Immunoglobulin G-induced single ionic channels in human alveolar macrophage membranes.

While it is well known that the engagement of IgG Fc receptors on the macrophage surface triggers a number of cellular responses, including particle ingestion, secretion, and respiratory burst activity, the mechanism of signal transmission following ligand binding remains poorly understood. To acquire more data in this area, we studied the electrical properties of the macrophage membrane and its response to oligomeric immunoglobulin G (IgG) using the patch-clamp technique on human alveolar macrophages that were obtained by bronchoalveolar lavage and maintained in short-term tissue culture. The results showed that cell resting potentials, as determined from whole-cell tight seal recordings, increased from -15 mV on the day of plating to -56 mV after the first day in culture and remained stable at this hyperpolarized level. Macrophages revealed an input resistance of 3.3 G omega, independent of age in culture. Extracellular application of heat-aggregated human IgG to cells voltage-clamped at -70 mV resulted in peak inward currents of approximately 470 pA. We identified an IgG-dependent, nonselective channel in both cell-attached and isolated membrane patches, with a unitary conductance of approximately 350 pS and a predominant subconductance level of 235 pS in symmetrical NaCl solutions. Single channel open times were observed to be in the range of seconds and, in addition, were dependent upon membrane voltage. Channel opening involved transitions between a number of kinetic states and subconductance levels. Channel events recorded in cell-attached patches showed characteristic exponential relaxations, which implied a variation in membrane potential as a result of a single ion channel opening. These data suggest that the IgG-dependent nonselective cation channel that we have characterized may provide the link between Fc receptor engagement and subsequent cellular activation.

Ibuprofen in canine endotoxin shock.

The participation of prostaglandins in the physiologic alterations of endotoxin shock has been well established with the aid of prostaglandin synthetase inhibitors. Our study was designed to investigate the potential of ibuprofen, a highly specific cyclooxygenase inhibitor, to reverse the hemodynamic and acid base abnormalities of canine endotoxin shock. Mean blood pressure fell to 49.8 +/- 6.6 mm Hg in dogs given endotoxin by 5 min after injection, and remained below 83 mm Hg for the duration of the 120-min observation period. In animals given endotoxin followed by ibuprofen, a similar initial drop of systemic blood pressure was seen, but it subsequently recovered to 150.2 +/- 4.1 mm Hg by 120 min (P less than 0.001). Cardiac index increased in animals given ibuprofen (2.3 +/- 0.28 liter/m2 per min) compared with animals given endotoxin alone (1.0 +/- 0.09 liter/m2 per min) by termination of the experiment. The arterial pH dropped in endotoxin treated animals to 7.18 +/- 0.03 by 120 min. Ibuprofen prevented the acidosis, the final pH in ibuprofen and endotoxin treated animals measuring 7.36 +/- 0.01. We conclude that ibuprofen protects against the hypotension, acidosis, and depression of cardiac index of canine endotoxin shock.

Determination of cardiac output in critically ill patients by dual beam Doppler echocardiography.

Recent technology in Doppler echocardiography has produced a dual beam Doppler instrument that is capable of insonating the total cross-sectional area of the ascending aorta. The purpose of this study was to evaluate the accuracy of this instrument in measuring cardiac output in critically ill patients by comparing results with those of the thermodilution-derived cardiac output. A technically adequate Doppler cardiac output measurement was attained in 71 (91%) of 78 patients. The range of thermodilution-derived cardiac output measurements was from 1.58 to 11.70 liters/min. To maximize thermodilution cardiac output reliability, several measurements were made for each patient. Those patients in whom the difference between the highest and lowest measurement varied by less than 10% from the averaged results were accepted into the 50 patient study. There was significant correlation between dual beam Doppler- and thermodilution-derived cardiac output (r = 0.96, SEE = 0.55 liters/min, p less than 0.0001). This study demonstrates that dual beam Doppler ultrasound is a promising noninvasive method of measuring cardiac output in the critically ill patient.

Modulators of coagulation. A critical appraisal of their role in sepsis.

Widespread intravascular coagulation is common in patients with sepsis. Coagulation abnormalities may result from exposure to endotoxin, from tumor necrosis factor alpha or interleukin 1 release, or from the actions of a more specific mediator, such as vascular permeability factor. The result is marked activation of the contact and coagulation systems; simultaneously, there is decreased fibrinolysis and depressed levels of the inhibitors of the contact and coagulation systems. Multiple agents are being studied to correct these abnormalities. Antithrombin III holds promise because it inhibits a number of factors important in contact and coagulation activation, not just thrombin. Plasminogen activators may prove helpful in increasing fibrinolysis during sepsis; because they have been associated with rebound thrombin generation, however, plasminogen activators may be most effective if used in conjunction with hirudin or a synthetic hirudin analogue. Bradykinin may offset hypotension in sepsis. Protein C may inhibit thrombin formation and also complex with plasminogen activator inhibitor 1, thereby promoting fibrinolysis. Other agents that may prove effective include alpha 1-antitrypsin Pittsburgh, C1-esterase inhibitor, monoclonal antibodies to contact factors, soybean trypsin inhibitors, thrombomodulin, prostaglandin I2, and aprotinin. There are no data to support the use of heparin or fibronectin, except in limited circumstances.

Gram-positive organisms and sepsis.

In recent years, the importance of gram-negative organisms in the genesis of sepsis has been emphasized. However, this emphasis may no longer be correct; recent studies show an increasing incidence of gram-positive sources of sepsis, and its is possible that these cases may predominate in the coming years. This increase results from more than just a greater prevalence of infection--it appears that gram-positive organisms may also be more virulent in fomenting the disease, as can be evidenced by the emergence of streptococcal toxic shock syndrome and the resurgence of acute rheumatic fever. This may result from the ability of gram-positive organisms to produce more inflammation-causing cell wall constituents, as well as unbound exotoxins. Despite the recent emphasis on gram-negative causes, sepsis resulting from gram-positive sources is increasingly common. Research on these causes of sepsis should be encouraged.

Thrombotic thrombocytopenic purpura in carbon monoxide poisoning. Report of a case.

A young, previously healthy man was arrested for bizarre behavior outside his poorly ventilated hotel room. He was found to have carbon monoxide poisoning and thrombotic thrombocytopenic purpura complicated by respiratory dysfuntion. The occurrence of these previously unrelated diseases in the same patient may be more than coincidence.

Interferon gamma-1b in the treatment of compensatory anti-inflammatory response syndrome. A new approach: proof of principle.

BACKGROUND: Immunoparalysis is defined as a decrease in the level of HLA-DR expression on monocytes during the course of sepsis. OBJECTIVE: To evaluate whether interferon gamma-1b has an immunoregulatory effect in patients with immunoparalysis during the compensatory anti-inflammatory response syndrome. METHODS: Of the patients admitted consecutively to the intensive care unit for the management of sepsis, 10 received interferon gamma-1b, 100 micrograms per 0.5 mL, after confirmation of HLA-DR expression of less than 30% on 2 consecutive days. The therapy was continued until HLA-DR expression remained more than 50% for 3 days. RESULTS: Interferon gamma-1b therapy resulted in the recovery of diminished levels of HLA-DR expression on monocytes. Of the 10 patients, 8 responded to treatment within 1 day. On the first day of interferon gamma-1b therapy, HLA-DR expression increased from mean (+/- SEM) pretreatment levels of 27% +/- 6% to 62% +/- 8% (P < .01) and remained high during the 28-day study period in 8 patients. The therapy was given to 2 patients a second time when HLA-DR expression on monocytes was less than 30%. The recovery of monocytic HLA-DR expression levels after administration of interferon gamma-1b was associated with restitution of monocytic function, reflected by a significant increase of plasma interleukin-6 (P < .05) and tumor necrosis factor alpha (P < .05) levels in 9 patients. CONCLUSIONS: This study shows that HLA-DR expression is a good marker of compensatory anti-inflammatory response syndrome. It also shows that interferon gamma-1b not only restored the levels of HLA-DR expression but also reestablished the ability of monocytes to secrete the cytokines interleukin-6 and tumor necrosis factor alpha.

Research on ibuprofen for sepsis and respiratory failure.

According to an experimental study in 26 dogs, ibuprofen reversed the hypotension, increased the cardiac index, prevented the acidosis associated with endotoxic shock, and apparently improved survival. In animals given endotoxin followed by ibuprofen, an initial decrease in systemic blood pressure subsequently recovered to 150.2 +/- 4.1 mm Hg in 120 minutes (p less than 0.001). Cardiac index increased in ibuprofen-treated animals (2.3 +/- 0.28 1/m2 per minute), compared with animals given endotoxin alone (1.0 +/- 0.09 1/m2 per minute) by termination of the experiment. In addition, although arterial pH decreased to 7.18 +/- 0.03 by 120 minutes in animals given only endotoxin, final pH was 7.36 +/- 0.01 in the ibuprofen-treated group.

Lymphomatoid granulomatosis. Report of a case and review of the literature.

A 24 year old man had a nonproductive cough and chest pain. Chest roentgenogram showed a diffuse infiltrate, and pulmonary function studies showed restrictive lung disease. Extremity weakness, deteriorating mental status and neuropathy progressed as pulmonary findings diminished on corticosteroid therapy. Lung biopsy showed lymphomatoid granulomatosis. The neurologic status deteriorated despite treatment with Cytoxan, intrathecal methotrexate and brain irradiation. Autopsy showed mass lesions of lymphomatoid granulomatosis in the brain and healed lesions in the lungs. A review of the neurologic and pulmonary findings in reported cases show that diminution of pulmonary disease with progression of neurologic disease manifest by mass lesion is unusual. Since the etiology, prognosis and prevalence of this disease remains undefined, all patients with this disease should be reported on.

Controlled oxygen administration in acute respiratory failure in chronic obstructive pulmonary disease: a reappraisal.

Controlled oxygen therapy may aggravate carbon dioxide retention during acute exacerbations of chronic obstructive pulmonary disease (COPD). Of 50 consecutive patients with COPD and acute respiratory failure, 13 required intubation because of carbon dioxide narcosis. With discriminant analysis of their arterial oxygen tension (PaO2) and pH on admission, a diagram separated patients into those at high risk and those at low risk for carbon dioxide narcosis. This diagram was then used to predict carbon dioxide narcosis in 73 patients with COPD and acute respiratory failure who were treated with controlled oxygen. In 16 of these patients carbon dioxide narcosis developed. Thirteen (81 per cent) were predicted by the diagram to be at high risk for this complication. Only two (4 per cent) patients judged by the diagram to be at low risk for carbon dioxide narcosis required mechanical ventilation. Utilizing an oxygen tension (PO2), carbon dioxide tension (PCO2) diagram a patient's ventilatory response was compared to that of ambulatory patients with COPD. These data suggest that hypoxemia and acidosis are more discriminatory for "carbon dioxide narcosis" than hypercapnia.

Intravascular coagulation associated with the adult respiratory distress syndrome.

In seven of 30 consecutive patients with the adult respiratory distress syndrome, disseminated intravascular coagulation (DIC) developed. Increasing respiratory dysfunction characterized by decreased effective static compliance and increased hypoxemia coincided with the development of DIC. Patients in whom DIC developed were characterized by a high incidence of bleeding, gangrene of the extremities, renal dysfunction, mortality and autopsy evidence of fibrin microthrombi in the lungs, kidney and skin. In 12 of 23 patients who did not meet the criteria for DIC, the platelet count decreased by at least 50 per cent of the initial values at some time during their illness. Fibrin microthrombi were found in the lungs in the majority of the patients subjected to autopsy. These data support the concept that depostion of platelet on damaged pulmonary capillary endothelium may be more common in the adult respiratory distress syndrome than the DIC syndrome.

Respiratory dysfunction in thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura is a rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, neurologic abnormalities, fever and renal dysfunction. in six of seven consecutive patients with thrombotic thrombocytopenic purpura seen in an eight month period, respiratory impairment was present. Respiratory dysfunction was characterized by tachypnea, hypoxemia nad infiltrates on chest roentgenogram. Five patients required mechanical ventilation. Two patients had cardiogenic pulmonary edema, but they remained hypoxemic despite treatment for pulmonary edema and maintenance of normal pulmonary capillary wedge pressure for more than 36 hours. Four patients died and autopsies revealed pulmonary edema, hemorrhage and hyaline thrombi. Pathologic examination of the heart also showed hyaline thrombi. Information from out patients with thrombotic thrombocytopenic purpura implicates respiratory dysfunction as a component of this disease as well as the classically described pentad. Cardiogenic and noncardiogenic pulmonary edema and possibly bleeding into the lung contributed to pulmonary impairment.

Effects of corticosteroids in the treatment of patients with gastric aspiration.

Forty-three of 88 patients suspected of having aspirated gastric contents met stringent criteria for the diagnosis of aspiration of gastric contents. One group of 25 patients was treated with corticosteroids and a second group of 18 patients was treated without corticosteroids. The two groups were clinically well matched according to all variables except that the patients who did not receive corticosteroids had greater hypoxemia and a higher incidence of infiltration on chest roentgenogram which would indicate that these patients had received greater pulmonary injury from aspiration of gastric contents. Thirty-two per cent of the patients who received steroids died compared to 28 per cent of those who did not receive steroids. Although the mortality rate difference was not statistically significant, the occurrence of gram-negative pneumonia five days after aspiration was more frequent in the patients treated with steroids.

Intracavitary amphotereicin B in the treatment of symptomatic pulmonary aspergillomas.

The optimal treatment of pulmonary aspergillomas is not established. Surgical resection is often impossible because of severe, underlying pulmonary impairment, and medical treatment has given negative or inconclusive results. Six patients with symptomatic pulmonary aspergillomas were treated with percutaneous instillation of intracavitary amphotericin B. Four patients who received the full course of therapy showed improvement and stabilization or reversal of progressive roentgenographic changes. Also, follow-up serologic studies of Aspergillus spp. precipitins were obtained in three and were negative. One patient did not tolerate this treatment because of repeated systemic reactions. Another patient did not respond clinically or roentgenographically. Intracavitary amphotericin B therapy should be considered in patients with symptomatic pulmonary aspergilloma, particularly when surgical resection is not feasible.

Desquamative interstitial pneumonia following long-term nitrofurantoin therapy.

Two patients with diffuse interstitial lung disease after long-term nitrofurantoin therapy were characterized clinically by exertional dyspnea and basilar rales, roentgenographically by diffuse interstitial infiltrate and physiologically by a restrictive lung defect. Pathologically, light microscopy revealed desquamative interstitial pneumonia. In one patient electron microscopy was characteristic of desquamative interstitial pneumonia. Immunofluorescent studies of one biopsy specimen showed specific fluorescence of interstitial cells with immunoglobulin E and third component of complement. In in vitro studies, nitrofurantoin therapy failed to induce lymphoblast transformation or histamine release. Treatment consisted of discontinuing the administration of nitro=furantoin and adding corticosteroids. Both patients felt better and showed clinical improvement. Our findings suggest that in some cases desquamative interstitial pneumonia may be drug related.

Primary Sjogren syndrome: clinical and immunopathologic features.

Primary Sjogren syndrome is an autoimmune condition in which dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) result from lymphocytic infiltration of lacrimal and salivary glands. Clinical and laboratory features of 60 primary Sjogren syndrome patients seen at our clinic during the past three years are presented. These patients illustrate the wide spectrum of extraglandular features that may occur as a result of lymphoid infiltration of lung, kidney, skin, stomach, liver, and muscle. They further emphasize the difficulty in classifying a patient as primary or secondary Sjogren syndrome (ie, sicca symptoms associated with systemic lupus erythematosus, rheumatoid arthritis, or scleroderma), particularly early in the disease course. As an initial step in understanding the pathogenesis, the lymphocytes that infiltrate the salivary glands and lymph nodes were characterized by using monoclonal antibodies that recognize distinct lymphocyte subsets and by using in vitro functional assays. These studies have demonstrated that affected tissues have infiltrates of T cells with helper/inducer activity and with a high frequency of "activation antigens." The immunohistologic techniques are useful in differentiating "benign" and "pseudolymphoma" lesions (both due predominantly to T cells) from non-Hodgkin lymphoma (usually due to B-cell infiltrates). Although there is no "cure" for primary Sjogren syndrome patient's symptoms may be significantly improved by measures aimed at prevention of ocular and dental complications and by the recognition of extraglandular features that may be amenable to specific treatment.

Gram-negative sepsis. Background, clinical features, and intervention.

Gram-negative sepsis remains an urgent medical problem, with more than 200,000 cases occurring each year in the United States and an associated mortality rate of 20 to 50 percent. Since the onset of shock greatly worsens prognosis and to encourage early intervention, the term sepsis syndrome was developed to describe the features of a preshock septic state. Early clinical and metabolic indicators are discussed, and current therapy is reviewed. Better understanding of the pathophysiology of endotoxin release from Gram-negative bacteria and advances in biotechnology have led to the development of potential new treatments for sepsis. One such development--monoclonal antibodies to endotoxin--has shown great promise in the effort to block the progression to septic shock, reduce mortality, and decrease the overall costs of sepsis to the patient and to the national economy.

Long-term ventilator care. A Chicago problem and a national problem.

Patients who require long-term ventilator care in an acute care setting may have a problem because diagnosis-related group (DRG) payments are less than the cost of their medical care. An alternative for quality medical care at lower cost includes admission to a long-term ventilator facility. In Chicago, only two dedicated long-term ventilator programs exist, with only 33 beds. Within 50 to 150 miles of the immediate Chicago area are three more units, with only 42 operational beds. All of the long-term care beds are full, and over 50 patients await transfer. Since acute care is reimbursed on a DRG designation and long-term ventilator care has no DRG category, there is a bias in acute care settings against these patients. Medicare patients are reimbursed up to 100 days, after which patients become eligible for public aid. Unfortunately, long-term ventilator patients often wait in acute care settings for this 100 days to elapse, even though medical care may be superior in a long-term ventilator unit. In addition to not providing the best care, this situation is economically wasteful. Solutions to these problems will require a coordinated national, state, and local plan. National medical societies should be consulted regarding solutions to health care problems that provide the best medical care at a reasonable cost for patients on long-term ventilation.

Diagnosis of causes for acute respiratory distress by pressure-volume curves.

The determination of effective dynamic and static relationships between pressure and volume aided in the diagnosis of pulmonary disease, its course, and the effects of therapy in 22 patients receiving continuous mechanical ventilation. These measurements were made on multiple occasions early in the course of mechanical ventilation and were repeated after any indication of clinical deterioration. Abrupt changes from control measurements provided supportive evidence for the presence of cardiogenic pulmonary edema in four patients, progressive pneumonia in four patients, bronchoconstriction in four patients, retained secretions in five patients, pneumothorax in two patients, intubation of main-stem bronchus in three patients, and atelectasis in two patients and were useful in evaluating the results of subsequent therapy. These determinations are simple, noninvasive, and can be accomplished within minutes. The equipment needed is the same as that needed for continuous mechanical ventilation.

Goals of asthma management. A step-care approach.

The past 15 years have seen a rise in mortality and morbidity resulting from asthma, despite a concurrent rise in general knowledge about the disease. The step-care strategy recognized these changes in its approach to asthma management; however, this approach should be used only with attempts to control environmental allergens. Step-care therapy requires that patients be categorized by the severity of illness. Step-one therapy is used for mild, infrequent symptoms and involves treatment based primarily on inhaled bronchodilators. Step-two therapy is instituted in all asthmatics except the mildest cases; it involves treatment by inhaled corticosteroids, cromolyn, or nedocromil. Step-three treatment targets cases of severe asthma through the use of oral corticosteroids. In all phases of treatment, however, it should be remembered that patient education is of critical importance. Education improves patient compliance and is critical to the successful treatment of asthma.