Case Reports

THE CASE

A 23-year-old woman with past medical history of bipolar II disorder and a REM-specific seizure disorder that resolved at age 9 presented after a syncopal episode. The patient reported an initial sensation of lightheadedness while at work, which was followed by a syncopal episode with brief (1-2 min) loss of consciousness and a minor head injury.

She denied other prodromal symptoms including chest pain, shortness of breath, ­palpitations, and nausea. She also did not experience convulsions, urinary/bowel incontinence, or confusion upon regaining consciousness.

She denied previous syncopal episodes. However, she reported that, 2 weeks prior, there had been an event similar to that of her presenting complaint. During that episode, she experienced lightheadedness and a fall without loss of consciousness.

The patient had been prescribed a regimen of sertraline 100 mg/d and aripiprazole 10 mg/d to maintain mood stability. She had self-discontinued these medications about 8 months prior to presentation. A recent return of her depressive features had prompted a restart of this regimen 1 week before her first fall, without an initial taper upward.

While in the emergency department, she became bradycardic (heart rate, 38 beats/min) and hypotensive (blood pressure, 70/40 mm Hg). She subsequently became increasingly somnolent and had 1 episode of emesis. An electrocardiogram (EKG) revealed sinus bradycardia without other acute abnormalities (FIGURE).

Blood work including a basic metabolic panel, complete blood count, and cardiac enzymes were all within normal limits. Computed tomography of the head revealed no intracranial pathology. Her vitals were initially unresponsive to a fluid bolus but improved and stabilized after administration of intravenous atropine 0.5 mg.

Aripiprazole was held and sertraline was decreased to 75 mg on hospital Day 1, with close monitoring of her mood. Cardiology was consulted and followed the patient ­during her stay. The patient was monitored on telemetry for 3 days, exhibiting only sinus ­bradycardia with a stable heart rate of 45-55 beats/min. Systolic blood pressures were ­stable within 120 to 130 mm Hg. Transthoracic echocardiogram performed on hospital Day 2 was unremarkable, revealing a normal left ventricular ejection fraction of 65% and no wall motion abnormalities. She had no recurrence of the syncope or emesis.

Continue to: THE DIAGNOSIS

Given her benign cardiac work-up and symptom onset coinciding with the abrupt resumption of high doses of aripiprazole after an 8-month abstinence, the patient’s presentation was attributed to a rather uncommon adverse drug reaction to aripiprazole. This has only been described in a few case reports.

DISCUSSION

Aripiprazole (Abilify) is an atypical antipsychotic frequently used in the treatment of psychiatric conditions, including bipolar disorder and schizophrenia. While the specific therapeutic mechanism is unknown, it is believed that drug efficacy is related to partial agonism at dopamine D₂, serotonin 5-HT_1A, and serotonin 5-HT_2A.¹ As aripiprazole works on a variety of receptors involved in other physiologic processes, clinical adverse effects have been reported, most of which are associated with the adrenergic alpha₁ receptors.¹ These include cognitive impairment and seizures. Cardiovascular adverse effects of aripiprazole include orthostatic hypotension, cardiac arrhythmia, prolonged QT interval, and syncope.^1-5

Family physicians should inquire about aripiprazole use in patients who present with cardiac symptoms.

Selective serotonin reuptake inhibitors (SSRIs) such as sertraline (Zoloft) have also been shown to cause cardiac arrhythmia and syncope.⁶ Although sertraline may have contributed to the patient’s cardiac symptoms, it is more likely that the aripiprazole was the direct cause, as she remained asymptomatic while on a therapeutic dose of sertraline. Furthermore, aripiprazole is primarily metabolized though hepatic CYP2D6, which sertraline has been shown to inhibit.^1,7 Therefore, the concomitant use of sertraline with no initial taper of either medication likely led to an increased effective dose of aripiprazole in our patient and subsequently to her presentation.

Few prior cases have identified aripiprazole as a cause of antipsychotic-associated bradycardic response.⁸ Based on the Adverse Drug Reaction Probability Scale, often referred to as the Naranjo Scale, we believe this to be a probable adverse response in our patient.⁹ Bradycardia followed a reasonable temporal sequence after aripiprazole use with a response previously described in the literature. Symptoms also improved after discontinuation of the drug and other etiologies of the bradycardia were ruled out.

Our patient was discharged with a 30-day cardiac event monitor and a scheduled appointment with Cardiology.

Continue to: THE TAKEAWAY

As this case suggests, there may be an association between aripiprazole and symptomatic bradycardia. Therefore, family physicians should inquire about aripiprazole use in patients who present with cardiac symptoms and consider tapering this medication if other causes cannot be identified. Additionally, given the potential cardiac adverse effects of atypical antipsychotics, physicians may consider ordering baseline and follow-up EKGs to monitor for arrhythmias in patients prescribed aripiprazole. This may be especially prudent when an atypical antipsychotic is combined with an SSRI, as potential cardiac adverse effects may occur more frequently.

CORRESPONDENCE
Kyle Fletke, MD, Department of Family and Community Medicine, University of Maryland School of Medicine, 29 South Paca Street, Baltimore, MD 21201; [email protected]

THE CASE

A 23-year-old woman with past medical history of bipolar II disorder and a REM-specific seizure disorder that resolved at age 9 presented after a syncopal episode. The patient reported an initial sensation of lightheadedness while at work, which was followed by a syncopal episode with brief (1-2 min) loss of consciousness and a minor head injury.

She denied other prodromal symptoms including chest pain, shortness of breath, ­palpitations, and nausea. She also did not experience convulsions, urinary/bowel incontinence, or confusion upon regaining consciousness.

She denied previous syncopal episodes. However, she reported that, 2 weeks prior, there had been an event similar to that of her presenting complaint. During that episode, she experienced lightheadedness and a fall without loss of consciousness.

The patient had been prescribed a regimen of sertraline 100 mg/d and aripiprazole 10 mg/d to maintain mood stability. She had self-discontinued these medications about 8 months prior to presentation. A recent return of her depressive features had prompted a restart of this regimen 1 week before her first fall, without an initial taper upward.

While in the emergency department, she became bradycardic (heart rate, 38 beats/min) and hypotensive (blood pressure, 70/40 mm Hg). She subsequently became increasingly somnolent and had 1 episode of emesis. An electrocardiogram (EKG) revealed sinus bradycardia without other acute abnormalities (FIGURE).

Blood work including a basic metabolic panel, complete blood count, and cardiac enzymes were all within normal limits. Computed tomography of the head revealed no intracranial pathology. Her vitals were initially unresponsive to a fluid bolus but improved and stabilized after administration of intravenous atropine 0.5 mg.

Aripiprazole was held and sertraline was decreased to 75 mg on hospital Day 1, with close monitoring of her mood. Cardiology was consulted and followed the patient ­during her stay. The patient was monitored on telemetry for 3 days, exhibiting only sinus ­bradycardia with a stable heart rate of 45-55 beats/min. Systolic blood pressures were ­stable within 120 to 130 mm Hg. Transthoracic echocardiogram performed on hospital Day 2 was unremarkable, revealing a normal left ventricular ejection fraction of 65% and no wall motion abnormalities. She had no recurrence of the syncope or emesis.

Continue to: THE DIAGNOSIS

Given her benign cardiac work-up and symptom onset coinciding with the abrupt resumption of high doses of aripiprazole after an 8-month abstinence, the patient’s presentation was attributed to a rather uncommon adverse drug reaction to aripiprazole. This has only been described in a few case reports.

DISCUSSION

Aripiprazole (Abilify) is an atypical antipsychotic frequently used in the treatment of psychiatric conditions, including bipolar disorder and schizophrenia. While the specific therapeutic mechanism is unknown, it is believed that drug efficacy is related to partial agonism at dopamine D₂, serotonin 5-HT_1A, and serotonin 5-HT_2A.¹ As aripiprazole works on a variety of receptors involved in other physiologic processes, clinical adverse effects have been reported, most of which are associated with the adrenergic alpha₁ receptors.¹ These include cognitive impairment and seizures. Cardiovascular adverse effects of aripiprazole include orthostatic hypotension, cardiac arrhythmia, prolonged QT interval, and syncope.^1-5

Family physicians should inquire about aripiprazole use in patients who present with cardiac symptoms.

Selective serotonin reuptake inhibitors (SSRIs) such as sertraline (Zoloft) have also been shown to cause cardiac arrhythmia and syncope.⁶ Although sertraline may have contributed to the patient’s cardiac symptoms, it is more likely that the aripiprazole was the direct cause, as she remained asymptomatic while on a therapeutic dose of sertraline. Furthermore, aripiprazole is primarily metabolized though hepatic CYP2D6, which sertraline has been shown to inhibit.^1,7 Therefore, the concomitant use of sertraline with no initial taper of either medication likely led to an increased effective dose of aripiprazole in our patient and subsequently to her presentation.

Few prior cases have identified aripiprazole as a cause of antipsychotic-associated bradycardic response.⁸ Based on the Adverse Drug Reaction Probability Scale, often referred to as the Naranjo Scale, we believe this to be a probable adverse response in our patient.⁹ Bradycardia followed a reasonable temporal sequence after aripiprazole use with a response previously described in the literature. Symptoms also improved after discontinuation of the drug and other etiologies of the bradycardia were ruled out.

Our patient was discharged with a 30-day cardiac event monitor and a scheduled appointment with Cardiology.

Continue to: THE TAKEAWAY

As this case suggests, there may be an association between aripiprazole and symptomatic bradycardia. Therefore, family physicians should inquire about aripiprazole use in patients who present with cardiac symptoms and consider tapering this medication if other causes cannot be identified. Additionally, given the potential cardiac adverse effects of atypical antipsychotics, physicians may consider ordering baseline and follow-up EKGs to monitor for arrhythmias in patients prescribed aripiprazole. This may be especially prudent when an atypical antipsychotic is combined with an SSRI, as potential cardiac adverse effects may occur more frequently.

CORRESPONDENCE
Kyle Fletke, MD, Department of Family and Community Medicine, University of Maryland School of Medicine, 29 South Paca Street, Baltimore, MD 21201; [email protected]

THE CASE

A 23-year-old woman with past medical history of bipolar II disorder and a REM-specific seizure disorder that resolved at age 9 presented after a syncopal episode. The patient reported an initial sensation of lightheadedness while at work, which was followed by a syncopal episode with brief (1-2 min) loss of consciousness and a minor head injury.

She denied other prodromal symptoms including chest pain, shortness of breath, ­palpitations, and nausea. She also did not experience convulsions, urinary/bowel incontinence, or confusion upon regaining consciousness.

She denied previous syncopal episodes. However, she reported that, 2 weeks prior, there had been an event similar to that of her presenting complaint. During that episode, she experienced lightheadedness and a fall without loss of consciousness.

The patient had been prescribed a regimen of sertraline 100 mg/d and aripiprazole 10 mg/d to maintain mood stability. She had self-discontinued these medications about 8 months prior to presentation. A recent return of her depressive features had prompted a restart of this regimen 1 week before her first fall, without an initial taper upward.

While in the emergency department, she became bradycardic (heart rate, 38 beats/min) and hypotensive (blood pressure, 70/40 mm Hg). She subsequently became increasingly somnolent and had 1 episode of emesis. An electrocardiogram (EKG) revealed sinus bradycardia without other acute abnormalities (FIGURE).

Blood work including a basic metabolic panel, complete blood count, and cardiac enzymes were all within normal limits. Computed tomography of the head revealed no intracranial pathology. Her vitals were initially unresponsive to a fluid bolus but improved and stabilized after administration of intravenous atropine 0.5 mg.

Aripiprazole was held and sertraline was decreased to 75 mg on hospital Day 1, with close monitoring of her mood. Cardiology was consulted and followed the patient ­during her stay. The patient was monitored on telemetry for 3 days, exhibiting only sinus ­bradycardia with a stable heart rate of 45-55 beats/min. Systolic blood pressures were ­stable within 120 to 130 mm Hg. Transthoracic echocardiogram performed on hospital Day 2 was unremarkable, revealing a normal left ventricular ejection fraction of 65% and no wall motion abnormalities. She had no recurrence of the syncope or emesis.

Continue to: THE DIAGNOSIS

Given her benign cardiac work-up and symptom onset coinciding with the abrupt resumption of high doses of aripiprazole after an 8-month abstinence, the patient’s presentation was attributed to a rather uncommon adverse drug reaction to aripiprazole. This has only been described in a few case reports.

DISCUSSION

Aripiprazole (Abilify) is an atypical antipsychotic frequently used in the treatment of psychiatric conditions, including bipolar disorder and schizophrenia. While the specific therapeutic mechanism is unknown, it is believed that drug efficacy is related to partial agonism at dopamine D₂, serotonin 5-HT_1A, and serotonin 5-HT_2A.¹ As aripiprazole works on a variety of receptors involved in other physiologic processes, clinical adverse effects have been reported, most of which are associated with the adrenergic alpha₁ receptors.¹ These include cognitive impairment and seizures. Cardiovascular adverse effects of aripiprazole include orthostatic hypotension, cardiac arrhythmia, prolonged QT interval, and syncope.^1-5

Family physicians should inquire about aripiprazole use in patients who present with cardiac symptoms.

Selective serotonin reuptake inhibitors (SSRIs) such as sertraline (Zoloft) have also been shown to cause cardiac arrhythmia and syncope.⁶ Although sertraline may have contributed to the patient’s cardiac symptoms, it is more likely that the aripiprazole was the direct cause, as she remained asymptomatic while on a therapeutic dose of sertraline. Furthermore, aripiprazole is primarily metabolized though hepatic CYP2D6, which sertraline has been shown to inhibit.^1,7 Therefore, the concomitant use of sertraline with no initial taper of either medication likely led to an increased effective dose of aripiprazole in our patient and subsequently to her presentation.

Few prior cases have identified aripiprazole as a cause of antipsychotic-associated bradycardic response.⁸ Based on the Adverse Drug Reaction Probability Scale, often referred to as the Naranjo Scale, we believe this to be a probable adverse response in our patient.⁹ Bradycardia followed a reasonable temporal sequence after aripiprazole use with a response previously described in the literature. Symptoms also improved after discontinuation of the drug and other etiologies of the bradycardia were ruled out.

Our patient was discharged with a 30-day cardiac event monitor and a scheduled appointment with Cardiology.

Continue to: THE TAKEAWAY

As this case suggests, there may be an association between aripiprazole and symptomatic bradycardia. Therefore, family physicians should inquire about aripiprazole use in patients who present with cardiac symptoms and consider tapering this medication if other causes cannot be identified. Additionally, given the potential cardiac adverse effects of atypical antipsychotics, physicians may consider ordering baseline and follow-up EKGs to monitor for arrhythmias in patients prescribed aripiprazole. This may be especially prudent when an atypical antipsychotic is combined with an SSRI, as potential cardiac adverse effects may occur more frequently.

CORRESPONDENCE
Kyle Fletke, MD, Department of Family and Community Medicine, University of Maryland School of Medicine, 29 South Paca Street, Baltimore, MD 21201; [email protected]

In less than a year, COVID-19 has infected nearly 100 million people worldwide and caused more than 2 million deaths and counting. Although the infection fatality rate is estimated to be 1% and the case fatality rate between 2% and 3%, COVID-19 has had a disproportionate effect on the older population and those with comorbidities. Some of these findings are mirrored in the US Department of Veterans Affairs (VA) population, which has seen a higher case fatality rate.^1-4

As a respiratory tract infection, the most dreaded presentation is severe pneumonia with acute hypoxemia, which may rapidly deteriorate to acute respiratory distress syndrome (ARDS) and respiratory failure.^5-7 This possibility has led to early intubation strategies aimed at preempting this rapid deterioration and minimizing viral exposure to health care workers. Intubation rates have varied widely with extremes of 6 to 88%.^8,9

However, this early intubation strategy has waned as some of the rationale behind its endorsement has been called into question. Early intubation bypasses alternatives to intubation; high-flow nasal cannula oxygen, noninvasive ventilation, and awake proning are all effective maneuvers in the appropriate patient.^10,11 The use of first-line high-flow nasal cannula oxygen and noninvasive ventilation has been widely reported. Reports of first-line use of high-flow nasal cannula oxygen has not demonstrated inferior outcomes, nor has the timing of intubation, suggesting a significant portion of patients could benefit from a trial of therapy and eventually avoid intubation.^11-14 Other therapies, such as systemic corticosteroids, confer a mortality benefit in those patients with COVID-19 who require oxygen or mechanical ventilation, but their impact on the progression of respiratory failure and need for intubation are undetermined.

There also are reports of patients who report no signs of respiratory distress or dyspnea with their COVID-19 pneumonia despite profound hypoxemia or high oxygen requirements. Various terms, including silent hypoxemia or happy hypoxia, are descriptive of the demeanor of these patients, and treatment has invariably included oxygen.^15,16 Nevertheless, low oxygen measurements have generally prompted higher levels of supplemental oxygen or more invasive therapies.

Treatment rendered may obscure the trajectory of response, which is important to understand to better position options for invasive therapies and other therapeutics. We recently encountered a patient with a course of illness that represented the natural history of COVID-19 pneumonia with low oxygen levels (referred to as hypoxemia for consistency) that highlighted several issues of management.

Case Presentation

A 62-year-old undomiciled woman with morbid obesity, prediabetes mellitus, long-standing schizophrenia, and bipolar disorder presented to our facility for evaluation of dry cough and need for tuberculosis clearance for admittance to a shelter. She appeared comfortable and was afebrile with blood pressure 111/74 mm Hg, heart rate 82 beats per minute. Her respiratory rate was 18 breaths per minute, but the pulse oximetry showed oxygen saturation of 70 to 75% on room air at rest. A chest X-ray showed bibasilar infiltrates (Figure 1), and a rapid COVID-19 nasopharyngeal polymerase chain reaction (PCR) test returned positive, confirmed by a second PCR test. Baseline inflammatory markers were elevated (Figure 2). In addition, the serum interleukin-6 also was elevated to 66.1 pg/mL (normal < 5.0), erythrocyte sedimentation rate elevated to 69 mm/h, but serum procalcitonin was essentially normal (0.22 ng/mL; normal < 20 ng/mL) as was the serum lactate (1.4 mmol/L).

The patient was admitted to the intensive care unit (ICU) for close monitoring in anticipation of the possibility of decompensation based on her age, hypoxia, and elevated inflammatory markers.¹⁷ Besides a subsequent low-grade fever (100.4 oF) and lymphopenia (manual count 550/uL), she remained clinically unchanged. Throughout her hospitalization, she maintained a persistent psychotic delusion that she did not have COVID-19, refusing all medical interventions, including a peripheral IV line and supplemental oxygen for the entire duration. Extensive efforts to identify family or a surrogate decision maker were unsuccessful. After consultation with Psychiatry, Bio-Ethics, and hospital leadership, the patient was deemed to lack decision-making capacity regarding treatment or disposition and was placed on a psychiatric hold. However, since any interventions against her will would require sedation, IV access, and potentially increase the risk of nosocomial COVID-19 transmission, she was allowed to remain untreated and was closely monitored for symptoms of worsening respiratory failure.

Discussion

The initial reports of COVID-19 pneumonia focused on ARDS and respiratory failure requiring mechanical ventilation with less emphasis on those with lower severity of illness. This was heightened by health care systems that were overwhelmed with large number of patients while faced with limited supplies and equipment. Given the risk to patients and providers of crash intubations, some recommended early intubation strategies.³ However, the natural history of COVID-19 pneumonia and the threshold for intubation of these patients remain poorly defined despite the creation of prognostic tools.¹⁷ This patient’s persistent hypoxemia and elevated inflammatory markers certainly met markers of disease associated with a high risk of progression.

The greatest concern would have been her level of hypoxemia. Acceptable thresholds of hypoxemia vary, but general consensus would classify pulse oximetry < 90% as hypoxemia and a threshold for administering supplemental oxygen. It is important to recognize how pulse oximetry readings translate to partial pressure of oxygen (PaO₂) measurements (Table 1). Pulse oximetry readings of 90% corresponds to a PaO₂ readings of 60 mm Hg in ideal conditions without the influence of acidosis, PaCO₂, or temperature. While lower readings are of concern, these do not represent absolute indications for assisted ventilatory support as lower levels are well tolerated in a variety of conditions. A common example are patients with chronic obstructive pulmonary disease. Long-term mortality benefits of continuous supplemental oxygen are well established in specific populations, but the threshold for correction in the acute setting remains a case-by-case decision. This decision is complex and is based on more than an absolute number or the amount of oxygen required to achieve a threshold level of oxygenation.

The severity of hypoxemia manifested by this patient may have elicited additional findings of respiratory distress, such as dyspnea and tachypnea. However, in patients with severe COVID-19 pneumonia, dyspnea was not a universal finding, reported in the 20 to 60% range of cohorts, higher in those with ARDS and mechanical ventilation, although some report near universal dyspnea in their series.^1,4,8,22,23 Tachypnea is another symptom of interest. Using a threshold of > 24 breaths/min, tachypnea was noted in 16 to 29% of patients with a much greater proportion (63%) in nonsurvivors.^6,24 Several explanations have been proposed for the discordance between the presence and severity of hypoxemia and lack of symptoms of dyspnea and tachypnea. It is important to recognize that misclassification of the severity of hypoxemia can occur due to technical issues and potential errors involving pulse oximetry measurement and shifts in the oxyhemoglobin dissociation curve. However, this is more pertinent for those with mild disease as the severity of hypoxemia in severe pneumonia is beyond what can be attributed to technical issues.

More important, the ventilatory response curve to hypoxemia may not be normal for some patients, blunted by as much as 50% in older patients, especially in those with diabetes mellitus.^7,25,26 In addition, the ventilatory response varies widely even among normal individuals. This would translate to lower levels of minute ventilation (less tachypnea or respiratory effort) with hypoxemia. Hypocapnic hypoxemia also blunts the ventilatory response to hypoxemia. Subjects do not increase their minute ventilation if the PaCO₂ remains low despite oxygen desaturation to < 70%, especially if PaCO₂ < 30 mm Hg or alternatively, increases in minute ventilation are not seen until the PaCO₂ exceeds 39 mm Hg.²⁷ Both scenarios occur in those with COVID-19 pneumonia and provide another explanation for the absence of respiratory symptoms or signs of respiratory distress in some patients.

The observation of more compliant lungs may help in the understanding of the variable presentation of these patients. Compliant lungs do not require the increased pressure needed to achieve a specific tidal volume that, in turn, may increase the work of breathing. This may add to the explanation of seemingly paradoxical silent hypoxemia in those patients where the combination of a blunted ventilatory response, hypocapnia, shunt physiology, and normal respiratory system compliance is represented by the absence of increased breathing effort despite severe hypoxemia.

If not for the patient’s refusal of medical services, this patient quite possibly would have been intubated due to hypoxemia and health care providers’ concern for her risk of deterioration. Reported intubation and mechanical ventilation rates have varied widely from extremes of from < 5 to 88% in severely ill patients.^9,22 About 75% will need oxygen, but many can be treated and recover without the need for intubation and mechanical ventilation.

As previously mentioned, options for treatment include standard and high-flow oxygen delivery, noninvasive ventilation, and awake prone ventilation. Their role in patient management has been recently outlined, and instead of an early intubation strategy, represents gradual escalation of support that may be sufficient to treat hypoxemia and avoid the need for intubation and mechanical ventilation (Table 2).

Conclusions

Since the emergence of the COVID-19, evidence has accumulated for the benefit of several adjunctive therapies in the treatment of this type of pneumonia, with corticosteroids providing a mortality benefit. Although unknown whether this patient’s experience can be generalized to others or whether it represents her unique response, this case provides another perspective for comparison of treatments and reinforces the need for prospective, randomized clinical trials to establish treatment efficacy. The exact nature of silent hypoxemia of COVID-19 remains incompletely understood; however, this case highlights the importance of treating the individual instead of clinical markers and provides a time course for recovery from pneumonia and severe hypoxemia that occurs without oxygen or any other treatment over about 2 weeks.

In less than a year, COVID-19 has infected nearly 100 million people worldwide and caused more than 2 million deaths and counting. Although the infection fatality rate is estimated to be 1% and the case fatality rate between 2% and 3%, COVID-19 has had a disproportionate effect on the older population and those with comorbidities. Some of these findings are mirrored in the US Department of Veterans Affairs (VA) population, which has seen a higher case fatality rate.^1-4

As a respiratory tract infection, the most dreaded presentation is severe pneumonia with acute hypoxemia, which may rapidly deteriorate to acute respiratory distress syndrome (ARDS) and respiratory failure.^5-7 This possibility has led to early intubation strategies aimed at preempting this rapid deterioration and minimizing viral exposure to health care workers. Intubation rates have varied widely with extremes of 6 to 88%.^8,9

However, this early intubation strategy has waned as some of the rationale behind its endorsement has been called into question. Early intubation bypasses alternatives to intubation; high-flow nasal cannula oxygen, noninvasive ventilation, and awake proning are all effective maneuvers in the appropriate patient.^10,11 The use of first-line high-flow nasal cannula oxygen and noninvasive ventilation has been widely reported. Reports of first-line use of high-flow nasal cannula oxygen has not demonstrated inferior outcomes, nor has the timing of intubation, suggesting a significant portion of patients could benefit from a trial of therapy and eventually avoid intubation.^11-14 Other therapies, such as systemic corticosteroids, confer a mortality benefit in those patients with COVID-19 who require oxygen or mechanical ventilation, but their impact on the progression of respiratory failure and need for intubation are undetermined.

There also are reports of patients who report no signs of respiratory distress or dyspnea with their COVID-19 pneumonia despite profound hypoxemia or high oxygen requirements. Various terms, including silent hypoxemia or happy hypoxia, are descriptive of the demeanor of these patients, and treatment has invariably included oxygen.^15,16 Nevertheless, low oxygen measurements have generally prompted higher levels of supplemental oxygen or more invasive therapies.

Treatment rendered may obscure the trajectory of response, which is important to understand to better position options for invasive therapies and other therapeutics. We recently encountered a patient with a course of illness that represented the natural history of COVID-19 pneumonia with low oxygen levels (referred to as hypoxemia for consistency) that highlighted several issues of management.

Case Presentation

A 62-year-old undomiciled woman with morbid obesity, prediabetes mellitus, long-standing schizophrenia, and bipolar disorder presented to our facility for evaluation of dry cough and need for tuberculosis clearance for admittance to a shelter. She appeared comfortable and was afebrile with blood pressure 111/74 mm Hg, heart rate 82 beats per minute. Her respiratory rate was 18 breaths per minute, but the pulse oximetry showed oxygen saturation of 70 to 75% on room air at rest. A chest X-ray showed bibasilar infiltrates (Figure 1), and a rapid COVID-19 nasopharyngeal polymerase chain reaction (PCR) test returned positive, confirmed by a second PCR test. Baseline inflammatory markers were elevated (Figure 2). In addition, the serum interleukin-6 also was elevated to 66.1 pg/mL (normal < 5.0), erythrocyte sedimentation rate elevated to 69 mm/h, but serum procalcitonin was essentially normal (0.22 ng/mL; normal < 20 ng/mL) as was the serum lactate (1.4 mmol/L).

The patient was admitted to the intensive care unit (ICU) for close monitoring in anticipation of the possibility of decompensation based on her age, hypoxia, and elevated inflammatory markers.¹⁷ Besides a subsequent low-grade fever (100.4 oF) and lymphopenia (manual count 550/uL), she remained clinically unchanged. Throughout her hospitalization, she maintained a persistent psychotic delusion that she did not have COVID-19, refusing all medical interventions, including a peripheral IV line and supplemental oxygen for the entire duration. Extensive efforts to identify family or a surrogate decision maker were unsuccessful. After consultation with Psychiatry, Bio-Ethics, and hospital leadership, the patient was deemed to lack decision-making capacity regarding treatment or disposition and was placed on a psychiatric hold. However, since any interventions against her will would require sedation, IV access, and potentially increase the risk of nosocomial COVID-19 transmission, she was allowed to remain untreated and was closely monitored for symptoms of worsening respiratory failure.

Discussion

The initial reports of COVID-19 pneumonia focused on ARDS and respiratory failure requiring mechanical ventilation with less emphasis on those with lower severity of illness. This was heightened by health care systems that were overwhelmed with large number of patients while faced with limited supplies and equipment. Given the risk to patients and providers of crash intubations, some recommended early intubation strategies.³ However, the natural history of COVID-19 pneumonia and the threshold for intubation of these patients remain poorly defined despite the creation of prognostic tools.¹⁷ This patient’s persistent hypoxemia and elevated inflammatory markers certainly met markers of disease associated with a high risk of progression.

The greatest concern would have been her level of hypoxemia. Acceptable thresholds of hypoxemia vary, but general consensus would classify pulse oximetry < 90% as hypoxemia and a threshold for administering supplemental oxygen. It is important to recognize how pulse oximetry readings translate to partial pressure of oxygen (PaO₂) measurements (Table 1). Pulse oximetry readings of 90% corresponds to a PaO₂ readings of 60 mm Hg in ideal conditions without the influence of acidosis, PaCO₂, or temperature. While lower readings are of concern, these do not represent absolute indications for assisted ventilatory support as lower levels are well tolerated in a variety of conditions. A common example are patients with chronic obstructive pulmonary disease. Long-term mortality benefits of continuous supplemental oxygen are well established in specific populations, but the threshold for correction in the acute setting remains a case-by-case decision. This decision is complex and is based on more than an absolute number or the amount of oxygen required to achieve a threshold level of oxygenation.

The severity of hypoxemia manifested by this patient may have elicited additional findings of respiratory distress, such as dyspnea and tachypnea. However, in patients with severe COVID-19 pneumonia, dyspnea was not a universal finding, reported in the 20 to 60% range of cohorts, higher in those with ARDS and mechanical ventilation, although some report near universal dyspnea in their series.^1,4,8,22,23 Tachypnea is another symptom of interest. Using a threshold of > 24 breaths/min, tachypnea was noted in 16 to 29% of patients with a much greater proportion (63%) in nonsurvivors.^6,24 Several explanations have been proposed for the discordance between the presence and severity of hypoxemia and lack of symptoms of dyspnea and tachypnea. It is important to recognize that misclassification of the severity of hypoxemia can occur due to technical issues and potential errors involving pulse oximetry measurement and shifts in the oxyhemoglobin dissociation curve. However, this is more pertinent for those with mild disease as the severity of hypoxemia in severe pneumonia is beyond what can be attributed to technical issues.

More important, the ventilatory response curve to hypoxemia may not be normal for some patients, blunted by as much as 50% in older patients, especially in those with diabetes mellitus.^7,25,26 In addition, the ventilatory response varies widely even among normal individuals. This would translate to lower levels of minute ventilation (less tachypnea or respiratory effort) with hypoxemia. Hypocapnic hypoxemia also blunts the ventilatory response to hypoxemia. Subjects do not increase their minute ventilation if the PaCO₂ remains low despite oxygen desaturation to < 70%, especially if PaCO₂ < 30 mm Hg or alternatively, increases in minute ventilation are not seen until the PaCO₂ exceeds 39 mm Hg.²⁷ Both scenarios occur in those with COVID-19 pneumonia and provide another explanation for the absence of respiratory symptoms or signs of respiratory distress in some patients.

The observation of more compliant lungs may help in the understanding of the variable presentation of these patients. Compliant lungs do not require the increased pressure needed to achieve a specific tidal volume that, in turn, may increase the work of breathing. This may add to the explanation of seemingly paradoxical silent hypoxemia in those patients where the combination of a blunted ventilatory response, hypocapnia, shunt physiology, and normal respiratory system compliance is represented by the absence of increased breathing effort despite severe hypoxemia.

If not for the patient’s refusal of medical services, this patient quite possibly would have been intubated due to hypoxemia and health care providers’ concern for her risk of deterioration. Reported intubation and mechanical ventilation rates have varied widely from extremes of from < 5 to 88% in severely ill patients.^9,22 About 75% will need oxygen, but many can be treated and recover without the need for intubation and mechanical ventilation.

As previously mentioned, options for treatment include standard and high-flow oxygen delivery, noninvasive ventilation, and awake prone ventilation. Their role in patient management has been recently outlined, and instead of an early intubation strategy, represents gradual escalation of support that may be sufficient to treat hypoxemia and avoid the need for intubation and mechanical ventilation (Table 2).

Conclusions

Since the emergence of the COVID-19, evidence has accumulated for the benefit of several adjunctive therapies in the treatment of this type of pneumonia, with corticosteroids providing a mortality benefit. Although unknown whether this patient’s experience can be generalized to others or whether it represents her unique response, this case provides another perspective for comparison of treatments and reinforces the need for prospective, randomized clinical trials to establish treatment efficacy. The exact nature of silent hypoxemia of COVID-19 remains incompletely understood; however, this case highlights the importance of treating the individual instead of clinical markers and provides a time course for recovery from pneumonia and severe hypoxemia that occurs without oxygen or any other treatment over about 2 weeks.

In less than a year, COVID-19 has infected nearly 100 million people worldwide and caused more than 2 million deaths and counting. Although the infection fatality rate is estimated to be 1% and the case fatality rate between 2% and 3%, COVID-19 has had a disproportionate effect on the older population and those with comorbidities. Some of these findings are mirrored in the US Department of Veterans Affairs (VA) population, which has seen a higher case fatality rate.^1-4

As a respiratory tract infection, the most dreaded presentation is severe pneumonia with acute hypoxemia, which may rapidly deteriorate to acute respiratory distress syndrome (ARDS) and respiratory failure.^5-7 This possibility has led to early intubation strategies aimed at preempting this rapid deterioration and minimizing viral exposure to health care workers. Intubation rates have varied widely with extremes of 6 to 88%.^8,9

However, this early intubation strategy has waned as some of the rationale behind its endorsement has been called into question. Early intubation bypasses alternatives to intubation; high-flow nasal cannula oxygen, noninvasive ventilation, and awake proning are all effective maneuvers in the appropriate patient.^10,11 The use of first-line high-flow nasal cannula oxygen and noninvasive ventilation has been widely reported. Reports of first-line use of high-flow nasal cannula oxygen has not demonstrated inferior outcomes, nor has the timing of intubation, suggesting a significant portion of patients could benefit from a trial of therapy and eventually avoid intubation.^11-14 Other therapies, such as systemic corticosteroids, confer a mortality benefit in those patients with COVID-19 who require oxygen or mechanical ventilation, but their impact on the progression of respiratory failure and need for intubation are undetermined.

There also are reports of patients who report no signs of respiratory distress or dyspnea with their COVID-19 pneumonia despite profound hypoxemia or high oxygen requirements. Various terms, including silent hypoxemia or happy hypoxia, are descriptive of the demeanor of these patients, and treatment has invariably included oxygen.^15,16 Nevertheless, low oxygen measurements have generally prompted higher levels of supplemental oxygen or more invasive therapies.

Treatment rendered may obscure the trajectory of response, which is important to understand to better position options for invasive therapies and other therapeutics. We recently encountered a patient with a course of illness that represented the natural history of COVID-19 pneumonia with low oxygen levels (referred to as hypoxemia for consistency) that highlighted several issues of management.

Case Presentation

A 62-year-old undomiciled woman with morbid obesity, prediabetes mellitus, long-standing schizophrenia, and bipolar disorder presented to our facility for evaluation of dry cough and need for tuberculosis clearance for admittance to a shelter. She appeared comfortable and was afebrile with blood pressure 111/74 mm Hg, heart rate 82 beats per minute. Her respiratory rate was 18 breaths per minute, but the pulse oximetry showed oxygen saturation of 70 to 75% on room air at rest. A chest X-ray showed bibasilar infiltrates (Figure 1), and a rapid COVID-19 nasopharyngeal polymerase chain reaction (PCR) test returned positive, confirmed by a second PCR test. Baseline inflammatory markers were elevated (Figure 2). In addition, the serum interleukin-6 also was elevated to 66.1 pg/mL (normal < 5.0), erythrocyte sedimentation rate elevated to 69 mm/h, but serum procalcitonin was essentially normal (0.22 ng/mL; normal < 20 ng/mL) as was the serum lactate (1.4 mmol/L).

The patient was admitted to the intensive care unit (ICU) for close monitoring in anticipation of the possibility of decompensation based on her age, hypoxia, and elevated inflammatory markers.¹⁷ Besides a subsequent low-grade fever (100.4 oF) and lymphopenia (manual count 550/uL), she remained clinically unchanged. Throughout her hospitalization, she maintained a persistent psychotic delusion that she did not have COVID-19, refusing all medical interventions, including a peripheral IV line and supplemental oxygen for the entire duration. Extensive efforts to identify family or a surrogate decision maker were unsuccessful. After consultation with Psychiatry, Bio-Ethics, and hospital leadership, the patient was deemed to lack decision-making capacity regarding treatment or disposition and was placed on a psychiatric hold. However, since any interventions against her will would require sedation, IV access, and potentially increase the risk of nosocomial COVID-19 transmission, she was allowed to remain untreated and was closely monitored for symptoms of worsening respiratory failure.

Discussion

The initial reports of COVID-19 pneumonia focused on ARDS and respiratory failure requiring mechanical ventilation with less emphasis on those with lower severity of illness. This was heightened by health care systems that were overwhelmed with large number of patients while faced with limited supplies and equipment. Given the risk to patients and providers of crash intubations, some recommended early intubation strategies.³ However, the natural history of COVID-19 pneumonia and the threshold for intubation of these patients remain poorly defined despite the creation of prognostic tools.¹⁷ This patient’s persistent hypoxemia and elevated inflammatory markers certainly met markers of disease associated with a high risk of progression.

The greatest concern would have been her level of hypoxemia. Acceptable thresholds of hypoxemia vary, but general consensus would classify pulse oximetry < 90% as hypoxemia and a threshold for administering supplemental oxygen. It is important to recognize how pulse oximetry readings translate to partial pressure of oxygen (PaO₂) measurements (Table 1). Pulse oximetry readings of 90% corresponds to a PaO₂ readings of 60 mm Hg in ideal conditions without the influence of acidosis, PaCO₂, or temperature. While lower readings are of concern, these do not represent absolute indications for assisted ventilatory support as lower levels are well tolerated in a variety of conditions. A common example are patients with chronic obstructive pulmonary disease. Long-term mortality benefits of continuous supplemental oxygen are well established in specific populations, but the threshold for correction in the acute setting remains a case-by-case decision. This decision is complex and is based on more than an absolute number or the amount of oxygen required to achieve a threshold level of oxygenation.

The severity of hypoxemia manifested by this patient may have elicited additional findings of respiratory distress, such as dyspnea and tachypnea. However, in patients with severe COVID-19 pneumonia, dyspnea was not a universal finding, reported in the 20 to 60% range of cohorts, higher in those with ARDS and mechanical ventilation, although some report near universal dyspnea in their series.^1,4,8,22,23 Tachypnea is another symptom of interest. Using a threshold of > 24 breaths/min, tachypnea was noted in 16 to 29% of patients with a much greater proportion (63%) in nonsurvivors.^6,24 Several explanations have been proposed for the discordance between the presence and severity of hypoxemia and lack of symptoms of dyspnea and tachypnea. It is important to recognize that misclassification of the severity of hypoxemia can occur due to technical issues and potential errors involving pulse oximetry measurement and shifts in the oxyhemoglobin dissociation curve. However, this is more pertinent for those with mild disease as the severity of hypoxemia in severe pneumonia is beyond what can be attributed to technical issues.

More important, the ventilatory response curve to hypoxemia may not be normal for some patients, blunted by as much as 50% in older patients, especially in those with diabetes mellitus.^7,25,26 In addition, the ventilatory response varies widely even among normal individuals. This would translate to lower levels of minute ventilation (less tachypnea or respiratory effort) with hypoxemia. Hypocapnic hypoxemia also blunts the ventilatory response to hypoxemia. Subjects do not increase their minute ventilation if the PaCO₂ remains low despite oxygen desaturation to < 70%, especially if PaCO₂ < 30 mm Hg or alternatively, increases in minute ventilation are not seen until the PaCO₂ exceeds 39 mm Hg.²⁷ Both scenarios occur in those with COVID-19 pneumonia and provide another explanation for the absence of respiratory symptoms or signs of respiratory distress in some patients.

The observation of more compliant lungs may help in the understanding of the variable presentation of these patients. Compliant lungs do not require the increased pressure needed to achieve a specific tidal volume that, in turn, may increase the work of breathing. This may add to the explanation of seemingly paradoxical silent hypoxemia in those patients where the combination of a blunted ventilatory response, hypocapnia, shunt physiology, and normal respiratory system compliance is represented by the absence of increased breathing effort despite severe hypoxemia.

If not for the patient’s refusal of medical services, this patient quite possibly would have been intubated due to hypoxemia and health care providers’ concern for her risk of deterioration. Reported intubation and mechanical ventilation rates have varied widely from extremes of from < 5 to 88% in severely ill patients.^9,22 About 75% will need oxygen, but many can be treated and recover without the need for intubation and mechanical ventilation.

As previously mentioned, options for treatment include standard and high-flow oxygen delivery, noninvasive ventilation, and awake prone ventilation. Their role in patient management has been recently outlined, and instead of an early intubation strategy, represents gradual escalation of support that may be sufficient to treat hypoxemia and avoid the need for intubation and mechanical ventilation (Table 2).

Conclusions

Since the emergence of the COVID-19, evidence has accumulated for the benefit of several adjunctive therapies in the treatment of this type of pneumonia, with corticosteroids providing a mortality benefit. Although unknown whether this patient’s experience can be generalized to others or whether it represents her unique response, this case provides another perspective for comparison of treatments and reinforces the need for prospective, randomized clinical trials to establish treatment efficacy. The exact nature of silent hypoxemia of COVID-19 remains incompletely understood; however, this case highlights the importance of treating the individual instead of clinical markers and provides a time course for recovery from pneumonia and severe hypoxemia that occurs without oxygen or any other treatment over about 2 weeks.

Metabolic alkalosis, a disorder that causes elevations in serum bicarbonate and arterial pH, is a common metabolic abnormality found in nearly half of hospitalized patients but is rare in patients with end-stage renal disease (ESRD) on hemodialysis (HD) during the pretreatment state. The problem seems to arise due to a high rate of older patients with multiple comorbidities and malnutrition who are undergoing HD. Metabolic alkalosis is associated with increased morbidity and mortality. In this report, we present a case of metabolic alkalosis, describe an innovative approach to manage metabolic alkalosis in the dialysis population, and review the pathophysiology.

Case Presentation

A 63-year-old female with emphysema, diabetic nephropathy, and ESRD on regular HD for 2 months by a tunneled subclavian vein catheter was admitted with 2 weeks of orthopnea and leg swelling. The review of systems was negative for chest pain, cough, wheeze, or sputum production. She was a former smoker with no alcohol or drug misuse. The patient was taking carvedilol 25 mg daily, furosemide 20 mg twice daily, basal insulin premeal, lisinopril 40 mg daily, pantoprazole 40 mg daily, calcium carbonate 400 mg 3 times daily, ferrous sulphate 325 mg daily, and a vilanterol/tiotropium inhaler once daily. Her dialysate outpatient prescription included sodium 140 mEq/L, potassium 2 mEq/L, calcium 2.5 mEq/L, and bicarbonate 36 mEq/L. Our dialysis unit used NaturaLyte dry pack for bicarbonate dialysis.

The patient appeared tachypneic with 26 respirations/min, oxygen saturation of 89% on room air, which improved to 94% on a 2 L nasal cannula. Her heart rate was 89 beats/min, blood pressure was 129/72 mm Hg, and body mass index was 21.2. The physical examination revealed jugular venous distension, lung crackles, reduced air entry, and pedal edema. Muscle wasting was noted in the arms and thighs. The tunnel catheter did not appear infected.

The patient’s blood work showed sodium, 136 (reference, 132-140) mmol/L; potassium, 4.3 (reference, 3.5-5.0) mmol/L; chloride, 89 (reference, 98-111) mmol/L; total CO₂, 36 (reference, 24-28) mEq/L; blood urea nitrogen, 21 (reference, 7-21) mg/dL; creatinine 3.4 (reference, 0.5-1.4) mg/dL; and albumin, 2.7 (reference, 3.7-5.0) mg/dL. Arterial gases showed pH, 7.56 (reference, 7.35-7.45), partial CO₂, 47 (reference, 35-45) mm Hg; bicarbonate, 42 (reference, 22-26) mEq/L; partial O₂, 54 (reference, 75 to 100) mm Hg. Brain natriuretic peptide was 2,800 (normal, < 100) pg/mL with a normal troponin. X-rays showed pulmonary congestion and bilateral pleural effusions that were transudative on fluid analysis. An echocardiogram showed ejection fraction of 20 to 25% with normal valves (baseline ejection fraction of 60%-65%). A coronary arteriogram revealed severe nonischemic cardiomyopathy.

Treatment

To reduce bicarbonate levels, 3 L of normal saline solution were infused prefilter during HD, and ultrafiltration (UF) of 4.5 L achieved a net UF of -1.5 L over 3.5 hours on lower dialysate bicarbonate (30 mEq/L). Good catheter flow was achieved with a blood flow rate of 350 mL/min and a dialysate flow of 700 mL/min. Venous blood gases and basic serum metabolic panels were obtained throughout the first HD session (Table 1). Improvement in pH from 7.5 to 7.43 and in total CO₂ from 36 to 30 mEq/L were noted after the treatment. Subsequently, we used the same membrane (Optiflux F160NRe) for 2 consecutive daily treatments to remove excess fluid and prevent worsening alkalosis using the same minimal bicarbonate bath, but no further normal saline solution was given.

Outcome

Volume overload was controlled as needed with UF. The bicarbonate did not drop after the second HD session, suggesting low organic acid production in the intradialytic period. By shortening the duration of dialysis to 3 hours and improving nutritional intake, we achieved dry weight, and the patient was discharged home with a total CO₂ of 25 mEq/L. Outpatient dialysis sessions were arranged to run at shorter duration (3 hours compared with 3.5 hours) and use low bicarbonate dialysate. The patient was admitted several times afterward for acute decompensated heart failure, but in all those admissions, her bicarbonate was in the normal-to-high range, between 23 and 30 mEq/L.

Discussion

Metabolic alkalosis is relatively rare in ESRD patients on HD. Particularly in the predialysis period, but with the growing number of older patients undergoing HD and the aggressive treatment of acidosis with relatively higher buffer concentrations; there has been an increase in the incidence of metabolic alkalosis in patients on HD. In the Fresenius Medical Care (FMC) prevalent HD patient study, predialysis bicarbonate levels have increased overtime from a mean (SD)22.9 (3.1) mEq/L in 2004 to a mean (SD) 24.1 (3.5) mEq/L in September 2011, with 25% of patients > 26.0 mEq/L compared with only 6% in 2004.¹ The condition has been associated with cardiac arrhythmia, intradialytic hypocalcemia, hypokalemia, hypercapnia, hypoxia, accelerated hypertension, and seizure.^2-4 Metabolic alkalosis may be associated with increased mortality.^5-7 However, the effect dissipated after adjusting for inflammation and nutritional status.⁶

Our patient had primary metabolic alkalosis evident by her high pH of 7.56 and high total CO₂ of 36 mEq/L. The serum total CO₂ reflects the metabolic status more accurately than the blood gas bicarbonate, which is prone to calculation error by the Henderson-Hasselbalch equation. Her respiratory compensation for the metabolic alkalosis was appropriate, with an increase of arterial PaCO₂ to 47 mm Hg (expected PaCO₂ = 40 + 0.7[HCO₃-24] = 48.4). She had normal baseline PaCO₂ in the weeks prior to admission. Due to lack of residual urine output, < 50 mL/d, her metabolic alkalosis could not be attributed to the generation of bicarbonate by the kidneys, or ameliorated by dumping of excess bicarbonate, which explained why her metabolic alkalosis was severe. On the other hand, respiratory distress may have hindered the appropriate CO₂ retention.

In patients with ESRD on HD who have no residual urine output, causes of metabolic alkalosis are limited to loss of net acid or gain of alkali through the gastrointestinal tract; our patient had none of these. Similarly, all renal causes of metabolic alkalosis are not applicable to our patient, including mineralocorticoid excess and contraction alkalosis. In patients with preserved kidney function, loop diuretics can induce alkalosis through enhanced tubular absorption of HCO₃. While acetazolamide can mitigate this scenario by blocking carbonic anhydrase in the luminal border of the collecting ducts resulting in excretion of bicarbonate in the urine, our patient had negligible urine output despite being on furosemide 20 mg twice daily, making this an unlikely cause.

Severe metabolic alkalosis in dialysis patients has been reported with cocaine use, pica ingestion, and citrate load as in plasma exchange, massive transfusions, and regional anticoagulation.^2,8-11 Although calcium carbonate intake can contribute to alkalosis, her small daily dose of 1,200 mg contains approximately 12 mEq of carbonate, which is not a significant contributor to the alkalosis.

With all other causes excluded, the metabolic alkalosis in our patient is presumed to result from the bicarbonate-rich dialysate. Since the majority of patients with ESRD are acidotic before dialysis, the dialysate bicarbonate is set at a higher than normal physiologic level to bring the pH close to or even higher than normal after dialysis. The patient had been dialyzed with NaturaLyte as an outpatient, which was set at the dialysis unit default mode of 36 mEq/L. This form of alkalosis has been reported to peak immediately after treatment but in most patients returns to the predialysis acidotic state due to endogenous acid production.^1,4,12 Normally, muscles play a significant role in buffering excess bicarbonate in patients with nonfunctioning kidneys; hence, malnutrition with muscle wasting tends to propagate and maintain alkalosis, as in our patient.

Managing alkalosis in patients on dialysis can be challenging and is often directed at identifying potential causes like overzealous bicarbonate dialysate and addressing comorbidities, especially malnutrition.^6,7 Bicarbonate delivery can be set on dialysis machines as low as 20 mEq/L. However, the reliability of correcting serum bicarbonate by adjusting bicarbonate-based dialysis products is in question as these products deliver additional buffering capacity through mixing and metabolism of acetate, acetic acid, or citric acid (Table 2).

Conclusions

Attention should be paid to detect elevated predialysis serum bicarbonate levels in ESRD patients on HD, especially those with values above 27 mmol/L due to higher mortality.^6,7 Treatment of these patients is more challenging than for those who are acidotic predialysis, especially when alkalosis is compounded by malnutrition. Mitigation of this problem is achieved by using a lower bicarbonate bath and the shortest effective dialysis duration that achieves adequate clearance. Poor clearance also deleteriously affects patient nutrition and well-being. We have shown that normal saline solution infusion with concurrent removal by UF can correct pretreatment metabolic alkalosis when other measures are inadequate.

Metabolic alkalosis, a disorder that causes elevations in serum bicarbonate and arterial pH, is a common metabolic abnormality found in nearly half of hospitalized patients but is rare in patients with end-stage renal disease (ESRD) on hemodialysis (HD) during the pretreatment state. The problem seems to arise due to a high rate of older patients with multiple comorbidities and malnutrition who are undergoing HD. Metabolic alkalosis is associated with increased morbidity and mortality. In this report, we present a case of metabolic alkalosis, describe an innovative approach to manage metabolic alkalosis in the dialysis population, and review the pathophysiology.

Case Presentation

A 63-year-old female with emphysema, diabetic nephropathy, and ESRD on regular HD for 2 months by a tunneled subclavian vein catheter was admitted with 2 weeks of orthopnea and leg swelling. The review of systems was negative for chest pain, cough, wheeze, or sputum production. She was a former smoker with no alcohol or drug misuse. The patient was taking carvedilol 25 mg daily, furosemide 20 mg twice daily, basal insulin premeal, lisinopril 40 mg daily, pantoprazole 40 mg daily, calcium carbonate 400 mg 3 times daily, ferrous sulphate 325 mg daily, and a vilanterol/tiotropium inhaler once daily. Her dialysate outpatient prescription included sodium 140 mEq/L, potassium 2 mEq/L, calcium 2.5 mEq/L, and bicarbonate 36 mEq/L. Our dialysis unit used NaturaLyte dry pack for bicarbonate dialysis.

The patient appeared tachypneic with 26 respirations/min, oxygen saturation of 89% on room air, which improved to 94% on a 2 L nasal cannula. Her heart rate was 89 beats/min, blood pressure was 129/72 mm Hg, and body mass index was 21.2. The physical examination revealed jugular venous distension, lung crackles, reduced air entry, and pedal edema. Muscle wasting was noted in the arms and thighs. The tunnel catheter did not appear infected.

The patient’s blood work showed sodium, 136 (reference, 132-140) mmol/L; potassium, 4.3 (reference, 3.5-5.0) mmol/L; chloride, 89 (reference, 98-111) mmol/L; total CO₂, 36 (reference, 24-28) mEq/L; blood urea nitrogen, 21 (reference, 7-21) mg/dL; creatinine 3.4 (reference, 0.5-1.4) mg/dL; and albumin, 2.7 (reference, 3.7-5.0) mg/dL. Arterial gases showed pH, 7.56 (reference, 7.35-7.45), partial CO₂, 47 (reference, 35-45) mm Hg; bicarbonate, 42 (reference, 22-26) mEq/L; partial O₂, 54 (reference, 75 to 100) mm Hg. Brain natriuretic peptide was 2,800 (normal, < 100) pg/mL with a normal troponin. X-rays showed pulmonary congestion and bilateral pleural effusions that were transudative on fluid analysis. An echocardiogram showed ejection fraction of 20 to 25% with normal valves (baseline ejection fraction of 60%-65%). A coronary arteriogram revealed severe nonischemic cardiomyopathy.

Treatment

To reduce bicarbonate levels, 3 L of normal saline solution were infused prefilter during HD, and ultrafiltration (UF) of 4.5 L achieved a net UF of -1.5 L over 3.5 hours on lower dialysate bicarbonate (30 mEq/L). Good catheter flow was achieved with a blood flow rate of 350 mL/min and a dialysate flow of 700 mL/min. Venous blood gases and basic serum metabolic panels were obtained throughout the first HD session (Table 1). Improvement in pH from 7.5 to 7.43 and in total CO₂ from 36 to 30 mEq/L were noted after the treatment. Subsequently, we used the same membrane (Optiflux F160NRe) for 2 consecutive daily treatments to remove excess fluid and prevent worsening alkalosis using the same minimal bicarbonate bath, but no further normal saline solution was given.

Outcome

Volume overload was controlled as needed with UF. The bicarbonate did not drop after the second HD session, suggesting low organic acid production in the intradialytic period. By shortening the duration of dialysis to 3 hours and improving nutritional intake, we achieved dry weight, and the patient was discharged home with a total CO₂ of 25 mEq/L. Outpatient dialysis sessions were arranged to run at shorter duration (3 hours compared with 3.5 hours) and use low bicarbonate dialysate. The patient was admitted several times afterward for acute decompensated heart failure, but in all those admissions, her bicarbonate was in the normal-to-high range, between 23 and 30 mEq/L.

Discussion

Metabolic alkalosis is relatively rare in ESRD patients on HD. Particularly in the predialysis period, but with the growing number of older patients undergoing HD and the aggressive treatment of acidosis with relatively higher buffer concentrations; there has been an increase in the incidence of metabolic alkalosis in patients on HD. In the Fresenius Medical Care (FMC) prevalent HD patient study, predialysis bicarbonate levels have increased overtime from a mean (SD)22.9 (3.1) mEq/L in 2004 to a mean (SD) 24.1 (3.5) mEq/L in September 2011, with 25% of patients > 26.0 mEq/L compared with only 6% in 2004.¹ The condition has been associated with cardiac arrhythmia, intradialytic hypocalcemia, hypokalemia, hypercapnia, hypoxia, accelerated hypertension, and seizure.^2-4 Metabolic alkalosis may be associated with increased mortality.^5-7 However, the effect dissipated after adjusting for inflammation and nutritional status.⁶

Our patient had primary metabolic alkalosis evident by her high pH of 7.56 and high total CO₂ of 36 mEq/L. The serum total CO₂ reflects the metabolic status more accurately than the blood gas bicarbonate, which is prone to calculation error by the Henderson-Hasselbalch equation. Her respiratory compensation for the metabolic alkalosis was appropriate, with an increase of arterial PaCO₂ to 47 mm Hg (expected PaCO₂ = 40 + 0.7[HCO₃-24] = 48.4). She had normal baseline PaCO₂ in the weeks prior to admission. Due to lack of residual urine output, < 50 mL/d, her metabolic alkalosis could not be attributed to the generation of bicarbonate by the kidneys, or ameliorated by dumping of excess bicarbonate, which explained why her metabolic alkalosis was severe. On the other hand, respiratory distress may have hindered the appropriate CO₂ retention.

In patients with ESRD on HD who have no residual urine output, causes of metabolic alkalosis are limited to loss of net acid or gain of alkali through the gastrointestinal tract; our patient had none of these. Similarly, all renal causes of metabolic alkalosis are not applicable to our patient, including mineralocorticoid excess and contraction alkalosis. In patients with preserved kidney function, loop diuretics can induce alkalosis through enhanced tubular absorption of HCO₃. While acetazolamide can mitigate this scenario by blocking carbonic anhydrase in the luminal border of the collecting ducts resulting in excretion of bicarbonate in the urine, our patient had negligible urine output despite being on furosemide 20 mg twice daily, making this an unlikely cause.

Severe metabolic alkalosis in dialysis patients has been reported with cocaine use, pica ingestion, and citrate load as in plasma exchange, massive transfusions, and regional anticoagulation.^2,8-11 Although calcium carbonate intake can contribute to alkalosis, her small daily dose of 1,200 mg contains approximately 12 mEq of carbonate, which is not a significant contributor to the alkalosis.

With all other causes excluded, the metabolic alkalosis in our patient is presumed to result from the bicarbonate-rich dialysate. Since the majority of patients with ESRD are acidotic before dialysis, the dialysate bicarbonate is set at a higher than normal physiologic level to bring the pH close to or even higher than normal after dialysis. The patient had been dialyzed with NaturaLyte as an outpatient, which was set at the dialysis unit default mode of 36 mEq/L. This form of alkalosis has been reported to peak immediately after treatment but in most patients returns to the predialysis acidotic state due to endogenous acid production.^1,4,12 Normally, muscles play a significant role in buffering excess bicarbonate in patients with nonfunctioning kidneys; hence, malnutrition with muscle wasting tends to propagate and maintain alkalosis, as in our patient.

Managing alkalosis in patients on dialysis can be challenging and is often directed at identifying potential causes like overzealous bicarbonate dialysate and addressing comorbidities, especially malnutrition.^6,7 Bicarbonate delivery can be set on dialysis machines as low as 20 mEq/L. However, the reliability of correcting serum bicarbonate by adjusting bicarbonate-based dialysis products is in question as these products deliver additional buffering capacity through mixing and metabolism of acetate, acetic acid, or citric acid (Table 2).

Conclusions

Attention should be paid to detect elevated predialysis serum bicarbonate levels in ESRD patients on HD, especially those with values above 27 mmol/L due to higher mortality.^6,7 Treatment of these patients is more challenging than for those who are acidotic predialysis, especially when alkalosis is compounded by malnutrition. Mitigation of this problem is achieved by using a lower bicarbonate bath and the shortest effective dialysis duration that achieves adequate clearance. Poor clearance also deleteriously affects patient nutrition and well-being. We have shown that normal saline solution infusion with concurrent removal by UF can correct pretreatment metabolic alkalosis when other measures are inadequate.

Metabolic alkalosis, a disorder that causes elevations in serum bicarbonate and arterial pH, is a common metabolic abnormality found in nearly half of hospitalized patients but is rare in patients with end-stage renal disease (ESRD) on hemodialysis (HD) during the pretreatment state. The problem seems to arise due to a high rate of older patients with multiple comorbidities and malnutrition who are undergoing HD. Metabolic alkalosis is associated with increased morbidity and mortality. In this report, we present a case of metabolic alkalosis, describe an innovative approach to manage metabolic alkalosis in the dialysis population, and review the pathophysiology.

Case Presentation

A 63-year-old female with emphysema, diabetic nephropathy, and ESRD on regular HD for 2 months by a tunneled subclavian vein catheter was admitted with 2 weeks of orthopnea and leg swelling. The review of systems was negative for chest pain, cough, wheeze, or sputum production. She was a former smoker with no alcohol or drug misuse. The patient was taking carvedilol 25 mg daily, furosemide 20 mg twice daily, basal insulin premeal, lisinopril 40 mg daily, pantoprazole 40 mg daily, calcium carbonate 400 mg 3 times daily, ferrous sulphate 325 mg daily, and a vilanterol/tiotropium inhaler once daily. Her dialysate outpatient prescription included sodium 140 mEq/L, potassium 2 mEq/L, calcium 2.5 mEq/L, and bicarbonate 36 mEq/L. Our dialysis unit used NaturaLyte dry pack for bicarbonate dialysis.

The patient appeared tachypneic with 26 respirations/min, oxygen saturation of 89% on room air, which improved to 94% on a 2 L nasal cannula. Her heart rate was 89 beats/min, blood pressure was 129/72 mm Hg, and body mass index was 21.2. The physical examination revealed jugular venous distension, lung crackles, reduced air entry, and pedal edema. Muscle wasting was noted in the arms and thighs. The tunnel catheter did not appear infected.

The patient’s blood work showed sodium, 136 (reference, 132-140) mmol/L; potassium, 4.3 (reference, 3.5-5.0) mmol/L; chloride, 89 (reference, 98-111) mmol/L; total CO₂, 36 (reference, 24-28) mEq/L; blood urea nitrogen, 21 (reference, 7-21) mg/dL; creatinine 3.4 (reference, 0.5-1.4) mg/dL; and albumin, 2.7 (reference, 3.7-5.0) mg/dL. Arterial gases showed pH, 7.56 (reference, 7.35-7.45), partial CO₂, 47 (reference, 35-45) mm Hg; bicarbonate, 42 (reference, 22-26) mEq/L; partial O₂, 54 (reference, 75 to 100) mm Hg. Brain natriuretic peptide was 2,800 (normal, < 100) pg/mL with a normal troponin. X-rays showed pulmonary congestion and bilateral pleural effusions that were transudative on fluid analysis. An echocardiogram showed ejection fraction of 20 to 25% with normal valves (baseline ejection fraction of 60%-65%). A coronary arteriogram revealed severe nonischemic cardiomyopathy.

Treatment

To reduce bicarbonate levels, 3 L of normal saline solution were infused prefilter during HD, and ultrafiltration (UF) of 4.5 L achieved a net UF of -1.5 L over 3.5 hours on lower dialysate bicarbonate (30 mEq/L). Good catheter flow was achieved with a blood flow rate of 350 mL/min and a dialysate flow of 700 mL/min. Venous blood gases and basic serum metabolic panels were obtained throughout the first HD session (Table 1). Improvement in pH from 7.5 to 7.43 and in total CO₂ from 36 to 30 mEq/L were noted after the treatment. Subsequently, we used the same membrane (Optiflux F160NRe) for 2 consecutive daily treatments to remove excess fluid and prevent worsening alkalosis using the same minimal bicarbonate bath, but no further normal saline solution was given.

Outcome

Volume overload was controlled as needed with UF. The bicarbonate did not drop after the second HD session, suggesting low organic acid production in the intradialytic period. By shortening the duration of dialysis to 3 hours and improving nutritional intake, we achieved dry weight, and the patient was discharged home with a total CO₂ of 25 mEq/L. Outpatient dialysis sessions were arranged to run at shorter duration (3 hours compared with 3.5 hours) and use low bicarbonate dialysate. The patient was admitted several times afterward for acute decompensated heart failure, but in all those admissions, her bicarbonate was in the normal-to-high range, between 23 and 30 mEq/L.

Discussion

Metabolic alkalosis is relatively rare in ESRD patients on HD. Particularly in the predialysis period, but with the growing number of older patients undergoing HD and the aggressive treatment of acidosis with relatively higher buffer concentrations; there has been an increase in the incidence of metabolic alkalosis in patients on HD. In the Fresenius Medical Care (FMC) prevalent HD patient study, predialysis bicarbonate levels have increased overtime from a mean (SD)22.9 (3.1) mEq/L in 2004 to a mean (SD) 24.1 (3.5) mEq/L in September 2011, with 25% of patients > 26.0 mEq/L compared with only 6% in 2004.¹ The condition has been associated with cardiac arrhythmia, intradialytic hypocalcemia, hypokalemia, hypercapnia, hypoxia, accelerated hypertension, and seizure.^2-4 Metabolic alkalosis may be associated with increased mortality.^5-7 However, the effect dissipated after adjusting for inflammation and nutritional status.⁶

Our patient had primary metabolic alkalosis evident by her high pH of 7.56 and high total CO₂ of 36 mEq/L. The serum total CO₂ reflects the metabolic status more accurately than the blood gas bicarbonate, which is prone to calculation error by the Henderson-Hasselbalch equation. Her respiratory compensation for the metabolic alkalosis was appropriate, with an increase of arterial PaCO₂ to 47 mm Hg (expected PaCO₂ = 40 + 0.7[HCO₃-24] = 48.4). She had normal baseline PaCO₂ in the weeks prior to admission. Due to lack of residual urine output, < 50 mL/d, her metabolic alkalosis could not be attributed to the generation of bicarbonate by the kidneys, or ameliorated by dumping of excess bicarbonate, which explained why her metabolic alkalosis was severe. On the other hand, respiratory distress may have hindered the appropriate CO₂ retention.

In patients with ESRD on HD who have no residual urine output, causes of metabolic alkalosis are limited to loss of net acid or gain of alkali through the gastrointestinal tract; our patient had none of these. Similarly, all renal causes of metabolic alkalosis are not applicable to our patient, including mineralocorticoid excess and contraction alkalosis. In patients with preserved kidney function, loop diuretics can induce alkalosis through enhanced tubular absorption of HCO₃. While acetazolamide can mitigate this scenario by blocking carbonic anhydrase in the luminal border of the collecting ducts resulting in excretion of bicarbonate in the urine, our patient had negligible urine output despite being on furosemide 20 mg twice daily, making this an unlikely cause.

Severe metabolic alkalosis in dialysis patients has been reported with cocaine use, pica ingestion, and citrate load as in plasma exchange, massive transfusions, and regional anticoagulation.^2,8-11 Although calcium carbonate intake can contribute to alkalosis, her small daily dose of 1,200 mg contains approximately 12 mEq of carbonate, which is not a significant contributor to the alkalosis.

With all other causes excluded, the metabolic alkalosis in our patient is presumed to result from the bicarbonate-rich dialysate. Since the majority of patients with ESRD are acidotic before dialysis, the dialysate bicarbonate is set at a higher than normal physiologic level to bring the pH close to or even higher than normal after dialysis. The patient had been dialyzed with NaturaLyte as an outpatient, which was set at the dialysis unit default mode of 36 mEq/L. This form of alkalosis has been reported to peak immediately after treatment but in most patients returns to the predialysis acidotic state due to endogenous acid production.^1,4,12 Normally, muscles play a significant role in buffering excess bicarbonate in patients with nonfunctioning kidneys; hence, malnutrition with muscle wasting tends to propagate and maintain alkalosis, as in our patient.

Managing alkalosis in patients on dialysis can be challenging and is often directed at identifying potential causes like overzealous bicarbonate dialysate and addressing comorbidities, especially malnutrition.^6,7 Bicarbonate delivery can be set on dialysis machines as low as 20 mEq/L. However, the reliability of correcting serum bicarbonate by adjusting bicarbonate-based dialysis products is in question as these products deliver additional buffering capacity through mixing and metabolism of acetate, acetic acid, or citric acid (Table 2).

Conclusions

Attention should be paid to detect elevated predialysis serum bicarbonate levels in ESRD patients on HD, especially those with values above 27 mmol/L due to higher mortality.^6,7 Treatment of these patients is more challenging than for those who are acidotic predialysis, especially when alkalosis is compounded by malnutrition. Mitigation of this problem is achieved by using a lower bicarbonate bath and the shortest effective dialysis duration that achieves adequate clearance. Poor clearance also deleteriously affects patient nutrition and well-being. We have shown that normal saline solution infusion with concurrent removal by UF can correct pretreatment metabolic alkalosis when other measures are inadequate.

THE CASE

A 37-year-old man with a history of asthma, schizoaffective disorder, and tobacco use (36 packs per year) presented to the clinic after 5 days of worsening cough, reproducible left-sided chest pain, and increasing shortness of breath. He also experienced chills, fatigue, nausea, and vomiting but was afebrile. The patient had not travelled recently nor had direct contact with anyone sick. He also denied intravenous (IV) drug use, alcohol use, and bloody sputum. Recently, he had intentionally lost weight, as recommended by his psychiatrist.

Medication review revealed that he was taking many central-acting agents for schizoaffective disorder, including alprazolam, aripiprazole, desvenlafaxine, and quetiapine. Due to his intermittent asthma since childhood, he used an albuterol inhaler as needed, which currently offered only minimal relief. He denied any history of hospitalization or intubation for asthma.

During the clinic visit, his blood pressure was 90/60 mm Hg and his heart rate was normal. His pulse oximetry was 92% on room air. On physical examination, he had normal-appearing dentition. Auscultation revealed bilateral expiratory wheezes with decreased breath sounds at the left lower lobe.

A plain chest radiograph (CXR) performed in the clinic (FIGURE 1) showed a large, thick-walled cavitary lesion with an air-fluid level in the left lower lobe. The patient was directly admitted to the Family Medicine Inpatient Service. Computed tomography (CT) of the chest with contrast was ordered to rule out empyema or malignancy. The chest CT confirmed the previous findings while also revealing a surrounding satellite nodularity in the left lower lobe (FIGURE 2). QuantiFERON-TB Gold and HIV tests were both negative.

THE DIAGNOSIS

The patient was given a diagnosis of a lung abscess based on symptoms and imaging. An extensive smoking history, as well as multiple sedating medications, increased his likelihood of aspiration.

DISCUSSION

Lung abscess is the probable diagnosis in a patient with indolent infectious symptoms (cough, fever, night sweats) developing over days to weeks and a CXR finding of pulmonary opacity, often with an air-fluid level.^1-4 A lung abscess is a circumscribed collection of pus in the lung parenchyma that develops as a result of microbial infection.⁴

Primary vs secondary abscess. Lung abscesses can be divided into 2 groups: primary and secondary abscesses. Primary abscesses (60%) occur without any other medical condition or in patients prone to aspiration.⁵ Secondary abscesses occur in the setting of a comorbid medical condition, such as lung disease, heart disease, bronchogenic neoplasm, or immunocompromised status.⁵

Continue to: With a primary lung abscess...

With a primary lung abscess, oropharyngeal contents are aspirated (generally while the patient is unconscious) and contain mixed flora.² The aspirate typically migrates to the posterior segments of the upper lobes and to the superior segments of the lower lobes. These abscesses are usually singular and have an air-fluid level.^1,2

Secondary lung abscesses occur in bronchial obstruction (by tumor, foreign body, or enlarged lymph nodes), with coexisting lung diseases (bronchiectasis, cystic fibrosis, infected pulmonary infarcts, lung contusion) or by direct spread (broncho-esophageal fistula, subphrenic abscess).⁶ Secondary abscesses are associated with a poorer prognosis, dependent on the patient’s general condition and underlying disease.⁷

What to rule out

The differential diagnosis of cavitary lung lesion includes tuberculosis, necrotizing pneumonia, bronchial carcinoma, pulmonary embolism, vasculitis (eg, Churg-Strauss syndrome), and localized pleural empyema.^1,4 A CT scan is helpful to differentiate between a parenchymal lesion and pleural collection, which may not be as clear on CXR.^1,4

Tuberculosis manifests with fatigue, weight loss, and night sweats; a chest CT will reveal a cavitating lesion (usually upper lobe) with a characteristic “rim sign” that includes caseous necrosis surrounded by a peripheral enhancing rim.⁸

Necrotizing pneumonia manifests as acute, fulminant infection. The most common causative organisms on sputum culture are Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas species. Plain radiography will reveal multiple cavities and often associated pleural effusion and empyema.⁹

Continue to: Excavating bronchogenic carcinomas

Excavating bronchogenic carcinomas differ from a lung abscess in that a patient with the latter is typically, but not always, febrile and has purulent sputum. On imaging, a bronchogenic carcinoma has a thicker and more irregular wall than a lung abscess.¹⁰

Treatment

When antibiotics first became available, penicillin was used to treat lung abscess.¹¹ Then IV clindamycin became the drug of choice after 2 trials demonstrated its superiority to IV penicillin.^12,13 More recently, clindamycin alone has fallen out of favor due to growing anaerobic resistance.¹⁴

Current therapy includes beta-lactam with beta-lactamase inhibitors.¹⁴ Lung abscesses are typically polymicrobial and thus carry different degrees of antibiotic resistance.^15,16 If culture data are available, targeted therapy is preferred, especially for secondary abscesses.⁷ Antibiotic therapy is usually continued until a CXR reveals a small lesion or is clear, which may require several months of outpatient oral antibiotic therapy.⁴

Our patient was treated with IV clindamycin for 3 days in the hospital. Clindamycin was chosen due to his penicillin allergy and started empirically without any culture data. He was transitioned to oral clindamycin and completed a total 3-week course as his CXR continued to show improvement (FIGURE 3). He did not undergo bronchoscopy. A follow-up CXR showed resolution of lung abscess at 9 months. (FIGURE 4).

THE TAKEAWAY

All patients with lung abscesses should have sputum culture with gram stain done—­ideally prior to starting antibiotics.^3,4 Bronchoscopy should be considered for patients with atypical presentations or those who fail standard therapy, but may be used in other cases, as well.³

CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, CO 80238; [email protected]

THE CASE

A 37-year-old man with a history of asthma, schizoaffective disorder, and tobacco use (36 packs per year) presented to the clinic after 5 days of worsening cough, reproducible left-sided chest pain, and increasing shortness of breath. He also experienced chills, fatigue, nausea, and vomiting but was afebrile. The patient had not travelled recently nor had direct contact with anyone sick. He also denied intravenous (IV) drug use, alcohol use, and bloody sputum. Recently, he had intentionally lost weight, as recommended by his psychiatrist.

Medication review revealed that he was taking many central-acting agents for schizoaffective disorder, including alprazolam, aripiprazole, desvenlafaxine, and quetiapine. Due to his intermittent asthma since childhood, he used an albuterol inhaler as needed, which currently offered only minimal relief. He denied any history of hospitalization or intubation for asthma.

During the clinic visit, his blood pressure was 90/60 mm Hg and his heart rate was normal. His pulse oximetry was 92% on room air. On physical examination, he had normal-appearing dentition. Auscultation revealed bilateral expiratory wheezes with decreased breath sounds at the left lower lobe.

A plain chest radiograph (CXR) performed in the clinic (FIGURE 1) showed a large, thick-walled cavitary lesion with an air-fluid level in the left lower lobe. The patient was directly admitted to the Family Medicine Inpatient Service. Computed tomography (CT) of the chest with contrast was ordered to rule out empyema or malignancy. The chest CT confirmed the previous findings while also revealing a surrounding satellite nodularity in the left lower lobe (FIGURE 2). QuantiFERON-TB Gold and HIV tests were both negative.

THE DIAGNOSIS

The patient was given a diagnosis of a lung abscess based on symptoms and imaging. An extensive smoking history, as well as multiple sedating medications, increased his likelihood of aspiration.

DISCUSSION

Lung abscess is the probable diagnosis in a patient with indolent infectious symptoms (cough, fever, night sweats) developing over days to weeks and a CXR finding of pulmonary opacity, often with an air-fluid level.^1-4 A lung abscess is a circumscribed collection of pus in the lung parenchyma that develops as a result of microbial infection.⁴

Primary vs secondary abscess. Lung abscesses can be divided into 2 groups: primary and secondary abscesses. Primary abscesses (60%) occur without any other medical condition or in patients prone to aspiration.⁵ Secondary abscesses occur in the setting of a comorbid medical condition, such as lung disease, heart disease, bronchogenic neoplasm, or immunocompromised status.⁵

Continue to: With a primary lung abscess...

With a primary lung abscess, oropharyngeal contents are aspirated (generally while the patient is unconscious) and contain mixed flora.² The aspirate typically migrates to the posterior segments of the upper lobes and to the superior segments of the lower lobes. These abscesses are usually singular and have an air-fluid level.^1,2

Secondary lung abscesses occur in bronchial obstruction (by tumor, foreign body, or enlarged lymph nodes), with coexisting lung diseases (bronchiectasis, cystic fibrosis, infected pulmonary infarcts, lung contusion) or by direct spread (broncho-esophageal fistula, subphrenic abscess).⁶ Secondary abscesses are associated with a poorer prognosis, dependent on the patient’s general condition and underlying disease.⁷

What to rule out

The differential diagnosis of cavitary lung lesion includes tuberculosis, necrotizing pneumonia, bronchial carcinoma, pulmonary embolism, vasculitis (eg, Churg-Strauss syndrome), and localized pleural empyema.^1,4 A CT scan is helpful to differentiate between a parenchymal lesion and pleural collection, which may not be as clear on CXR.^1,4

Tuberculosis manifests with fatigue, weight loss, and night sweats; a chest CT will reveal a cavitating lesion (usually upper lobe) with a characteristic “rim sign” that includes caseous necrosis surrounded by a peripheral enhancing rim.⁸

Necrotizing pneumonia manifests as acute, fulminant infection. The most common causative organisms on sputum culture are Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas species. Plain radiography will reveal multiple cavities and often associated pleural effusion and empyema.⁹

Continue to: Excavating bronchogenic carcinomas

Excavating bronchogenic carcinomas differ from a lung abscess in that a patient with the latter is typically, but not always, febrile and has purulent sputum. On imaging, a bronchogenic carcinoma has a thicker and more irregular wall than a lung abscess.¹⁰

Treatment

When antibiotics first became available, penicillin was used to treat lung abscess.¹¹ Then IV clindamycin became the drug of choice after 2 trials demonstrated its superiority to IV penicillin.^12,13 More recently, clindamycin alone has fallen out of favor due to growing anaerobic resistance.¹⁴

Current therapy includes beta-lactam with beta-lactamase inhibitors.¹⁴ Lung abscesses are typically polymicrobial and thus carry different degrees of antibiotic resistance.^15,16 If culture data are available, targeted therapy is preferred, especially for secondary abscesses.⁷ Antibiotic therapy is usually continued until a CXR reveals a small lesion or is clear, which may require several months of outpatient oral antibiotic therapy.⁴

Our patient was treated with IV clindamycin for 3 days in the hospital. Clindamycin was chosen due to his penicillin allergy and started empirically without any culture data. He was transitioned to oral clindamycin and completed a total 3-week course as his CXR continued to show improvement (FIGURE 3). He did not undergo bronchoscopy. A follow-up CXR showed resolution of lung abscess at 9 months. (FIGURE 4).

THE TAKEAWAY

All patients with lung abscesses should have sputum culture with gram stain done—­ideally prior to starting antibiotics.^3,4 Bronchoscopy should be considered for patients with atypical presentations or those who fail standard therapy, but may be used in other cases, as well.³

CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, CO 80238; [email protected]

THE CASE

A 37-year-old man with a history of asthma, schizoaffective disorder, and tobacco use (36 packs per year) presented to the clinic after 5 days of worsening cough, reproducible left-sided chest pain, and increasing shortness of breath. He also experienced chills, fatigue, nausea, and vomiting but was afebrile. The patient had not travelled recently nor had direct contact with anyone sick. He also denied intravenous (IV) drug use, alcohol use, and bloody sputum. Recently, he had intentionally lost weight, as recommended by his psychiatrist.

Medication review revealed that he was taking many central-acting agents for schizoaffective disorder, including alprazolam, aripiprazole, desvenlafaxine, and quetiapine. Due to his intermittent asthma since childhood, he used an albuterol inhaler as needed, which currently offered only minimal relief. He denied any history of hospitalization or intubation for asthma.

During the clinic visit, his blood pressure was 90/60 mm Hg and his heart rate was normal. His pulse oximetry was 92% on room air. On physical examination, he had normal-appearing dentition. Auscultation revealed bilateral expiratory wheezes with decreased breath sounds at the left lower lobe.

A plain chest radiograph (CXR) performed in the clinic (FIGURE 1) showed a large, thick-walled cavitary lesion with an air-fluid level in the left lower lobe. The patient was directly admitted to the Family Medicine Inpatient Service. Computed tomography (CT) of the chest with contrast was ordered to rule out empyema or malignancy. The chest CT confirmed the previous findings while also revealing a surrounding satellite nodularity in the left lower lobe (FIGURE 2). QuantiFERON-TB Gold and HIV tests were both negative.

THE DIAGNOSIS

The patient was given a diagnosis of a lung abscess based on symptoms and imaging. An extensive smoking history, as well as multiple sedating medications, increased his likelihood of aspiration.

DISCUSSION

Lung abscess is the probable diagnosis in a patient with indolent infectious symptoms (cough, fever, night sweats) developing over days to weeks and a CXR finding of pulmonary opacity, often with an air-fluid level.^1-4 A lung abscess is a circumscribed collection of pus in the lung parenchyma that develops as a result of microbial infection.⁴

Primary vs secondary abscess. Lung abscesses can be divided into 2 groups: primary and secondary abscesses. Primary abscesses (60%) occur without any other medical condition or in patients prone to aspiration.⁵ Secondary abscesses occur in the setting of a comorbid medical condition, such as lung disease, heart disease, bronchogenic neoplasm, or immunocompromised status.⁵

Continue to: With a primary lung abscess...

With a primary lung abscess, oropharyngeal contents are aspirated (generally while the patient is unconscious) and contain mixed flora.² The aspirate typically migrates to the posterior segments of the upper lobes and to the superior segments of the lower lobes. These abscesses are usually singular and have an air-fluid level.^1,2

Secondary lung abscesses occur in bronchial obstruction (by tumor, foreign body, or enlarged lymph nodes), with coexisting lung diseases (bronchiectasis, cystic fibrosis, infected pulmonary infarcts, lung contusion) or by direct spread (broncho-esophageal fistula, subphrenic abscess).⁶ Secondary abscesses are associated with a poorer prognosis, dependent on the patient’s general condition and underlying disease.⁷

What to rule out

The differential diagnosis of cavitary lung lesion includes tuberculosis, necrotizing pneumonia, bronchial carcinoma, pulmonary embolism, vasculitis (eg, Churg-Strauss syndrome), and localized pleural empyema.^1,4 A CT scan is helpful to differentiate between a parenchymal lesion and pleural collection, which may not be as clear on CXR.^1,4

Tuberculosis manifests with fatigue, weight loss, and night sweats; a chest CT will reveal a cavitating lesion (usually upper lobe) with a characteristic “rim sign” that includes caseous necrosis surrounded by a peripheral enhancing rim.⁸

Necrotizing pneumonia manifests as acute, fulminant infection. The most common causative organisms on sputum culture are Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas species. Plain radiography will reveal multiple cavities and often associated pleural effusion and empyema.⁹

Continue to: Excavating bronchogenic carcinomas

Excavating bronchogenic carcinomas differ from a lung abscess in that a patient with the latter is typically, but not always, febrile and has purulent sputum. On imaging, a bronchogenic carcinoma has a thicker and more irregular wall than a lung abscess.¹⁰

Treatment

When antibiotics first became available, penicillin was used to treat lung abscess.¹¹ Then IV clindamycin became the drug of choice after 2 trials demonstrated its superiority to IV penicillin.^12,13 More recently, clindamycin alone has fallen out of favor due to growing anaerobic resistance.¹⁴

Current therapy includes beta-lactam with beta-lactamase inhibitors.¹⁴ Lung abscesses are typically polymicrobial and thus carry different degrees of antibiotic resistance.^15,16 If culture data are available, targeted therapy is preferred, especially for secondary abscesses.⁷ Antibiotic therapy is usually continued until a CXR reveals a small lesion or is clear, which may require several months of outpatient oral antibiotic therapy.⁴

Our patient was treated with IV clindamycin for 3 days in the hospital. Clindamycin was chosen due to his penicillin allergy and started empirically without any culture data. He was transitioned to oral clindamycin and completed a total 3-week course as his CXR continued to show improvement (FIGURE 3). He did not undergo bronchoscopy. A follow-up CXR showed resolution of lung abscess at 9 months. (FIGURE 4).

THE TAKEAWAY

All patients with lung abscesses should have sputum culture with gram stain done—­ideally prior to starting antibiotics.^3,4 Bronchoscopy should be considered for patients with atypical presentations or those who fail standard therapy, but may be used in other cases, as well.³

CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, CO 80238; [email protected]

Evidence of human exposure to mercury dates as far back as the Egyptians in 1500 bc . ¹ The ancient Chinese believed mercury could prolong life, heal bones, and maintain vitality. ² Western medicine has utilized mercury in diuretics, laxatives, antibacterial agents, and antiseptics. ³ Health effects caused by chronic mercury exposure became increasingly apparent in the 1800s after hat makers who had inhaled mercuric nitrate vapors began to present with a host of neurologic symptoms, which is where the p hrase "mad as a hatter" was derived. ^4,5 In 1889, French neurologist Jean-Martin Charcot attributed rapid tremors to mercury poisoning. ⁶ By 1940, Kinnier Wilson ⁷ further characterized the effects of mercury, describing mercury-induced cognitive impairments. In the 1960s, Japanese researchers correlated elevated urinary mercury levels with an outbreak of Minamata disease, a condition characterized by tremors, sensory loss, ataxia, and visual constrictions. ⁸ The World Health Organization considers mercury to be one of the top 10 chemicals of major public health concern. ⁹

Mercury release in the environment primarily is a function of human activity, including coal-fired power plants, residential heating, and mining.^9,10 Mercury from these sources is commonly found in the sediment of lakes and bays, where it is enzymatically converted to methylmercury by aquatic microorganisms; subsequent food chain biomagnification results in elevated mercury levels in apex predators. Substantial release of mercury into the environment also can be attributed to health care facilities from their use of thermometers containing 0.5 to 3 g of elemental mercury,¹¹ blood pressure monitors, and medical waste incinerators.⁵

Mercury has been reported as the second most common cause of heavy metal poisoning after lead.¹² Standards from the US Food and Drug Administration dictate that methylmercury levels in fish and wheat products must not exceed 1 ppm.¹³ Most plant and animal food sources contain methylmercury at levels between 0.0001 and 0.01 ppm; mercury concentrations are especially high in tuna, averaging 0.4 ppm, while larger predatory fish contain levels in excess of 1 ppm.¹⁴ The use of mercury-containing cosmetic products also presents a substantial exposure risk to consumers.^5,10 In one study, 3.3% of skin-lightening creams and soaps purchased within the United States contained concentrations of mercury exceeding 1000 ppm.¹⁵

We describe a case of mercury toxicity resulting from intentional injection of liquid mercury into the right antecubital fossa in a suicide attempt.

Case Report

A 31-year-old woman presented to the family practice center for evaluation of a firm stained area on the skin of the right arm. She reported increasing anxiety, depression, tremors, irritability, and difficulty concentrating over the last 6 months. She denied headache and joint or muscle pain. Four years earlier, she had broken apart a thermometer and injected approximately 0.7 mL of its contents into the right arm in a suicide attempt. She intended to inject the thermometer’s contents directly into a vein, but the material instead entered the surrounding tissue. She denied notable pain or itching overlying the injection site. Her medications included aripiprazole and buspirone. She noted that she smoked half a pack of cigarettes per day and had a history of methamphetamine abuse. She was homeless and unemployed. Physical examination revealed an anxious tremulous woman with an erythematous to bluish gray, firm plaque on the right antecubital fossa (Figure 1). There were no notable tremors and no gait disturbance.

Her blood mercury level was greater than 100 µg/L and urine mercury was 477 µg/g (reference ranges, 1–8 μg/L and 4–5 μg/L, respectively). A radiograph of the right elbow area revealed scattered punctate foci of increased density within or overlying the anterolateral elbow soft tissues. She was diagnosed with mercury granuloma causing chronic mercury elevation. She underwent excision of the granuloma (Figure 2) with endovascular surgery via an elliptical incision. The patient was subsequently lost to follow-up.

Comment

Elemental mercury is a silver liquid at room temperature that spontaneously evaporates to form mercury vapor, an invisible, odorless, toxic gas. Accidental cutaneous exposure typically is safely managed by washing exposed skin with soap and water,¹⁶ though there is a potential risk for systemic absorption, especially when the skin is inflamed. When metallic mercury is subcutaneously injected, it is advised to promptly excise all subcutaneous areas containing mercury, regardless of any symptoms of systemic toxicity. Patients should subsequently be monitored for signs of both central nervous system (CNS) and renal deficits, undergo chelation therapy when systemic effects are apparent, and finally receive psychiatric consultation and treatment when necessary.¹⁷

Inorganic mercury compounds are formed when elemental mercury combines with sulfur or oxygen and often take the form of mercury salts, which appear as white crystals.¹⁶ These salts occur naturally in the environment and are used in pesticides, antiseptics, and skin-lightening creams and soaps.¹⁸

Methylmercury is a highly toxic, organic compound that is capable of crossing the placental and blood-brain barriers. It is the most common organic mercury compound found in the environment.¹⁶ Most humans have trace amounts of methylmercury in their bodies, typically as a result of consuming seafood.⁵

Exposure to mercury most commonly occurs through chronic consumption of methylmercury in seafood or acute inhalation of elemental mercury vapors.⁹ Iatrogenic cases of mercury exposure via injection also have been reported in the literature, including a case resulting in acute poisoning due to peritoneal lavage with mercury bichloride.¹⁹ Acute mercury-induced pulmonary damage typically resolves completely. However, there have been reported cases of exposure progressing to interstitial emphysema, pneumatocele, pneumothorax, pneumomediastinum, interstitial fibrosis, and chronic respiratory insufficiency, with examples of fatal acute respiratory distress syndrome being reported.^5,16,20 Although individuals who inhale mercury vapors initially may be unaware of exposure due to little upper airway irritation, symptoms following an initial acute exposure may include ptyalism, a metallic taste, dysphagia, enteritis, diarrhea, nausea, renal damage, and CNS effects.¹⁶ Additionally, exposure may lead to confusion with signs and symptoms of metal fume fever, including shortness of breath, pleuritic chest pain, stomatitis, lethargy, and vomiting.²⁰

Chronic exposure to mercury vapor can result in accumulation of mercury in the body, leading to neuropsychiatric, dermatologic, oropharyngeal, and renal manifestations. Sore throat, fever, headache, fatigue, dyspnea, chest pain, and pneumonitis are common.¹⁶ Typically, low-level exposure to elemental mercury does not lead to long-lasting health effects. However, individuals exposed to high-level elemental mercury vapors may require hospitalization. Treatment of acute mercury poisoning consists of removing the source of exposure, followed by cardiopulmonary support.¹⁶

Specific assays for mercury levels in blood and urine are useful to assess the level of exposure and risk to the patient. Blood mercury concentrations of 20 µg/L or below are considered within reference range; however, once blood and urine concentrations of mercury exceed 100 µg/L, clinical signs of acute mercury poisoning typically manifest.²¹ Chest radiographs can reveal pulmonary damage, while complete blood cell count, metabolic panel, and urinalysis can assess damage to other organs. Neuropsychiatric testing and nerve conduction studies may provide objective evidence of CNS toxicity. Assays for N-acetyl-β-D-glucosaminidase can provide an indication of early renal tubular dysfunction.¹⁶

Elemental mercury is not absorbed from the gastrointestinal tract, posing minimal risk for acute toxicity from ingestion. Generally, less than 10% of ingested inorganic mercury is absorbed from the gut, while elemental mercury is nonabsorbable.¹⁰ If an individual ingests a large amount of mercury, it may persist in the gastrointestinal tract for an extended period. Mercury is radiopaque, and abdominal radiographs should be obtained in all cases of ingestion.¹⁶

Mercury is toxic to the CNS and peripheral nervous system, resulting in erethism mercurialis, a constellation of neuropsychologic signs and symptoms including restlessness, irritability, insomnia, emotional lability, difficulty concentrating, and impaired memory. In severe cases, delirium and psychosis may develop. Other CNS effects include tremors, paresthesia, dysarthria, neuromuscular changes, headaches, polyneuropathy, and cerebellar ataxia, as well as ophthalmologic and audiologic impairment.^5,16

Upon inhalation exposure, patients with respiratory concerns should be given oxygen. Bronchospasms are treated with bronchodilators; however, if multiple chemical exposures are suspected, bronchial-sensitizing agents may pose additional risks. Corticosteroids and antibiotics have been recommended for treatment of chemical pneumonitis, but their efficacy has not been substantiated.¹⁶

Skin reactions associated with skin contact to elemental mercury are rare. However, hives and dermatitis have been observed following accidental contact with inorganic mercury compounds.⁵ Manifestation in children chronically exposed to mercury includes a nonallergic hypersensitivity (acrodynia),^5,17 which is characterized by pain and dusky pink discoloration in the hands and feet, most often seen in children chronically exposed to mercury absorbed from vapor inhalation or cutaneous exposure.¹⁶

Renal conditions associated with acute inhalation of elemental mercury vapor include proteinuria, nephrotic syndrome, temporary tubular dysfunction, acute tubular necrosis, and oliguric renal failure.¹⁶ Chronic exposure to inorganic mercury compounds also has been reported to cause renal damage.⁵ Chelation therapy should be performed for any symptomatic patient with a clear history of acute elemental mercury exposure.¹⁶ The most frequently used chelation agent in cases of acute inorganic mercury exposures is dimercaprol. In rare cases of mercury intoxication, hemodialysis is required in the treatment of renal failure and to expedite removal of dimercaprol-mercury complexes.¹⁶

Cardiovascular symptoms associated with acute inhalation of high levels of elemental mercury include tachycardia and hypertension.¹⁶ Increases in blood pressure, palpitations, and heart rate also have been observed in instances of acute elemental mercury exposure. Studies show that exposure to mercury increases both the risk for acute myocardial infarction as well as death from coronary heart and cardiovascular diseases.⁵

Conclusion

Mercury poisoning presents with varied neuropsychologic signs and symptoms. Our case provides insight into a unique route of exposure for mercury toxicity. In addition to the unusual presentation of a mercury granuloma, our case illustrates how surgical techniques can aid in removal of cutaneous reservoirs in the setting of percutaneous exposure.

Evidence of human exposure to mercury dates as far back as the Egyptians in 1500 bc . ¹ The ancient Chinese believed mercury could prolong life, heal bones, and maintain vitality. ² Western medicine has utilized mercury in diuretics, laxatives, antibacterial agents, and antiseptics. ³ Health effects caused by chronic mercury exposure became increasingly apparent in the 1800s after hat makers who had inhaled mercuric nitrate vapors began to present with a host of neurologic symptoms, which is where the p hrase "mad as a hatter" was derived. ^4,5 In 1889, French neurologist Jean-Martin Charcot attributed rapid tremors to mercury poisoning. ⁶ By 1940, Kinnier Wilson ⁷ further characterized the effects of mercury, describing mercury-induced cognitive impairments. In the 1960s, Japanese researchers correlated elevated urinary mercury levels with an outbreak of Minamata disease, a condition characterized by tremors, sensory loss, ataxia, and visual constrictions. ⁸ The World Health Organization considers mercury to be one of the top 10 chemicals of major public health concern. ⁹

Mercury release in the environment primarily is a function of human activity, including coal-fired power plants, residential heating, and mining.^9,10 Mercury from these sources is commonly found in the sediment of lakes and bays, where it is enzymatically converted to methylmercury by aquatic microorganisms; subsequent food chain biomagnification results in elevated mercury levels in apex predators. Substantial release of mercury into the environment also can be attributed to health care facilities from their use of thermometers containing 0.5 to 3 g of elemental mercury,¹¹ blood pressure monitors, and medical waste incinerators.⁵

Mercury has been reported as the second most common cause of heavy metal poisoning after lead.¹² Standards from the US Food and Drug Administration dictate that methylmercury levels in fish and wheat products must not exceed 1 ppm.¹³ Most plant and animal food sources contain methylmercury at levels between 0.0001 and 0.01 ppm; mercury concentrations are especially high in tuna, averaging 0.4 ppm, while larger predatory fish contain levels in excess of 1 ppm.¹⁴ The use of mercury-containing cosmetic products also presents a substantial exposure risk to consumers.^5,10 In one study, 3.3% of skin-lightening creams and soaps purchased within the United States contained concentrations of mercury exceeding 1000 ppm.¹⁵

We describe a case of mercury toxicity resulting from intentional injection of liquid mercury into the right antecubital fossa in a suicide attempt.

Case Report

A 31-year-old woman presented to the family practice center for evaluation of a firm stained area on the skin of the right arm. She reported increasing anxiety, depression, tremors, irritability, and difficulty concentrating over the last 6 months. She denied headache and joint or muscle pain. Four years earlier, she had broken apart a thermometer and injected approximately 0.7 mL of its contents into the right arm in a suicide attempt. She intended to inject the thermometer’s contents directly into a vein, but the material instead entered the surrounding tissue. She denied notable pain or itching overlying the injection site. Her medications included aripiprazole and buspirone. She noted that she smoked half a pack of cigarettes per day and had a history of methamphetamine abuse. She was homeless and unemployed. Physical examination revealed an anxious tremulous woman with an erythematous to bluish gray, firm plaque on the right antecubital fossa (Figure 1). There were no notable tremors and no gait disturbance.

Her blood mercury level was greater than 100 µg/L and urine mercury was 477 µg/g (reference ranges, 1–8 μg/L and 4–5 μg/L, respectively). A radiograph of the right elbow area revealed scattered punctate foci of increased density within or overlying the anterolateral elbow soft tissues. She was diagnosed with mercury granuloma causing chronic mercury elevation. She underwent excision of the granuloma (Figure 2) with endovascular surgery via an elliptical incision. The patient was subsequently lost to follow-up.

Comment

Elemental mercury is a silver liquid at room temperature that spontaneously evaporates to form mercury vapor, an invisible, odorless, toxic gas. Accidental cutaneous exposure typically is safely managed by washing exposed skin with soap and water,¹⁶ though there is a potential risk for systemic absorption, especially when the skin is inflamed. When metallic mercury is subcutaneously injected, it is advised to promptly excise all subcutaneous areas containing mercury, regardless of any symptoms of systemic toxicity. Patients should subsequently be monitored for signs of both central nervous system (CNS) and renal deficits, undergo chelation therapy when systemic effects are apparent, and finally receive psychiatric consultation and treatment when necessary.¹⁷

Inorganic mercury compounds are formed when elemental mercury combines with sulfur or oxygen and often take the form of mercury salts, which appear as white crystals.¹⁶ These salts occur naturally in the environment and are used in pesticides, antiseptics, and skin-lightening creams and soaps.¹⁸

Methylmercury is a highly toxic, organic compound that is capable of crossing the placental and blood-brain barriers. It is the most common organic mercury compound found in the environment.¹⁶ Most humans have trace amounts of methylmercury in their bodies, typically as a result of consuming seafood.⁵

Exposure to mercury most commonly occurs through chronic consumption of methylmercury in seafood or acute inhalation of elemental mercury vapors.⁹ Iatrogenic cases of mercury exposure via injection also have been reported in the literature, including a case resulting in acute poisoning due to peritoneal lavage with mercury bichloride.¹⁹ Acute mercury-induced pulmonary damage typically resolves completely. However, there have been reported cases of exposure progressing to interstitial emphysema, pneumatocele, pneumothorax, pneumomediastinum, interstitial fibrosis, and chronic respiratory insufficiency, with examples of fatal acute respiratory distress syndrome being reported.^5,16,20 Although individuals who inhale mercury vapors initially may be unaware of exposure due to little upper airway irritation, symptoms following an initial acute exposure may include ptyalism, a metallic taste, dysphagia, enteritis, diarrhea, nausea, renal damage, and CNS effects.¹⁶ Additionally, exposure may lead to confusion with signs and symptoms of metal fume fever, including shortness of breath, pleuritic chest pain, stomatitis, lethargy, and vomiting.²⁰

Chronic exposure to mercury vapor can result in accumulation of mercury in the body, leading to neuropsychiatric, dermatologic, oropharyngeal, and renal manifestations. Sore throat, fever, headache, fatigue, dyspnea, chest pain, and pneumonitis are common.¹⁶ Typically, low-level exposure to elemental mercury does not lead to long-lasting health effects. However, individuals exposed to high-level elemental mercury vapors may require hospitalization. Treatment of acute mercury poisoning consists of removing the source of exposure, followed by cardiopulmonary support.¹⁶

Specific assays for mercury levels in blood and urine are useful to assess the level of exposure and risk to the patient. Blood mercury concentrations of 20 µg/L or below are considered within reference range; however, once blood and urine concentrations of mercury exceed 100 µg/L, clinical signs of acute mercury poisoning typically manifest.²¹ Chest radiographs can reveal pulmonary damage, while complete blood cell count, metabolic panel, and urinalysis can assess damage to other organs. Neuropsychiatric testing and nerve conduction studies may provide objective evidence of CNS toxicity. Assays for N-acetyl-β-D-glucosaminidase can provide an indication of early renal tubular dysfunction.¹⁶

Elemental mercury is not absorbed from the gastrointestinal tract, posing minimal risk for acute toxicity from ingestion. Generally, less than 10% of ingested inorganic mercury is absorbed from the gut, while elemental mercury is nonabsorbable.¹⁰ If an individual ingests a large amount of mercury, it may persist in the gastrointestinal tract for an extended period. Mercury is radiopaque, and abdominal radiographs should be obtained in all cases of ingestion.¹⁶

Mercury is toxic to the CNS and peripheral nervous system, resulting in erethism mercurialis, a constellation of neuropsychologic signs and symptoms including restlessness, irritability, insomnia, emotional lability, difficulty concentrating, and impaired memory. In severe cases, delirium and psychosis may develop. Other CNS effects include tremors, paresthesia, dysarthria, neuromuscular changes, headaches, polyneuropathy, and cerebellar ataxia, as well as ophthalmologic and audiologic impairment.^5,16

Upon inhalation exposure, patients with respiratory concerns should be given oxygen. Bronchospasms are treated with bronchodilators; however, if multiple chemical exposures are suspected, bronchial-sensitizing agents may pose additional risks. Corticosteroids and antibiotics have been recommended for treatment of chemical pneumonitis, but their efficacy has not been substantiated.¹⁶

Skin reactions associated with skin contact to elemental mercury are rare. However, hives and dermatitis have been observed following accidental contact with inorganic mercury compounds.⁵ Manifestation in children chronically exposed to mercury includes a nonallergic hypersensitivity (acrodynia),^5,17 which is characterized by pain and dusky pink discoloration in the hands and feet, most often seen in children chronically exposed to mercury absorbed from vapor inhalation or cutaneous exposure.¹⁶

Renal conditions associated with acute inhalation of elemental mercury vapor include proteinuria, nephrotic syndrome, temporary tubular dysfunction, acute tubular necrosis, and oliguric renal failure.¹⁶ Chronic exposure to inorganic mercury compounds also has been reported to cause renal damage.⁵ Chelation therapy should be performed for any symptomatic patient with a clear history of acute elemental mercury exposure.¹⁶ The most frequently used chelation agent in cases of acute inorganic mercury exposures is dimercaprol. In rare cases of mercury intoxication, hemodialysis is required in the treatment of renal failure and to expedite removal of dimercaprol-mercury complexes.¹⁶

Cardiovascular symptoms associated with acute inhalation of high levels of elemental mercury include tachycardia and hypertension.¹⁶ Increases in blood pressure, palpitations, and heart rate also have been observed in instances of acute elemental mercury exposure. Studies show that exposure to mercury increases both the risk for acute myocardial infarction as well as death from coronary heart and cardiovascular diseases.⁵

Conclusion

Mercury poisoning presents with varied neuropsychologic signs and symptoms. Our case provides insight into a unique route of exposure for mercury toxicity. In addition to the unusual presentation of a mercury granuloma, our case illustrates how surgical techniques can aid in removal of cutaneous reservoirs in the setting of percutaneous exposure.

Evidence of human exposure to mercury dates as far back as the Egyptians in 1500 bc . ¹ The ancient Chinese believed mercury could prolong life, heal bones, and maintain vitality. ² Western medicine has utilized mercury in diuretics, laxatives, antibacterial agents, and antiseptics. ³ Health effects caused by chronic mercury exposure became increasingly apparent in the 1800s after hat makers who had inhaled mercuric nitrate vapors began to present with a host of neurologic symptoms, which is where the p hrase "mad as a hatter" was derived. ^4,5 In 1889, French neurologist Jean-Martin Charcot attributed rapid tremors to mercury poisoning. ⁶ By 1940, Kinnier Wilson ⁷ further characterized the effects of mercury, describing mercury-induced cognitive impairments. In the 1960s, Japanese researchers correlated elevated urinary mercury levels with an outbreak of Minamata disease, a condition characterized by tremors, sensory loss, ataxia, and visual constrictions. ⁸ The World Health Organization considers mercury to be one of the top 10 chemicals of major public health concern. ⁹

Mercury release in the environment primarily is a function of human activity, including coal-fired power plants, residential heating, and mining.^9,10 Mercury from these sources is commonly found in the sediment of lakes and bays, where it is enzymatically converted to methylmercury by aquatic microorganisms; subsequent food chain biomagnification results in elevated mercury levels in apex predators. Substantial release of mercury into the environment also can be attributed to health care facilities from their use of thermometers containing 0.5 to 3 g of elemental mercury,¹¹ blood pressure monitors, and medical waste incinerators.⁵

Mercury has been reported as the second most common cause of heavy metal poisoning after lead.¹² Standards from the US Food and Drug Administration dictate that methylmercury levels in fish and wheat products must not exceed 1 ppm.¹³ Most plant and animal food sources contain methylmercury at levels between 0.0001 and 0.01 ppm; mercury concentrations are especially high in tuna, averaging 0.4 ppm, while larger predatory fish contain levels in excess of 1 ppm.¹⁴ The use of mercury-containing cosmetic products also presents a substantial exposure risk to consumers.^5,10 In one study, 3.3% of skin-lightening creams and soaps purchased within the United States contained concentrations of mercury exceeding 1000 ppm.¹⁵

We describe a case of mercury toxicity resulting from intentional injection of liquid mercury into the right antecubital fossa in a suicide attempt.

Case Report

A 31-year-old woman presented to the family practice center for evaluation of a firm stained area on the skin of the right arm. She reported increasing anxiety, depression, tremors, irritability, and difficulty concentrating over the last 6 months. She denied headache and joint or muscle pain. Four years earlier, she had broken apart a thermometer and injected approximately 0.7 mL of its contents into the right arm in a suicide attempt. She intended to inject the thermometer’s contents directly into a vein, but the material instead entered the surrounding tissue. She denied notable pain or itching overlying the injection site. Her medications included aripiprazole and buspirone. She noted that she smoked half a pack of cigarettes per day and had a history of methamphetamine abuse. She was homeless and unemployed. Physical examination revealed an anxious tremulous woman with an erythematous to bluish gray, firm plaque on the right antecubital fossa (Figure 1). There were no notable tremors and no gait disturbance.

Her blood mercury level was greater than 100 µg/L and urine mercury was 477 µg/g (reference ranges, 1–8 μg/L and 4–5 μg/L, respectively). A radiograph of the right elbow area revealed scattered punctate foci of increased density within or overlying the anterolateral elbow soft tissues. She was diagnosed with mercury granuloma causing chronic mercury elevation. She underwent excision of the granuloma (Figure 2) with endovascular surgery via an elliptical incision. The patient was subsequently lost to follow-up.

Comment

Elemental mercury is a silver liquid at room temperature that spontaneously evaporates to form mercury vapor, an invisible, odorless, toxic gas. Accidental cutaneous exposure typically is safely managed by washing exposed skin with soap and water,¹⁶ though there is a potential risk for systemic absorption, especially when the skin is inflamed. When metallic mercury is subcutaneously injected, it is advised to promptly excise all subcutaneous areas containing mercury, regardless of any symptoms of systemic toxicity. Patients should subsequently be monitored for signs of both central nervous system (CNS) and renal deficits, undergo chelation therapy when systemic effects are apparent, and finally receive psychiatric consultation and treatment when necessary.¹⁷

Inorganic mercury compounds are formed when elemental mercury combines with sulfur or oxygen and often take the form of mercury salts, which appear as white crystals.¹⁶ These salts occur naturally in the environment and are used in pesticides, antiseptics, and skin-lightening creams and soaps.¹⁸

Methylmercury is a highly toxic, organic compound that is capable of crossing the placental and blood-brain barriers. It is the most common organic mercury compound found in the environment.¹⁶ Most humans have trace amounts of methylmercury in their bodies, typically as a result of consuming seafood.⁵

Exposure to mercury most commonly occurs through chronic consumption of methylmercury in seafood or acute inhalation of elemental mercury vapors.⁹ Iatrogenic cases of mercury exposure via injection also have been reported in the literature, including a case resulting in acute poisoning due to peritoneal lavage with mercury bichloride.¹⁹ Acute mercury-induced pulmonary damage typically resolves completely. However, there have been reported cases of exposure progressing to interstitial emphysema, pneumatocele, pneumothorax, pneumomediastinum, interstitial fibrosis, and chronic respiratory insufficiency, with examples of fatal acute respiratory distress syndrome being reported.^5,16,20 Although individuals who inhale mercury vapors initially may be unaware of exposure due to little upper airway irritation, symptoms following an initial acute exposure may include ptyalism, a metallic taste, dysphagia, enteritis, diarrhea, nausea, renal damage, and CNS effects.¹⁶ Additionally, exposure may lead to confusion with signs and symptoms of metal fume fever, including shortness of breath, pleuritic chest pain, stomatitis, lethargy, and vomiting.²⁰

Chronic exposure to mercury vapor can result in accumulation of mercury in the body, leading to neuropsychiatric, dermatologic, oropharyngeal, and renal manifestations. Sore throat, fever, headache, fatigue, dyspnea, chest pain, and pneumonitis are common.¹⁶ Typically, low-level exposure to elemental mercury does not lead to long-lasting health effects. However, individuals exposed to high-level elemental mercury vapors may require hospitalization. Treatment of acute mercury poisoning consists of removing the source of exposure, followed by cardiopulmonary support.¹⁶

Specific assays for mercury levels in blood and urine are useful to assess the level of exposure and risk to the patient. Blood mercury concentrations of 20 µg/L or below are considered within reference range; however, once blood and urine concentrations of mercury exceed 100 µg/L, clinical signs of acute mercury poisoning typically manifest.²¹ Chest radiographs can reveal pulmonary damage, while complete blood cell count, metabolic panel, and urinalysis can assess damage to other organs. Neuropsychiatric testing and nerve conduction studies may provide objective evidence of CNS toxicity. Assays for N-acetyl-β-D-glucosaminidase can provide an indication of early renal tubular dysfunction.¹⁶

Elemental mercury is not absorbed from the gastrointestinal tract, posing minimal risk for acute toxicity from ingestion. Generally, less than 10% of ingested inorganic mercury is absorbed from the gut, while elemental mercury is nonabsorbable.¹⁰ If an individual ingests a large amount of mercury, it may persist in the gastrointestinal tract for an extended period. Mercury is radiopaque, and abdominal radiographs should be obtained in all cases of ingestion.¹⁶

Mercury is toxic to the CNS and peripheral nervous system, resulting in erethism mercurialis, a constellation of neuropsychologic signs and symptoms including restlessness, irritability, insomnia, emotional lability, difficulty concentrating, and impaired memory. In severe cases, delirium and psychosis may develop. Other CNS effects include tremors, paresthesia, dysarthria, neuromuscular changes, headaches, polyneuropathy, and cerebellar ataxia, as well as ophthalmologic and audiologic impairment.^5,16

Upon inhalation exposure, patients with respiratory concerns should be given oxygen. Bronchospasms are treated with bronchodilators; however, if multiple chemical exposures are suspected, bronchial-sensitizing agents may pose additional risks. Corticosteroids and antibiotics have been recommended for treatment of chemical pneumonitis, but their efficacy has not been substantiated.¹⁶

Skin reactions associated with skin contact to elemental mercury are rare. However, hives and dermatitis have been observed following accidental contact with inorganic mercury compounds.⁵ Manifestation in children chronically exposed to mercury includes a nonallergic hypersensitivity (acrodynia),^5,17 which is characterized by pain and dusky pink discoloration in the hands and feet, most often seen in children chronically exposed to mercury absorbed from vapor inhalation or cutaneous exposure.¹⁶

Renal conditions associated with acute inhalation of elemental mercury vapor include proteinuria, nephrotic syndrome, temporary tubular dysfunction, acute tubular necrosis, and oliguric renal failure.¹⁶ Chronic exposure to inorganic mercury compounds also has been reported to cause renal damage.⁵ Chelation therapy should be performed for any symptomatic patient with a clear history of acute elemental mercury exposure.¹⁶ The most frequently used chelation agent in cases of acute inorganic mercury exposures is dimercaprol. In rare cases of mercury intoxication, hemodialysis is required in the treatment of renal failure and to expedite removal of dimercaprol-mercury complexes.¹⁶

Cardiovascular symptoms associated with acute inhalation of high levels of elemental mercury include tachycardia and hypertension.¹⁶ Increases in blood pressure, palpitations, and heart rate also have been observed in instances of acute elemental mercury exposure. Studies show that exposure to mercury increases both the risk for acute myocardial infarction as well as death from coronary heart and cardiovascular diseases.⁵

Conclusion

Mercury poisoning presents with varied neuropsychologic signs and symptoms. Our case provides insight into a unique route of exposure for mercury toxicity. In addition to the unusual presentation of a mercury granuloma, our case illustrates how surgical techniques can aid in removal of cutaneous reservoirs in the setting of percutaneous exposure.

Anagen effluvium during chemotherapy is common, typically beginning within 1 month of treatment onset and resolving by 6 months after the final course.¹ Permanent chemotherapy-induced alopecia (PCIA), in which hair loss persists beyond 6 months after chemotherapy without recovery to original density, was first reported in patients following high-dose chemotherapy regimens for allogeneic bone marrow transplantation.² There are now increasing reports of PCIA in patients with breast cancer; at least 400 such cases have been documented.^3-16 In addition to chemotherapy, patients often receive adjuvant endocrine therapy with selective estrogen receptor modulators, aromatase inhibitors, or gonadotropin-releasing hormone agonists.^5-16 Endocrine therapies also can lead to alopecia, but their role in PCIA has not been well defined.^15,16 We describe 3 patients with breast cancer who experienced PCIA following chemotherapy with taxanes with or without endocrine therapies. We also review the literature on non–bone marrow transplantation PCIA to better characterize this entity and explore the role of endocrine therapies in PCIA.

Case Reports

Patient 1
A 62-year-old woman with a history of stage II invasive ductal carcinoma presented with persistent hair loss 5 years after completing chemotherapy. She underwent 6 cycles of docetaxel and carboplatin along with radiation therapy as well as 1 year of trastuzumab and did not receive endocrine therapy. At the current presentation, she reported patchy hair regrowth that gradually filled in but failed to return to full density. Physical examination revealed the hair was diffusely thin, especially bitemporally (Figures 1A and 1B), and she did not experience any loss of body hair. She had no family history of hair loss. Her medical history was notable for hypertension, chronic obstructive bronchitis, osteopenia, and depression. Her thyroid stimulating hormone (TSH) level was within reference range. Medications included lisinopril, metoprolol, escitalopram, and trazodone. A biopsy from the occipital scalp showed nonscarring alopecia with variation of hair follicle size, a decreased number of hair follicles, and a decreased anagen to telogen ratio (Figure 1C). She was treated with clobetasol solution and minoxidil solution 5% for 1 year with mild improvement. She experienced no further hair loss but did not regain original hair density.

Patient 2
A 35-year-old woman with a history of stage II invasive ductal carcinoma presented with persistent hair loss 10 months after chemotherapy. She underwent 4 cycles of doxorubicin and cyclophosphamide followed by 4 cycles of paclitaxel and was started on trastuzumab. Tamoxifen was initiated 1 month after completing chemotherapy. She received radiation therapy the following month and continued trastuzumab for 1 year. At the current presentation, the patient noted that hair regrowth had started 1 month after the last course of chemotherapy but had progressed slowly. She denied body hair loss. Physical examination revealed diffuse thinning, especially over the crown, with scattered broken hairs throughout the scalp and several miniaturized hairs over the crown. She was evaluated as grade 3 on the Sinclair clinical grading scale used to evaluate female pattern hair loss (FPHL).¹⁷ Her family history was remarkable for FPHL in her maternal grandmother. She had no notable medical history, her TSH was normal, and she was taking tamoxifen and trastuzumab. Biopsy was not performed. The patient was started on minoxidil solution 2% and had mild improvement with no further broken-off hairs after 10 months. At that point, she was evaluated as grade 2 to 3 on the Sinclair scale.¹⁷

Patient 3
A 51-year-old woman with a history of papillary carcinoma and extensive ductal carcinoma in situ presented with persistent hair loss for 3.5 years following chemotherapy for recurrent breast cancer. After her initial diagnosis in the left breast, she received cyclophosphamide, methotrexate, and 5-fluorouracil but did not receive endocrine therapy. Her hair thinned during chemotherapy but returned to normal density within 1 year. She had a recurrence of the cancer in the right breast 14 years later and received 6 cycles of chemotherapy with cyclophosphamide and docetaxel followed by radiation therapy. After this course, her hair loss incompletely recovered. One year after chemotherapy, she underwent bilateral salpingo-oophorectomy and started anastrozole. Three months later, she noticed increased shedding and progressive thinning of the hair. Physical examination revealed diffuse thinning that was most pronounced over the crown. She also experienced lateral thinning of the eyebrows, decreased eyelashes, and dystrophic fingernails. Fluocinonide solution was discontinued by the patient due to scalp burning. She had a brother with bitemporal recession. Her medical history was notable for Hashimoto thyroiditis, vitamin D deficiency, and peripheral neuropathy. Her TSH occasionally was elevated, and she was intermittently on levothyroxine; however, her free T4 was maintained within reference range on all records. Her medications at the time of evaluation were anastrozole and gabapentin. Biopsies taken from the right and left temporal scalp revealed decreased follicle density with a majority of follicles in anagen, scattered miniaturized follicles, and a mild perivascular and perifollicular lymphoid infiltrate. Mild dermal fibrosis was present without evidence of frank scarring (Figure 2). She declined treatment, and there was no change in her condition over 3 years of follow-up.

Comment

Classification of Chemotherapy-Induced Hair Loss
Chemotherapy-induced alopecia is typically an anagen effluvium that is reversed within 6 months following the final course of chemotherapy. When incomplete regrowth persists, the patient is considered to have PCIA.¹ The pathophysiology of PCIA is unclear.

Traditional grading for chemotherapy-induced alopecia does not account for the patterns of loss seen in PCIA, of which the most common appears to be a female pattern with accentuated hair loss in androgen-dependent regions of the scalp.¹⁸ Other patterns include a diffuse type with body hair loss, patchy alopecia, and complete alopecia with or without body hair loss (Table).^3-8 Whether these patterns all can be attributed to chemotherapy remains to be explored.

Furthermore, endocrine therapies used in breast cancer treatment decrease estrogen levels or antagonize estrogen receptors, creating an environment of relative hyperandrogenism that may contribute to FPHL in genetically susceptible women.¹⁸ Although taxanes may cause irreversible hair loss in these patients, the action of endocrine therapies on the remaining hair follicles may affect the typical female pattern seen clinically. Patients 2 and 3 who presented with FPHL received adjuvant endocrine therapies and had positive family history, while patient 1 did not. Of note, patient 3 experienced worsening hair loss following the addition of anastrozole, which suggests a contribution of endocrine therapy to her PCIA. Our limited cases do not allow for evaluation of a worsened outcome with the combination of taxanes and endocrine therapies; however, we suggest further evaluation for a synergistic effect that may be contributing to PCIA.

Conclusion

Permanent alopecia in breast cancer patients appears to be a true potential adverse effect of taxanes and endocrine therapies, and it is important to characterize it appropriately so that its mechanism can be understood and appropriate treatment and counseling can take place. Although it may not influence clinical decision-making, patients should be informed that hair loss with chemotherapy can be permanent. Treatment with scalp cooling can reduce the risk for severe chemotherapy-induced alopecia, but it is unclear if it reduces risk for PCIA.^12,15 Topical or oral minoxidil may be helpful in the treatment of PCIA once it has developed.^7,8,15,22 Better characterization of these cases may elucidate risk factors for developing permanent alopecia, allowing for more appropriate risk stratification, counseling, and treatment.

Anagen effluvium during chemotherapy is common, typically beginning within 1 month of treatment onset and resolving by 6 months after the final course.¹ Permanent chemotherapy-induced alopecia (PCIA), in which hair loss persists beyond 6 months after chemotherapy without recovery to original density, was first reported in patients following high-dose chemotherapy regimens for allogeneic bone marrow transplantation.² There are now increasing reports of PCIA in patients with breast cancer; at least 400 such cases have been documented.^3-16 In addition to chemotherapy, patients often receive adjuvant endocrine therapy with selective estrogen receptor modulators, aromatase inhibitors, or gonadotropin-releasing hormone agonists.^5-16 Endocrine therapies also can lead to alopecia, but their role in PCIA has not been well defined.^15,16 We describe 3 patients with breast cancer who experienced PCIA following chemotherapy with taxanes with or without endocrine therapies. We also review the literature on non–bone marrow transplantation PCIA to better characterize this entity and explore the role of endocrine therapies in PCIA.

Case Reports

Patient 1
A 62-year-old woman with a history of stage II invasive ductal carcinoma presented with persistent hair loss 5 years after completing chemotherapy. She underwent 6 cycles of docetaxel and carboplatin along with radiation therapy as well as 1 year of trastuzumab and did not receive endocrine therapy. At the current presentation, she reported patchy hair regrowth that gradually filled in but failed to return to full density. Physical examination revealed the hair was diffusely thin, especially bitemporally (Figures 1A and 1B), and she did not experience any loss of body hair. She had no family history of hair loss. Her medical history was notable for hypertension, chronic obstructive bronchitis, osteopenia, and depression. Her thyroid stimulating hormone (TSH) level was within reference range. Medications included lisinopril, metoprolol, escitalopram, and trazodone. A biopsy from the occipital scalp showed nonscarring alopecia with variation of hair follicle size, a decreased number of hair follicles, and a decreased anagen to telogen ratio (Figure 1C). She was treated with clobetasol solution and minoxidil solution 5% for 1 year with mild improvement. She experienced no further hair loss but did not regain original hair density.

Patient 2
A 35-year-old woman with a history of stage II invasive ductal carcinoma presented with persistent hair loss 10 months after chemotherapy. She underwent 4 cycles of doxorubicin and cyclophosphamide followed by 4 cycles of paclitaxel and was started on trastuzumab. Tamoxifen was initiated 1 month after completing chemotherapy. She received radiation therapy the following month and continued trastuzumab for 1 year. At the current presentation, the patient noted that hair regrowth had started 1 month after the last course of chemotherapy but had progressed slowly. She denied body hair loss. Physical examination revealed diffuse thinning, especially over the crown, with scattered broken hairs throughout the scalp and several miniaturized hairs over the crown. She was evaluated as grade 3 on the Sinclair clinical grading scale used to evaluate female pattern hair loss (FPHL).¹⁷ Her family history was remarkable for FPHL in her maternal grandmother. She had no notable medical history, her TSH was normal, and she was taking tamoxifen and trastuzumab. Biopsy was not performed. The patient was started on minoxidil solution 2% and had mild improvement with no further broken-off hairs after 10 months. At that point, she was evaluated as grade 2 to 3 on the Sinclair scale.¹⁷

Patient 3
A 51-year-old woman with a history of papillary carcinoma and extensive ductal carcinoma in situ presented with persistent hair loss for 3.5 years following chemotherapy for recurrent breast cancer. After her initial diagnosis in the left breast, she received cyclophosphamide, methotrexate, and 5-fluorouracil but did not receive endocrine therapy. Her hair thinned during chemotherapy but returned to normal density within 1 year. She had a recurrence of the cancer in the right breast 14 years later and received 6 cycles of chemotherapy with cyclophosphamide and docetaxel followed by radiation therapy. After this course, her hair loss incompletely recovered. One year after chemotherapy, she underwent bilateral salpingo-oophorectomy and started anastrozole. Three months later, she noticed increased shedding and progressive thinning of the hair. Physical examination revealed diffuse thinning that was most pronounced over the crown. She also experienced lateral thinning of the eyebrows, decreased eyelashes, and dystrophic fingernails. Fluocinonide solution was discontinued by the patient due to scalp burning. She had a brother with bitemporal recession. Her medical history was notable for Hashimoto thyroiditis, vitamin D deficiency, and peripheral neuropathy. Her TSH occasionally was elevated, and she was intermittently on levothyroxine; however, her free T4 was maintained within reference range on all records. Her medications at the time of evaluation were anastrozole and gabapentin. Biopsies taken from the right and left temporal scalp revealed decreased follicle density with a majority of follicles in anagen, scattered miniaturized follicles, and a mild perivascular and perifollicular lymphoid infiltrate. Mild dermal fibrosis was present without evidence of frank scarring (Figure 2). She declined treatment, and there was no change in her condition over 3 years of follow-up.

Comment

Classification of Chemotherapy-Induced Hair Loss
Chemotherapy-induced alopecia is typically an anagen effluvium that is reversed within 6 months following the final course of chemotherapy. When incomplete regrowth persists, the patient is considered to have PCIA.¹ The pathophysiology of PCIA is unclear.

Traditional grading for chemotherapy-induced alopecia does not account for the patterns of loss seen in PCIA, of which the most common appears to be a female pattern with accentuated hair loss in androgen-dependent regions of the scalp.¹⁸ Other patterns include a diffuse type with body hair loss, patchy alopecia, and complete alopecia with or without body hair loss (Table).^3-8 Whether these patterns all can be attributed to chemotherapy remains to be explored.

Furthermore, endocrine therapies used in breast cancer treatment decrease estrogen levels or antagonize estrogen receptors, creating an environment of relative hyperandrogenism that may contribute to FPHL in genetically susceptible women.¹⁸ Although taxanes may cause irreversible hair loss in these patients, the action of endocrine therapies on the remaining hair follicles may affect the typical female pattern seen clinically. Patients 2 and 3 who presented with FPHL received adjuvant endocrine therapies and had positive family history, while patient 1 did not. Of note, patient 3 experienced worsening hair loss following the addition of anastrozole, which suggests a contribution of endocrine therapy to her PCIA. Our limited cases do not allow for evaluation of a worsened outcome with the combination of taxanes and endocrine therapies; however, we suggest further evaluation for a synergistic effect that may be contributing to PCIA.

Conclusion

Permanent alopecia in breast cancer patients appears to be a true potential adverse effect of taxanes and endocrine therapies, and it is important to characterize it appropriately so that its mechanism can be understood and appropriate treatment and counseling can take place. Although it may not influence clinical decision-making, patients should be informed that hair loss with chemotherapy can be permanent. Treatment with scalp cooling can reduce the risk for severe chemotherapy-induced alopecia, but it is unclear if it reduces risk for PCIA.^12,15 Topical or oral minoxidil may be helpful in the treatment of PCIA once it has developed.^7,8,15,22 Better characterization of these cases may elucidate risk factors for developing permanent alopecia, allowing for more appropriate risk stratification, counseling, and treatment.

Anagen effluvium during chemotherapy is common, typically beginning within 1 month of treatment onset and resolving by 6 months after the final course.¹ Permanent chemotherapy-induced alopecia (PCIA), in which hair loss persists beyond 6 months after chemotherapy without recovery to original density, was first reported in patients following high-dose chemotherapy regimens for allogeneic bone marrow transplantation.² There are now increasing reports of PCIA in patients with breast cancer; at least 400 such cases have been documented.^3-16 In addition to chemotherapy, patients often receive adjuvant endocrine therapy with selective estrogen receptor modulators, aromatase inhibitors, or gonadotropin-releasing hormone agonists.^5-16 Endocrine therapies also can lead to alopecia, but their role in PCIA has not been well defined.^15,16 We describe 3 patients with breast cancer who experienced PCIA following chemotherapy with taxanes with or without endocrine therapies. We also review the literature on non–bone marrow transplantation PCIA to better characterize this entity and explore the role of endocrine therapies in PCIA.

Case Reports

Patient 1
A 62-year-old woman with a history of stage II invasive ductal carcinoma presented with persistent hair loss 5 years after completing chemotherapy. She underwent 6 cycles of docetaxel and carboplatin along with radiation therapy as well as 1 year of trastuzumab and did not receive endocrine therapy. At the current presentation, she reported patchy hair regrowth that gradually filled in but failed to return to full density. Physical examination revealed the hair was diffusely thin, especially bitemporally (Figures 1A and 1B), and she did not experience any loss of body hair. She had no family history of hair loss. Her medical history was notable for hypertension, chronic obstructive bronchitis, osteopenia, and depression. Her thyroid stimulating hormone (TSH) level was within reference range. Medications included lisinopril, metoprolol, escitalopram, and trazodone. A biopsy from the occipital scalp showed nonscarring alopecia with variation of hair follicle size, a decreased number of hair follicles, and a decreased anagen to telogen ratio (Figure 1C). She was treated with clobetasol solution and minoxidil solution 5% for 1 year with mild improvement. She experienced no further hair loss but did not regain original hair density.

Patient 2
A 35-year-old woman with a history of stage II invasive ductal carcinoma presented with persistent hair loss 10 months after chemotherapy. She underwent 4 cycles of doxorubicin and cyclophosphamide followed by 4 cycles of paclitaxel and was started on trastuzumab. Tamoxifen was initiated 1 month after completing chemotherapy. She received radiation therapy the following month and continued trastuzumab for 1 year. At the current presentation, the patient noted that hair regrowth had started 1 month after the last course of chemotherapy but had progressed slowly. She denied body hair loss. Physical examination revealed diffuse thinning, especially over the crown, with scattered broken hairs throughout the scalp and several miniaturized hairs over the crown. She was evaluated as grade 3 on the Sinclair clinical grading scale used to evaluate female pattern hair loss (FPHL).¹⁷ Her family history was remarkable for FPHL in her maternal grandmother. She had no notable medical history, her TSH was normal, and she was taking tamoxifen and trastuzumab. Biopsy was not performed. The patient was started on minoxidil solution 2% and had mild improvement with no further broken-off hairs after 10 months. At that point, she was evaluated as grade 2 to 3 on the Sinclair scale.¹⁷

Patient 3
A 51-year-old woman with a history of papillary carcinoma and extensive ductal carcinoma in situ presented with persistent hair loss for 3.5 years following chemotherapy for recurrent breast cancer. After her initial diagnosis in the left breast, she received cyclophosphamide, methotrexate, and 5-fluorouracil but did not receive endocrine therapy. Her hair thinned during chemotherapy but returned to normal density within 1 year. She had a recurrence of the cancer in the right breast 14 years later and received 6 cycles of chemotherapy with cyclophosphamide and docetaxel followed by radiation therapy. After this course, her hair loss incompletely recovered. One year after chemotherapy, she underwent bilateral salpingo-oophorectomy and started anastrozole. Three months later, she noticed increased shedding and progressive thinning of the hair. Physical examination revealed diffuse thinning that was most pronounced over the crown. She also experienced lateral thinning of the eyebrows, decreased eyelashes, and dystrophic fingernails. Fluocinonide solution was discontinued by the patient due to scalp burning. She had a brother with bitemporal recession. Her medical history was notable for Hashimoto thyroiditis, vitamin D deficiency, and peripheral neuropathy. Her TSH occasionally was elevated, and she was intermittently on levothyroxine; however, her free T4 was maintained within reference range on all records. Her medications at the time of evaluation were anastrozole and gabapentin. Biopsies taken from the right and left temporal scalp revealed decreased follicle density with a majority of follicles in anagen, scattered miniaturized follicles, and a mild perivascular and perifollicular lymphoid infiltrate. Mild dermal fibrosis was present without evidence of frank scarring (Figure 2). She declined treatment, and there was no change in her condition over 3 years of follow-up.

Comment

Classification of Chemotherapy-Induced Hair Loss
Chemotherapy-induced alopecia is typically an anagen effluvium that is reversed within 6 months following the final course of chemotherapy. When incomplete regrowth persists, the patient is considered to have PCIA.¹ The pathophysiology of PCIA is unclear.

Traditional grading for chemotherapy-induced alopecia does not account for the patterns of loss seen in PCIA, of which the most common appears to be a female pattern with accentuated hair loss in androgen-dependent regions of the scalp.¹⁸ Other patterns include a diffuse type with body hair loss, patchy alopecia, and complete alopecia with or without body hair loss (Table).^3-8 Whether these patterns all can be attributed to chemotherapy remains to be explored.

Furthermore, endocrine therapies used in breast cancer treatment decrease estrogen levels or antagonize estrogen receptors, creating an environment of relative hyperandrogenism that may contribute to FPHL in genetically susceptible women.¹⁸ Although taxanes may cause irreversible hair loss in these patients, the action of endocrine therapies on the remaining hair follicles may affect the typical female pattern seen clinically. Patients 2 and 3 who presented with FPHL received adjuvant endocrine therapies and had positive family history, while patient 1 did not. Of note, patient 3 experienced worsening hair loss following the addition of anastrozole, which suggests a contribution of endocrine therapy to her PCIA. Our limited cases do not allow for evaluation of a worsened outcome with the combination of taxanes and endocrine therapies; however, we suggest further evaluation for a synergistic effect that may be contributing to PCIA.

Conclusion

Permanent alopecia in breast cancer patients appears to be a true potential adverse effect of taxanes and endocrine therapies, and it is important to characterize it appropriately so that its mechanism can be understood and appropriate treatment and counseling can take place. Although it may not influence clinical decision-making, patients should be informed that hair loss with chemotherapy can be permanent. Treatment with scalp cooling can reduce the risk for severe chemotherapy-induced alopecia, but it is unclear if it reduces risk for PCIA.^12,15 Topical or oral minoxidil may be helpful in the treatment of PCIA once it has developed.^7,8,15,22 Better characterization of these cases may elucidate risk factors for developing permanent alopecia, allowing for more appropriate risk stratification, counseling, and treatment.

Generalized pustular psoriasis of pregnancy (GPPP), formerly known as impetigo herpetiformis, is a rare dermatosis that causes maternal and fetal morbidity and mortality. It is characterized by widespread, circular, erythematous plaques with pustules at the periphery.¹ Conventional first-line treatment includes systemic corticosteroids and cyclosporine. The National Psoriasis Foundation Medical Board also has included infliximab among the first-line treatment options for GPPP.² Herein, we report a case of GPPP treated with infliximab at 30 weeks’ gestation and during the postpartum period.

Case Report

A 22-year-old woman was admitted to our inpatient clinic at 20 weeks’ gestation in her second pregnancy for evaluation of cutaneous eruptions covering the entire body. The lesions first appeared 3 to 4 days prior to her admission and dramatically progressed. She had a history of psoriasis vulgaris diagnosed during her first pregnancy 2 years prior that was treated with topical steroids throughout the pregnancy and methotrexate during lactation for a total of 11 months. She then was started on cyclosporine, which she used for 6 months due to ineffectiveness of the methotrexate, but she stopped treatment 4 months before the second pregnancy.

At the current presentation, physical examination revealed erythroderma and widespread pustules on the chest, abdomen, arms, and legs, including the intertriginous regions, that tended to coalesce and form lakes of pus over an erythematous base (Figure 1). The mucosae were normal. She exhibited a low blood pressure (85/50 mmHg) and high body temperature (102 °F [38.9 °C]). Routine laboratory examination revealed anemia and a normal leukocyte count. Her erythrocyte sedimentation rate (57 mm/h [reference range, <20 mm/h]) and C-reactive protein level (102 mg/L [reference range, <6 mg/L]) were elevated, whereas total calcium (8.11 mg/dL [reference range, 8.2–10.6 mg/dL]) and albumin (3.15 g/dL [reference range, >4.0 g/dL]) levels were low.

The patient returned to the clinic 3 weeks postpartum with a few pustules on erythematous plaques on the chest, abdomen, and back. At this time, she received a third infusion of infliximab 8 weeks after the second dose. For the past 5 years, the patient has been undergoing infliximab maintenance treatment, which she receives at the hospital every 8 weeks with excellent response. She has had no further pregnancies to date.

Comment

Generalized pustular psoriasis of pregnancy is a rare condition that typically occurs in the third trimester but also can start in the first and second trimesters. It may result in maternal and fetal morbidity by causing fluid and electrolyte imbalance and/or placental insufficiency, resulting in an increased risk for fetal abnormalities, stillbirth, and neonatal death.³ In subsequent pregnancies, GPPP has been observed to recur at an earlier gestational age with a more severe presentation.^1,3

Generalized pustular psoriasis of pregnancy usually involves an eruption that begins symmetrically in the intertriginous areas and spreads to the rest of the body. The lesions present as erythematous annular plaques with pustules on the periphery and desquamation in the center due to older pustules.^1,3 The mucous membranes also may be involved with erosive and exfoliative plaques, and there may be nail involvement. Patients often present with systemic symptoms such as fever, malaise, diarrhea, and vomiting.¹ Laboratory investigations may reveal neutrophilic leukocytosis, high erythrocyte sedimentation rate, hypocalcemia, and hypoalbuminemia.⁴ Cultures from blood and pustules show no bacterial growth. A skin biopsy is helpful in diagnosis, with features similar to generalized pustular psoriasis, demonstrating spongiform pustules containing neutrophils, lymphocytic and neutrophilic infiltrates in the papillary dermis, and negative direct immunofluorescence.³

The differential diagnosis of GPPP includes subcorneal pustular dermatosis, dermatitis herpetiformis, herpes gestationis, impetigo, and acute generalized exanthematous pustulosis.^1,3 Due to concerns of fetal implications, treatment options in GPPP are somewhat limited; however, the condition requires treatment because it may result in unfavorable pregnancy outcomes. Topical corticosteroids may be an option for limited disease.^5,6 Systemic corticosteroids (eg, prednisone 60–80 mg/d) were previously considered as first-line agents, although they have shown limited efficacy in our case as well as in other case reports.⁷ Their ineffectiveness and risk for flare-up after dose tapering should be kept in mind when starting GPPP patients on systemic corticosteroids. Systemic cyclosporine (2–3 mg/kg/d) may be added to increase the efficacy of systemic steroids, which was done in several cases in literature.^1,6,8 Although cyclosporine has been classified as a pregnancy category C drug, an analysis of pregnancy outcomes of 629 renal transplant patients revealed no association with adverse pregnancy outcomes compared to the general population and no increase in fetal malformations.⁹ Therefore, cyclosporine is a safe treatment option and was classified as a first-line drug for GPPP in a 2012 review by the National Psoriasis Foundation Medical Board.² Narrowband UVB also has been reported to be used for the treatment of GPPP.¹⁰ Methotrexate and retinoids have been used in cases with lesions that persisted postpartum.¹

Anti–tumor necrosis factor (TNF) α agents are another effective option for treatment of GPPP. Anti-TNF agents are classified as pregnancy category B due to results showing that anti-mouse TNF-α monoclonal antibodies did not cause embryotoxicity or teratogenicity in pregnant mice.¹¹ Although Carter et al¹² published a review of US Food and Drug Administration data on pregnant women receiving anti-TNF treatment and concluded that these agents were associated with the VACTERL group of malformations (vertebral defects, anal atresia, cardiac defect, tracheoesophageal fistula with esophageal atresia, cardiac defects, renal and limb anomalies), no such association was found in further studies. A 2014 study showed no difference in the rate of major malformations in infants born to women who were treated with anti-TNF drugs compared to the disease-matched group not treated with these agents and pregnant women counselled for nonteratogenic exposure.¹³ The same study detected an increase in preterm and low-birth-weight deliveries and suggested this might be caused by the increased severity of disease in patients requiring anti-TNF medication. The British Society of Rheumatology Biologics Register published data on pregnancy outcomes in 130 rheumatoid arthritis patients who had been exposed to anti-TNF agents.¹⁴ The results suggested an increased rate of spontaneous abortions in women exposed to anti-TNF treatment around the time of conception, especially in those taking these medications together with methotrexate or leflunomide; however, results also indicated that disease activity may have had an impact on the rate of spontaneous abortions in these patients. In a 2013 review of 462 women with inflammatory bowel disease who had been exposed to anti-TNF agents during pregnancy, the investigators concluded that pregnancy outcomes and the rate of congenital anomalies did not significantly differ from other inflammatory bowel disease patients not receiving anti-TNF drugs or the general population.¹⁵

In 2012, the National Board of the National Psoriasis Foundation put infliximab amongst the first-line treatment modalities for GPPP.² In one case of GPPP in which the eruption persisted after delivery, the patient was treated with infliximab 7 weeks postpartum due to failure to control the disease with prednisolone 60 mg daily and cyclosporine 7.5 mg/kg daily. Unlike our patient, this patient was only started on an infliximab regimen after delivery.¹⁶ In another case reported in 2010, the patient was started on infliximab during the postpartum period of her first pregnancy following a pustular flare of previously diagnosed plaque psoriasis (not a generalized pustular psoriasis, as in our case).¹⁷ As a good response was obtained, infliximab treatment was continued in the patient throughout her second pregnancy.

Our case is unique in that infliximab was started during pregnancy because of intractable disease leading to systemic symptoms. Our patient showed an excellent response to infliximab after a 10-week disease course with repeated flare-ups and impairment to her overall condition. Delivery occurred at 36 weeks’ gestation due to suspected intrauterine growth retardation; however, the neonate was born with a 5-minute APGAR score of 10 and required no special medical care, which suggests that the low birth weight was constitutional due to the patient’s small frame (her height was 4 ft 11 in). The breast milk of patients with inflammatory bowel disease has been detected to contain very small amounts of infliximab (101 ng/mL, about 1/200 of the therapeutic blood level).¹⁸ Considering the large molecular weight of this agent and possible proteolysis in the stomach and intestines, infliximab is unlikely to affect the neonate.¹⁵ Thus, we encouraged our patient to breastfeed her baby. A case of fatal disseminated Bacille-Calmette-Guérin infection in an infant whose mother received infliximab treatment during pregnancy has been reported.¹⁹ It has been suggested that live vaccines should be avoided in neonates exposed to anti-TNF agents at least for the first 6 months of life or until the agent is no longer detectable in their blood.¹⁵ We therefore informed our patient’s family practitioner about this data.

Conclusion

We report a case of infliximab treatment for GPPP that was continued during the postpartum period. Infliximab was an effective treatment option in our patient with no detected serious adverse events and may be considered in other cases of GPPP that are not responsive to systemic steroids. However, further studies are warranted to evaluate the safety and efficacy of infliximab treatment for GPPP and psoriasis in pregnancy.

Generalized pustular psoriasis of pregnancy (GPPP), formerly known as impetigo herpetiformis, is a rare dermatosis that causes maternal and fetal morbidity and mortality. It is characterized by widespread, circular, erythematous plaques with pustules at the periphery.¹ Conventional first-line treatment includes systemic corticosteroids and cyclosporine. The National Psoriasis Foundation Medical Board also has included infliximab among the first-line treatment options for GPPP.² Herein, we report a case of GPPP treated with infliximab at 30 weeks’ gestation and during the postpartum period.

Case Report

A 22-year-old woman was admitted to our inpatient clinic at 20 weeks’ gestation in her second pregnancy for evaluation of cutaneous eruptions covering the entire body. The lesions first appeared 3 to 4 days prior to her admission and dramatically progressed. She had a history of psoriasis vulgaris diagnosed during her first pregnancy 2 years prior that was treated with topical steroids throughout the pregnancy and methotrexate during lactation for a total of 11 months. She then was started on cyclosporine, which she used for 6 months due to ineffectiveness of the methotrexate, but she stopped treatment 4 months before the second pregnancy.

At the current presentation, physical examination revealed erythroderma and widespread pustules on the chest, abdomen, arms, and legs, including the intertriginous regions, that tended to coalesce and form lakes of pus over an erythematous base (Figure 1). The mucosae were normal. She exhibited a low blood pressure (85/50 mmHg) and high body temperature (102 °F [38.9 °C]). Routine laboratory examination revealed anemia and a normal leukocyte count. Her erythrocyte sedimentation rate (57 mm/h [reference range, <20 mm/h]) and C-reactive protein level (102 mg/L [reference range, <6 mg/L]) were elevated, whereas total calcium (8.11 mg/dL [reference range, 8.2–10.6 mg/dL]) and albumin (3.15 g/dL [reference range, >4.0 g/dL]) levels were low.

The patient returned to the clinic 3 weeks postpartum with a few pustules on erythematous plaques on the chest, abdomen, and back. At this time, she received a third infusion of infliximab 8 weeks after the second dose. For the past 5 years, the patient has been undergoing infliximab maintenance treatment, which she receives at the hospital every 8 weeks with excellent response. She has had no further pregnancies to date.

Comment

Generalized pustular psoriasis of pregnancy is a rare condition that typically occurs in the third trimester but also can start in the first and second trimesters. It may result in maternal and fetal morbidity by causing fluid and electrolyte imbalance and/or placental insufficiency, resulting in an increased risk for fetal abnormalities, stillbirth, and neonatal death.³ In subsequent pregnancies, GPPP has been observed to recur at an earlier gestational age with a more severe presentation.^1,3

Generalized pustular psoriasis of pregnancy usually involves an eruption that begins symmetrically in the intertriginous areas and spreads to the rest of the body. The lesions present as erythematous annular plaques with pustules on the periphery and desquamation in the center due to older pustules.^1,3 The mucous membranes also may be involved with erosive and exfoliative plaques, and there may be nail involvement. Patients often present with systemic symptoms such as fever, malaise, diarrhea, and vomiting.¹ Laboratory investigations may reveal neutrophilic leukocytosis, high erythrocyte sedimentation rate, hypocalcemia, and hypoalbuminemia.⁴ Cultures from blood and pustules show no bacterial growth. A skin biopsy is helpful in diagnosis, with features similar to generalized pustular psoriasis, demonstrating spongiform pustules containing neutrophils, lymphocytic and neutrophilic infiltrates in the papillary dermis, and negative direct immunofluorescence.³

The differential diagnosis of GPPP includes subcorneal pustular dermatosis, dermatitis herpetiformis, herpes gestationis, impetigo, and acute generalized exanthematous pustulosis.^1,3 Due to concerns of fetal implications, treatment options in GPPP are somewhat limited; however, the condition requires treatment because it may result in unfavorable pregnancy outcomes. Topical corticosteroids may be an option for limited disease.^5,6 Systemic corticosteroids (eg, prednisone 60–80 mg/d) were previously considered as first-line agents, although they have shown limited efficacy in our case as well as in other case reports.⁷ Their ineffectiveness and risk for flare-up after dose tapering should be kept in mind when starting GPPP patients on systemic corticosteroids. Systemic cyclosporine (2–3 mg/kg/d) may be added to increase the efficacy of systemic steroids, which was done in several cases in literature.^1,6,8 Although cyclosporine has been classified as a pregnancy category C drug, an analysis of pregnancy outcomes of 629 renal transplant patients revealed no association with adverse pregnancy outcomes compared to the general population and no increase in fetal malformations.⁹ Therefore, cyclosporine is a safe treatment option and was classified as a first-line drug for GPPP in a 2012 review by the National Psoriasis Foundation Medical Board.² Narrowband UVB also has been reported to be used for the treatment of GPPP.¹⁰ Methotrexate and retinoids have been used in cases with lesions that persisted postpartum.¹

Anti–tumor necrosis factor (TNF) α agents are another effective option for treatment of GPPP. Anti-TNF agents are classified as pregnancy category B due to results showing that anti-mouse TNF-α monoclonal antibodies did not cause embryotoxicity or teratogenicity in pregnant mice.¹¹ Although Carter et al¹² published a review of US Food and Drug Administration data on pregnant women receiving anti-TNF treatment and concluded that these agents were associated with the VACTERL group of malformations (vertebral defects, anal atresia, cardiac defect, tracheoesophageal fistula with esophageal atresia, cardiac defects, renal and limb anomalies), no such association was found in further studies. A 2014 study showed no difference in the rate of major malformations in infants born to women who were treated with anti-TNF drugs compared to the disease-matched group not treated with these agents and pregnant women counselled for nonteratogenic exposure.¹³ The same study detected an increase in preterm and low-birth-weight deliveries and suggested this might be caused by the increased severity of disease in patients requiring anti-TNF medication. The British Society of Rheumatology Biologics Register published data on pregnancy outcomes in 130 rheumatoid arthritis patients who had been exposed to anti-TNF agents.¹⁴ The results suggested an increased rate of spontaneous abortions in women exposed to anti-TNF treatment around the time of conception, especially in those taking these medications together with methotrexate or leflunomide; however, results also indicated that disease activity may have had an impact on the rate of spontaneous abortions in these patients. In a 2013 review of 462 women with inflammatory bowel disease who had been exposed to anti-TNF agents during pregnancy, the investigators concluded that pregnancy outcomes and the rate of congenital anomalies did not significantly differ from other inflammatory bowel disease patients not receiving anti-TNF drugs or the general population.¹⁵

In 2012, the National Board of the National Psoriasis Foundation put infliximab amongst the first-line treatment modalities for GPPP.² In one case of GPPP in which the eruption persisted after delivery, the patient was treated with infliximab 7 weeks postpartum due to failure to control the disease with prednisolone 60 mg daily and cyclosporine 7.5 mg/kg daily. Unlike our patient, this patient was only started on an infliximab regimen after delivery.¹⁶ In another case reported in 2010, the patient was started on infliximab during the postpartum period of her first pregnancy following a pustular flare of previously diagnosed plaque psoriasis (not a generalized pustular psoriasis, as in our case).¹⁷ As a good response was obtained, infliximab treatment was continued in the patient throughout her second pregnancy.

Our case is unique in that infliximab was started during pregnancy because of intractable disease leading to systemic symptoms. Our patient showed an excellent response to infliximab after a 10-week disease course with repeated flare-ups and impairment to her overall condition. Delivery occurred at 36 weeks’ gestation due to suspected intrauterine growth retardation; however, the neonate was born with a 5-minute APGAR score of 10 and required no special medical care, which suggests that the low birth weight was constitutional due to the patient’s small frame (her height was 4 ft 11 in). The breast milk of patients with inflammatory bowel disease has been detected to contain very small amounts of infliximab (101 ng/mL, about 1/200 of the therapeutic blood level).¹⁸ Considering the large molecular weight of this agent and possible proteolysis in the stomach and intestines, infliximab is unlikely to affect the neonate.¹⁵ Thus, we encouraged our patient to breastfeed her baby. A case of fatal disseminated Bacille-Calmette-Guérin infection in an infant whose mother received infliximab treatment during pregnancy has been reported.¹⁹ It has been suggested that live vaccines should be avoided in neonates exposed to anti-TNF agents at least for the first 6 months of life or until the agent is no longer detectable in their blood.¹⁵ We therefore informed our patient’s family practitioner about this data.

Conclusion

We report a case of infliximab treatment for GPPP that was continued during the postpartum period. Infliximab was an effective treatment option in our patient with no detected serious adverse events and may be considered in other cases of GPPP that are not responsive to systemic steroids. However, further studies are warranted to evaluate the safety and efficacy of infliximab treatment for GPPP and psoriasis in pregnancy.

Generalized pustular psoriasis of pregnancy (GPPP), formerly known as impetigo herpetiformis, is a rare dermatosis that causes maternal and fetal morbidity and mortality. It is characterized by widespread, circular, erythematous plaques with pustules at the periphery.¹ Conventional first-line treatment includes systemic corticosteroids and cyclosporine. The National Psoriasis Foundation Medical Board also has included infliximab among the first-line treatment options for GPPP.² Herein, we report a case of GPPP treated with infliximab at 30 weeks’ gestation and during the postpartum period.

Case Report

A 22-year-old woman was admitted to our inpatient clinic at 20 weeks’ gestation in her second pregnancy for evaluation of cutaneous eruptions covering the entire body. The lesions first appeared 3 to 4 days prior to her admission and dramatically progressed. She had a history of psoriasis vulgaris diagnosed during her first pregnancy 2 years prior that was treated with topical steroids throughout the pregnancy and methotrexate during lactation for a total of 11 months. She then was started on cyclosporine, which she used for 6 months due to ineffectiveness of the methotrexate, but she stopped treatment 4 months before the second pregnancy.

At the current presentation, physical examination revealed erythroderma and widespread pustules on the chest, abdomen, arms, and legs, including the intertriginous regions, that tended to coalesce and form lakes of pus over an erythematous base (Figure 1). The mucosae were normal. She exhibited a low blood pressure (85/50 mmHg) and high body temperature (102 °F [38.9 °C]). Routine laboratory examination revealed anemia and a normal leukocyte count. Her erythrocyte sedimentation rate (57 mm/h [reference range, <20 mm/h]) and C-reactive protein level (102 mg/L [reference range, <6 mg/L]) were elevated, whereas total calcium (8.11 mg/dL [reference range, 8.2–10.6 mg/dL]) and albumin (3.15 g/dL [reference range, >4.0 g/dL]) levels were low.

The patient returned to the clinic 3 weeks postpartum with a few pustules on erythematous plaques on the chest, abdomen, and back. At this time, she received a third infusion of infliximab 8 weeks after the second dose. For the past 5 years, the patient has been undergoing infliximab maintenance treatment, which she receives at the hospital every 8 weeks with excellent response. She has had no further pregnancies to date.

Comment

Generalized pustular psoriasis of pregnancy is a rare condition that typically occurs in the third trimester but also can start in the first and second trimesters. It may result in maternal and fetal morbidity by causing fluid and electrolyte imbalance and/or placental insufficiency, resulting in an increased risk for fetal abnormalities, stillbirth, and neonatal death.³ In subsequent pregnancies, GPPP has been observed to recur at an earlier gestational age with a more severe presentation.^1,3

Generalized pustular psoriasis of pregnancy usually involves an eruption that begins symmetrically in the intertriginous areas and spreads to the rest of the body. The lesions present as erythematous annular plaques with pustules on the periphery and desquamation in the center due to older pustules.^1,3 The mucous membranes also may be involved with erosive and exfoliative plaques, and there may be nail involvement. Patients often present with systemic symptoms such as fever, malaise, diarrhea, and vomiting.¹ Laboratory investigations may reveal neutrophilic leukocytosis, high erythrocyte sedimentation rate, hypocalcemia, and hypoalbuminemia.⁴ Cultures from blood and pustules show no bacterial growth. A skin biopsy is helpful in diagnosis, with features similar to generalized pustular psoriasis, demonstrating spongiform pustules containing neutrophils, lymphocytic and neutrophilic infiltrates in the papillary dermis, and negative direct immunofluorescence.³

The differential diagnosis of GPPP includes subcorneal pustular dermatosis, dermatitis herpetiformis, herpes gestationis, impetigo, and acute generalized exanthematous pustulosis.^1,3 Due to concerns of fetal implications, treatment options in GPPP are somewhat limited; however, the condition requires treatment because it may result in unfavorable pregnancy outcomes. Topical corticosteroids may be an option for limited disease.^5,6 Systemic corticosteroids (eg, prednisone 60–80 mg/d) were previously considered as first-line agents, although they have shown limited efficacy in our case as well as in other case reports.⁷ Their ineffectiveness and risk for flare-up after dose tapering should be kept in mind when starting GPPP patients on systemic corticosteroids. Systemic cyclosporine (2–3 mg/kg/d) may be added to increase the efficacy of systemic steroids, which was done in several cases in literature.^1,6,8 Although cyclosporine has been classified as a pregnancy category C drug, an analysis of pregnancy outcomes of 629 renal transplant patients revealed no association with adverse pregnancy outcomes compared to the general population and no increase in fetal malformations.⁹ Therefore, cyclosporine is a safe treatment option and was classified as a first-line drug for GPPP in a 2012 review by the National Psoriasis Foundation Medical Board.² Narrowband UVB also has been reported to be used for the treatment of GPPP.¹⁰ Methotrexate and retinoids have been used in cases with lesions that persisted postpartum.¹

Anti–tumor necrosis factor (TNF) α agents are another effective option for treatment of GPPP. Anti-TNF agents are classified as pregnancy category B due to results showing that anti-mouse TNF-α monoclonal antibodies did not cause embryotoxicity or teratogenicity in pregnant mice.¹¹ Although Carter et al¹² published a review of US Food and Drug Administration data on pregnant women receiving anti-TNF treatment and concluded that these agents were associated with the VACTERL group of malformations (vertebral defects, anal atresia, cardiac defect, tracheoesophageal fistula with esophageal atresia, cardiac defects, renal and limb anomalies), no such association was found in further studies. A 2014 study showed no difference in the rate of major malformations in infants born to women who were treated with anti-TNF drugs compared to the disease-matched group not treated with these agents and pregnant women counselled for nonteratogenic exposure.¹³ The same study detected an increase in preterm and low-birth-weight deliveries and suggested this might be caused by the increased severity of disease in patients requiring anti-TNF medication. The British Society of Rheumatology Biologics Register published data on pregnancy outcomes in 130 rheumatoid arthritis patients who had been exposed to anti-TNF agents.¹⁴ The results suggested an increased rate of spontaneous abortions in women exposed to anti-TNF treatment around the time of conception, especially in those taking these medications together with methotrexate or leflunomide; however, results also indicated that disease activity may have had an impact on the rate of spontaneous abortions in these patients. In a 2013 review of 462 women with inflammatory bowel disease who had been exposed to anti-TNF agents during pregnancy, the investigators concluded that pregnancy outcomes and the rate of congenital anomalies did not significantly differ from other inflammatory bowel disease patients not receiving anti-TNF drugs or the general population.¹⁵

In 2012, the National Board of the National Psoriasis Foundation put infliximab amongst the first-line treatment modalities for GPPP.² In one case of GPPP in which the eruption persisted after delivery, the patient was treated with infliximab 7 weeks postpartum due to failure to control the disease with prednisolone 60 mg daily and cyclosporine 7.5 mg/kg daily. Unlike our patient, this patient was only started on an infliximab regimen after delivery.¹⁶ In another case reported in 2010, the patient was started on infliximab during the postpartum period of her first pregnancy following a pustular flare of previously diagnosed plaque psoriasis (not a generalized pustular psoriasis, as in our case).¹⁷ As a good response was obtained, infliximab treatment was continued in the patient throughout her second pregnancy.

Our case is unique in that infliximab was started during pregnancy because of intractable disease leading to systemic symptoms. Our patient showed an excellent response to infliximab after a 10-week disease course with repeated flare-ups and impairment to her overall condition. Delivery occurred at 36 weeks’ gestation due to suspected intrauterine growth retardation; however, the neonate was born with a 5-minute APGAR score of 10 and required no special medical care, which suggests that the low birth weight was constitutional due to the patient’s small frame (her height was 4 ft 11 in). The breast milk of patients with inflammatory bowel disease has been detected to contain very small amounts of infliximab (101 ng/mL, about 1/200 of the therapeutic blood level).¹⁸ Considering the large molecular weight of this agent and possible proteolysis in the stomach and intestines, infliximab is unlikely to affect the neonate.¹⁵ Thus, we encouraged our patient to breastfeed her baby. A case of fatal disseminated Bacille-Calmette-Guérin infection in an infant whose mother received infliximab treatment during pregnancy has been reported.¹⁹ It has been suggested that live vaccines should be avoided in neonates exposed to anti-TNF agents at least for the first 6 months of life or until the agent is no longer detectable in their blood.¹⁵ We therefore informed our patient’s family practitioner about this data.

Conclusion

We report a case of infliximab treatment for GPPP that was continued during the postpartum period. Infliximab was an effective treatment option in our patient with no detected serious adverse events and may be considered in other cases of GPPP that are not responsive to systemic steroids. However, further studies are warranted to evaluate the safety and efficacy of infliximab treatment for GPPP and psoriasis in pregnancy.

The risk of perioperative stroke in noncardiac, nonneurologic, nonvascular surgery ranges from 0.1 to 1.9% and is associated with increased mortality.^1,2 Stroke mechanisms include both ischemia (large and small vessel occlusion, cardioembolism, anemic-tissue hypoxia, cerebral hypoperfusion) and hemorrhage.¹ Risk factors for perioperative stroke include prior cerebral vascular accident (CVA), hypertension, aged > 62 years, acute renal insufficiency, dialysis, and recent myocardial infarction (MI).²

Introduction

COVID-19 was declared a pandemic by the World Health Organization in March 2020.³ COVID-19 has certainly affected the veteran population; between February and May 2020, more than 60,000 veterans were tested for COVID-19 with a positive rate of about 9%.⁴ While primarily affecting the respiratory system, there are increasing reports of COVID-19 neurologic manifestations: headache, hypogeusia, hyposomia, seizure, encephalitis, and acute stroke.⁵ In an early case series from Wuhan, China, 36% of 214 patients with COVID-19 reported neurologic complications, and acute CVAs were more common in patients with severe (compared to milder) viral disease presentations (5.7% vs 0.8%).⁶ Large vessel stroke was a presenting feature in another report of 5 patients aged < 50 years.⁷

The mechanism of ischemic stroke in the setting of COVID-19 is unclear.⁸ Indeed, stroke and COVID-19 share similar risk factors (eg, hypertension, diabetes mellitus [DM], older age), and immobile critically ill patients may already be prone to developing stroke.^5,9 However, COVID-19 is associated with arterial and venous thromboembolism, elevated D-dimer and fibrinogen levels, and antiphospholipid antibody production. This prothrombotic state may be linked to cytokine-induced endothelial damage, mononuclear cell activation, tissue factor expression, and ultimately thrombin propagation and platelet activation.⁸

The rates of perioperative stroke may change as more patients with COVID-19 present for surgery, and the anesthesiology care team must prioritize mitigation efforts in high-risk patients, including veterans. Reducing the elevated stroke burden within the US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) is a public health priority.¹⁰ We present the case of a veteran with prior CVA and recent positive COVID-19 testing who experienced transient weakness and dysarthria following plastic surgery. The patient discussed provided written Health Insurance Portability and Accountability Act consent for publication of this report.

Case Presentation 

A 75-year-old male veteran presented to the Minneapolis VA Medical Center in Minnesota with chronic left foot ulceration necessitating debridement and flap coverage. His medical history was significant for hypertension, type 2 DM, anemia of chronic disease, and coronary artery disease (left ventricular ejection fraction, 50%). Additionally, he had prior ischemic strokes in the oculomotor nucleus (in 2004 with internuclear ophthalmoplegia) and left ventral medulla (in 2019 with right hemiparesis). During his 2019 poststroke rehabilitation, he was diagnosed with mild neurocognitive deficit not attributable to his strokes. The patient’s medications included amlodipine, lisinopril, atorvastatin, clopidogrel (lifelong for secondary stroke prevention), metformin, and glipizide. The debridement procedure was initially delayed 3 weeks due to positive routine preoperative COVID-19 nasopharyngeal testing, though he reported no respiratory symptoms or fever. During the delay, the primary team prescribed daily oral rivaroxaban for thrombosis prophylaxis in addition to clopidogrel. One week prior to surgery, his repeat COVID-19 test was negative and prophylactic anticoagulation stopped.

On the day of surgery, the patient was hemodynamically stable: heart rate 86 beats/min, blood pressure 167/93 mm Hg (baseline 120-150 mm Hg systolic pressure), respiratory rate 16 breaths/min, oxygen saturation 99% without supplemental oxygen, temperature 97.1 °F. He received amlodipine and clopidogrel, but not lisinopril, that morning. No focal neurologic deficits were appreciated on preoperative examination, and resolution of symptoms related to the 2 prior MIs was confirmed. Preoperative glucose was 163 mg/dL. Femoral and sciatic peripheral nerve blocks were done for postoperative analgesia. A preinduction arterial line was placed and 2 mg of midazolam was administered for anxiolysis. Induction of general anesthesia with oral endotracheal intubation proceeded uneventfully; he was positioned prone.

Given his stroke risk factors, mean arterial pressure was maintained > 70 mm Hg for the duration of surgery. No vasoactive infusions were necessary and no β-blocking agents were administered. Insulin infusion was required; the maximum-recorded glucose was 219 mg/dL. Arterial blood gas samples were routinely drawn; acid-base balance was well maintained, PaO₂ was > 185 mm Hg, and PaCO₂ ranged from 29.4 to 38.5 mm Hg. The patient received 2 units of packed red blood cells for nadir hemoglobin of 7.5 mg/dL. At surgery end, we fully reversed neuromuscular blockade with suggamadex. The patient was returned to a supine position and extubated uneventfully after demonstrating the ability to follow commands.

During postanesthesia care unit (PACU) handoff, the patient exhibited acute speech impairment. He was able to state his name on repetition but seemed confused and sedated. Prompt formal neurology evaluation (stroke code) was sought. Initial National Institutes of Health (NIH) stroke scale score was 8 (1 for level of consciousness, 1 for minor right facial droop, 1 for right arm drift, 3 for right leg with no effort against gravity, 1 for right partial sensory loss, and 1 for mild dysarthria). The patient was oriented only to self. Other findings included mild right facial droop and dysarthria. On a 5-point strength scale, he scored 4 for the right deltoid, biceps, triceps, wrist extensors, right knee flexion, right dorsiflexion, and plantarflexion, 2 for right hip flexion, and ≥ 4 for right knee extension. Positive sensory findings were notable for decreased pin prick sensation on the right limbs.

We obtained emergent head computed tomography (CT) that was negative for acute abnormalities; CT angiography was negative for large vessel occlusion or clinically significant stenosis (Figure). On returning to the PACU from the CT scanner, the patient regained symmetric strength in both arms, right leg was antigravity, and his speech had normalized. Prior to PACU discharge 2 hours later, the patient was back to his prehospitalization neurologic function and NIH stroke scale was 0. Given this rapid clinical resolution, no acute stroke interventions were done, though permissive hypertension was recommended by the neurologist during PACU recovery.

Discussion

We report a veteran with prior stroke and COVID-19 who experienced postoperative speech and motor deficit despite deliberate risk factor mitigation. This case calls for increased vigilance by anesthesia providers to employ proper perioperative stroke management and anticoagulation strategies, and to be prepared for prompt intervention with COVID-19-sensitive practices should the need for advanced airway management or thrombectomy arises.

The exact etiology of the postoperative neurologic deficit in our patient is unknown. The most likely possibility is that this represents poststroke recrudescence (PSR), knowing he had a previous left medullary infarct that presented similarly.¹¹ PSR is a phenomenon in which prior stroke symptoms recur acutely and transiently in the setting of physiologic stressors—also known as locus minoris resistantiae.¹² Triggers include γ aminobutyric acid (GABA) mediating anesthetic agents such as midazolam, opioids (eg, fentanyl or hydromorphone), infection, or relative cerebral hypoperfusion.^11,13,14 The focality of our patient’s presentation favors PSR in the context of brief POD; of note, these entities share similar risk factors.¹⁵ Our patient did indeed receive low-dose preoperative midazolam in the context of mild preoperative neurocognitive deficit, which may have predisposed him to POD.

Conclusions

We discuss a surgical patient with prior SARS-CoV-2 infection at elevated stroke risk that experienced recurrence of neurologic deficits postoperatively. This case informs anesthesia providers of the broad differential diagnosis for focal neurological deficits to include PSR and the possible contribution of COVID-19 to elevated acute stroke risk. Perioperative physicians, including VHA practitioners, with knowledge of current COVID-19 practices are primed to coordinate multidisciplinary efforts during stroke codes and ensuring appropriate anticoagulation.

Acknowledgments

The authors would like to thank perioperative care teams across the world caring for COVID-19 patients safely.

The risk of perioperative stroke in noncardiac, nonneurologic, nonvascular surgery ranges from 0.1 to 1.9% and is associated with increased mortality.^1,2 Stroke mechanisms include both ischemia (large and small vessel occlusion, cardioembolism, anemic-tissue hypoxia, cerebral hypoperfusion) and hemorrhage.¹ Risk factors for perioperative stroke include prior cerebral vascular accident (CVA), hypertension, aged > 62 years, acute renal insufficiency, dialysis, and recent myocardial infarction (MI).²

Introduction

COVID-19 was declared a pandemic by the World Health Organization in March 2020.³ COVID-19 has certainly affected the veteran population; between February and May 2020, more than 60,000 veterans were tested for COVID-19 with a positive rate of about 9%.⁴ While primarily affecting the respiratory system, there are increasing reports of COVID-19 neurologic manifestations: headache, hypogeusia, hyposomia, seizure, encephalitis, and acute stroke.⁵ In an early case series from Wuhan, China, 36% of 214 patients with COVID-19 reported neurologic complications, and acute CVAs were more common in patients with severe (compared to milder) viral disease presentations (5.7% vs 0.8%).⁶ Large vessel stroke was a presenting feature in another report of 5 patients aged < 50 years.⁷

The mechanism of ischemic stroke in the setting of COVID-19 is unclear.⁸ Indeed, stroke and COVID-19 share similar risk factors (eg, hypertension, diabetes mellitus [DM], older age), and immobile critically ill patients may already be prone to developing stroke.^5,9 However, COVID-19 is associated with arterial and venous thromboembolism, elevated D-dimer and fibrinogen levels, and antiphospholipid antibody production. This prothrombotic state may be linked to cytokine-induced endothelial damage, mononuclear cell activation, tissue factor expression, and ultimately thrombin propagation and platelet activation.⁸

The rates of perioperative stroke may change as more patients with COVID-19 present for surgery, and the anesthesiology care team must prioritize mitigation efforts in high-risk patients, including veterans. Reducing the elevated stroke burden within the US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) is a public health priority.¹⁰ We present the case of a veteran with prior CVA and recent positive COVID-19 testing who experienced transient weakness and dysarthria following plastic surgery. The patient discussed provided written Health Insurance Portability and Accountability Act consent for publication of this report.

Case Presentation 

A 75-year-old male veteran presented to the Minneapolis VA Medical Center in Minnesota with chronic left foot ulceration necessitating debridement and flap coverage. His medical history was significant for hypertension, type 2 DM, anemia of chronic disease, and coronary artery disease (left ventricular ejection fraction, 50%). Additionally, he had prior ischemic strokes in the oculomotor nucleus (in 2004 with internuclear ophthalmoplegia) and left ventral medulla (in 2019 with right hemiparesis). During his 2019 poststroke rehabilitation, he was diagnosed with mild neurocognitive deficit not attributable to his strokes. The patient’s medications included amlodipine, lisinopril, atorvastatin, clopidogrel (lifelong for secondary stroke prevention), metformin, and glipizide. The debridement procedure was initially delayed 3 weeks due to positive routine preoperative COVID-19 nasopharyngeal testing, though he reported no respiratory symptoms or fever. During the delay, the primary team prescribed daily oral rivaroxaban for thrombosis prophylaxis in addition to clopidogrel. One week prior to surgery, his repeat COVID-19 test was negative and prophylactic anticoagulation stopped.

On the day of surgery, the patient was hemodynamically stable: heart rate 86 beats/min, blood pressure 167/93 mm Hg (baseline 120-150 mm Hg systolic pressure), respiratory rate 16 breaths/min, oxygen saturation 99% without supplemental oxygen, temperature 97.1 °F. He received amlodipine and clopidogrel, but not lisinopril, that morning. No focal neurologic deficits were appreciated on preoperative examination, and resolution of symptoms related to the 2 prior MIs was confirmed. Preoperative glucose was 163 mg/dL. Femoral and sciatic peripheral nerve blocks were done for postoperative analgesia. A preinduction arterial line was placed and 2 mg of midazolam was administered for anxiolysis. Induction of general anesthesia with oral endotracheal intubation proceeded uneventfully; he was positioned prone.

Given his stroke risk factors, mean arterial pressure was maintained > 70 mm Hg for the duration of surgery. No vasoactive infusions were necessary and no β-blocking agents were administered. Insulin infusion was required; the maximum-recorded glucose was 219 mg/dL. Arterial blood gas samples were routinely drawn; acid-base balance was well maintained, PaO₂ was > 185 mm Hg, and PaCO₂ ranged from 29.4 to 38.5 mm Hg. The patient received 2 units of packed red blood cells for nadir hemoglobin of 7.5 mg/dL. At surgery end, we fully reversed neuromuscular blockade with suggamadex. The patient was returned to a supine position and extubated uneventfully after demonstrating the ability to follow commands.

During postanesthesia care unit (PACU) handoff, the patient exhibited acute speech impairment. He was able to state his name on repetition but seemed confused and sedated. Prompt formal neurology evaluation (stroke code) was sought. Initial National Institutes of Health (NIH) stroke scale score was 8 (1 for level of consciousness, 1 for minor right facial droop, 1 for right arm drift, 3 for right leg with no effort against gravity, 1 for right partial sensory loss, and 1 for mild dysarthria). The patient was oriented only to self. Other findings included mild right facial droop and dysarthria. On a 5-point strength scale, he scored 4 for the right deltoid, biceps, triceps, wrist extensors, right knee flexion, right dorsiflexion, and plantarflexion, 2 for right hip flexion, and ≥ 4 for right knee extension. Positive sensory findings were notable for decreased pin prick sensation on the right limbs.

We obtained emergent head computed tomography (CT) that was negative for acute abnormalities; CT angiography was negative for large vessel occlusion or clinically significant stenosis (Figure). On returning to the PACU from the CT scanner, the patient regained symmetric strength in both arms, right leg was antigravity, and his speech had normalized. Prior to PACU discharge 2 hours later, the patient was back to his prehospitalization neurologic function and NIH stroke scale was 0. Given this rapid clinical resolution, no acute stroke interventions were done, though permissive hypertension was recommended by the neurologist during PACU recovery.

Discussion

We report a veteran with prior stroke and COVID-19 who experienced postoperative speech and motor deficit despite deliberate risk factor mitigation. This case calls for increased vigilance by anesthesia providers to employ proper perioperative stroke management and anticoagulation strategies, and to be prepared for prompt intervention with COVID-19-sensitive practices should the need for advanced airway management or thrombectomy arises.

The exact etiology of the postoperative neurologic deficit in our patient is unknown. The most likely possibility is that this represents poststroke recrudescence (PSR), knowing he had a previous left medullary infarct that presented similarly.¹¹ PSR is a phenomenon in which prior stroke symptoms recur acutely and transiently in the setting of physiologic stressors—also known as locus minoris resistantiae.¹² Triggers include γ aminobutyric acid (GABA) mediating anesthetic agents such as midazolam, opioids (eg, fentanyl or hydromorphone), infection, or relative cerebral hypoperfusion.^11,13,14 The focality of our patient’s presentation favors PSR in the context of brief POD; of note, these entities share similar risk factors.¹⁵ Our patient did indeed receive low-dose preoperative midazolam in the context of mild preoperative neurocognitive deficit, which may have predisposed him to POD.

Conclusions

We discuss a surgical patient with prior SARS-CoV-2 infection at elevated stroke risk that experienced recurrence of neurologic deficits postoperatively. This case informs anesthesia providers of the broad differential diagnosis for focal neurological deficits to include PSR and the possible contribution of COVID-19 to elevated acute stroke risk. Perioperative physicians, including VHA practitioners, with knowledge of current COVID-19 practices are primed to coordinate multidisciplinary efforts during stroke codes and ensuring appropriate anticoagulation.

Acknowledgments

The authors would like to thank perioperative care teams across the world caring for COVID-19 patients safely.

The risk of perioperative stroke in noncardiac, nonneurologic, nonvascular surgery ranges from 0.1 to 1.9% and is associated with increased mortality.^1,2 Stroke mechanisms include both ischemia (large and small vessel occlusion, cardioembolism, anemic-tissue hypoxia, cerebral hypoperfusion) and hemorrhage.¹ Risk factors for perioperative stroke include prior cerebral vascular accident (CVA), hypertension, aged > 62 years, acute renal insufficiency, dialysis, and recent myocardial infarction (MI).²

Introduction

COVID-19 was declared a pandemic by the World Health Organization in March 2020.³ COVID-19 has certainly affected the veteran population; between February and May 2020, more than 60,000 veterans were tested for COVID-19 with a positive rate of about 9%.⁴ While primarily affecting the respiratory system, there are increasing reports of COVID-19 neurologic manifestations: headache, hypogeusia, hyposomia, seizure, encephalitis, and acute stroke.⁵ In an early case series from Wuhan, China, 36% of 214 patients with COVID-19 reported neurologic complications, and acute CVAs were more common in patients with severe (compared to milder) viral disease presentations (5.7% vs 0.8%).⁶ Large vessel stroke was a presenting feature in another report of 5 patients aged < 50 years.⁷

The mechanism of ischemic stroke in the setting of COVID-19 is unclear.⁸ Indeed, stroke and COVID-19 share similar risk factors (eg, hypertension, diabetes mellitus [DM], older age), and immobile critically ill patients may already be prone to developing stroke.^5,9 However, COVID-19 is associated with arterial and venous thromboembolism, elevated D-dimer and fibrinogen levels, and antiphospholipid antibody production. This prothrombotic state may be linked to cytokine-induced endothelial damage, mononuclear cell activation, tissue factor expression, and ultimately thrombin propagation and platelet activation.⁸

The rates of perioperative stroke may change as more patients with COVID-19 present for surgery, and the anesthesiology care team must prioritize mitigation efforts in high-risk patients, including veterans. Reducing the elevated stroke burden within the US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) is a public health priority.¹⁰ We present the case of a veteran with prior CVA and recent positive COVID-19 testing who experienced transient weakness and dysarthria following plastic surgery. The patient discussed provided written Health Insurance Portability and Accountability Act consent for publication of this report.

Case Presentation 

A 75-year-old male veteran presented to the Minneapolis VA Medical Center in Minnesota with chronic left foot ulceration necessitating debridement and flap coverage. His medical history was significant for hypertension, type 2 DM, anemia of chronic disease, and coronary artery disease (left ventricular ejection fraction, 50%). Additionally, he had prior ischemic strokes in the oculomotor nucleus (in 2004 with internuclear ophthalmoplegia) and left ventral medulla (in 2019 with right hemiparesis). During his 2019 poststroke rehabilitation, he was diagnosed with mild neurocognitive deficit not attributable to his strokes. The patient’s medications included amlodipine, lisinopril, atorvastatin, clopidogrel (lifelong for secondary stroke prevention), metformin, and glipizide. The debridement procedure was initially delayed 3 weeks due to positive routine preoperative COVID-19 nasopharyngeal testing, though he reported no respiratory symptoms or fever. During the delay, the primary team prescribed daily oral rivaroxaban for thrombosis prophylaxis in addition to clopidogrel. One week prior to surgery, his repeat COVID-19 test was negative and prophylactic anticoagulation stopped.

On the day of surgery, the patient was hemodynamically stable: heart rate 86 beats/min, blood pressure 167/93 mm Hg (baseline 120-150 mm Hg systolic pressure), respiratory rate 16 breaths/min, oxygen saturation 99% without supplemental oxygen, temperature 97.1 °F. He received amlodipine and clopidogrel, but not lisinopril, that morning. No focal neurologic deficits were appreciated on preoperative examination, and resolution of symptoms related to the 2 prior MIs was confirmed. Preoperative glucose was 163 mg/dL. Femoral and sciatic peripheral nerve blocks were done for postoperative analgesia. A preinduction arterial line was placed and 2 mg of midazolam was administered for anxiolysis. Induction of general anesthesia with oral endotracheal intubation proceeded uneventfully; he was positioned prone.

Given his stroke risk factors, mean arterial pressure was maintained > 70 mm Hg for the duration of surgery. No vasoactive infusions were necessary and no β-blocking agents were administered. Insulin infusion was required; the maximum-recorded glucose was 219 mg/dL. Arterial blood gas samples were routinely drawn; acid-base balance was well maintained, PaO₂ was > 185 mm Hg, and PaCO₂ ranged from 29.4 to 38.5 mm Hg. The patient received 2 units of packed red blood cells for nadir hemoglobin of 7.5 mg/dL. At surgery end, we fully reversed neuromuscular blockade with suggamadex. The patient was returned to a supine position and extubated uneventfully after demonstrating the ability to follow commands.

During postanesthesia care unit (PACU) handoff, the patient exhibited acute speech impairment. He was able to state his name on repetition but seemed confused and sedated. Prompt formal neurology evaluation (stroke code) was sought. Initial National Institutes of Health (NIH) stroke scale score was 8 (1 for level of consciousness, 1 for minor right facial droop, 1 for right arm drift, 3 for right leg with no effort against gravity, 1 for right partial sensory loss, and 1 for mild dysarthria). The patient was oriented only to self. Other findings included mild right facial droop and dysarthria. On a 5-point strength scale, he scored 4 for the right deltoid, biceps, triceps, wrist extensors, right knee flexion, right dorsiflexion, and plantarflexion, 2 for right hip flexion, and ≥ 4 for right knee extension. Positive sensory findings were notable for decreased pin prick sensation on the right limbs.

We obtained emergent head computed tomography (CT) that was negative for acute abnormalities; CT angiography was negative for large vessel occlusion or clinically significant stenosis (Figure). On returning to the PACU from the CT scanner, the patient regained symmetric strength in both arms, right leg was antigravity, and his speech had normalized. Prior to PACU discharge 2 hours later, the patient was back to his prehospitalization neurologic function and NIH stroke scale was 0. Given this rapid clinical resolution, no acute stroke interventions were done, though permissive hypertension was recommended by the neurologist during PACU recovery.

Discussion

We report a veteran with prior stroke and COVID-19 who experienced postoperative speech and motor deficit despite deliberate risk factor mitigation. This case calls for increased vigilance by anesthesia providers to employ proper perioperative stroke management and anticoagulation strategies, and to be prepared for prompt intervention with COVID-19-sensitive practices should the need for advanced airway management or thrombectomy arises.

The exact etiology of the postoperative neurologic deficit in our patient is unknown. The most likely possibility is that this represents poststroke recrudescence (PSR), knowing he had a previous left medullary infarct that presented similarly.¹¹ PSR is a phenomenon in which prior stroke symptoms recur acutely and transiently in the setting of physiologic stressors—also known as locus minoris resistantiae.¹² Triggers include γ aminobutyric acid (GABA) mediating anesthetic agents such as midazolam, opioids (eg, fentanyl or hydromorphone), infection, or relative cerebral hypoperfusion.^11,13,14 The focality of our patient’s presentation favors PSR in the context of brief POD; of note, these entities share similar risk factors.¹⁵ Our patient did indeed receive low-dose preoperative midazolam in the context of mild preoperative neurocognitive deficit, which may have predisposed him to POD.

Conclusions

We discuss a surgical patient with prior SARS-CoV-2 infection at elevated stroke risk that experienced recurrence of neurologic deficits postoperatively. This case informs anesthesia providers of the broad differential diagnosis for focal neurological deficits to include PSR and the possible contribution of COVID-19 to elevated acute stroke risk. Perioperative physicians, including VHA practitioners, with knowledge of current COVID-19 practices are primed to coordinate multidisciplinary efforts during stroke codes and ensuring appropriate anticoagulation.

Acknowledgments

The authors would like to thank perioperative care teams across the world caring for COVID-19 patients safely.

Speech-language pathologists (SLPs) are integral to the comprehensive treatment of mild traumatic brain injury (mTBI), yet the evaluation and treatment options they offer may not be known to all primary care providers (PCPs). As the research on the management and treatment of mTBI continues to evolve, the PCPs role in referring patients with mTBI to the appropriate resources becomes imperative.

mTBI is a common injury in both military and civilian settings, but it can be difficult to diagnose and is not always well understood. Long-term debilitating effects have been associated with mTBI, with literature linking it to an increased risk of developing Alzheimer disease, motor neuron disease, and Parkinson disease.¹ In addition, mTBI is a strong predictor for the development of posttraumatic stress disorder (PTSD). Among returning Iraq and Afghanistan service members, the incidence of mTBI associated mental health conditions have been reported to be as high as 22.8%, affecting > 320,000 veterans.^2-5

The US Department of Veteran Affairs (VA) health care system offers these returning veterans a comprehensive, multidisciplinary treatment strategy. The care is often coordinated by the veteran’s patient aligned care team (PACT) that consists of a PCP, nurses, and a medical support associate. The US Department of Defense (DoD) and VA also facilitated the development of a clinical practice guideline (CPG) that can be used by the PACT and other health care providers to support evidence based patient-centered care. This CPG is extensive and has recommendations for evaluation and treatment of mTBI and the symptoms associated such as impaired memory and alterations in executive function.⁶

The following hypothetical case is based on an actual patient. This case illustrates the role of speech pathology in caring for patients with mTBI.

Case Presentation

A 25-year-old male combat veteran presented to his VA PACT team for a new patient visit. As part of the screening of his medical history, mTBI was fully defined for the patient to include “alteration” in consciousness. This reminded the patient of an injury that occurred 1 year prior to presentation during a routine convoy mission. He was riding in the back of a Humvee when it hit a large pothole slamming his head into the side of the vehicle. He reported that he felt “dazed and dizzy” with “ringing” in his ears immediately following the event, without an overt loss of consciousness. He was unable to seek medical attention secondary to the urgency of the convoy mission, so he “shook it off” and kept going. Later that week he noted headache and insomnia. He was seen and evaluated by his health care provider for insomnia, but when questioned he reported no head trauma as he had forgotten the incident. Upon follow-up with his PCP, he reported his headaches were manageable, and his insomnia was somewhat improved with recommended life-style modifications and good sleep hygiene.

He still had frequent headaches, dizziness, and some insomnia. However, his chief concern was that he was struggling with new schoolwork. He noted that he was a straight-A student prior to his military service. A review of his medical history in his medical chart showed that a previous PCP had treated his associated symptoms of insomnia and headache without improvement. In addition, he had recently been diagnosed with PTSD. As his symptoms had lasted > 90 days, not resolved with initial treatment in primary care, and were causing a significant impact on his activities of daily living, his PCP placed a consult to Speech Pathology for cognitive-linguistic assessment and treatment, if indicated, noting that he may have had a mTBI.⁶ Although not intended to be comprehensive, Table 1 describes several clinical areas where a speech pathology referral may be appropriate.

The Role of the Speech-Language Pathologist

The speech-language pathologist takes an additional history of the patient. This better quantifies specific details of the veteran’s functional concerns pertaining to possible difficulty with attention, memory, executive function, visuospatial awareness, etc. Examples might include difficulty with attention/memory, including not remembering what to get at the store, forgetting to take medications, forgetting appointments, and difficulty in school, among many others. Reports of feeling “stupid” also are common. Assessment varies by clinician, but it is not uncommon for the SLP to administer a battery of evaluations to help identify a range of possible impairments. Choosing testing that is sensitive to even mild impairment is important and should be used in combination with subjective complaints. Mild deficits can sometimes be missed in those with average performance, but whose premorbid intelligence was above average. One combination of test batteries sometimes utilized is the Wechsler Test of Adult Reading (WTAR), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Ruff Figural Fluency Test (RFFT), the Controlled Oral Word Association Test (COWAT), and Trails A and B (Table 2).

The initial testing results are discussed with the veteran. If patient concerns and/or testing reveal impairment that is amenable to treatment and the veteran wishes to proceed, subsequent treatment sessions are scheduled. The first treatment session is spent establishing and prioritizing functional goals specific to that individual and their needs (eg, for daily life, work, school). In a case of subacute or older mTBI, as is often seen in veterans coming to the VA, intervention often targets strategies and techniques that can help the individual compensate for current deficits.

Many patients already own a smartphone, so this device often is used functionally as a cognitive prosthetic as early as the first treatment session. In an effort to immediately start addressing important issues like medication management and attending appointments, the veteran is educated to the benefit of entering important information into the calendar and/or reminder apps on their phone and setting associated alarms that would serve as a reminder for what was entered. Patients are often encouraged by the positive impact of these initial strategies and look forward to future treatment sessions to address compensation for their functional deficits.

If a veteran with TBI has numerous needs, it can be beneficial for the care team to discuss the care plan at an interdisciplinary team meeting. It is not uncommon for veterans like the one discussed above to be referred to neurology (persistent headaches and further neurological evaluation); mental health (PTSD treatment and family support/counseling options); occupational therapy (visuospatial needs); and audiology (vestibular concerns). Social work involvement is often extremely beneficial for coordination of care in more complex cases. If patient is having difficulty making healthy eating choices or with meal preparation, a consult to a dietitian may prove invaluable. Concerns related to trouble with medication adherence (beyond memory-related adherence issues that speech pathology would address) or polypharmacy can be directed to a clinical pharmacy specialist, who could prepare a medication chart, review optimal medication timing, and provide education on adverse effects. A veteran's communication with the team can be facilitated through secure messaging (a method of secure emailing) and encouraging use of the My HealtheVet portal. With this modality, patients could review chart notes and results and share them with non-VA health care providers and/or family members as indicated.

A whole health approach also may appeal to some mTBI patients. This approach focuses on the totality of patient needs for healthy living and on patient-centered goal setting. Services provided may differ at various VA medical centers, but the PACT team can connect the veteran to the services of interest.

Conclusions

A team approach to veterans with mTBI provides a comprehensive way to treat the various problems associated with the condition. Further research into the role of multidisciplinary teams in the management of mTBI was recommended in the 2016 CPG.⁶ The unique role that the speech-language pathologist plays as part of this team has been highlighted, as it is important that PCP’s be aware of the extent of evaluation and treatment services they offer. Beyond mTBI, speech pathologists evaluate and treat patients with several conditions that are seen regularly in primary care.

Speech-language pathologists (SLPs) are integral to the comprehensive treatment of mild traumatic brain injury (mTBI), yet the evaluation and treatment options they offer may not be known to all primary care providers (PCPs). As the research on the management and treatment of mTBI continues to evolve, the PCPs role in referring patients with mTBI to the appropriate resources becomes imperative.

mTBI is a common injury in both military and civilian settings, but it can be difficult to diagnose and is not always well understood. Long-term debilitating effects have been associated with mTBI, with literature linking it to an increased risk of developing Alzheimer disease, motor neuron disease, and Parkinson disease.¹ In addition, mTBI is a strong predictor for the development of posttraumatic stress disorder (PTSD). Among returning Iraq and Afghanistan service members, the incidence of mTBI associated mental health conditions have been reported to be as high as 22.8%, affecting > 320,000 veterans.^2-5

The US Department of Veteran Affairs (VA) health care system offers these returning veterans a comprehensive, multidisciplinary treatment strategy. The care is often coordinated by the veteran’s patient aligned care team (PACT) that consists of a PCP, nurses, and a medical support associate. The US Department of Defense (DoD) and VA also facilitated the development of a clinical practice guideline (CPG) that can be used by the PACT and other health care providers to support evidence based patient-centered care. This CPG is extensive and has recommendations for evaluation and treatment of mTBI and the symptoms associated such as impaired memory and alterations in executive function.⁶

The following hypothetical case is based on an actual patient. This case illustrates the role of speech pathology in caring for patients with mTBI.

Case Presentation

A 25-year-old male combat veteran presented to his VA PACT team for a new patient visit. As part of the screening of his medical history, mTBI was fully defined for the patient to include “alteration” in consciousness. This reminded the patient of an injury that occurred 1 year prior to presentation during a routine convoy mission. He was riding in the back of a Humvee when it hit a large pothole slamming his head into the side of the vehicle. He reported that he felt “dazed and dizzy” with “ringing” in his ears immediately following the event, without an overt loss of consciousness. He was unable to seek medical attention secondary to the urgency of the convoy mission, so he “shook it off” and kept going. Later that week he noted headache and insomnia. He was seen and evaluated by his health care provider for insomnia, but when questioned he reported no head trauma as he had forgotten the incident. Upon follow-up with his PCP, he reported his headaches were manageable, and his insomnia was somewhat improved with recommended life-style modifications and good sleep hygiene.

He still had frequent headaches, dizziness, and some insomnia. However, his chief concern was that he was struggling with new schoolwork. He noted that he was a straight-A student prior to his military service. A review of his medical history in his medical chart showed that a previous PCP had treated his associated symptoms of insomnia and headache without improvement. In addition, he had recently been diagnosed with PTSD. As his symptoms had lasted > 90 days, not resolved with initial treatment in primary care, and were causing a significant impact on his activities of daily living, his PCP placed a consult to Speech Pathology for cognitive-linguistic assessment and treatment, if indicated, noting that he may have had a mTBI.⁶ Although not intended to be comprehensive, Table 1 describes several clinical areas where a speech pathology referral may be appropriate.

The Role of the Speech-Language Pathologist

The speech-language pathologist takes an additional history of the patient. This better quantifies specific details of the veteran’s functional concerns pertaining to possible difficulty with attention, memory, executive function, visuospatial awareness, etc. Examples might include difficulty with attention/memory, including not remembering what to get at the store, forgetting to take medications, forgetting appointments, and difficulty in school, among many others. Reports of feeling “stupid” also are common. Assessment varies by clinician, but it is not uncommon for the SLP to administer a battery of evaluations to help identify a range of possible impairments. Choosing testing that is sensitive to even mild impairment is important and should be used in combination with subjective complaints. Mild deficits can sometimes be missed in those with average performance, but whose premorbid intelligence was above average. One combination of test batteries sometimes utilized is the Wechsler Test of Adult Reading (WTAR), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Ruff Figural Fluency Test (RFFT), the Controlled Oral Word Association Test (COWAT), and Trails A and B (Table 2).

The initial testing results are discussed with the veteran. If patient concerns and/or testing reveal impairment that is amenable to treatment and the veteran wishes to proceed, subsequent treatment sessions are scheduled. The first treatment session is spent establishing and prioritizing functional goals specific to that individual and their needs (eg, for daily life, work, school). In a case of subacute or older mTBI, as is often seen in veterans coming to the VA, intervention often targets strategies and techniques that can help the individual compensate for current deficits.

Many patients already own a smartphone, so this device often is used functionally as a cognitive prosthetic as early as the first treatment session. In an effort to immediately start addressing important issues like medication management and attending appointments, the veteran is educated to the benefit of entering important information into the calendar and/or reminder apps on their phone and setting associated alarms that would serve as a reminder for what was entered. Patients are often encouraged by the positive impact of these initial strategies and look forward to future treatment sessions to address compensation for their functional deficits.

If a veteran with TBI has numerous needs, it can be beneficial for the care team to discuss the care plan at an interdisciplinary team meeting. It is not uncommon for veterans like the one discussed above to be referred to neurology (persistent headaches and further neurological evaluation); mental health (PTSD treatment and family support/counseling options); occupational therapy (visuospatial needs); and audiology (vestibular concerns). Social work involvement is often extremely beneficial for coordination of care in more complex cases. If patient is having difficulty making healthy eating choices or with meal preparation, a consult to a dietitian may prove invaluable. Concerns related to trouble with medication adherence (beyond memory-related adherence issues that speech pathology would address) or polypharmacy can be directed to a clinical pharmacy specialist, who could prepare a medication chart, review optimal medication timing, and provide education on adverse effects. A veteran's communication with the team can be facilitated through secure messaging (a method of secure emailing) and encouraging use of the My HealtheVet portal. With this modality, patients could review chart notes and results and share them with non-VA health care providers and/or family members as indicated.

A whole health approach also may appeal to some mTBI patients. This approach focuses on the totality of patient needs for healthy living and on patient-centered goal setting. Services provided may differ at various VA medical centers, but the PACT team can connect the veteran to the services of interest.

Conclusions

A team approach to veterans with mTBI provides a comprehensive way to treat the various problems associated with the condition. Further research into the role of multidisciplinary teams in the management of mTBI was recommended in the 2016 CPG.⁶ The unique role that the speech-language pathologist plays as part of this team has been highlighted, as it is important that PCP’s be aware of the extent of evaluation and treatment services they offer. Beyond mTBI, speech pathologists evaluate and treat patients with several conditions that are seen regularly in primary care.

Speech-language pathologists (SLPs) are integral to the comprehensive treatment of mild traumatic brain injury (mTBI), yet the evaluation and treatment options they offer may not be known to all primary care providers (PCPs). As the research on the management and treatment of mTBI continues to evolve, the PCPs role in referring patients with mTBI to the appropriate resources becomes imperative.

mTBI is a common injury in both military and civilian settings, but it can be difficult to diagnose and is not always well understood. Long-term debilitating effects have been associated with mTBI, with literature linking it to an increased risk of developing Alzheimer disease, motor neuron disease, and Parkinson disease.¹ In addition, mTBI is a strong predictor for the development of posttraumatic stress disorder (PTSD). Among returning Iraq and Afghanistan service members, the incidence of mTBI associated mental health conditions have been reported to be as high as 22.8%, affecting > 320,000 veterans.^2-5

The US Department of Veteran Affairs (VA) health care system offers these returning veterans a comprehensive, multidisciplinary treatment strategy. The care is often coordinated by the veteran’s patient aligned care team (PACT) that consists of a PCP, nurses, and a medical support associate. The US Department of Defense (DoD) and VA also facilitated the development of a clinical practice guideline (CPG) that can be used by the PACT and other health care providers to support evidence based patient-centered care. This CPG is extensive and has recommendations for evaluation and treatment of mTBI and the symptoms associated such as impaired memory and alterations in executive function.⁶

The following hypothetical case is based on an actual patient. This case illustrates the role of speech pathology in caring for patients with mTBI.

Case Presentation

A 25-year-old male combat veteran presented to his VA PACT team for a new patient visit. As part of the screening of his medical history, mTBI was fully defined for the patient to include “alteration” in consciousness. This reminded the patient of an injury that occurred 1 year prior to presentation during a routine convoy mission. He was riding in the back of a Humvee when it hit a large pothole slamming his head into the side of the vehicle. He reported that he felt “dazed and dizzy” with “ringing” in his ears immediately following the event, without an overt loss of consciousness. He was unable to seek medical attention secondary to the urgency of the convoy mission, so he “shook it off” and kept going. Later that week he noted headache and insomnia. He was seen and evaluated by his health care provider for insomnia, but when questioned he reported no head trauma as he had forgotten the incident. Upon follow-up with his PCP, he reported his headaches were manageable, and his insomnia was somewhat improved with recommended life-style modifications and good sleep hygiene.

He still had frequent headaches, dizziness, and some insomnia. However, his chief concern was that he was struggling with new schoolwork. He noted that he was a straight-A student prior to his military service. A review of his medical history in his medical chart showed that a previous PCP had treated his associated symptoms of insomnia and headache without improvement. In addition, he had recently been diagnosed with PTSD. As his symptoms had lasted > 90 days, not resolved with initial treatment in primary care, and were causing a significant impact on his activities of daily living, his PCP placed a consult to Speech Pathology for cognitive-linguistic assessment and treatment, if indicated, noting that he may have had a mTBI.⁶ Although not intended to be comprehensive, Table 1 describes several clinical areas where a speech pathology referral may be appropriate.

The Role of the Speech-Language Pathologist

The speech-language pathologist takes an additional history of the patient. This better quantifies specific details of the veteran’s functional concerns pertaining to possible difficulty with attention, memory, executive function, visuospatial awareness, etc. Examples might include difficulty with attention/memory, including not remembering what to get at the store, forgetting to take medications, forgetting appointments, and difficulty in school, among many others. Reports of feeling “stupid” also are common. Assessment varies by clinician, but it is not uncommon for the SLP to administer a battery of evaluations to help identify a range of possible impairments. Choosing testing that is sensitive to even mild impairment is important and should be used in combination with subjective complaints. Mild deficits can sometimes be missed in those with average performance, but whose premorbid intelligence was above average. One combination of test batteries sometimes utilized is the Wechsler Test of Adult Reading (WTAR), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Ruff Figural Fluency Test (RFFT), the Controlled Oral Word Association Test (COWAT), and Trails A and B (Table 2).

The initial testing results are discussed with the veteran. If patient concerns and/or testing reveal impairment that is amenable to treatment and the veteran wishes to proceed, subsequent treatment sessions are scheduled. The first treatment session is spent establishing and prioritizing functional goals specific to that individual and their needs (eg, for daily life, work, school). In a case of subacute or older mTBI, as is often seen in veterans coming to the VA, intervention often targets strategies and techniques that can help the individual compensate for current deficits.

Many patients already own a smartphone, so this device often is used functionally as a cognitive prosthetic as early as the first treatment session. In an effort to immediately start addressing important issues like medication management and attending appointments, the veteran is educated to the benefit of entering important information into the calendar and/or reminder apps on their phone and setting associated alarms that would serve as a reminder for what was entered. Patients are often encouraged by the positive impact of these initial strategies and look forward to future treatment sessions to address compensation for their functional deficits.

If a veteran with TBI has numerous needs, it can be beneficial for the care team to discuss the care plan at an interdisciplinary team meeting. It is not uncommon for veterans like the one discussed above to be referred to neurology (persistent headaches and further neurological evaluation); mental health (PTSD treatment and family support/counseling options); occupational therapy (visuospatial needs); and audiology (vestibular concerns). Social work involvement is often extremely beneficial for coordination of care in more complex cases. If patient is having difficulty making healthy eating choices or with meal preparation, a consult to a dietitian may prove invaluable. Concerns related to trouble with medication adherence (beyond memory-related adherence issues that speech pathology would address) or polypharmacy can be directed to a clinical pharmacy specialist, who could prepare a medication chart, review optimal medication timing, and provide education on adverse effects. A veteran's communication with the team can be facilitated through secure messaging (a method of secure emailing) and encouraging use of the My HealtheVet portal. With this modality, patients could review chart notes and results and share them with non-VA health care providers and/or family members as indicated.

A whole health approach also may appeal to some mTBI patients. This approach focuses on the totality of patient needs for healthy living and on patient-centered goal setting. Services provided may differ at various VA medical centers, but the PACT team can connect the veteran to the services of interest.

Conclusions

A team approach to veterans with mTBI provides a comprehensive way to treat the various problems associated with the condition. Further research into the role of multidisciplinary teams in the management of mTBI was recommended in the 2016 CPG.⁶ The unique role that the speech-language pathologist plays as part of this team has been highlighted, as it is important that PCP’s be aware of the extent of evaluation and treatment services they offer. Beyond mTBI, speech pathologists evaluate and treat patients with several conditions that are seen regularly in primary care.