Search PubMed⌕ Search

Biomedical subjects

F L Glauser

Publications and source records attributed to F L Glauser.

At least 37 records · Page 2Linked to original sources
PubMed1989

Nonspecific cytotoxicity of recombinant interleukin-2 activated lymphocytes.

The administration of interleukin-2 (IL-2) and lymphokine activated killer (LAK) cells to patients with advanced metastatic cancer has yielded encouraging results. The purported ability of LAK cells to be discriminatively tumoricidal, thus sparing normal host tissue, represents a major advance over conventional chemotherapy. However, IL-2 adoptive immunotherapy results in dose-limiting toxicity characterized by weight gain, dyspnea, ascites, and peripheral-pulmonary edema suggestive of a vascular leak syndrome. It is unclear whether the observed toxicity is directly related to IL-2 and/or LAK cells. The authors examined the cytolytic nature of human LAK cells against human endothelial, epithelial, and fibroblast cell lines. Bovine endothelial cells also were studied. Using a 51Cr release assay, the cytolytic potential, time course, and effect of reactive oxygen intermediate inhibitors were studied. LAK cells were uniformly toxic against all cell lines, in contrast to high dose rIL-2 and excipient. Significant cytolysis was observed within 30 minutes and increased over the first 2 hours of LAK cells coming in contact with target cells. Reactive oxygen intermediate inhibitors did not reduce cytolytic activity. The authors thus found human LAK cells to be rapidly cytolytic against a variety of human and bovine cell lines. This cytolysis was independent of reactive oxygen intermediates.

Animals↗
PubMed1989

Cardiorespiratory and cellular changes with interleukin 2 infusion in sheep.

Recombinant interleukin 2 (rIL-2) administration, a new form of therapy for patients with far-advanced cancer, is associated with a "third space" syndrome, i.e., pulmonary edema, respiratory distress, and hypoxemia, which limits the dose and duration of treatment. To extend our knowledge regarding this toxicity, we established a sheep chronic lung lymph fistula model and measured hemodynamics, arterial blood gases, caudal mediastinal (lung) lymph flow (QL), and blood and lung lymph cellular changes before, during, and after (recovery) a 3-day continuous rIL-2 infusion (9 x 10(5) U/kg). Moderate systemic hypotension, mild pulmonary hypertension, and an increase in alveolar-arterial PO2 gradient was present on day 3 of rIL-2 infusion. QL increased from a base line of 1.9 +/- 0.2 to a maximum of 4.3 +/- 1.1 ml/15 min on day 3 of rIL-2 infusion. At no time was there a change in lymph-to-plasma protein ratio. The leukocyte count increased significantly to 16.1 +/- 4.5 x 10(3) cells/mm3 at recovery day 1. The percentage of blood lymphocytes decreased significantly by day 1 of rIL-2 infusion, returned to base-line levels on day 3, and significantly increased on day 2 of recovery. Lung lymph lymphocytes decreased significantly on days 1 and 2 of rIL-2 infusion. There was a shift in their size; i.e., their area increased from 32 +/- 7 to 57 +/- 19 micron 2 (P less than 0.05) by day 2 of rIL-2 infusion. By day 1 of recovery, lung lymph lymphocyte counts increased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Pulmonary response to foreign body microemboli in dogs: release of neutrophil chemoattractant activity by vascular endothelial cells.

Pulmonary hypertension and foreign body granulomas are complications of the chronic intravenous injection of crushed, suspended pentazocine (Talwin) tablets. To evaluate the early cellular mechanisms underlying the response of the lung to foreign body microemboli, we examined lung histopathology and bronchoalveolar lavage (BAL) fluid in dogs for accumulation of inflammatory cells shortly after the injection of crushed, suspended pentazocine tablets. We found that the injection of suspended pentazocine tablets is associated with the rapid accumulation of neutrophils around intravascular talc crystals but not within the alveolar airspaces. To determine the cause of the observed neutrophil accumulation, we assayed plasma and lavage fluid for neutrophil chemoattractant activity (NCA). NCA appeared in pulmonary arterial (PA) and left ventricular (LV) plasma within 60 s of injection of the suspended tablets. However, there was no evidence of NCA in BAL. To determine whether appearance of chemoattractant activity found in plasma was modified by inhibitors of arachidonic acid metabolism, we infused dogs with indomethacin, diethylcarbamazine (DEC), or FPL 55712 and assayed plasma for NCA after the injection of suspended pentazocine tablets. We found that the appearance of NCA is prevented by the infusion of either DEC or FPL 55712 but not by the infusion of indomethacin. We found that cultured pulmonary arterial or aortic endothelial cells also release NCA when incubated with either the suspended pentazocine tablets or talc. Extraction with acidified diethyl ether partitioned all the NCA into the organic phase. The release of NCA from cultured endothelial cells was likewise prevented by coincubation with DEC or FPL 55712 but not by coincubation with indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

A comparison of the cardiopulmonary effects of continuous versus bolus infusion of recombinant interleukin-2 in sheep.

The systemic administration of recombinant interleukin-2 (rIL-2) is used for the treatment of patients with far advanced cancer. However, treatment may be limited by a so-called "third space" syndrome. Whether these side effects are due to the total dose used or the method of administration is unclear. To define whether the continuous (Group 2) or bolus (Group 3) i.v. infusion of 9 x 10(5) units/kg rIL-2 over 72 h is associated with similar toxicities, we established a chronic sheep model and monitored changes in systemic and pulmonary vascular pressures, cardiac function, and gas exchange. At 72 h lung lymph flow, lymph/plasma protein ratios, lung histology, and extravascular lung water/dry lung weight were obtained. In both groups the infusion of rIL-2 resulted in an increase in high protein lung lymph flow, an increase in cardiac output, and a decrease in systemic vascular resistance. Large lymphoid cells were found by histology to be infiltrating the lung interstitium. In Group 2, in addition, there were mild pulmonary hypertension [pulmonary artery pressures increased from 14 +/- 5 to 22 +/- 6 mmHg (P less than 0.05)], systemic hypotension [81 +/- 7 compared to a baseline of 95 +/- 9 mmHg (P less than 0.01)], and worsening gas exchange. We conclude that a 72-h continuous or bolus infusion of equivalent doses of rIL-2 are associated with cardiopulmonary toxicity; however, pulmonary hypertension, systemic hypotension, and gas exchange are worse in animals receiving the continuous infusion.

Animals↗
PubMed1988

Cardiopulmonary toxicity of adoptive immunotherapy.

Adoptive immunotherapy, the administration of interleukin-2 (IL-2) and interleukin-2 activated cells, leads to tumor regression in some patients with advanced cancer. Although this new therapeutic modality offers hope for the future, at present, a multitude of toxicities limit the total dose and duration of therapy. Among the toxic side effects a purported third space or vascular leak syndrome is the most serious. In this review, we detail the evidence for a third space syndrome (peripheral edema, ascites, oliguria, elevated serum creatinine levels) and cardiopulmonary dysfunction (hypotension, respiratory distress, pulmonary edema, hypoxemia) with adoptive immunotherapy in human and animal studies. We conclude that IL-2 administration is associated with increased pulmonary microvascular permeability, infiltration of the lung parenchyma with large esterase negative lymphoid cells, hypoxemia, systemic hypotension, positive fluid balance and, in animals, transient pulmonary hypertension. These abnormalities do not seem to be caused by IL-2 directly; the causes may be mediated by IL-2 activated lymphocytes or other IL-2 activated cellular mediators.

Animals↗
PubMed1988

Cardiopulmonary effects of recombinant interleukin-2 infusion in sheep.

The systemic administration of recombinant interleukin-2 (rIL-2) with or without lymphokine-activated killer (LAK) cells, a new treatment for patients with advanced cancer, is associated with a presumed "third-space" syndrome. To further define the extent and time course of this toxicity, we established a chronic sheep model and monitored changes in systemic and central vascular pressures, cardiac function, and gas exchange during a 72-h continuous intravenous infusion of rIL-2 at a total dose of 5 (group 3) or 9 x 10(5) U/kg (group 4). At 72 h, caudal mediastinal lymph flow, histology, and extravascular lung water-to-dry lung weight ratio (EVLW/DLW) were obtained. During the rIL-2 infusion there was a dose-dependent significant decrease in systemic blood pressure and arterial Po2 and an increase in core temperature. In group 4, pulmonary arterial pressure increased from a base line of 13 +/- 5 to 21 +/- 6 mmHg (P less than 0.05). Lung lymph flow was significantly increased in groups 3 and 4 compared with animals receiving 0.9% NaCl or excipient infusions (groups 1 and 2). EVLW/DLW values were elevated in groups 3 and 4 (P less than 0.01). In animals receiving rIL-2, histological evaluation revealed a dose-dependent infiltration of lung tissue by lymphoblastoid cells that stained esterase negative. We conclude that rIL-2 infusion in doses comparable to those given to humans results in alterations in systemic and central hemodynamics, gas exchange, high-protein lung lymph flow, and infiltration of lymphoblastoid cells into the lung parenchyma.

Animals↗
PubMed1988

Effects of platelet-activating factor antagonist SRI 63-441 on endotoxemia in sheep.

We investigated whether platelet-activating factor (PAF) mediates endotoxin-induced systemic and pulmonary vascular derangements by studying the effects of a selective PAF receptor antagonist, SRI 63-441, during endotoxemia in sheep. Endotoxin infusion (1.3 micrograms/kg over 0.5 h) caused a rapid, transient rise in pulmonary arterial pressure (Ppa) from 16 +/- 3 to 36 +/- 10 mmHg (P less than 0.001) and pulmonary vascular resistance (PVR) from 187 +/- 84 to 682 +/- 340 dyn.s.cm-5 (P less than 0.05) at 0.5 h, followed by a persistent elevation in Ppa to 22 +/- 3 mmHg and in PVR to 522 +/- 285 dyn.s.cm-5 at 5 h in anesthetized sheep. Arterial PO2 (PaO2) decreased from 341 +/- 79 to 198 +/- 97 (P less than 0.01) and 202 +/- 161 Torr at 0.5 and 5 h, respectively (inspired O2 fraction = 1.0). SRI 63-441, 20 mg.kg-1.h-1 infused for 5 h, blocked the early rise in Ppa and PVR and fall in PaO2, but had no effect on the late phase pulmonary hypertension or hypoxemia. Endotoxin caused a gradual decrease in mean aortic pressure, which was unaffected by SRI 63-441. Infusion of SRI 63-441 alone caused no hemodynamic alterations. In follow-up studies, endotoxin caused an increase in lung lymph flow (QL) from 3.8 +/- 1.1 to 14.1 +/- 8.0 (P less than 0.05) and 12.7 +/- 8.6 ml/h at 1 and 4 h, respectively. SRI 63-441 abolished the early and attenuated the late increase in QL.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Worsening oxygenation in the mechanically ventilated patient. Causes, mechanisms, and early detection.

Hypoxemia or worsening oxygenation is a common problem in the ICU. Ventilator-related problems, patient-related problems, including progression of the underlying disease process or superimposed disorders, and interventions, procedures, and medications can all adversely affect the patient's oxygenation status. Each of these causes should be sought for in a rapid and expeditious manner and appropriate corrective actions taken.

Equipment Failure↗
PubMed1988

Bronchoalveolar lavage in an animal model of acute lung injury. Relationship between enhanced membrane permeability and transvascular neutrophil flux.

Results of studies utilizing bronchoalveolar lavage (BAL) have led workers to propose that the neutrophil serves as the pivotal cellular element responsible for promoting enhanced alveolar capillary membrane (ACM) permeability in certain forms of acute lung injury. The authors performed BAL on anesthetized, intubated, instrumented sheep before and after the administration of 15 mg/kg ethchlorvynol, a known pulmonary edemagenic agent. Bronchoalveolar lavage fluid (BALF) protein content increased from 0.62 +/- 0.05 to 1.5 +/- 0.15 mg/ml, and the percentage of neutrophils recovered from 2% +/- 1% at baseline to 35% +/- 7% (P less than 0.01) 60 minutes after infusion of ethchlorvynol. After ethchlorvynol infusion into neutropenic sheep (less than 500 cells/microliter), BALF protein content increased from 0.35 +/- 0.08 to 1.5 +/- 0.69 mg/ml (P less than 0.01) with no increase in BALF neutrophil count. In 3 non-neutropenic sheep BAL was performed at 15 and 30 minutes after ethchlorvynol infusion. BALF protein content increased significantly within 15 minutes, whereas the percentage of neutrophils did not change. These findings suggest coexistent ACM injury as reflected by increases in BALF protein content and increased number of neutrophils in BALF does not necessarily imply a cause-and-effect relationship in certain forms of acute lung injury.

Acute Disease↗
PubMed1987

Increase of rat pulmonary microvascular permeability to albumin by recombinant interleukin-2.

Immunotherapy with the lymphokine interleukin-2 (IL-2), with or without lymphokine activated killer (LAK) cells, offers a new approach to the treatment of solid tumors. Unfortunately, most patients receiving IL-2 and LAK cells develop a "third space syndrome" from a presumed generalized increase of vascular permeability. We have investigated the role of IL-2 on lung fluid balance, by measuring changes in lung water and albumin intake. Rats were injected with IL-2 500,000 U i.p. three times a day for 1 to 4 days. At the completion of the injections, lungs were isolated and perfused, and total lung water (TLW) and 125I-albumin uptake were measured. After 1 day of injections, TLW increased from 4.90 +/- 0.14 to 5.57 +/- 0.34 ml/g dry lung and albumin uptake nearly doubled from 0.47 +/- 0.08 to 0.91 +/- 0.28 cm3/s/g dry lung X 10(-3). Longer injection periods increased both TLW and albumin uptake further. After 2 days, TLW and albumin uptake were also significantly increased by 160,000 U i.p. three times a day, but not by 40,000 or 10,000 U. To eliminate possible contributions to increased permeability by (a) LAK cells generated in vivo, or (b) circulating leukocytes, we isolated lungs from normal rats and perfused them for 5 min with a cell-free perfusate containing IL-2 (2, 10, or 5 X 10(-3) U/ml) excipient or 0.9% NaCl placebo. TLW was similar in all groups, but albumin uptake was significantly increased by 10,000 and 50,000 U/ml (0.94 +/- 0.15 and 0.82 +/- 0.16 cm3/s/g dry lung X 10(-3), respectively), but not by 2,000 U/ml. We conclude that lung microvascular albumin permeability is increased following administration of IL-2 in vivo and in vitro. We suggest that LAK cells are not required for the initiation of increased permeability and that IL-2 may have some direct effect on the pulmonary microvasculature.

Albumins↗
PubMed1987

Ethchlorvynol-induced pulmonary edema: a chronically instrumented, awake sheep model mimicking human disease.

Ethchlorvynol injection in humans leads to a clinical picture consistent with increased permeability pulmonary edema, ie, the adult respiratory distress syndrome. There has been only one such case reported in which the pulmonary wedge pressure was measured. In an attempt to mimic the human disease, the authors established the awake, unanesthetized chronic sheep lung lymph fistula model and injected 15 mg/kg of ethchlorvynol intravenously after a baseline period. There were transient increases in pulmonary artery and systemic blood pressure with decreases in cardiac output. Lymph flow increased five-fold and remained elevated for 24 hr, returning to normal by 48 hr. All animals survived. Pulmonary morphologic changes consisted of alveolar and interstitial edema and some disruption of endothelial and epithelial cells. These findings resolved by 48 hr postinjection. The authors conclude that this model mimics the findings in humans who have injected ethchlorvynol intravenously.

Animals↗
PubMed1987

Central venous cannulation done by house officers in the intensive care unit: a prospective study.

Central venous cannulation (CVC) is a procedure frequently performed by house staff in the intensive care units of teaching hospitals. In the medical ICUs of our two hospitals, CVC was successfully done by house officers in 172 cases requiring 231 attempts (one operator at one insertion site), for a success rate of 74%. There were 14 complications (6.1%), five requiring intervention, but none fatal. The overall success rate was higher for the internal jugular approach and lower for the external jugular approach than for other sites. The success rate for Swan-Ganz catheterization was higher for the internal jugular than for the subclavian approach. CVC during resuscitation was frequently unsuccessful (41%) and/or complicated (13.6%). Although success rates were comparable, complications were more common among experienced house officers than among interns, perhaps reflecting patient selection. There was a trend toward fewer and/or less severe complications during the course of the month and of the study.

Adult↗
PubMed1987

Protamine sulfate causes pulmonary hypertension and edema in isolated rat lungs.

The polycation protamine sulfate increases microvascular permeability in the kidney by reducing glomerular charge. We have exposed the pulmonary vasculature to protamine sulfate to determine whether electrical charges play a role in protein permeability in lung vascular beds. In anephric rats, protamine sulfate increased hematocrit approximately 25%. With protamine sulfate doses of 0.08 and 0.04 mg/g body wt, lung blood-free wet-to-dry weight ratios were increased (5.24 +/- 0.8 and 4.89 +/- 0.7) compared with control (3.85 +/- 0.3) (P less than 0.05). In isolated, ventilated, and perfused lungs 0.04 mg/g body wt protamine sulfate increased pulmonary arterial pressure from 5.2 +/- 1.4 to 16.3 +/- 3.9 mmHg (P less than 0.01). These lungs gained weight and lung wet-to-dry weight ratios were significantly increased (15.33 +/- 4.26 compared with 6.04 +/- 0.24 for control lungs). Poly-L-lysine, another polycation, also caused significant increases in pulmonary arterial pressure, lung weight, and lung wet-to-dry weight ratios. The addition of diphenhydramine to the perfusate 10 min before the addition of protamine sulfate did not prevent these changes. Heparin (90 U/mg protamine sulfate) reversed the abnormalities. Pulmonary arterial pressure (7.0 +/- 1.1 mmHg) was not significantly different from the control value, lung weight did not increase, and the lung wet-to-dry weight ratio was 6.24 +/- 0.23 (P greater than 0.05). We conclude that polycations have a significant effect on pulmonary vascular resistance and perhaps on permeability.

Animals↗
PubMed1987

Effects of protamine, heparinase, and hyaluronidase on endothelial permeability and surface charge.

We undertook studies in the isolated perfused rat lung to determine 1) the effects of endothelial charge neutralization with the polycation protamine sulfate on microvascular permeability, lung water, and anionic ferritin binding to the endothelium and 2) the role of heparan sulfate and hyaluronate, negatively charged cell surface glycosaminoglycans, on permeability. Capillary permeability was determined by tissue 125I-albumin accumulation in isolated perfused rat lungs. In control lungs the 5-min albumin uptake was 0.50 +/- 0.05 cm3.s-1.g dry tissue-1 X 10(-3). It was increased by 132 +/- 7.8% (P less than 0.001) by protamine (0.08 mg/ml) and 65 +/- 12% (P less than 0.01) by heparinase (5 U/ml), whereas hyaluronidase (25 NFU/ml) was without effect. In control lungs total water was 4.83 +/- 0.15 ml g/dry tissue. Protamine increased lung water 12 +/- 2% (P less than 0.05). Heparinase caused a 9 +/- 3% increase (P less than 0.05), and hyaluronidase had no effect. Electron microscopy demonstrated that protamine increased anionic ferritin binding to the surface of endothelial cells. We conclude that protamine sulfate neutralization of negative charge in the pulmonary microcirculation leads to increased microvascular permeability. Heparin sulfate may be responsible for this charge effect.

Animals↗
PubMed1986

Increased pulmonary artery pressure in association with Raynaud's phenomenon.

Pulmonary artery vasospasm is a hypothesized antecedent and etiologic factor in the pulmonary hypertension associated with progressive systemic sclerosis. Recent clinical data refute the existence of pulmonary vasospasm in a cohort of patients with scleroderma and normal baseline pulmonary artery pressure. A case of episodic pulmonary hypertension associated with a digital Raynaud's response is reported, and a cardiac mechanism is hypothesized.

Adult↗
PubMed1986

Indomethacin and ketanserin block ethchlorvynol-induced hypoxemia in dogs.

Intravenous injection of ethchlorvynol (ECV) leads to hypoxemia and a permeability pulmonary edema. Whether the hypoxemia is directly attributable to the pulmonary edema or caused by release of mediators has not been explored. Three groups of dogs were studied: (1) ECV, (2) indomethacin--ECV, and (3) ketanserin--ECV. In group 1, 25 to 30 mg/kg of ECV caused a significant fall in PaO2 at 4 min (92 +/- 12.6 to 77 +/- 21 mm Hg, p less than 0.05), which persisted throughout the experiment. The P(A-a)O2 gradient widened significantly at 3 min (22 +/- 11 to 31 +/- 16.8 mm Hg, p less than 0.05) and remained abnormal for the remainder of the experiment. There was no significant fall in PaO2 in groups 2 and 3. Lung tissue water to dry weight ratio increased significantly in all groups at 60 min. Lung tissue water to dry weight ratios were normal at 10 min after ECV injection in additional groups. It was concluded that ECV causes hypoxemia, which is mediated by cyclooxygenase products and 5 hydroxytryptamine. This hypoxemia can be prevented by the administration of drugs that block these products.

Animals↗