered an intraoperative left subinsular stroke followed by nonconvulsive status epilepticus. The tracing demonstrates typical morphology with the positive sharp transient preceded and followed by smaller amplitude negative deflections. Symmetric, frontal predominance of findings seen is this tracing is common
Figure 2: Mrs. M’s EEG results
This is a representative tracing of Mrs. M’s 3 EEGs revealing an 8.5 to 9 Hz dominant alpha rhythm. There is superimposed frontally dominant beta fast activity, which is consistent with known administration of benzodiazepines
The authors’ observations
Mrs. M had repeated admissions for alcohol dependence and subsequent liver failure. Her recent hospitalization was complicated by a TIPS procedure done 1 month ago. The incidence of hepatic encephalopathy in patients undergoing TIPS is >30%, especially in the first month post-procedure, which raised suspicion that hepatic encephalopathy played a significant role in Mrs. M’s delirium.8
Because of frequent hospitalization, Mrs. M was well known to the internal medicine, neurology, and psychiatry teams, and each used different terms to describe her mental state. Internal medicine used the phrase “acute mental status change,” which covers a broad differential. Neurology used “encephalopathy,” which also is a general term. Psychiatry used “delirium,” which has narrower and more specific diagnostic criteria. Engel et al9 described the delirious patient as having “cerebral insufficiency” with universally abnormal EEG. Regardless of terminology, based on Mrs. M’s acute confusion, one would expect an abnormal EEG, but repeat EEGs were unremarkable.
Interpreting EEG
EEG is one of the few tools available for measuring acute changes in cerebral function, and an EEG slowing remains a hallmark in encephalopathic processes.10,11 Initially, the 3 specialties agreed that Mrs. M’s presentation likely was caused by underlying medical issues or substances (alcohol or others). EEG can help recognize delirium, and, in some cases, elucidate the underlying cause.10,12 It was surprising that Mrs. M’s EEGs were normal despite a clinical presentation of delirium. Because of the normal EEG findings, neurology leaned toward a primary psychiatric (“functional”) etiology as the cause of her delirium vs a general medical condition or alcohol withdrawal (“organic”).
A literature search in regards to sensitivity of EEG in delirium revealed conflicting statements and data. A standard textbook in neurology and psychiatry states that “a normal EEG virtually excludes a toxic-metabolic encephalopathy.”13 The American Psychiatric Association’s (APA) practice guidelines for delirium states: “The presence of EEG abnormalities has fairly good sensitivities for delirium (in one study, the sensitivity was found to be 75%), but the absence does not rule out the diagnosis; thus the EEG is no substitute for careful clinical observation.”6
At the beginning of Mrs. M’s care, in discussion with the neurology and internal medicine teams, we argued that Mrs. M was experiencing delirium despite her initial normal EEG. We did not expect that 2 subsequent EEGs would be normal, especially because the teams witnessed the final EEG being performed while Mrs. M was clinically evaluated and observed to be in a state of delirium.
OUTCOME: Cause still unknown
By the 6th day of hospitalization, Mrs. M’s vitals are normal and she remains hemodynamically stable. Differential diagnosis remains wide and unclear. The psychiatry team feels she could have atypical catatonia due to an underlying mood disorder. One hour after a trial of IV lorazepam, 1 mg, Mrs. M is more lucid and fully oriented, with MMSE of 28/30 (recall was 1/3), indicating normal cognition. During the exam, a psychiatry resident notes Mrs. M winks and feigns a yawn at the medical students and nurses in the room, displaying her boredom with the interview and simplicity of the mental status exam questions. Later that evening, Mrs. M exhibits bizarre sexual gestures toward male hospital staff, including licking a male nursing staff member’s hand.
Although Mrs. M’s initial confusion resolved, the severity of her comorbid psychiatric history warrants inpatient psychiatric hospitalization. She agrees to transfer to the psychiatric ward after she confesses anxiety regarding death, intense demoralization, and guilt related to her condition and her relationship with her 12-year-old daughter. She tearfully reports that she discontinued her psychotropic medications shortly after stopping alcohol 4 months ago. Shortly before her transfer, psychiatry is called back to the medicine floor because of Mrs. M’s disruptive behavior.
The team finds Mrs. M in her hospital gown, pursuing her husband in the hallway as he is leaving, yelling profanities and blaming him for her horrible experience in the hospital. Based on her demeanor, the team determines that she is back to her baseline mental state despite her mood disorder, and that her upcoming inpatient psychiatric stay likely would be too short to address her comorbid personality disorder. The next day she signs out of the hospital against medical advice.
The authors’ observations
We never clearly identified the specific etiology responsible for Mrs. M’s delirium. We assume at the initial presentation she had toxic-metabolic encephalopathy that rapidly resolved with lactulose treatment and lowering her ammonia. She then had a single tonic-clonic seizure, perhaps related to stopping and then restarting her psychotropics. Her subsequent confusion, bizarre sexual behavior, and demeanor on her final hospital days were more indicative of her psychiatric diagnoses. We now suspect that Mrs. M’s delirium was briefer than presumed and she returned to her baseline borderline personality, resulting in some factitious staging of delirium to confuse her 3 treating teams (a psychoanalyst may say this was a form of projective identification).
We felt that if Mrs. M truly was delirious due to metabolic or hepatic dysfunction or alcohol withdrawal, she would have had abnormal EEG findings. We discovered that the notion of “75% sensitivity” of EEG abnormalities cited in the APA guidelines comes from studies that include patients with “psychogenic” and “organic” delirium. Acute manias and agitated psychoses were termed “psychogenic delirium” and acute confusion due to medical conditions or substance issues was termed “organic delirium.”9,12,14-16
This poses a circular reasoning in the diagnostic criteria and clinical approach to delirium. The fallacy is that, according to DSM-IV-TR, delirium is supposed to be the result of a direct physiological consequence of a general medical condition or substance use (criterion D), and cannot be due to psychosis (eg, schizophrenia) or mania (eg, BD). We question the presumptive 75% sensitivity of EEG abnormalities in patients with delirium because it is possible that when some of these studies were conducted the definition of delirium was not solidified or fully understood. We suspect the sensitivity would be much higher if the correct definition of delirium according to DSM-IV-TR is used in future studies. To improve interdisciplinary communication and future research, it would be constructive if all disciplines could agree on a single term, with the same diagnostic criteria, when evaluating a patient with acute confusion.
Related Resources
- Meagher D. Delirium: the role of psychiatry. Advances in Psychiatric Treatment. 2001;7:433-442.
- Casey DA, DeFazio JV Jr, Vansickle K, et al. Delirium. Quick recognition, careful evaluation, and appropriate treatment. Postgrad Med. 1996;100(1):121-4, 128, 133-134.
Drug Brand Names
- Clonazepam • Klonopin
- Docusate • Surfak
- Haloperidol • Haldol
- Lamotrigine • Lamictal
- Lorazepam • Ativan
- Levothyroxine • Levoxyl, Synthtoid
- Venlafaxine XR • Effexor XR
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Acknowledgment
The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government. The authors are employees of the U.S. Government. This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the U.S. Government.” Title 17 U.S.C. 101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties.
CASE: Agitation
Mrs. M, age 39, presents to the emergency department (ED) with altered mental status. She is escorted by her husband and the police. She has a history of severe alcohol dependence, bipolar disorder (BD), anxiety, borderline personality disorder (BPD), hypothyroidism, and bulimia, and had gastric bypass surgery 4 years ago. Her husband called 911 when he could no longer manage Mrs. M’s agitated state. The police found her to be extremely paranoid, restless, and disoriented. Her husband reports that she shouted “the world is going to end” before she escaped naked into her neighborhood streets.
On several occasions Mrs. M had been admitted to the same hospital for alcohol withdrawal and dependence with subsequent liver failure, leading to jaundice, coagulopathy, and ascites. During these hospitalizations, she exhibited poor behavioral tendencies, unhealthy psychological defenses, and chronic maladaptive coping and defense mechanisms congruent with her BPD diagnosis. Specifically, she engaged in splitting of hospital staff, ranging from extreme flattery to overt devaluation and hostility. Other defense mechanisms included denial, distortion, acting out, and passive-aggressive behavior. During these admissions, Mrs. M often displayed deficits in recall and attention on Mini-Mental State Examination (MMSE), but these deficits were associated with concurrent alcohol use and improved rapidly during her stay.
In her current presentation, Mrs. M’s mental status change is more pronounced and atypical compared with earlier admissions. Her outpatient medication regimen includes lamotrigine, 100 mg/d, levothyroxine, 88 mcg/d, venlafaxine extended release (XR), 75 mg/d, clonazepam, 3 mg/d, docusate as needed for constipation, and a daily multivitamin.
The authors’ observations
Delirium is a disturbance of consciousness manifested by a reduced clarity of awareness (impairment in attention) and change in cognition (impairment in orientation, memory, and language).1,2 The disturbance develops over a short time and tends to fluctuate during the day. Delirium is a direct physiological consequence of a general medical condition, substance use (intoxication or withdrawal), or both (Table).3
Delirium generally is a reversible mental disorder but can progress to irreversible brain damage. Prompt and accurate diagnosis of delirium is essential,4 although the condition often is underdiagnosed or misdiagnosed because of lack of recognition.
Table
DSM-IV-TR diagnostic criteria for delirium
|
| Source: Reference 3 |
Patients who have convoluted histories, such as Mrs. M, are common and difficult to manage and treat. These patients become substantially more complex when they are admitted to inpatient medical or surgical services. The need to clarify between delirium (primarily medical) and depression (primarily psychiatric) becomes paramount when administering treatment and evaluating decision-making capacity.5 In Mrs. M’s case, internal medicine, neurology, and psychiatry teams each had a different approach to altered mental status. Each team’s different terminology, assessment, and objectives further complicated an already challenging case.6
EVALUATION: Confounding results
The ED physicians offer a working diagnosis of acute mental status change, administer IV lorazepam, 4 mg, and order restraints for Mrs. M’s severe agitation. Her initial vital signs reveal slightly elevated blood pressure (140/90 mm Hg) and tachycardia (115 beats per minute). Internal medicine clinicians note that Mrs. M is not in acute distress, although she refuses to speak and has a small amount of dried blood on her lips, presumably from a struggle with the police before coming to the hospital, but this is not certain. Her abdomen is not tender; she has normal bowel sounds, and no asterixis is noted on neurologic exam. Physical exam is otherwise normal. A noncontrast head CT scan shows no acute process. Initial lab values show elevations in ammonia (277 μg/dL) and γ-glutamyl transpeptidase (68 U/L). Thyroid-stimulating hormone is 1.45 mlU/L, prothrombin time is 19.5 s, partial thromboplastin time is 40.3 s, and international normalized ratio is 1.67. The internal medicine team admits Mrs. M to the intensive care unit (ICU) for further management of her mental status change with alcohol withdrawal or hepatic encephalopathy as the most likely etiologies.
Mrs. M’s husband says that his wife has not consumed alcohol in the last 4 months in preparation for a possible liver transplant; however, past interactions with Mrs. M’s family suggest they are unreliable. The Clinical Institute Withdrawal Assessment (CIWA) protocol is implemented in case her symptoms are caused by alcohol withdrawal. Her vital signs are stable and IV lorazepam, 4 mg, is administered once for agitation. Mrs. M’s husband also reports that 1 month ago his wife underwent a transjugular intrahepatic portosystemic shunt (TIPS) procedure for portal hypertension. Outpatient psychotropics (lamotrigine, 100 mg/d, and venlafaxine XR, 75 mg/d) are restarted because withdrawal from these drugs may exacerbate her symptoms. In the ICU Mrs. M experiences a tonic-clonic seizure with fecal incontinence and bitten tongue, which results in a consultation from neurology and the psychiatry consultation-liaison service.
Psychiatry recommends withholding psychotropics, stopping CIWA, and using vital sign parameters along with objective signs of diaphoresis and tremors as indicators of alcohol withdrawal for lorazepam administration. Mrs. M receives IV haloperidol, 1 mg, once during her second day in the hospital for severe agitation, but this medication is discontinued because of concern about lowering her seizure threshold.7 After treatment with lactulose, her ammonia levels trend down to 33 μg/dL, but her altered mental state persists with significant deficits in attention and orientation.
The neurology service performs an EEG that shows no slow-wave, triphasic waves, or epileptiform activity, which likely would be present in delirium or seizures. See Figure 1 for an example of triphasic waves on an EEG and Figure 2 for Mrs. M's EEG results. Subsequent lumbar puncture, MRI, and a second EEG are unremarkable. By the fifth hospital day, Mrs. M is calm and her paranoia has subsided, but she still is confused and disoriented. Psychiatry orders a third EEG while she is in this confused state; it shows no pathologic process. Based on these examinations, neurology posits that Mrs. M is not encephalopathic.
Figure 1: Representative sample of triphasic waves
This EEG tracing is from a 54-year-old woman who underwent prolonged abdominal surgery for lysis of adhesions during which she suffered an intraoperative left subinsular stroke followed by nonconvulsive status epilepticus. The tracing demonstrates typical morphology with the positive sharp transient preceded and followed by smaller amplitude negative deflections. Symmetric, frontal predominance of findings seen is this tracing is common
Figure 2: Mrs. M’s EEG results
This is a representative tracing of Mrs. M’s 3 EEGs revealing an 8.5 to 9 Hz dominant alpha rhythm. There is superimposed frontally dominant beta fast activity, which is consistent with known administration of benzodiazepines
The authors’ observations
Mrs. M had repeated admissions for alcohol dependence and subsequent liver failure. Her recent hospitalization was complicated by a TIPS procedure done 1 month ago. The incidence of hepatic encephalopathy in patients undergoing TIPS is >30%, especially in the first month post-procedure, which raised suspicion that hepatic encephalopathy played a significant role in Mrs. M’s delirium.8
Because of frequent hospitalization, Mrs. M was well known to the internal medicine, neurology, and psychiatry teams, and each used different terms to describe her mental state. Internal medicine used the phrase “acute mental status change,” which covers a broad differential. Neurology used “encephalopathy,” which also is a general term. Psychiatry used “delirium,” which has narrower and more specific diagnostic criteria. Engel et al9 described the delirious patient as having “cerebral insufficiency” with universally abnormal EEG. Regardless of terminology, based on Mrs. M’s acute confusion, one would expect an abnormal EEG, but repeat EEGs were unremarkable.
Interpreting EEG
EEG is one of the few tools available for measuring acute changes in cerebral function, and an EEG slowing remains a hallmark in encephalopathic processes.10,11 Initially, the 3 specialties agreed that Mrs. M’s presentation likely was caused by underlying medical issues or substances (alcohol or others). EEG can help recognize delirium, and, in some cases, elucidate the underlying cause.10,12 It was surprising that Mrs. M’s EEGs were normal despite a clinical presentation of delirium. Because of the normal EEG findings, neurology leaned toward a primary psychiatric (“functional”) etiology as the cause of her delirium vs a general medical condition or alcohol withdrawal (“organic”).
A literature search in regards to sensitivity of EEG in delirium revealed conflicting statements and data. A standard textbook in neurology and psychiatry states that “a normal EEG virtually excludes a toxic-metabolic encephalopathy.”13 The American Psychiatric Association’s (APA) practice guidelines for delirium states: “The presence of EEG abnormalities has fairly good sensitivities for delirium (in one study, the sensitivity was found to be 75%), but the absence does not rule out the diagnosis; thus the EEG is no substitute for careful clinical observation.”6
At the beginning of Mrs. M’s care, in discussion with the neurology and internal medicine teams, we argued that Mrs. M was experiencing delirium despite her initial normal EEG. We did not expect that 2 subsequent EEGs would be normal, especially because the teams witnessed the final EEG being performed while Mrs. M was clinically evaluated and observed to be in a state of delirium.
OUTCOME: Cause still unknown
By the 6th day of hospitalization, Mrs. M’s vitals are normal and she remains hemodynamically stable. Differential diagnosis remains wide and unclear. The psychiatry team feels she could have atypical catatonia due to an underlying mood disorder. One hour after a trial of IV lorazepam, 1 mg, Mrs. M is more lucid and fully oriented, with MMSE of 28/30 (recall was 1/3), indicating normal cognition. During the exam, a psychiatry resident notes Mrs. M winks and feigns a yawn at the medical students and nurses in the room, displaying her boredom with the interview and simplicity of the mental status exam questions. Later that evening, Mrs. M exhibits bizarre sexual gestures toward male hospital staff, including licking a male nursing staff member’s hand.
Although Mrs. M’s initial confusion resolved, the severity of her comorbid psychiatric history warrants inpatient psychiatric hospitalization. She agrees to transfer to the psychiatric ward after she confesses anxiety regarding death, intense demoralization, and guilt related to her condition and her relationship with her 12-year-old daughter. She tearfully reports that she discontinued her psychotropic medications shortly after stopping alcohol 4 months ago. Shortly before her transfer, psychiatry is called back to the medicine floor because of Mrs. M’s disruptive behavior.
The team finds Mrs. M in her hospital gown, pursuing her husband in the hallway as he is leaving, yelling profanities and blaming him for her horrible experience in the hospital. Based on her demeanor, the team determines that she is back to her baseline mental state despite her mood disorder, and that her upcoming inpatient psychiatric stay likely would be too short to address her comorbid personality disorder. The next day she signs out of the hospital against medical advice.
The authors’ observations
We never clearly identified the specific etiology responsible for Mrs. M’s delirium. We assume at the initial presentation she had toxic-metabolic encephalopathy that rapidly resolved with lactulose treatment and lowering her ammonia. She then had a single tonic-clonic seizure, perhaps related to stopping and then restarting her psychotropics. Her subsequent confusion, bizarre sexual behavior, and demeanor on her final hospital days were more indicative of her psychiatric diagnoses. We now suspect that Mrs. M’s delirium was briefer than presumed and she returned to her baseline borderline personality, resulting in some factitious staging of delirium to confuse her 3 treating teams (a psychoanalyst may say this was a form of projective identification).
We felt that if Mrs. M truly was delirious due to metabolic or hepatic dysfunction or alcohol withdrawal, she would have had abnormal EEG findings. We discovered that the notion of “75% sensitivity” of EEG abnormalities cited in the APA guidelines comes from studies that include patients with “psychogenic” and “organic” delirium. Acute manias and agitated psychoses were termed “psychogenic delirium” and acute confusion due to medical conditions or substance issues was termed “organic delirium.”9,12,14-16
This poses a circular reasoning in the diagnostic criteria and clinical approach to delirium. The fallacy is that, according to DSM-IV-TR, delirium is supposed to be the result of a direct physiological consequence of a general medical condition or substance use (criterion D), and cannot be due to psychosis (eg, schizophrenia) or mania (eg, BD). We question the presumptive 75% sensitivity of EEG abnormalities in patients with delirium because it is possible that when some of these studies were conducted the definition of delirium was not solidified or fully understood. We suspect the sensitivity would be much higher if the correct definition of delirium according to DSM-IV-TR is used in future studies. To improve interdisciplinary communication and future research, it would be constructive if all disciplines could agree on a single term, with the same diagnostic criteria, when evaluating a patient with acute confusion.
Related Resources
- Meagher D. Delirium: the role of psychiatry. Advances in Psychiatric Treatment. 2001;7:433-442.
- Casey DA, DeFazio JV Jr, Vansickle K, et al. Delirium. Quick recognition, careful evaluation, and appropriate treatment. Postgrad Med. 1996;100(1):121-4, 128, 133-134.
Drug Brand Names
- Clonazepam • Klonopin
- Docusate • Surfak
- Haloperidol • Haldol
- Lamotrigine • Lamictal
- Lorazepam • Ativan
- Levothyroxine • Levoxyl, Synthtoid
- Venlafaxine XR • Effexor XR
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Acknowledgment
The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government. The authors are employees of the U.S. Government. This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the U.S. Government.” Title 17 U.S.C. 101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties.
1. Katz IR, Mossey J, Sussman N, et al. Bedside clinical and electrophysiological assessment: assessment of change in vulnerable patients. Int Psychogeriatr. 1991;3(2):289-300.
2. Inouye SK. Delirium in older persons. N Engl J Med. 2006;354(11):1157-1165.
3. Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington DC: American Psychiatric Association; 2000.
4. McPhee SJ, Papadakis M, Rabow MW. CURRENT medical diagnosis and treatment. New York NY: McGraw Hill Medical; 2012.
5. Brody B. Who has capacity? N Engl J Med. 2009;361(3):232-233.
6. Practice guideline for the treatment of patients with delirium. American Psychiatric Association. Am J Psychiatry. 1999;156(5 suppl):1-20.
7. Fricchione GL, Nejad SH, Esses JA, et al. Postoperative delirium. Am J Psychiatry. 2008;165(7):803-812.
8. Sanyal AJ, Freedman AM, Shiffman ML, et al. Portosystemic encephalopathy after transjugular intrahepatic portosystemic shunt: results of a prospective controlled study. Hepatology. 1994;20(1 pt 1):46-55.
9. Engel GL, Romano J. Delirium a syndrome of cerebral insufficiency. 1959. J Neuropsychiatry Clin Neurosci. 2004;16(4):526-538.
10. Pro JD, Wells CE. The use of the electroencephalogram in the diagnosis of delirium. Dis Nerv Syst. 1977;38(10):804-808.
11. Sidhu KS, Balon R, Ajluni V, et al. Standard EEG and the difficult-to-assess mental status. Ann Clin Psychiatry. 2009;21(2):103-108.
12. Brenner RP. Utility of EEG in delirium: past views and current practice. Int Psychogeriatr. 1991;3(2):211-229.
13. Kaufman DM. Clinical neurology for psychiatrists. 5th ed. Philadelphia PA: Saunders; 2001: 230-232.
14. Bond TC. Recognition of acute delirious mania. Arch Gen Psychiatry. 1980;37(5):553-554.
15. Krauthammer C, Klerman GL. Secondary mania: manic syndromes associated with antecedent physical illness or drugs. Arch Gen Psychiatry. 1978;35(11):1333-1339.
16. Larson EW, Richelson E. Organic causes of mania. Mayo Clin Proc. 1988;63(9):906-912.
1. Katz IR, Mossey J, Sussman N, et al. Bedside clinical and electrophysiological assessment: assessment of change in vulnerable patients. Int Psychogeriatr. 1991;3(2):289-300.
2. Inouye SK. Delirium in older persons. N Engl J Med. 2006;354(11):1157-1165.
3. Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington DC: American Psychiatric Association; 2000.
4. McPhee SJ, Papadakis M, Rabow MW. CURRENT medical diagnosis and treatment. New York NY: McGraw Hill Medical; 2012.
5. Brody B. Who has capacity? N Engl J Med. 2009;361(3):232-233.
6. Practice guideline for the treatment of patients with delirium. American Psychiatric Association. Am J Psychiatry. 1999;156(5 suppl):1-20.
7. Fricchione GL, Nejad SH, Esses JA, et al. Postoperative delirium. Am J Psychiatry. 2008;165(7):803-812.
8. Sanyal AJ, Freedman AM, Shiffman ML, et al. Portosystemic encephalopathy after transjugular intrahepatic portosystemic shunt: results of a prospective controlled study. Hepatology. 1994;20(1 pt 1):46-55.
9. Engel GL, Romano J. Delirium a syndrome of cerebral insufficiency. 1959. J Neuropsychiatry Clin Neurosci. 2004;16(4):526-538.
10. Pro JD, Wells CE. The use of the electroencephalogram in the diagnosis of delirium. Dis Nerv Syst. 1977;38(10):804-808.
11. Sidhu KS, Balon R, Ajluni V, et al. Standard EEG and the difficult-to-assess mental status. Ann Clin Psychiatry. 2009;21(2):103-108.
12. Brenner RP. Utility of EEG in delirium: past views and current practice. Int Psychogeriatr. 1991;3(2):211-229.
13. Kaufman DM. Clinical neurology for psychiatrists. 5th ed. Philadelphia PA: Saunders; 2001: 230-232.
14. Bond TC. Recognition of acute delirious mania. Arch Gen Psychiatry. 1980;37(5):553-554.
15. Krauthammer C, Klerman GL. Secondary mania: manic syndromes associated with antecedent physical illness or drugs. Arch Gen Psychiatry. 1978;35(11):1333-1339.
16. Larson EW, Richelson E. Organic causes of mania. Mayo Clin Proc. 1988;63(9):906-912.
One twin has cerebral palsy; $103M verdict … and more
AFTER PREMATURE RUPTURE OF MEMBRANES at 25 weeks’ gestation, a woman went to the emergency department (ED) and was later released. Eight days later, she returned to the ED with abdominal pain; a soporific drug was administered. After several hours, it was determined that she was in labor. Twins were delivered vaginally. One child has cerebral palsy and requires assistance in daily activities, although her cognitive function is intact.
PARENTS’ CLAIM The mother should not have been released after premature rupture of her membranes. The nurses and ObGyns failed to timely recognize that the mother was in labor, and failed to prevent premature delivery. Proper recognition of contractions would have allowed for administration of a tocolytic to delay delivery. That drug had been effectively administered during the first two trimesters of the pregnancy. A cesarean delivery should have been performed.
DEFENDANTS’ DEFENSE There was no negligence. The hospital argued that fetal heart-rate monitors did not suggest contractions.
VERDICT A $103 million New York verdict was returned against the hospital; a defense verdict was returned for the physicians.
Perforated uterus and severed iliac artery after D&C
A GYNECOLOGIC SURGEON performed a dilation and curettage (D&C) on a 47-year-old woman. During surgery, the patient suffered a perforated uterus and a severed iliac artery, resulting in a myocardial infarction.
PATIENT’S CLAIM The surgeon failed to dilate the cervix appropriately to assess the cervical and endometrial cavity length, and then failed to use proper instrumentation in the uterus. He did not assess uterine shape before the D&C. The patient suffered cognitive and emotional injuries, and will require additional surgery.
PHYSICIAN’S DEFENSE The patient’s anatomy is abnormal. A perforation is a known complication of a D&C.
VERDICT A $350,000 Wisconsin settlement was reached.
Failure to monitor a high-risk patient
A WOMAN WITH A HEART CONDITION who routinely took a beta-blocker plus migraine medication also had lupus. Her pregnancy was therefore at high risk for developing intrauterine growth restriction. Her US Navy ObGyn was advised by a maternal-fetal medicine (MFM) specialist to monitor the pregnancy closely with frequent ultrasonography and other tests that were never performed.
The baby was born by emergency cesarean delivery at 36 weeks’ gestation. The child suffered severe hypoxia and a brain hemorrhage just before delivery, which caused serious, permanent physical and neurologic injuries. He needs 24-hour care, is confined to a wheelchair, and requires a feeding tube.
PATIENT’S CLAIM The ObGyn failed to monitor the mother for fetal growth restriction as recommended by the MFM specialist.
DEFENDANTS’ DEFENSE There was no negligence; the mother was treated properly.
VERDICT After a $28 million Virginia verdict was awarded, the parties continued to dispute whether the judgment would be paid under California law (where the child was born) or Virginia law (where the case was filed). Prior to a rehearing, a $25 million settlement was reached.
Uterine cancer went undiagnosed
A WOMAN IN HER 50s saw her gynecologist in March 2004 to report vaginal staining. She did not return to the physician’s office until January 2005, when she reported daily vaginal bleeding. Ultrasonography showed a 4-cm mass in the endometrial cavity, consistent with a large polyp. A hysteroscopy and biopsy revealed that the woman had uterine cancer. She underwent a hysterectomy and radiation therapy, but the cancer metastasized to her lungs and she died in October 2006.
ESTATE’S CLAIM The gynecologist failed to diagnose uterine cancer in a timely manner.
PHYSICIAN’S DEFENSE The patient’s cancer was aggressive; an earlier diagnosis would not have changed the outcome.
VERDICT A $820,000 Massachusetts settlement was reached.
WHEN A 51-YEAR-OLD WOMAN NOTICED A BULGE in her vagina, she consulted her gynecologist. He determined the cause to be a cystocele and rectocele, and recommended a tension-free vaginal tape–obturator (TVT-O) procedure with anterior and posterior colporrhaphy.
The patient awoke from surgery in severe pain and was told that she had lost a lot of blood. Two weeks later, the physician explained that the stitches, not yet absorbed, were causing an abrasion, and that more vaginal tissue had been removed than planned.
Two more weeks passed, and the patient used a mirror to look at her vagina but could not see the opening. The TVT-O tape had created a ridge of tissue in the anterior vagina, causing severe stenosis. Vaginal dilators were required to expand the vagina. Entrapment of the dorsal clitoral nerve by the TVT-O tape was also discovered. The patient continues to experience dyspareunia and groin pain.
PATIENT’S CLAIM The gynecologist failed to tell her that, 2 months before surgery, the FDA had issued a public health warning about complications associated with transvaginal placement of surgical mesh during prolapse and urinary incontinence repair. Nor was she informed that the defendant had just completed training in TVT-O surgery, was not fully credentialed, and was proctored during the procedure.
PHYSICIAN’S DEFENSE The case was settled before the trial concluded.
VERDICT A $390,000 Virginia settlement was reached.
Lumpectomy, though no mass palpated
A 52-YEAR-OLD WOMAN FOUND A LUMP in her left breast. Her internist ordered mammography, which identified a 2-cm oval, asymmetrical density in the upper inner quadrant of the left breast. The radiologist recommended ultrasonography (US).
The patient consulted a surgical oncologist, who performed fine-needle aspiration. Pathology identified “clusters of malignant cells consistent with carcinoma,” and suggested a confirmatory biopsy. The oncologist recommended lumpectomy and sentinel node biopsy.
On the day of surgery, the patient could not locate the mass. The oncologist testified that he had palpated it. During surgery, gross examination did not show a mass or tumor. Frozen sections of sentinel nodes did not reveal evidence of cancer.
The patient suffered postsurgical seromas and lymphedema. The lymphedema has partially resolved, but causes pain in her left arm and breast.
PATIENT’S CLAIM The surgical oncologist should have performed US before surgery. It was negligent to continue with surgery when there were negative intraoperative findings for cancer or a mass.
PHYSICIAN’S DEFENSE Proper care was provided.
VERDICT A $950,000 Illinois verdict was returned.
Genetic testing fails to identify cystic fibrosis in one twin
AFTER HAVING ONE CHILD with cystic fibrosis (CF), parents underwent genetic testing. Embryos were prepared for in vitro fertilization (IVF) and sent to a genetic-testing laboratory. The lab reported that the embryos were negative for CF. Two embryos were implanted, and the mother gave birth to twins, one of which has CF.
PARENTS’ CLAIM Multiple errors by the genetic-testing laboratory led to an incorrect report on the embryos. The parents claimed wrongful birth.
DEFENDANTS’ DEFENSE The testing laboratory and physician owner argued that amniocentesis should have been performed during the pregnancy to rule out CF.
VERDICT The trial judge denied the use of the amniocentesis defense because an abortion would have been the only option available, and abortion is against the public policy of Tennessee. The court entered summary judgment on liability for the parents.
A $13 million verdict was returned, including $7 million to the parents for emotional distress.
These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.
We want to hear from you! Tell us what you think.
AFTER PREMATURE RUPTURE OF MEMBRANES at 25 weeks’ gestation, a woman went to the emergency department (ED) and was later released. Eight days later, she returned to the ED with abdominal pain; a soporific drug was administered. After several hours, it was determined that she was in labor. Twins were delivered vaginally. One child has cerebral palsy and requires assistance in daily activities, although her cognitive function is intact.
PARENTS’ CLAIM The mother should not have been released after premature rupture of her membranes. The nurses and ObGyns failed to timely recognize that the mother was in labor, and failed to prevent premature delivery. Proper recognition of contractions would have allowed for administration of a tocolytic to delay delivery. That drug had been effectively administered during the first two trimesters of the pregnancy. A cesarean delivery should have been performed.
DEFENDANTS’ DEFENSE There was no negligence. The hospital argued that fetal heart-rate monitors did not suggest contractions.
VERDICT A $103 million New York verdict was returned against the hospital; a defense verdict was returned for the physicians.
Perforated uterus and severed iliac artery after D&C
A GYNECOLOGIC SURGEON performed a dilation and curettage (D&C) on a 47-year-old woman. During surgery, the patient suffered a perforated uterus and a severed iliac artery, resulting in a myocardial infarction.
PATIENT’S CLAIM The surgeon failed to dilate the cervix appropriately to assess the cervical and endometrial cavity length, and then failed to use proper instrumentation in the uterus. He did not assess uterine shape before the D&C. The patient suffered cognitive and emotional injuries, and will require additional surgery.
PHYSICIAN’S DEFENSE The patient’s anatomy is abnormal. A perforation is a known complication of a D&C.
VERDICT A $350,000 Wisconsin settlement was reached.
Failure to monitor a high-risk patient
A WOMAN WITH A HEART CONDITION who routinely took a beta-blocker plus migraine medication also had lupus. Her pregnancy was therefore at high risk for developing intrauterine growth restriction. Her US Navy ObGyn was advised by a maternal-fetal medicine (MFM) specialist to monitor the pregnancy closely with frequent ultrasonography and other tests that were never performed.
The baby was born by emergency cesarean delivery at 36 weeks’ gestation. The child suffered severe hypoxia and a brain hemorrhage just before delivery, which caused serious, permanent physical and neurologic injuries. He needs 24-hour care, is confined to a wheelchair, and requires a feeding tube.
PATIENT’S CLAIM The ObGyn failed to monitor the mother for fetal growth restriction as recommended by the MFM specialist.
DEFENDANTS’ DEFENSE There was no negligence; the mother was treated properly.
VERDICT After a $28 million Virginia verdict was awarded, the parties continued to dispute whether the judgment would be paid under California law (where the child was born) or Virginia law (where the case was filed). Prior to a rehearing, a $25 million settlement was reached.
Uterine cancer went undiagnosed
A WOMAN IN HER 50s saw her gynecologist in March 2004 to report vaginal staining. She did not return to the physician’s office until January 2005, when she reported daily vaginal bleeding. Ultrasonography showed a 4-cm mass in the endometrial cavity, consistent with a large polyp. A hysteroscopy and biopsy revealed that the woman had uterine cancer. She underwent a hysterectomy and radiation therapy, but the cancer metastasized to her lungs and she died in October 2006.
ESTATE’S CLAIM The gynecologist failed to diagnose uterine cancer in a timely manner.
PHYSICIAN’S DEFENSE The patient’s cancer was aggressive; an earlier diagnosis would not have changed the outcome.
VERDICT A $820,000 Massachusetts settlement was reached.
WHEN A 51-YEAR-OLD WOMAN NOTICED A BULGE in her vagina, she consulted her gynecologist. He determined the cause to be a cystocele and rectocele, and recommended a tension-free vaginal tape–obturator (TVT-O) procedure with anterior and posterior colporrhaphy.
The patient awoke from surgery in severe pain and was told that she had lost a lot of blood. Two weeks later, the physician explained that the stitches, not yet absorbed, were causing an abrasion, and that more vaginal tissue had been removed than planned.
Two more weeks passed, and the patient used a mirror to look at her vagina but could not see the opening. The TVT-O tape had created a ridge of tissue in the anterior vagina, causing severe stenosis. Vaginal dilators were required to expand the vagina. Entrapment of the dorsal clitoral nerve by the TVT-O tape was also discovered. The patient continues to experience dyspareunia and groin pain.
PATIENT’S CLAIM The gynecologist failed to tell her that, 2 months before surgery, the FDA had issued a public health warning about complications associated with transvaginal placement of surgical mesh during prolapse and urinary incontinence repair. Nor was she informed that the defendant had just completed training in TVT-O surgery, was not fully credentialed, and was proctored during the procedure.
PHYSICIAN’S DEFENSE The case was settled before the trial concluded.
VERDICT A $390,000 Virginia settlement was reached.
Lumpectomy, though no mass palpated
A 52-YEAR-OLD WOMAN FOUND A LUMP in her left breast. Her internist ordered mammography, which identified a 2-cm oval, asymmetrical density in the upper inner quadrant of the left breast. The radiologist recommended ultrasonography (US).
The patient consulted a surgical oncologist, who performed fine-needle aspiration. Pathology identified “clusters of malignant cells consistent with carcinoma,” and suggested a confirmatory biopsy. The oncologist recommended lumpectomy and sentinel node biopsy.
On the day of surgery, the patient could not locate the mass. The oncologist testified that he had palpated it. During surgery, gross examination did not show a mass or tumor. Frozen sections of sentinel nodes did not reveal evidence of cancer.
The patient suffered postsurgical seromas and lymphedema. The lymphedema has partially resolved, but causes pain in her left arm and breast.
PATIENT’S CLAIM The surgical oncologist should have performed US before surgery. It was negligent to continue with surgery when there were negative intraoperative findings for cancer or a mass.
PHYSICIAN’S DEFENSE Proper care was provided.
VERDICT A $950,000 Illinois verdict was returned.
Genetic testing fails to identify cystic fibrosis in one twin
AFTER HAVING ONE CHILD with cystic fibrosis (CF), parents underwent genetic testing. Embryos were prepared for in vitro fertilization (IVF) and sent to a genetic-testing laboratory. The lab reported that the embryos were negative for CF. Two embryos were implanted, and the mother gave birth to twins, one of which has CF.
PARENTS’ CLAIM Multiple errors by the genetic-testing laboratory led to an incorrect report on the embryos. The parents claimed wrongful birth.
DEFENDANTS’ DEFENSE The testing laboratory and physician owner argued that amniocentesis should have been performed during the pregnancy to rule out CF.
VERDICT The trial judge denied the use of the amniocentesis defense because an abortion would have been the only option available, and abortion is against the public policy of Tennessee. The court entered summary judgment on liability for the parents.
A $13 million verdict was returned, including $7 million to the parents for emotional distress.
AFTER PREMATURE RUPTURE OF MEMBRANES at 25 weeks’ gestation, a woman went to the emergency department (ED) and was later released. Eight days later, she returned to the ED with abdominal pain; a soporific drug was administered. After several hours, it was determined that she was in labor. Twins were delivered vaginally. One child has cerebral palsy and requires assistance in daily activities, although her cognitive function is intact.
PARENTS’ CLAIM The mother should not have been released after premature rupture of her membranes. The nurses and ObGyns failed to timely recognize that the mother was in labor, and failed to prevent premature delivery. Proper recognition of contractions would have allowed for administration of a tocolytic to delay delivery. That drug had been effectively administered during the first two trimesters of the pregnancy. A cesarean delivery should have been performed.
DEFENDANTS’ DEFENSE There was no negligence. The hospital argued that fetal heart-rate monitors did not suggest contractions.
VERDICT A $103 million New York verdict was returned against the hospital; a defense verdict was returned for the physicians.
Perforated uterus and severed iliac artery after D&C
A GYNECOLOGIC SURGEON performed a dilation and curettage (D&C) on a 47-year-old woman. During surgery, the patient suffered a perforated uterus and a severed iliac artery, resulting in a myocardial infarction.
PATIENT’S CLAIM The surgeon failed to dilate the cervix appropriately to assess the cervical and endometrial cavity length, and then failed to use proper instrumentation in the uterus. He did not assess uterine shape before the D&C. The patient suffered cognitive and emotional injuries, and will require additional surgery.
PHYSICIAN’S DEFENSE The patient’s anatomy is abnormal. A perforation is a known complication of a D&C.
VERDICT A $350,000 Wisconsin settlement was reached.
Failure to monitor a high-risk patient
A WOMAN WITH A HEART CONDITION who routinely took a beta-blocker plus migraine medication also had lupus. Her pregnancy was therefore at high risk for developing intrauterine growth restriction. Her US Navy ObGyn was advised by a maternal-fetal medicine (MFM) specialist to monitor the pregnancy closely with frequent ultrasonography and other tests that were never performed.
The baby was born by emergency cesarean delivery at 36 weeks’ gestation. The child suffered severe hypoxia and a brain hemorrhage just before delivery, which caused serious, permanent physical and neurologic injuries. He needs 24-hour care, is confined to a wheelchair, and requires a feeding tube.
PATIENT’S CLAIM The ObGyn failed to monitor the mother for fetal growth restriction as recommended by the MFM specialist.
DEFENDANTS’ DEFENSE There was no negligence; the mother was treated properly.
VERDICT After a $28 million Virginia verdict was awarded, the parties continued to dispute whether the judgment would be paid under California law (where the child was born) or Virginia law (where the case was filed). Prior to a rehearing, a $25 million settlement was reached.
Uterine cancer went undiagnosed
A WOMAN IN HER 50s saw her gynecologist in March 2004 to report vaginal staining. She did not return to the physician’s office until January 2005, when she reported daily vaginal bleeding. Ultrasonography showed a 4-cm mass in the endometrial cavity, consistent with a large polyp. A hysteroscopy and biopsy revealed that the woman had uterine cancer. She underwent a hysterectomy and radiation therapy, but the cancer metastasized to her lungs and she died in October 2006.
ESTATE’S CLAIM The gynecologist failed to diagnose uterine cancer in a timely manner.
PHYSICIAN’S DEFENSE The patient’s cancer was aggressive; an earlier diagnosis would not have changed the outcome.
VERDICT A $820,000 Massachusetts settlement was reached.
WHEN A 51-YEAR-OLD WOMAN NOTICED A BULGE in her vagina, she consulted her gynecologist. He determined the cause to be a cystocele and rectocele, and recommended a tension-free vaginal tape–obturator (TVT-O) procedure with anterior and posterior colporrhaphy.
The patient awoke from surgery in severe pain and was told that she had lost a lot of blood. Two weeks later, the physician explained that the stitches, not yet absorbed, were causing an abrasion, and that more vaginal tissue had been removed than planned.
Two more weeks passed, and the patient used a mirror to look at her vagina but could not see the opening. The TVT-O tape had created a ridge of tissue in the anterior vagina, causing severe stenosis. Vaginal dilators were required to expand the vagina. Entrapment of the dorsal clitoral nerve by the TVT-O tape was also discovered. The patient continues to experience dyspareunia and groin pain.
PATIENT’S CLAIM The gynecologist failed to tell her that, 2 months before surgery, the FDA had issued a public health warning about complications associated with transvaginal placement of surgical mesh during prolapse and urinary incontinence repair. Nor was she informed that the defendant had just completed training in TVT-O surgery, was not fully credentialed, and was proctored during the procedure.
PHYSICIAN’S DEFENSE The case was settled before the trial concluded.
VERDICT A $390,000 Virginia settlement was reached.
Lumpectomy, though no mass palpated
A 52-YEAR-OLD WOMAN FOUND A LUMP in her left breast. Her internist ordered mammography, which identified a 2-cm oval, asymmetrical density in the upper inner quadrant of the left breast. The radiologist recommended ultrasonography (US).
The patient consulted a surgical oncologist, who performed fine-needle aspiration. Pathology identified “clusters of malignant cells consistent with carcinoma,” and suggested a confirmatory biopsy. The oncologist recommended lumpectomy and sentinel node biopsy.
On the day of surgery, the patient could not locate the mass. The oncologist testified that he had palpated it. During surgery, gross examination did not show a mass or tumor. Frozen sections of sentinel nodes did not reveal evidence of cancer.
The patient suffered postsurgical seromas and lymphedema. The lymphedema has partially resolved, but causes pain in her left arm and breast.
PATIENT’S CLAIM The surgical oncologist should have performed US before surgery. It was negligent to continue with surgery when there were negative intraoperative findings for cancer or a mass.
PHYSICIAN’S DEFENSE Proper care was provided.
VERDICT A $950,000 Illinois verdict was returned.
Genetic testing fails to identify cystic fibrosis in one twin
AFTER HAVING ONE CHILD with cystic fibrosis (CF), parents underwent genetic testing. Embryos were prepared for in vitro fertilization (IVF) and sent to a genetic-testing laboratory. The lab reported that the embryos were negative for CF. Two embryos were implanted, and the mother gave birth to twins, one of which has CF.
PARENTS’ CLAIM Multiple errors by the genetic-testing laboratory led to an incorrect report on the embryos. The parents claimed wrongful birth.
DEFENDANTS’ DEFENSE The testing laboratory and physician owner argued that amniocentesis should have been performed during the pregnancy to rule out CF.
VERDICT The trial judge denied the use of the amniocentesis defense because an abortion would have been the only option available, and abortion is against the public policy of Tennessee. The court entered summary judgment on liability for the parents.
A $13 million verdict was returned, including $7 million to the parents for emotional distress.
These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.
We want to hear from you! Tell us what you think.
These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.
We want to hear from you! Tell us what you think.
The new year brings refinements to CPT and Medicare codes
Ms. Witt reports no financial relationships relevant to this article.
Among changes to Current Procedural Terminology (CPT) that took effect on January 1 are several of interest to our specialty:
- the addition of “typical” times to the evaluation and management (E/M) codes for same-day admission and discharge
- a new code for bladder injection
- bundling of imaging guidance associated with percutaneous implantation of a neurostimulator electrode array, if performed, using code 64561, Percutaneous implantation of neurostimulator electrode array; sacral nerve (transforaminal placement).
In addition, CPT made it clear that all E/M codes can be reported by qualified nonphysician health-care providers, as well as physicians. As for Medicare, coding for administration of depot medroxyprogesterone acetate (Depo-Provera) has been modified, as has the billing process for interpretation of ultrasonography performed outside of the office.
Because of requirements in the Health Insurance Portability and Accountability Act (HIPAA), insurers were required to accept the new codes and revisions on January 1.
Providers can now characterize their level of service by how long it took to provide
As I mentioned, typical times have been added to the set of observation and inpatient care codes that involve admission and discharge on the same date of service. Until now, these codes did not have a pre-assigned typical time, and the provider had to select the level of service based solely on three key components: history, examination, and medical decision-making. The addition of times allows the provider to select the level of service based on counseling or coordination of care, if that activity dominated the visit.
The typical times are:
- 99234, 40 minutes
- 99235, 50 minutes
- 99236, 55 minutes.
Chemodenervation of the bladder gets its own code
A new code, 52287, cystourethroscopy, with injection(s) for chemodenervation of the bladder, has been added to CPT. This procedure is performed to treat idiopathic overactive bladder that can’t be managed any other way. It typically involves the injection of botulinum. Before January 1, this procedure was reported using codes 52000 and 64614, but this approach represented an inexact match.
Payers will be looking closely at diagnostic coding for this procedure. The most frequently accepted diagnostic codes are:
- 596.51, hypertonicity of bladder
- 596.54, neurogenic bladder NOS
- 596.55, detrusor sphincter dyssynergia
- 596.59, other functional disorder of bladder
- 788.41, urinary frequency.
Because costs will vary, depending on the chemotoxin used, the agent may be reported separately using the descriptive “J” code or another Medicare-designated alphanumeric code, such as J0585, injection of botulinum toxin type A, 1 unit.
Qualified providers now include nonphysicians as well as physicians
CPT has clarified that all E/M codes can be reported not only by physicians but by qualified nonphysicians as well.
CPT also changed wording in each of the codes so that the use of counseling time applies to all providers when counseling dominates the visit. In other words, if a payer allows someone other than a physician to provide and bill for a service, the CPT E/M codes can be used by all providers who qualify and have documented the service. These changes have no effect on the codes themselves.
Please note, however, that registered nurses and licensed practical nurses are not normally recognized as billing providers and will still be restricted to code 99211, Office or other outpatient visit for the evaluation and management of an established patient, that may not require the presence of a physician. Usually, with this code, presenting problems are minimal. Typically, 5 minutes are spent performing or supervising these services. This code is often referred to as the “nurse-only” code.
As a result of this clarification, references to physicians have been removed from CPT code 59300, Episiotomy or vaginal repair, by other than attending. This change signifies that this code may be reported by any qualified provider who did not perform the delivery or was not covering for a physician group who billed for the delivery.
Three new codes for the flu vaccine
Two of the new codes are CPT codes, and the other is for Medicare:
- 90653, Influenza vaccine, inactivated, subunit, adjuvanted, for intramuscular use
- 90672, Influenza virus vaccine, live, for intranasal use
- Q2034, Agriflu.
Keep in mind that the administration of the flu vaccine is reported differently for Medicare, compared with private payers. Administration code G0008 and diagnosis code V04.81 would be reported in conjunction with the appropriate vaccine code for Medicare. CPT requires that code 90471 be reported for administration.
CPT also revised all flu vaccine codes (90655–90660) to include the term “trivalent” to signify that all flu vaccines are made up of three strains of the virus.
Medicare refines billing for MPA administration
When billing for MPA or MPA in combination with estradiol, be aware that Medicare has eliminated the J codes for these drugs, replacing them with a single new code.
The deleted codes are:
- J1051, medroxyprogesterone acetate, 50 mg
- J1055, medroxyprogesterone acetate, 150 mg, for contraceptive use
- J1056, medroxyprogesterone acetate/ estradiol cypionate, 5 mg/25 mg.
The new code is J1050, medroxyprogesterone acetate, 1 mg. To use it, you must indicate the dosage as a quantity. For example, if you injected 150 mg, you would use code J1050 x 150 on the claim. The diagnosis code will indicate the reason for the injection—that is, medical treatment or contraception. In the event that the combination drug is being administered, separate billing of J1000, Injection, depo-estradiol cypionate, up to 5 mg, would need to be reported in addition to J1050.
Medicare has also issued a national policy on Place of Service (POS) billing because the office of the inspector general has found that physicians and other suppliers frequently report an incorrect POS, and Medicare pays more for some sites. Medicare rules for the billing of POS for the professional component of an imaging service are changing, effective April 1, 2013. This rule was postponed from its original date of October 1, 2012. Under this rule, when the professional and technical components of a service are performed in different locations, the appropriate POS to report for the interpretive aspect is the location where the technical component was performed. This change would apply to an ObGyn practice that contracts out for the technical component of an ultrasound but performs the interpretation in the office. In that case, the POS should not be listed as “office” or POS 11, but should match the POS of the imaging contractor.
We want to hear from you! Tell us what you think.
Ms. Witt reports no financial relationships relevant to this article.
Among changes to Current Procedural Terminology (CPT) that took effect on January 1 are several of interest to our specialty:
- the addition of “typical” times to the evaluation and management (E/M) codes for same-day admission and discharge
- a new code for bladder injection
- bundling of imaging guidance associated with percutaneous implantation of a neurostimulator electrode array, if performed, using code 64561, Percutaneous implantation of neurostimulator electrode array; sacral nerve (transforaminal placement).
In addition, CPT made it clear that all E/M codes can be reported by qualified nonphysician health-care providers, as well as physicians. As for Medicare, coding for administration of depot medroxyprogesterone acetate (Depo-Provera) has been modified, as has the billing process for interpretation of ultrasonography performed outside of the office.
Because of requirements in the Health Insurance Portability and Accountability Act (HIPAA), insurers were required to accept the new codes and revisions on January 1.
Providers can now characterize their level of service by how long it took to provide
As I mentioned, typical times have been added to the set of observation and inpatient care codes that involve admission and discharge on the same date of service. Until now, these codes did not have a pre-assigned typical time, and the provider had to select the level of service based solely on three key components: history, examination, and medical decision-making. The addition of times allows the provider to select the level of service based on counseling or coordination of care, if that activity dominated the visit.
The typical times are:
- 99234, 40 minutes
- 99235, 50 minutes
- 99236, 55 minutes.
Chemodenervation of the bladder gets its own code
A new code, 52287, cystourethroscopy, with injection(s) for chemodenervation of the bladder, has been added to CPT. This procedure is performed to treat idiopathic overactive bladder that can’t be managed any other way. It typically involves the injection of botulinum. Before January 1, this procedure was reported using codes 52000 and 64614, but this approach represented an inexact match.
Payers will be looking closely at diagnostic coding for this procedure. The most frequently accepted diagnostic codes are:
- 596.51, hypertonicity of bladder
- 596.54, neurogenic bladder NOS
- 596.55, detrusor sphincter dyssynergia
- 596.59, other functional disorder of bladder
- 788.41, urinary frequency.
Because costs will vary, depending on the chemotoxin used, the agent may be reported separately using the descriptive “J” code or another Medicare-designated alphanumeric code, such as J0585, injection of botulinum toxin type A, 1 unit.
Qualified providers now include nonphysicians as well as physicians
CPT has clarified that all E/M codes can be reported not only by physicians but by qualified nonphysicians as well.
CPT also changed wording in each of the codes so that the use of counseling time applies to all providers when counseling dominates the visit. In other words, if a payer allows someone other than a physician to provide and bill for a service, the CPT E/M codes can be used by all providers who qualify and have documented the service. These changes have no effect on the codes themselves.
Please note, however, that registered nurses and licensed practical nurses are not normally recognized as billing providers and will still be restricted to code 99211, Office or other outpatient visit for the evaluation and management of an established patient, that may not require the presence of a physician. Usually, with this code, presenting problems are minimal. Typically, 5 minutes are spent performing or supervising these services. This code is often referred to as the “nurse-only” code.
As a result of this clarification, references to physicians have been removed from CPT code 59300, Episiotomy or vaginal repair, by other than attending. This change signifies that this code may be reported by any qualified provider who did not perform the delivery or was not covering for a physician group who billed for the delivery.
Three new codes for the flu vaccine
Two of the new codes are CPT codes, and the other is for Medicare:
- 90653, Influenza vaccine, inactivated, subunit, adjuvanted, for intramuscular use
- 90672, Influenza virus vaccine, live, for intranasal use
- Q2034, Agriflu.
Keep in mind that the administration of the flu vaccine is reported differently for Medicare, compared with private payers. Administration code G0008 and diagnosis code V04.81 would be reported in conjunction with the appropriate vaccine code for Medicare. CPT requires that code 90471 be reported for administration.
CPT also revised all flu vaccine codes (90655–90660) to include the term “trivalent” to signify that all flu vaccines are made up of three strains of the virus.
Medicare refines billing for MPA administration
When billing for MPA or MPA in combination with estradiol, be aware that Medicare has eliminated the J codes for these drugs, replacing them with a single new code.
The deleted codes are:
- J1051, medroxyprogesterone acetate, 50 mg
- J1055, medroxyprogesterone acetate, 150 mg, for contraceptive use
- J1056, medroxyprogesterone acetate/ estradiol cypionate, 5 mg/25 mg.
The new code is J1050, medroxyprogesterone acetate, 1 mg. To use it, you must indicate the dosage as a quantity. For example, if you injected 150 mg, you would use code J1050 x 150 on the claim. The diagnosis code will indicate the reason for the injection—that is, medical treatment or contraception. In the event that the combination drug is being administered, separate billing of J1000, Injection, depo-estradiol cypionate, up to 5 mg, would need to be reported in addition to J1050.
Medicare has also issued a national policy on Place of Service (POS) billing because the office of the inspector general has found that physicians and other suppliers frequently report an incorrect POS, and Medicare pays more for some sites. Medicare rules for the billing of POS for the professional component of an imaging service are changing, effective April 1, 2013. This rule was postponed from its original date of October 1, 2012. Under this rule, when the professional and technical components of a service are performed in different locations, the appropriate POS to report for the interpretive aspect is the location where the technical component was performed. This change would apply to an ObGyn practice that contracts out for the technical component of an ultrasound but performs the interpretation in the office. In that case, the POS should not be listed as “office” or POS 11, but should match the POS of the imaging contractor.
We want to hear from you! Tell us what you think.
Ms. Witt reports no financial relationships relevant to this article.
Among changes to Current Procedural Terminology (CPT) that took effect on January 1 are several of interest to our specialty:
- the addition of “typical” times to the evaluation and management (E/M) codes for same-day admission and discharge
- a new code for bladder injection
- bundling of imaging guidance associated with percutaneous implantation of a neurostimulator electrode array, if performed, using code 64561, Percutaneous implantation of neurostimulator electrode array; sacral nerve (transforaminal placement).
In addition, CPT made it clear that all E/M codes can be reported by qualified nonphysician health-care providers, as well as physicians. As for Medicare, coding for administration of depot medroxyprogesterone acetate (Depo-Provera) has been modified, as has the billing process for interpretation of ultrasonography performed outside of the office.
Because of requirements in the Health Insurance Portability and Accountability Act (HIPAA), insurers were required to accept the new codes and revisions on January 1.
Providers can now characterize their level of service by how long it took to provide
As I mentioned, typical times have been added to the set of observation and inpatient care codes that involve admission and discharge on the same date of service. Until now, these codes did not have a pre-assigned typical time, and the provider had to select the level of service based solely on three key components: history, examination, and medical decision-making. The addition of times allows the provider to select the level of service based on counseling or coordination of care, if that activity dominated the visit.
The typical times are:
- 99234, 40 minutes
- 99235, 50 minutes
- 99236, 55 minutes.
Chemodenervation of the bladder gets its own code
A new code, 52287, cystourethroscopy, with injection(s) for chemodenervation of the bladder, has been added to CPT. This procedure is performed to treat idiopathic overactive bladder that can’t be managed any other way. It typically involves the injection of botulinum. Before January 1, this procedure was reported using codes 52000 and 64614, but this approach represented an inexact match.
Payers will be looking closely at diagnostic coding for this procedure. The most frequently accepted diagnostic codes are:
- 596.51, hypertonicity of bladder
- 596.54, neurogenic bladder NOS
- 596.55, detrusor sphincter dyssynergia
- 596.59, other functional disorder of bladder
- 788.41, urinary frequency.
Because costs will vary, depending on the chemotoxin used, the agent may be reported separately using the descriptive “J” code or another Medicare-designated alphanumeric code, such as J0585, injection of botulinum toxin type A, 1 unit.
Qualified providers now include nonphysicians as well as physicians
CPT has clarified that all E/M codes can be reported not only by physicians but by qualified nonphysicians as well.
CPT also changed wording in each of the codes so that the use of counseling time applies to all providers when counseling dominates the visit. In other words, if a payer allows someone other than a physician to provide and bill for a service, the CPT E/M codes can be used by all providers who qualify and have documented the service. These changes have no effect on the codes themselves.
Please note, however, that registered nurses and licensed practical nurses are not normally recognized as billing providers and will still be restricted to code 99211, Office or other outpatient visit for the evaluation and management of an established patient, that may not require the presence of a physician. Usually, with this code, presenting problems are minimal. Typically, 5 minutes are spent performing or supervising these services. This code is often referred to as the “nurse-only” code.
As a result of this clarification, references to physicians have been removed from CPT code 59300, Episiotomy or vaginal repair, by other than attending. This change signifies that this code may be reported by any qualified provider who did not perform the delivery or was not covering for a physician group who billed for the delivery.
Three new codes for the flu vaccine
Two of the new codes are CPT codes, and the other is for Medicare:
- 90653, Influenza vaccine, inactivated, subunit, adjuvanted, for intramuscular use
- 90672, Influenza virus vaccine, live, for intranasal use
- Q2034, Agriflu.
Keep in mind that the administration of the flu vaccine is reported differently for Medicare, compared with private payers. Administration code G0008 and diagnosis code V04.81 would be reported in conjunction with the appropriate vaccine code for Medicare. CPT requires that code 90471 be reported for administration.
CPT also revised all flu vaccine codes (90655–90660) to include the term “trivalent” to signify that all flu vaccines are made up of three strains of the virus.
Medicare refines billing for MPA administration
When billing for MPA or MPA in combination with estradiol, be aware that Medicare has eliminated the J codes for these drugs, replacing them with a single new code.
The deleted codes are:
- J1051, medroxyprogesterone acetate, 50 mg
- J1055, medroxyprogesterone acetate, 150 mg, for contraceptive use
- J1056, medroxyprogesterone acetate/ estradiol cypionate, 5 mg/25 mg.
The new code is J1050, medroxyprogesterone acetate, 1 mg. To use it, you must indicate the dosage as a quantity. For example, if you injected 150 mg, you would use code J1050 x 150 on the claim. The diagnosis code will indicate the reason for the injection—that is, medical treatment or contraception. In the event that the combination drug is being administered, separate billing of J1000, Injection, depo-estradiol cypionate, up to 5 mg, would need to be reported in addition to J1050.
Medicare has also issued a national policy on Place of Service (POS) billing because the office of the inspector general has found that physicians and other suppliers frequently report an incorrect POS, and Medicare pays more for some sites. Medicare rules for the billing of POS for the professional component of an imaging service are changing, effective April 1, 2013. This rule was postponed from its original date of October 1, 2012. Under this rule, when the professional and technical components of a service are performed in different locations, the appropriate POS to report for the interpretive aspect is the location where the technical component was performed. This change would apply to an ObGyn practice that contracts out for the technical component of an ultrasound but performs the interpretation in the office. In that case, the POS should not be listed as “office” or POS 11, but should match the POS of the imaging contractor.
We want to hear from you! Tell us what you think.
Drug interactions with tobacco smoke: Implications for patient care
- Tobacco smokers often are treated with medications that are metabolized by hepatic cytochrome (CYP) 1A2 enzymes. Starting or stopping tobacco smoking may cause drug interactions because polycyclic aromatic hydrocarbons in cigarette smoke induce CYP1A2 enzymes.
- Drugs that are significantly metabolized by CYP1A2 (major substrates) are more likely to be impacted by changes in tobacco smoking compared with minor substrates.
- Induction of hepatic CYP1A2 enzymes may be greater in heavy or moderate smokers compared with light smokers (eg, <10 cigarettes per day).
- Evidence-based approaches for treating tobacco use in health care settings should address the risk of CYP1A2 drug interactions in tobacco smokers and how this impacts their clinical care.
Mrs. C, age 51, experiences exacerbated asthma and difficulty breathing and is admitted to a non-smoking hospital. She also has chronic obstructive pulmonary disease, type 2 diabetes mellitus, hypertension, hypercholesterolemia, hypothyroidism, gastroesophageal reflux disease, overactive bladder, muscle spasms, fibromyalgia, bipolar disorder, insomnia, and nicotine and caffeine dependence. She takes 19 prescribed and over-the-counter medications, drinks up to 8 cups of coffee per day, and smokes 20 to 30 cigarettes per day. In the emergency room, she receives albuterol/ipratropium inhalation therapy to help her breathing and a 21-mg nicotine replacement patch to avoid nicotine withdrawal.
In the United States, 19% of adults smoke cigarettes.1 Heavy tobacco smoking and nicotine dependence are common among psychiatric patients and contribute to higher rates of tobacco-related morbidity and mortality.2 When smokers stop smoking or are admitted to smoke-free facilities and are forced to abstain, nicotine withdrawal symptoms and changes in drug metabolism can develop over several days.3-5
Smokers such as Mrs. C are at risk for cytochrome (CYP) P450 drug interactions when they are admitted to or discharged from a smoke-free facility. Nine of Mrs. C’s medications are substrates of CYP1A2 (acetaminophen, caffeine, cyclobenzaprine, diazepam, duloxetine, melatonin, olanzapine, ondansetron, and zolpidem). When Mrs. C stops smoking while in the hospital, she could experience higher serum concentrations and adverse effects of these medications. If Mrs. C resumes smoking after bring discharged, metabolism and clearance of any medications started while she was hospitalized that are substrates of CYP1A2 enzymes could be increased, which could lead to reduced efficacy and poor clinical outcomes.
Pharmacokinetic effects
Polycyclic aromatic hydrocarbons in tobacco smoke induce hepatic CYP1A1, 1A2, and possibly 2E1 isoenzymes.6-12 CYP1A2 is a hepatic enzyme responsible for metabolizing and eliminating several classes of substrates (eg, drugs, hormones, endogenous compounds, and procarcinogens).6,13 Genetic, epigenetic, and environmental factors such as smoking impact the expression and activity of CYP1A2 and result in large interpatient variability in pharmacokinetic drug interactions.6,12,13 CYP1A2 enzymes can be induced or inhibited by drugs and substances, which can result in decreased or increased serum concentrations of substrates, respectively. When individuals stop smoking and switch to other nicotine products or devices, CYP1A2 induction of hepatic enzymes will revert to normal metabolism over several weeks to a month.10 Besides tobacco smoke, other CYP1A2 inducers include charbroiled food, carbamazepine, omeprazole, phenobarbital, primidone, and rifampin.4,5 Nicotine replacement products—such as gum, inhalers, lozenges, patches, and nasal spray—and nicotine delivery devices such as electronic cigarettes do not induce hepatic CYP1A2 enzymes or cause the same drug interactions as cigarette smoking.
Table 13-11 and Table 23-11 list commonly prescribed CYP1A2 substrates that could be affected by tobacco smoke. There are no specific guidelines for how to assess, monitor, or manage pharmacokinetic drug interactions with tobacco smoke.6-13 Induction of hepatic CYP1A2 enzymes by cigarette smoke may require increased dosages of some psychotropics—such as tricyclic antidepressants, duloxetine, mirtazapine, and some first- and second-generation antipsychotics (SGAs)—to achieve serum concentrations adequate for clinical efficacy. Serum concentrations may increase to toxic levels and result in adverse effects when a person quits smoking cigarettes or if a CYP1A2 inhibitor, such as amlodipine, cimetidine, ciprofloxacin, diclofenac, fluoxetine, fluvoxamine, or nifedipine, is added.5
Table 1
Common major cytochrome P450 (CYP) 1A2 substrates
| Drug | Class |
|---|---|
| Alosetron3,5,6 | Irritable bowel syndrome: serotonin 3 antagonist |
| Aminophylline3,5 | Bronchodilator: theophylline derivative |
| Betaxolol3,5 | β-1 selective adrenergic receptor blocking agent |
| Caffeine3-9 | Stimulant |
| Clomipramine3-11 | Tricyclic antidepressant |
| Clozapine3-10 | Second-generation antipsychotic |
| Cyclobenzaprine3-7 | Skeletal muscle relaxant |
| Doxepin3,7,10,11 | Tricyclic antidepressant |
| Duloxetine3-6 | Serotonin-norepinephrine reuptake inhibitor |
| Estradiol3,5-8 | Estrogen (active) |
| Estrogens: conjugated and estropipate3,5; estrone3,7 | Estrogen (derivatives) |
| Fluvoxamine3,8,9 | Selective serotonin reuptake inhibitor |
| Guanabenz3,5-7 | α-2 adrenergic agonist |
| Mirtazapine3-7 | Antidepressant: α-2 antagonist/serotonin 2A, 2C antagonist |
| Olanzapine3-11 | Second-generation antipsychotic |
| Pimozide3,5,7 | First-generation antipsychotic |
| Propranolol3-11 | β-adrenergic blocker |
| Ramelteon3,5,10 | Melatonin receptor agonist |
| Rasagiline3,5 | Antiparkinson: type B monoamine oxidase inhibitor |
| Riluzole3-7,10 | Glutamate inhibitor |
| Ropinirole3,5-7 | Antiparkinson: dopamine agonist |
| Theophylline3-6,8-11 | Bronchodilator: methylxanthine |
| Thiothixene3,5 | First-generation antipsychotic |
| Trifluoperazine3,5,9 | First-generation antipsychotic |
| Several classes of CYP1A2 substrates are not included and may cause toxicity with smoking cessation or require dosage increases in tobacco smokers (eg, antiarrhythmic, antifungal, antimalarial, antineoplastic, antiretroviral, and anthelmintic agents and the antibiotic quinolone). Clinicians should be most concerned about drugs with a narrow therapeutic index and those that may be toxic with smoking cessation (eg, bleeding from warfarin and clopidogrel; high serum concentrations of caffeine, clozapine, olanzapine, propranolol, and theophylline) | |
Table 2
Common minor cytochrome P450 (CYP) 1A2 substrates
| Drug | Class |
|---|---|
| Acetaminophen3-9 | Analgesic |
| Almotriptan6 | Antimigraine: serotonin 1B, 1D receptor agonist |
| Amitriptyline3-7,9-11 | Tricyclic antidepressant |
| Asenapine9 | Second-generation antipsychotic |
| Carvedilol5-7 | β and α adrenergic blocking activity |
| Chlorpromazine3,4,7-9,11 | First-generation antipsychotic |
| Chlorzoxazone4,7 | Skeletal muscle relaxant |
| Clopidogrel5 | Antiplatelet |
| Desipramine4,7,10,11 | Tricyclic antidepressant |
| Diazepam4,7,9,10 | Benzodiazepine |
| Diclofenac5,7 | Nonsteroidal anti-inflammatory drug |
| Diphenhydramine6 | Antihistamine |
| Febuxostat5 | Xanthine oxidase inhibitor |
| Fluphenazine3,9 | First-generation antipsychotic |
| Frovatriptan3 | Antimigraine: serotonin 1 agonist |
| Haloperidol3,4,6,8,9 | First-generation antipsychotic |
| Imipramine3,4,6-11 | Tricyclic antidepressant |
| Maprotiline6 | Tetracyclic antidepressant |
| Melatonin3,4,6,7 | Sleep-regulating hormone |
| Metoclopramide3 | Antiemetic: prokinetic gastrointestinal agent |
| Nabumetone6 | Nonsteroidal anti-inflammatory drug |
| Naproxen3,4,6,7 | Nonsteroidal anti-inflammatory drug |
| Naratriptan10 | Antimigraine: serotonin 1B, 1D receptor agonist |
| Nicardipine3,7 | Calcium channel blocker |
| Nortriptyline4,6,7,9-11 | Tricyclic antidepressant |
| Ondansetron3,4,6,7 | Antiemetic: serotonin 3 antagonist |
| Palonosetron5 | Antiemetic: serotonin 3 antagonist |
| Perphenazine3,7 | First-generation antipsychotic |
| Progesterone5,7 | Progestin |
| Propofol4,6,7 | General anesthetic |
| Ranitidine5,7 | H2 antagonist |
| Rivastigmine10 | Acetylcholinesterase inhibitor |
| Selegiline6,7 | Antiparkinson: type B monoamine oxidase inhibitor |
| Thioridazine3,4,6 | First-generation antipsychotic |
| Tizanidine3-6 | Skeletal muscle relaxant: α-2 adrenergic agonist |
| Trazodone6,9 | Serotonin reuptake inhibitor and antagonist |
| Triamterene6 | Diuretic: potassium sparing |
| Verapamil3,4,6,7,10 | Calcium channel blocker |
| Warfarin3,4,6-10 | Anticoagulant: coumarin derivative |
| Zileuton3,4,6,7 | Asthma agent: 5-lipoxygenase inhibitor |
| Ziprasidone3,4 | Second-generation antipsychotic |
| Zolmitriptan3,6,7 | Antimigraine: serotonin 1B, 1D receptor agonist |
| Zolpidem4,6,7 | Nonbenzodiazepine hypnotic |
| Several classes of CYP1A2 substrates are not included and may cause toxicity with smoking cessation or require dosage increases in tobacco smokers (eg, antiarrhythmic, antifungal, antimalarial, antineoplastic, antiretroviral and anthelmintic agents and the antibiotic quinolone). Clinicians should be most concerned about drugs with a narrow therapeutic index and those that may be toxic with smoking cessation (eg, bleeding from warfarin and clopidogrel; high serum concentrations of caffeine, clozapine, olanzapine, propranolol, and theophylline) | |
SGA such as clozapine and olanzapine are major substrates of CYP1A2 and dosages may need to be adjusted when smoking status changes, depending on clinical efficacy and adverse effects.10,14,15 Maximum induction of clozapine and olanzapine metabolism may occur with 7 to 12 cigarettes per day and smokers may have 40% to 50% lower serum concentrations compared with nonsmokers.14 When a patient stops smoking, clozapine and olanzapine dosages may need to be reduced by 30% to 40% (eg, a stepwise 10% reduction in daily dose until day 4) to avoid elevated serum concentrations and risk of toxicity symptoms.15
Tobacco smokers can tolerate high daily intake of caffeinated beverages because of increased metabolism and clearance of caffeine, a major substrate of CYP1A2.11 When patients stop smoking, increased caffeine serum concentrations may cause anxiety, irritability, restlessness, insomnia, tremors, palpitations, and tachycardia. Caffeine toxicity also can mimic symptoms of nicotine withdrawal; therefore, smokers should be advised to reduce their caffeine intake by half to avoid adverse effects when they stop smoking.10,11
Adjusting dosing
Factors such as the amount and frequency of tobacco smoking, how quickly CYP1A2 enzymes change when starting and stopping smoking, exposure to secondhand smoke, and other concomitant drugs contribute to variability in pharmacokinetic drug interactions. Heavy smokers (≥30 cigarettes per day) should be closely monitored because variations in drug serum concentrations may be affected significantly by changes in smoking status.4,9,11 Dosage reductions of potentially toxic drugs should be done immediately when a heavy tobacco user stops smoking.10 For CYP1A2 substrates with a narrow therapeutic range, a conservative approach is to reduce the daily dose by 10% per day for several days after smoking cessation.11,16 The impact on drug metabolism may continue for weeks to a month after the person stops smoking; therefore, there may be a delay until CYP1A2 enzymes return to normal hepatic metabolism.4,8,9,15 In most situations, smoking cessation reverses induction of hepatic CYP1A2 enzymes back to normal metabolism and causes serum drug concentrations to increase.10 Because secondhand smoke induces hepatic CYP1A2 enzymes, those exposed to smoke may have changes in drug metabolism due to environmental smoke exposure.11
Tobacco smokers who take medications and hormones that are metabolized by CYP1A2 enzymes should be closely monitored because dosage adjustments may be necessary when they start or stop smoking cigarettes. An assessment of CYP drug interactions and routine monitoring of efficacy and/or toxicity should be done to avoid potential adverse effects from medications and to determine if changes in dosages and disease state management are required.
Related Resources
- Rx for Change. Drug interactions with smoking. http://smokingcessationleadership.ucsf.edu/interactions.pdf.
- Fiore MC, Baker TB. Treating smokers in the health care setting. N Engl J Med. 2011;365(13):1222-1231.
Drug Brand Names
- Albuterol/ipratropium • Combivent
- Almotriptan • Axert
- Alosetron • Lotronex
- Aminophylline • Phyllocontin, Truphylline
- Amitriptyline • Elavil
- Amlodipine • Norvasc
- Asenapine • Saphris
- Betaxolol • Kerlone
- Carbamazepine • Carbatrol, Tegretol
- Carvedilol • Coreg
- Chlorpromazine • Thorazine
- Chlorzoxazone • Parafon Forte
- Cimetidine • Tagamet
- Ciprofloxacin • Cipro
- Clomipramine • Anafranil
- Clopidogrel • Plavix
- Clozapine • Clozaril
- Cyclobenzaprine • Flexeril
- Desipramine • Norpramin
- Diazepam • Valium
- Diclofenac • Voltaren
- Diphenhydramine • Benadryl
- Doxepin • Silenor, Sinequan
- Duloxetine • Cymbalta
- Estradiol • Estrace
- Estrogens (conjugated) • Cenestin, Premarin
- Estropipate • Ogen
- Febuxostat • Uloric
- Fluoxetine • Prozac
- Fluphenazine • Prolixin
- Fluvoxamine • Luvox
- Frovatriptan • Frova
- Guanabenz • Wytensin
- Haloperidol • Haldol
- Imipramine • Tofranil
- Maprotiline • Ludiomil
- Metoclopramide • Reglan
- Mirtazapine • Remeron
- Nabumetone • Relafen
- Naratriptan • Amerge
- Nicardipine • Cardene
- Nifedipine • Adalat, Procardia
- Nortriptyline • Aventyl, Pamelor
- Olanzapine • Zyprexa
- Omeprazole • Prilosec
- Ondansetron • Zofran
- Palonosetron • Aloxi
- Perphenazine • Trilafon
- Pimozide • Orap
- Primidone • Mysoline
- Progesterone • Prometrium
- Propofol • Diprivan
- Propranolol • Inderal
- Ramelteon • Rozerem
- Ranitidine • Zantac
- Rasagiline • Azilect
- Rifampin • Rifadin, Rimactane
- Riluzole • Rilutek
- Rivastigmine • Exelon
- Ropinirole • Requip
- Selegiline • Eldepryl, EMSAM, others
- Theophylline • Elixophyllin
- Thioridazine • Mellaril
- Thiothixene • Navane
- Tizanidine • Zanaflex
- Trazodone • Desyrel, Oleptro
- Triamterene • Dyrenium
- Trifluoperazine • Stelazine
- Verapamil • Calan, Verelan
- Warfarin • Coumadin, Jantoven
- Zileuton • Zyflo
- Ziprasidone • Geodon
- Zolmitriptan • Zomig
- Zolpidem • Ambien, Edluar
Disclosure
Ms. Fankhauser reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Centers for Disease Control and Prevention (CDC). Vital signs: current cigarette smoking among adults aged ≥18 years—United States 2005-2010. MMWR Morb Mortal Wkly Rep. 2011;60(35):1207-1212.
2. Ziedonis D, Hitsman B, Beckham JC, et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res. 2008;10(12):1691-1715.
3. Choe JY. Drug actions and interactions. New York NY: McGraw-Hill Medical; 2011.
4. Tatro DS. Drug interaction facts. St. Louis MO: Wolters Kluwer Health; 2011.
5. Lacy CF, Armstrong LL, Goldman MP, et al. eds. Drug information handbook, 20th ed. Hudson, OH: Lexicomp; 2011.
6. Zhou SF, Yang LP, Zhou ZW, et al. Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2. AAPS J. 2009;11(3):481-494.
7. Rendic S. Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002;34(1-2):83-448.
8. Zevin S, Benowitz NL. Drug interactions with tobacco smoking. An update. Clin Pharmacokinet. 1999;36(6):425-438.
9. Desai HD, Seabolt J, Jann MW. Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective. CNS Drugs. 2001;15(6):469-494.
10. Schaffer SD, Yoon S, Zadezensky I. A review of smoking cessation: potentially risky effects on prescribed medications. J Clin Nurs. 2009;18(11):1533-1540.
11. Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm. 2007;64(18):1917-1921.
12. Plowchalk DR, Yeo KR. Prediction of drug clearance in a smoking population: modeling the impact of variable cigarette consumption on the induction of CYP1A2. Eur J Pharmacol. 2012;68(6):951-960.
13. Faber MS, Jetter A, Fuhr U. Assessment of CYP1A2 activity in clinical practice: why how, and when? Basic Clin Pharmacol Toxicol. 2005;97(3):125-134.
14. Haslemo T, Eikeseth PH, Tanum L, et al. The effect of variable cigarette consumption on the interaction with clozapine and olanzapine. Eur J Clin Pharmacol. 2006;62(12):1049-1053.
15. Lowe EJ, Ackman ML. Impact of tobacco smoking cessation on stable clozapine or olanzapine treatment. Ann Pharmacother. 2010;44(4):727-732.
16. Faber MS, Fuhr U. Time response of cytochrome P4501A2 activity on cessation of heavy smoking. Clin Pharmacol Ther. 2004;76(2):178-184.
Martha P. Fankhauser, MS Pharm, FASHP, BCPP
Clinical Professor, Department of Pharmacy Practice and Science, College of Pharmacy and Pharmacotherapy Specialist, Arizona Smokers' Helpline, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ
Vicki L. Ellingrod, PharmD, BCPP, FCCP
Series Editor
Martha P. Fankhauser, MS Pharm, FASHP, BCPP
Clinical Professor, Department of Pharmacy Practice and Science, College of Pharmacy and Pharmacotherapy Specialist, Arizona Smokers' Helpline, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ
Vicki L. Ellingrod, PharmD, BCPP, FCCP
Series Editor
Martha P. Fankhauser, MS Pharm, FASHP, BCPP
Clinical Professor, Department of Pharmacy Practice and Science, College of Pharmacy and Pharmacotherapy Specialist, Arizona Smokers' Helpline, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ
Vicki L. Ellingrod, PharmD, BCPP, FCCP
Series Editor
- Tobacco smokers often are treated with medications that are metabolized by hepatic cytochrome (CYP) 1A2 enzymes. Starting or stopping tobacco smoking may cause drug interactions because polycyclic aromatic hydrocarbons in cigarette smoke induce CYP1A2 enzymes.
- Drugs that are significantly metabolized by CYP1A2 (major substrates) are more likely to be impacted by changes in tobacco smoking compared with minor substrates.
- Induction of hepatic CYP1A2 enzymes may be greater in heavy or moderate smokers compared with light smokers (eg, <10 cigarettes per day).
- Evidence-based approaches for treating tobacco use in health care settings should address the risk of CYP1A2 drug interactions in tobacco smokers and how this impacts their clinical care.
Mrs. C, age 51, experiences exacerbated asthma and difficulty breathing and is admitted to a non-smoking hospital. She also has chronic obstructive pulmonary disease, type 2 diabetes mellitus, hypertension, hypercholesterolemia, hypothyroidism, gastroesophageal reflux disease, overactive bladder, muscle spasms, fibromyalgia, bipolar disorder, insomnia, and nicotine and caffeine dependence. She takes 19 prescribed and over-the-counter medications, drinks up to 8 cups of coffee per day, and smokes 20 to 30 cigarettes per day. In the emergency room, she receives albuterol/ipratropium inhalation therapy to help her breathing and a 21-mg nicotine replacement patch to avoid nicotine withdrawal.
In the United States, 19% of adults smoke cigarettes.1 Heavy tobacco smoking and nicotine dependence are common among psychiatric patients and contribute to higher rates of tobacco-related morbidity and mortality.2 When smokers stop smoking or are admitted to smoke-free facilities and are forced to abstain, nicotine withdrawal symptoms and changes in drug metabolism can develop over several days.3-5
Smokers such as Mrs. C are at risk for cytochrome (CYP) P450 drug interactions when they are admitted to or discharged from a smoke-free facility. Nine of Mrs. C’s medications are substrates of CYP1A2 (acetaminophen, caffeine, cyclobenzaprine, diazepam, duloxetine, melatonin, olanzapine, ondansetron, and zolpidem). When Mrs. C stops smoking while in the hospital, she could experience higher serum concentrations and adverse effects of these medications. If Mrs. C resumes smoking after bring discharged, metabolism and clearance of any medications started while she was hospitalized that are substrates of CYP1A2 enzymes could be increased, which could lead to reduced efficacy and poor clinical outcomes.
Pharmacokinetic effects
Polycyclic aromatic hydrocarbons in tobacco smoke induce hepatic CYP1A1, 1A2, and possibly 2E1 isoenzymes.6-12 CYP1A2 is a hepatic enzyme responsible for metabolizing and eliminating several classes of substrates (eg, drugs, hormones, endogenous compounds, and procarcinogens).6,13 Genetic, epigenetic, and environmental factors such as smoking impact the expression and activity of CYP1A2 and result in large interpatient variability in pharmacokinetic drug interactions.6,12,13 CYP1A2 enzymes can be induced or inhibited by drugs and substances, which can result in decreased or increased serum concentrations of substrates, respectively. When individuals stop smoking and switch to other nicotine products or devices, CYP1A2 induction of hepatic enzymes will revert to normal metabolism over several weeks to a month.10 Besides tobacco smoke, other CYP1A2 inducers include charbroiled food, carbamazepine, omeprazole, phenobarbital, primidone, and rifampin.4,5 Nicotine replacement products—such as gum, inhalers, lozenges, patches, and nasal spray—and nicotine delivery devices such as electronic cigarettes do not induce hepatic CYP1A2 enzymes or cause the same drug interactions as cigarette smoking.
Table 13-11 and Table 23-11 list commonly prescribed CYP1A2 substrates that could be affected by tobacco smoke. There are no specific guidelines for how to assess, monitor, or manage pharmacokinetic drug interactions with tobacco smoke.6-13 Induction of hepatic CYP1A2 enzymes by cigarette smoke may require increased dosages of some psychotropics—such as tricyclic antidepressants, duloxetine, mirtazapine, and some first- and second-generation antipsychotics (SGAs)—to achieve serum concentrations adequate for clinical efficacy. Serum concentrations may increase to toxic levels and result in adverse effects when a person quits smoking cigarettes or if a CYP1A2 inhibitor, such as amlodipine, cimetidine, ciprofloxacin, diclofenac, fluoxetine, fluvoxamine, or nifedipine, is added.5
Table 1
Common major cytochrome P450 (CYP) 1A2 substrates
| Drug | Class |
|---|---|
| Alosetron3,5,6 | Irritable bowel syndrome: serotonin 3 antagonist |
| Aminophylline3,5 | Bronchodilator: theophylline derivative |
| Betaxolol3,5 | β-1 selective adrenergic receptor blocking agent |
| Caffeine3-9 | Stimulant |
| Clomipramine3-11 | Tricyclic antidepressant |
| Clozapine3-10 | Second-generation antipsychotic |
| Cyclobenzaprine3-7 | Skeletal muscle relaxant |
| Doxepin3,7,10,11 | Tricyclic antidepressant |
| Duloxetine3-6 | Serotonin-norepinephrine reuptake inhibitor |
| Estradiol3,5-8 | Estrogen (active) |
| Estrogens: conjugated and estropipate3,5; estrone3,7 | Estrogen (derivatives) |
| Fluvoxamine3,8,9 | Selective serotonin reuptake inhibitor |
| Guanabenz3,5-7 | α-2 adrenergic agonist |
| Mirtazapine3-7 | Antidepressant: α-2 antagonist/serotonin 2A, 2C antagonist |
| Olanzapine3-11 | Second-generation antipsychotic |
| Pimozide3,5,7 | First-generation antipsychotic |
| Propranolol3-11 | β-adrenergic blocker |
| Ramelteon3,5,10 | Melatonin receptor agonist |
| Rasagiline3,5 | Antiparkinson: type B monoamine oxidase inhibitor |
| Riluzole3-7,10 | Glutamate inhibitor |
| Ropinirole3,5-7 | Antiparkinson: dopamine agonist |
| Theophylline3-6,8-11 | Bronchodilator: methylxanthine |
| Thiothixene3,5 | First-generation antipsychotic |
| Trifluoperazine3,5,9 | First-generation antipsychotic |
| Several classes of CYP1A2 substrates are not included and may cause toxicity with smoking cessation or require dosage increases in tobacco smokers (eg, antiarrhythmic, antifungal, antimalarial, antineoplastic, antiretroviral, and anthelmintic agents and the antibiotic quinolone). Clinicians should be most concerned about drugs with a narrow therapeutic index and those that may be toxic with smoking cessation (eg, bleeding from warfarin and clopidogrel; high serum concentrations of caffeine, clozapine, olanzapine, propranolol, and theophylline) | |
Table 2
Common minor cytochrome P450 (CYP) 1A2 substrates
| Drug | Class |
|---|---|
| Acetaminophen3-9 | Analgesic |
| Almotriptan6 | Antimigraine: serotonin 1B, 1D receptor agonist |
| Amitriptyline3-7,9-11 | Tricyclic antidepressant |
| Asenapine9 | Second-generation antipsychotic |
| Carvedilol5-7 | β and α adrenergic blocking activity |
| Chlorpromazine3,4,7-9,11 | First-generation antipsychotic |
| Chlorzoxazone4,7 | Skeletal muscle relaxant |
| Clopidogrel5 | Antiplatelet |
| Desipramine4,7,10,11 | Tricyclic antidepressant |
| Diazepam4,7,9,10 | Benzodiazepine |
| Diclofenac5,7 | Nonsteroidal anti-inflammatory drug |
| Diphenhydramine6 | Antihistamine |
| Febuxostat5 | Xanthine oxidase inhibitor |
| Fluphenazine3,9 | First-generation antipsychotic |
| Frovatriptan3 | Antimigraine: serotonin 1 agonist |
| Haloperidol3,4,6,8,9 | First-generation antipsychotic |
| Imipramine3,4,6-11 | Tricyclic antidepressant |
| Maprotiline6 | Tetracyclic antidepressant |
| Melatonin3,4,6,7 | Sleep-regulating hormone |
| Metoclopramide3 | Antiemetic: prokinetic gastrointestinal agent |
| Nabumetone6 | Nonsteroidal anti-inflammatory drug |
| Naproxen3,4,6,7 | Nonsteroidal anti-inflammatory drug |
| Naratriptan10 | Antimigraine: serotonin 1B, 1D receptor agonist |
| Nicardipine3,7 | Calcium channel blocker |
| Nortriptyline4,6,7,9-11 | Tricyclic antidepressant |
| Ondansetron3,4,6,7 | Antiemetic: serotonin 3 antagonist |
| Palonosetron5 | Antiemetic: serotonin 3 antagonist |
| Perphenazine3,7 | First-generation antipsychotic |
| Progesterone5,7 | Progestin |
| Propofol4,6,7 | General anesthetic |
| Ranitidine5,7 | H2 antagonist |
| Rivastigmine10 | Acetylcholinesterase inhibitor |
| Selegiline6,7 | Antiparkinson: type B monoamine oxidase inhibitor |
| Thioridazine3,4,6 | First-generation antipsychotic |
| Tizanidine3-6 | Skeletal muscle relaxant: α-2 adrenergic agonist |
| Trazodone6,9 | Serotonin reuptake inhibitor and antagonist |
| Triamterene6 | Diuretic: potassium sparing |
| Verapamil3,4,6,7,10 | Calcium channel blocker |
| Warfarin3,4,6-10 | Anticoagulant: coumarin derivative |
| Zileuton3,4,6,7 | Asthma agent: 5-lipoxygenase inhibitor |
| Ziprasidone3,4 | Second-generation antipsychotic |
| Zolmitriptan3,6,7 | Antimigraine: serotonin 1B, 1D receptor agonist |
| Zolpidem4,6,7 | Nonbenzodiazepine hypnotic |
| Several classes of CYP1A2 substrates are not included and may cause toxicity with smoking cessation or require dosage increases in tobacco smokers (eg, antiarrhythmic, antifungal, antimalarial, antineoplastic, antiretroviral and anthelmintic agents and the antibiotic quinolone). Clinicians should be most concerned about drugs with a narrow therapeutic index and those that may be toxic with smoking cessation (eg, bleeding from warfarin and clopidogrel; high serum concentrations of caffeine, clozapine, olanzapine, propranolol, and theophylline) | |
SGA such as clozapine and olanzapine are major substrates of CYP1A2 and dosages may need to be adjusted when smoking status changes, depending on clinical efficacy and adverse effects.10,14,15 Maximum induction of clozapine and olanzapine metabolism may occur with 7 to 12 cigarettes per day and smokers may have 40% to 50% lower serum concentrations compared with nonsmokers.14 When a patient stops smoking, clozapine and olanzapine dosages may need to be reduced by 30% to 40% (eg, a stepwise 10% reduction in daily dose until day 4) to avoid elevated serum concentrations and risk of toxicity symptoms.15
Tobacco smokers can tolerate high daily intake of caffeinated beverages because of increased metabolism and clearance of caffeine, a major substrate of CYP1A2.11 When patients stop smoking, increased caffeine serum concentrations may cause anxiety, irritability, restlessness, insomnia, tremors, palpitations, and tachycardia. Caffeine toxicity also can mimic symptoms of nicotine withdrawal; therefore, smokers should be advised to reduce their caffeine intake by half to avoid adverse effects when they stop smoking.10,11
Adjusting dosing
Factors such as the amount and frequency of tobacco smoking, how quickly CYP1A2 enzymes change when starting and stopping smoking, exposure to secondhand smoke, and other concomitant drugs contribute to variability in pharmacokinetic drug interactions. Heavy smokers (≥30 cigarettes per day) should be closely monitored because variations in drug serum concentrations may be affected significantly by changes in smoking status.4,9,11 Dosage reductions of potentially toxic drugs should be done immediately when a heavy tobacco user stops smoking.10 For CYP1A2 substrates with a narrow therapeutic range, a conservative approach is to reduce the daily dose by 10% per day for several days after smoking cessation.11,16 The impact on drug metabolism may continue for weeks to a month after the person stops smoking; therefore, there may be a delay until CYP1A2 enzymes return to normal hepatic metabolism.4,8,9,15 In most situations, smoking cessation reverses induction of hepatic CYP1A2 enzymes back to normal metabolism and causes serum drug concentrations to increase.10 Because secondhand smoke induces hepatic CYP1A2 enzymes, those exposed to smoke may have changes in drug metabolism due to environmental smoke exposure.11
Tobacco smokers who take medications and hormones that are metabolized by CYP1A2 enzymes should be closely monitored because dosage adjustments may be necessary when they start or stop smoking cigarettes. An assessment of CYP drug interactions and routine monitoring of efficacy and/or toxicity should be done to avoid potential adverse effects from medications and to determine if changes in dosages and disease state management are required.
Related Resources
- Rx for Change. Drug interactions with smoking. http://smokingcessationleadership.ucsf.edu/interactions.pdf.
- Fiore MC, Baker TB. Treating smokers in the health care setting. N Engl J Med. 2011;365(13):1222-1231.
Drug Brand Names
- Albuterol/ipratropium • Combivent
- Almotriptan • Axert
- Alosetron • Lotronex
- Aminophylline • Phyllocontin, Truphylline
- Amitriptyline • Elavil
- Amlodipine • Norvasc
- Asenapine • Saphris
- Betaxolol • Kerlone
- Carbamazepine • Carbatrol, Tegretol
- Carvedilol • Coreg
- Chlorpromazine • Thorazine
- Chlorzoxazone • Parafon Forte
- Cimetidine • Tagamet
- Ciprofloxacin • Cipro
- Clomipramine • Anafranil
- Clopidogrel • Plavix
- Clozapine • Clozaril
- Cyclobenzaprine • Flexeril
- Desipramine • Norpramin
- Diazepam • Valium
- Diclofenac • Voltaren
- Diphenhydramine • Benadryl
- Doxepin • Silenor, Sinequan
- Duloxetine • Cymbalta
- Estradiol • Estrace
- Estrogens (conjugated) • Cenestin, Premarin
- Estropipate • Ogen
- Febuxostat • Uloric
- Fluoxetine • Prozac
- Fluphenazine • Prolixin
- Fluvoxamine • Luvox
- Frovatriptan • Frova
- Guanabenz • Wytensin
- Haloperidol • Haldol
- Imipramine • Tofranil
- Maprotiline • Ludiomil
- Metoclopramide • Reglan
- Mirtazapine • Remeron
- Nabumetone • Relafen
- Naratriptan • Amerge
- Nicardipine • Cardene
- Nifedipine • Adalat, Procardia
- Nortriptyline • Aventyl, Pamelor
- Olanzapine • Zyprexa
- Omeprazole • Prilosec
- Ondansetron • Zofran
- Palonosetron • Aloxi
- Perphenazine • Trilafon
- Pimozide • Orap
- Primidone • Mysoline
- Progesterone • Prometrium
- Propofol • Diprivan
- Propranolol • Inderal
- Ramelteon • Rozerem
- Ranitidine • Zantac
- Rasagiline • Azilect
- Rifampin • Rifadin, Rimactane
- Riluzole • Rilutek
- Rivastigmine • Exelon
- Ropinirole • Requip
- Selegiline • Eldepryl, EMSAM, others
- Theophylline • Elixophyllin
- Thioridazine • Mellaril
- Thiothixene • Navane
- Tizanidine • Zanaflex
- Trazodone • Desyrel, Oleptro
- Triamterene • Dyrenium
- Trifluoperazine • Stelazine
- Verapamil • Calan, Verelan
- Warfarin • Coumadin, Jantoven
- Zileuton • Zyflo
- Ziprasidone • Geodon
- Zolmitriptan • Zomig
- Zolpidem • Ambien, Edluar
Disclosure
Ms. Fankhauser reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
- Tobacco smokers often are treated with medications that are metabolized by hepatic cytochrome (CYP) 1A2 enzymes. Starting or stopping tobacco smoking may cause drug interactions because polycyclic aromatic hydrocarbons in cigarette smoke induce CYP1A2 enzymes.
- Drugs that are significantly metabolized by CYP1A2 (major substrates) are more likely to be impacted by changes in tobacco smoking compared with minor substrates.
- Induction of hepatic CYP1A2 enzymes may be greater in heavy or moderate smokers compared with light smokers (eg, <10 cigarettes per day).
- Evidence-based approaches for treating tobacco use in health care settings should address the risk of CYP1A2 drug interactions in tobacco smokers and how this impacts their clinical care.
Mrs. C, age 51, experiences exacerbated asthma and difficulty breathing and is admitted to a non-smoking hospital. She also has chronic obstructive pulmonary disease, type 2 diabetes mellitus, hypertension, hypercholesterolemia, hypothyroidism, gastroesophageal reflux disease, overactive bladder, muscle spasms, fibromyalgia, bipolar disorder, insomnia, and nicotine and caffeine dependence. She takes 19 prescribed and over-the-counter medications, drinks up to 8 cups of coffee per day, and smokes 20 to 30 cigarettes per day. In the emergency room, she receives albuterol/ipratropium inhalation therapy to help her breathing and a 21-mg nicotine replacement patch to avoid nicotine withdrawal.
In the United States, 19% of adults smoke cigarettes.1 Heavy tobacco smoking and nicotine dependence are common among psychiatric patients and contribute to higher rates of tobacco-related morbidity and mortality.2 When smokers stop smoking or are admitted to smoke-free facilities and are forced to abstain, nicotine withdrawal symptoms and changes in drug metabolism can develop over several days.3-5
Smokers such as Mrs. C are at risk for cytochrome (CYP) P450 drug interactions when they are admitted to or discharged from a smoke-free facility. Nine of Mrs. C’s medications are substrates of CYP1A2 (acetaminophen, caffeine, cyclobenzaprine, diazepam, duloxetine, melatonin, olanzapine, ondansetron, and zolpidem). When Mrs. C stops smoking while in the hospital, she could experience higher serum concentrations and adverse effects of these medications. If Mrs. C resumes smoking after bring discharged, metabolism and clearance of any medications started while she was hospitalized that are substrates of CYP1A2 enzymes could be increased, which could lead to reduced efficacy and poor clinical outcomes.
Pharmacokinetic effects
Polycyclic aromatic hydrocarbons in tobacco smoke induce hepatic CYP1A1, 1A2, and possibly 2E1 isoenzymes.6-12 CYP1A2 is a hepatic enzyme responsible for metabolizing and eliminating several classes of substrates (eg, drugs, hormones, endogenous compounds, and procarcinogens).6,13 Genetic, epigenetic, and environmental factors such as smoking impact the expression and activity of CYP1A2 and result in large interpatient variability in pharmacokinetic drug interactions.6,12,13 CYP1A2 enzymes can be induced or inhibited by drugs and substances, which can result in decreased or increased serum concentrations of substrates, respectively. When individuals stop smoking and switch to other nicotine products or devices, CYP1A2 induction of hepatic enzymes will revert to normal metabolism over several weeks to a month.10 Besides tobacco smoke, other CYP1A2 inducers include charbroiled food, carbamazepine, omeprazole, phenobarbital, primidone, and rifampin.4,5 Nicotine replacement products—such as gum, inhalers, lozenges, patches, and nasal spray—and nicotine delivery devices such as electronic cigarettes do not induce hepatic CYP1A2 enzymes or cause the same drug interactions as cigarette smoking.
Table 13-11 and Table 23-11 list commonly prescribed CYP1A2 substrates that could be affected by tobacco smoke. There are no specific guidelines for how to assess, monitor, or manage pharmacokinetic drug interactions with tobacco smoke.6-13 Induction of hepatic CYP1A2 enzymes by cigarette smoke may require increased dosages of some psychotropics—such as tricyclic antidepressants, duloxetine, mirtazapine, and some first- and second-generation antipsychotics (SGAs)—to achieve serum concentrations adequate for clinical efficacy. Serum concentrations may increase to toxic levels and result in adverse effects when a person quits smoking cigarettes or if a CYP1A2 inhibitor, such as amlodipine, cimetidine, ciprofloxacin, diclofenac, fluoxetine, fluvoxamine, or nifedipine, is added.5
Table 1
Common major cytochrome P450 (CYP) 1A2 substrates
| Drug | Class |
|---|---|
| Alosetron3,5,6 | Irritable bowel syndrome: serotonin 3 antagonist |
| Aminophylline3,5 | Bronchodilator: theophylline derivative |
| Betaxolol3,5 | β-1 selective adrenergic receptor blocking agent |
| Caffeine3-9 | Stimulant |
| Clomipramine3-11 | Tricyclic antidepressant |
| Clozapine3-10 | Second-generation antipsychotic |
| Cyclobenzaprine3-7 | Skeletal muscle relaxant |
| Doxepin3,7,10,11 | Tricyclic antidepressant |
| Duloxetine3-6 | Serotonin-norepinephrine reuptake inhibitor |
| Estradiol3,5-8 | Estrogen (active) |
| Estrogens: conjugated and estropipate3,5; estrone3,7 | Estrogen (derivatives) |
| Fluvoxamine3,8,9 | Selective serotonin reuptake inhibitor |
| Guanabenz3,5-7 | α-2 adrenergic agonist |
| Mirtazapine3-7 | Antidepressant: α-2 antagonist/serotonin 2A, 2C antagonist |
| Olanzapine3-11 | Second-generation antipsychotic |
| Pimozide3,5,7 | First-generation antipsychotic |
| Propranolol3-11 | β-adrenergic blocker |
| Ramelteon3,5,10 | Melatonin receptor agonist |
| Rasagiline3,5 | Antiparkinson: type B monoamine oxidase inhibitor |
| Riluzole3-7,10 | Glutamate inhibitor |
| Ropinirole3,5-7 | Antiparkinson: dopamine agonist |
| Theophylline3-6,8-11 | Bronchodilator: methylxanthine |
| Thiothixene3,5 | First-generation antipsychotic |
| Trifluoperazine3,5,9 | First-generation antipsychotic |
| Several classes of CYP1A2 substrates are not included and may cause toxicity with smoking cessation or require dosage increases in tobacco smokers (eg, antiarrhythmic, antifungal, antimalarial, antineoplastic, antiretroviral, and anthelmintic agents and the antibiotic quinolone). Clinicians should be most concerned about drugs with a narrow therapeutic index and those that may be toxic with smoking cessation (eg, bleeding from warfarin and clopidogrel; high serum concentrations of caffeine, clozapine, olanzapine, propranolol, and theophylline) | |
Table 2
Common minor cytochrome P450 (CYP) 1A2 substrates
| Drug | Class |
|---|---|
| Acetaminophen3-9 | Analgesic |
| Almotriptan6 | Antimigraine: serotonin 1B, 1D receptor agonist |
| Amitriptyline3-7,9-11 | Tricyclic antidepressant |
| Asenapine9 | Second-generation antipsychotic |
| Carvedilol5-7 | β and α adrenergic blocking activity |
| Chlorpromazine3,4,7-9,11 | First-generation antipsychotic |
| Chlorzoxazone4,7 | Skeletal muscle relaxant |
| Clopidogrel5 | Antiplatelet |
| Desipramine4,7,10,11 | Tricyclic antidepressant |
| Diazepam4,7,9,10 | Benzodiazepine |
| Diclofenac5,7 | Nonsteroidal anti-inflammatory drug |
| Diphenhydramine6 | Antihistamine |
| Febuxostat5 | Xanthine oxidase inhibitor |
| Fluphenazine3,9 | First-generation antipsychotic |
| Frovatriptan3 | Antimigraine: serotonin 1 agonist |
| Haloperidol3,4,6,8,9 | First-generation antipsychotic |
| Imipramine3,4,6-11 | Tricyclic antidepressant |
| Maprotiline6 | Tetracyclic antidepressant |
| Melatonin3,4,6,7 | Sleep-regulating hormone |
| Metoclopramide3 | Antiemetic: prokinetic gastrointestinal agent |
| Nabumetone6 | Nonsteroidal anti-inflammatory drug |
| Naproxen3,4,6,7 | Nonsteroidal anti-inflammatory drug |
| Naratriptan10 | Antimigraine: serotonin 1B, 1D receptor agonist |
| Nicardipine3,7 | Calcium channel blocker |
| Nortriptyline4,6,7,9-11 | Tricyclic antidepressant |
| Ondansetron3,4,6,7 | Antiemetic: serotonin 3 antagonist |
| Palonosetron5 | Antiemetic: serotonin 3 antagonist |
| Perphenazine3,7 | First-generation antipsychotic |
| Progesterone5,7 | Progestin |
| Propofol4,6,7 | General anesthetic |
| Ranitidine5,7 | H2 antagonist |
| Rivastigmine10 | Acetylcholinesterase inhibitor |
| Selegiline6,7 | Antiparkinson: type B monoamine oxidase inhibitor |
| Thioridazine3,4,6 | First-generation antipsychotic |
| Tizanidine3-6 | Skeletal muscle relaxant: α-2 adrenergic agonist |
| Trazodone6,9 | Serotonin reuptake inhibitor and antagonist |
| Triamterene6 | Diuretic: potassium sparing |
| Verapamil3,4,6,7,10 | Calcium channel blocker |
| Warfarin3,4,6-10 | Anticoagulant: coumarin derivative |
| Zileuton3,4,6,7 | Asthma agent: 5-lipoxygenase inhibitor |
| Ziprasidone3,4 | Second-generation antipsychotic |
| Zolmitriptan3,6,7 | Antimigraine: serotonin 1B, 1D receptor agonist |
| Zolpidem4,6,7 | Nonbenzodiazepine hypnotic |
| Several classes of CYP1A2 substrates are not included and may cause toxicity with smoking cessation or require dosage increases in tobacco smokers (eg, antiarrhythmic, antifungal, antimalarial, antineoplastic, antiretroviral and anthelmintic agents and the antibiotic quinolone). Clinicians should be most concerned about drugs with a narrow therapeutic index and those that may be toxic with smoking cessation (eg, bleeding from warfarin and clopidogrel; high serum concentrations of caffeine, clozapine, olanzapine, propranolol, and theophylline) | |
SGA such as clozapine and olanzapine are major substrates of CYP1A2 and dosages may need to be adjusted when smoking status changes, depending on clinical efficacy and adverse effects.10,14,15 Maximum induction of clozapine and olanzapine metabolism may occur with 7 to 12 cigarettes per day and smokers may have 40% to 50% lower serum concentrations compared with nonsmokers.14 When a patient stops smoking, clozapine and olanzapine dosages may need to be reduced by 30% to 40% (eg, a stepwise 10% reduction in daily dose until day 4) to avoid elevated serum concentrations and risk of toxicity symptoms.15
Tobacco smokers can tolerate high daily intake of caffeinated beverages because of increased metabolism and clearance of caffeine, a major substrate of CYP1A2.11 When patients stop smoking, increased caffeine serum concentrations may cause anxiety, irritability, restlessness, insomnia, tremors, palpitations, and tachycardia. Caffeine toxicity also can mimic symptoms of nicotine withdrawal; therefore, smokers should be advised to reduce their caffeine intake by half to avoid adverse effects when they stop smoking.10,11
Adjusting dosing
Factors such as the amount and frequency of tobacco smoking, how quickly CYP1A2 enzymes change when starting and stopping smoking, exposure to secondhand smoke, and other concomitant drugs contribute to variability in pharmacokinetic drug interactions. Heavy smokers (≥30 cigarettes per day) should be closely monitored because variations in drug serum concentrations may be affected significantly by changes in smoking status.4,9,11 Dosage reductions of potentially toxic drugs should be done immediately when a heavy tobacco user stops smoking.10 For CYP1A2 substrates with a narrow therapeutic range, a conservative approach is to reduce the daily dose by 10% per day for several days after smoking cessation.11,16 The impact on drug metabolism may continue for weeks to a month after the person stops smoking; therefore, there may be a delay until CYP1A2 enzymes return to normal hepatic metabolism.4,8,9,15 In most situations, smoking cessation reverses induction of hepatic CYP1A2 enzymes back to normal metabolism and causes serum drug concentrations to increase.10 Because secondhand smoke induces hepatic CYP1A2 enzymes, those exposed to smoke may have changes in drug metabolism due to environmental smoke exposure.11
Tobacco smokers who take medications and hormones that are metabolized by CYP1A2 enzymes should be closely monitored because dosage adjustments may be necessary when they start or stop smoking cigarettes. An assessment of CYP drug interactions and routine monitoring of efficacy and/or toxicity should be done to avoid potential adverse effects from medications and to determine if changes in dosages and disease state management are required.
Related Resources
- Rx for Change. Drug interactions with smoking. http://smokingcessationleadership.ucsf.edu/interactions.pdf.
- Fiore MC, Baker TB. Treating smokers in the health care setting. N Engl J Med. 2011;365(13):1222-1231.
Drug Brand Names
- Albuterol/ipratropium • Combivent
- Almotriptan • Axert
- Alosetron • Lotronex
- Aminophylline • Phyllocontin, Truphylline
- Amitriptyline • Elavil
- Amlodipine • Norvasc
- Asenapine • Saphris
- Betaxolol • Kerlone
- Carbamazepine • Carbatrol, Tegretol
- Carvedilol • Coreg
- Chlorpromazine • Thorazine
- Chlorzoxazone • Parafon Forte
- Cimetidine • Tagamet
- Ciprofloxacin • Cipro
- Clomipramine • Anafranil
- Clopidogrel • Plavix
- Clozapine • Clozaril
- Cyclobenzaprine • Flexeril
- Desipramine • Norpramin
- Diazepam • Valium
- Diclofenac • Voltaren
- Diphenhydramine • Benadryl
- Doxepin • Silenor, Sinequan
- Duloxetine • Cymbalta
- Estradiol • Estrace
- Estrogens (conjugated) • Cenestin, Premarin
- Estropipate • Ogen
- Febuxostat • Uloric
- Fluoxetine • Prozac
- Fluphenazine • Prolixin
- Fluvoxamine • Luvox
- Frovatriptan • Frova
- Guanabenz • Wytensin
- Haloperidol • Haldol
- Imipramine • Tofranil
- Maprotiline • Ludiomil
- Metoclopramide • Reglan
- Mirtazapine • Remeron
- Nabumetone • Relafen
- Naratriptan • Amerge
- Nicardipine • Cardene
- Nifedipine • Adalat, Procardia
- Nortriptyline • Aventyl, Pamelor
- Olanzapine • Zyprexa
- Omeprazole • Prilosec
- Ondansetron • Zofran
- Palonosetron • Aloxi
- Perphenazine • Trilafon
- Pimozide • Orap
- Primidone • Mysoline
- Progesterone • Prometrium
- Propofol • Diprivan
- Propranolol • Inderal
- Ramelteon • Rozerem
- Ranitidine • Zantac
- Rasagiline • Azilect
- Rifampin • Rifadin, Rimactane
- Riluzole • Rilutek
- Rivastigmine • Exelon
- Ropinirole • Requip
- Selegiline • Eldepryl, EMSAM, others
- Theophylline • Elixophyllin
- Thioridazine • Mellaril
- Thiothixene • Navane
- Tizanidine • Zanaflex
- Trazodone • Desyrel, Oleptro
- Triamterene • Dyrenium
- Trifluoperazine • Stelazine
- Verapamil • Calan, Verelan
- Warfarin • Coumadin, Jantoven
- Zileuton • Zyflo
- Ziprasidone • Geodon
- Zolmitriptan • Zomig
- Zolpidem • Ambien, Edluar
Disclosure
Ms. Fankhauser reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Centers for Disease Control and Prevention (CDC). Vital signs: current cigarette smoking among adults aged ≥18 years—United States 2005-2010. MMWR Morb Mortal Wkly Rep. 2011;60(35):1207-1212.
2. Ziedonis D, Hitsman B, Beckham JC, et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res. 2008;10(12):1691-1715.
3. Choe JY. Drug actions and interactions. New York NY: McGraw-Hill Medical; 2011.
4. Tatro DS. Drug interaction facts. St. Louis MO: Wolters Kluwer Health; 2011.
5. Lacy CF, Armstrong LL, Goldman MP, et al. eds. Drug information handbook, 20th ed. Hudson, OH: Lexicomp; 2011.
6. Zhou SF, Yang LP, Zhou ZW, et al. Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2. AAPS J. 2009;11(3):481-494.
7. Rendic S. Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002;34(1-2):83-448.
8. Zevin S, Benowitz NL. Drug interactions with tobacco smoking. An update. Clin Pharmacokinet. 1999;36(6):425-438.
9. Desai HD, Seabolt J, Jann MW. Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective. CNS Drugs. 2001;15(6):469-494.
10. Schaffer SD, Yoon S, Zadezensky I. A review of smoking cessation: potentially risky effects on prescribed medications. J Clin Nurs. 2009;18(11):1533-1540.
11. Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm. 2007;64(18):1917-1921.
12. Plowchalk DR, Yeo KR. Prediction of drug clearance in a smoking population: modeling the impact of variable cigarette consumption on the induction of CYP1A2. Eur J Pharmacol. 2012;68(6):951-960.
13. Faber MS, Jetter A, Fuhr U. Assessment of CYP1A2 activity in clinical practice: why how, and when? Basic Clin Pharmacol Toxicol. 2005;97(3):125-134.
14. Haslemo T, Eikeseth PH, Tanum L, et al. The effect of variable cigarette consumption on the interaction with clozapine and olanzapine. Eur J Clin Pharmacol. 2006;62(12):1049-1053.
15. Lowe EJ, Ackman ML. Impact of tobacco smoking cessation on stable clozapine or olanzapine treatment. Ann Pharmacother. 2010;44(4):727-732.
16. Faber MS, Fuhr U. Time response of cytochrome P4501A2 activity on cessation of heavy smoking. Clin Pharmacol Ther. 2004;76(2):178-184.
1. Centers for Disease Control and Prevention (CDC). Vital signs: current cigarette smoking among adults aged ≥18 years—United States 2005-2010. MMWR Morb Mortal Wkly Rep. 2011;60(35):1207-1212.
2. Ziedonis D, Hitsman B, Beckham JC, et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res. 2008;10(12):1691-1715.
3. Choe JY. Drug actions and interactions. New York NY: McGraw-Hill Medical; 2011.
4. Tatro DS. Drug interaction facts. St. Louis MO: Wolters Kluwer Health; 2011.
5. Lacy CF, Armstrong LL, Goldman MP, et al. eds. Drug information handbook, 20th ed. Hudson, OH: Lexicomp; 2011.
6. Zhou SF, Yang LP, Zhou ZW, et al. Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2. AAPS J. 2009;11(3):481-494.
7. Rendic S. Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002;34(1-2):83-448.
8. Zevin S, Benowitz NL. Drug interactions with tobacco smoking. An update. Clin Pharmacokinet. 1999;36(6):425-438.
9. Desai HD, Seabolt J, Jann MW. Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective. CNS Drugs. 2001;15(6):469-494.
10. Schaffer SD, Yoon S, Zadezensky I. A review of smoking cessation: potentially risky effects on prescribed medications. J Clin Nurs. 2009;18(11):1533-1540.
11. Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm. 2007;64(18):1917-1921.
12. Plowchalk DR, Yeo KR. Prediction of drug clearance in a smoking population: modeling the impact of variable cigarette consumption on the induction of CYP1A2. Eur J Pharmacol. 2012;68(6):951-960.
13. Faber MS, Jetter A, Fuhr U. Assessment of CYP1A2 activity in clinical practice: why how, and when? Basic Clin Pharmacol Toxicol. 2005;97(3):125-134.
14. Haslemo T, Eikeseth PH, Tanum L, et al. The effect of variable cigarette consumption on the interaction with clozapine and olanzapine. Eur J Clin Pharmacol. 2006;62(12):1049-1053.
15. Lowe EJ, Ackman ML. Impact of tobacco smoking cessation on stable clozapine or olanzapine treatment. Ann Pharmacother. 2010;44(4):727-732.
16. Faber MS, Fuhr U. Time response of cytochrome P4501A2 activity on cessation of heavy smoking. Clin Pharmacol Ther. 2004;76(2):178-184.