Conservation of small-airway function by tacrolimus/cyclosporine conversion in the management of bronchiolitis obliterans following lung transplantation.

We studied serial lung function in 11 patients with bronchiolitis obliterans syndrome who were treated with tacrolimus conversion following lung or heart-lung transplantation. Our results show that tacrolimus conversion slows the decline of lung function in bronchiolitis obliterans syndrome. The attenuation continues for at least 1 year following conversion.

Prevention of remote organ injury in cardiopulmonary bypass: the impact of flow generation technique.

The purpose of this study was to investigate the effects of 3 different types of flow generation for cardiopulmonary bypass on gastrointestinal permeability and on neutrophil expression of CD11b, a surface marker of neutrophil activation. Fourteen patients undergoing elective coronary revascularization were selected randomly to receive 1 of the 3 flow generation techniques (roller, pulsatile, or centrifugal). Intestinal permeability was assessed by the fraction of an oral dose of 51chromium-ethylenediaminetetraacetate (51Cr-EDTA) recovered in the urine over 24 h. Neutrophil activation was determined by expression of CD11b markers at 6 time points. Overall, the 14 patients showed significant increases in intestinal permeability. It was not possible to demonstrate statistically significant differences among the flow generation groups; however, when compared to both roller pump groups, the centrifugal pump group showed a 3.2% reduction in intestinal permeability. There was no change in the expression of CD11b receptors throughout the time points, nor was there a relationship of CD11b markers to the flow generation technique.

Novel approach to investigate a source of microbial contamination of central venous catheters.

The potential route of contamination by skin microorganisms onto the distal tip of central venous catheters during insertion was investigated. Thirty patients undergoing cardiac surgery who required a central venous catheter (CVC) as part of their clinical management were studied. Following catheter placement, the device insertion equipment and the skin at the insertion site were sampled for microorganisms. The distal tips of the CVCs were also sampled in situ within 90 min post insertion. Bacteria were isolated from 20 of 30 (66%) CVC skin insertion sites, from 15 of 30 (50%) guidewires, and from five of 30 (16%) catheter distal tips in situ. These findings suggest that despite rigorous skin disinfection and strict aseptic technique, viable microorganisms are impacted during insertion onto the distal tip of the CVC, which may act as a subsequent nidus of infection.

Healing of the bronchus in pulmonary transplantation.

OBJECTIVE: To review the results of bronchial healing in a consecutive series of 100 isolated pulmonary transplants, performed at one centre between 1987 and 1994. METHODS: A retrospective review of 123 assessable bronchi (61 in single lung and 62 in bilateral lung) transplants was carried out. All anastomoses were assessed by bronchoscopy at 7-10 days, and follow up was from one to seven years. The effect on bronchial dehiscence or stenosis requiring endobronchial stent, of suture technique, pre and post operative steroid administration, bronchial wrap, donor ischaemic time and time to first rejection episode was assessed. RESULTS: Complications of airways healing occurred in four patients: stenosis in two and dehiscence in two (1.6% of bronchi at risk in both groups). Airway complication was not affected by steroids, pre-operative diagnosis, presence of a wrap (34 with pericardium or omentum, 89 with peribronchial tissue alone) or any other variable. There was a higher incidence of dehiscence (2/36) with continuous rather then interrupted (0/87) suture, but this was not statistically significant. There was one airway-related death. Two patients who required anastomotic stenting remain alive and well. CONCLUSIONS: A very low complication rate can be achieved without recourse to bronchial wrapping, telescoping anastomoses or steroid avoidance. Combined heart-lung transplantation or bronchial revascularisation are not required to achieve reliable bronchial healing.

Inhibition of neutrophil adhesion during cardiopulmonary bypass.

Blood contact with synthetic surfaces during cardiopulmonary bypass (CPB) causes a diffuse inflammatory reaction that includes neutrophil activation. The purpose of this study was to determine if inhibition of neutrophil adhesion with a new antiinflammatory agent NPC 15669 (N-(9H-(2,7-dimethylfluorenyl-9-methoxy)-carbonyl)-L-leucine) could reduce pulmonary injury in a porcine model of CPB. NPC 15669 blocks adherence of activated neutrophils by inhibiting upregulation of the Mac-1 (CD11b/CD18) adhesion molecule. Sixteen piglets underwent 2 hours of hypothermic CPB followed by 2 hours of observation; 8 received NPC 15669 (10 mg/kg intravenous bolus followed by 6 mg.kg-1.h-1 intravenous infusion) and 8 received equal volumes of vehicle. After 90 minutes of CPB, expression of neutrophil adhesion molecule subunit CD18 increased 118% in control piglets but only 36% in piglets treated with NPC 15669 (p < 0.01). Although neutropenia developed in all animals during CPB, lung tissue myeloperoxidase content was significantly lower in treated than in control animals 2 hours after CPB (94.9 +/- 10.4 versus 46.9 +/- 5.5 mumol.10 mg-1.min-1; p < 0.002). Free radical-mediated lipid peroxidation (quantitated by spectrophotometric assay of plasma conjugated dienes) was significantly reduced by treatment with NPC 15669 during and after CPB. Pulmonary function was better in NPC 15669-treated animals: 2 hours after CPB, pulmonary vascular resistance increased 477% in control piglets but only 140% in piglets receiving NPC 15669 (p < 0.03); arterial oxygen tension was significantly greater in piglets receiving NPC 15669 (428 +/- 33 mm Hg) than in controls (141 +/- 46; p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of neutrophil adhesion reduces myocardial infarct size.

Neutrophil accumulation and activation within the myocardium during ischemia and reperfusion has been shown to play a prominent role in the development of myocardial stunning and infarction. To determine if a simple inhibitor of neutrophil adhesion could reduce myocardial infarct size, we administered NPC 15669 (a new antiinflammatory agent that inhibits neutrophil adhesion) to 12 pigs (6 controls, 6 NPC-treated) in a porcine model of ischemia and reperfusion injury. Each animal received a continuous infusion of either NPC (10 mg/kg intravenous bolus followed by 6 mg.kg-1 x h-1 intravenous infusion) or an equal volume of normal saline solution during 1 hour of left anterior descending artery occlusion and 2 hours of reperfusion. There were no significant differences in the pre-ischemia, mid-ischemia, or postischemia rate-pressure product between control and experimental groups. The regions at risk were similar in both groups. However, the mean myocardial infarct size was reduced by 51% with administration of NPC 15669 (30.7% +/- 6.8%) compared with controls (62.3% +/- 5.4%; p < 0.01). These data indicate that NPC 15669, an inhibitor of neutrophil adhesion, substantially reduces myocardial infarct size after transient left anterior descending artery occlusion and that adhesion of the white cell to vascular endothelium may be an important element of the pathogenesis of myocardial infarction.

Temporary leukocyte depletion reduces ventricular dysfunction during prolonged postischemic reperfusion.

Leukocyte depletion improves early postischemic ventricular performance in neonatal models of global myocardial ischemia. However, the rate of leukocyte reaccumulation after cardiopulmonary bypass and its subsequent impact on myocardial function is not known. This laboratory study examined the effect of leukocyte depletion on myocardial performance during the initial 6-hour period after bypass in an in situ, in vivo porcine model of neonatal cardiac surgery. Fifteen 3- to 5-day-old piglets (eight control and seven leukocyte depleted animals) were instrumented by placement of left ventricular short-axis sonomicrometry crystals and an intraventricular micromanometer catheter. Mechanical leukocyte depletion was achieved with Pall RC100 filters (Pall Biomedical, Inc., Fajardo, Puerto Rico) in the cardiopulmonary bypass circuit. Neonatal hearts were subjected to 90 minutes of hypothermic ischemia after a single dose of cold crystalloid cardioplegia. Two control animals died after the operation and were excluded from data analysis. Leukocyte filtration reduced the granulocyte count during initial myocardial reperfusion to 0.8% of control values. However, circulating granulocyte counts increased in leukocyte depleted animals throughout the postoperative period, reaching 68% of control values by 6 hours. Despite this rapid return of circulating granulocytes, animals subjected to leukocyte depletion had significantly better preservation of left ventricular performance (measured by preload recruitable stroke work, p < or = 0.02), left ventricular systolic function (measured by end-systolic pressure-volume relationship, p < or = 0.05), and ventricular compliance (p < or = 0.04) during the experiment. These changes in ventricular function were associated with a significant increase in left ventricular water content (p < or = 0.02) and tissue myeloperoxidase activity (p < or = 0.005) in control animals compared with leukocyte depleted animals. This study demonstrates that leukocyte depletion during initial reperfusion results in sustained improvement in postischemic left ventricular function despite the rapid return of granulocytes to the circulation.

Leukocyte depletion in a neonatal model of cardiac surgery.

Neonatal cardiac surgical procedures continue to be associated with a considerable incidence of severe post-operative ventricular dysfunction. The role of neutrophils in mediating such injury has recently been proposed but remains controversial. The present study was undertaken to examine the potential benefits of leukocyte depletion for myocardial preservation using an in situ, in vivo porcine model of neonatal cardiac surgery. Sixteen 3- to 5-day-old piglets, 8 controls and 8 leukocyte-depleted animals (LD group), underwent 90 minutes of hypothermic ischemia. Mechanical leukocyte filtration during cardiopulmonary bypass reduced the granulocyte count in the initial reperfusate to 0.7% of controls. This was associated with a reduction in leukocyte sequestration in the coronary vascular bed (p < 0.005), a decrease in myocardial creatine kinase release (p < 0.02), and a reduction in coronary vascular resistance (p < 0.03). These changes in physiological response to ischemia were associated with improved postischemic recovery of left ventricular systolic function in LD animals (p < 0.05), although there was no significant improvement in diastolic function. Application of this technique in neonatal cardiac operations may improve myocardial protection and reduce the associated morbidity and mortality.

NPC 15669 blocks neutrophil CD18 increase and lung injury during cardiopulmonary bypass in pigs.

During cardiopulmonary bypass (CPB), neutrophils become activated due to contact with extracorporeal surfaces and binding of complement fragments C3a and C5a, leading to extravasation and subsequent tissue damage. In this study, the effects of the leumedin NPC 15669 (N [9H - (2,7 dimethylfluorenyl - 9 - methoxy) car bonyl]-L-leucine), a leukocyte recruitment inhibitor, were evaluated in a pig model of CPB. NPC 15669 caused significant inhibition of CPB associated increase in CD18 upregulation, lung tissue myeloperoxidase content, and percentage wet weight compared to controls. Lung histology revealed clear airways and minimal neutrophil infiltration in treated animals vs. significant oedema and cellular infiltration in controls. It is concluded that CPB causes a dramatic increase in neutrophil CD18, and that leumedins are effective in inhibiting neutrophil activation and subsequent tissue injury when administered during CPB.

Thyrotropin-releasing hormone (TRH) in abstinent alcoholic men.

Chronic alcoholics who had been abstinent from alcohol for more than 2 years were evaluated with the thyrotropin-releasing hormone (TRH) test. The findings suggest the following profound disturbances in the hypothalamic-pituitary-thyroid axis: 1) a "euthyroid sick syndrome," evidenced by low levels of triiodothyronine (T3), high levels of reverse T3, and normal levels of thyroxine (T4) (this syndrome implies a decreased 5'-deiodination of T4 to T3 and of reverse T3 to its lesser iodinated metabolites), 2) an increased binding capacity for thyroid hormones, evidenced by a decreased T3-uptake value and an increased level of T4-binding globulin, and 3) thyroid-stimulating hormone (TSH) blunting in 31% of patients. Paradoxically, there was a positive correlation between basal T4 and delta max TSH in subjects with blunted TSH, but baseline TSH levels were reduced in subjects with and without blunted TSH.

Is there a tardive dysmentia?

A change in the phenomenology of schizophrenia has been observed over the past several decades; affective disturbances and phasic courses have become more evident. Although there is no obvious single explanation for these changes, several ideas have been considered. The advent and use of antipsychotic drugs over the past 30 years stands out as the most significant change. Because it is well known that chronic treatment with antipsychotic drugs can induce tardive dyskinesia and has been hypothesized to induce a supersensitivity psychosis, it is reasonable to believe that other behavioral changes may occur over time. We here describe a behavioral disorder that we have termed tardive dysmentia, involving changes in affect, activation level, and interpersonal interaction. A relationship between tardive dysmentia and tardive dyskinesia is suggested. It is our hypothesis that tardive dysmentia contributes to the changing course of schizophrenia and occurs after long-term treatment with antipsychotic drugs.

Endocrine and behavioral changes in depression after thyrotropin-releasing hormone (TRH). Alteration by pretreatment with thyroid hormones.

The effects of pretreatment with a single dose of thyroid hormones (TH) on the subsequent endocrine and behavioral response to TRH was evaluated in unipolar depressed women. TH pretreatment altered neither serum levels of thyroid hormones nor the TRH-induced TSH response. It antagonized, however, the behavioral response to TRH. This was apparent in 2 self-assessment scales but not in an objective rating scale. Taken together the data suggest that (a) there is an impaired pituitary response to TH feedback in depressed patients; (b) TH pretreatment may affect self-assessment of behavioral effects of TRH in depression.

Psychological and thyroid-stimulating hormone changes after thyrotropin-releasing hormone in normal women: antagonism by pretreatment with thyroid hormones.

In a double-blind crossover design we treated 20 normal women with thyrotropin-releasing hormone (TRH), 0.5 mg i.v., and saline in a random sequence. Both injections were preceded, 48 hours before, by a single dose of oral thyroid hormones (TH). TRH caused a shift toward mild euphoria, both on objective and subjective ratings. Although statistically significant, the effect was less than that observed in a previous study of normal women in which TH pretreatment was not used. Thus, TH pretreatment appeared partly to block psychological response to TRH. As expected, TH pretreatment also partly blocked thyroid-stimulating hormone (TSH) responses to TRH. Nevertheless, just as in our previous study, psychological responses were significantly negatively correlated with TSH responses. TH appears to exert two independent negative feedback effects: one on the brain (dimished psychological response); and one on the anterior pituitary (diminished TSH response).

Adverse effects of anticholinergic antiparkinsonian drugs in tardive dyskinesia. An investigation of mechanism.

10 long-term schizophrenic patients with tardive dyskinesia were studied over 14 weeks and maintained on their usual neuroleptic medications while anticholinergic antiparkinson drugs were employed and then discontinued, and the cycle then repeated. Discontinuation of anticholinergic medications resulted in improvement in dyskinetic movements and vice versa. Estimation of haloperidol equivalents in serum at four times suggested that changes in severity of tardive dyskinesia were not caused by changes in blood levels of neuroleptics. Levels of pituitary hormones were also estimated at four times. Prolactin levels tended to diminish in men over the course of the experiment. Growth hormone and thyrotropin values were mainly stable. However, the growth hormone levels peaked during the final 'off anticholinergic' condition and thyrotropin levels were consistently elevated.

Behavioral and endocrine responses of schizophrenic patients to TRH (protirelin).

We studied the effects of intravenous protirelin (thyrotropin-releasing hormone) in 17 schizophrenic patients and 17 normal subjects. A total of 12 patients received protirelin, 0.5 mg, and, on another occasion, niacin, 2 mg, in a double-blind, crossover design. Both behavioral and endocrine data were collected. Five patients received protirelin in an open trial; only endocrine data were collected. Protirelin caused about a 50% prompt decrease in psychotic symptoms. Patients then tended slowly to experience a relapse. Side effects were about as infrequent after protirelin as after niacin. We assayed serum prolactin (PRL), growth hormone (GH), thyroid-stimulating hormone (TSH), L-triiodothyronine (T3) and thyroxine (T4). Free T4 (FT4) index was calculated. The values for PRL, GH, and TSH at baseline and after protirelin stimulation were normal. Patients showed lower T3 values at baseline, but a brisker T3 response to protirelin, than controls. Their FT4 indices were higher at baseline. Patients showed diminished T4 binding sites rather than increased total T4. The causes of these alterations in thyroid dynamics are unidentified.

TRH (protirelin) in depressed alcoholic men. Behavioral changes and endocrine responses.

Chronic alcoholics with secondary depression were treated with protirelin in a double-blind, placebo-controlled study. Behavioral data, collected only during the acute alcohol withdrawal state, indicated a beneficial effect of protirelin three hours after injection, but not during subsequent days. Injections caused only mild and infrequent subjective side effects and no cardiovascular effects. Endocrine data were recorded in the acute withdrawal state and after clinical remission. Findings in the acute state suggested thyroid activation and increased central dopaminergic activity, as evidenced by elevated baseline levels of growth hormone, low baseline levels of prolactin, and blunted thyroid-stimulating hormone (TSH) response to protirelin. The first two abnormalities returned to normal levels in the remission state. A blunted TSH response was observed in both the acute and the remission states. Partial persistence of this finding suggests that TSH blunting may not be solely state-dependent. In the acute withdrawal state, TSH blunting was associated with favorable behavioral responses to protirelin.