A prospective study of amylase-rich pleural effusions with special reference to amylase isoenzyme analysis.

By analysis of pleural effusions from 200 patients, 25 cases of amylase-rich effusions were identified, for an overall incidence of 13 percent. Four of the 25 patients (16 percent) had evidence of pancreatitis. These patients had higher mean ratios of pleural fluid to serum amylase levels (18 +/- 6.3 [SEM] vs 4.8 +/- 1.3) compared to patients with nonpancreatic diseases (p = 0.003); all four exhibited a predominant pancreatic isoenzyme profile. Of the 21 patients with nonpancreatic amylase-rich effusions, lung cancer was the most commonly associated condition (8 patients). In 14 of the 21 patients in whom an isoenzyme profile was obtained, salivary-type amylase was predominant. Amylase-rich pleural effusions occur frequently, and pleural fluid isoamylase determination is specific for pancreatitis-associated effusions. The finding of a pleural effusion rich in salivary isoamylase should prompt an evaluation for carcinoma (particularly of lung primary), but may also be seen in other pleural inflammatory conditions.

Synergism between platelet-activating factor (PAF-acether) and prostaglandin E2 in man.

In animal experiments the oedema in the acute inflammatory response is dependent on both increased blood flow and increased vasopermeability (the two component hypothesis). We have confirmed the validity of this hypothesis in man by demonstrating synergistic interaction between PAF-acether (a permeability agent) and prostaglandin E2 (a vasodilator). The mixture of PAF-acether and PGE2 (50 ng; 0.5 micrograms) produced a larger cutaneous wheal volume response than could be accounted for either by summation of the responses to the individual mediators or by the slopes of their dose response curves.

Lung vascular permeability in patients with acute pancreatitis.

Acute pancreatitis may be complicated by acute lung injury associated with increased lung vascular permeability to plasma protein. The pulmonary accumulation of the plasma protein transferrin, radiolabelled in vivo with indium-113m, was monitored using a portable probe radiation detector in sixteen patients with acute pancreatitis. Plasma protein accumulation (PPA) indices were within normal limits (less than 0.5 X 10(-3)min-1) in all survivors (n = 10) and elevated in all but one of the non-survivors. All non-survivors had severe acute pancreatitis as judged by standard criteria. Thus increased lung vascular permeability was not a constant feature of uncomplicated acute pancreatitis and was only observed in patients with multisystem failure accompanied by clinically evident acute lung injury.

High dose parenteral ciprofloxacin in pleuro-pulmonary disease: a comparative pharmacolinetics of 400 and 200 mg intravenous.

In this study we determined the pharmacokinetics of higher IV doses of ciprofloxacin (Cipro) in patients with pleuro-pulmonary diseases undergoing treatment for various bacterial infections. Cipro IV was infused over 30-45 min in 11 patients (seven on 400 mg bid, four on 200 mg bid). Blood samples were taken at intervals of up to 4 h and assayed for Cipro using the HPLC method. The 'mean' peak concentration (C(max)) was 6.9 +/- 2.2 (S.D.) and 11.8 +/- 5.2 (S.D.) for the 200 and 400 mg groups, respectively. The mean concentrations at 1.5 h were 1.2 and 2.6 mg/l and the area under the curve in 0-4 h was 4.6 +/- 0.9 (S.D.) and 7.5 +/- 2.4 (S.D.), respectively for the 200 and 400 mg groups. Steady state serum concentrations of 400 mg were approximately double those for the 200 mg group. IV 200 mg did not reach the required levels to cover the minimum inhibitory concentrations (MICs), whereas, 400 mg IV dose clearly will provide an improved coverage for the commonly encountered organisms with MICs in the 1-4 mg/l range.

Is high-dose fluticasone propionate via a metered-dose inhaler and Volumatic as efficacious as nebulized budesonide in adult asthmatics?

The efficacy and tolerability of fluticasone propionate (FP) 2 mg daily via a metered-dose inhaler and Volumatic (Glaxo Wellcome) spacer device was compared with nebulized budesonide (nBUD), 2 and 4 mg daily, in a multi-centre, open-label, cross-over study of adult asthmatics. Patients received, in random order, either 4 weeks of treatment with FP followed by 4 weeks of treatment with nBUD, or vice versa, with an intervening 4 week 'wash-out' period between treatments. Thirty patients completed the study, of whom 24 were evaluable. In terms of the primary efficacy parameter, change in mean morning peak expiratory flow (PEF) (l min-1) from baseline to the fourth week of each treatment period, FP was more effective than nBUD [mean difference (FP-nBUD) 21.1 l min-1, P = 0.007, 95% CI (6.5, 35.7)]. Sub-group analysis demonstrated FP to be superior to the 4 mg nBUD [mean treatment difference (FP-nBUD) 42.9 l min-1, P = 0.026, 95% CI (7.1, 78.8)] and at least as efficacious as the 2 mg nBUD sub-group [mean treatment difference (FP-nBUD) 10.2 l min-1, P = 0.211, 95% CI (-6.5, 26.9)]. Furthermore, larger reductions in diurnal variation were observed during FP treatment [mean treatment difference (FP-nBUD) -4.4 percentage points, P = 0.028, 95% CI (-8.4, -0.5)]. There was no significant difference between the treatments for the proportion of symptom-free 24 h periods. Of those expressing a preference, significantly more patients found FP via a metered-dose inhaler and spacer device both easier to administer (78%, P = 0.007) and more convenient to take (76%, P = 0.008) than nebulized budesonide. In addition, cost per patient analysis showed that nebulized budesonide was from 1.7 to 3.5 times more expensive than FP.

A dual-isotope method for studying protein kinetics in pleural effusions in humans.

A method is described for studying protein kinetics in pleural effusions in humans. In 15 patients with pleural effusions from a variety of causes, protein inflow was monitored by measuring the rate of appearance in the effusion of the plasma protein transferrin, radiolabelled in vivo by intravenous injection of 113InmCl3. Protein outflow was measured from the rate of appearance in the blood of intrapleurally administered 125I-albumin. Compartmental analysis has been used to determine rate constants k(in) and kout for the movement of labelled proteins into and out of the effusion, respectively. The mean value of k(in) for 15 patients was 9.4 x 10(-4) h-1 (range 2.2-21.4). The mean value of kout in the same patients was 28 x 10(-4) h-1 (range 6-68). Using appropriate assumptions where necessary, the absolute transfer rates of albumin and transferrin were also estimated. For albumin, the mean rate of outflow was 66 mg h-1 (range 27-158), compared to mean estimated inflow of 133 mg h-1 (range 36-381). Protein inflow was highest in a case of metastatic ovarian carcinoma with pleural and peritoneal seedlings, indicating high vascular permeability. Protein outflow was very low in a case of mesothelioma, suggesting severely impaired lymphatic drainage. The technique may prove to be a useful tool for studying mechanisms resulting in the formation of malignant and nonmalignant pleural effusions, and may also be useful for studying the effects of putative therapeutic intervention.

A noninvasive technique for monitoring lung vascular permeability in man.

Increased microvascular permeability resulting in increased plasma protein extravasation is the hallmark of acute inflammatory oedema and hence radiolabelled proteins can be used to monitor this process. The adult respiratory distress syndrome (ARDS) is characterized by acute inflammatory oedema and thus provides an ideal model for studying this type of oedema in the human lung. A noninvasive technique applicable to the intensive care unit has been developed for monitoring the pulmonary accumulation of the plasma protein transferrin. Transferrin was radiolabelled in vivo with indium-113m and its accumulation was monitored using a portable probe radiation detector. After correcting for changes in intrathoracic blood distribution, by simultaneously monitoring the accumulation of technetium-99m-labelled red blood cells, an index of plasma protein accumulation was calculated. In all patients with established ARDS (n = 10) the index values were greater than 1.0 X 10(-3) min-1 and these were clearly separate from the values of less than 0.5 X 10(-3) min-1 in all healthy volunteers (n = 5; P less than 0.001). The technique can clearly detect raised plasma protein accumulation indices in the lungs of patients with established inflammatory oedema of ARDS and hence may provide a pharmacological tool for the rapid evaluation in these conditions of the effects of drugs (like corticosteroids) which are known to modulate inflammatory oedema.

Monitoring pulmonary vascular permeability using radiolabeled transferrin.

A simple, noninvasive technique for monitoring pulmonary vascular permeability in patients in critical care units is discussed. High vascular permeability is observed in patients with clinically defined adult respiratory distress syndrome (ARDS) but not in patients with hydrostatic pulmonary edema or in patients with minor pulmonary insults who are considered to be at risk of developing ARDS. The technique has been used in the field of therapeutics and pharmacology to test the effects of the putative antipermeability agents methylprednisolone and terbutaline sulfate. There appears to be a good correlation between the acute inhibitory effect of either drug on transferrin exudation and patient prognosis. Thus, a byproduct of such drug studies may be an index of survival in patients with established ARDS.

Pleural effusion: a clinical review.

Pleural effusion is a problem commonly encountered by chest physicians, accounting for approximately 4% of all attendances to the chest clinic. In spite of extensive investigations, a significant proportion (approximately 20%) of effusions defy a diagnostic label. This article discusses the role of established, and some of the newer, techniques which are now available for investigating pleural disease in a clinical setting. The initial approach towards a diagnosis usually begins by distinguishing between transudates and exudates, based on protein and lactate dehydrogenase (LDH) concentrations in fluid (usually in relation to their concentration in serum). The exact role of amylase and LDH (and their isoenzymes) may provide additional information towards a differential diagnosis of various exudative pleural effusions. With newer cytochemical staining techniques on pleural fluid, the diagnostic yield of malignant pleural effusions may be increased by up to 80%. Ultrasound (US) and computed tomographic (CT) scan of the chest have further enhanced the diagnostic yield of undiagnosed pleural effusions, especially in relation to the US or CT guided needle biopsy. The re-emergence of thoracoscopy as the latest diagnostic and therapeutic (e.g. pleurodesis) tool for undiagnosed or recurrent pleural effusions, may help in narrowing the diagnostic dilemma faced by clinicians.

Anticholinergic premedication for fibreoptic bronchoscopy.

Atropine is routinely used as part of the premedication regimen for fibreoptic bronchoscopy. This study was performed, firstly, to evaluate the effect of anticholinergic agents on the ease of bronchoscopy, haemodynamic parameters and patient comfort during the procedure; and secondly, to compare atropine with glycopyrrolate, a newer acetylcholine antagonist which is claimed to cause less tachycardia and sedation, whilst suppressing salivation more effectively. One hundred and ninety consecutive patients were randomly allocated to three treatment groups: diazepam 5 mg; diazepam 5 mg + atropine 600 micrograms; and diazepam 5 mg + glycopyrrolate 300 micrograms. Diazepam was given orally one hour before bronchoscopy, and glycopyrrolate/atropine intramuscularly 30 min before bronchoscopy. All patients received thalamonal intravenously, lignocaine gel into one nostril, and lignocaine by transtracheal injection just prior to the procedure. The incidence of bronchoscopy related haemodynamic problems was similar in all three groups. Troublesome coughing, as observed by the operator, was less frequent with glycopyrrolate (control 51%, atropine 42%, glycopyrrolate 30%), as was patient movement (40%, 32%, 19%, respectively). Uncomfortable dryness of the mouth was most common with glycopyrrolate (37%, 32%, 66%, respectively), but overall assessment of discomfort, and the number of patients who would agree to a repeat bronchoscopy (73%, 76%, 70%, respectively) were very similar in all three groups. In conclusion, the differences between the three groups were slight. Glycopyrrolate made the bronchoscopy slightly easier for the operator because of significantly improved cough and movement suppression, though atropine was marginally preferable in terms of patient comfort.

Penetration of intravenous and oral ciprofloxacin into sterile and empyemic human pleural fluid.

OBJECTIVE: To compare the penetration of oral and intravenously administered ciprofloxacin into infected (empyemic) and noninfected (sterile) human pleural fluid. DESIGN: Eleven men and 5 women (aged 29-76) were consecutively selected from adult patients referred to the respiratory unit for pleural effusion. In this open-label, prospective trial, 13 patients with sterile pleural effusions were nonrandomly assigned to receive either ciprofloxacin 200 mg (single intravenous dose), 750 mg (single oral dose), or 750 mg (two oral doses per day for 3 days); 3 patients with infected pleural effusions received 750 mg oral doses for 10 days. Simultaneous pleural fluid and venous blood specimens were drawn over 5 hours after single dose or when steady-state was attained, and ciprofloxacin concentrations were measured by HPLC. RESULTS: Pleural fluid concentrations of ciprofloxacin equaled plasma concentrations 1.5 hours after 200 mg was given intravenously and the pleural/plasma ratio remained > or = 0.9 for 4 hours. After a single 750-mg oral dose, pleural ciprofloxacin concentrations rose from 0 to 1.4 micrograms/mL over 5 hours with the highest pleural fluid/plasma ratio (0.7) at 5 hours. Average steady-state ciprofloxacin concentrations in sterile pleural fluid after 750 mg administered twice daily for 3 days, ranged between 1.1 and 1.8 micrograms/mL with ratios between 0.3 and 0.9 over 4 hours. In empyemic pleural fluid at the same dosage, average steady-state ciprofloxacin concentrations ranged between 1.9 and 3.4 micrograms/mL with ratios between 1.0 and 2.0 over 5 hours. CONCLUSIONS: Oral ciprofloxacin penetrates into sterile and empyemic pleural fluid with concentrations 30-90 percent and 100-200 percent of plasma concentrations, respectively.

Intrathoracic complications of acute pancreatitis.

Acute pancreatitis has an incidence of approximately 50 cases per million of the United Kingdom population and a mortality of 10-18%. Intrathoracic complications have been implicated as the major factor in 22-29% and a contributing factor in a further 29-39% of all deaths. Sixty per cent of deaths occur in the first week of hospital admission and in these the pleuropulmonary complication rate is 94%. In the survivors there is little residual lung damage and the recovery of the pulmonary function is invariably complete. Knowledge of the pleuropulmonary complications of acute pancreatitis may aid with the identification of high risk groups so that supportive measures (including mechanical ventilation) can be implemented early in the course of the illness. This article reviews the major intrathoracic complications of acute pancreatitis (Fig. 1) under the broad headings of: 1. pleural effusion 2. acute pulmonary dysfunction (a) hypoxaemia without pulmonary infiltrates (b) hypoxaemia with pulmonary infiltrates (including the adult respiratory distress syndrome; ARDS).

Beta-adrenoceptor agonist responses in the skin and lungs of asthmatic subjects.

Concomitant intradermal injection of salbutamol inhibits histamine-induced weal volume in the skin of atopic asthmatic subjects and the degree of this inhibition (index of beta-adrenergic effect in the skin) correlates with the bronchodilator effect of inhaled salbutamol in the same subjects (index of beta-adrenergic effect in the lung).

Respiratory failure in acute pancreatitis.

There are a number of important pulmonary complications of acute pancreatitis which make a significant contribution to the morbidity and mortality of the condition. The pathophysiology and management guidelines are given for each and approaches towards better treatment in the future are discussed.

Beta-2-adrenoceptor agonists as inhibitors of lung vascular permeability to radiolabelled transferrin in the adult respiratory distress syndrome in man.

Increased lung vascular permeability leading to increased plasma protein extravasation and accumulation (PPA) is a characteristic feature of acute lung injury. Using a previously described technique, PPA was monitored in the lungs of patients with the adult respiratory distress syndrome (ARDS)--an extreme example of acute lung injury in man. An external radiation probe detector was used to monitor the pulmonary accumulation of the plasma protein transferrin radiolabelled in-vivo with 113mIn. Ten patients with ARDS exhibiting increased PPA indices (greater than 1.0 x 10(-3)/min) were given an intravenous infusion of terbutaline (7 micrograms/kg) over 30 min. Of the four patients in whom the post-drug PPA indices remained within the ARDS range, none survived, whilst five of the six patients in whom the post-drug PPA indices were reduced to below 1.0 x 10(-3)/min survived. PPA indices prior to the administration of terbutaline were not significantly different between the survivor (n = 5) and non-survivor (n = 5) groups. There was a significant decrease in the PPA indices following terbutaline in survivors (p less than 0.01) but not in non-survivors. Thus beta-2-agonists in therapeutic doses can inhibit increased lung vascular permeability in man. These findings may have prognostic and therapeutic implications for beta-2-agonists in ARDS.

The effect of methylprednisolone on the pulmonary accumulation of transferrin in the adult respiratory distress syndrome.

Plasma protein accumulation (PPA) was monitored in the lungs of patients with the adult respiratory distress syndrome (ARDS). Transferrin radiolabelled in vivo with indium-113m was used as the plasma protein marker. Ten patients with clinically defined ARDS, exhibiting increased PPA indices (greater than 1.0 X 10(-3) min-1), were given intravenous infusion of methylprednisolone (MP; 30 mg kg-1 over 10 min). The four patients in whom the PPA indices were reduced to below 0.5 X 10(-3) min-1 within 1 h of completion of MP infusion all survived. In the remaining six patients PPA indices remained above 0.5 X 10(-3) min-1 and five of them died. The PPA indices prior to administration of MP were not significantly different in the survivors (n = 5) and non-survivors (n = 5); however, after MP they were significantly lower in the survivors compared with the non-survivors (P less than 0.02). Thus the response to an infusion of MP, monitored as PPA, may provide a predictor of survival in ARDS.

Is the pleural fluid transudate or exudate? A revisit of the diagnostic criteria.

BACKGROUND: Pleural effusions are classified into transudates and exudates based on criteria developed in the 1970s. However, their accuracy has not been evaluated. We compared the performance of the pleural fluid absolute lactic dehydrogenase level (FLDH), fluid to serum ratio of LDH (LDHR), and fluid to serum ratio of total protein (TPR). TPR has been used instead of the absolute value of fluid protein based on the observation that fluid protein is influenced by changes in the serum protein concentration. However, the rationale for using LDHR remains unexplored. METHODS: Of 212 consecutive patients with pleural effusions, four with multiple causes and eight with an uncertain diagnosis were excluded. ROC curves were generated using sensitivity and 1-specificity values for TPR, FLDH, and LDHR and positive likelihood ratios (LR+ve) were computed using the optimum cut off values. The correlation between pleural fluid and serum concentrations of total protein and LDH was also estimated. RESULTS: Of 200 effusions studied, 156 were exudates and 44 were transudates. The optimum cut off levels were: FLDH 163 IU/l, TPR 0.5, LDHR 0.6, and the FLDH-TPR combination 163 and 0.4, respectively. The area under the curve (AUC) with 95% confidence interval (CI) was: 0.89 (0.86 to 0.96) for FLDH, 0.86 (0.80 to 0.91) for TPR, 0.82 (0.77 to 0.89) for LDHR, and 0.90 (0.86 to 95) for FLDH-TPR. A significant correlation was observed between serum and pleural fluid protein levels in transudates and exudates (r=0.5 and 0.6, respectively), but the correlation between serum and pleural fluid LDH levels was insignificant. CONCLUSION: FLDH is the most accurate marker for the diagnostic separation of transudates and exudates and LDHR has no role in this process. Combining TPR with FLDH appears to improve the diagnostic accuracy slightly.

Evidence in man of synergistic interaction between putative mediators of acute inflammation and asthma.

The two-component hypothesis of acute inflammation postulates that the acute inflammatory response depends on both increased local blood flow and increased microvascular permeability: the validity of this concept has previously been established in animals and was tested here in man. A mixture of the mediators prostaglandin E2 and bradykinin produces a larger cutaneous wheal (volume) response than can be accounted for either by summation of the responses to the individual substances or by the slopes of their dose-response curves. This enhanced response is inhibited by noradrenaline (consistent with the vasoconstrictor property of noradrenaline) and by salbutamol (consistent with the anti-permeability property of salbutamol). These observations indicate that the two-component hypothesis of acute inflammation applies to man as well as animals; this finding is important in the evaluation of the role of putative mediators in the pathogenesis of asthma and other diseases in which inflammation plays a part.