Cerebral blood flow in rats with renal and spontaneous hypertension: resetting of the lower limit of autoregulation.

The effect of chronic hypertension on cerebral blood flow (CBF) was studied in anaesthetised rats. CBF was measured with the intracarotid 133Xe injection method. Rats with spontaneous and renal hypertension were compared with normotensive controls. The lower limit of autoregulation was determined during controlled haemorrhage. In the normotensive rats, CBF remained constant until mean arterial pressure (MAP) had decreased to the range of 50-69 mm Hg. Thereafter, CBF decreased with each further decrease in MAP. In both types of hypertensive rats, CBF remained constant until MAP had decreased to the range of 70-89 mm Hg. Thus, a 20-mm Hg shift of the lower limit of CBF autoregulation was found in both spontaneous and renal hypertensive rats. A neuropathological study revealed ischaemic brains lesions in half of the hypertensive rats following hypotension, whereas only a single lesion was found in one of six normotensive rats. No ischaemic brain lesions were found in a control study in which CBF was shown to be stable over a 21/2-h period. In conclusion, hypertensive rats showed a shift of the lower limit of CBF autoregulation as well as an increased susceptibility to ischaemic brain damage during hypotension. These findings presumably reflect hypertensive structural changes in the cerebral circulation.

Effects of amiloride on plasma and total body potassium, blood pressure, and the renin-angiotensin-aldosterone system in thiazide-treated hypertensive patients.

Total body potassium content, plasma potassium concentration, blood pressure, and plasma concentrations of renin, angiotensin II, and aldosterone were measured in patients with essential hypertension after a run-in period of 8 wk on a regimen of hydrochlorothiazide (median dosage 75 mg/day). Patients were then randomly assigned to continued hydrochlorothiazide therapy (group I) or to receive adjunctive treatment with amiloride (group II, median dosage 15 mg/day or 5 mg per 25 mg hydrochlorothiazide) for the following 3 mo. There were no changes in group I patients during 3 mo on hydrochlorothiazide in plasma potassium, total body potassium content, or the renin-angiotensin-aldosterone system. Blood pressure was also unchanged. In group II patients addition of amiloride to hydrochlorothiazide induced a rise in plasma and total body potassium of approximately 15% and 4%. The potassium-retaining effect was maintained throughout the 12-wk period, although the maximal changes were observed after 8 wk of treatment. Supine blood pressure did not change, but there was a significant decrease in standing systolic blood pressure. There was a marked rise in plasma concentrations of renin, angiotensin II, and aldosterone.

Effects of acute volume loading on kidney function in patients with essential hypertension, as estimated by the lithium clearance method.

This study investigated the mechanism underlying the exaggerated natriuresis seen in patients with essential hypertension. The study used the lithium clearance method, which permits accurate determination of both proximal and distal sodium reabsorption in man. One litre of isotonic sodium chloride, intravenously (i.v.), produced a significant increase in sodium excretion in patients with essential hypertension, both during and after the infusion. This increase in sodium excretion was accompanied by a significant increase in the clearance of lithium, indicating an increased output of isotonic fluid from the proximal tubules. The calculated distal reabsorption of sodium increased during the natriuresis. In the normotensive controls, sodium excretion increased only after the infusion of 1 l isotonic saline. This was accompanied by a modest increase in absolute distal sodium reabsorption. However, when the amount of saline was increased to 2 l, similar changes to those seen in hypertensives given 1 l of saline occurred in normotensive subjects. Furthermore, chronic antihypertensive treatment abolished the phenomenon of exaggerated natriuresis. It is concluded that the exaggerated natriuresis represents the normal response to sodium loading being reset to a lower level. This resetting may be a secondary consequence of the high blood pressure, since lowering the pressure abolishes the phenomenon.

Necrotizing vasculitis in athymic rats with infarct kidney hypertension.

Infarct kidney hypertension was induced in congenital athymic nude rats and in their haired normal littermates. In both groups a significant and similar elevation of blood pressure was observed. The mesenteric vessels were studied histologically five, 12 and 20 days after operation. Necrotizing vasculitis with and without perivascular inflammatory reactions was found in mesenteric arteries and arterioles in six out of six athymic and in six out of 11 control rats. In sham operated athymic rats and in haired littermates neither hypertension nor vasculitis was observed. These observations indicate that the thymus play no role in the pathogenesis of acute hypertensive vascular disease.

Association between HLA-DRB3*0101 and immunoglobulin-E responsiveness to Bet v I.

The relationship between HLA-DRB3 antigens and specific IgE responsiveness to highly purified major allergen from white birch (Betula verrucosa), Bet v I, was studied in 43 patients, who were skin-prick test positive to birch pollen extract. Specific IgE to Bet v I was measured using an assay based on the principle of the Magic Lite method. HLA-DR and -DQ typings were performed by standard restriction fragment-length polymorphism techniques and HLA-DRB3 typing by the use of polymerase chain reaction and sequence-specific oligonucleotide. Of the 43 patients, 41 (95%) exhibited Bet v I-specific IgE. The data showed a significant association between HLA-DRB3*0101 and specific IgE to Bet v I (pc = 0.02). Furthermore, it was shown that this association was linked to the overall IgE responsiveness and not to a limited area of IgE sensitivity. The present study confirms and further identifies the association of DRB3*0101/0301 earlier described in an Austrian population to be present also in a Danish study group. This underlines the importance of this particular allele in the allergic immune response to birch pollen and emphasizes the importance of investigating the molecular basis of human allergic immune responsiveness.

Medium-term patency and anatomic changes after direct bronchial artery revascularization in lung and heart-lung transplantation with the internal thoracic artery conduit.

OBJECTIVE: Our purpose was to study the 2-year patency of direct bronchial artery revascularization in lung transplantation. We wanted to clarify whether the revascularized bronchial artery system is functional after 2 years, whether bronchial artery vascularity changes with time, and whether posttransplantation bronchial artery disease is arteriographically evident after 2 years. METHODS: Bronchial artery revascularization is performed by anastomosing the internal thoracic artery to as many bronchial artery orifices in the donor descending aorta as possible. Twenty-three patients surviving 2 years or more have had internal thoracic artery-bronchial arteriography performed 1 month and 2 years after transplantation. One-month and 2-year arteriograms have been compared. RESULTS: Two-year patency of the internal thoracic artery conduit was 100%. The appearance of the bronchial arteries was unchanged after 2 years in 11 patients. A unilateral or bilateral increase in vascularity was found in two and seven patients, respectively. In three patients new vessels, not visible on the first arteriogram, had appeared. In four patients one or more small vessels visible on the first arteriogram had disappeared on the second arteriogram. We have found no arteriographic signs of bronchial artery disease, such as stenosis of the bronchial arteries, and no arteriographic evidence of arteriosclerotic disease in the internal thoracic artery. CONCLUSION: The internal thoracic artery is an excellent conduit for bronchial artery revascularization, with a 2-year patency of 100% in 23 patients. Only minor changes in the bronchial arteriograms have been found.

Apoptosis in acute pulmonary allograft rejection and cytomegalovirus infection.

Apoptosis is a form of programmed cell death, characterized by activation of endonucleases that cleave DNA into oligonucleosomal fragments, which can be identified by in situ terminal deoxyribonucleotide transferase-mediated dUTP nick-end labeling (TUNEL). This process has recently been implicated in cardiac and hepatic allograft rejection, and we investigated its contribution to acute pulmonary allograft rejection and cytomegalovirus (CMV) pneumonitis by in situ TUNEL of transbronchial biopsy specimens. In situ TUNEL was performed on 70 transbronchial biopsy samples collected from 25 pulmonary allograft recipients for diagnosis of acute rejection or CMV pneumonitis, and the number of apoptotic nuclei/mm2 was correlated with the rejection grade (International Society of Heart and Lung Transplantation classification). During acute pulmonary allograft rejection, apoptotic nuclei were demonstrated in pulmonary parenchymal cells and mononuclear infiltrating cells, and the number of apoptotic cells was positively correlated with the rejection grade. In addition, a marked increase in the density of apoptotic cells was found in pulmonary allografts with CMV pneumonitis. We conclude that apoptosis contributes to cell death during acute pulmonary allograft rejection and CMV infection.

Macrophage and lymphocyte chimerism in bronchoalveolar lavage cells from human lung allograft recipients.

BACKGROUND: Chimerism is suggested to predict a more favourable prognosis in solid organ transplantation. MATERIAL AND METHOD: Forty-eight bronchoalveolar lavages from 10 patients (5 females and 5 males) who had received sex-mismatched donor lungs were monitored for varying periods of time, of up to 2 years, at regular intervals (median 3.0 (0.5-24) months). To investigate the chimerism in macrophages and lymphocytes in bronchoalveolar lavage cells a cloned 2.12 kilobase large biotinylated Y-chromosome-specific DNA-probe was used for in situ hybridization. RESULTS: Donor macrophages disappeared in seven patients within the first 6 months after surgery (median 3.0 (1-6) months). But 15% donor macrophages could be detected in one patient 1 year and 10% in 2 patients two years after surgery. Donor lymphocytes disappeared in all patients within 3 months (median 1 (0.5-3) months). There was no correlation between periods or severity of acute rejection and percentage of donor macrophages and donor lymphocytes in bronchoalveolar lavage. None of the patients developed obliterative bronchiolitis. CONCLUSION: Macrophage chimerism in lung may exist for several years. Whilst our results do not elucidate the role of local macrophage chimerism, they do not currently support the view that chimerism prevents rejection.

Apoptosis and formation of peroxynitrite in the lungs of patients with obliterative bronchiolitis.

BACKGROUND: Obliterative bronchiolitis (OB) is the principal long-term complication of lung and heart-lung transplantation. OB is characterized histologically by inflammation, epithelial cell loss, fibrosis, and obliteration of the terminal airways. The contribution of apoptosis and peroxynitrite formation in OB was examined and assessed whether immunohistochemical markers of these reactions in transbronchial biopsy specimens were predictive of OB development. METHODS: Pulmonary tissue samples from lung transplant recipients with OB (n = 5) or without OB (control group; n = 7) were investigated by in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and nitrotyrosine immunohistochemistry. Furthermore, TUNEL and nitrotyrosine expression was compared between matched transbronchial biopsy specimens from the two patient groups. RESULTS: Sections with active OB displayed a significantly increased number of TUNEL-positive epithelial cells and macrophages compared with very little TUNEL in control specimens. TUNEL was almost absent in inactive OB. Nitrotyrosine was detected in all samples of pulmonary tissue, but nitrotyrosine expression was more intense in patients with active OB. There was no apparent temporospatial correlation of TUNEL and nitrotyrosine expression, and in matched transbronchial specimens, these immunohistochemical markers failed to identify patients with imminent risk of developing OB. CONCLUSIONS: Apoptosis contributes to the pathophysiology of active OB but is apparently not directly paralleled by tissue peroxynitrite formation. In transbronchial biopsy specimens, markers of apoptosis and peroxynitrite formation are not valid predictors of OB and more studies are required to deliniate the role of these mechanisms in pulmonary allograft rejection.

Surgical and arteriographic results of bronchial artery revascularization in lung and heart lung transplantation.

BACKGROUND: On the basis of our experience with bronchial artery revascularization (BAR) in lung transplantation since its introduction in Copenhagen in 1992, a description of the surgical anatomy of the bronchial arteries and the results of attempted BAR in these patients will be presented. METHODS: Since June 1992, BAR was performed in 50 en bloc double lung, six single lung, and nine heart-lung transplantations. The location, number, type, and size of each bronchial artery identified and revascularized were recorded. Our choice of conduit for BAR was the internal mammary artery. Routine internal mammary-bronchial arteriography was performed early after the transplantation to evaluate the result of BAR. All arteriograms were carefully studied together with the surgical records. The arteriographic results after attempted BAR were classified as complete, incomplete (bilateral, hemilateral, or poor), or failed. The surgical and arteriographic anatomy of the bronchial arteries has been described, and nomenclature for the as yet unnamed bronchial arteries has been developed. RESULTS: During surgery 128 bronchial arteries were identified in the descending aorta of the 64 donor lung blocs. Internal mammary-bronchial arteriography was performed in 53 patients. BAR was complete in 32, incomplete in 18, and failed in 3. The number of bronchial arteries identified and revascularized in each case increased with experience. The central and intrapulmonary bronchial artery anatomy was described, and different patterns have been identified. CONCLUSIONS: Bronchial artery identification is reliable, but a learning process is involved. BAR is possible with a high success rate. Complete BAR is an obtainable goal in most cases.

Direct bronchial artery revascularization and en bloc double lung transplantation--surgical techniques and early outcome.

BACKGROUND: Lung transplantation including direct bronchial artery revascularization (BAR) has produced promising early results in small clinical series. METHODS: In Copenhagen primary en bloc double lung transplantation with BAR, with the left mammary artery used as conduit, has been performed in 47 patients from 1992 to the end of 1995. After introduction of the bloc into the recipient, the mammary-to-bronchial artery anastomosis is performed as the first anastomosis, allowing perfect exposure and early reperfusion. Internal mammary-bronchial artery arteriography has been performed routinely after operation. RESULTS: Bronchoscopic examination performed in all patients documented normal airway healing in 42, disturbed in two, and complicated in three. Arteriography performed in 42 patients demonstrated complete BAR in 25, incomplete in 15, and failed BAR in 2. Failed BAR was associated with complicated airway healing. The 1- and 2-year survival rate (Kaplan-Meyer) is 83%. Eleven patients have died, only one within 30 days. The total incidence of bronchiolitis obliterans syndrome at 3 years (with Kaplan-Meier technique) is 33%. Successful BAR has also been performed with an adjusted technique in a limited number of heart-lung and single lung transplantations. Our total experience of BAR in any type of lung transplantation includes 65 patients with an arteriographic BAR success rate of 94% (50 of 53 examined patients). CONCLUSIONS: Experience has improved the surgical technique and has made BAR reliable and safe, be it double lung, single lung, or heart-lung transplantation. Early results are good, but only follow-up will show if long-term results after lung transplantation will be improved by BAR. Already today, en bloc double lung transplantation with BAR is a viable alternative to sequential bilateral lung transplantation.

Revascularization of the bronchial arteries in lung transplantation: an overview.

Development of the surgical technique has minimized the incidence of airway problems associated with single as well as sequential bilateral lung transplantation. Although early results are good, long-term results remain unsatisfactory. The main problems after lung transplantation are pulmonary infections and the bronchiolitis obliterans syndrome. The bronchiolitis obliterans syndrome is usually considered to be chronic rejection, but a multifactorial genesis including airway ischemia has been suggested. We reviewed the literature relevant to direct bronchial artery revascularization during lung transplantation. Although information is limited, there are good reasons to believe that reestablishment of the dual blood supply to the transplanted lung is beneficial not only for healing of the airway anastomoses, but also for the airway and the lung responses to pathologic conditions. In small series, methods of bronchial artery revascularization have proved successful and have been associated with good early results. We believe it is justified to test the impact of direct bronchial artery revascularization on outcome after lung transplantation in large clinical series.

Cardiopulmonary function at rest and during exercise after resection for bronchial carcinoma.

BACKGROUND: Measurements of postoperative spirometric values after pneumonectomy and lobectomy vary considerably, and few researchers have studied the changes in exercise capacity during maximal work after lung resection. The purpose of this study was to describe the postoperative alterations in cardiopulmonary function. METHODS: Ninety-seven consecutive patients with lung malignancy were prospectively examined with maximal exercise test, spirometry, and arterial gas tensions. Fifty-seven patients were reinvestigated 6 months postoperatively. RESULTS: In patients having lobectomy, forced expiratory volume in 1 second decreased 8%, and exercise capacity, expressed by maximal oxygen uptake and maximal work rate, significantly decreased 13%. In patients having pneumonectomy forced expiratory volume in 1 second significantly decreased 23%, but the loss in lung volume was partly compensated as measured by exercise capacity, which decreased only 16%. Generally patients with the smallest preoperative forced vital capacity had the smallest postoperative deterioration expressed in percentages. We found a weak correlation between alterations in maximal oxygen uptake and lung function after resection. CONCLUSIONS: Lobectomy is associated with only minor deterioration of lung function and exercise capacity. Pneumonectomy causes a decrease in pulmonary volumes to about 75% of the preoperative values, partly compensated in better oxygen uptake, which postoperatively was about 85% of the preoperative values. Alteration in forced expiratory volume in 1 second is a poor predictor of change in exercise capacity after pulmonary resection.

Early experience of double-lung transplantation with bronchial artery revascularization using mammary artery.

En-bloc double-lung transplantation with tracheal and bronchial revascularization using the left internal mammary artery has been performed in 14 Danish patients. Primary healing of the tracheal anastomosis was observed in 12 patients, in 10 of whom a successful revascularization has been verified by angiography. Two patients have been operated recently and not yet examined by angiography. Mucosal necrosis and subsequent development of bronchial stenosis had to be treated by left-sided pneumonectomy in two patients with failed revascularization. All patients were early survivors (1-14 months). We conclude that bronchial revascularization with the internal mammary artery is possible with an acceptable success rate and is associated with primary healing of the tracheal anastomosis. The impact on long-term results remains to be seen.

Comparability of albuterol delivered by a piezoelectric device versus metered dose inhaler in patients with chronic obstructive airways disease.

In recent years, there has been increased interest in developing propellant-free inhalers for the treatment of patients with chronic obstructive airways disease. Various powder inhalators have been developed. A recent alternative to the dose-metered aerosols has been produced using the piezoelectric effect. This double-blind, double-dummy, randomized, dual-dose, four-period crossover study was designed to compare the effect of albuterol inhaled from the piezoelectric device (PED) and albuterol inhaled from the metered dose inhaler (MDI). The primary efficacy variables were forced expiratory volume in one second (FEV1) and area under the curve (AUC). Although we found a statistically significant device effect for the primary efficacy variables, the two treatments (PED [test] and MDI [reference]) are comparable. The only variable for which comparability was not found was time of onset. We found no dose differences. In conclusion, we found a similar effect of albuterol inhaled by a PED versus an MDI in patients with chronic obstructive airways disease.

Comparison between different techniques for measuring nasal patency in a group of unselected patients.

Many techniques for measuring nasal patency have been developed in search for a reliable, easily performed and reproducible method. Rhinomanometry is easily performed in the clinic but daily records of nasal blocking cannot be obtained. In this study we examined the correlation between posterior rhinomanometry (PR), nasal peak flow (nPF), the ratio nasal patency index (NPI), and the opening interrupter method (Rtn) for measuring nasal patency. Twenty-eight subjects with no symptoms of rhinitis and 20 patients with diagnosed rhinitis were investigated. A significant (p less than 0.05) correlation was found between PR and nPF after stratification according to the diagnosis of rhinitis and between nPF, PR, and height. All other correlations tested proved non-significant. We conclude that PR is the method which ought to be used in the hospital, but nPF is an easy way to measure nasal patency and might even be used by the patient at home.

[Monoclonal interleukin-2 receptor antibodies and their use in clinical kidney transplantation: basiliximab and daclizumab]. / Monoklonale interleukin-2-receptorantistoffer og deres anvendelse ved klinisk nyretransplantation: basiliximab og daclizumab.

Basiliximab and daclizumab are analogous immunosuppressive agents approved for clinical renal transplantation. Both drugs are gene manipulated chimeric human/murine monoclonal antibodies with specificity against the alpha-chain of the interleukin-2 receptor (IL-2R) on activated T lymphocytes. By combining the drugs with calcineurin inhibitor based immunosuppression, an inhibition of the interleukin-2 (IL-2) synthesis as well as the IL-2/IL-2R reception is obtained. Consequently, the allogeneic immune response is suppressed and the risk of acute rejection of the transplant is reduced. By treatment with basiliximab or daclizumab in the recommended doses, a blockade of the IL-2R is obtained for up to 12 weeks. The incidence of acute rejection episodes is reduced by approx. 33%. The incorporation of human amino acid sequences has almost eliminated the immunogenicity of the drugs and reduced their rates of elimination. The side effects of prophylactic treatment with basiliximab/daclizumab do not differ from those of placebo.

[Lung transplantation]. / Lungetransplantation.

Isolated lung transplantation or combined heart and lung transplantation provides a new therapeutic possibility for patients with certain benign terminal pulmonary diseases. This method of treatment makes great demands on not only the donors but also the recipients. Following operation, which is undertaken in selected centres, life-long clinical control with immune suppressive treatment is essential. The method of treatment is associated with a series of complications and long-term survival does not appear to be optimal yet. A series of Danish patients have received lung transplantation abroad and are now followed in Danish special departments in cooperation with their own general practitioners.

[The significance of incorrect spray technic on the consumption of terbutaline in patients with chronic obstructive lung disease]. / Betydningen af fejlagtig sprayteknik på terbutalinforbruget hos patienter med kronisk obstruktiv lungesygdom.

A total of 140 patients with chronic obstructive pulmonary disease was included in this multicentre parallel group investigation with the object of assessing whether poor inhalation technique results in increased consumption of beta 2-agonist. On the basis of measurements of pulmonary function, the patients were stratified into two groups with good and poor inhalation techniques, respectively, and these were subdivided at random to inhalation of terbutaline via either a freon spray (aerosol) or Turbohaler (powder). During a period of four weeks the daily terbutaline consumption, the symptoms and pulmonary function were noted. Patients with poor inhalation technique did not have significantly increased terbutaline consumption. The consumption of terbutaline was independent of the method of administration. The Turbohaler was just as effective as the spray and the patients preferred this method, (p less than 0.05).

[CFC gases in medicinal sprays]. / CFC-gasser i medicinske spray.

In 1987, approximately 1.18 million aerosol dispensers for medicinal use were sold in Denmark. These contained approximately 29 tons of completely halogenized CFC gases ("Freon") and the preparations were employed for the treatment of bronchial asthma and rhinitis. The possibilities of substitutes are discussed in this article. Preparations are already available which do not contain CFC. Producers of CFC are also attempting to develop new aerosol gases which do not damage the environment. Perhaps these will be found in medicinal preparations in the future.