Explanation for apparent hypoxemia associated with extreme leukocytosis: leukocytic oxygen consumption

We investigated the hypoxemia associated with extreme leukocytosis in leukemic patients. In vitro experiments showed that the rate of decrease in the partial pressure of oxygen in the blood samples from such patients was proportional to the white cell count. In the presence of normal white cell count no drop in PO2 was observed. We conclude that a low arterial oxygen tension in the presence of extreme leukocytosis reflects oxygen consumption by leukocytes rather than true hypoxemia. Both normal as well as leukemic leukocytes appear to exhibit this phenomenon.     

Deterioration of oxygenation and abnormal lung microvascular permeability during resolution of leukopenia in patients with diffuse lung injury

To determine whether circulating leukocytes contribute to gas exchange abnormalities in diffuse lung injury, we retrospectively examined oxygenation in 6 patients who met 3 criteria: leukopenia caused by marrow aplasia from remission-inducing chemotherapy for myelogenous leukemia, the eventual resolution of leukopenia, and concurrent acute respiratory failure diagnosed clinically as increased permeability pulmonary edema. Four of the 6 patients abruptly developed overt clinical evidence of pulmonary dysfunction within the 96 h preceding the resolution of the peripheral leukopenia. In all 6 patients, the alveolar to arterial oxygen tension difference increased between leukocyte counts. The mean value for the alveolar to arterial oxygen tension difference for the group doubled during this period (148 +/- 37 mmHg 3 days prior to resolution; 290 +/- 37 mmHg 1 day after resolution; p less than 0.05). As an index of lung capillary permeability, we measured the lung permeability-surface area product for urea (PSu) for an additional patient with oxygen toxicity and drug-induced leukopenia whose hypoxemia increased immediately before the resolution of leukopenia. The PSu in this patient was high, in the range previously reported as being highly specific for increased permeability pulmonary edema with a fatal outcome. We conclude that such diffuse lung injury resembling the adult respiratory distress syndrome can occur in leukopenic patients, but the resolution of leukopenia in such patients may be associated with worsening oxygenation and with abnormally high pulmonary microvascular permeability. These observations do not prove a causal relationship but provide a clinical parallel to several leukocyte-depletion studies reported in animal models of increased permeability pulmonary edema that implicate white blood cells in the pathogenesis of hypoxemia and lung edema.     

Leukocyte larceny: a cause of spurious hypoxemia.

Multiple blood specimens with different leukocyte counts from two patients with extreme leukocytosis secondary to leukemia and unexplained hypoxemia were tonometered with a gas of known oxygen concentration and the decay of oxygen tension (PO2) was measured over time. The decay in PO2 in the first 2 minutes for blood with leukocyte counts of between 55.2 X 10(3)/mm3 and 490.0 X 10(3)/mm3 ranged from 13 to 72 torr. The degree of PO2 decay was blunted by placing the blood on ice and was obliterated by adding potassium cyanide. Thus, extreme leukocytosis secondary to leukemia can cause spurious hypoxemia and spurious lowering of the mixed venous PO2 due to oxygen consumption by leukocytes ("leukocyte larceny").     

Management of life-threatening pulmonary leukostasis with single agent imatinib mesylate during CML myeloid blast crisis

Pulmonary leukostasis is a rare but serious and often fatal complication of chronic myeloid leukemia (CML) in blast crisis and acute myeloid leukemia. Treatment options are limited for these patients. Imatinib mesylate (STI-571, Gleevec, Novartis) is a potent and selective inhibitor of the BCR-abl tyrosine kinase, the molecular abnormality that causes CML. The case of a 74-year-old man with a history of CML who presented in myeloid blast crisis with pulmonary leukostasis characterized by increasing dyspnea, hypoxemia, fever, and impending respiratory failure is reported. The patient was treated with single agent imatinib mesylate (IM) with rapid decrease in his white blood cell count (WBC) and marked improvement in his respiratory status. No electrolyte abnormalities consistent with tumor lysis syndrome were observed. IM may be an effective single agent therapy for pulmonary leukostasis in patients with CML blast crisis who are at the risk for tumor lysis.     

A new observation in the clinical spectrums of erythroleukemia. A report of 46 cases.

Erythroleukemia is a disease manifested by an abnormal proliferation of erythroid and myeloid precursors, generally consisting of a primary erythroid phase (chronic erythemic myelosis), a transition phase involving erythroid and myeloid precursors (erythroleukemia) and, finally, the purely myeloblastic (acute myeloblastic leukemia) phase. The experience at Memorial Sloan-Kettering Cancer Center is reported. Presenting signs and symptoms are consistent with prior reports. The chemotherapy results in the past have been poor; because of the poor results, chemotherapy is started only if one of the following criteria are present: (1) frequent transfusion requirements; (2) rapidly increasing peripheral white blood cell count or percentage of leukemic blast forms; (3) frequent recurrent infectious and/or hemorrhagic complications. A hitherto unrecognized association of erythroleukemia and symptomatic rheumatic disease and numerous immunologic abberations are reported. The symptoms related to this rheumatic disorder do not seem to be relieved by therapy directed at the leukemic process, but rather by the use of simple anti-inflammatory agents.     

Dialysis hypoxemia. Role of dialyzer membrane and dialysate delivery system

Arterial blood gas values, carbon monoxide diffusion capacity, oxygen consumption, carbon dioxide production, respiratory quotient, minute ventilation, and pulmonary capillary blood flow were determined before and during hemodialysis. In addition, the effect of single passage through the dialyzer on blood carbon dioxide tension, pH, and bicarbonate concentration was evaluated. Acetate-based dialysate was used in all experiments. Cellulosic dialyzer with single-pass dialysate delivery system was used in one group, and polyacrylonitrile dialyzers with recirculating delivery system in another. Although hypoxemia occurred in both groups, it was more severe in the former group. Dialyzer carbon dioxide loss was significantly greater with single-pass dialysate delivery system and cellulosic dialyzers than with recirculating delivery system and polyacrylonitrile dialyzer. To differentiate the role of dialysate delivery system from that of the membrane, the experiments were repeated using recirculating delivery system and cellulosic dialyzer. This resulted in marked attenuation of hypoxemia and dialyzer carbon dioxide tension losses. Since other experimental conditions were the same, the observed differences were thought to be due to the difference in the mode of dialysate delivery. It thus appears that the mode of dialysate delivery per se can modify the changes in arterial oxygen tension during hemodialysis and should be added to the list of factors implicated in the genesis of dialysis hypoxemia.     

Lung function in children with sickle cell anemia.

Lung volumes and expiratory flows were measured in 12 children with sickle cell anemia and 12 height-matched black control subjects. Diffusing capacity of the lung for CO, pulmonary capillary blood volume, the membrane component of diffusing capacity, arterial blood gases on breathing room air and 100 per cent O2 were measured in the subjects with sickle cell anemia. The lung volumes and expiratory flows of subjects with sickle cell anemia were no different from those of the control subjects. Diffusing capacity for CO was maintined in the noraml range despite the severe anemia by increases in pulmonary capillary blood volume and the membrane component of diffusing capacity. All subjects with sickle cell anemia had mild hypoxemia and abnormal increases in calculated shunt. Pulmonary function in children with sickle cell anemia appears to be determined by their race and anemia.     

Metabolic and therapeutic studies of a patient with acute leukemia and severe lactic acidosis of prolonged duration

A young man with acute nonlymphocytic leukemia had severe lactic acidosis for 11 months from the time of diagnosis until shortly before death except for a period of 3 weeks during which his leukemia was in complete remission. Severe respiratory alkalosis followed that brief remission. The clearance rate of neither fructose nor lactate from the blood was abnormal, but the clearance of blood glucose was accelerated. These data suggest that elevated blood lactate levels resulted from an overproduction of lactate from glucose. In vitro peripheral blood leukocyte incubation failed to demonstrate increased lactate production by these cells. However, the severity of acidosis correlated with peripheral white cell counts and with the percentage of blast forms in bone marrow aspirates obtained serially throughout the patient's course. These studies suggest that marrow leukemic cells or leukemic cells infiltrating parenchymal organs such as the liver may be responsible for the excess production of lactate. Despite arterial lactate concentrations as great as 42 meq/liter, the patient was ambulatory and felt well when given enough alkali to maintain a near normal arterial pH. When the requirement for sodium bicarbonate reached 2,400 meq/day intravenously, oral sodium and potassium acetate therapy was better tolerated and found to be at least equally as effective. Such therapy allows the patient to be mobile and represents an advance in the therapy of lactic acidosis in the conscious patient.     

Renal artery stenosis, pheochromocytoma and erythrocytosis

We present a patient with renal artery stenosis, pheochromocytoma and erythrocytosis. Erythrocytosis preceded the history of hypertension by five to six years and was characterized by an increased red blood cell mass. The plasma volume was normal, as were the white blood cell count, reticulocyte count, platelet count, pulmonary function studies and leukocyte alkaline phosphatase. Erythropoietin assays were negative on blood and urine.     

Recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes--a phase I/II trial

In a phase I/II study, 11 patients with myelodysplastic syndromes (MDS) and severe transfusion-dependent cytopenia were treated with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to investigate the effects of rhGM-CSF on normal hematopoiesis and leukemic cells. The treatment schedule included dose escalation from 15 micrograms/m2 to 150 micrograms/m2 administered by continuous intravenous (IV) infusion for seven to 14 days and was repeated after a two-week treatment-free interval. The blood leukocyte counts increased dose dependently by 130% to 1,800% in ten patients; a rise of monocytes and eosinophils occurred in seven and six patients, respectively. No sustained increase in reticulocytes or platelets was observed. Lymphocyte counts increased in all patients affecting both T- helper and T-suppressor cells; however, the lymphocytes were not activated as analyzed by the expression of the interleukin-2 receptor. In four of the patients, all with greater than 14% blast cells in the bone marrow, the percentage of bone marrow blast cells increased during treatment with rhGM-CSF. Cytogenetic data indicated induction of both proliferation and differentiation of the leukemic clones by rhGM-CSF. Toxic side effects were minor with slight fever, phlebitis at the infusion site, and bone pain in the minority of patients. In conclusion, rhGM-CSF effectively stimulates hematopoiesis in vivo in patients with myelodysplastic syndromes. However, as the leukemic cell population can be stimulated in patients with a higher initial blast cell count, the combination of rhGM-CSF with other differentiation- inducing or cytotoxic agents has to be considered.     

吸入一氧化氮对犬烟雾吸入性损伤肺组织ACE活性的影响

血管紧张素转换酶（ACE）已作为肺毛细血管内皮细胞受损的指示性指标，本研究旨在评价吸入一氧化氮（NO）对吸入性损伤后肺血管内皮细胞的影响。用21只犬随机分为3组，烟雾吸入后，吸氧组（n=8）单纯吸氧（FiO2，0．45）；NO治疗组（n=9）吸氧（FiO2，0．45）＋0．0045％（45PPm）NO，连续监测12小时动脉血ACE活性变化；正常组（n＝4）不致伤，用于建立组织学对照。动脉血数据行多个样本均数间方差分析，支气管肺泡灌洗液（BALF）和肺组织ACE活性行两样本均数t检验。结果治疗组血浆ACE活性比对照组降低（P＜0．05）；BALF和肺组织中，治疗组ACE活性也明显低于对照组（P＜0．01）。吸入NO对犬烟雾吸入性损伤肺毛细血管内皮细胞有一定减轻损害作用。     

Prostaglandin E1 prevents increased lung microvascular permeability during intravascular complement activation in sheep

Prostaglandin E1 (PGE1) inhibits a variety of functions of activated neutrophils including respiratory burst, release of leukotriene B4, and adherence to endothelial cells. To determine if PGE, alters the pathophysiology of complement-induced lung vascular injury, experiments were conducted in anesthetized sheep with lung lymph fistulas given a 1-hour infusion of zymosan-activated plasma. PGE1 (30 ng/min/kg) or its saline vehicle was infused intravenously for 90 minutes beginning 30 minutes before the infusion of activated plasma. PGE1 had no effect on leukocyte count, the initial hypoxemia and thromboxane A2 release, or the development of acute pulmonary hypertension. However, PGE1 prevented steady-state increases in lung lymph flow that in vehicle-treated sheep signaled an increase in lung microvascular permeability. Furthermore, extraction of PGE1 by pulmonary endothelial cells was unaffected by the infusion of activated plasma. We propose that PGE1 prevented the increase in lung vascular permeability by inhibiting adherence of activated neutrophils to endothelial cells.     

Oxygen and resolution of lung injury

We investigated the effects of varying inspired oxygen concentrations on the resolution of oleic acid-induced lung injury in rabbits. Rabbits were injected intravenously with oleic acid and maintained in room air, or exposed to 60, 70, or 80% oxygen for periods of 7 or 10 days. Oleic acid caused hemorrhagic pulmonary edema with hypoxemia. Hypoxemia was more profound in the oxygen-treated animals, a difference that was significant after 7 days' exposure to 60 and 70% oxygen, and after 4 days to 80% oxygen. Mortality was increased in the animals maintained in 80% oxygen. The data suggest that environmental oxygen concentrations greater than 60% interfere with the return to normal lung function following oleic acid injury in rabbits. The hypoxemia may be due to either mismatching of ventilation and perfusion or to a diffusion block resulting from the increased septal width. There was no evidence of massive pulmonary edema as a cause of the hypoxemia. It was not possible to distinguish between injury primarily caused by oxygen and its interference with the healing process.     

Leukocyte count is associated with reduced endothelial reactivity

BACKGROUND: Leukocyte count has been associated with cardiovascular and cerebrovascular disease in several studies. We hypothesized that white blood cell count is associated with endothelial reactivity. METHODS AND RESULTS: Leukocyte count was measured in a sample of stroke-free community participants undergoing brachial artery testing for endothelial reactivity. Flow-mediated dilation (FMD) during reactive hyperemia was assessed in each subject using high-resolution B-mode ultrasound. Multivariate linear regression was used to calculate the effect of leukocyte count on endothelial reactivity after adjusting for potential confounding factors. Mean age of the 868 participants was 66.7+/-8.8 years; 57% were women. Mean leukocyte count was (6.1+/-1.8)x10(9)/L. Each unit increase in leukocyte count was associated with a mean 0.18% decrease in FMD (p = 0.01). After adjusting for other atherosclerosis risk factors, including age, sex, hypertension, diabetes, hyperlipidemia, and smoking, the relationship persisted (mean decrease in FMD per unit leukocyte count = 0.17%, p = 0.02). There was a linear decrease in FMD by quartile of leukocyte count (p = 0.0014). The effect of leukocyte count on FMD was greater for women, those under age 70, and non-diabetics. CONCLUSIONS: Relative elevations in leukocyte count are associated with a reduction in brachial artery endothelial reactivity. These findings are consistent with current hypotheses regarding the inflammatory or infectious etiology of risk of atherosclerosis and stroke, but also suggest interactions with demographic and other risk factors.     

Cytarabine and thioguanine for acute nonlymphocytic leukemia. Another look.

A modification of the protocol of cytarabine and thioguanine was used for remission induction in patients with acute nonlymphocytic leukemia. First, synchronization of the mitotically active leukemia cells was attempted by administering cytarabine alone in a dose of 5 mg/kg of body weight 24 hours prior to initiating daily therapy with both drugs. Second, in order to recover dormant leukemic cells into the proliferative pool, both drugs were continued without interruption and without regard to the suppression of the circulating leukocyte and platelet count until bone marrow aspirates, repeated daily if necessary, were free of leukemic blast cells. This usually resulted in severe but reversible bone marrow hypoplasia, and 16 of 21 patients (76%) so treated achieved complete hematologic remission.     

Pulmonary angiotensin-converting enzyme activity in the oxygen-toxic sheep

Despite the potential utility of endothelial metabolic substrates for the early clinical detection of acute lung injury, the relationship between lung capillary injury and pulmonary endothelial metabolic function remains incompletely understood. Previous studies have shown that lung capillaries are damaged by oxygen toxicity in the sheep; however, metabolic functions of the pulmonary endothelium have not been examined in this otherwise well-characterized animal model of lung injury. Therefore, we studied the activity of pulmonary endothelial angiotensin-converting enzyme (ACE) in five unanesthetized adult sheep that breathed 100% O2 via tracheostomy for 3 days and in four other sheep that breathed compressed air. In contrast to the sheep that breathed air, the sheep that breathed O2 developed substantial arterial hypoxemia and hypercapnia, an increased alveolar-to-arterial O2 gradient and a slight respiratory acidosis. Morphological examination of lungs from sheep that breathed O2 revealed a multifocal distribution of injury, including interstitial edema, capillary endothelial damage, and alveolar epithelial damage. Indicator-dilution methods were used to assess first-pass pulmonary metabolism of the ACE substrate [3H]Benzoyl-Phe-Ala-Pro (BPAP) and the apparent kinetics (KM and Vmax) of ACE activity. Pulmonary metabolism of BPAP exhibited saturability, was reduced by an ACE inhibitor (enalaprit), and did not result from the activity of circulating plasma ACE. There was no difference between the 2 groups of sheep in the percent metabolism of either 0.1 mumol BPAP/kg or 1.0 mumol BPAP/kg or in the KM of BPAP metabolism. In both groups, the Vmax and Vmax/KM decreased as a result of reductions in cardiac output and volume distribution.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relation between hemodynamic and ventilatory responses in determining exercise capacity in severe congestive heart failure

The cause of exercise intolerance in congestive heart failure is unclear. Hemodynamic and ventilatory responses were measured during symptomatic maximal upright bicycle exercise in 28 patients with chronic severe left ventricular failure who achieved a maximal oxygen uptake of only 12 +/- 4 ml/min/kg (+/- standard deviation). All patients reached anaerobic metabolism as the respiratory exchange ratio rose and arterial pH fell significantly. Pulmonary capillary wedge pressure increased from 20 +/- 10 mm Hg at rest to 38 +/- 9 mm Hg at peak exercise and cardiac index increased from 2.51 +/- 0.73 to 4.54 +/- 1.65 liters/min/m2 (both p less than 0.001). Systemic vascular resistance decreased, but pulmonary vascular resistance did not change during exercise. Despite the marked pulmonary venous hypertension at peak exercise, blood gases were unchanged (PaO2, 96 +/- 15 mm Hg; PaCO2, 35 +/- 7 mm Hg). Systemic arterial oxygen content increased from 16 +/- 2 to 17 +/- 2 vol% (p less than 0.01). Changes in pulmonary capillary wedge pressure did not correlate with changes in arterial oxygen content. Results were similar whether patients were limited by dyspnea or fatigue. Thus, exercise intolerance in patients with severe left ventricular failure is associated with marked elevation of pulmonary capillary wedge pressure and anaerobic metabolism without hypoxemia or altered carbon dioxide tension. These findings suggest that exercise ability in congestive heart failure is more dependent on cardiac output than on ventilatory consequences of pulmonary congestion.     

L-arginine effects on myocardial stress in cardiac surgery: preliminary results.

BACKGROUND: L-arginine in addition to cardioplegia stimulates the release of nitric oxide and increases coronary blood flow, decreasing platelet activation and leukocyte adhesion. The aim of our study was to determine the feasibility and the efficacy of the addition of L-arginine to antegrade and retrograde blood cardioplegia in reducing myocardial damage and stress. METHODS: Twenty-eight consecutive patients who underwent coronary artery bypass grafting were randomized to receive 7.5 g of L-arginine in 500 ml of cardioplegic solution. To assess safety of use of L-arginine, hemodynamic evaluation was performed before sternum opening, at sternum closure, and 1 hour after arrival in the intensive care unit to measure cardiac index, systemic and pulmonary vascular resistances, and pulmonary capillary wedge pressure. Moreover, transesophageal echocardiography was performed to assess myocardial contractility. To determine the effects on myocardial stress, blood samples were taken from the retrograde coronary sinus catheter for lactate, interleukin (IL)-2 receptor, IL-6 and tumor necrosis factor (TNF)-alpha levels. Serum samples (preoperatively, 2, 18 and 42 hours after aortic cross-clamping removal) were also analyzed to measure creatine phosphokinase, creatine kinase-MB mass, cardiac troponin T, platelets, and leukocytes. RESULTS: We found statistical differences for IL-2 receptor, IL-6, TNF-alpha, platelets and leukocytes, in favor of the treated group, and decreasing trends in creatine kinase-MB mass and troponin T levels. CONCLUSIONS: The present study shows the positive effects of the addition of L-arginine to cardioplegia. Reduced IL-2 receptor, IL-6 and TNF-alpha indicate a decrease in myocardial stress. Safety of Larginine is related to lower values of systemic vascular resistances and pulmonary capillary wedge pressure observed in group A postoperatively that could improve the patient's outcome in terms of a reduced need for inotropic support. Moreover, the decrease in platelet and leukocyte count in the treated group might express a reduced no-reflow phenomenon and a better reperfusion, limiting endothelial injury from oxygen radical production.     

Granulopoiesis in chronic myeloid leukemia. II. serial cloning of blood and bone marrow cells in agar culture.

Colony-forming cells (CFC) and CFC in S-phase were assayed in chronic myeloid leukemia (CML). A correlation was found between leukocyte counts and CFC of blood, suggesting that the leukocytosis of CML depended on expansion of the committed granulopoietic stem cell compartment. Serial studies performed in four cases demonstrated a decrease of the CFC in S-phase during early stages of developing leukocytosis, which was consistent with the operation of growth control mechanisms. During later stages, serial studies revealed that sudden increments of CFC S-phase coincided with rapidly growing leukocytosis, which was consistent with leukemic cell populations escaping growth control. H-thymidine labeling indices for differentiated precursor cells showed slight variations not coinciding with variations of the CFC S-phase fraction. Cyclic oscillations of the white cell count were observed in one case. The white cell count and the fraction of CFC in S-phase displayed a direct relationship, indicating that the occurence of cycles was not likely to be due to a negative feedback mechanism elaborated by mature granulocytes. In another case, marked cycling of the CFC S-phase fraction was found without distinct oscillations of the white cell count. The present work has emphasized the necessity for serial assays of parameters of cell kinetics in vitro in CML since changing relationships were found between stem cell and differentiated cell kinetics during different phases of the disease.     

Localized leukemic pulmonary infiltrates. Diagnosis by bronchoscopy and resolution with therapy

Although commonly found at autopsy, leukemic infiltration of the lung is rarely recognized as a cause of respiratory symptoms or roentgenographic densities. Previously reported cases of patients who had symptomatic or roentgenographic acute leukemic lung diseases invariably presented with diffuse pulmonary infiltrates. We describe three patients with leukemic involvement of the lung who presented with cough, fever, and localized roentgenographic infiltrates suggestive of bacterial pneumonia. In each case, the diagnosis was made by transbronchial biopsy specimen and confirmed by complete response to chemotherapy. In common with the other reported cases, all of our patients had peripheral blast counts above 40 percent (greater than 6,000 blasts per ml3) at the time the pulmonary diagnosis was made. Leukemic invasion of the lung should be considered in patients with acute leukemia who develop lung infiltrates--whether diffuse or focal--in association with a high peripheral blast count.