Recent Publications by CFE Educators

Previous results from this laboratory demonstrated that plasma extravasation produced by intra-articular infusion of bradykinin in the rat is mediated by an action on the sympathetic terminals in the knee joint and that adrenal medullary epinephrine regulates the plasma extravasation provoked by bradykinin. Because the release of epinephrine is under cholinergic control, we have now evaluated the effect of nicotinic and muscarinic cholinergic agonists on bradykinin-induced plasma extravasation in the knee joint of the rat. We report that s.c. administration of nicotine and carbachol attenuated plasma extravasation induced by bradykinin; this attenuation was significantly antagonized by systemic injection of hexamethonium and atropine, respectively. The nicotine and carbachol effects were also significantly attenuated after removal of the adrenal medulla. These results indicate that both nicotine and carbachol can inhibit bradykinin-induced plasma extravasation and that this inhibition is mediated, at least in part, through activation of nicotinic and muscarinic receptors in the adrenal medulla. Finally, local perfusion of the knee joint with hexamethonium did not affect the inhibition of bradykinin-induced plasma extravasation produced by systemic nicotine. Intra-articular perfusion of atropine potentiated the inhibition of bradykinin-induced plasma extravasation by systemic carbachol, indicating that muscarinic receptors in the synovium also contribute to plasma extravasation. The inhibitory action of nicotine on plasma extravasation may contribute, in part, to the reported increased severity of arthritis in individuals who smoke.

Collagen deposition is a prime determinant of clinical course in idiopathic pulmonary fibrosis (IPF). Identification of a marker of connective tissue metabolism would significantly enhance the ability to stage the disease and monitor the course of these patients. Prior studies of IPF have indicated that N-terminal Type III procollagen peptide (N-PIIIP) levels in blood and bronchoalveolar lavage BAL fluid are elevated. We hypothesized that elevated levels of procollagen peptides are a marker of enhanced collagen deposition, which is associated with interstitial fibrosis characterizing active disease. The purpose of the present study was to explore the relationship between N-PIIIP recovery and physiologic parameters of lung function. N-PIIIP levels in sera and bronchoalveolar lavage (BAL) from 24 patients with IPF and 29 volunteers were measured by radioimmunoassay. The extent of disease in IPF was assessed by clinical history, physical examination, chest radiograph, pulmonary physiology evaluation, and confirmatory open-lung biopsy. The severity of disease was graded using a previously described clinical, radiologic, and physiologic (CRP) scoring system. N-PIIIP normalized to albumin was higher in BAL than in serum for both volunteers (1.6-fold; p less than 0.05) and IPF patients (24-fold; p less than 0.05), consistent with local pulmonary production. BAL N-PIIIP was significantly elevated in IPF patients, whether expressed as concentration (healthy volunteer 0.11 +/- 0.06 ng/ml; IPF, 5.0 +/- 14.4; mean +/- SD; p less than 0.05) or normalized to albumin (healthy volunteer, 2.8 +/- 1.2; IPF, 73 +/- 106; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE

Hypersensitivity pneumonitis refers to a group of pulmonary disorders caused by inhalation of organic or inorganic particulates by sensitized persons. The diagnosis relies on a constellation of findings: exposure to an offending antigen, characteristic signs and symptoms, abnormal chest findings on physical examination, and abnormalities on pulmonary function tests and radiographic evaluation. In population-based studies, the sensitivity of chest radiography for detection of this disease is relatively low. The aim of this study was to determine the sensitivity of high-resolution CT (HRCT) for detection of hypersensitivity pneumonitis diagnosed in a population of swimming-pool employees.

SUBJECTS AND METHODS

Thirty-one symptomatic employees of a recreation center who were referred because of possible hypersensitivity pneumonitis were examined by using chest radiography, HRCT, and fiberoptic bronchoscopy with bronchoalveolar lavage and transbronchial biopsy. Hypersensitivity pneumonitis was diagnosed in subjects who had two or more work-related signs or symptoms, abnormal results on transbronchial biopsies, and abnormal lymphocytosis as shown by examination of bronchoalveolar lavage fluid. The chest radiographs and HRCT scans were interpreted by consensus by two observers who were unaware of the clinical diagnosis.

RESULTS

Only one of 11 subjects with a diagnosis of hypersensitivity pneumonitis had abnormal findings on a chest radiograph. Five had abnormal HRCT findings. The abnormality in each case consisted of small, poorly defined centrilobular nodules with variable profusion. No subject without the disease had abnormal HRCT findings. Those who had granulomas shown by lung biopsy were more likely to have abnormal HRCT findings than were those who had more subtle histologic abnormalities.

CONCLUSION

The sensitivity of HRCT for the detection of hypersensitivity pneumonitis in a population-based study is greater than that of chest radiography. The finding of poorly defined centrilobular nodules on HRCT scans should prompt consideration of this disease.

In a search for CO2 chemoreceptor neurons in the brain stem, we used immunocytochemistry to monitor the expression of neuronal c-fos, a marker of increased activity, after 1 h of exposure to CO2 in five groups of Sprague-Dawley rats (294 +/- 20 g): five air breathing controls, three breathing 10% CO2, three breathing 13% CO2, three breathing 15% CO2, and three breathing 15% CO2 and treated with morphine (10 mg/kg sc). After exposure the rats were anesthetized with pentobarbital sodium and perfused intracardially with 4% paraformaldehyde. The brain stem was removed and cryoprotected, and then 50-microns frozen sections were cut and immunostained for the fos protein. Brain stem fos-immunoreactive neurons were plotted and counted in the superficial 0.5 mm of the ventral medullary surface. Thirteen to 15% CO2 evoked fos-like immunoreactivity (FLI) in 321 +/- 146 neurons/rat. Significant CO2-induced labeling was confined within the superficial 150 microns: 67% of identified cells were less than 50 microns below the surface, greater than 90% between 1.0 and 3.0 mm from the midline, and approximately 60% in the rostral half of the medulla. Thirteen to 15% CO2 also evoked FLI in the area of the nucleus tractus solitarius but not in other medullary regions. Morphine (10 mg/kg sc) did not suppress high CO2-evoked FLI in either the ventral medullary surface or the nucleus tractus solitarius, although it eliminated excitement and hyperventilation. We suggest that respiratory CO2 chemoreceptor neurons can be identified in rats by their expression of c-fos after 1 h of hypercapnia.(ABSTRACT TRUNCATED AT 250 WORDS)

We describe a microdialysis probe with attached side catheter for making submicroliter injections at the site of the probe in the awake, freely moving rat. This design allows the local application of drugs which cannot be applied in the perfusion medium either because of their inability to pass through the dialysis membrane or because of their interference with chromatographic detection of compounds of interest.

Cryptogenic organizing pneumonitis is a clinical and pathologic syndrome characterized by a "pneumonia-like" illness with excessive proliferation of granulation tissue within small airways and alveolar ducts associated with chronic inflammation in the surrounding alveoli. The duration of illness prior to lung biopsy is short, usually less than 2 months, and it is markedly different from that of IPF. Interestingly, unlike in IPF where the patient has difficulty remembering the exact onset of symptoms, patients with COP are frequently very specific about the timing of their disease onset. This is because the disease onset is recent and is often dramatic with the development of a severe flulike illness, ie, cough, fever, malaise, fatigue, and weight loss. Inspiratory crackles are frequently present on chest examination. Pulmonary function is usually impaired with a restrictive defect being most common. Gas exchange abnormalities are extremely common with a reduction in Dco and resting hypoxemia being almost universal findings. The roentgenographic manifestations are quite distinctive with a pattern of bilateral, diffuse but inhomogeneous, ground-glass or alveolar opacities being present in the majority of the cases. Bronchoalveolar lavage findings are nonspecific but usually reveal a lymphocytosis. The response to corticosteroid treatment is quite favorable and death from progressive disease is uncommon in COP, especially if treatment is instituted early in the course of the disease. In our experience, the cases with the worse prognosis are those associated with another disease process, in particular, connective tissue disorders like rheumatoid arthritis. In fact, these patients are prone to develop a rapidly progressive form of BOOP with a clinical course similar to the "Hamman-Rich syndrome." Recurrences are relatively frequent, consequently, withdrawal of treatment should be done with extreme caution. Corticosteroids have been the conventional initial treatment of COP, although to our knowledge, there are no controlled clinical trials to support it use. Antibiotics are not effective in treating this syndrome. Thus, based solely on our experience and that of others, we believe that high-dose corticosteroid therapy should be used to treat COP, usually initiated with 1 to 1.5 mg/kg/day (using ideal body weight) not to exceed 100 mg/day. Prednisone is given as a single oral dose in the morning. We recommended maintaining this dose for 4 to 8 weeks. If the patient's condition is stable or improved, the prednisone dosage is gradually tapered to 0.5 to 1 mg/kg/day (using ideal body weight) for the ensuing 4 to 6 weeks.(ABSTRACT TRUNCATED AT 400 WORDS)

OBJECTIVE

To describe and compare with standard cardiopulmonary resuscitation (CPR) in humans a new form of CPR that involves both active compression and active decompression of the chest.

DESIGN

Patients in cardiac arrest in whom standard advanced cardiac life support failed were randomized to receive 2 minutes of either standard or active compression-decompression (ACD) CPR using a custom, hand-held suction device, followed by 2 minutes of the alternate technique. The ACD device was applied midsternum and used to perform CPR according to the guidelines of the American Heart Association: 80 compressions per minute, compression depth of 3.8 to 5 cm, 50% duty cycle, and constant-volume ventilation. Mechanical Thumper CPR was also compared in five patients. End-tidal carbon dioxide (ETCO2) concentrations and hemodynamic variables were measured. Transesophageal Doppler echocardiography was used to assess contractility, the velocity time integral (an analogue of cardiac output), and diastolic myocardial filling times.

RESULTS

Ten patients were enrolled. The mean +/- SD ETCO2 was 4.3 +/- 3.8 mm Hg with standard CPR and 9.0 +/- 3.9 mm Hg with ACD CPR (P less than .0001). Systolic arterial pressure with standard CPR was 52.5 +/- 14.0 mm Hg and with ACD CPR, 88.9 +/- 24.7 mm Hg (P less than .003). The velocity time integral increased from 7.3 +/- 2.6 cm with standard CPR to 17.5 +/- 5.6 cm with ACD CPR (P less than .0001), and diastolic filling times increased from 0.23 +/- .09 seconds with standard CPR to 0.37 +/- .12 seconds with ACD CPR (P less than .004). Mechanical Thumper CPR consistently underperformed both standard and ACD CPR. Minute ventilation obtained in four patients during ACD CPR without endotracheal ventilation was 6.6 +/- 0.9 L/min. After 1 hour of standard CPR failed, three of 10 patients randomized to ACD CPR rapidly converted to a hemodynamically stable rhythm following 2 minutes of ACD CPR.

CONCLUSION

ACD CPR is a simple manual technique that improved cardiopulmonary circulation in 10 patients during cardiac arrest. Although ACD CPR may have produced a return of spontaneous circulation in three patients refractory to standard measures, its impact on survival when used early in cardiac arrest remains to be determined.

Bronchoalveolar lavage (BAL) allows the recovery of cellular and fluid constituents that are derived from the epithelial surface of the lower respiratory tract. BAL fluid and cell analysis has become an important tool for understanding human pulmonary disease. Changes in the quantities and patterns of BAL cells and secretions have been described in a number of chronic lung disorders, especially the diffuse interstitial lung diseases. Specific BAL alterations have correlated with patient outcome and response to therapy. The connective tissue diseases have been associated with serious pleural and/or pulmonary pathology and may be a major cause of morbidity and mortality. BAL appears to be a useful semi-invasive tool in the evaluation and management of lung disease in patients with connective tissue diseases. The article describes the BAL findings in various connective tissue diseases and assesses the usefulness of BAL in the clinical management of patients with pulmonary complications.

Between January 1986 and October 1991 255 patients with rectal tumors were treated by local excision. In 239 patients local excision was performed by transanal endoscopic microsurgery, 16 tumors were removed with the retractor developed by Parks. Operative mortality was 1% in 189 local removed adenomas, complications were observed in two patients (2.1%), local recurrences in seven patients (3.7%). 66 rectal carcinomas were treated by local excision (operative mortality 1%, complication rate 3%). In one of 28 local excised "low risk" T1-carcinomas a recurrence was observed. Five of eleven local treated patients with "high risk" tumors developed a recurrence. Endosonography was of utmost importance in preoperative staging of rectal tumors. Between June 1987 and October 1991 204 patients with rectal tumors (92 sessile adenomas, 30 T1-carcinomas and 82 advanced carcinomas) were examined preoperatively by endosonography. The diagnosis of an adenoma or a T1-carcinoma was made with a sensitivity of 0.9, although no differentiation was possible between adenomas and T1-carcinomas. Results of digital examination were comparable to endosonography, under condition that digital examination was complete. Insufficient information was obtained from the endosonographic detection of lymph-node metastatic spread.