Articles

No significant difference in combination therapy vs ICS alone

In 2013, a Cochrane review analyzed the risk of mortality and nonfatal serious adverse events in patients treated with the LABA salmeterol in combination with ICS, compared with patients receiving the same dose of ICS alone.¹ The review included 35 RCTs of moderate quality with 13,447 adolescents and adults and 5 RCTs with 1862 children. Patients had all stages of asthma; mean study duration was 34 weeks in adult trials and 15 weeks in trials of children.

Seven deaths from all causes occurred in both the salmeterol-plus-ICS group and the ICS-alone group (35 trials, N=13,447; Peto odds ratio [OR]=0.90; 95% confidence interval [CI], 0.31-2.6). No deaths in children and no asthma-related deaths occurred in any study participants (40 trials, N=15,309).

Adults treated with ICS alone showed no significant difference from adults receiving combination therapy in the frequency of serious adverse events (defined as life threatening, requiring hospitalization or prolongation of existing hospitalization, or resulting in persistent or significant disability or incapacity). Adults on ICS had 21 events per 1000 compared with 24 per 1000 in adults on combination treatment (35 trials, N=13,447; Peto OR=1.2; 95% CI, 0.91-1.4).

Asthma-related serious adverse events were reported in 29 of 6986 adults in the combination group and 23 of 6461 in the ICS-alone group, a nonsignificant difference (35 trials, N=13,447; Peto OR=1.1; 95% CI, 0.65-1.9).

Only one serious asthma-related adverse event occurred in each group of children (ICS- and combination-treated); (5 trials, N=1862; Peto OR=0.99; 95% CI, 0.6-16). Because the number of events was so small and the results were so imprecise, a relative increase in all-cause mortality or nonfatal adverse events can’t be completely ruled out.

Inconsistent dosages mar trials that show more catastrophic events

A systematic review of 7 RCTs with 7253 asthmatic patients compared LABA plus ICS or ICS alone at various doses. All of the trials included at least one catastrophic event, defined as an asthma-related intubation or death.² The mean ages of the patients varied from 11 to 48 years, and the length of the studies from 12 to 52 weeks. The risk of catastrophic events was greater in the LABA plus ICS groups than ICS alone (OR=3.7; 95% CI, 1.4-9.6).

Only one of the 7 trials was included in the 2013 Cochrane review. The others were excluded because the control groups used different doses of ICS than the LABA-plus-ICS groups. In one trial, for example, the ICS group used 4 times the dose of budesonide used in the LABA-plus-ICS group. The difference in outcomes may therefore reflect the variation in ICS dose rather than the presence or absence of LABA.

Because of these conflicting results, the US Food and Drug Administration has mandated continued evaluation of LABAs by manufacturers.³ Five clinical trials that are multinational, randomized, double-blind, and lasting at least 6 months will evaluate the safety of LABAs plus fixed-dose ICS compared with fixed-dose ICS alone. A total of 6200 children and 46,800 adults will be enrolled in the studies, whose results should be available in 2017.

No significant difference in combination therapy vs ICS alone

In 2013, a Cochrane review analyzed the risk of mortality and nonfatal serious adverse events in patients treated with the LABA salmeterol in combination with ICS, compared with patients receiving the same dose of ICS alone.¹ The review included 35 RCTs of moderate quality with 13,447 adolescents and adults and 5 RCTs with 1862 children. Patients had all stages of asthma; mean study duration was 34 weeks in adult trials and 15 weeks in trials of children.

Seven deaths from all causes occurred in both the salmeterol-plus-ICS group and the ICS-alone group (35 trials, N=13,447; Peto odds ratio [OR]=0.90; 95% confidence interval [CI], 0.31-2.6). No deaths in children and no asthma-related deaths occurred in any study participants (40 trials, N=15,309).

Adults treated with ICS alone showed no significant difference from adults receiving combination therapy in the frequency of serious adverse events (defined as life threatening, requiring hospitalization or prolongation of existing hospitalization, or resulting in persistent or significant disability or incapacity). Adults on ICS had 21 events per 1000 compared with 24 per 1000 in adults on combination treatment (35 trials, N=13,447; Peto OR=1.2; 95% CI, 0.91-1.4).

Asthma-related serious adverse events were reported in 29 of 6986 adults in the combination group and 23 of 6461 in the ICS-alone group, a nonsignificant difference (35 trials, N=13,447; Peto OR=1.1; 95% CI, 0.65-1.9).

Only one serious asthma-related adverse event occurred in each group of children (ICS- and combination-treated); (5 trials, N=1862; Peto OR=0.99; 95% CI, 0.6-16). Because the number of events was so small and the results were so imprecise, a relative increase in all-cause mortality or nonfatal adverse events can’t be completely ruled out.

Inconsistent dosages mar trials that show more catastrophic events

A systematic review of 7 RCTs with 7253 asthmatic patients compared LABA plus ICS or ICS alone at various doses. All of the trials included at least one catastrophic event, defined as an asthma-related intubation or death.² The mean ages of the patients varied from 11 to 48 years, and the length of the studies from 12 to 52 weeks. The risk of catastrophic events was greater in the LABA plus ICS groups than ICS alone (OR=3.7; 95% CI, 1.4-9.6).

Only one of the 7 trials was included in the 2013 Cochrane review. The others were excluded because the control groups used different doses of ICS than the LABA-plus-ICS groups. In one trial, for example, the ICS group used 4 times the dose of budesonide used in the LABA-plus-ICS group. The difference in outcomes may therefore reflect the variation in ICS dose rather than the presence or absence of LABA.

Because of these conflicting results, the US Food and Drug Administration has mandated continued evaluation of LABAs by manufacturers.³ Five clinical trials that are multinational, randomized, double-blind, and lasting at least 6 months will evaluate the safety of LABAs plus fixed-dose ICS compared with fixed-dose ICS alone. A total of 6200 children and 46,800 adults will be enrolled in the studies, whose results should be available in 2017.

No significant difference in combination therapy vs ICS alone

In 2013, a Cochrane review analyzed the risk of mortality and nonfatal serious adverse events in patients treated with the LABA salmeterol in combination with ICS, compared with patients receiving the same dose of ICS alone.¹ The review included 35 RCTs of moderate quality with 13,447 adolescents and adults and 5 RCTs with 1862 children. Patients had all stages of asthma; mean study duration was 34 weeks in adult trials and 15 weeks in trials of children.

Seven deaths from all causes occurred in both the salmeterol-plus-ICS group and the ICS-alone group (35 trials, N=13,447; Peto odds ratio [OR]=0.90; 95% confidence interval [CI], 0.31-2.6). No deaths in children and no asthma-related deaths occurred in any study participants (40 trials, N=15,309).

Adults treated with ICS alone showed no significant difference from adults receiving combination therapy in the frequency of serious adverse events (defined as life threatening, requiring hospitalization or prolongation of existing hospitalization, or resulting in persistent or significant disability or incapacity). Adults on ICS had 21 events per 1000 compared with 24 per 1000 in adults on combination treatment (35 trials, N=13,447; Peto OR=1.2; 95% CI, 0.91-1.4).

Asthma-related serious adverse events were reported in 29 of 6986 adults in the combination group and 23 of 6461 in the ICS-alone group, a nonsignificant difference (35 trials, N=13,447; Peto OR=1.1; 95% CI, 0.65-1.9).

Only one serious asthma-related adverse event occurred in each group of children (ICS- and combination-treated); (5 trials, N=1862; Peto OR=0.99; 95% CI, 0.6-16). Because the number of events was so small and the results were so imprecise, a relative increase in all-cause mortality or nonfatal adverse events can’t be completely ruled out.

Inconsistent dosages mar trials that show more catastrophic events

A systematic review of 7 RCTs with 7253 asthmatic patients compared LABA plus ICS or ICS alone at various doses. All of the trials included at least one catastrophic event, defined as an asthma-related intubation or death.² The mean ages of the patients varied from 11 to 48 years, and the length of the studies from 12 to 52 weeks. The risk of catastrophic events was greater in the LABA plus ICS groups than ICS alone (OR=3.7; 95% CI, 1.4-9.6).

Only one of the 7 trials was included in the 2013 Cochrane review. The others were excluded because the control groups used different doses of ICS than the LABA-plus-ICS groups. In one trial, for example, the ICS group used 4 times the dose of budesonide used in the LABA-plus-ICS group. The difference in outcomes may therefore reflect the variation in ICS dose rather than the presence or absence of LABA.

Because of these conflicting results, the US Food and Drug Administration has mandated continued evaluation of LABAs by manufacturers.³ Five clinical trials that are multinational, randomized, double-blind, and lasting at least 6 months will evaluate the safety of LABAs plus fixed-dose ICS compared with fixed-dose ICS alone. A total of 6200 children and 46,800 adults will be enrolled in the studies, whose results should be available in 2017.

A 22-year-old woman with a history of attention-deficit/hyperactivity disorder and childhood asthma came to the emergency department (ED) for treatment of a cramping, substernal, pleuritic chest pain she’d had for a week and the feeling of a “lump in her throat” that made it difficult and painful for her to swallow. The patient’s vital signs were normal and her substernal chest pain was reproducible with palpation. An anteroposterior (AP) chest x-ray (CXR) was unremarkable.

A “GI cocktail” (lidocaine, Mylanta and Donnatal), ketorolac, morphine, and lorazepam were administered in the ED, but did not provide the patient with any relief. She was admitted to the hospital to rule out acute coronary syndrome and was kept NPO overnight. A repeat CXR with posteroanterior (PA) and lateral views was also obtained (FIGURE 1A AND 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The PA and lateral view CXRs revealed the presence of retrosternal air, suggesting the patient had pneumomediastinum. A computed tomography (CT) scan of the chest also showed retrosternal air (FIGURE 2A AND 2B, arrows) and confirmed this diagnosis. To rule out esophageal perforation, the team ordered Gastrografin and barium swallow studies. The patient was kept NPO until both studies were confirmed to be negative.

Patients with pneumomediastinum will report retrosternal, pleuritic pain and may also have difficulty swallowing.

Pneumomediastinum—the presence of free air in the mediastinum—can develop spontaneously (as was the case with our patient) or in response to trauma. Common causes include respiratory diseases such as asthma, and trauma to the esophagus secondary to mechanical ventilation, endoscopy, and excessive vomiting.¹ Other possible causes include respiratory infections, foreign body aspiration, recent dental extraction, diabetic ketoacidosis, esophageal perforation, barotrauma (due to activities such as flying or scuba diving), and use of illicit drugs.¹

Patients with pneumomediastinum often complain of retrosternal, pleuritic pain that radiates to their back, shoulders, and arms. They may also have difficulty swallowing (globus pharyngeus), a nasal voice, and/or dyspnea. Physical findings can include subcutaneous emphysema in the neck and supraclavicular fossa as manifested by Hamman’s sign (a precordial “crunching” sound heard during systole), a fever, and distended neck veins.¹

Differential diagnosis includes inflammatory conditions

The differential diagnosis for pneumomediastinum includes pericarditis, mediastinitis, Boerhaave syndrome, and acute coronary syndrome.

Pericarditis. In a patient with inflammation of the pericardium, you would hear reduced heart sounds and observe electrocardiogram (EKG) changes (eg, diffuse ST elevation in acute pericarditis). These signs typically would not be present in a patient with pneumomediastinum.¹

Mediastinitis. Patients with mediastinitis—inflammation of the mediastinum—are more likely to have hypotension and shock.¹

Boerhaave syndrome, or spontaneous esophageal perforation, has a similar presentation to pneumomediastinum but is more likely to be accompanied by hypotension and shock. Additionally, there would be extravasation of the contrast agent during swallow studies.²

Acute coronary syndrome is also part of the differential. However, in ACS, you would see ST changes on the patient’s EKG and elevated cardiac enzymes.¹

Lateral x-rays are especially useful in making the diagnosis

Diagnosis is made by CXR and/or chest CT. On a CXR, retrosternal air is best seen in the lateral projection. Small amounts of air can appear as linear lucencies outlining mediastinal contours. This air can be seen under the skin, surrounding the pericardium, around the pulmonary and/or aortic vasculature, and/or between the parietal pleura and diaphragm.² A pleural effusion—particularly on the patient’s left side—should raise concern for esophageal perforation.

For most patients, rest and pain control are key

Because pneumomediastinum is generally a self-limiting condition, patients who don’t have severe symptoms, such as respiratory distress or signs of inflammation, should be observed for 2 days, managed with rest and pain control, and discharged home.

If severe symptoms or inflammatory signs are present, a Gastrografin swallow study is recommended to rule out esophageal perforation. If the result of this test is abnormal, a follow-up study with barium is recommended.³ Gastrografin swallow studies are the preferred initial study.³ A barium swallow study is more sensitive, but has a higher risk of causing pneumomediastinitis if an esophageal perforation is present.²

If the swallow study reveals a perforation, surgical decompression and antibiotics may be necessary.^1,4,5

Our patient received subsequent serial CXRs that showed improvement in pneumomediastinum. Once our patient’s pain was well controlled with oral nonsteroidal anti-inflammatory drugs, she was discharged home after a 3-day hospitalization with close follow-up. One week later, she had no further complaints and her pain had almost entirely resolved.

CORRESPONDENCE
Breanna Gawrys, DO, Fort Belvoir Community Hospital Family Medicine Residency, 9300 DeWitt Loop, Fort Belvoir, VA 22060; [email protected]

A 22-year-old woman with a history of attention-deficit/hyperactivity disorder and childhood asthma came to the emergency department (ED) for treatment of a cramping, substernal, pleuritic chest pain she’d had for a week and the feeling of a “lump in her throat” that made it difficult and painful for her to swallow. The patient’s vital signs were normal and her substernal chest pain was reproducible with palpation. An anteroposterior (AP) chest x-ray (CXR) was unremarkable.

A “GI cocktail” (lidocaine, Mylanta and Donnatal), ketorolac, morphine, and lorazepam were administered in the ED, but did not provide the patient with any relief. She was admitted to the hospital to rule out acute coronary syndrome and was kept NPO overnight. A repeat CXR with posteroanterior (PA) and lateral views was also obtained (FIGURE 1A AND 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The PA and lateral view CXRs revealed the presence of retrosternal air, suggesting the patient had pneumomediastinum. A computed tomography (CT) scan of the chest also showed retrosternal air (FIGURE 2A AND 2B, arrows) and confirmed this diagnosis. To rule out esophageal perforation, the team ordered Gastrografin and barium swallow studies. The patient was kept NPO until both studies were confirmed to be negative.

Patients with pneumomediastinum will report retrosternal, pleuritic pain and may also have difficulty swallowing.

Pneumomediastinum—the presence of free air in the mediastinum—can develop spontaneously (as was the case with our patient) or in response to trauma. Common causes include respiratory diseases such as asthma, and trauma to the esophagus secondary to mechanical ventilation, endoscopy, and excessive vomiting.¹ Other possible causes include respiratory infections, foreign body aspiration, recent dental extraction, diabetic ketoacidosis, esophageal perforation, barotrauma (due to activities such as flying or scuba diving), and use of illicit drugs.¹

Patients with pneumomediastinum often complain of retrosternal, pleuritic pain that radiates to their back, shoulders, and arms. They may also have difficulty swallowing (globus pharyngeus), a nasal voice, and/or dyspnea. Physical findings can include subcutaneous emphysema in the neck and supraclavicular fossa as manifested by Hamman’s sign (a precordial “crunching” sound heard during systole), a fever, and distended neck veins.¹

Differential diagnosis includes inflammatory conditions

The differential diagnosis for pneumomediastinum includes pericarditis, mediastinitis, Boerhaave syndrome, and acute coronary syndrome.

Pericarditis. In a patient with inflammation of the pericardium, you would hear reduced heart sounds and observe electrocardiogram (EKG) changes (eg, diffuse ST elevation in acute pericarditis). These signs typically would not be present in a patient with pneumomediastinum.¹

Mediastinitis. Patients with mediastinitis—inflammation of the mediastinum—are more likely to have hypotension and shock.¹

Boerhaave syndrome, or spontaneous esophageal perforation, has a similar presentation to pneumomediastinum but is more likely to be accompanied by hypotension and shock. Additionally, there would be extravasation of the contrast agent during swallow studies.²

Acute coronary syndrome is also part of the differential. However, in ACS, you would see ST changes on the patient’s EKG and elevated cardiac enzymes.¹

Lateral x-rays are especially useful in making the diagnosis

Diagnosis is made by CXR and/or chest CT. On a CXR, retrosternal air is best seen in the lateral projection. Small amounts of air can appear as linear lucencies outlining mediastinal contours. This air can be seen under the skin, surrounding the pericardium, around the pulmonary and/or aortic vasculature, and/or between the parietal pleura and diaphragm.² A pleural effusion—particularly on the patient’s left side—should raise concern for esophageal perforation.

For most patients, rest and pain control are key

Because pneumomediastinum is generally a self-limiting condition, patients who don’t have severe symptoms, such as respiratory distress or signs of inflammation, should be observed for 2 days, managed with rest and pain control, and discharged home.

If severe symptoms or inflammatory signs are present, a Gastrografin swallow study is recommended to rule out esophageal perforation. If the result of this test is abnormal, a follow-up study with barium is recommended.³ Gastrografin swallow studies are the preferred initial study.³ A barium swallow study is more sensitive, but has a higher risk of causing pneumomediastinitis if an esophageal perforation is present.²

If the swallow study reveals a perforation, surgical decompression and antibiotics may be necessary.^1,4,5

Our patient received subsequent serial CXRs that showed improvement in pneumomediastinum. Once our patient’s pain was well controlled with oral nonsteroidal anti-inflammatory drugs, she was discharged home after a 3-day hospitalization with close follow-up. One week later, she had no further complaints and her pain had almost entirely resolved.

CORRESPONDENCE
Breanna Gawrys, DO, Fort Belvoir Community Hospital Family Medicine Residency, 9300 DeWitt Loop, Fort Belvoir, VA 22060; [email protected]

A 22-year-old woman with a history of attention-deficit/hyperactivity disorder and childhood asthma came to the emergency department (ED) for treatment of a cramping, substernal, pleuritic chest pain she’d had for a week and the feeling of a “lump in her throat” that made it difficult and painful for her to swallow. The patient’s vital signs were normal and her substernal chest pain was reproducible with palpation. An anteroposterior (AP) chest x-ray (CXR) was unremarkable.

A “GI cocktail” (lidocaine, Mylanta and Donnatal), ketorolac, morphine, and lorazepam were administered in the ED, but did not provide the patient with any relief. She was admitted to the hospital to rule out acute coronary syndrome and was kept NPO overnight. A repeat CXR with posteroanterior (PA) and lateral views was also obtained (FIGURE 1A AND 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The PA and lateral view CXRs revealed the presence of retrosternal air, suggesting the patient had pneumomediastinum. A computed tomography (CT) scan of the chest also showed retrosternal air (FIGURE 2A AND 2B, arrows) and confirmed this diagnosis. To rule out esophageal perforation, the team ordered Gastrografin and barium swallow studies. The patient was kept NPO until both studies were confirmed to be negative.

Patients with pneumomediastinum will report retrosternal, pleuritic pain and may also have difficulty swallowing.

Pneumomediastinum—the presence of free air in the mediastinum—can develop spontaneously (as was the case with our patient) or in response to trauma. Common causes include respiratory diseases such as asthma, and trauma to the esophagus secondary to mechanical ventilation, endoscopy, and excessive vomiting.¹ Other possible causes include respiratory infections, foreign body aspiration, recent dental extraction, diabetic ketoacidosis, esophageal perforation, barotrauma (due to activities such as flying or scuba diving), and use of illicit drugs.¹

Patients with pneumomediastinum often complain of retrosternal, pleuritic pain that radiates to their back, shoulders, and arms. They may also have difficulty swallowing (globus pharyngeus), a nasal voice, and/or dyspnea. Physical findings can include subcutaneous emphysema in the neck and supraclavicular fossa as manifested by Hamman’s sign (a precordial “crunching” sound heard during systole), a fever, and distended neck veins.¹

Differential diagnosis includes inflammatory conditions

The differential diagnosis for pneumomediastinum includes pericarditis, mediastinitis, Boerhaave syndrome, and acute coronary syndrome.

Pericarditis. In a patient with inflammation of the pericardium, you would hear reduced heart sounds and observe electrocardiogram (EKG) changes (eg, diffuse ST elevation in acute pericarditis). These signs typically would not be present in a patient with pneumomediastinum.¹

Mediastinitis. Patients with mediastinitis—inflammation of the mediastinum—are more likely to have hypotension and shock.¹

Boerhaave syndrome, or spontaneous esophageal perforation, has a similar presentation to pneumomediastinum but is more likely to be accompanied by hypotension and shock. Additionally, there would be extravasation of the contrast agent during swallow studies.²

Acute coronary syndrome is also part of the differential. However, in ACS, you would see ST changes on the patient’s EKG and elevated cardiac enzymes.¹

Lateral x-rays are especially useful in making the diagnosis

Diagnosis is made by CXR and/or chest CT. On a CXR, retrosternal air is best seen in the lateral projection. Small amounts of air can appear as linear lucencies outlining mediastinal contours. This air can be seen under the skin, surrounding the pericardium, around the pulmonary and/or aortic vasculature, and/or between the parietal pleura and diaphragm.² A pleural effusion—particularly on the patient’s left side—should raise concern for esophageal perforation.

For most patients, rest and pain control are key

Because pneumomediastinum is generally a self-limiting condition, patients who don’t have severe symptoms, such as respiratory distress or signs of inflammation, should be observed for 2 days, managed with rest and pain control, and discharged home.

If severe symptoms or inflammatory signs are present, a Gastrografin swallow study is recommended to rule out esophageal perforation. If the result of this test is abnormal, a follow-up study with barium is recommended.³ Gastrografin swallow studies are the preferred initial study.³ A barium swallow study is more sensitive, but has a higher risk of causing pneumomediastinitis if an esophageal perforation is present.²

If the swallow study reveals a perforation, surgical decompression and antibiotics may be necessary.^1,4,5

Our patient received subsequent serial CXRs that showed improvement in pneumomediastinum. Once our patient’s pain was well controlled with oral nonsteroidal anti-inflammatory drugs, she was discharged home after a 3-day hospitalization with close follow-up. One week later, she had no further complaints and her pain had almost entirely resolved.

CORRESPONDENCE
Breanna Gawrys, DO, Fort Belvoir Community Hospital Family Medicine Residency, 9300 DeWitt Loop, Fort Belvoir, VA 22060; [email protected]

THE CASE

A 21-year-old college student was referred to us by the counseling center at our university for a psychiatric evaluation after 11 psychotherapy sessions over 3 months had failed to reduce her feelings of anxiety and panic.

During our evaluation, the patient described feeling “not quite right” for many months. She had been experiencing mental fogginess, fatigue, and worsening concentration/ memory. Her anxiety, which had been gradually increasing, was the result of being unsure about her gait. She first noticed this while walking down some bleachers; she felt dizzy, was afraid of falling, and couldn’t walk down without assistance. All episodes of “panic” occurred in situations where she experienced disequilibrium, unsteady gait, and fear of falling. She grew fearful of driving or going anywhere without assistance.

The patient had celiac disease that was well controlled with a gluten-free diet. She had no personal or family psychiatric history and no history of substance abuse.

THE DIAGNOSIS

Physical exam and lab studies, including a complete blood count, comprehensive metabolic panel, and thyrotropin and folate levels, were normal. Her homocysteine level was 11.8 μmol/L (reference range, 5.4-11.9 μmol/L) and vitamin B₁₂ level was 292 pg/mL (reference range, 200-1100 pg/mL). Her lab report included a note that read, “Although the reference range for vitamin B₁₂ is 200 to 1100 pg/mL, it has been reported that between 5% and 10% of patients with values between 200 and 400 pg/mL may experience neuropsychiatric and hematologic abnormalities due to occult B₁₂ deficiency; <1% of patients with values >400 pg/mL will have symptoms.”

Based on this vitamin B₁₂ level, the patient’s symptoms, and her borderline high homocysteine level, we diagnosed vitamin B₁₂ deficiency.

DISCUSSION

There are no recommendations by the US Preventive Services Task Force or any other major US medical society for routine vitamin B₁₂ screening.¹ In Canada, the Medical Services Commission of the British Columbia Ministry of Health recommends B₁₂ screening for patients who present with macrocytic anemia or unexplained neurologic symptoms (eg, paresthesia, numbness, poor motor coordination, memory lapses, or cognitive or personality changes).²

Vitamin B₁₂ deficiency can be caused by numerous conditions, including those that cause malabsorption (such as gastric bypass). It can also be caused by diseases such as human immunodeficiency virus infection or Crohn’s disease, long-term adherence to a vegetarian or vegan diet, or by any other lack of dietary intake.¹ The condition can cause hematologic-related signs and symptoms such as megaloblastic anemia, fatigue, and syncope. It also can have neurologic manifestations, including paresthesia, weakness, motor disturbances (including gait abnormalities), vision loss, and a wide range of cognitive and behavioral changes.¹ Anemia is uncommon because since 1998, the US Food and Drug Administration has required fortification of all enriched grain and cereal products with folic acid; thus, vitamin B₁₂ deficiency may proceed without anemia revealing its presence.¹

A controversial topic. Vitamin B₁₂ deficiency is a complicated and controversial subject. Specifically, there is uncertainty about the clinical importance of lower serum levels of vitamin B₁₂ (200-400 pg/mL), their impact on well-being, and the need for treatment. In addition to measuring a patient’s serum B₁₂ level, testing a second biomarker (such as homocysteine or methylmalonic acid) can be helpful in establishing a diagnosis of B₁₂ deficiency.¹ Levels of each of these are elevated in patients with B₁₂ deficiency.¹

Some evidence suggests B₁₂ supplementation may improve symptoms of depression and anxiety.

Although vitamin B₁₂ deficiency has been well studied in older patients,³ little has been published about the condition in young adults. National Health and Nutrition Examination Survey (NHANES) data from 2000 to 2004 shows that almost 40% of people ages 19 to 30 years have a B₁₂ level <400 pg/mL.¹ How many of these individuals are at risk of complications of B₁₂ deficiency is unknown.

B₁₂ supplementation might improve depression, anxiety

B₁₂ supplementation is inexpensive and has no significant adverse effects.¹ It can be administered orally, parenterally (intramuscularly or subcutaneously), or intranasally.¹ A common oral regimen is 1 mg/d; parental regimens vary widely, but might include a 1-mg injection once a week for 8 weeks, then once a month for life.¹

Some evidence suggests B₁₂ supplementation may improve symptoms of depression and anxiety. A Pakistani study randomized 73 patients with depression and “low normal” B₁₂ levels (190-300 pg/mL) to an antidepressant only (equivalent to imipramine 100-250 mg/d or fluoxetine 20-40 mg/d) or an antidepressant plus parenteral B₁₂ (1000 mcg once a week).⁴ At 3 months follow-up, 100% of the treatment group showed at least a 20% reduction in their Hamilton Depression Rating Scale (HAM-D) score, compared to 69% in the control arm (P<.001).⁴

A Swedish study analyzed the effects of several B vitamins, including 0.5 mg/d of B₁₂ vs placebo on mood in 65 celiac patients on a gluten-free diet who had borderline/low normal B₁₂ levels (>191 pg/mL).⁵ Patients who scored low on a measure of psychological well-being at the beginning of the study and who received B₁₂ experienced significant improvements in anxiety and depressed mood compared to those who received placebo.

Our patient

Because neurologic and psychiatric symptoms require assured compliance and urgent treatment, our patient received vitamin B₁₂ parenterally as cyanocobalamin 1 mg/mL. She was given this dosage intramuscularly once a day for 5 days, then once a week for 4 weeks. She will continue to receive it once a month indefinitely.

The patient was advised that if she wished to switch to oral therapy, she could do so after several months of parenteral treatment, as long as she had close follow-up with frequent B₁₂ measurements to assure that she was absorbing oral therapy. Her anxiety and mood symptoms resolved within one month, and her disequilibrium was almost entirely resolved within 3 months of treatment.

THE TAKEAWAY

Although more common in older patients, vitamin B₁₂ deficiency can also affect younger patients. “Low normal” B₁₂ levels (200-400 pg/mL) may affect psychological well-being.

Consider testing serum B₁₂ and a second biomarker—such as homocysteine or methylmalonic acid, if indicated—in patients who present with depressed mood, anxiety, cognitive symptoms, and/or fatigue. Vitamin B₁₂ supplementation can be administered orally and has no major adverse effects.

THE CASE

A 21-year-old college student was referred to us by the counseling center at our university for a psychiatric evaluation after 11 psychotherapy sessions over 3 months had failed to reduce her feelings of anxiety and panic.

During our evaluation, the patient described feeling “not quite right” for many months. She had been experiencing mental fogginess, fatigue, and worsening concentration/ memory. Her anxiety, which had been gradually increasing, was the result of being unsure about her gait. She first noticed this while walking down some bleachers; she felt dizzy, was afraid of falling, and couldn’t walk down without assistance. All episodes of “panic” occurred in situations where she experienced disequilibrium, unsteady gait, and fear of falling. She grew fearful of driving or going anywhere without assistance.

The patient had celiac disease that was well controlled with a gluten-free diet. She had no personal or family psychiatric history and no history of substance abuse.

THE DIAGNOSIS

Physical exam and lab studies, including a complete blood count, comprehensive metabolic panel, and thyrotropin and folate levels, were normal. Her homocysteine level was 11.8 μmol/L (reference range, 5.4-11.9 μmol/L) and vitamin B₁₂ level was 292 pg/mL (reference range, 200-1100 pg/mL). Her lab report included a note that read, “Although the reference range for vitamin B₁₂ is 200 to 1100 pg/mL, it has been reported that between 5% and 10% of patients with values between 200 and 400 pg/mL may experience neuropsychiatric and hematologic abnormalities due to occult B₁₂ deficiency; <1% of patients with values >400 pg/mL will have symptoms.”

Based on this vitamin B₁₂ level, the patient’s symptoms, and her borderline high homocysteine level, we diagnosed vitamin B₁₂ deficiency.

DISCUSSION

There are no recommendations by the US Preventive Services Task Force or any other major US medical society for routine vitamin B₁₂ screening.¹ In Canada, the Medical Services Commission of the British Columbia Ministry of Health recommends B₁₂ screening for patients who present with macrocytic anemia or unexplained neurologic symptoms (eg, paresthesia, numbness, poor motor coordination, memory lapses, or cognitive or personality changes).²

Vitamin B₁₂ deficiency can be caused by numerous conditions, including those that cause malabsorption (such as gastric bypass). It can also be caused by diseases such as human immunodeficiency virus infection or Crohn’s disease, long-term adherence to a vegetarian or vegan diet, or by any other lack of dietary intake.¹ The condition can cause hematologic-related signs and symptoms such as megaloblastic anemia, fatigue, and syncope. It also can have neurologic manifestations, including paresthesia, weakness, motor disturbances (including gait abnormalities), vision loss, and a wide range of cognitive and behavioral changes.¹ Anemia is uncommon because since 1998, the US Food and Drug Administration has required fortification of all enriched grain and cereal products with folic acid; thus, vitamin B₁₂ deficiency may proceed without anemia revealing its presence.¹

A controversial topic. Vitamin B₁₂ deficiency is a complicated and controversial subject. Specifically, there is uncertainty about the clinical importance of lower serum levels of vitamin B₁₂ (200-400 pg/mL), their impact on well-being, and the need for treatment. In addition to measuring a patient’s serum B₁₂ level, testing a second biomarker (such as homocysteine or methylmalonic acid) can be helpful in establishing a diagnosis of B₁₂ deficiency.¹ Levels of each of these are elevated in patients with B₁₂ deficiency.¹

Some evidence suggests B₁₂ supplementation may improve symptoms of depression and anxiety.

Although vitamin B₁₂ deficiency has been well studied in older patients,³ little has been published about the condition in young adults. National Health and Nutrition Examination Survey (NHANES) data from 2000 to 2004 shows that almost 40% of people ages 19 to 30 years have a B₁₂ level <400 pg/mL.¹ How many of these individuals are at risk of complications of B₁₂ deficiency is unknown.

B₁₂ supplementation might improve depression, anxiety

B₁₂ supplementation is inexpensive and has no significant adverse effects.¹ It can be administered orally, parenterally (intramuscularly or subcutaneously), or intranasally.¹ A common oral regimen is 1 mg/d; parental regimens vary widely, but might include a 1-mg injection once a week for 8 weeks, then once a month for life.¹

Some evidence suggests B₁₂ supplementation may improve symptoms of depression and anxiety. A Pakistani study randomized 73 patients with depression and “low normal” B₁₂ levels (190-300 pg/mL) to an antidepressant only (equivalent to imipramine 100-250 mg/d or fluoxetine 20-40 mg/d) or an antidepressant plus parenteral B₁₂ (1000 mcg once a week).⁴ At 3 months follow-up, 100% of the treatment group showed at least a 20% reduction in their Hamilton Depression Rating Scale (HAM-D) score, compared to 69% in the control arm (P<.001).⁴

A Swedish study analyzed the effects of several B vitamins, including 0.5 mg/d of B₁₂ vs placebo on mood in 65 celiac patients on a gluten-free diet who had borderline/low normal B₁₂ levels (>191 pg/mL).⁵ Patients who scored low on a measure of psychological well-being at the beginning of the study and who received B₁₂ experienced significant improvements in anxiety and depressed mood compared to those who received placebo.

Our patient

Because neurologic and psychiatric symptoms require assured compliance and urgent treatment, our patient received vitamin B₁₂ parenterally as cyanocobalamin 1 mg/mL. She was given this dosage intramuscularly once a day for 5 days, then once a week for 4 weeks. She will continue to receive it once a month indefinitely.

The patient was advised that if she wished to switch to oral therapy, she could do so after several months of parenteral treatment, as long as she had close follow-up with frequent B₁₂ measurements to assure that she was absorbing oral therapy. Her anxiety and mood symptoms resolved within one month, and her disequilibrium was almost entirely resolved within 3 months of treatment.

THE TAKEAWAY

Although more common in older patients, vitamin B₁₂ deficiency can also affect younger patients. “Low normal” B₁₂ levels (200-400 pg/mL) may affect psychological well-being.

Consider testing serum B₁₂ and a second biomarker—such as homocysteine or methylmalonic acid, if indicated—in patients who present with depressed mood, anxiety, cognitive symptoms, and/or fatigue. Vitamin B₁₂ supplementation can be administered orally and has no major adverse effects.

THE CASE

A 21-year-old college student was referred to us by the counseling center at our university for a psychiatric evaluation after 11 psychotherapy sessions over 3 months had failed to reduce her feelings of anxiety and panic.

During our evaluation, the patient described feeling “not quite right” for many months. She had been experiencing mental fogginess, fatigue, and worsening concentration/ memory. Her anxiety, which had been gradually increasing, was the result of being unsure about her gait. She first noticed this while walking down some bleachers; she felt dizzy, was afraid of falling, and couldn’t walk down without assistance. All episodes of “panic” occurred in situations where she experienced disequilibrium, unsteady gait, and fear of falling. She grew fearful of driving or going anywhere without assistance.

The patient had celiac disease that was well controlled with a gluten-free diet. She had no personal or family psychiatric history and no history of substance abuse.

THE DIAGNOSIS

Physical exam and lab studies, including a complete blood count, comprehensive metabolic panel, and thyrotropin and folate levels, were normal. Her homocysteine level was 11.8 μmol/L (reference range, 5.4-11.9 μmol/L) and vitamin B₁₂ level was 292 pg/mL (reference range, 200-1100 pg/mL). Her lab report included a note that read, “Although the reference range for vitamin B₁₂ is 200 to 1100 pg/mL, it has been reported that between 5% and 10% of patients with values between 200 and 400 pg/mL may experience neuropsychiatric and hematologic abnormalities due to occult B₁₂ deficiency; <1% of patients with values >400 pg/mL will have symptoms.”

Based on this vitamin B₁₂ level, the patient’s symptoms, and her borderline high homocysteine level, we diagnosed vitamin B₁₂ deficiency.

DISCUSSION

There are no recommendations by the US Preventive Services Task Force or any other major US medical society for routine vitamin B₁₂ screening.¹ In Canada, the Medical Services Commission of the British Columbia Ministry of Health recommends B₁₂ screening for patients who present with macrocytic anemia or unexplained neurologic symptoms (eg, paresthesia, numbness, poor motor coordination, memory lapses, or cognitive or personality changes).²

Vitamin B₁₂ deficiency can be caused by numerous conditions, including those that cause malabsorption (such as gastric bypass). It can also be caused by diseases such as human immunodeficiency virus infection or Crohn’s disease, long-term adherence to a vegetarian or vegan diet, or by any other lack of dietary intake.¹ The condition can cause hematologic-related signs and symptoms such as megaloblastic anemia, fatigue, and syncope. It also can have neurologic manifestations, including paresthesia, weakness, motor disturbances (including gait abnormalities), vision loss, and a wide range of cognitive and behavioral changes.¹ Anemia is uncommon because since 1998, the US Food and Drug Administration has required fortification of all enriched grain and cereal products with folic acid; thus, vitamin B₁₂ deficiency may proceed without anemia revealing its presence.¹

A controversial topic. Vitamin B₁₂ deficiency is a complicated and controversial subject. Specifically, there is uncertainty about the clinical importance of lower serum levels of vitamin B₁₂ (200-400 pg/mL), their impact on well-being, and the need for treatment. In addition to measuring a patient’s serum B₁₂ level, testing a second biomarker (such as homocysteine or methylmalonic acid) can be helpful in establishing a diagnosis of B₁₂ deficiency.¹ Levels of each of these are elevated in patients with B₁₂ deficiency.¹

Some evidence suggests B₁₂ supplementation may improve symptoms of depression and anxiety.

Although vitamin B₁₂ deficiency has been well studied in older patients,³ little has been published about the condition in young adults. National Health and Nutrition Examination Survey (NHANES) data from 2000 to 2004 shows that almost 40% of people ages 19 to 30 years have a B₁₂ level <400 pg/mL.¹ How many of these individuals are at risk of complications of B₁₂ deficiency is unknown.

B₁₂ supplementation might improve depression, anxiety

B₁₂ supplementation is inexpensive and has no significant adverse effects.¹ It can be administered orally, parenterally (intramuscularly or subcutaneously), or intranasally.¹ A common oral regimen is 1 mg/d; parental regimens vary widely, but might include a 1-mg injection once a week for 8 weeks, then once a month for life.¹

Some evidence suggests B₁₂ supplementation may improve symptoms of depression and anxiety. A Pakistani study randomized 73 patients with depression and “low normal” B₁₂ levels (190-300 pg/mL) to an antidepressant only (equivalent to imipramine 100-250 mg/d or fluoxetine 20-40 mg/d) or an antidepressant plus parenteral B₁₂ (1000 mcg once a week).⁴ At 3 months follow-up, 100% of the treatment group showed at least a 20% reduction in their Hamilton Depression Rating Scale (HAM-D) score, compared to 69% in the control arm (P<.001).⁴

A Swedish study analyzed the effects of several B vitamins, including 0.5 mg/d of B₁₂ vs placebo on mood in 65 celiac patients on a gluten-free diet who had borderline/low normal B₁₂ levels (>191 pg/mL).⁵ Patients who scored low on a measure of psychological well-being at the beginning of the study and who received B₁₂ experienced significant improvements in anxiety and depressed mood compared to those who received placebo.

Our patient

Because neurologic and psychiatric symptoms require assured compliance and urgent treatment, our patient received vitamin B₁₂ parenterally as cyanocobalamin 1 mg/mL. She was given this dosage intramuscularly once a day for 5 days, then once a week for 4 weeks. She will continue to receive it once a month indefinitely.

The patient was advised that if she wished to switch to oral therapy, she could do so after several months of parenteral treatment, as long as she had close follow-up with frequent B₁₂ measurements to assure that she was absorbing oral therapy. Her anxiety and mood symptoms resolved within one month, and her disequilibrium was almost entirely resolved within 3 months of treatment.

THE TAKEAWAY

Although more common in older patients, vitamin B₁₂ deficiency can also affect younger patients. “Low normal” B₁₂ levels (200-400 pg/mL) may affect psychological well-being.

Consider testing serum B₁₂ and a second biomarker—such as homocysteine or methylmalonic acid, if indicated—in patients who present with depressed mood, anxiety, cognitive symptoms, and/or fatigue. Vitamin B₁₂ supplementation can be administered orally and has no major adverse effects.

THE CASE

One month after moving into her mother’s apartment, a 27-year-old woman sought care at our clinic for fatigue, headache, blurred vision, nausea, and morning vomiting. She had weakness and difficulty sleeping, but denied any fever, rashes, neck stiffness, recent travel, trauma, or tobacco or illicit drug use. She did, however, have a 6-year history of migraines. Her physical exam was normal. She was sent home with a prescription for tramadol 50 mg bid for her headaches.

The patient subsequently went to the emergency department 3 times for the same complaints; none of the treatments she received there (mostly acetaminophen with codeine) relieved her symptoms. Three weeks later she returned to our clinic. She was distressed that the symptoms hadn’t gone away, and noted that her family was now experiencing similar symptoms.

Her temperature was 98.1°F (36.7°C), blood pressure was 131/88 mm Hg, pulse  was 85 beats/min, and respiratory rate was 18 breaths/min. Physical and neurologic exams were normal.

THE DIAGNOSIS

Although most of the patient’s lab test results were within normal ranges, her carboxyhemoglobin (COHb) level was 4.2%. COHb levels of >2% to 3% in nonsmokers or >9% to 10% in smokers suggest carbon monoxide (CO) poisoning.^1,2 Based on this finding and our patient’s symptoms, we diagnosed unintentional CO poisoning. We recommended that she and her mother vacate the apartment and have it inspected.

DISCUSSION

CO is the leading cause of poisoning mortality in the United States, and causes half of all fatal poisonings worldwide.^1,3,4 It is a colorless, odorless, and tasteless gas that is produced by the incomplete combustion of carbon-based products, such as coal or gas.^5,6 Exposure can occur from car exhaust fumes, faulty room heaters, and other sources (TABLE 1).⁶ The incidence of CO poisoning is higher during the winter months and after natural disasters. Individuals who have a lowered oxygen capacity, such as older adults, pregnant women (and their fetuses), infants, and patients with anemia, cardiovascular disease, or cerebrovascular disease, are more susceptible to CO poisoning.^5,6

COHb, a stable complex of CO that forms in red blood cells when CO is inhaled, impairs oxygen delivery and peripheral utilization, resulting in cellular hypoxia.¹ Signs and symptoms of CO poisoning are nonspecific and require a high degree of clinical suspicion for early diagnosis and treatment. Although cherry-red lips, peripheral cyanosis, and retinal hemorrhages are often described as “classic” symptoms of CO poisoning, these are rarely seen.⁶ The most common symptoms are actually headache (90%), dizziness (82%), and weakness (53%).⁷ Other symptoms include nausea, vomiting, confusion, visual disturbances, loss of consciousness, angina, seizure, and fatigue.^6,7 Symptoms of chronic CO poisoning may differ from those of acute poisoning and can include chronic fatigue, neuropathy, and memory deficit.⁸

The differential diagnosis for CO poisoning includes flu-like syndrome/influenza/other viral illnesses, migraine or tension headaches, depression, transient ischemic attack, encephalitis, coronary artery disease, gastroenteritis or food poisoning, seizures, and dysrhythmias.^1,4 Lab testing for COHb can help narrow the diagnosis. CO poisoning can be classified as mild, moderate, or severe based on COHb levels and the patient’s signs and symptoms (TABLE 2).⁶ However, COHb level is a poor predictor of clinical presentation and should not be used to dictate management.^2,7

Oxygen therapy is the recommended treatment

Early treatment with supplemental oxygen is recommended to reduce the length of time red blood cells are exposed to CO.¹ A COHb level >25% is the criterion for hyperbaric oxygen therapy.^1,3 Patients should receive treatment until their symptoms become less intense.

The 3 most common symptoms of CO poisoning are headache, dizziness, and weakness.

Delayed neuropsychiatric sequelae (DNS) can occur in up to one-third of patients with acute CO poisoning more than a month after apparent recovery.^1,6,9 DNS symptoms include cognitive changes, emotional lability, visual disturbances, disorientation, depression, dementia, psychotic behavior, parkinsonism, amnesia, and incontinence.^1,6,9 Approximately 50% to 75% of patients with DNS recover spontaneously within a year with symptomatic treatment.^1,6,9

Our patient

After recommending that our patient (and her mother) leave the apartment and have it inspected, we later learned that the fire department was unable to determine the source of the CO. A CO detector was installed and our patient was advised to keep the windows in the apartment open to allow for adequate oxygen flow. One month later she returned to our clinic and reported that her symptoms resolved; serum COHb was negative upon repeat lab tests.

THE TAKEAWAY

Patients who present with headaches, dizziness and/or fatigue should be evaluated for CO poisoning. The patient’s environmental history should be reviewed carefully, especially because CO poisoning is more common during the winter months. Oxygen therapy is the mainstay of treatment. Up to one-third of patients with acute poisoning may develop delayed neuropsychiatric sequelae, including cognitive changes, emotional lability, visual disturbances, disorientation, and depression, that may resolve within one year.

THE CASE

One month after moving into her mother’s apartment, a 27-year-old woman sought care at our clinic for fatigue, headache, blurred vision, nausea, and morning vomiting. She had weakness and difficulty sleeping, but denied any fever, rashes, neck stiffness, recent travel, trauma, or tobacco or illicit drug use. She did, however, have a 6-year history of migraines. Her physical exam was normal. She was sent home with a prescription for tramadol 50 mg bid for her headaches.

The patient subsequently went to the emergency department 3 times for the same complaints; none of the treatments she received there (mostly acetaminophen with codeine) relieved her symptoms. Three weeks later she returned to our clinic. She was distressed that the symptoms hadn’t gone away, and noted that her family was now experiencing similar symptoms.

Her temperature was 98.1°F (36.7°C), blood pressure was 131/88 mm Hg, pulse  was 85 beats/min, and respiratory rate was 18 breaths/min. Physical and neurologic exams were normal.

THE DIAGNOSIS

Although most of the patient’s lab test results were within normal ranges, her carboxyhemoglobin (COHb) level was 4.2%. COHb levels of >2% to 3% in nonsmokers or >9% to 10% in smokers suggest carbon monoxide (CO) poisoning.^1,2 Based on this finding and our patient’s symptoms, we diagnosed unintentional CO poisoning. We recommended that she and her mother vacate the apartment and have it inspected.

DISCUSSION

CO is the leading cause of poisoning mortality in the United States, and causes half of all fatal poisonings worldwide.^1,3,4 It is a colorless, odorless, and tasteless gas that is produced by the incomplete combustion of carbon-based products, such as coal or gas.^5,6 Exposure can occur from car exhaust fumes, faulty room heaters, and other sources (TABLE 1).⁶ The incidence of CO poisoning is higher during the winter months and after natural disasters. Individuals who have a lowered oxygen capacity, such as older adults, pregnant women (and their fetuses), infants, and patients with anemia, cardiovascular disease, or cerebrovascular disease, are more susceptible to CO poisoning.^5,6

COHb, a stable complex of CO that forms in red blood cells when CO is inhaled, impairs oxygen delivery and peripheral utilization, resulting in cellular hypoxia.¹ Signs and symptoms of CO poisoning are nonspecific and require a high degree of clinical suspicion for early diagnosis and treatment. Although cherry-red lips, peripheral cyanosis, and retinal hemorrhages are often described as “classic” symptoms of CO poisoning, these are rarely seen.⁶ The most common symptoms are actually headache (90%), dizziness (82%), and weakness (53%).⁷ Other symptoms include nausea, vomiting, confusion, visual disturbances, loss of consciousness, angina, seizure, and fatigue.^6,7 Symptoms of chronic CO poisoning may differ from those of acute poisoning and can include chronic fatigue, neuropathy, and memory deficit.⁸

The differential diagnosis for CO poisoning includes flu-like syndrome/influenza/other viral illnesses, migraine or tension headaches, depression, transient ischemic attack, encephalitis, coronary artery disease, gastroenteritis or food poisoning, seizures, and dysrhythmias.^1,4 Lab testing for COHb can help narrow the diagnosis. CO poisoning can be classified as mild, moderate, or severe based on COHb levels and the patient’s signs and symptoms (TABLE 2).⁶ However, COHb level is a poor predictor of clinical presentation and should not be used to dictate management.^2,7

Oxygen therapy is the recommended treatment

Early treatment with supplemental oxygen is recommended to reduce the length of time red blood cells are exposed to CO.¹ A COHb level >25% is the criterion for hyperbaric oxygen therapy.^1,3 Patients should receive treatment until their symptoms become less intense.

The 3 most common symptoms of CO poisoning are headache, dizziness, and weakness.

Delayed neuropsychiatric sequelae (DNS) can occur in up to one-third of patients with acute CO poisoning more than a month after apparent recovery.^1,6,9 DNS symptoms include cognitive changes, emotional lability, visual disturbances, disorientation, depression, dementia, psychotic behavior, parkinsonism, amnesia, and incontinence.^1,6,9 Approximately 50% to 75% of patients with DNS recover spontaneously within a year with symptomatic treatment.^1,6,9

Our patient

After recommending that our patient (and her mother) leave the apartment and have it inspected, we later learned that the fire department was unable to determine the source of the CO. A CO detector was installed and our patient was advised to keep the windows in the apartment open to allow for adequate oxygen flow. One month later she returned to our clinic and reported that her symptoms resolved; serum COHb was negative upon repeat lab tests.

THE TAKEAWAY

Patients who present with headaches, dizziness and/or fatigue should be evaluated for CO poisoning. The patient’s environmental history should be reviewed carefully, especially because CO poisoning is more common during the winter months. Oxygen therapy is the mainstay of treatment. Up to one-third of patients with acute poisoning may develop delayed neuropsychiatric sequelae, including cognitive changes, emotional lability, visual disturbances, disorientation, and depression, that may resolve within one year.

THE CASE

One month after moving into her mother’s apartment, a 27-year-old woman sought care at our clinic for fatigue, headache, blurred vision, nausea, and morning vomiting. She had weakness and difficulty sleeping, but denied any fever, rashes, neck stiffness, recent travel, trauma, or tobacco or illicit drug use. She did, however, have a 6-year history of migraines. Her physical exam was normal. She was sent home with a prescription for tramadol 50 mg bid for her headaches.

The patient subsequently went to the emergency department 3 times for the same complaints; none of the treatments she received there (mostly acetaminophen with codeine) relieved her symptoms. Three weeks later she returned to our clinic. She was distressed that the symptoms hadn’t gone away, and noted that her family was now experiencing similar symptoms.

Her temperature was 98.1°F (36.7°C), blood pressure was 131/88 mm Hg, pulse  was 85 beats/min, and respiratory rate was 18 breaths/min. Physical and neurologic exams were normal.

THE DIAGNOSIS

Although most of the patient’s lab test results were within normal ranges, her carboxyhemoglobin (COHb) level was 4.2%. COHb levels of >2% to 3% in nonsmokers or >9% to 10% in smokers suggest carbon monoxide (CO) poisoning.^1,2 Based on this finding and our patient’s symptoms, we diagnosed unintentional CO poisoning. We recommended that she and her mother vacate the apartment and have it inspected.

DISCUSSION

CO is the leading cause of poisoning mortality in the United States, and causes half of all fatal poisonings worldwide.^1,3,4 It is a colorless, odorless, and tasteless gas that is produced by the incomplete combustion of carbon-based products, such as coal or gas.^5,6 Exposure can occur from car exhaust fumes, faulty room heaters, and other sources (TABLE 1).⁶ The incidence of CO poisoning is higher during the winter months and after natural disasters. Individuals who have a lowered oxygen capacity, such as older adults, pregnant women (and their fetuses), infants, and patients with anemia, cardiovascular disease, or cerebrovascular disease, are more susceptible to CO poisoning.^5,6

COHb, a stable complex of CO that forms in red blood cells when CO is inhaled, impairs oxygen delivery and peripheral utilization, resulting in cellular hypoxia.¹ Signs and symptoms of CO poisoning are nonspecific and require a high degree of clinical suspicion for early diagnosis and treatment. Although cherry-red lips, peripheral cyanosis, and retinal hemorrhages are often described as “classic” symptoms of CO poisoning, these are rarely seen.⁶ The most common symptoms are actually headache (90%), dizziness (82%), and weakness (53%).⁷ Other symptoms include nausea, vomiting, confusion, visual disturbances, loss of consciousness, angina, seizure, and fatigue.^6,7 Symptoms of chronic CO poisoning may differ from those of acute poisoning and can include chronic fatigue, neuropathy, and memory deficit.⁸

The differential diagnosis for CO poisoning includes flu-like syndrome/influenza/other viral illnesses, migraine or tension headaches, depression, transient ischemic attack, encephalitis, coronary artery disease, gastroenteritis or food poisoning, seizures, and dysrhythmias.^1,4 Lab testing for COHb can help narrow the diagnosis. CO poisoning can be classified as mild, moderate, or severe based on COHb levels and the patient’s signs and symptoms (TABLE 2).⁶ However, COHb level is a poor predictor of clinical presentation and should not be used to dictate management.^2,7

Oxygen therapy is the recommended treatment

Early treatment with supplemental oxygen is recommended to reduce the length of time red blood cells are exposed to CO.¹ A COHb level >25% is the criterion for hyperbaric oxygen therapy.^1,3 Patients should receive treatment until their symptoms become less intense.

The 3 most common symptoms of CO poisoning are headache, dizziness, and weakness.

Delayed neuropsychiatric sequelae (DNS) can occur in up to one-third of patients with acute CO poisoning more than a month after apparent recovery.^1,6,9 DNS symptoms include cognitive changes, emotional lability, visual disturbances, disorientation, depression, dementia, psychotic behavior, parkinsonism, amnesia, and incontinence.^1,6,9 Approximately 50% to 75% of patients with DNS recover spontaneously within a year with symptomatic treatment.^1,6,9

Our patient

After recommending that our patient (and her mother) leave the apartment and have it inspected, we later learned that the fire department was unable to determine the source of the CO. A CO detector was installed and our patient was advised to keep the windows in the apartment open to allow for adequate oxygen flow. One month later she returned to our clinic and reported that her symptoms resolved; serum COHb was negative upon repeat lab tests.

THE TAKEAWAY

Patients who present with headaches, dizziness and/or fatigue should be evaluated for CO poisoning. The patient’s environmental history should be reviewed carefully, especially because CO poisoning is more common during the winter months. Oxygen therapy is the mainstay of treatment. Up to one-third of patients with acute poisoning may develop delayed neuropsychiatric sequelae, including cognitive changes, emotional lability, visual disturbances, disorientation, and depression, that may resolve within one year.

EVIDENCE SUMMARY

A systematic review of 7 RCTs with a total of 477 adults that examined the efficacy of ICS compared with placebo for treating subacute (3-8 weeks) and chronic (>8 weeks) cough found inconsistent, but mostly negative results.¹ Most trials combined patients with nonspecific subacute and chronic cough.

The evaluated steroids included beclomethasone, budesonide, fluticasone, and mometasone; daily “budesonide equivalent” doses ranged from 320 mcg to 1600 mcg. Six of the 7 trials found that ICS didn’t improve cough. The seventh didn’t treat patients with postviral cough. The authors of the review couldn’t pool data because of heterogeneity.

Steroids don’t affect methacholine challenge in teens

A double-blind, placebo-controlled RCT of 56 adolescents found that giving ICS after viral upper respiratory infection didn’t change the methacholine dosing necessary to produce a 20% reduction in the forced expiratory volume in one second (FEV₁).² Investigators included patients if they had a previous diagnosis of asthma but no use of asthma medications in 2 years, a baseline FEV₁ greater than 70% of predicted, and a concentration of methacholine that produced a 20% fall in FEV₁ less than 8 mg/mL.

They randomized patients to inhaled budesonide (2 200-mcg puffs bid) or placebo (2 500-mcg puffs micronized lactose bid). Patients underwent spirometry and methacholine challenge testing every 3 months over a 9-month period. The groups didn’t differ in bronchial hyperresponsiveness or FEV₁.

Lower respiratory symptoms don’t respond to ICS in nonasthmatic children

A systematic review of 5 RCTs with a total of 339 patients found that in 4 of the 5, ICS didn’t improve lower respiratory symptoms in children with episodic viral wheeze and no history of asthma.³ Investigators evaluated ICS efficacy using lower respiratory symptom scores (based primarily on cough and wheeze) and decreased use of oral steroids or reduced emergency room visits.

Four trials found no benefit from ICS; one trial (52 children with viral-induced wheeze) found that nebulized budesonide (400 mg qid for 2 days, then bid for 7 days) decreased respiratory symptom scores (weighted mean difference= -0.17; 95% confidence interval, -0.34 to -0.003) compared with placebo. Investigators didn’t assess cough separately from wheezing, however.

EVIDENCE SUMMARY

A systematic review of 7 RCTs with a total of 477 adults that examined the efficacy of ICS compared with placebo for treating subacute (3-8 weeks) and chronic (>8 weeks) cough found inconsistent, but mostly negative results.¹ Most trials combined patients with nonspecific subacute and chronic cough.

The evaluated steroids included beclomethasone, budesonide, fluticasone, and mometasone; daily “budesonide equivalent” doses ranged from 320 mcg to 1600 mcg. Six of the 7 trials found that ICS didn’t improve cough. The seventh didn’t treat patients with postviral cough. The authors of the review couldn’t pool data because of heterogeneity.

Steroids don’t affect methacholine challenge in teens

A double-blind, placebo-controlled RCT of 56 adolescents found that giving ICS after viral upper respiratory infection didn’t change the methacholine dosing necessary to produce a 20% reduction in the forced expiratory volume in one second (FEV₁).² Investigators included patients if they had a previous diagnosis of asthma but no use of asthma medications in 2 years, a baseline FEV₁ greater than 70% of predicted, and a concentration of methacholine that produced a 20% fall in FEV₁ less than 8 mg/mL.

They randomized patients to inhaled budesonide (2 200-mcg puffs bid) or placebo (2 500-mcg puffs micronized lactose bid). Patients underwent spirometry and methacholine challenge testing every 3 months over a 9-month period. The groups didn’t differ in bronchial hyperresponsiveness or FEV₁.

Lower respiratory symptoms don’t respond to ICS in nonasthmatic children

A systematic review of 5 RCTs with a total of 339 patients found that in 4 of the 5, ICS didn’t improve lower respiratory symptoms in children with episodic viral wheeze and no history of asthma.³ Investigators evaluated ICS efficacy using lower respiratory symptom scores (based primarily on cough and wheeze) and decreased use of oral steroids or reduced emergency room visits.

Four trials found no benefit from ICS; one trial (52 children with viral-induced wheeze) found that nebulized budesonide (400 mg qid for 2 days, then bid for 7 days) decreased respiratory symptom scores (weighted mean difference= -0.17; 95% confidence interval, -0.34 to -0.003) compared with placebo. Investigators didn’t assess cough separately from wheezing, however.

EVIDENCE SUMMARY

A systematic review of 7 RCTs with a total of 477 adults that examined the efficacy of ICS compared with placebo for treating subacute (3-8 weeks) and chronic (>8 weeks) cough found inconsistent, but mostly negative results.¹ Most trials combined patients with nonspecific subacute and chronic cough.

The evaluated steroids included beclomethasone, budesonide, fluticasone, and mometasone; daily “budesonide equivalent” doses ranged from 320 mcg to 1600 mcg. Six of the 7 trials found that ICS didn’t improve cough. The seventh didn’t treat patients with postviral cough. The authors of the review couldn’t pool data because of heterogeneity.

Steroids don’t affect methacholine challenge in teens

A double-blind, placebo-controlled RCT of 56 adolescents found that giving ICS after viral upper respiratory infection didn’t change the methacholine dosing necessary to produce a 20% reduction in the forced expiratory volume in one second (FEV₁).² Investigators included patients if they had a previous diagnosis of asthma but no use of asthma medications in 2 years, a baseline FEV₁ greater than 70% of predicted, and a concentration of methacholine that produced a 20% fall in FEV₁ less than 8 mg/mL.

They randomized patients to inhaled budesonide (2 200-mcg puffs bid) or placebo (2 500-mcg puffs micronized lactose bid). Patients underwent spirometry and methacholine challenge testing every 3 months over a 9-month period. The groups didn’t differ in bronchial hyperresponsiveness or FEV₁.

Lower respiratory symptoms don’t respond to ICS in nonasthmatic children

A systematic review of 5 RCTs with a total of 339 patients found that in 4 of the 5, ICS didn’t improve lower respiratory symptoms in children with episodic viral wheeze and no history of asthma.³ Investigators evaluated ICS efficacy using lower respiratory symptom scores (based primarily on cough and wheeze) and decreased use of oral steroids or reduced emergency room visits.

Four trials found no benefit from ICS; one trial (52 children with viral-induced wheeze) found that nebulized budesonide (400 mg qid for 2 days, then bid for 7 days) decreased respiratory symptom scores (weighted mean difference= -0.17; 95% confidence interval, -0.34 to -0.003) compared with placebo. Investigators didn’t assess cough separately from wheezing, however.