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Biomedical subjects

T L Chen

Publications and source records attributed to T L Chen.

At least 55 records · Page 3Linked to original sources
PubMed1998

Increased 9-aminocamptothecin dose requirements in patients on anticonvulsants. NABTT CNS Consortium. The New Approaches to Brain Tumor Therapy.

BACKGROUND: High grade astrocytomas remain uniformly fatal despite aggressive surgery and radiotherapy. As existing chemotherapeutic agents are of limited benefit, clinical trials are underway to screen new drugs, such as 9-aminocamptothecin (9-AC), for activity in high grade astrocytomas. PURPOSE: This study was designed to estimate the efficacy of 9-AC in patients with newly diagnosed glioblastoma multiforme and recurrent high grade astrocytomas. The planned dose of 9-AC for this trial was 850 microg/m2 per 24 h as a 72-h continuous intravenous infusion every 2 weeks. This was the maximum tolerated dose (MTD) on this schedule in multiple phase I studies in patients with systemic malignancies. However, we found this dose subtherapeutic in our patient population. As a result, the purpose of the study was altered to determine the MTD. METHODS: A group of 32 patients were studied using 850 microg/m2 per 24 h with a provision to escalate to 1000 microg/m2 per 24 h if the first three cycles of 9-AC were without significant hematologic toxicity. Once it was determined that myelosuppression did not occur in patients on anticonvulsants, dose escalations were initiated using the continual reassessment method. Dose escalations were conducted independently in newly diagnosed and recurrent patients and in those taking and not taking hepatic enzyme-inducing anticonvulsants. Pharmacologic studies were conducted during the first cycle of 9-AC. Toxicity was determined using the NCI common toxicity criteria and efficacy was assessed using serial volumetric brain scans. RESULTS: 9-AC was administered to 59 patients, 31 with newly diagnosed glioblastoma multiforme and 28 with recurrent high grade astrocytomas. No grade III-IV myelosuppression was noted in the 29 patients (128 cycles) on phenytoin, carbamazepine, phenobarbital, and/ or valproic acid who received 850 microg/m2 per 24 h. In contrast, two of three patients (five cycles) who were not taking anticonvulsants developed grade IV myelosuppression. Steady-state total 9-AC plasma levels were lower in patients on anticonvulsants (median 25.3 nM) than in patients who were not taking anticonvulsants (median 76.5 nM). Dose escalations performed in 27 additional patients determined the MTD in patients taking anticonvulsants to be 1776 microg/m2 per 24 h for patients with newly diagnosed tumors and 1611 microg/m2 per 24 h for patients with recurrent disease. CONCLUSIONS: We describe a new and unexpected drug interaction between 9-AC and anticonvulsants. This is similar to recent findings with paclitaxel, and suggests that higher than "usual" doses of some chemotherapeutic agents are required in patients on anticonvulsants. Prospectively defined dose escalations and pharmacologic studies are essential for the careful evaluation of new chemotherapeutic agents in patients with brain tumors.

Adolescent↗
PubMed1998

Cell-type-specific rescue of myosin function during Dictyostelium development defines two distinct cell movements required for culmination.

Mutant Dictyostelium cells lacking any of the component polypeptides of myosin II exhibit developmental defects. To define myosin's role in establishing Dictyostelium's developmental pattern, we have rescued myosin function in a myosin regulatory light chain null mutant (mlcR-) using cell-type-specific promoters. While mlcR- cells fail to progress beyond the mound stage, expression of RLC from the prestalk promoter, ecmA, produces culminants with normal stalks but with defects in spore cell localization. When GFP-marked prestalk and prespore cells expressing ecmA-RLC are mixed with wild-type cells, the mislocalization of prestalk cells, but not prespore cells, is rescued. Time-lapse video recording of ecmA-RLC cells showed that the posterior prespore zone failed to undergo a contraction important for the upward movement of prespore cells. Prespore cells marked with green fluorescent protein (GFP) failed to move toward the tip with the spiral motion typical of wild type. In contrast, expression of RLC in prespore cells using the psA promoter produced balloon-like structures reminiscent of sorocarps but lacking stalks. GFP-labeled prespore cells showed a spiral movement toward the top of the structures. Expression of RLC from the psA promoter restores the normal localization of psA-GFP cells, but not ecmA-GFP cells. These results define two distinct, myosin-dependent movements that are required for establishing a Dictyostelium fruiting body: stalk extension and active movement of the prespore zone that ensures proper placement of the spores atop the stalk. The approach used in these studies provides a direct means of testing the role of cell motility in distinct cell types during a morphogenetic program.

Animals↗
PubMed1998

[Effects of Gu Chi paste on PGE(2) in periodontitis tissues of guinea pigs]

OBJECTIVE: Study the effects of Gu Chi paste on PGE(2) in gingiva and alveolar bone and its mechanism to treating periodontitis. METHODS: Periodontitis were formed with silk thread suture and high sugar diet,fed guinea pigs on Gu Chi paste and indomethacin.The prostaglandin E(2)(PGE(2)) in gingiva and alveolar bone were measured with radioimmunoassay (RIA). RESULTS: The Gingival Index(GI) and Pocket Deep(PD) of group Periodontitis (PE) were bigger than group Normal(N),the alveolar bone absorbed more severe,the PGE(2) level in gingiva and alveolar bone in PE was higherthan that in N.The GI and PD of group Gu Chi paste(Gu) were lower than that of PE,its alveolar bone absorbed more slight.There were more significant difference of PGE(2) in alveolar bone between Gu and group indomethacin(IND).The PGE(2) level of Gu in gingiva were similar as that of IND. CONCUSION: Gu Chi paste can inhibite the formation of experimental periodontitis and the contents of PGE(2) in gingiva and alveolar bone,and the effect on PGE(2) in alveolar was more severe. The mechanism of Gu Chi paste to periodontitis has inhibitory effects on PGE(2) in gingiva and alveolar bone.

Journal Article↗
PubMed1998

Sequence-dependent hematological toxicity associated with the 3-hour paclitaxel/cyclophosphamide doublet.

Paclitaxel is active in metastatic breast cancer. Combination studies have demonstrated complex interactions between paclitaxel and other cytotoxic agents, including sequence-dependent cytotoxic, toxicological, and pharmacological effects. The principal objectives of this study were to determine the maximum tolerated doses of paclitaxel (3-h infusion) and cyclophosphamide (1-h infusion) administered every 3 weeks with granulocyte colony-stimulating factor (Filgrastim) and to determine if the sequence-dependent toxicological effects that have previously been observed with this combination when paclitaxel was administered over 24 h were evident when paclitaxel was administered over 3 h. Fifteen women with metastatic breast cancer were treated. Starting doses were 200 mg/m2 paclitaxel and 1600 mg/m2 cyclophosphamide, with granulocyte colony-stimulating factor (5 micrograms/kg/day) given s.c. beginning 24 h after chemotherapy. Doses of both drugs were escalated in cohorts of at least four patients. The sequence of drug administration was alternated with each consecutive patient and with each subsequent course of therapy in each individual patient, enabling the evaluation of sequence-dependent toxicological and pharmacological effects. Severe myelosuppression was the principal dose-limiting toxicity for this regimen, precluding dose escalation above 200 mg/m2 paclitaxel and 1600 mg/m2 cyclophosphamide, the maximum tolerated dose for this combination on this schedule. As has been previously demonstrated with this combination, when paclitaxel is administered over 24 h, the hematopoietic toxicity was sequence dependent. Paired analysis of toxicity data using each patient as her own control indicated more severe hematological toxicity in courses in which paclitaxel was administered first. There was no evidence of sequence-dependent effects on the pharmacokinetics of these drugs that might account for this phenomenon. The impact of drug sequencing on toxicity should be considered in the further development of combination therapy containing alkylating agents and paclitaxel, when the latter is administered over 3 h.

Adult↗
PubMed1998

Comparison of hemodynamics and recovery of sevoflurane and isoflurane anesthesia in Chinese adult patients.

BACKGROUND: The new inhalational anesthetic sevoflurane would be expected to provide a rapid emergence from anesthesia due to its low blood/gas partition coefficient. In this study, we compared the hemodynamic effects, speed and quality of emergence, in ASA class I-II Chinese adult surgical patients receiving either sevoflurane or isoflurane anesthesia. METHODS: Eighty adult Chinese patients, ASA class I-II, scheduled for elective gynecological or general surgical procedures, were randomized to receive sevoflurane (n = 40) or isoflurane (n = 40) anesthesia. Ventilation is controlled via endotracheal intubation with anesthesia facilitated by either agent at anesthetic concentration of 1-1.5 MAC under the fresh gas flow 2 L/min. Heart rate, arterial blood pressure, temperature, SpO2 and end-tidal CO2 were continuously monitored. Any adverse effect such as airway irritation, nausea or vomiting was recorded during induction and emergence from anesthesia. The emergence time was assessed by various questionales for orientation during recovery. In the post-anesthetic recovery period, pain was monitored and managed by objective pain discomfort scale for analgesic supplements. Complaints of nausea and vomiting were recorded and followed up by a research nurse who visited the patient within 24 h following surgery. RESULTS: The extent of exposure to anesthetic (MAC x hours) was similar in both groups. Sevoflurane and isoflurane caused similar alterations in systolic and diastolic arterial pressure during maintenance. After surgical incision, the heart rate accelerated more in patients receiving isoflurane (p < 0.05). During emergence, time of response to command was significantly shorter in patients receiving sevoflurane than patients receiving isoflurane (5.6 +/- 0.4 min versus 15.2 +/- 3.0 min, p < 0.001). Side effects such as nausea and vomiting were comparable in both groups. CONCLUSIONS: Compared with isoflurane, sevoflurane anesthesia had the clinical advantages of maintaining stable hemodynamics and rapid recovery in Chinese adult patients.

Adult↗
PubMed1998

A phase II "window" study of topotecan in untreated patients with high risk adult acute lymphoblastic leukemia.

To further evaluate the activity of topotecan (TPT) in acute leukemia, TPT was administered (2.1 mg/m2/day for 5 days by continuous i.v. infusion) to adult patients with previously untreated acute lymphoblastic leukemia (ALL) with high-risk features (13 patients) or relapsed ALL (1 patient). Patients achieving a partial response or significant hematological improvement received a second course. All patients subsequently received standard treatment for ALL. Because complete response was achieved in only 1 of 14 patients, the study was terminated prematurely. An additional patient achieved minimal response, and a third patient normalized her hemogram despite ongoing leukemia in the marrow. Overall, six patients had significant hematological improvement (normalization of platelet and/or absolute neutrophil count). Two patients expired due to infections during induction chemotherapy. The primary nonhematological toxicities were mucositis and diarrhea. Exposure to TPT did not appear to influence the response to subsequent standard chemotherapy. The mean steady-state TPT plasma concentration, 16.1+/-1 nM, overlapped the range of LD90 values of primary human leukemia specimens. Cellular topo I content varied over a 3-fold range, encompassing levels found previously in relapsed patients. No relationship was found between topo I expression and markers of cellular proliferation or response to therapy. In contrast, low expression of the apoptosis inhibitor Bcl-2 was associated with response to TPT therapy. TPT has significant, albeit modest, single-agent activity against high-risk adult ALL. This study demonstrates the feasibility of evaluating promising new therapeutic agents in untreated patients with acute leukemia at high risk for failure with conventional therapy.

Adult↗
PubMed1997

Novel high-performance liquid chromatographic assay using fluorescence detection for the quantitation of plasma gamma-methylene-10-deazaaminopterin and its major metabolite, 7-hydroxy-gamma-methylene-10-deazaaminopterin, in patients with solid cancers in a phase I trial.

Gamma-methylene-10-deazaaminopterin (MDAM), a unique dihydrofolate reductase inhibitor, has demonstrated antitumor activity against a broad spectrum of human solid tumors in preclinical studies. A novel reversed-phase, ion-pair high-performance liquid chromatography (HPLC) assay that uses fluorescence detection has been developed to quantitate levels of MDAM and its major metabolite, 7-hydroxy-gamma-methylene-10-deazaaminopterin (7-OH-MDAM), in human plasma. The recovery of MDAM and 7-OH-MDAM from plasma was >97% by a simple one-step deproteinization process using tetrabutylammonium bromide (TBABr) and methanol. MDAM and 7-OH-MDAM remained stable in plasma over a 28-day test period at ambient temperatures, and neither compound was light-sensitive. The limit of quantitation was 0.005 microM for both MDAM and 7-OH-MDAM. This assay has been found to be simple, sensitive and reproducible in determining plasma concentrations of MDAM and 7-OH-MDAM in patients with solid cancers in a phase I trial.

Aminopterin↗
PubMed1997

Phase I and pharmacologic study of penclomedine, a novel alkylating agent, in patients with solid tumors.

PURPOSE: To determine the maximum-tolerated dose (MTD), principal toxicities, and pharmacologic behavior of penclomedine, a novel alkylating agent. PATIENTS AND METHODS: Penclomedine (45 to 550 mg/ m2/d every 3 weeks) was administered as a 1- or 3-hour intravenous (IV) infusion for 5 consecutive days to patients with solid tumors. RESULTS: On a 1-hour dosing schedule, ataxia, vertigo, nystagmus, and a motor aphasia were the principal toxicities of penclomedine. These neurologic effects were dose-related, and evolved from complaints of somnolence and dizziness, to more pronounced signs and symptoms of cerebellar dysfunction. Up to and including doses of 415 mg/m2, these effects were well tolerated and resolved within 2 hours posttreatment. In contrast, both patients treated at the 550-mg/m2 dose level experienced a dose-limiting constellation of perinfusional aphasia and vertigo, with either ataxia of over 2 weeks' duration or recurrent dizziness. Prolongation of the infusion duration to 3 hours at this dose level resulted in less neurotoxicity; however, delayed trilineage hematologic toxicity precluded timely administration on this schedule. A statistically significant relationship was demonstrated between the development of ataxia and maximum plasma concentrations of penclomedine. CONCLUSION: Neurotoxicity was the dose-limiting toxicity (DLT) of penclomedine administered as a 1-hour infusion daily for 5 days every 3 weeks, and the recommended dose for further evaluations was 415 mg/m2. The nature of the principal toxicities and the lack of any detectible antitumor activity indicate that phase II evaluations of penclomedine on this administration schedule should be focused on specific disease settings, such as breast cancer and intracerebral tumors, in which antitumor activity has been demonstrated.

Adult↗
PubMed1997

Vitrectomy for endogenous Klebsiella pneumoniae endophthalmitis with massive subretinal abscess.

A 39-year-old man with pyogenic liver abscess had bilateral endogenous Klebsiella pneumoniae endophthalmitis. At presentation, the left eye had a localized subretinal abscess. Despite repeated intravitreal amikacin and dexamethasone injections, a subretinal abscess spread and detached all of the retina. Pars plana vitrectomy with drainage of the subretinal abscess was performed. The retina was reattached, and the patient had 5/200 vision 5 months postoperatively. Early vitrectomy with drainage of the subretinal abscess may save some eyes with endogenous Klebsiella pneumoniae endophthalmitis.

Abscess↗
PubMed1997

Nonlinear pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide in patients with metastatic breast cancer receiving high-dose chemotherapy followed by autologous bone marrow transplantation.

The pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide has been evaluated in 12 patients with metastatic breast cancer undergoing high-dose chemotherapy followed by bone marrow transplantation. Each patient received an initial dose of 4 g/m2 of cyclophosphamide over 90 min to prime peripheral blood progenitor cells (the first course), and 3 weeks later, 6 g/m2 of cyclophosphamide with 800 mg/m2 of thiotepa by 96-hr infusion before marrow stem cell infusion (the second course). Whole blood cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide concentrations were measured by a GC-EIMS method using deuterium labeled compounds as internal standards. In addition, plasma and urine cyclophosphamide concentrations were determined by a GC assay. Whole blood concentrations of cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide vs. time data and urinary excretion of cyclophosphamide data from the first course were co-modeled using a one-compartment model with Michaelis-Menten saturable elimination in parallel with first-order renal elimination (N = 7) or first-order metabolic and renal elimination (N = 5) for cyclophosphamide and one-compartment model with first-order elimination for 4-hydroxycyclophosphamide/aldophosphamide. The parallelism between cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide disposition curves implies that the pharmacokinetics of 4-hydroxycyclophosphamide/aldophosphamide is formation limited; only the fractional 4-hydroxycyclophosphamide/ aldophosphamide clearance rate (Clmet/Fmet) can be estimated. The mean Vmax and Km for cyclophosphamide were 0.78 microM/min and 247 microM, respectively. The mean nonrenal clearance (Clnr) of cyclophosphamide for five patients with apparent first-order elimination of cyclophosphamide was 67 ml/min. The mean Clmet/Fmet of 4-hydroxycyclophosphamide/aldophosphamide was 2982 ml/min. The mean renal clearance (Clr) of cyclophosphamide was 29 ml/min and 24 ml/min for the first course and the second course, respectively. The correlations between cyclophosphamide AUCs and 4-hydroxycyclophosphamide/aldophosphamide AUCs were sought for both drug courses. Blood and plasma cyclophosphamide concentrations were remarkably similar, indicating that cyclophosphamide partitions equally in the red cell and plasma volume. Computer simulation of the effect of potential alterations in Michaelis-Menten saturable elimination and renal clearance on 4-hydroxycyclophosphamide/aldophosphamide has been used to illustrate the complex relationship between the exposure to parent compound and active metabolite.

Adult↗
PubMed1997

Metabolic characteristics and enflurane defluorination of cytochrome P450-dependent monooxygenases in human hepatocellular carcinoma.

BACKGROUND: Xenobiotic metabolism and defluorination capacity of microsomal monooxygenases were investigated in vitro through the surgical specimens of liver resected from patients with hepatocellular carcinoma and patients of extrahepatic pathology as control. METHODS: In microsomes of hepatocellular carcinoma tissues, the activities of cytochrome P450-dependent monooxygenase isoenzymes 1A1, 2B1, and 2E1 were evaluated in vitro by reacting with the specific marker substrates benzo(a)pyrene, benzphetamine and aniline, respectively, in the generating incubation system. The distant normal liver tissues and tissues from control patients with extrahepatic lesion were also investigated for comparison. The ability of enflurane defluorination was assessed by Orion combined for detection of free fluoride ion production. RESULTS: Concentrations of P450 total content, cytochrome b5, and NADPH-cytochrome c reductase showed parallel and marked reduction in tumor tissues when compared with its distant normal regions or normal livers. The monooxygenase functions displayed significant decreases within the tumor tissues as benzo(a)pyrene hydroxylation > or = benzphetamine demethylation > aniline hydroxylation in magnitude. Defluorination of enflurane also markedly decreased in tumor tissues comparing with normal livers. CONCLUSIONS: These marked reductions in the compositions and in vitro metabolic activities, including defluorination of anesthetics, in the cytochrome P450-dependent monooxygenases within the tumor tissues characterize the unique pattern of xenobiotic metabolism in patients with hepatocellular carcinoma.

Aged↗
PubMed1996

Phase I and pharmacologic studies of topotecan in patients with impaired hepatic function.

BACKGROUND: Topotecan, a topoisomerase I inhibitor that has demonstrated anticancer activity toward leukemias and solid tumors in clinical trials, is eliminated via hepatic and renal routes. However, dosing guidelines for the administration of topotecan to patients with impaired hepatic function have not yet been established. PURPOSE: We compared the maximum tolerated doses (MTDs), the toxic effects, and the pharmacokinetics and pharmacodynamics of topotecan in patients who had refractory, malignant, solid tumors and who either had or lacked hepatic injury. The potential role of three substrate markers of liver function (indocyanin green [ICG]-- a marker of hepatic blood flow; lorazepam--a substrate marker of hepatic glucuronidation; and antipyrine--a substrate marker for cytochrome P450 activity) in optimizing topotecan doses for patients with liver injury was also evaluated. METHODS: Twenty-one cancer patients, 14 of whom had hepatic injury due to metastatic disease, biliary obstruction, or cirrhosis, were treated with intravenously delivered courses of topotecan consisting of 0.5, 1.0, or 1.5 mg/m2 of drug per day for 5 days. Most patients received more than one course of treatment, with new courses initiated at 3-week intervals. Patient responses (evaluated by tumor measurements) and treatment-induced toxic effects were assessed. Prior to the initiation of topotecan treatment, patients were given intravenous injections of ICG, lorazepam, and antipyrine to determine the plasma pharmacokinetics of these compounds. The pharmacokinetics of topotecan (both the lactone and the carboxylate forms) were determined by analysis of plasma and urine samples collected on the first day of the first course of drug treatment. Scatter plots of area under the plasma concentration versus time curves in relation to percent decreases in either absolute neutrophil count or platelet count were used to explore the pharmacodynamics of topotecan. The Student's t test and the Mann-Whitney U test were used to compare pharmacokinetic parameters between patients with and without abnormal hepatic function. Correlations were assessed using the Spearman's rank correlation coefficient (rs). Reported P values are based on two-tailed tests of significance. RESULTS: Patients with hepatic injury tolerated topotecan doses up to 1.5 mg/m2, i.e., the MTD of this drug established in previous studies. The nature and severity of treatment-induced toxic effects and the pharmacokinetics of topotecan were similar in patients with and without liver injury. No differences were observed in the urinary excretion of topotecan between the two patient groups. Clearances of total topotecan and its lactone species correlated only with clearance of ICG (rs = .64, P = .004; and rs = .68, P = .0017, respectively). The pharmacodynamic effects of topotecan were not altered by liver dysfunction. CONCLUSIONS AND IMPLICATIONS: Cancer patients with hepatic injury can be treated with topotecan at a starting dose of 1.5 mg/m2, given daily for 5 days and administered every 3 weeks. Topotecan dose modifications do not appear to be required for patients with hepatic dysfunction and normal renal function.

Adult↗
PubMed1996

Anaesthetic managements for conjoined twins with complex cardiac anomalies.

PURPOSE: To describe the perioperative assessment and anaesthetic management for surgical separation of three sets of conjoined twins with complex cardiac anomalies threatened with arterial desaturation and haemodynamic instability. CLINICAL FEATURES: Three sets of conjoined twins, one omphaloischiopagus, one omphalopagus, and one thoraco-omphalopagus, were considered for separation during the perinatal or infantile period. Preoperative functional evaluation including continuous pulse oximetry, capnography, and cardiac electrophysiological studies were considered to be as important as anatomical evaluation of the cardiac anomalies and cross-circulation by angiography in assessing the feasibility of surgical separation. Ipsilateral infusion of prostaglandin E1 and phenylephrine were applied to the cyanotic and healthy twins respectively, to restore arterial oxygenation intraoperatively and to avoid profound hypoxaemia. CONCLUSION: Surgical separation and anaesthesia should be well planned and rehearsed before clinical deterioration of the weaker twin. Aggressive pharmacological intervention and understanding of the cross-circulation pathophysiology is necessary to manage critical situations during surgical separation and in the postoperative period.

Anesthesia↗
PubMed1996

Induction and suppression of renal and hepatic cytochrome P450-dependent monooxygenases by acute and chronic streptozotocin diabetes in hamsters.

The acute and chronic effects of streptozotocin diabetes on kidney and liver microsomal monooxygenases were studied using hamsters 2 days and 6 weeks following treatment with the diabetogen, respectively. Acute diabetes increased aniline hydroxylation and N-nitrosodimethylamine demethylation, decreased pentoxyresorufin O-dealkylation, without affecting benzo(a)pyrene hydroxylation and 7-ethoxycoumarin O-deethylation in kidney and liver microsomes. The effects of chronic diabetes on the microsomal monooxygenases were similar to the effects of acute diabetes, except that the chronic diabetic condition markedly decreased benzo(a)pyrene and 7-ethoxycoumarin oxidations in kidney microsomes. Total cytochrome P450 content and NADPH-cytochrome P450 reductase activity in kidney and liver microsomes of the diabetic hamsters were similar to the controls. Gel electrophoresis of microsomes from control and streptozoptocin treated hamster tissues revealed that diabetes enhanced the intensity of protein band(s) in the P450 molecular weight region. Immunoblotting of microsomal proteins showed that acute and chronic streptozotocin diabetes induced proteins immunorelated to P450s 2E1 and 1A in kidney and liver. In marked contrast, the acute and chronic diabetic conditions decreased the level of a P450 2B-immunorelated protein(s) in kidney and liver. The present study demonstrates that acute and chronic streptozotocin diabetes has the ability to induce P450 2E1 and 1A and suppress P450 2B in hamster kidney and liver and that the hamster monooxygenase responds to diabetes differently from the rat enzyme.

Acute Disease↗
PubMed1996

Endothelin-1 concentrations and optimisation of arterial oxygenation and venous admixture by selective pulmonary artery infusion of prostaglandin E1 during thoracotomy.

In order to improve arterial oxygenation and venous admixture during one lung ventilation, the effect of selective infusion of prostaglandin E1 into the pulmonary artery of the ventilated lung was investigated in 12 adult patients undergoing thoracotomy. Patients' bronchi were intubated with a Mallinckrodt bronchial tube and ventilated with 66% oxygen in air. Cardiopulmonary factors such as systemic and pulmonary arterial pressures, pulmonary vascular resistance, blood gas analyses, cardiac output and airway pressure were measured before and during one-lung ventilation; venous admixture (Qs/Qt) was calculated. Serial blood samples were taken from the pulmonary artery of the ventilated lung for endothelin-1 estimation. One lung ventilation reduced the mean PaO2 from 42.1 (2.3) kPa to 11.8 (1.4) kPa (p < 0.001) and increased Qs/Qt from 10.8 (3.2)% to 39.2 (4.7)% (p < 0.001). Pulmonary vascular resistance also increased from 167 (24) dyne.s.cm-5 to 262 (38) dyne.s.cm-5 (p < 0.05) with a corresponding increase of plasma endothelin-1 (p < 0.05). After 30 min of one lung ventilation, PGE1 was infused continuously into the pulmonary artery of the ventilated lung at a rate which increased incrementally from 0.04-0.10 micrograms.kg-1.min-1. PaO2 increased to 20.7 (2.6) kPa (p < 0.01) and Qs/Qt decreased to 30.6 (3.5)% (p < 0.05). During the infusion, pulmonary vascular resistance reduced to 173 (30) dyne.s.cm-5 (p < 0.01). The plasma endothelin-1 concentration reached a plateau between the end of one lung ventilation (before closing the thorax) and 6 h postoperatively. This correlated inversely with the pre-operative forced expiratory volume in one second (r = -0.68, p < 0.005), declining to normal values 72 h after operation. The selective infusion of PGE1 into the pulmonary artery of the ventilated lung corrected pulmonary vasoconstriction and improved both arterial oxygenation and venous admixture during one lung ventilation for thoracotomy.

Aged↗
PubMed1996

Improvement of arterial oxygenation by selective infusion of prostaglandin E1 to ventilated lung during one-lung ventilation.

BACKGROUND: One-lung anesthesia provides a better surgical field for thoracic procedures but also impairs the arterial oxygenation and venous admixture. During one-lung ventilation, pulmonary vasoconstriction is assumed to be present within both ventilated and collapsed lungs. We propose that arterial oxygenation could be optimized by offsetting the vasoconstriction within the microcirculation of ventilated lung. METHOD: In an anesthetized dog model, incremental doses of prostaglandin E1 (PGE1) were selectively infused into the main trunk of the pulmonary artery of the ventilated lung after one-lung ventilation for 60 min (PGE1 group, n = 9). Arterial oxygenation and calculated venous admixture (Qs/Qt) was also assessed in a time-course control group (Control group, n = 5). During two-lung ventilation (FIO2: 0.66), arterial PO2 and venous admixture was 44.2 +/- 3.5 kPa and 10.7 +/- 2.3%, respectively. One-lung ventilation (FIO2: 0.66) with left lung collapsed reduced arterial PO2 to 11.6 +/- 1.7 kPa and increased venous admixture to 40.7 +/- 5.8% (P<0.001). Venous O2 tension also decreased from 6.3 +/- 0.7 kPa to 5.0 +/- 0.6 kPa with a slight increase in mean pulmonary artery pressure and pulmonary vascular resistance (P<0.05). RESULTS: During selective infusion of PGE1 at a dose of 0.04 to 0.2 mu g kg-1 min-1, there was a dose-dependent improvement in arterial PO2 with a parallel reduction of venous admixture during one-lung ventilation. Arterial PO2 increased to a maximum of 23.0 +/- 4.3 kPa, and the venous admixture decreased significantly to a minimum of 27.4 +/- 4.2% by PGE1 at a dose of 0.04-0.4 mu g kg-1 min-1 (P<0.01). PGE1 resulted in a small increase in cardiac output and decreases of pulmonary pressure and pulmonary vascular resistance at a relatively high dose of 0.4 mu g kg-1 min-1 during selective infusion (P<0.05). CONCLUSIONS: These results suggest that a selective pulmonary artery infusion of PGE1 to the ventilated lung within the dose range of 0.04-0.4 mu g kg-1 min-1 is practical and effective to improve arterial oxygenation and reduce venous admixture during one-lung ventilation.

Alprostadil↗
PubMed1996

The optimal tidal volume delivered by ventilator after pulmonary resection: its effect on cardiopulmonary hemodynamics.

Pulmonary function and gas exchange deteriorate after pulmonary resection. The vital capacity, tidal volume, and functional capacity decrease after pulmonary resection because of loss of effective lung volume and, therefore, affect the setting of the ventilator. Nineteen patients undergoing pulmonary resection were included in this study on the optimal tidal volume delivered by a ventilator. Five patients received mediastinal surgery or wedge resection of the lung, 4 had pneumonectomy, and 10 had lobectomy. Immediately after the pulmonary surgery, they were maintained with ventilatory support. Subsequently, a different setting of tidal volume on the ventilator was given for each patient, i.e., 6 ml/kg, 8 ml/kg, 10 mg/kg, and 14 ml/kg. For each setting of tidal volume, a hemodynamic study was performed including cardiac output and other parameters. With the examination of Wilk's Lambda test, there was no difference in association with different settings of tidal volume on blood pressure (F = 0.92, p = 0.51), pulmonary artery pressure (F = 0.95, p = 0.43), pulmonary vascular resistance (F = 0.24, p = 0.97), systemic vascular resistance (F = 0.42, p = 0.78), and cardiac output (F = 0.35, p = 0.93) in 3 different groups of patients. It is concluded that after pulmonary resection a patient's lungs can be inflated with a tidal volume to 14 ml/kg during ventilatory support without compromise of cardiovascular performance.

Adult↗