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Reversible respiratory failure due to intravascular leukostasis in chronic myelogenous leukemia
Reversible Respiratory Failure Due to Intravascular Leukostasis in Chronic Myelogenous Leukemia Relationship of Oxygen Transfer to Leukocyte Count
ROBERT BLOOM, M.D.* ANGELO M. ‘I’AVEIRA DA SILVA, M.D. AR’I’HI JR BRACEY. M.D. 12’clsl,lngton.I).(:.
From the Department of Medicine and the Department of Pathology. Georgetown University School of Medicine, Washington, D.C. Requests for reprints should be addressed to Dr. Angelo M. T,lvcira Da Silva, Pulmonary Disease Division, Georgetown University Hospital, Washington, D.C. 20007. Manuscript accepted April 13,1979. * Present address: 7 Corners Professional Building, 6319 Castle Place, Falls Church. Virginia 22044.
In a 49 year old man with blast crisis and massive leukocytosis due to chronic myelogenous leukemia, severe hypoxic respiratory failure developed despite a normal chest film. Correction of hypoxemia was observed after reduction of the white blood cell count by hydroxyurea therapy. A similar episode occurred prior to death, and necropsy examination revealed extensive plugging of the pulmonary vasculature by leukemic blast cells but no infection or pulmonary edema. An inverse linear correlation was demonstrated between the peripheral white blood cell count and the efficiency of oxygen transfer in the lung as determined by the arterial to alveolar oxygen tension ratio. We postulate that mechanical obstruction and/or leukocyte mediated capillary endothelial injury caused the severe hypoxemia. Abnormalities of pulmonary gas exchange may be common in leukemic patients with markedly increased leukocyte counts. Intravascular aggregates of leukocytes occur frequently in acute or chronic granulocytic leukemia when the peripheral white blood cell count exceeds 50,00O/mm” and almost invariably with a Mshite blood cell count greater than 200,00O/mm~~ [l]. Obstruction to flow in small blood vessels may cause central nervous system hemorrhages [2] or cardiopulmonary dysfunction [3,4]. Although dyspnea has been described in the majority of patients in whom death was attributed to intravascular leukostasis, data relating to alterations in lung function are scanty [1,4]. We have recently treated a patient in the blast phase of chronic myclogenous leukemia who manifested coma and respiratory failure due to leukostasis. Treatment with high doses of hydroxyurca resulted in a dramatic reduction of the patient’s white blood cell count with a concomitant correction of respiratory and neurologic abnormalities. An inverse correlation was observed between changes in the leukocyte count and gas exchange in the lung during two episodes of acute rospiratory failure. CASE REPORT A 4;) year old white man was admitted
to Georgetown Onivcrsity Hospital (GrJHj on May 17. 1977, with seizures. In 1973. the diagnosis 01 chronic myelogenous leukemia was made and therapy with Myleran@ \yas started. In
October 1979
The American
Journal of Medicine
Volume 67
679
REVERSIBLE RESPIRATORY FAILURE IN CHRONIC MYELOGENOUS LEUKEMIA-BLOOM
Figure 1. Chest roentgenogram taken on May 23, 1977 showing no evidence of parenchymal lung disease. June 1976, he was readmitted to GUH with headaches, vomiting and lethargy, and a right subdural hematoma was evacuated. Despite hydroxyurea therapy, over the next six months an increase in the white blood cell count was noted. In February 1977. a bone marrow examination showed greater than 50 per cent blast forms whereas the peripheral white blaod cell count was 69,000/mm3 with 14 per cent blast forms. Two weeks prior to admission the patient noted persistent headaches. Left-sided seizures with loss of consciousness develoned on the dav of admission. Hydroxyurea therapy was discontinued. Physical examination revealed a middle-aged man who was lethargic but awake. There was bilateral papilledema with hemorrhage in the left retina. Examination of the heart and lungs disclosed no abnormalities. The white blood cell count was 175,000/mm3 with 28 per cent blast forms, the hematocrit value was 29 ner cent and the ulatelet count 70.000/mm3. A computerized axial tomographic scan and a cerebral arteriogram showed a I.5 cm lesion in the right parietal area. At craniotomy, a leukemic mass was found and resected. In the postoperative period, the patient was febrile with temperatures to 39%. but the chest roentgenogram remained within normal limits (see Figure 1). On the third postoperative day, progressive hypoxemia developed and endotracheal intubation followed by mechanical ventilation and positive end-expiratory pressure (PEEP) were begun. The white blood cell count was noted to be 264,00O/mm” with 50 per cent blast forms. Hydroxyurea therapy was restarted, and the dosage rapidly increased to 4 g/day. The patient remained on the respirator requiring inspired oxygen concentrations (FlO,) of 50 to 80 per cent in order to maintain an arterial oxygen partial pressure (PaOz) of 60 to 90 mm Hg. The administration of cephazolin and gentamicin was begun, but multiple cultures of blood, sputum and urine were negative for pathogens. Repeated chest films failed to show the presence of pulmonary infiltrates. On the eighth postoperative day, the white blood cell count dropped below lO0,00O/mms; on the following day it was
680
October 1979
The American
Journal
of Medicine
ET AL
27.000/mm3. At the same time his oxygenation improved allowing him to be weaned off the respirator and extubated. He was maintained on a 35 per cent F102 Venturi mask with adequate arterial blood gases. He regained consciousness, and physical examination revealed no neurologic impairment. He was discharged during his ninth hospital week in stable condition with a white blood cell count of 42,000/mm3 and normal arterial blood gases. The patient was readmitted to GUH on August 8,1977, with upper gastrointestinal bleeding. Physical examination disclosed no abnormalities. White blood cell count was 163.000/mm3 with 40 per cent blast forms. Vincristine, 2 mg, was given intravenously, and the administration of 80 mg of prednisone/day was begun. Hydroxyurea was continued at a dose of I g/day. On the 14th hospital day, the patient became lethargic and a lumbar puncture demonstrated xanthochromic spinal fluid. The white blood cell count was 306,000/mm3 with 90 per cent blast forms and the PaOz was 50 mm Hg on 60 per cent FlOs. The chest roentgenogram was within normal limits. Nafcillin, gentamicin and carbenicillin were administered and an additional 1.5 g of hydroxyurea was given. On the 16th hospital day, the patient was intubated and started on mechanical ventilation and PEEP. Arterial blood gases showed a Pa02 of 95 mm Hg on 100 per cent FlOz. Arterial blood gases obtained 8 hours later, however, showed a PaOz of I70 mm Hg on 80 per cent FlOz and the patient was then maintained on an FlOs of 50 per cent with adequate arterial blood gases. A repeat white blood cell count obtained simultaneously with the latter arterial blood gas showed a decrease in the white blood cell count to 118,000/mm3. Blood cultures grew Staphylococcus aureus. Despite supportive therapy, the patient remained comatose and died on the 17th hospital day. METHODS Arterial blood was collected into heparin coated 3 cc plastic syringes and then immediately placed on wet-ice. Air bubbles present in the syringe after the collection of the blood samples were eliminated and the syringes promptly capped. Blood gases and pH were measured with a blood gas analyzer (IL 213, Instrumentation Laboratories Inc., Lexington, Massachusetts] within 15 minutes of collecting the arterial blood samples. The blood gas analyzer was calibrated daily by means of a tonometric technique. In addition, calibration prior to the actual measurements with solutions and gases of known composition was always performed. Oxygen exchange in the lungs was assessed by means of the arterial to alveolar oxygen tension ratio (a:APOs). This index of oxygen transfer is calculated by dividing the arterial PaOz by the alveolar oxygen tension (PAOz). The PA02 was calculated from the simplified alveolar air equation assuming a respiratory quotient of 0.8. PA02 = FlOz (PB-47) X PaC02/0.8 where PB is the barometric pressure in millimeters of mercury and PaGO is the partial pressure of carbon dioxide in the arterial blood. The normal value for the a:APOz is approximately 0.8 with only small variations due to changes in F102. A decrease of this ratio below 0.8 indicates impairment of oxygen transfer in the lung [5,6]. The correlation between the leukocyte count and the a:AP02 ratio was evaluated by means of linear regression analysis. The line of best fit was determined by the least squares method.
Volume
67
REVERSIBLE
RESPIRATORY
FAILURE
The statistical significance of the correlation coefficient was
evaluated by means of the t test. RESULTS Necropsy examination showed infiltration of lymph nodes, liver, spleen and brain by leukemic cells. The lungs weighed 500 g each. There was no evidence of pulmonary edema or infection. The pulmonary vascular bed was extensively obliterated by leukemic cells (Figure 2). Areas of infarction with alveolar hemorrhage were seen adjacent to obliterated vessels. There were no morphologic abnormalities of the bronchi and bronchioli and the alveolar walls and spaces had normal appearance. No inclusion bodies were seen. Lung tissue cultures for bacteria, fungi and virus were negative. Leukocyte counts and a:APOs ratios throughout both hospitalizations are shown in Figure 3. A high white blood cell count was almost always accompanied by a low a:APOZ ratio. When the white blood cell count was above 180,000 the a:AP02 ratio was less than 0.5, representing severe impairment in gas exchange. After initiation of high dose hydroxyurea therapy, the white blood cell count decreased and the a:AP02 ratio increased towards normal. In Figure 4, the peripheral white blood cell count was plotted against the a:AP02 ratio. The correlation coefficient is -0.82. This correlation is highly significant (P
IN CHRONIC
MYELOGENOUS
LEUKEMIA--BL.OOM
ET AL.
myelocytic leukemia [7,8]. The presence of infiltrates is often clinically undetectable and does not correlate with the total white blood cell count [8,9]. In contrast, intravascular leukostasis occurs most frequently in granulocytic leukemia in association with circulating myeloblasts and marked leukocytosis [l]. It is frequently accompanied by dyspnea. hypoxemia and right ventricular failure in the presence of a normal chest roentgenogram. In a recent autopsy series, this complication was implicated as the cause of death in 31 of 50 patients with myelogenous leukemia, most of whom had white blood cell counts exceeding 100,000/mm3
[Il. Detailed physiologic data have not been obtained in patients with leukemic infiltrates or intravascular leukostasis. Green et al. [lo] reported alveolocapillary block with a PaOz of 42 mm Hg in a patient with chronic lymphocytic leukemia; necropsy examination revealed infiltration of alveolar septums with leukemic cells. Resnick et al. [3], demonstrated arterial hypoxemia and restrictive lung disease in a patient with acute monocytic leukemia. Although postmortem examination revealed septal infiltration and clogging of the lung capillaries with blast cells, the peripheral white blood cell count was not determined at the time pulmonary function tests were performed. Two recent cases of intravascular leukostasis with arterial hypoxemia have been reported [4]. However, we are unaware of prior sequential studies of pulmonary function in patients undergoing treatment for the leukostasis syndrome. In the patient in this report hypoxemic respiratory failure developed twice in the presence of a white blood cell count greater than 25O,OOO/mm” with more than 50 per cent myeloblasts. During the first episode, the di-
Figure 2. This low power photomicrograph of a pulmonary artery branch demonstrates engorgement of the vessel by leukemic blast forms. This was a characteristic feature of many pulmonary arteries studied. Note that the majority of the alveolar spaces in this field are free of leukemic cells. Hematoxylin and eosin stain, magnification X 25, reduced by 36 per cent.
October
1979
The American Journal of Medicine
Volume 67
661
REVERSIBLE RESPIRATORY FAILURE IN CHRONIC MYELOGENOUS
LEUKEMIA-BLOOM
ET AL.
Respirator
I
Respirator
I
260
220
100
60 Hydroxyurea
4g Q O+
20 1 5119
2
3
4
5
6 8123 Hospital
Days
:igure 3. Daily changes in leukocyte count and a:AP02 ratio. A high leukocyte count is accompanied by a low a:AP02 ratio reflecting impaiied oxygen exchange in the lung. Vertical lines denote tests obtained simultaneously; other paired data were obtained no more than 3 hours apart.
a I A PO2 ratio: 0 Patient on respirator o Patient breathing spontaneously r - -0.82 p < .DDl I
I
I
I
I
20
40
60
80
100
I
I
120 140
I
I
180
I
I
220
I
I
I
260
I
1
300
WBC x 103
Figure 4. Correlation between leukocyte these two variables is highly significant.
682
October 1979
The American
Journal of Medicine
count and a:AP02 ratio. The correlation
Volume 67
between
REVERSIBLE RESPIRATORY FAILURE IN
agnosis of pulmonary leukostasis was based on systematic exclusion of other causes of respiratory failure. There was no evidence of aspiration of gastric content, fluid overload or increased intracranial pressure. Bacterial, fungal and viral cultures were negative. The chest film rema‘ined within normal limits. Although this patient was at an increased risk for the development of opportunistic lung infections, it would be unlikely for such pathogens to cause catastrophic respiratory failure with a persistently normal chest film. The diagnosis of leukostasis is further supported by rapid improvement in the a:AP02 ratio in concert with a decrease in the white blood cell count (Figure 3). When respiratory failure occurred preterminally in association with a massive increase in the white blood cell count, bacteremia and intracranial bleeding were also present. However, at necropsy, the lungs revealed only intravascular leukostasis, pulmonary infarctions and minimal interstitial edema. Leukocytes may cause abnormalities of lung function in several ways. Leukocyte proteases may damage capillary endothelium in the presence of immunoglobulins, endotoxin or complement [ll]. Complement-mediated intrapulmonary sequestration of leukocytes may contribute to abnormalities of oxygenation that are often noted in patients undergoing hemodialysis [12,13]. In addition, the presence of leukoagglutinins in transfused blood may cause aggregation of white cells in the lung and lead to a noncardiogenic form of pulmonary edema [la]. Capillary endothelial damage due to the release of lcukocytc proteases or complement activation cannot be unequivocally excluded as the cause of respiratory
CHRONIC
MYELOGENOIJS LEIIKEMlA~-RL?)OM ET AL.
failure in this patient. However, the absence of pulmonary edema on chest roentgenograms and in tissue specimens, and the relatively low weight of the lungs at necropsy (1,000 g) do not support that explanation. In this patient, massive plugging of the pulmonary arteries and arterioles with blast cells was present, and a significant inverse linear correlation was observed between the peripheral white blood cell count and oxygen transfer (Figure 4). This implies that the pulmonary vascular bed was progressively compromised by leukocyte aggregates as the peripheral white cell count increased. This hypothesis is supported by studies demonstrating that myeloblasts are large rigid cells with abnormal surface properties and viscosity that predispose them to adhere to capillary endothelium and cause intravascular obstruction [15,16]. These intravascular aggregates must also be capable of rapid dissolution, since gas exchange improved within hours after a decrease in the number of circulating leukocytes. We conclude that intravascular leukostasis must be considered a cause of respiratory failure in patients with acute or chronic myelogenous leukemia and white blood cell counts greater than 100,000/mm3, particularly when roentgenographic changes are minimal. Vigorous measures to lower the white blood cell count using chemotherapy or leukophoresis [17-191 may cause rapid, although temporary, reversal of this complication. In view of the inverse correlation between the white blood cell count and pulmonary oxygen transfer observed in this patient, one can speculate that in leukemic patients abnormalities of gas exchange may commonly occur as the leukocyte count increases, even though overt symptoms are absent.
REFERENCES 1. 2. 3. 4. 5.
McKee LC, Collins RD: Intravascular leukocyte thrombi and aggregates as a cause of morbidity and mortality in leukemia. Medicine (Baltimore) 53: 463, 1974. Frcireich EJ. Thomas LB, Frei E III. et al.: A distinctive type of intraccrcbral hemorrhage associated with a “blastic crisis” in patients with leukemia. Cancer 13: 146, 1960. Resnick ME, Berkowitz RD, Rodman T: Diffuse interstitial leukemic infiltration of the lungs producing the alveolarcapillary block syndrome. Am ] Med 31: 149, 1961. Lokich JJ, Moloney WC: Fatal pulmonary leukostasis following treatment in acute mveloaenous leukemia. Arch InternMed 130: 759,1972. . (:ilbcrt R, Keighley JF: The arterial alveolar oxygen tension ratio: an index of gas exchange applicable to varying instjired oxvycn concentrations. Am Rev ResDir Dis 109: 142. i974.
..’
to leukemic infiltration of the lung. .4m Rev Respir Dis 130: 895,1959. ‘Il. Report of National Heart, Lung, and Blood Institute Division of Lung Diseases. Workshop on mechanisms of acute respiratory failure, DHEW Publication No (NIH) 77-981. p 3. 12. Craddock PR. Fehr J, Brigham KL, et al.: Complement and leukocyte-mediated pulmonary disfunction in hemodialysis. N Engl J Med 296: 769, 1977. 13. Craddock PR. Hammerschmidt D, White JG. et al.: Complemcnt (C5a)-induced granulocvtc aggregation in vitro. A possible mechanism Gf complemen~~me&ated leukostasis and leukopcnia. J Chn Invest 60: 260. 1977. 14. Ward HN: Pulmonary infiltrates associated with leukoagghltinin transfusion reactions. Ann Intern Med 73: 689,
IGO.
ti. Gilbert R. Auchincloss JH, Kuppinger M, et al.: The arterial-alveolar oxygen partial pressure difference (A-aD02) and the arterial/alveolar oxygen partial pressure ratio (a/APOz). Am Rev Respir Dis 117: 2, 1978. 7. Green, RA. Nichols NJ: Pulmonary involvement in leukemia. Am Rev Respir Dis 80: 833,1959.. 8. Klatte EC, Yardley J, Smith EB, et al.: The pulmonary manifcstations and complications of leukemia. Am J Roentgen01 89: 598, 1963. 9. Nathan DJ, Sanders M: Manifestations of acute leukemia in the parenchyma of the lung. N Engl J Med 252: 797, 1955. IO. Green RA. Nichols NJ, King EJ: Alveolar-capillary block due
15. Steinberg MH, Charm SE: Effect of high concentrations of leukocytes on whole blood viscosity. Blood 38: 299.1971. 16. Lichtman MA: Rheology of leukocytes, leukocyte suspensions and blood in leukemia. J Clin Invest 52: 350.,1973. 17. Schwartz JH. Canellos GP: Hydroxyurea in the management of the hematologic complications of chronic granulocytic leukemia. Blood 46: 11.1975. 18. Grund FM, Armitage JO, Burns P: Hydroxyurea in the prevention of the effects of leukostasis in acute leukemia. Arch Intern Mcd 137: 1246,1977. 19. Preston FE, Sokol RJ, Lilleyman JS. et al.: Cellular hyperviscosity as a cause of neurological symptoms in leukemia. Br Med J 1: 476,1978.
October 1979
The American Journal of Medicine
Volume 67
683
ROBERT BLOOM, M.D.* ANGELO M. ‘I’AVEIRA DA SILVA, M.D. AR’I’HI JR BRACEY. M.D. 12’clsl,lngton.I).(:.
From the Department of Medicine and the Department of Pathology. Georgetown University School of Medicine, Washington, D.C. Requests for reprints should be addressed to Dr. Angelo M. T,lvcira Da Silva, Pulmonary Disease Division, Georgetown University Hospital, Washington, D.C. 20007. Manuscript accepted April 13,1979. * Present address: 7 Corners Professional Building, 6319 Castle Place, Falls Church. Virginia 22044.
In a 49 year old man with blast crisis and massive leukocytosis due to chronic myelogenous leukemia, severe hypoxic respiratory failure developed despite a normal chest film. Correction of hypoxemia was observed after reduction of the white blood cell count by hydroxyurea therapy. A similar episode occurred prior to death, and necropsy examination revealed extensive plugging of the pulmonary vasculature by leukemic blast cells but no infection or pulmonary edema. An inverse linear correlation was demonstrated between the peripheral white blood cell count and the efficiency of oxygen transfer in the lung as determined by the arterial to alveolar oxygen tension ratio. We postulate that mechanical obstruction and/or leukocyte mediated capillary endothelial injury caused the severe hypoxemia. Abnormalities of pulmonary gas exchange may be common in leukemic patients with markedly increased leukocyte counts. Intravascular aggregates of leukocytes occur frequently in acute or chronic granulocytic leukemia when the peripheral white blood cell count exceeds 50,00O/mm” and almost invariably with a Mshite blood cell count greater than 200,00O/mm~~ [l]. Obstruction to flow in small blood vessels may cause central nervous system hemorrhages [2] or cardiopulmonary dysfunction [3,4]. Although dyspnea has been described in the majority of patients in whom death was attributed to intravascular leukostasis, data relating to alterations in lung function are scanty [1,4]. We have recently treated a patient in the blast phase of chronic myclogenous leukemia who manifested coma and respiratory failure due to leukostasis. Treatment with high doses of hydroxyurca resulted in a dramatic reduction of the patient’s white blood cell count with a concomitant correction of respiratory and neurologic abnormalities. An inverse correlation was observed between changes in the leukocyte count and gas exchange in the lung during two episodes of acute rospiratory failure. CASE REPORT A 4;) year old white man was admitted
to Georgetown Onivcrsity Hospital (GrJHj on May 17. 1977, with seizures. In 1973. the diagnosis 01 chronic myelogenous leukemia was made and therapy with Myleran@ \yas started. In
October 1979
The American
Journal of Medicine
Volume 67
679
REVERSIBLE RESPIRATORY FAILURE IN CHRONIC MYELOGENOUS LEUKEMIA-BLOOM
Figure 1. Chest roentgenogram taken on May 23, 1977 showing no evidence of parenchymal lung disease. June 1976, he was readmitted to GUH with headaches, vomiting and lethargy, and a right subdural hematoma was evacuated. Despite hydroxyurea therapy, over the next six months an increase in the white blood cell count was noted. In February 1977. a bone marrow examination showed greater than 50 per cent blast forms whereas the peripheral white blaod cell count was 69,000/mm3 with 14 per cent blast forms. Two weeks prior to admission the patient noted persistent headaches. Left-sided seizures with loss of consciousness develoned on the dav of admission. Hydroxyurea therapy was discontinued. Physical examination revealed a middle-aged man who was lethargic but awake. There was bilateral papilledema with hemorrhage in the left retina. Examination of the heart and lungs disclosed no abnormalities. The white blood cell count was 175,000/mm3 with 28 per cent blast forms, the hematocrit value was 29 ner cent and the ulatelet count 70.000/mm3. A computerized axial tomographic scan and a cerebral arteriogram showed a I.5 cm lesion in the right parietal area. At craniotomy, a leukemic mass was found and resected. In the postoperative period, the patient was febrile with temperatures to 39%. but the chest roentgenogram remained within normal limits (see Figure 1). On the third postoperative day, progressive hypoxemia developed and endotracheal intubation followed by mechanical ventilation and positive end-expiratory pressure (PEEP) were begun. The white blood cell count was noted to be 264,00O/mm” with 50 per cent blast forms. Hydroxyurea therapy was restarted, and the dosage rapidly increased to 4 g/day. The patient remained on the respirator requiring inspired oxygen concentrations (FlO,) of 50 to 80 per cent in order to maintain an arterial oxygen partial pressure (PaOz) of 60 to 90 mm Hg. The administration of cephazolin and gentamicin was begun, but multiple cultures of blood, sputum and urine were negative for pathogens. Repeated chest films failed to show the presence of pulmonary infiltrates. On the eighth postoperative day, the white blood cell count dropped below lO0,00O/mms; on the following day it was
680
October 1979
The American
Journal
of Medicine
ET AL
27.000/mm3. At the same time his oxygenation improved allowing him to be weaned off the respirator and extubated. He was maintained on a 35 per cent F102 Venturi mask with adequate arterial blood gases. He regained consciousness, and physical examination revealed no neurologic impairment. He was discharged during his ninth hospital week in stable condition with a white blood cell count of 42,000/mm3 and normal arterial blood gases. The patient was readmitted to GUH on August 8,1977, with upper gastrointestinal bleeding. Physical examination disclosed no abnormalities. White blood cell count was 163.000/mm3 with 40 per cent blast forms. Vincristine, 2 mg, was given intravenously, and the administration of 80 mg of prednisone/day was begun. Hydroxyurea was continued at a dose of I g/day. On the 14th hospital day, the patient became lethargic and a lumbar puncture demonstrated xanthochromic spinal fluid. The white blood cell count was 306,000/mm3 with 90 per cent blast forms and the PaOz was 50 mm Hg on 60 per cent FlOs. The chest roentgenogram was within normal limits. Nafcillin, gentamicin and carbenicillin were administered and an additional 1.5 g of hydroxyurea was given. On the 16th hospital day, the patient was intubated and started on mechanical ventilation and PEEP. Arterial blood gases showed a Pa02 of 95 mm Hg on 100 per cent FlOz. Arterial blood gases obtained 8 hours later, however, showed a PaOz of I70 mm Hg on 80 per cent FlOz and the patient was then maintained on an FlOs of 50 per cent with adequate arterial blood gases. A repeat white blood cell count obtained simultaneously with the latter arterial blood gas showed a decrease in the white blood cell count to 118,000/mm3. Blood cultures grew Staphylococcus aureus. Despite supportive therapy, the patient remained comatose and died on the 17th hospital day. METHODS Arterial blood was collected into heparin coated 3 cc plastic syringes and then immediately placed on wet-ice. Air bubbles present in the syringe after the collection of the blood samples were eliminated and the syringes promptly capped. Blood gases and pH were measured with a blood gas analyzer (IL 213, Instrumentation Laboratories Inc., Lexington, Massachusetts] within 15 minutes of collecting the arterial blood samples. The blood gas analyzer was calibrated daily by means of a tonometric technique. In addition, calibration prior to the actual measurements with solutions and gases of known composition was always performed. Oxygen exchange in the lungs was assessed by means of the arterial to alveolar oxygen tension ratio (a:APOs). This index of oxygen transfer is calculated by dividing the arterial PaOz by the alveolar oxygen tension (PAOz). The PA02 was calculated from the simplified alveolar air equation assuming a respiratory quotient of 0.8. PA02 = FlOz (PB-47) X PaC02/0.8 where PB is the barometric pressure in millimeters of mercury and PaGO is the partial pressure of carbon dioxide in the arterial blood. The normal value for the a:APOz is approximately 0.8 with only small variations due to changes in F102. A decrease of this ratio below 0.8 indicates impairment of oxygen transfer in the lung [5,6]. The correlation between the leukocyte count and the a:AP02 ratio was evaluated by means of linear regression analysis. The line of best fit was determined by the least squares method.
Volume
67
REVERSIBLE
RESPIRATORY
FAILURE
The statistical significance of the correlation coefficient was
evaluated by means of the t test. RESULTS Necropsy examination showed infiltration of lymph nodes, liver, spleen and brain by leukemic cells. The lungs weighed 500 g each. There was no evidence of pulmonary edema or infection. The pulmonary vascular bed was extensively obliterated by leukemic cells (Figure 2). Areas of infarction with alveolar hemorrhage were seen adjacent to obliterated vessels. There were no morphologic abnormalities of the bronchi and bronchioli and the alveolar walls and spaces had normal appearance. No inclusion bodies were seen. Lung tissue cultures for bacteria, fungi and virus were negative. Leukocyte counts and a:APOs ratios throughout both hospitalizations are shown in Figure 3. A high white blood cell count was almost always accompanied by a low a:APOZ ratio. When the white blood cell count was above 180,000 the a:AP02 ratio was less than 0.5, representing severe impairment in gas exchange. After initiation of high dose hydroxyurea therapy, the white blood cell count decreased and the a:AP02 ratio increased towards normal. In Figure 4, the peripheral white blood cell count was plotted against the a:AP02 ratio. The correlation coefficient is -0.82. This correlation is highly significant (P
IN CHRONIC
MYELOGENOUS
LEUKEMIA--BL.OOM
ET AL.
myelocytic leukemia [7,8]. The presence of infiltrates is often clinically undetectable and does not correlate with the total white blood cell count [8,9]. In contrast, intravascular leukostasis occurs most frequently in granulocytic leukemia in association with circulating myeloblasts and marked leukocytosis [l]. It is frequently accompanied by dyspnea. hypoxemia and right ventricular failure in the presence of a normal chest roentgenogram. In a recent autopsy series, this complication was implicated as the cause of death in 31 of 50 patients with myelogenous leukemia, most of whom had white blood cell counts exceeding 100,000/mm3
[Il. Detailed physiologic data have not been obtained in patients with leukemic infiltrates or intravascular leukostasis. Green et al. [lo] reported alveolocapillary block with a PaOz of 42 mm Hg in a patient with chronic lymphocytic leukemia; necropsy examination revealed infiltration of alveolar septums with leukemic cells. Resnick et al. [3], demonstrated arterial hypoxemia and restrictive lung disease in a patient with acute monocytic leukemia. Although postmortem examination revealed septal infiltration and clogging of the lung capillaries with blast cells, the peripheral white blood cell count was not determined at the time pulmonary function tests were performed. Two recent cases of intravascular leukostasis with arterial hypoxemia have been reported [4]. However, we are unaware of prior sequential studies of pulmonary function in patients undergoing treatment for the leukostasis syndrome. In the patient in this report hypoxemic respiratory failure developed twice in the presence of a white blood cell count greater than 25O,OOO/mm” with more than 50 per cent myeloblasts. During the first episode, the di-
Figure 2. This low power photomicrograph of a pulmonary artery branch demonstrates engorgement of the vessel by leukemic blast forms. This was a characteristic feature of many pulmonary arteries studied. Note that the majority of the alveolar spaces in this field are free of leukemic cells. Hematoxylin and eosin stain, magnification X 25, reduced by 36 per cent.
October
1979
The American Journal of Medicine
Volume 67
661
REVERSIBLE RESPIRATORY FAILURE IN CHRONIC MYELOGENOUS
LEUKEMIA-BLOOM
ET AL.
Respirator
I
Respirator
I
260
220
100
60 Hydroxyurea
4g Q O+
20 1 5119
2
3
4
5
6 8123 Hospital
Days
:igure 3. Daily changes in leukocyte count and a:AP02 ratio. A high leukocyte count is accompanied by a low a:AP02 ratio reflecting impaiied oxygen exchange in the lung. Vertical lines denote tests obtained simultaneously; other paired data were obtained no more than 3 hours apart.
a I A PO2 ratio: 0 Patient on respirator o Patient breathing spontaneously r - -0.82 p < .DDl I
I
I
I
I
20
40
60
80
100
I
I
120 140
I
I
180
I
I
220
I
I
I
260
I
1
300
WBC x 103
Figure 4. Correlation between leukocyte these two variables is highly significant.
682
October 1979
The American
Journal of Medicine
count and a:AP02 ratio. The correlation
Volume 67
between
REVERSIBLE RESPIRATORY FAILURE IN
agnosis of pulmonary leukostasis was based on systematic exclusion of other causes of respiratory failure. There was no evidence of aspiration of gastric content, fluid overload or increased intracranial pressure. Bacterial, fungal and viral cultures were negative. The chest film rema‘ined within normal limits. Although this patient was at an increased risk for the development of opportunistic lung infections, it would be unlikely for such pathogens to cause catastrophic respiratory failure with a persistently normal chest film. The diagnosis of leukostasis is further supported by rapid improvement in the a:AP02 ratio in concert with a decrease in the white blood cell count (Figure 3). When respiratory failure occurred preterminally in association with a massive increase in the white blood cell count, bacteremia and intracranial bleeding were also present. However, at necropsy, the lungs revealed only intravascular leukostasis, pulmonary infarctions and minimal interstitial edema. Leukocytes may cause abnormalities of lung function in several ways. Leukocyte proteases may damage capillary endothelium in the presence of immunoglobulins, endotoxin or complement [ll]. Complement-mediated intrapulmonary sequestration of leukocytes may contribute to abnormalities of oxygenation that are often noted in patients undergoing hemodialysis [12,13]. In addition, the presence of leukoagglutinins in transfused blood may cause aggregation of white cells in the lung and lead to a noncardiogenic form of pulmonary edema [la]. Capillary endothelial damage due to the release of lcukocytc proteases or complement activation cannot be unequivocally excluded as the cause of respiratory
CHRONIC
MYELOGENOIJS LEIIKEMlA~-RL?)OM ET AL.
failure in this patient. However, the absence of pulmonary edema on chest roentgenograms and in tissue specimens, and the relatively low weight of the lungs at necropsy (1,000 g) do not support that explanation. In this patient, massive plugging of the pulmonary arteries and arterioles with blast cells was present, and a significant inverse linear correlation was observed between the peripheral white blood cell count and oxygen transfer (Figure 4). This implies that the pulmonary vascular bed was progressively compromised by leukocyte aggregates as the peripheral white cell count increased. This hypothesis is supported by studies demonstrating that myeloblasts are large rigid cells with abnormal surface properties and viscosity that predispose them to adhere to capillary endothelium and cause intravascular obstruction [15,16]. These intravascular aggregates must also be capable of rapid dissolution, since gas exchange improved within hours after a decrease in the number of circulating leukocytes. We conclude that intravascular leukostasis must be considered a cause of respiratory failure in patients with acute or chronic myelogenous leukemia and white blood cell counts greater than 100,000/mm3, particularly when roentgenographic changes are minimal. Vigorous measures to lower the white blood cell count using chemotherapy or leukophoresis [17-191 may cause rapid, although temporary, reversal of this complication. In view of the inverse correlation between the white blood cell count and pulmonary oxygen transfer observed in this patient, one can speculate that in leukemic patients abnormalities of gas exchange may commonly occur as the leukocyte count increases, even though overt symptoms are absent.
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McKee LC, Collins RD: Intravascular leukocyte thrombi and aggregates as a cause of morbidity and mortality in leukemia. Medicine (Baltimore) 53: 463, 1974. Frcireich EJ. Thomas LB, Frei E III. et al.: A distinctive type of intraccrcbral hemorrhage associated with a “blastic crisis” in patients with leukemia. Cancer 13: 146, 1960. Resnick ME, Berkowitz RD, Rodman T: Diffuse interstitial leukemic infiltration of the lungs producing the alveolarcapillary block syndrome. Am ] Med 31: 149, 1961. Lokich JJ, Moloney WC: Fatal pulmonary leukostasis following treatment in acute mveloaenous leukemia. Arch InternMed 130: 759,1972. . (:ilbcrt R, Keighley JF: The arterial alveolar oxygen tension ratio: an index of gas exchange applicable to varying instjired oxvycn concentrations. Am Rev ResDir Dis 109: 142. i974.
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to leukemic infiltration of the lung. .4m Rev Respir Dis 130: 895,1959. ‘Il. Report of National Heart, Lung, and Blood Institute Division of Lung Diseases. Workshop on mechanisms of acute respiratory failure, DHEW Publication No (NIH) 77-981. p 3. 12. Craddock PR. Fehr J, Brigham KL, et al.: Complement and leukocyte-mediated pulmonary disfunction in hemodialysis. N Engl J Med 296: 769, 1977. 13. Craddock PR. Hammerschmidt D, White JG. et al.: Complemcnt (C5a)-induced granulocvtc aggregation in vitro. A possible mechanism Gf complemen~~me&ated leukostasis and leukopcnia. J Chn Invest 60: 260. 1977. 14. Ward HN: Pulmonary infiltrates associated with leukoagghltinin transfusion reactions. Ann Intern Med 73: 689,
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ti. Gilbert R. Auchincloss JH, Kuppinger M, et al.: The arterial-alveolar oxygen partial pressure difference (A-aD02) and the arterial/alveolar oxygen partial pressure ratio (a/APOz). Am Rev Respir Dis 117: 2, 1978. 7. Green, RA. Nichols NJ: Pulmonary involvement in leukemia. Am Rev Respir Dis 80: 833,1959.. 8. Klatte EC, Yardley J, Smith EB, et al.: The pulmonary manifcstations and complications of leukemia. Am J Roentgen01 89: 598, 1963. 9. Nathan DJ, Sanders M: Manifestations of acute leukemia in the parenchyma of the lung. N Engl J Med 252: 797, 1955. IO. Green RA. Nichols NJ, King EJ: Alveolar-capillary block due
15. Steinberg MH, Charm SE: Effect of high concentrations of leukocytes on whole blood viscosity. Blood 38: 299.1971. 16. Lichtman MA: Rheology of leukocytes, leukocyte suspensions and blood in leukemia. J Clin Invest 52: 350.,1973. 17. Schwartz JH. Canellos GP: Hydroxyurea in the management of the hematologic complications of chronic granulocytic leukemia. Blood 46: 11.1975. 18. Grund FM, Armitage JO, Burns P: Hydroxyurea in the prevention of the effects of leukostasis in acute leukemia. Arch Intern Mcd 137: 1246,1977. 19. Preston FE, Sokol RJ, Lilleyman JS. et al.: Cellular hyperviscosity as a cause of neurological symptoms in leukemia. Br Med J 1: 476,1978.
October 1979
The American Journal of Medicine
Volume 67
683