Case 17-2005 — A 22-Year-Old Woman with Back and Leg Pain and Respiratory Failure
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《新英格兰医药杂志》
Presentation of Case
A 22-year-old black woman was transferred to this hospital because of respiratory failure.
A diagnosis of sickle cell anemia had been made when the patient was a child, at six years of age. She had last been hospitalized for a sickle cell crisis 12 years earlier. One month before admission, she had bilateral arm pain after jogging and went to a local hospital. A chest radiographic study obtained with a portable unit showed no abnormalities except for bibasilar hazy opacities, which were thought to be due to overlying soft tissues. Laboratory test results are shown in Table 1. Morphine sulfate, hydrocodone, acetaminophen, and fluids were administered, and the symptoms resolved.
Table 1. Hematologic Laboratory Values.
Six days before admission, the patient fell backward while ice-skating. She did not have head trauma. The day after the fall, she had mild nausea and a headache that was relieved by ibuprofen. Two days before admission, while shopping in the frozen-food section of a grocery, she experienced low back pain that radiated to her thighs and the back of her knees. The pain was constant and interfered with walking. She took ibuprofen that evening, which provided some relief. At 2 a.m., she awoke with increased pain and, four hours later, was seen in the emergency room of another hospital.
In the emergency room, the patient reported severe pain (10 on a scale of 1 to 10, with 1 being the lowest level of pain and 10 the highest) in her back, thighs, and knees. She was nauseated and had vomited once; she did not have chest pain, shortness of breath, fever, chills, abdominal pain, dysuria, constipation, or diarrhea.
The patient was a student and resided with her parents in the southern United States. She was working in New England for the summer. She was not sexually active, occasionally drank alcohol, and did not smoke. She had no allergies and took folic acid (1 mg per day). Her parents both carried the sickle cell trait.
On physical examination, she was alert, oriented, and breathing normally. The blood pressure was 132/78 mm Hg, the pulse 116 beats per minute, the respiratory rate 20 breaths per minute, and the temperature 36.1°C. The oxygen saturation was 100 percent while the patient was breathing two liters of oxygen by nasal cannula. The lungs were clear, and the remainder of the examination revealed no abnormalities. The urine was clear, and testing showed a pH of 5 and a specific gravity of 1.015. The urine was positive for urobilinogen (1+); there were 0 to 2 white cells and rare red cells per high-power field. Other laboratory values are shown in Table 1 and Table 2. A chest radiographic study showed opacities in the left lower lobe of the lungs.
Table 2. Chemistry Laboratory Values.
Treatment consisting of intravenous meperidine hydrochloride, diphenhydramine, morphine sulfate, ketorolac tromethamine, and fentanyl was administered. The patient received 2 liters of normal saline, and a third liter was begun. After three hours, the oxygen saturation decreased to 98 percent, and oxygen was increased to 3 liters by nasal cannula. She continued to have severe pain.
Five and a half hours after admission, the oxygen saturation decreased to 76 percent with a respiratory rate of 24 breaths per minute. Blood gas results are shown in Table 3. The lungs were clear. Oxygen (100 percent) was administered to the patient with a nonrebreathing mask, and 25 minutes later the respiratory rate was 14 breaths per minute and oxygen saturation 100 percent. Over the course of the next hour, she reported a need to cough, and the respiratory rate increased to 45 breaths per minute; rales were heard bilaterally, and the oxygen saturation decreased to 73 percent. A chest radiograph revealed increased interstitial markings and an enlarged cardiac silhouette, as compared with the results of the radiograph obtained 10 hours earlier. Continuous positive airway pressure was begun at 7.5 cm of water. Oxygen saturation improved to 98 percent. Furosemide and additional morphine sulfate were given. Specimens of blood and urine were sent for culture, and 1 unit of packed red cells was transfused.
Table 3. Arterial Blood Gas Values.
Ten hours after the patient presented, the oxygen saturation decreased to 40 percent and the trachea was intubated; vomitus was noted in the trachea during the procedure. She was transferred to the intensive care unit. A chest radiograph obtained after intubation revealed the endotracheal tube in proper position; an infiltrate was present in the right lung. An attempt at placement of a Swan–Ganz line was unsuccessful. A second unit of packed red cells was transfused, and ceftriaxone, clindamycin, gentamicin, and hydrocortisone were administered. Over the next three hours her respiratory status continued to deteriorate (Table 3). She was placed in the prone position, sedated and paralyzed with vecuronium, with ventilation settings set at pressure control ventilation of 25 cm of water, at 100 percent oxygen, tidal volume of 500 to 550 cc, positive end-expiratory pressure (PEEP) of 22 cm of water, peak inspiratory pressure of 47 cm of water, and a respiratory rate of 20 breaths per minute. Over the next eight hours, the oxygen saturation ranged from 95 to 97 percent. Transport to this hospital was arranged for the patient.
She was admitted to the medical intensive care unit of this hospital 23.5 hours after her presentation to the other hospital. She remained sedated and paralyzed in the prone position. The temperature was 35.7°C, the blood pressure 155/93 mm Hg, the pulse 130 beats per minute, the respiratory rate set at 24 breaths per minute, and the mean arterial pressure 116 mm Hg. There was no scleral icterus, the neck was supple, and coarse breathing sounds were heard bilaterally without crackles. No heart murmur, rub, or gallop was heard. Laboratory tests results are in Table 1, Table 2, and Table 3. A chest radiograph obtained with a portable device showed endotracheal and esophagogastric tubes in place and bilateral patchy airspace opacities. Specimens of blood, sputum, nasal swab, and stool were sent for culture, and ceftriaxone, azithromycin, and vancomycin were administered. Nitric oxide treatment was begun. A pulmonary arterial line was placed; the mean pulmonary-artery pressure was 46 mm Hg, and the pulmonary-artery occlusion pressure was 18 mm Hg.
Four hours after admission, the temperature was 36.1°C, blood pressure 110/66 mm Hg, pulse 117 beats per minute, pulmonary-artery pressure 58/38 mm Hg, central venous pressure 17 mm Hg, and pulmonary-artery occlusion pressure 18 mm Hg. The results of hemoglobin electrophoresis are shown in Table 1. An echocardiogram revealed an estimated left ventricular ejection fraction of 52 percent, mild pulmonary insufficiency, and an estimated right ventricular systolic pressure of 54 mm Hg. The right ventricle was dilated, and the interatrial septum was stretched and displaced to the left, which was consistent with right atrial volume overload.
Eight hours after admission, an automated exchange transfusion of 5 units of packed red cells was performed. The results of repeated hemoglobin electrophoresis are shown in Table 1. Computed tomography of the brain showed opacified sinuses and mild soft-tissue edema, with no intracranial hemorrhage or infarction. The results of screening panels for toxins were negative. Over the next 12 hours, the patient's respiratory status continued to deteriorate (Table 3). The results of laboratory tests performed during this time in her hospital stay are shown in Table 2. Twenty hours after her admission to this hospital, 2 units of 5 percent albumin were administered. Ninety minutes later, cannulation for extracorporeal membrane oxygenation was initiated at the bedside. During the procedure, the patient's blood pressure dropped, transiently responded to the administration of norepinephrine and vasopressin, and then became unresponsive to maximal treatment with norepinephrine, vasopressin, phenylephrine, dopamine, epinephrine, and atropine. Cardiopulmonary resuscitation was unsuccessful, and the patient was pronounced dead 23 hours after her admission.
An autopsy was performed.
Differential Diagnosis
Dr. Benjamin D. Medoff: May we review the radiology studies?
Dr. Jo-Anne O. Shepard: A chest radiograph obtained on admission to this hospital with a portable device (Figure 1) shows an endotracheal tube in appropriate position and a nasogastric tube in the stomach. There were bilateral, confluent air-space opacities throughout both lungs in a symmetric fashion that might have represented edema, pneumonia, or pulmonary hemorrhage. There were no pleural effusions. The cardiac silhouette was at the upper limit of normal.
Figure 1. Image Obtained from Portable Chest Radiography.
The bilateral patchy opacities are consistent with pneumonia, edema, or hemorrhage. An endotracheal tube, nasogastric tube, and Swan–Ganz catheter are in place.
Dr. Medoff: This is a tragic case of a young woman with sickle cell anemia who presented with severe acute respiratory distress syndrome (ARDS). I was peripherally involved in the care of this patient and aware of the final diagnosis. In this discussion, I will focus on the pathophysiology of her disease and the management of catastrophic respiratory failure, especially in the setting of sickle cell anemia.
ARDS
This patient had acute respiratory failure with features that met the consensus criteria for ARDS: bilateral infiltrates on chest radiography, severe hypoxemia (defined by a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen that is less than or equal to 200), and no sign of left atrial hypertension.1 ARDS occurs when a severe injury to the lung results in damage to the alveolar epithelial and endothelial cell barriers, leading to leakage of fluid into the air spaces, followed by surfactant dysfunction and inflammation.
Although ARDS is most often seen in association with infections and trauma, it can result from numerous uncommon causes that may necessitate specific management strategies (Table 4).2 One such situation is ARDS in patients with sickle cell anemia, called the acute chest syndrome. The management of this syndrome has unique aspects.
Table 4. Uncommon Causes of the Acute Respiratory Distress Syndrome.
The Acute Chest Syndrome
The acute chest syndrome is a life-threatening disorder that is the leading cause of death in people with sickle cell anemia. It is defined as the presence of a new pulmonary infiltrate on chest radiographs, with chest pain, fever, cough, dyspnea, or an elevated white-cell count in a patient with sickle cell anemia. The patient we are discussing today clearly meets these criteria. The acute chest syndrome occurs in the majority of patients with sickle cell disease at least once during their lives and is the second most common cause of hospital admission after painful vaso-occlusive crises.3,4,5
The acute chest syndrome is the result of the occlusion of pulmonary vessels by sickled red cells. Since hypoxemia is the chief stimulus for polymerization of hemoglobin S, lung disease of any type poses a particular threat to the patient with sickle cell anemia. Furthermore, vascular occlusion in the lung leads to hypoxemia and more sickling of red cells, setting up a vicious circle that can dramatically amplify the extent and severity of the crisis.4 This was probably the scenario in the case of this patient, in whom mild disease escalated rapidly to fulminant respiratory failure.
There are four major precipitants of the acute chest syndrome: infection, bone marrow emboli, thromboembolism, and atelectasis. In this case, since the patient's initial symptom was severe leg pain, rather than dyspnea or cough, bone marrow emboli to the lungs from the release of infarcted marrow into the blood are the most likely cause of the ARDS. In addition, atelectasis, which often develops as a result of the hypoventilation that accompanies rib pain and the use of opiates in patients with vaso-occlusive crises, could have contributed. Pulmonary thromboembolism was also considered; however, this tends to occur with acute hemodynamic collapse in patients with sickle cell anemia since many have chronic pulmonary hypertension.6,7 This patient's final cardiac arrest was probably due to progressive right ventricular failure, secondary to pulmonary hypertension from the ARDS; however, there could also have been a late thromboembolism.
Management of ARDS
Basic Principles
The mainstay of treatment for patients with ARDS from any cause is supportive care and mechanical ventilation.1 Although the ventilator can be lifesaving, it has been shown to be a source of further lung injury in patients with ARDS — so-called ventilator-associated lung injury. The lung collapse that occurs in ARDS reduces the volume of lung available for ventilation, so that the use of normal tidal volumes overdistends the ventilated regions of the lung, causing injury. In addition, the collapsed regions may be exposed to shear forces when adjacent regions of open lung are stretched during tidal ventilation. On the basis of these concepts, currently used management strategies include low-tidal-volume ventilation, limitation of the fraction of inspired oxygen, and lung recruitment with PEEP, all of which were implemented in this patient when she arrived at this hospital.8
Management of Catastrophic ARDS
The most dramatic aspect of this case was the refractory nature of the patient's hypoxemia. In general, I consider cases of ARDS catastrophic when the partial pressure of arterial oxygen remains less than 80 mm Hg despite 100 percent inspired oxygen and PEEP that is greater than 15 cm of water. Although recent strides have been made in our understanding of the management of patients with ARDS,8 cases like this one fall outside the norm and often require therapies that have minimal data to support their effectiveness. When one is considering treatment for this type of patient, maintaining adequate oxygenation is a matter of life or death, and the risk of ventilator-associated lung injury may have to be ignored. In Table 5, I have listed some salvage therapies, grouped according to the physiological causes of hypoxemia. I will discuss several of the specific therapies attempted in this case.
Table 5. Causes of Hypoxemia and Specific Therapies.
Lung Recruitment
ARDS is characterized by areas of edematous lung that are collapsed. These, in turn, create multiple areas of shunting, in which blood flows through areas of lung with minimal or no gas exchange. Recruitment — the opening up — of collapsed regions of the lungs should reduce such shunting and improve oxygenation. In this patient, recruitment of collapsed lung was attempted with use of a combination of PEEP, recruitment maneuvers, and prone positioning. PEEP works by preventing the lung from collapsing during the exhalation phase of mechanical ventilation9; however, delivery of a high-pressure (30 to 40 cm of water), prolonged breath (40 to 120 seconds) with the ventilator (the so-called recruitment maneuver) may be required to open up severely affected lungs.10,11
Recruitment maneuvers can have dramatic effects on oxygenation in carefully selected patients,12,13 but there are no data that show improved outcomes with their use.14 At this hospital, we use recruitment maneuvers in patients who have persistent hypoxemia despite the use of an elevated PEEP level (10 to 15 cm of water). In this case, we performed a recruitment maneuver (the use of ventilation at 40 cm of water pressure for 40 seconds), but there was no improvement in the patient's oxygenation. Turning a patient to the prone position can also frequently result in improved oxygenation, presumably by improving ventilation-to-perfusion matching and recruiting dependent areas of the lung. However, a randomized trial did not show that this approach led to improvements in mortality.15 A subgroup analysis showed benefit in the most severely ill patients, suggesting that this maneuver may be useful as a salvage therapy for catastrophic ARDS.16 Unfortunately, there was no benefit in this patient.
Nitric Oxide
Nitric oxide is a potent vasodilator that, when inhaled, causes pulmonary vasodilation. Since the gas is distributed in the areas of the lung with the most ventilation, it should lead to preferential blood flow to the well-ventilated regions, leading to an increase in ventilation-to-perfusion matching.17 Several trials of nitric oxide in ARDS have shown that it can increase oxygenation in the short term, but they have not shown any effect on mortality or the number of ventilator-free days.18,19 Nitric oxide, therefore, is not recommended as standard therapy, but it can be used in catastrophic cases in which small improvements can be lifesaving. In addition, nitric oxide has been shown to increase the oxygen affinity of hemoglobin S, making sickling of the red cells less likely to occur,20 although clinical experience with this therapy is limited.3 In this patient, because of her persistent hypoxemia and her sickle cell disease, this treatment was instituted, but it did not reverse the problem.
Pulmonary-Artery Catheters
In ARDS, leaking of fluid into the interstitial space can reduce the ability of oxygen to diffuse into the bloodstream. In addition, elevation of pulmonary capillary pressure can increase the movement of fluid out of the vasculature into the interstitium.21 Accordingly, lowering the cardiac filling pressures with diuresis and colloid infusion has been shown to improve oxygenation in ARDS.22 In this patient, a pulmonary arterial catheter was placed and used for precise titration of cardiac filling pressures, cardiac output, and mixed venous oxygen saturation during the red-cell exchange and infusion of colloid.
Combination Therapy
Unfortunately, in patients as severely ill as this woman was, a single therapy is rarely enough for stabilization. Combinations of the therapies listed above can have additive effects. A flow chart shows an incremental approach to a patient with catastrophic ARDS, which we followed in this case (Figure 2). The final measure is the use of extracorporeal membrane oxygenation. Although a previous randomized trial in adults did not show a benefit23 in terms of mortality, we use extracorporeal membrane oxygenation as a final effort for patients whom we believe will die on standard support. The anecdotal experience at this hospital is that it can have some benefit in carefully selected adult patients with ARDS,24 and we continue to offer it to patients, such as the one discussed in this case, for whom there are no other options. Unfortunately, she died as preparations were being made to institute this intervention.
Figure 2. An Incremental Approach to the Management of Catastrophic ARDS.
A high-level recruitment maneuver is used only in patients who are without neurologic disease and bacterial pneumonia and who have adequate blood pressure, filling pressures, and cardiac output. PEEP denotes positive end-expiratory pressure, FiO2 fraction of inspired oxygen, and PAOP pulmonary-artery occlusion pressure.
Management of Respiratory Failure in the Acute Chest Syndrome
In the acute chest syndrome, the resulting hypoxemia continues to promote red-cell sickling and can lead to rapidly progressive disease, as seen in this case. Early intervention with measures such as incentive spirometry and oxygen supplementation is indicated if oxygen saturation falls more than 3 percent from the patient's baseline level. If symptoms progress, the patient should be aggressively treated with antibiotics (including coverage for atypical pathogens) and fluids. If the patient does not improve, more aggressive options should be considered early, such as the use of exchange transfusion and possibly nitric oxide. Although the criteria for exchange transfusion have not been defined, I would initiate this therapy in patients with rapidly increasing oxygen requirements (every one to three hours), hypoxemia despite delivery of more than 60 percent oxygen by face mask, shock and hypoxemia despite delivery of more than 40 percent oxygen by face mask, a history of pulmonary hypertension or chronic lung disease and in any patient intubated for respiratory failure. Early intervention with mechanical ventilation and even extracorporeal membrane oxygenation4 may be warranted for seriously ill patients, to prevent hypoxemia and further sickling of cells.
Dr. Nancy Lee Harris (Pathology): Dr. Kratz will discuss the use of transfusion therapy in the acute chest syndrome and in this patient.
Transfusion Therapy for the Acute Chest Syndrome
Dr. Alexander Kratz: A crucial intervention in the acute chest syndrome is to reduce the percentage of hemoglobin S in the patient's blood. In an acute setting, two therapeutic interventions are available: transfusion of packed red cells and red-cell exchange.4,5
Transfusion of packed red cells can reduce the percentage of hemoglobin S and increase the oxygen-carrying capacity of the patient's blood, but it can also increase blood volume and viscosity.25 In contrast, red-cell exchanges allow the replacement of large percentages of the patient's hemoglobin S–containing blood with donor blood containing hemoglobin A, while keeping blood volume and viscosity unchanged. As Dr. Medoff pointed out, there are no randomized trials comparing transfusion with exchange for the acute chest syndrome.5 However, most centers perform red-cell exchange in a patient who deteriorates despite standard transfusion therapy. This patient had received 2 units of red cells at the other hospital, and her condition had not improved. Therefore, we proceeded to exchange transfusion.
We used an automated instrument that allows the continuous replacement of the patient's hemoglobin S with hemoglobin A. Pheresis will not lead to the total replacement of the patient's red cells with healthy donor cells; the exchange of one blood volume will lead to the replacement of approximately two thirds of the patient's hemoglobin S with hemoglobin A. In a patient such as this woman, we aim to reduce the proportion of hemoglobin S to well below 30 percent. We use blood that has been confirmed to be negative for hemoglobin S and also, usually, that has undergone leukocyte reduction, to minimize the possibility of HLA immunization and of nonhemolytic febrile transfusion reactions. Many centers use red cells that have been matched for minor blood-group antigens in order to prevent the development of alloantibodies.
Patients with sickle cell disease should be very closely monitored for transfusion reactions, because they have often had multiple transfusions and have preformed antibodies to red-cell antigens. It can be difficult sometimes to distinguish a hemolytic transfusion reaction in these patients from sickling-induced hemolysis. A rare complication of blood transfusion or exchange is the syndrome of sickle cell hemolytic transfusion reaction, in which severe anemia develops after the administration of red cells.26,27
This patient had already received red-cell transfusions before the results of a hemoglobin electrophoresis performed before the exchange were obtained (Table 1). This study showed 52.3 percent hemoglobin A and 35.6 percent hemoglobin S. She also had an elevated hemoglobin F level, which is known to be protective against sickling and which may explain the relatively benign clinical course of the disease until this episode. After the red-cell exchange, her hemoglobin S level decreased to 19.8 percent. Unfortunately, her condition did not improve.
Dr. Benjamin D. Medoff's Diagnosis
Acute chest syndrome, due to bone marrow emboli.
Pathological Discussion
Dr. R. Neal Smith: At autopsy, the combined weight of the lungs was 1560 g, about 400 g more than normal but less than the weight criterion for diffuse alveolar damage (2000 g), and the lungs were very edematous. Two small, wedge-shaped subpleural infarcts were present in the right upper lobe. Thrombi were seen macroscopically within the small pulmonary arteries of both lungs. Microscopically, these were bone marrow emboli (Figure 3A and Figure 3B). In addition, fibrin thrombi were identified within alveolar capillaries. A small focus of aspiration pneumonitis was present. Hyaline membranes were not identified.
Figure 3. Photomicrographs of Lung and Bone Marrow (Hematoxylin and Eosin).
Bone marrow emboli, consisting of particles of bone marrow surrounded by fibrin, are present in small pulmonary arteries (Panels A and B). In Panel C, a section of bone marrow shows the absence of cellular detail, indicating infarction (left), as compared with a section of normal bone marrow from the same patient (right).
Although the patient's disease met the clinical criteria for ARDS, the autopsy findings were insufficient for a diagnosis of diffuse alveolar damage, the usual pathological diagnosis that corresponds to ARDS. Massive edema is the first sign of ARDS, leading to diffuse alveolar damage, and appears during the first day. Hyaline membranes follow beginning on day 2. The absence of hyaline membranes may reflect the relatively rapid clinical course in this patient. There was no histologic evidence of pulmonary hypertension, a known complication of sickle cell disease.28,29,30
An evaluation of sections of bone marrow identified extensive infarction (Figure 3C). There was bilirubin cholelithiasis, a small spleen (32 g) with evidence of old infarcts, prominent sickled red cells (Figure 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org), and hemosiderosis of the liver; the other organs appeared to be normal.
The cause of death was sickle cell disease with the acute chest syndrome resulting from a vaso-occlusive crisis that caused bone marrow infarction and pulmonary bone marrow emboli.
A Physician: Are there any warning signs that the acute chest syndrome will occur in a given patient?
Dr. Medoff: You have touched on one of the most difficult aspects of the management of this disease. The patients are often only mildly ill, with atelectasis, and then rapidly progress to respiratory failure. I think the pace of the disease is the best predictor. If the oxygen saturations drop despite oxygen supplementation, I would begin aggressive treatment with exchange transfusions. This approach may end up overtreating some patients, but it may help prevent some tragic cases like the one presented today.
Anatomical Diagnosis
Sickle cell disease with the acute chest syndrome, caused by infarction of the bone marrow and embolization to the lungs.
Dr. Medoff reports having received consulting fees from MEDACorp and grant support from Merck. Dr. Kratz reports having received consulting fees from Vitex.
Source Information
From the Pulmonary and Critical Care Unit, Center for Immunology and Inflammatory Diseases, Department of Medicine (B.D.M.), and the Departments of Radiology (J.O.S.) and Pathology (R.N.S., A.K.), Massachusetts General Hospital; and the Departments of Medicine (B.D.M.), Radiology (J.O.S.), and Pathology (R.N.S., A.K.), Harvard Medical School.
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A 22-year-old black woman was transferred to this hospital because of respiratory failure.
A diagnosis of sickle cell anemia had been made when the patient was a child, at six years of age. She had last been hospitalized for a sickle cell crisis 12 years earlier. One month before admission, she had bilateral arm pain after jogging and went to a local hospital. A chest radiographic study obtained with a portable unit showed no abnormalities except for bibasilar hazy opacities, which were thought to be due to overlying soft tissues. Laboratory test results are shown in Table 1. Morphine sulfate, hydrocodone, acetaminophen, and fluids were administered, and the symptoms resolved.
Table 1. Hematologic Laboratory Values.
Six days before admission, the patient fell backward while ice-skating. She did not have head trauma. The day after the fall, she had mild nausea and a headache that was relieved by ibuprofen. Two days before admission, while shopping in the frozen-food section of a grocery, she experienced low back pain that radiated to her thighs and the back of her knees. The pain was constant and interfered with walking. She took ibuprofen that evening, which provided some relief. At 2 a.m., she awoke with increased pain and, four hours later, was seen in the emergency room of another hospital.
In the emergency room, the patient reported severe pain (10 on a scale of 1 to 10, with 1 being the lowest level of pain and 10 the highest) in her back, thighs, and knees. She was nauseated and had vomited once; she did not have chest pain, shortness of breath, fever, chills, abdominal pain, dysuria, constipation, or diarrhea.
The patient was a student and resided with her parents in the southern United States. She was working in New England for the summer. She was not sexually active, occasionally drank alcohol, and did not smoke. She had no allergies and took folic acid (1 mg per day). Her parents both carried the sickle cell trait.
On physical examination, she was alert, oriented, and breathing normally. The blood pressure was 132/78 mm Hg, the pulse 116 beats per minute, the respiratory rate 20 breaths per minute, and the temperature 36.1°C. The oxygen saturation was 100 percent while the patient was breathing two liters of oxygen by nasal cannula. The lungs were clear, and the remainder of the examination revealed no abnormalities. The urine was clear, and testing showed a pH of 5 and a specific gravity of 1.015. The urine was positive for urobilinogen (1+); there were 0 to 2 white cells and rare red cells per high-power field. Other laboratory values are shown in Table 1 and Table 2. A chest radiographic study showed opacities in the left lower lobe of the lungs.
Table 2. Chemistry Laboratory Values.
Treatment consisting of intravenous meperidine hydrochloride, diphenhydramine, morphine sulfate, ketorolac tromethamine, and fentanyl was administered. The patient received 2 liters of normal saline, and a third liter was begun. After three hours, the oxygen saturation decreased to 98 percent, and oxygen was increased to 3 liters by nasal cannula. She continued to have severe pain.
Five and a half hours after admission, the oxygen saturation decreased to 76 percent with a respiratory rate of 24 breaths per minute. Blood gas results are shown in Table 3. The lungs were clear. Oxygen (100 percent) was administered to the patient with a nonrebreathing mask, and 25 minutes later the respiratory rate was 14 breaths per minute and oxygen saturation 100 percent. Over the course of the next hour, she reported a need to cough, and the respiratory rate increased to 45 breaths per minute; rales were heard bilaterally, and the oxygen saturation decreased to 73 percent. A chest radiograph revealed increased interstitial markings and an enlarged cardiac silhouette, as compared with the results of the radiograph obtained 10 hours earlier. Continuous positive airway pressure was begun at 7.5 cm of water. Oxygen saturation improved to 98 percent. Furosemide and additional morphine sulfate were given. Specimens of blood and urine were sent for culture, and 1 unit of packed red cells was transfused.
Table 3. Arterial Blood Gas Values.
Ten hours after the patient presented, the oxygen saturation decreased to 40 percent and the trachea was intubated; vomitus was noted in the trachea during the procedure. She was transferred to the intensive care unit. A chest radiograph obtained after intubation revealed the endotracheal tube in proper position; an infiltrate was present in the right lung. An attempt at placement of a Swan–Ganz line was unsuccessful. A second unit of packed red cells was transfused, and ceftriaxone, clindamycin, gentamicin, and hydrocortisone were administered. Over the next three hours her respiratory status continued to deteriorate (Table 3). She was placed in the prone position, sedated and paralyzed with vecuronium, with ventilation settings set at pressure control ventilation of 25 cm of water, at 100 percent oxygen, tidal volume of 500 to 550 cc, positive end-expiratory pressure (PEEP) of 22 cm of water, peak inspiratory pressure of 47 cm of water, and a respiratory rate of 20 breaths per minute. Over the next eight hours, the oxygen saturation ranged from 95 to 97 percent. Transport to this hospital was arranged for the patient.
She was admitted to the medical intensive care unit of this hospital 23.5 hours after her presentation to the other hospital. She remained sedated and paralyzed in the prone position. The temperature was 35.7°C, the blood pressure 155/93 mm Hg, the pulse 130 beats per minute, the respiratory rate set at 24 breaths per minute, and the mean arterial pressure 116 mm Hg. There was no scleral icterus, the neck was supple, and coarse breathing sounds were heard bilaterally without crackles. No heart murmur, rub, or gallop was heard. Laboratory tests results are in Table 1, Table 2, and Table 3. A chest radiograph obtained with a portable device showed endotracheal and esophagogastric tubes in place and bilateral patchy airspace opacities. Specimens of blood, sputum, nasal swab, and stool were sent for culture, and ceftriaxone, azithromycin, and vancomycin were administered. Nitric oxide treatment was begun. A pulmonary arterial line was placed; the mean pulmonary-artery pressure was 46 mm Hg, and the pulmonary-artery occlusion pressure was 18 mm Hg.
Four hours after admission, the temperature was 36.1°C, blood pressure 110/66 mm Hg, pulse 117 beats per minute, pulmonary-artery pressure 58/38 mm Hg, central venous pressure 17 mm Hg, and pulmonary-artery occlusion pressure 18 mm Hg. The results of hemoglobin electrophoresis are shown in Table 1. An echocardiogram revealed an estimated left ventricular ejection fraction of 52 percent, mild pulmonary insufficiency, and an estimated right ventricular systolic pressure of 54 mm Hg. The right ventricle was dilated, and the interatrial septum was stretched and displaced to the left, which was consistent with right atrial volume overload.
Eight hours after admission, an automated exchange transfusion of 5 units of packed red cells was performed. The results of repeated hemoglobin electrophoresis are shown in Table 1. Computed tomography of the brain showed opacified sinuses and mild soft-tissue edema, with no intracranial hemorrhage or infarction. The results of screening panels for toxins were negative. Over the next 12 hours, the patient's respiratory status continued to deteriorate (Table 3). The results of laboratory tests performed during this time in her hospital stay are shown in Table 2. Twenty hours after her admission to this hospital, 2 units of 5 percent albumin were administered. Ninety minutes later, cannulation for extracorporeal membrane oxygenation was initiated at the bedside. During the procedure, the patient's blood pressure dropped, transiently responded to the administration of norepinephrine and vasopressin, and then became unresponsive to maximal treatment with norepinephrine, vasopressin, phenylephrine, dopamine, epinephrine, and atropine. Cardiopulmonary resuscitation was unsuccessful, and the patient was pronounced dead 23 hours after her admission.
An autopsy was performed.
Differential Diagnosis
Dr. Benjamin D. Medoff: May we review the radiology studies?
Dr. Jo-Anne O. Shepard: A chest radiograph obtained on admission to this hospital with a portable device (Figure 1) shows an endotracheal tube in appropriate position and a nasogastric tube in the stomach. There were bilateral, confluent air-space opacities throughout both lungs in a symmetric fashion that might have represented edema, pneumonia, or pulmonary hemorrhage. There were no pleural effusions. The cardiac silhouette was at the upper limit of normal.
Figure 1. Image Obtained from Portable Chest Radiography.
The bilateral patchy opacities are consistent with pneumonia, edema, or hemorrhage. An endotracheal tube, nasogastric tube, and Swan–Ganz catheter are in place.
Dr. Medoff: This is a tragic case of a young woman with sickle cell anemia who presented with severe acute respiratory distress syndrome (ARDS). I was peripherally involved in the care of this patient and aware of the final diagnosis. In this discussion, I will focus on the pathophysiology of her disease and the management of catastrophic respiratory failure, especially in the setting of sickle cell anemia.
ARDS
This patient had acute respiratory failure with features that met the consensus criteria for ARDS: bilateral infiltrates on chest radiography, severe hypoxemia (defined by a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen that is less than or equal to 200), and no sign of left atrial hypertension.1 ARDS occurs when a severe injury to the lung results in damage to the alveolar epithelial and endothelial cell barriers, leading to leakage of fluid into the air spaces, followed by surfactant dysfunction and inflammation.
Although ARDS is most often seen in association with infections and trauma, it can result from numerous uncommon causes that may necessitate specific management strategies (Table 4).2 One such situation is ARDS in patients with sickle cell anemia, called the acute chest syndrome. The management of this syndrome has unique aspects.
Table 4. Uncommon Causes of the Acute Respiratory Distress Syndrome.
The Acute Chest Syndrome
The acute chest syndrome is a life-threatening disorder that is the leading cause of death in people with sickle cell anemia. It is defined as the presence of a new pulmonary infiltrate on chest radiographs, with chest pain, fever, cough, dyspnea, or an elevated white-cell count in a patient with sickle cell anemia. The patient we are discussing today clearly meets these criteria. The acute chest syndrome occurs in the majority of patients with sickle cell disease at least once during their lives and is the second most common cause of hospital admission after painful vaso-occlusive crises.3,4,5
The acute chest syndrome is the result of the occlusion of pulmonary vessels by sickled red cells. Since hypoxemia is the chief stimulus for polymerization of hemoglobin S, lung disease of any type poses a particular threat to the patient with sickle cell anemia. Furthermore, vascular occlusion in the lung leads to hypoxemia and more sickling of red cells, setting up a vicious circle that can dramatically amplify the extent and severity of the crisis.4 This was probably the scenario in the case of this patient, in whom mild disease escalated rapidly to fulminant respiratory failure.
There are four major precipitants of the acute chest syndrome: infection, bone marrow emboli, thromboembolism, and atelectasis. In this case, since the patient's initial symptom was severe leg pain, rather than dyspnea or cough, bone marrow emboli to the lungs from the release of infarcted marrow into the blood are the most likely cause of the ARDS. In addition, atelectasis, which often develops as a result of the hypoventilation that accompanies rib pain and the use of opiates in patients with vaso-occlusive crises, could have contributed. Pulmonary thromboembolism was also considered; however, this tends to occur with acute hemodynamic collapse in patients with sickle cell anemia since many have chronic pulmonary hypertension.6,7 This patient's final cardiac arrest was probably due to progressive right ventricular failure, secondary to pulmonary hypertension from the ARDS; however, there could also have been a late thromboembolism.
Management of ARDS
Basic Principles
The mainstay of treatment for patients with ARDS from any cause is supportive care and mechanical ventilation.1 Although the ventilator can be lifesaving, it has been shown to be a source of further lung injury in patients with ARDS — so-called ventilator-associated lung injury. The lung collapse that occurs in ARDS reduces the volume of lung available for ventilation, so that the use of normal tidal volumes overdistends the ventilated regions of the lung, causing injury. In addition, the collapsed regions may be exposed to shear forces when adjacent regions of open lung are stretched during tidal ventilation. On the basis of these concepts, currently used management strategies include low-tidal-volume ventilation, limitation of the fraction of inspired oxygen, and lung recruitment with PEEP, all of which were implemented in this patient when she arrived at this hospital.8
Management of Catastrophic ARDS
The most dramatic aspect of this case was the refractory nature of the patient's hypoxemia. In general, I consider cases of ARDS catastrophic when the partial pressure of arterial oxygen remains less than 80 mm Hg despite 100 percent inspired oxygen and PEEP that is greater than 15 cm of water. Although recent strides have been made in our understanding of the management of patients with ARDS,8 cases like this one fall outside the norm and often require therapies that have minimal data to support their effectiveness. When one is considering treatment for this type of patient, maintaining adequate oxygenation is a matter of life or death, and the risk of ventilator-associated lung injury may have to be ignored. In Table 5, I have listed some salvage therapies, grouped according to the physiological causes of hypoxemia. I will discuss several of the specific therapies attempted in this case.
Table 5. Causes of Hypoxemia and Specific Therapies.
Lung Recruitment
ARDS is characterized by areas of edematous lung that are collapsed. These, in turn, create multiple areas of shunting, in which blood flows through areas of lung with minimal or no gas exchange. Recruitment — the opening up — of collapsed regions of the lungs should reduce such shunting and improve oxygenation. In this patient, recruitment of collapsed lung was attempted with use of a combination of PEEP, recruitment maneuvers, and prone positioning. PEEP works by preventing the lung from collapsing during the exhalation phase of mechanical ventilation9; however, delivery of a high-pressure (30 to 40 cm of water), prolonged breath (40 to 120 seconds) with the ventilator (the so-called recruitment maneuver) may be required to open up severely affected lungs.10,11
Recruitment maneuvers can have dramatic effects on oxygenation in carefully selected patients,12,13 but there are no data that show improved outcomes with their use.14 At this hospital, we use recruitment maneuvers in patients who have persistent hypoxemia despite the use of an elevated PEEP level (10 to 15 cm of water). In this case, we performed a recruitment maneuver (the use of ventilation at 40 cm of water pressure for 40 seconds), but there was no improvement in the patient's oxygenation. Turning a patient to the prone position can also frequently result in improved oxygenation, presumably by improving ventilation-to-perfusion matching and recruiting dependent areas of the lung. However, a randomized trial did not show that this approach led to improvements in mortality.15 A subgroup analysis showed benefit in the most severely ill patients, suggesting that this maneuver may be useful as a salvage therapy for catastrophic ARDS.16 Unfortunately, there was no benefit in this patient.
Nitric Oxide
Nitric oxide is a potent vasodilator that, when inhaled, causes pulmonary vasodilation. Since the gas is distributed in the areas of the lung with the most ventilation, it should lead to preferential blood flow to the well-ventilated regions, leading to an increase in ventilation-to-perfusion matching.17 Several trials of nitric oxide in ARDS have shown that it can increase oxygenation in the short term, but they have not shown any effect on mortality or the number of ventilator-free days.18,19 Nitric oxide, therefore, is not recommended as standard therapy, but it can be used in catastrophic cases in which small improvements can be lifesaving. In addition, nitric oxide has been shown to increase the oxygen affinity of hemoglobin S, making sickling of the red cells less likely to occur,20 although clinical experience with this therapy is limited.3 In this patient, because of her persistent hypoxemia and her sickle cell disease, this treatment was instituted, but it did not reverse the problem.
Pulmonary-Artery Catheters
In ARDS, leaking of fluid into the interstitial space can reduce the ability of oxygen to diffuse into the bloodstream. In addition, elevation of pulmonary capillary pressure can increase the movement of fluid out of the vasculature into the interstitium.21 Accordingly, lowering the cardiac filling pressures with diuresis and colloid infusion has been shown to improve oxygenation in ARDS.22 In this patient, a pulmonary arterial catheter was placed and used for precise titration of cardiac filling pressures, cardiac output, and mixed venous oxygen saturation during the red-cell exchange and infusion of colloid.
Combination Therapy
Unfortunately, in patients as severely ill as this woman was, a single therapy is rarely enough for stabilization. Combinations of the therapies listed above can have additive effects. A flow chart shows an incremental approach to a patient with catastrophic ARDS, which we followed in this case (Figure 2). The final measure is the use of extracorporeal membrane oxygenation. Although a previous randomized trial in adults did not show a benefit23 in terms of mortality, we use extracorporeal membrane oxygenation as a final effort for patients whom we believe will die on standard support. The anecdotal experience at this hospital is that it can have some benefit in carefully selected adult patients with ARDS,24 and we continue to offer it to patients, such as the one discussed in this case, for whom there are no other options. Unfortunately, she died as preparations were being made to institute this intervention.
Figure 2. An Incremental Approach to the Management of Catastrophic ARDS.
A high-level recruitment maneuver is used only in patients who are without neurologic disease and bacterial pneumonia and who have adequate blood pressure, filling pressures, and cardiac output. PEEP denotes positive end-expiratory pressure, FiO2 fraction of inspired oxygen, and PAOP pulmonary-artery occlusion pressure.
Management of Respiratory Failure in the Acute Chest Syndrome
In the acute chest syndrome, the resulting hypoxemia continues to promote red-cell sickling and can lead to rapidly progressive disease, as seen in this case. Early intervention with measures such as incentive spirometry and oxygen supplementation is indicated if oxygen saturation falls more than 3 percent from the patient's baseline level. If symptoms progress, the patient should be aggressively treated with antibiotics (including coverage for atypical pathogens) and fluids. If the patient does not improve, more aggressive options should be considered early, such as the use of exchange transfusion and possibly nitric oxide. Although the criteria for exchange transfusion have not been defined, I would initiate this therapy in patients with rapidly increasing oxygen requirements (every one to three hours), hypoxemia despite delivery of more than 60 percent oxygen by face mask, shock and hypoxemia despite delivery of more than 40 percent oxygen by face mask, a history of pulmonary hypertension or chronic lung disease and in any patient intubated for respiratory failure. Early intervention with mechanical ventilation and even extracorporeal membrane oxygenation4 may be warranted for seriously ill patients, to prevent hypoxemia and further sickling of cells.
Dr. Nancy Lee Harris (Pathology): Dr. Kratz will discuss the use of transfusion therapy in the acute chest syndrome and in this patient.
Transfusion Therapy for the Acute Chest Syndrome
Dr. Alexander Kratz: A crucial intervention in the acute chest syndrome is to reduce the percentage of hemoglobin S in the patient's blood. In an acute setting, two therapeutic interventions are available: transfusion of packed red cells and red-cell exchange.4,5
Transfusion of packed red cells can reduce the percentage of hemoglobin S and increase the oxygen-carrying capacity of the patient's blood, but it can also increase blood volume and viscosity.25 In contrast, red-cell exchanges allow the replacement of large percentages of the patient's hemoglobin S–containing blood with donor blood containing hemoglobin A, while keeping blood volume and viscosity unchanged. As Dr. Medoff pointed out, there are no randomized trials comparing transfusion with exchange for the acute chest syndrome.5 However, most centers perform red-cell exchange in a patient who deteriorates despite standard transfusion therapy. This patient had received 2 units of red cells at the other hospital, and her condition had not improved. Therefore, we proceeded to exchange transfusion.
We used an automated instrument that allows the continuous replacement of the patient's hemoglobin S with hemoglobin A. Pheresis will not lead to the total replacement of the patient's red cells with healthy donor cells; the exchange of one blood volume will lead to the replacement of approximately two thirds of the patient's hemoglobin S with hemoglobin A. In a patient such as this woman, we aim to reduce the proportion of hemoglobin S to well below 30 percent. We use blood that has been confirmed to be negative for hemoglobin S and also, usually, that has undergone leukocyte reduction, to minimize the possibility of HLA immunization and of nonhemolytic febrile transfusion reactions. Many centers use red cells that have been matched for minor blood-group antigens in order to prevent the development of alloantibodies.
Patients with sickle cell disease should be very closely monitored for transfusion reactions, because they have often had multiple transfusions and have preformed antibodies to red-cell antigens. It can be difficult sometimes to distinguish a hemolytic transfusion reaction in these patients from sickling-induced hemolysis. A rare complication of blood transfusion or exchange is the syndrome of sickle cell hemolytic transfusion reaction, in which severe anemia develops after the administration of red cells.26,27
This patient had already received red-cell transfusions before the results of a hemoglobin electrophoresis performed before the exchange were obtained (Table 1). This study showed 52.3 percent hemoglobin A and 35.6 percent hemoglobin S. She also had an elevated hemoglobin F level, which is known to be protective against sickling and which may explain the relatively benign clinical course of the disease until this episode. After the red-cell exchange, her hemoglobin S level decreased to 19.8 percent. Unfortunately, her condition did not improve.
Dr. Benjamin D. Medoff's Diagnosis
Acute chest syndrome, due to bone marrow emboli.
Pathological Discussion
Dr. R. Neal Smith: At autopsy, the combined weight of the lungs was 1560 g, about 400 g more than normal but less than the weight criterion for diffuse alveolar damage (2000 g), and the lungs were very edematous. Two small, wedge-shaped subpleural infarcts were present in the right upper lobe. Thrombi were seen macroscopically within the small pulmonary arteries of both lungs. Microscopically, these were bone marrow emboli (Figure 3A and Figure 3B). In addition, fibrin thrombi were identified within alveolar capillaries. A small focus of aspiration pneumonitis was present. Hyaline membranes were not identified.
Figure 3. Photomicrographs of Lung and Bone Marrow (Hematoxylin and Eosin).
Bone marrow emboli, consisting of particles of bone marrow surrounded by fibrin, are present in small pulmonary arteries (Panels A and B). In Panel C, a section of bone marrow shows the absence of cellular detail, indicating infarction (left), as compared with a section of normal bone marrow from the same patient (right).
Although the patient's disease met the clinical criteria for ARDS, the autopsy findings were insufficient for a diagnosis of diffuse alveolar damage, the usual pathological diagnosis that corresponds to ARDS. Massive edema is the first sign of ARDS, leading to diffuse alveolar damage, and appears during the first day. Hyaline membranes follow beginning on day 2. The absence of hyaline membranes may reflect the relatively rapid clinical course in this patient. There was no histologic evidence of pulmonary hypertension, a known complication of sickle cell disease.28,29,30
An evaluation of sections of bone marrow identified extensive infarction (Figure 3C). There was bilirubin cholelithiasis, a small spleen (32 g) with evidence of old infarcts, prominent sickled red cells (Figure 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org), and hemosiderosis of the liver; the other organs appeared to be normal.
The cause of death was sickle cell disease with the acute chest syndrome resulting from a vaso-occlusive crisis that caused bone marrow infarction and pulmonary bone marrow emboli.
A Physician: Are there any warning signs that the acute chest syndrome will occur in a given patient?
Dr. Medoff: You have touched on one of the most difficult aspects of the management of this disease. The patients are often only mildly ill, with atelectasis, and then rapidly progress to respiratory failure. I think the pace of the disease is the best predictor. If the oxygen saturations drop despite oxygen supplementation, I would begin aggressive treatment with exchange transfusions. This approach may end up overtreating some patients, but it may help prevent some tragic cases like the one presented today.
Anatomical Diagnosis
Sickle cell disease with the acute chest syndrome, caused by infarction of the bone marrow and embolization to the lungs.
Dr. Medoff reports having received consulting fees from MEDACorp and grant support from Merck. Dr. Kratz reports having received consulting fees from Vitex.
Source Information
From the Pulmonary and Critical Care Unit, Center for Immunology and Inflammatory Diseases, Department of Medicine (B.D.M.), and the Departments of Radiology (J.O.S.) and Pathology (R.N.S., A.K.), Massachusetts General Hospital; and the Departments of Medicine (B.D.M.), Radiology (J.O.S.), and Pathology (R.N.S., A.K.), Harvard Medical School.
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