Can We protect workers from developing the adverse respiratory effects of isocyanate exposure?

In this review, the authors have attempted to present the difficulty in defining a permissible exposure limit (PEL) to agents that act as sensitizers and may induce asthma-even at exposure levels less than the PEL. One approach to this relatively unaddressed problem may be to define the separate aspects of exposure to the specific sensitizing agent. The first effect is an accelerated rate of decline in lung function in nonsensitized individuals who are exposed to the agent (in this case the model used is isocyanates). The second effect is sensitization. Rules for developing a PEL might take this sensitizing effect into account, and this group of agents with such dual effects may be defined as "sensitizers." Exposure to agents with this designation would require special educational and surveillance initiatives to facilitate early detection. The elimination of sensitization may be a greater challenge. An important form of prevention is medical screening of exposed workers, yet it is unclear which screening approach best identifies workers with early isocyanate asthma.

Trace element homeostasis during continuous sedation with propofol containing EDTA versus other sedatives in critically ill patients.

OBJECTIVE: To evaluate changes in serum and urinary zinc, cobalt, copper, iron, and calcium concentrations in critically ill patients receiving propofol containing disodium edetate (disodium ethylenediaminetetraacetic acid [EDTA]) versus sedative agents without EDTA. DESIGN: This was a randomised, open-label, parallel-group study with randomisation stratified by baseline Acute Physiology and Chronic Health Evaluation (APACHE II) scores. SETTING: Intensive care units (ICU) in 23 medical centres. PATIENTS: Medical, surgical, or trauma ICU patients 17 years of age or older who required mechanical ventilator support and sedation. INTERVENTIONS: A total of 106 patients received propofol containing 0.005 % EDTA (propofol EDTA), and 104 received other sedative agents without EDTA (non-EDTA). Only the first 108 patients were assessed for urinary trace metal excretion. Twenty-four-hour urine samples were collected on days 2, 3, and 7 and every 7 days thereafter for determination of zinc, cobalt, copper, iron, and calcium excretion; EDTA levels; urine osmolality; albumin levels; and glucose levels. The first 143 patients were assessed for serum concentration of zinc, cobalt, copper, iron, and calcium; creatinine; blood urea nitrogen; and albumin at baseline and once during each 24-hour urine collection. MEASUREMENTS AND RESULTS: For the assessment of trace metals, patients receiving propofol EDTA demonstrated increased mean urinary excretion of zinc, copper, and iron compared with the normal range. All patients receiving sedatives demonstrated increased urinary excretion of zinc and copper above normal reference values. Compared with the non-EDTA sedative group, the propofol EDTA group demonstrated increased urinary excretion of zinc and iron. Mean serum concentrations of zinc and total calcium were decreased in both patient groups. Serum zinc concentrations increased from baseline to day 3 in the non-EDTA sedative group but not in the propofol EDTA group. Renal function, measured by blood urea nitrogen, serum creatinine, and creatinine clearance, did not deteriorate during ICU sedation with either regimen. CONCLUSION: This study showed that critical illness is associated with increased urinary losses of zinc, copper, and iron. Propofol EDTA-treated patients had greater urinary losses of zinc and iron and lower serum zinc concentrations compared with the non-EDTA sedative group. No adverse events indicative of trace metal deficiency were observed in either group. The clinical significance of trace metal losses during critical illness is unclear and requires further study.

E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: a randomized controlled trial. E5 Study Investigators.

CONTEXT: Knowledge and understanding of gram-negative sepsis have grown over the past 20 years, but the ability to treat severe sepsis successfully has not. OBJECTIVE: To assess the efficacy and safety of E5 in the treatment of patients with severe gram-negative sepsis. DESIGN: A multicenter, double-blind, randomized, placebo-controlled trial conducted at 136 US medical centers from April 1993 to April 1997, designed with 90% power to detect a 25% relative risk reduction, incorporating 2 planned interim analyses. SETTING: Intensive care units at university medical centers, Veterans Affairs medical centers, and community hospitals. PATIENTS: Adults aged 18 years or older, with signs and symptoms consistent with severe sepsis and documented or probable gram-negative infection. INTERVENTION: Patients were assigned to receive 2 doses of either E5, a murine monoclonal antibody directed against endotoxin (n = 550; 2 mg/kg per day by intravenous infusion 24 hours apart) or placebo (n = 552). MAIN OUTCOME MEASURES: The primary end point was mortality at day 14; secondary end points were mortality at day 28, adverse event rates, and 14-day and 28-day mortality in the subgroup without shock at presentation. RESULTS: The trial was stopped after the second interim analysis. A total of 1090 patients received study medication and 915 had gram-negative infection confirmed by culture. There were no statistically significant differences in mortality between the E5 and placebo groups at either day 14 (29.7% vs 31.1%; P = .67) or day 28 (38.5% vs 40.3%; P = .56). Patients presenting without shock had a slightly lower mortality when treated with E5 but the difference was not significant (28.9% vs 33.0% for the E5 and placebo groups, respectively, at day 28; P = .32). There was a similar profile of adverse event rates between E5 and placebo. CONCLUSIONS: Despite adequate sample size and high enrollment of patients with confirmed gram-negative sepsis, E5 did not improve short-term survival. Current study rationale and designs should be carefully reviewed before further large-scale studies of patients with sepsis are conducted.

Inhalation of toluene diisocyanate is associated with increased production of nitric oxide by rat bronchoalveolar lavage cells.

Isocyanates are used commercially, particularly in the manufacture of polyurethane coatings and foam. These compounds can pose an occupational health hazard since there is a risk of respiratory disease following isocyanate exposure. The purpose of the present study was to investigate whether a single, sublethal isocyanate inhalation is associated with increased production of the free radical nitric oxide (NO). Mature male Sprague-Dawley rats were exposed to air or toluene diisocyanate (TDI; 2 ppm) for 4 hr. Indices of pulmonary function were assessed before and after exposure to TDI fumes. At 20 hr postexposure, bronchoalveolar lavage cells (BALC) and fluid were harvested. NO synthase (NOS)-dependent reactive species production by alveolar macrophages was assessed by determining N(omega)-nitro-L-arginine methyl ester-inhibitable chemiluminescence following stimulation with unopsonized zymosan. Northern blot analysis was used to index inducible NOS mRNA levels in BALC, while nitrite and nitrate (NOx) levels were measured to determine NOx levels in the lavage fluid and the production of NO by cultured adherent BALC was indexed by measuring nitrite levels. Exposure to aerosolized TDI was associated with an increase in the number of alveolar macrophages, lymphocytes, and polymorphonuclear leukocytes harvested by bronchoalveolar lavage, relative to that from air-exposed rats. NOx levels in the lavage fluid and NOS-dependent production of reactive species by alveolar macrophages were increased following TDI exposure. In addition, inducible NO production by BALC (i.e., mRNA levels and nitrite levels in BALC conditioned media) was elevated following TDI treatment. These findings indicate that pulmonary inflammatory responses induced by TDI exposure are associated with increases in inducible NO production. Therefore, the potential role of NO in the initial pulmonary response to TDI exposure warrants further investigation.

Reduction of lung dust burden in pneumoconiosis by whole-lung lavage.

Pneumoconioses are characterized as irreversible, progressive respiratory diseases. No effective therapy exists to prevent progression of these diseases. Whole-lung lavage (WLL) might limit the rate of disease progression through the removal of dust, inflammatory cells, and cytokines. We performed WLL on a 54-year-old underground miner employed as a motorman and roof bolter and a 55-year-old driller at a surface coal mine. Both demonstrated normal lung function and chest radiographs showing ILO profusion category 2 nodular interstitial changes. From Subject 1, we recovered 5.24 x 10(8) cells (90% macrophages) from the right lung and 3.45 x 10(8) cells (94% macrophages) from the left lung. WLL removed 1.82 g of mineral dust (non-coal) on the right and 1.64 g on the left. From Subject 2, we recovered 7.49 x 10(8) cells (46% macrophages) from the right and 9.78 x 10(8) cells (69% macrophages) from the left lung. WLL removed 0.40 g of mineral dust on the right and 0.53 g on the left. Proinflammatory cytokines, growth factors, and cellular enzymes were also recovered. In cases of pneumoconiosis, WLL is capable of removing relatively large quantities of dust, cells, and soluble materials from the lungs. Only long-term follow-ups of individuals with progressive dust-induced disease who receive WLL therapy in the context of a clinical trial will provide information regarding the importance of removing mineral dust and inflammatory cells from the lung.

Hyperoxia-induced alterations of rat alveolar lavage composition and properties.

Although lethal exposures of most animal species to oxygen result in a reduced amount of surfactant phospholipids (PL), hyperoxia in rats leads to elevated levels of PL on the alveolar surface. Because of this different response, a study was made of the amount, composition, surface properties, and subfraction distribution (obtained by differential centrifugation) of alveolar lavage materials from rats exposed to > 95% oxygen for 64 h. The exposures lead to severe lung damage, which includes the appearance of pleural effusion, pulmonary edema, and increased protein levels on the alveolar surface. However, the PL levels of lavage fluid are increased two- to threefold, and the PL composition is altered. In O2-exposed rats, only 39(+/- 1)% of the phospholipid is disaturated phosphatidylcholine (DSPC), the major surface active component of surfactant, as compared to 46(+/- 1)% DSPC in lavage from control animals. The distribution of PL and DSPC in subfractions of lavage materials obtained by differential centrifugation is approximately reversed following hyperoxia. In lavage from control animals, 36% of the PL is in the heavier, more dense subfractions and 64% is in the lighter, less dense subfractions, while 72% is heavier and 28% lighter in lavage from O2-exposed animals. Measurements of surface properties with the Wilhelmy balance indicate that the ability of the lavage materials to reduce surface tension is impaired following hyperoxia. Thus, lethal exposures of rats to oxygen lead to increased amounts of surfactant on the alveolar surface, but the surface properties of the surfactant are impaired, probably due to reduced levels of DSPC, increased amounts of protein, and alterations in its physical form.

Pulmonary response to hyperoxia: effects of magnesium.

Animals and humans rapidly develop respiratory failure and die within a few days when exposed to 100% oxygen. Postmortem examination of the lungs shows histopathologic features characteristic of diffuse alveolar damage, clinically recognized as adult respiratory distress syndrome (ARDS). At the present time, there is no effective therapy available to alter outcomes in ARDS. Importantly, hypomagnesemia also is frequently observed in critically ill patients at risk of developing ARDS. In a model of hyperoxic lung injury, rats were exposed to 100% oxygen for 48, 64, and 96 hr and several experiments were performed. First, changes in the features of bronchoalveolar lavage and in alveolar macrophage function were compared in rats exposed to room air and those exposed to hyperoxia. Second, we studied the effect of hypomagnesemia on the severity of hyperoxic lung injury. Third, we evaluated the pulmonary responses to high-dose and normal-dose Mg therapy in rats exposed to hyperoxia. In all groups, hyperoxia induced significant changes in the total and differential cell counts with increased lipid peroxidation of lavaged cells, enhanced chemiluminescence from alveolar macrophages, and protein leakage into the alveolar spaces. After 48 hr of hyperoxia, oxygen-free radical formation and hydrogen peroxide production by the alveolar macrophage were diminished compared to baseline, implying a toxic effect of hyperoxia on the alveolar macrophages. Overall, hypomagnesemia tended to magnify the degree of hyperoxic lung injury, while high-dose Mg therapy tended to attenuate the effects of hyperoxia. In conclusion, in this animal model of diffuse alveolar damage, alterations in host serum magnesium levels may modulate the degree of lung damage.

Exposure of rats to hyperoxia: alteration of lavagate parameters and macrophage function.

Exposure of rats to hyperoxia (100% oxygen for 64 h) resulted in striking alterations in the properties of samples obtained by bronchoalveolar lavage. The yield of neutrophils, lymphocytes, and red blood cells was increased, while the number of harvested alveolar macrophages decreased. The acellular lavage fluid level of protein was elevated, indicating lung damage. However, acellular phospholipid levels were unchanged. The ability of alveolar macrophages to produce reactive forms of oxygen in response to zymosan was significantly decreased by oxygen exposure. This impaired function was not fully explained by a decrease in viability of these phagocytes. In contrast, stimulant-induced chemiluminescence was elevated after hyperoxia. This rise was not due to a change in cellular antioxidant levels or to a discernible increase in arachidonic acid metabolites. However, it was associated with increased cellular lipid peroxidation.

Retrieval of an aspirated bullet fragment by flexible bronchoscopy in a mechanically ventilated patient.

We report the case of a 28-year-old man who aspirated a bullet fragment following a gunshot. Review of the literature indicates this to be a rare finding. Bedside flexible bronchoscopy provided visualization of the foreign body and facilitated its removal while the patient was on a ventilator. The benefits of flexible bronchoscopy in similar conditions are discussed.

High-dose magnesium sulfate attenuates pulmonary oxygen toxicity.

BACKGROUND AND METHODS: Rats rapidly develop respiratory distress when exposed to 100% oxygen and die within a few days. Autopsy of the lung shows severe histologic damage characteristic of the adult respiratory distress syndrome. The purpose of this study was to evaluate the effects of magnesium sulfate loading in a rat model of acute oxygen toxicity. Thirty-four rats were divided into three groups. Group 1 (n = 18) served as a control (no magnesium therapy), while group 2 (n = 8) and group 3 (n = 8) received varying amounts of magnesium sulfate. All animals were exposed to 100% oxygen for 96 hrs or until death. Lung damage was quantitated by measuring the lung injury score on histologic examination. RESULTS: Administering magnesium sulfate in moderate doses at infrequent intervals to rats (group 2) resulted in less severe oxygen-induced lung damage than that which occurred in rats not receiving magnesium (control group). However, the difference was not statistically significant. Rats (group 3) given doses of magnesium sulfate in amount and frequency adequate to maintain a serum magnesium concentration recognized as therapeutic in eclampsia significantly reduced oxygen-induced lung damage. CONCLUSION: High-dose magnesium sulfate therapy can reduce lung injury caused by acute oxygen toxicity in rats.

Positive-pressure ventilation with positive end-expiratory pressure and atrial natriuretic peptide release.

The effect of positive-pressure ventilation (PPV) with PEEP on the release of alpha-atrial natriuretic peptide (ANP) was investigated in both humans and an experimental model. In the human study, systemic artery blood samples from 22 critically ill patients were analyzed for ANP. Seventeen of these patients received PPV with different levels of PEEP (5 to 15 cm H2O). The remaining five patients were breathing spontaneously (0 PEEP). There was no significant difference in plasma levels of ANP obtained at different levels of PEEP, and no correlation between ANP vs. wedge pressure or CVP was found. For the experimental group, in six dogs a PEEP dose-response curve was established (PEEP 0, 5, 10, 15, 0 cm H2O every 45 min). Blood samples from pulmonary and systemic arteries were obtained for ANP determination, and urine and Na excretion were measured at the end of each period. Neither significant interaction between PEEP and ANP was observed, nor did levels of this peptide correlate with the decrease in cardiac output (p less than .05) and urine output (p less than .05), or with the increase in CVP (p less than .05) observed during PEEP. ANP concentrations in the pulmonary and systemic arteries were similar. In 14 human samples, ANP was determined by radioimmunoassay and radioreceptor assay systems, but the level obtained by both methods did not significantly correlate.(ABSTRACT TRUNCATED AT 250 WORDS)

Beneficial effect of norepinephrine in the treatment of circulatory shock caused by tricyclic antidepressant overdose.

The beneficial effect of dopamine in circulatory shock induced by tricyclic antidepressants (TCA) overdose may be decreased due to compromise of the endogenous stores of norepinephrine caused by TCA. The successful outcome of two cases of TCA overdose complicated by hypotension, unresponsive to an initial treatment with physostigmine fluid challenge and dopamine (greater than 15 micrograms/kg/min) but subsequently responsive to an infusion of norepinephrine is reported.

Long-term survival after endobronchial fire during treatment of severe malignant airway obstruction with the Nd:YAG laser.

We present a case of Nd:YAG laser treatment of nearly total airway obstruction by malignant tumor in which an endobronchial fire occurred. The patient survived without complications of the fire and was followed-up until death over 22 months after the fire. The events leading to the fire are presented and recommendations provided to prevent similar occurrences.

Beneficial effect of thyrotropin-releasing hormone in canine hemorrhagic shock.

The effects of thyrotropin-releasing hormone (TRH) on hemodynamic variables, oxygen delivery (DO2), and oxygen consumption (VO2) variables in canine hemorrhagic shock were studied. Anesthetized adult dogs were bled over 30 min to a mean arterial pressure (MAP) of 50 mm Hg. Shock was maintained at this level for half an hour. The animals were divided alternatively into two groups. In the first group (n = 5) a bolus of TRH (2 mg/kg) was given intravenously. The second group (n = 5) served as control and received equal amounts of D5W. Blood samples were obtained regularly up to 120 minutes after TRH or placebo. Differences in the two groups were statistically tested. After TRH, MAP pressure, cardiac output, and systemic vascular resistance increased significantly. DO2 improved after TRH but VO2 remained unchanged. In all dogs, sequential beta endorphin level were measured and were shown to rise after induction of shock. This data indicates that TRH may be of therapeutic benefit in the treatment of hemorrhagic shock and that beta endorphin may be an important pathophysiologic factor.

Evolution of cardiorespiratory variables in myxedema coma--a case report.

Normalization of hemodynamic, oxygen transport and oxygen consumption indices occurred within a week of treatment in a patient with myxedema coma. Ventilatory weaning and extubation was achieved using aminophylline, physical therapy and pleural drainage. Before extubation, naloxone was administered without any significant ventilatory improvement or change in endorphin levels.