CASE REPORT
Acute dyspnea in a postpartum patient Kenneth Fittro, PA-C; William Nichols, DO
CASE A 29-year-old woman was admitted to the hospital at 40 weeks and 3 days gestation for induction of labor because of previous macrosomia. The patient had had five pregnancies previously and had given birth twice. She had a rapid progression from a 5-cm diameter cervical os to complete vaginal delivery in 20 minutes. Subsequently, she developed postpartum hemorrhage and uterine atony that was unresponsive to uterotonics. The ongoing hemorrhage was greater than 2 L and the patient was supported with blood transfusions and cryoprecipitate. The bleeding could not be controlled, so the patient was taken to the OR. Intraoperatively, no vaginal or cervical tears were found. Retained products of conception were thought to be the cause of the bleeding, so intrauterine curettage was performed. The bleeding continued and ultimately an emergency hysterectomy was performed. The patient was in hypovolemic shock and developed a consumptive coagulopathy. She was resuscitated with a combination of crystalloids, colloids, and blood products. In the following days, the patient developed an acute kidney injury as evidenced by a decreased urine output, increasing creatinine, and increasing edema. This was likely ischemic acute tubular necrosis, secondary to the acute blood loss. The patient would eventually require dialysis and a tunneled catheter was placed. At Borgess Medical Center in Kalamazoo, Mich., Kenneth Fittro is a PA on the rapid response team, and William Nichols practices critical care. The authors have indicated no relationships to disclose relating to the content of this article. DOI: 10.1097/01.JAA.0000438531.84515.95 Copyright © 2014 American Academy of Physician Assistants
© B. BOISSONNET / BSIP
ABSTRACT Topical benzocaine sprays used to relieve perineal pain in postpartum patients can, rarely, lead to methemoglobinemia. In patients with other medical issues, such as anemia, methemoglobinemia can become symptomatic, causing acute dyspnea and potentially becoming life-threatening. Keywords: postpartum, acute dyspnea, methemoglobinemia, methylene blue, benzocaine, topical
The patient’s past medical history included hypothyroidism, gastroesophageal reflux disease, and migraine headaches. Her medications included daily doses of 150 mcg of levothyroxine, 30 mg of lansoprazole, and a prenatal vitamin. The patient had quit smoking several years ago. She rarely drank alcohol before the pregnancy and denied any alcohol use during the pregnancy. She denied any recreational drug use. Her record revealed a drug allergy to sulfa drugs, but her reaction to these was not documented. Seven days after the delivery, the rapid response team was called because the patient’s oxygen saturation on routine check was noted to be in the low 80s. The patient
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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29
CASE REPORT
Key points Acquired methemoglobinemia is a rare medical condition that can be life-threatening. The most common cause of acquired methemoglobinemia is exposure to an oxidizing agent that overwhelms the body’s methemoglobin-reducing systems. Conditions that impair oxygen delivery, such as anemia, can cause an otherwise well-tolerated, asymptomatic methemoglobinemia to become symptomatic. Methylene blue is the drug of choice for treatment of methemoglobinemia, except in patients with a known glucose 6-phosphate dehydrogenase deficiency and those taking serotonergic psychiatric medications.
was placed on a 100% oxygen non-rebreather mask, but her oxygen saturation did not increase. At that time she revealed that over the previous 3 days she had noted increasing fatigue. She could not catch her breath if she were to lie flat, but she otherwise denied any dyspnea, although she had been previously ambulating in the halls every day. She also admitted to having a frontal headache, but denied any chest pain, back pain, abdominal pain (other than at the incision site), calf pain, palpations, lightheadedness, cough, or fever. On physical examination, the patient was alert and coherent, and partially sitting up in bed. She was breathing comfortably and speaking in complete sentences. Her vital signs were BP, 154/101 mm Hg; heart rate, 93 beats/minute; respirations, 16; Spo2, 85% on a 100% oxygen nonrebreather mask. Her weight was 96.1 kg (213.5 pounds). Her lips were cyanotic, but she had no other skin discoloration. She had no jugular venous distension. Auscultation of the heart revealed a distinct S1 and S2 without any murmurs, gallops, or rubs. Her lungs were clear to auscultation with full breath sounds throughout. Her abdomen had normoactive bowel sounds and was tender only at the incision site. She had no guarding or rigidity. Her calves were equal in size and nontender with squeezing. She had 2+ edema in both lower extremities and 2+ dorsalis pedis pulses present bilaterally. A 12-lead ECG reading was normal. A single anteroposterior portable chest radiograph revealed no pneumothorax, consolidation, effusion, pulmonary vascular congestion, or edema. A complete blood cell (CBC) count revealed a white blood cell count of 16,600 cells/mm3 (normal range, 4,500 to 11,000 cells/mm3); hemoglobin, 8.9 g/dL (normal range, 12 to 15 g/dL); hematocrit, 26.6% (normal range, 36% to 46%), and red blood cell count, 2.93 million cells/mm3 (normal range, 3.8 million to 4.8 million cells/mm3). The remainder of the CBC count was within normal limits. The basic metabolic panel revealed carbon dioxide, 15 mmol/L (normal range, 22 to 32 mmol/L); blood urea 30
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nitrogen, 79 mg/dL (normal range, 8 to 20 mg/dL); serum creatinine, 12.5 mg/dL (normal range, 0.4 to 1.2 mg/dL); and anion gap, 19 mmol/L (normal range, 5 to 17 mmol/L). Serum sodium, potassium, chloride, and glucose were within normal limits. The arterial blood gas (ABG) analysis revealed a pH of 7.45 (normal range, 7.35 to 7.45), Paco2 of 20 mm Hg (normal range, 34 to 46 mm Hg), Pao2 of 292 mm Hg (normal range, 75 to 85 mm Hg), bicarbonate of 14 mEq/L (normal range, 22 to 26 mEq/L), base excess of -8.8 mmol/L (normal range, -3 to +3 mmol/L), carboxyhemoglobin of 1.4% (normal range, 0 to 2%), methemoglobin of 16.7% (normal range, 0.4% to 1.5%), and Sao2 of 81.7% (normal range, 95% to 98%). The blood drawn for the ABG analysis was noted to be very dark. Based on the patient’s methemoglobin level of 16.7%, she was diagnosed with methemoglobinemia. A search for a cause revealed that the patient had been using a topical analgesic spray (20% benzocaine and 0.5% menthol) on her vulvar area every time she urinated since giving birth 6 days earlier. The patient admitted to using one 2-ounce (56 gram) can every day. This spray is commonly given to patients after a vaginal birth to decrease the pain of urination secondary to perineal tenderness. The patient was given 100 mg of IV methylene blue over 5 minutes, and her symptoms rapidly resolved. One hour after administration of the methylene blue, the patient was asymptomatic and her oxygen saturation was 96% on a non-rebreather mask. A repeat ABG at this time revealed a pH of 7.38, Paco2 of 25 mm Hg, Pao2 of 308 mm Hg, bicarbonate of 14 mEq/L, base excess of -9.9 mmol/L, carboxyhemoglobin of 2.2%, methemoglobin of 4.3%, and Sao2 of 93.2%. The patient had no return of her methemoglobinemia symptoms. She was gradually weaned off the oxygen and was advised to stop using the benzocaine spray. DISCUSSION One of the most important intrinsic factors affecting hemoglobin’s oxygen-carrying capacity is the slow, continuous oxidation of iron from the ferrous to the ferric state. Heme containing iron in the ferric state (such as occurs in the methemoglobin complex) cannot carry oxygen. Furthermore, the presence of one methemoglobin molecule within a hemoglobin tetramer causes the remaining heme molecules to have an increased affinity for oxygen. This hinders the off-loading of oxygen to the tissues (that is, it causes a leftward shift of the oxyhemoglobin dissociation curve). The normal erythrocyte has mechanisms to keep iron in the ferrous state. The cytochrome b5 methemoglobin reductase pathway is the predominant pathway to reduce iron in methemoglobin. An alternate pathway (which accounts for less than 5%) involves a reduced nicotine adenine dinucleotide phosphate diaphorase that enzymatically reduces a flavin, which in turn nonenzymatically reduces methemoglobin. Volume 27 • Number 1 • January 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Acute dyspnea in a postpartum patient
Methemoglobinemia can be either congenital or acquired. Acquired methemoglobinemia is a rare medical condition that can be life-threatening. The most common cause of acquired methemoglobinemia is exposure to an oxidizing agent that overwhelms the body’s methemoglobin-reducing systems. Many agents are associated with acquired methemoglobinemia through both direct and indirect oxidation of the iron atom. In most cases, the precise mechanism that leads to methemoglobinemia is unknown. Dapsone and benzocaine appear to be among the most common causes of acquired methemoglobinemia, but the list of medications that can potentially cause this condition is long. Our patient was applying topical benzocaine spray to her vulva and perineal area. Benzocaine (ethyl 4-aminobenzoate) is an ester type anesthetic, poorly water-soluble and therefore only used topically. Normally, benzocaine is absorbed too slowly to be toxic. But our patient was applying a substantial amount of benzocaine to mucous membranes and the thin skin of the perineum. Furthermore, trauma during childbirth can cause inflamed and/or broken skin that allows for increased absorption. Normal levels of methemoglobin are typically less than 1% of the total hemoglobin content. Methemoglobin levels below 10% typically cause no symptoms. Cyanosis and symptoms of end-organ tissue hypoxia (fatigue and headache in this case) are usually evident with methemoglobin levels between 10% and 20%, and the severity of symptoms usually correlate with the level of methemoglobin. Levels above 30% to 50% can be life-threatening. Interestingly, Pao2 levels usually remain normal even in cases of severe methemoglobinemia. Other factors can play a role in the symptomatology of methemoglobinemia. Any condition that impairs oxygen delivery can cause an otherwise well-tolerated, asymptomatic methemoglobinemia to become symptomatic. Reduced cardiac output or poor gas exchange in the lungs (such as during pulmonary edema or pneumonia) reduce the functional reserve of oxygen delivery to the tissues. In our case,
the patient’s anemia made her more susceptible to the symptoms of her condition because of her blood’s reduced oxygen-carrying capacity. Methylene blue is the drug of choice for treatment of methemoglobinemia. Exceptions include patients with a known glucose 6-phosphate dehydrogenase deficiency and patients taking serotonergic psychiatric medications. The recommended dosage of methylene blue is 1 to 2 mg/kg of a 1% solution given IV over 5 minutes. This is typically recommended only for patients with a high methemoglobin percentage and accompanying symptoms. The dose can be repeated every hour as needed up to a total dose of 7 mg/kg. Methylene blue is a thiazine dye that acts as an electron transporter, thereby activating the normally quiescent nicotine adenine dinucleotide phosphate diaphorase pathway. Methylene blue is reduced by nicotine adenine dinucleotide phosphate diaphorase to leukomethylene blue, which then nonenzymatically reduces methemoglobin to deoxyhemoglobin. Results are normally seen in 20 to 30 minutes. If methemoglobinemia is refractory to methylene blue, treatment with exchange transfusion or hyperbaric oxygen has been suggested.1 Because of methylene blue’s short half-life, closely monitor the patient for recurring symptoms. SUMMARY Our patient demonstrated a very common presentation of an uncommon cause of acute dyspnea in a postpartum patient. Her symptoms and laboratory findings were classic for methemoglobinemia, and her use of topical benzocaine spray represented one of the most common precipitants for this ailment. JAAPA REFERENCE 1. Centers for Disease Control. Agency for Toxic Substances & Disease Registry. Medical management guidelines for aniline. March 3, 2011. http://www.atsdr.cdc.gov/mmg/mmg. asp?id=448&tid=79. Accessed June 3, 2013.
in
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Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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Acute dyspnea in a postpartum patient Kenneth Fittro, PA-C; William Nichols, DO
CASE A 29-year-old woman was admitted to the hospital at 40 weeks and 3 days gestation for induction of labor because of previous macrosomia. The patient had had five pregnancies previously and had given birth twice. She had a rapid progression from a 5-cm diameter cervical os to complete vaginal delivery in 20 minutes. Subsequently, she developed postpartum hemorrhage and uterine atony that was unresponsive to uterotonics. The ongoing hemorrhage was greater than 2 L and the patient was supported with blood transfusions and cryoprecipitate. The bleeding could not be controlled, so the patient was taken to the OR. Intraoperatively, no vaginal or cervical tears were found. Retained products of conception were thought to be the cause of the bleeding, so intrauterine curettage was performed. The bleeding continued and ultimately an emergency hysterectomy was performed. The patient was in hypovolemic shock and developed a consumptive coagulopathy. She was resuscitated with a combination of crystalloids, colloids, and blood products. In the following days, the patient developed an acute kidney injury as evidenced by a decreased urine output, increasing creatinine, and increasing edema. This was likely ischemic acute tubular necrosis, secondary to the acute blood loss. The patient would eventually require dialysis and a tunneled catheter was placed. At Borgess Medical Center in Kalamazoo, Mich., Kenneth Fittro is a PA on the rapid response team, and William Nichols practices critical care. The authors have indicated no relationships to disclose relating to the content of this article. DOI: 10.1097/01.JAA.0000438531.84515.95 Copyright © 2014 American Academy of Physician Assistants
© B. BOISSONNET / BSIP
ABSTRACT Topical benzocaine sprays used to relieve perineal pain in postpartum patients can, rarely, lead to methemoglobinemia. In patients with other medical issues, such as anemia, methemoglobinemia can become symptomatic, causing acute dyspnea and potentially becoming life-threatening. Keywords: postpartum, acute dyspnea, methemoglobinemia, methylene blue, benzocaine, topical
The patient’s past medical history included hypothyroidism, gastroesophageal reflux disease, and migraine headaches. Her medications included daily doses of 150 mcg of levothyroxine, 30 mg of lansoprazole, and a prenatal vitamin. The patient had quit smoking several years ago. She rarely drank alcohol before the pregnancy and denied any alcohol use during the pregnancy. She denied any recreational drug use. Her record revealed a drug allergy to sulfa drugs, but her reaction to these was not documented. Seven days after the delivery, the rapid response team was called because the patient’s oxygen saturation on routine check was noted to be in the low 80s. The patient
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
www.JAAPA.com
29
CASE REPORT
Key points Acquired methemoglobinemia is a rare medical condition that can be life-threatening. The most common cause of acquired methemoglobinemia is exposure to an oxidizing agent that overwhelms the body’s methemoglobin-reducing systems. Conditions that impair oxygen delivery, such as anemia, can cause an otherwise well-tolerated, asymptomatic methemoglobinemia to become symptomatic. Methylene blue is the drug of choice for treatment of methemoglobinemia, except in patients with a known glucose 6-phosphate dehydrogenase deficiency and those taking serotonergic psychiatric medications.
was placed on a 100% oxygen non-rebreather mask, but her oxygen saturation did not increase. At that time she revealed that over the previous 3 days she had noted increasing fatigue. She could not catch her breath if she were to lie flat, but she otherwise denied any dyspnea, although she had been previously ambulating in the halls every day. She also admitted to having a frontal headache, but denied any chest pain, back pain, abdominal pain (other than at the incision site), calf pain, palpations, lightheadedness, cough, or fever. On physical examination, the patient was alert and coherent, and partially sitting up in bed. She was breathing comfortably and speaking in complete sentences. Her vital signs were BP, 154/101 mm Hg; heart rate, 93 beats/minute; respirations, 16; Spo2, 85% on a 100% oxygen nonrebreather mask. Her weight was 96.1 kg (213.5 pounds). Her lips were cyanotic, but she had no other skin discoloration. She had no jugular venous distension. Auscultation of the heart revealed a distinct S1 and S2 without any murmurs, gallops, or rubs. Her lungs were clear to auscultation with full breath sounds throughout. Her abdomen had normoactive bowel sounds and was tender only at the incision site. She had no guarding or rigidity. Her calves were equal in size and nontender with squeezing. She had 2+ edema in both lower extremities and 2+ dorsalis pedis pulses present bilaterally. A 12-lead ECG reading was normal. A single anteroposterior portable chest radiograph revealed no pneumothorax, consolidation, effusion, pulmonary vascular congestion, or edema. A complete blood cell (CBC) count revealed a white blood cell count of 16,600 cells/mm3 (normal range, 4,500 to 11,000 cells/mm3); hemoglobin, 8.9 g/dL (normal range, 12 to 15 g/dL); hematocrit, 26.6% (normal range, 36% to 46%), and red blood cell count, 2.93 million cells/mm3 (normal range, 3.8 million to 4.8 million cells/mm3). The remainder of the CBC count was within normal limits. The basic metabolic panel revealed carbon dioxide, 15 mmol/L (normal range, 22 to 32 mmol/L); blood urea 30
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nitrogen, 79 mg/dL (normal range, 8 to 20 mg/dL); serum creatinine, 12.5 mg/dL (normal range, 0.4 to 1.2 mg/dL); and anion gap, 19 mmol/L (normal range, 5 to 17 mmol/L). Serum sodium, potassium, chloride, and glucose were within normal limits. The arterial blood gas (ABG) analysis revealed a pH of 7.45 (normal range, 7.35 to 7.45), Paco2 of 20 mm Hg (normal range, 34 to 46 mm Hg), Pao2 of 292 mm Hg (normal range, 75 to 85 mm Hg), bicarbonate of 14 mEq/L (normal range, 22 to 26 mEq/L), base excess of -8.8 mmol/L (normal range, -3 to +3 mmol/L), carboxyhemoglobin of 1.4% (normal range, 0 to 2%), methemoglobin of 16.7% (normal range, 0.4% to 1.5%), and Sao2 of 81.7% (normal range, 95% to 98%). The blood drawn for the ABG analysis was noted to be very dark. Based on the patient’s methemoglobin level of 16.7%, she was diagnosed with methemoglobinemia. A search for a cause revealed that the patient had been using a topical analgesic spray (20% benzocaine and 0.5% menthol) on her vulvar area every time she urinated since giving birth 6 days earlier. The patient admitted to using one 2-ounce (56 gram) can every day. This spray is commonly given to patients after a vaginal birth to decrease the pain of urination secondary to perineal tenderness. The patient was given 100 mg of IV methylene blue over 5 minutes, and her symptoms rapidly resolved. One hour after administration of the methylene blue, the patient was asymptomatic and her oxygen saturation was 96% on a non-rebreather mask. A repeat ABG at this time revealed a pH of 7.38, Paco2 of 25 mm Hg, Pao2 of 308 mm Hg, bicarbonate of 14 mEq/L, base excess of -9.9 mmol/L, carboxyhemoglobin of 2.2%, methemoglobin of 4.3%, and Sao2 of 93.2%. The patient had no return of her methemoglobinemia symptoms. She was gradually weaned off the oxygen and was advised to stop using the benzocaine spray. DISCUSSION One of the most important intrinsic factors affecting hemoglobin’s oxygen-carrying capacity is the slow, continuous oxidation of iron from the ferrous to the ferric state. Heme containing iron in the ferric state (such as occurs in the methemoglobin complex) cannot carry oxygen. Furthermore, the presence of one methemoglobin molecule within a hemoglobin tetramer causes the remaining heme molecules to have an increased affinity for oxygen. This hinders the off-loading of oxygen to the tissues (that is, it causes a leftward shift of the oxyhemoglobin dissociation curve). The normal erythrocyte has mechanisms to keep iron in the ferrous state. The cytochrome b5 methemoglobin reductase pathway is the predominant pathway to reduce iron in methemoglobin. An alternate pathway (which accounts for less than 5%) involves a reduced nicotine adenine dinucleotide phosphate diaphorase that enzymatically reduces a flavin, which in turn nonenzymatically reduces methemoglobin. Volume 27 • Number 1 • January 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Acute dyspnea in a postpartum patient
Methemoglobinemia can be either congenital or acquired. Acquired methemoglobinemia is a rare medical condition that can be life-threatening. The most common cause of acquired methemoglobinemia is exposure to an oxidizing agent that overwhelms the body’s methemoglobin-reducing systems. Many agents are associated with acquired methemoglobinemia through both direct and indirect oxidation of the iron atom. In most cases, the precise mechanism that leads to methemoglobinemia is unknown. Dapsone and benzocaine appear to be among the most common causes of acquired methemoglobinemia, but the list of medications that can potentially cause this condition is long. Our patient was applying topical benzocaine spray to her vulva and perineal area. Benzocaine (ethyl 4-aminobenzoate) is an ester type anesthetic, poorly water-soluble and therefore only used topically. Normally, benzocaine is absorbed too slowly to be toxic. But our patient was applying a substantial amount of benzocaine to mucous membranes and the thin skin of the perineum. Furthermore, trauma during childbirth can cause inflamed and/or broken skin that allows for increased absorption. Normal levels of methemoglobin are typically less than 1% of the total hemoglobin content. Methemoglobin levels below 10% typically cause no symptoms. Cyanosis and symptoms of end-organ tissue hypoxia (fatigue and headache in this case) are usually evident with methemoglobin levels between 10% and 20%, and the severity of symptoms usually correlate with the level of methemoglobin. Levels above 30% to 50% can be life-threatening. Interestingly, Pao2 levels usually remain normal even in cases of severe methemoglobinemia. Other factors can play a role in the symptomatology of methemoglobinemia. Any condition that impairs oxygen delivery can cause an otherwise well-tolerated, asymptomatic methemoglobinemia to become symptomatic. Reduced cardiac output or poor gas exchange in the lungs (such as during pulmonary edema or pneumonia) reduce the functional reserve of oxygen delivery to the tissues. In our case,
the patient’s anemia made her more susceptible to the symptoms of her condition because of her blood’s reduced oxygen-carrying capacity. Methylene blue is the drug of choice for treatment of methemoglobinemia. Exceptions include patients with a known glucose 6-phosphate dehydrogenase deficiency and patients taking serotonergic psychiatric medications. The recommended dosage of methylene blue is 1 to 2 mg/kg of a 1% solution given IV over 5 minutes. This is typically recommended only for patients with a high methemoglobin percentage and accompanying symptoms. The dose can be repeated every hour as needed up to a total dose of 7 mg/kg. Methylene blue is a thiazine dye that acts as an electron transporter, thereby activating the normally quiescent nicotine adenine dinucleotide phosphate diaphorase pathway. Methylene blue is reduced by nicotine adenine dinucleotide phosphate diaphorase to leukomethylene blue, which then nonenzymatically reduces methemoglobin to deoxyhemoglobin. Results are normally seen in 20 to 30 minutes. If methemoglobinemia is refractory to methylene blue, treatment with exchange transfusion or hyperbaric oxygen has been suggested.1 Because of methylene blue’s short half-life, closely monitor the patient for recurring symptoms. SUMMARY Our patient demonstrated a very common presentation of an uncommon cause of acute dyspnea in a postpartum patient. Her symptoms and laboratory findings were classic for methemoglobinemia, and her use of topical benzocaine spray represented one of the most common precipitants for this ailment. JAAPA REFERENCE 1. Centers for Disease Control. Agency for Toxic Substances & Disease Registry. Medical management guidelines for aniline. March 3, 2011. http://www.atsdr.cdc.gov/mmg/mmg. asp?id=448&tid=79. Accessed June 3, 2013.
in
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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31
