C-Reactive Protein Levels and the Risk of Incident Cardiovascular and Cerebrovascular Events in Patients with Obstructive Sleep Apnea.

PURPOSE: Patients with obstructive sleep apnea (OSA) are at increased risk of cardiovascular and cerebrovascular disease (CVD) but it is unclear who are at greatest risk. We determined whether the inflammatory marker, C-reactive protein (CRP), could be a useful prognostic biomarker. METHODS: Adult patients referred for polysomnography (PSG) with OSA were studied. Serum CRP levels were measured using ELISA the morning after PSG. Validated CV events within 4 years of PSG were ascertained by linking to provincial research datasets. RESULTS: 155 patients with OSA (AHI ≥ 5/h) had CRP measured. Median age was 53 and median AHI was 21/h. 10 patients (7.1%) suffered at least one event, but rates varied substantially by CRP (0/35 patients in the lowest quartile, and 7/39 in the highest CRP quartile). In the unadjusted analysis, patients in the highest CRP quartile (≥ 2.38 mg/L) were significantly more likely to suffer an event (odds ratio = 9.72 (95% CI 2.43-38.84), p = 0.001). CRP continued to be a significant predictor after controlling for multiple confounders. OSA severity and desaturation were not significantly associated with prospective events. CONCLUSIONS: In this small preliminary study, OSA patients with an elevated CRP were significantly more likely to suffer a CVD event in the 4 years after PSG. Although these findings need to be confirmed in larger prospective cohorts, CRP may be useful in risk stratifying OSA patients to guide therapy or to identify patients that might be most appropriate for clinical trials of CVD prevention.

Wood smoke exposure induces a pulmonary and systemic inflammatory response in firefighters.

Epidemiological studies report an association between exposure to biomass smoke and cardiopulmonary morbidity. The mechanisms for this association are unclear. The aim of the present study was to characterise the acute pulmonary and systemic inflammatory effects of exposure to forest fire smoke. Seasonal forest firefighters (n = 52) were recruited before and/or after a day of fire-fighting. Exposure was assessed by questionnaires and measurement of carbon monoxide levels (used to estimate respirable particulate matter exposure). The pulmonary response was assessed by questionnaires, spirometry and sputum induction. Peripheral blood cell counts and inflammatory cytokines were measured to define the systemic response. Estimated respirable particulate matter exposure was high (peak levels >2 mg x m(-3)) during fire-fighting activities. Respiratory symptoms were reported by 65% of the firefighters. The percentage sputum granulocytes increased significantly from 6.5 to 10.9% following fire-fighting shifts, with concurrent increases in circulating white blood cells (5.55x10(9) to 7.06x10(9) cells x L(-1)) and band cells (0.11x10(9) to 0.16x10(9) cells x L(-1)). Serum interleukin (IL)-6, IL-8 and monocyte chemotactic protein-1 levels significantly increased following fire-fighting. There were no changes in band cells, IL-6, and IL-8 following strenuous physical exertion without fire-fighting. There was a significant association between changes in sputum macrophages containing phagocytosed particles and circulating band cells. In conclusion, acute exposure to air pollution from forest fire smoke elicits inflammation within the lungs, as well as a systemic inflammatory response.

The reliability of short-term measurement of heart rate variability during spontaneous breathing in people with chronic obstructive pulmonary disease.

BACKGROUND: Reduced heart rate variability (HRV), a marker of autonomic system dysfunction, has been reported in patients with chronic obstructive pulmonary disease (COPD). Yet, limited data exists on the reliability of HRV measurement in this population. Here we investigated the reliability of short-term HRV measurement performed during spontaneous breathing in patients with COPD. METHODS: Thirteen individuals (8 males) with moderate-to-severe COPD (FEV1 46±16% predicted; FEV1/FVC 49±13) underwent standard time and frequency domain HRV measurements derived from 5-minute electrocardiograms collected on two separate days using a SphygmoCor device. Absolute and relative reliability was assessed by a number of coefficients including within-subject random variation, systematic change in the mean, and retest correlations. RESULTS: Within-subject coefficients of variation (CV) ranged from 4.3% to 193.4%. The intraclass correlation coefficients (ICCs) ranged from 0.72 to 0.93 for parameters related to overall HRV, and from 0.57 to 0.59 for those related to parasympathetic tone in both time and frequency domains. Mean heart rate was the only parameter that showed excellent absolute and relative reliability (CV=4.3%, ICC=0.93). CONCLUSION: The HRV measurements showed overall moderate-to-substantial reliability during spontaneous breathing in COPD population. Our findings support the use of HRV parameters for diagnosis and cardiac risk assessment, but only mean heart rate can be used reliably for monitoring changes in autonomic status following rehabilitation intervention in this population.

Organophosphate and carbamate poisoning.

Organophosphate insecticides may cause serious poisoning either accidentally or by deliberate ingestion. Toxic symptoms are produced by acetylcholine accumulation at cholinergic receptors. Diagnosis is based on history of exposure or ingestion, symptoms and signs of cholinergic overactivity and a decrease in serum pseudocholinesterase levels. Following diagnosis, grading of disease severity may identify patients with serious poisoning who should receive treatment in intensive care using adequate doses of anticholinergic drugs. Complications, particularly ventricular arrhythmias, central nervous system depression or seizures, and respiratory failure, should be anticipated and treated. Relapse may occur after seemingly successful treatment. Public education with regard to symptoms of toxicity must be encouraged, and physicians must provide skilled treatment for a potentially lethal condition.

The use of flow cytometry to measure neutrophil function.

Neutrophils are important professional phagocytic cells that provide the host with a first line of defense against acute bacterial and fungal diseases and recurrent, severe or unusual infections are associated with inherited defects of neutrophil function. Furthermore, abundant evidence links inappropriate neutrophil-mediated tissue damage to the pathogenesis of conditions such as acute respiratory distress syndrome, septicemia with multiorgan failure, ischemia-reperfusion injury and rheumatoid arthritis. Flow cytometry has been increasingly used to evaluate the functional capabilities of neutrophils. In this review, we discuss the use of flow cytometry to assess neutrophil functional responses including calcium mobilization, F-actin assembly, adhesion, aggregation, degranulation, phagocytosis and reactive oxygen species (ROS) production. The use of flow cytometry to identify neutrophil priming is also discussed. The advantage of flow cytometry is that the majority of neutrophil functions can be measured using a small volume of whole blood that reduces artifactual changes in function caused by purification procedures. The advent of numerous new fluorochromes and multiparametric analysis allows the simultaneous measurement of several neutrophil functions in the same population of cells. Flow cytometric analysis provides a rapid screen for abnormalities of neutrophil function and reflects more accurately their behavior in vivo.

Treatment of multiple rib fractures. Randomized controlled trial comparing ventilatory with nonventilatory management.

We studied the treatment of multiple rib fractures in NIC, comparing ventilatory with nonventilatory methods in 69 patients who were randomly allocated to one of the following two treatments: (1) a CPAP mask combined with regional analgesia (n = 36); or (2) endotracheal intubation and mechanical ventilation with PEEP (n = 33). Clinical outcome was as follows: mean duration of treatment, 4.5 +/- 2.3 days for the group with CPAP and 7.3 +/- 3.7 days for the intubated group (p = 0.0003); mean number of days spent in intensive care, 5.3 +/- 2.9 days and 9.5 +/- 4.4 days, respectively (p = less than 0.0001); mean period of hospitalization, 8.4 +/- 7.1 days and 14.6 +/- 8.6 days, respectively (p = 0.0019); and patients developing complications: 28 percent (10/36) and 73 percent (24/33), respectively. Infections caused the difference in complications, primarily pneumonias, which occurred in 14 percent (5/36) of the group with CPAP but in 48 percent (16/33) of the intubated group. We conclude that treatment with a CPAP mask combined with regional analgesia can shorten and simplify treatment in these patients, mainly through a decreased infection rate, when compared with intubation and mechanical ventilation, and we recommend this treatment in patients similar to our sample.

Ventilation-perfusion imaging in evaluating regional lung function in nonpenetrating injury to the chest.

The extent of chest wall and lung injury after nonpenetrating injury to the chest (NIC) determine how aggressive and invasive management modalities should be. We investigated the value of ventilation (133Xe) and perfusion (99mTc) studies as indicators of extent of lung injury in 28 patients with moderate to severe unilateral NIC. The ventilation-perfusion (V/Q) abnormalities were compared with parameters conventionally used to evaluate NIC. All studies were carried out within 24 h of NIC and repeated 24 h later. Ventilation (p less than 0.001) and perfusion (p less than 0.01) abnormalities were more extensive soon after NIC than suggested by chest roentgenograms. Chest x-ray film changes lagged behind V/Q changes on admission and also after 24 h. The extent of ventilation, perfusion, and chest x-ray film abnormalities on admission were all predictors of increased morbidity. V/Q studies may be useful to define the extent as well as the changes in regional lung function following NIC.

Polymorphonuclear leukocytes released from the bone marrow by granulocyte colony-stimulating factor: intravascular behavior.

INTRODUCTION: Granulocyte-colony stimulating factor (G-CSF) treatment stimulates the bone marrow and releases polymorphonuclear leukocytes (PMN) into the circulation. This study was designed to measure the intravascular margination, demargination and survival of PMN released from the marrow by G-CSF. MATERIALS AND METHODS: To trace PMN in the circulation, dividing PMN in the bone marrow of rabbits were labeled with 5'-bromo-2'-deoxyuridine (BrdU) and the effects of a single dose of G-CSF (12.5 microg/kg) on the behavior of these labeled cells in the circulation were measured. RESULTS: The results show that G-CSF induced a granulocytosis that peaked 12 h after treatment. This granulocytosis was associated with stimulation of the bone marrow characterized by shortening of the transit time of PMN through the marrow (97.3+/-2.5 h n=4 control vs 78.9+/-3.6 h n=5 G-CSF) particularly in the post-mitotic pool (P<0.01). Morphometric studies of the lung show a reduced sequestration of BrdU-labeled PMN in lung microvessels in G-CSF-treated animals (P<0.05) and a approximately 14-fold (G-CSF-group) vs a approximately 65-fold (control-group) enrichment of BrdU-labeled PMN in lung tissue if compared to circulating blood. The effect of G-CSF on demargination of PMN was measured by transferring BrdU-labeled PMN from donor animals treated with G-CSF to recipients. G-CSF did not cause demargination of intravascular PMN but delayed the clearance of G-CSF-treated PMN in the circulation. This delayed clearance was associated with inhibition of apoptosis in circulating PMN when measured both by morphology (17.7+/-2.3 vs 7.5+/-1.4%, P<0.01) and flow cytometry (16.2+/-1.1 vs 5+/-1.9%, P<0.01) using a DNA end-labeling method (control vs G-CSF group). CONCLUSION: We conclude that PMN released from the bone marrow by G-CSF sequestered less in the lung microvessels and have a prolonged intravascular life span.

Neutrophil structural changes associated with chronic endotoxemia and lung injury.

Previous studies showed that chronic endotoxemia induces thickening of the alveolar wall of rabbits. The present study examines cellular changes associated with this process and attempts to define the role of PMN in this response. Rabbits received i.v. injections of either Escherichia coli lipopolysaccharide (LPS) or saline (control), 2-3 times weekly, for 28 weeks. Peripheral blood mature and immature polymorphonuclear leukocyte (PMN) cell counts were determined on Wright-stained blood smears. Lung histological analysis was performed by both light and electron microscopy. FITC-Maclura pomifera was used to identify type II cells and diaminobenzidine tetrahydrochloride-H2O2 was employed to localize peroxidase. The results show that the LPS-induced neutrophilia is associated with an increase in the circulating band cells which is consistent with active bone marrow release. PMN in the pulmonary microvessels display structural features characteristic of phagocytosis and active macromolecule synthesis. Endothelial cells, adjacent to these PMN, show numerous coated pits and large inclusions suggestive of endocytosis. The LPS-induced thickening of the alveolar wall is associated with leukocyte migration into the interstitial and alveolar spaces. Some interstitial PMN are fragmented and surrounded by dispersed elements of the connective tissue, while others appear activated and are closely associated with hyperactive fibroblasts and alveolar type II cells. The number of alveolar type II cells has increased twofold. These results show that chronic endotoxemia in rabbits causes structural changes in PMN, endothelium, interstitium, and epithelium. PMN structural changes are consistent with enhanced functional properties and their close association with modified regions of the lung parenchyma suggest that PMN play an important role in the process of this lung injury and repair.

Effect of mechanical deformation of neutrophils on their CD18/ICAM-1-dependent adhesion.

Mechanical deformation of polymorphonuclear leukocytes (PMN) changes their expression of the surface adhesion molecule CD11b/CD18. We tested the hypothesis that mechanical deformation of PMN enhances their adhesiveness. Purified human PMN were deformed through either 5- or 3-microm polycarbonate membrane filters and allowed to adhere to 96-well plates coated with human recombinant intercellular adhesion molecule-1 (ICAM-1). Flow cytometric studies showed that deformation of PMN increased CD11b/CD18 expression (P < 0.01). PMN adhesion to ICAM-1-coated plates was dependent on the magnitude of cell deformation (5 microm, 63.8 +/- 8.1%, P < 0.04; 3 microm, 232.4 +/- 20.9%, P < 0.01). Priming of PMN (0.5 nM N-formyl-methionyl-leucyl-phenylalanine) before deformation (5 microm) increased PMN adhesion (63.8 +/- 8.1 vs. 105.3 +/- 16.4%; P < 0.04). Stimulation (5% zymosan-activated plasma) of PMN after deformation resulted in increased adhesion, and the degree of increase was dependent on the magnitude of PMN deformation (stimulation, 50.6 +/- 4%; 5-microm filtration and stimulation, 62.9 +/- 6.6%; 3-microm filtration and stimulation, 249.9 +/- 24.2%; P < 0.01). This study shows that mechanical deformation of PMN causes an increase in PMN adhesiveness to ICAM-1 that was enhanced by both priming of PMN before deformation and stimulation after cell deformation.

Expression of the cell adhesion molecules on leukocytes that demarginate during acute maximal exercise.

The pulmonary vascular bed is an important reservoir for the marginated pool of leukocytes that can be mobilized by exercise or catecholamines. This study was designed to determine the phenotypic characteristics of leukocytes that are mobilized into the circulation during exercise. Twenty healthy volunteers performed incremental exercise to exhaustion [maximal O2 consumption (VO2 max)] on a cycle ergometer. Blood was collected at baseline, at 3-min intervals during exercise, at VO2 max, and 30 min after exercise. Total white cell, polymorphonuclear leukocyte (PMN), and lymphocyte counts increased with exercise to VO2 max (P < 0.05). Flow cytometric analysis showed that the mean fluorescence intensity of L-selectin on PMN (from 14.9 +/- 1 at baseline to 9.5 +/- 1.6 at VO2 max, P < 0.05) and lymphocytes (from 11.7 +/- 1.2 at baseline to 8 +/- 0.8 at VO2 max, P < 0.05) decreased with exercise. Mean fluorescence intensity of CD11b on PMN increased with exercise (from 10.2 +/- 0.6 at baseline to 25 +/- 2.5 at VO2 max, P < 0.002) but remained unchanged on lymphocytes. Myeloperoxidase levels in PMN did not change with exercise. In vitro studies showed that neither catecholamines nor plasma collected at VO2 max during exercise changed leukocyte L-selectin or CD11b levels. We conclude that PMN released from the marginated pool during exercise express low levels of L-selectin and high levels of CD11b.

Effect of mechanical deformation on structure and function of polymorphonuclear leukocytes.

The present studies were designed to test the hypothesis that mechanical deformation of polymorphonuclear leukocytes (PMN) leads to functional changes that might influence their transit in the pulmonary capillaries. Human leukocytes were passed through 5- or 3-micron-pore polycarbonate filters under controlled conditions. Morphometric analysis showed that the majority of PMN were deformed and that this deformation persisted longer after filtration through 3-micron filters than through 5-micron filters (P < 0.05) but did not result in the cytoskeletal polarization characteristic of migrating cells. Flow cytometric studies of the filtered PMN showed that there was a transient increase in the cytosolic free Ca2+ concentration after both 3- and 5-micron filtration (P < 0.01) with an increase in F-actin content after 3-micron filtration (P < 0.05). Although L-selectin expression on PMN was not changed by either 5- or 3-micron filtration, CD18 and CD11b were increased by 3-micron filtration (P < 0.05). Priming of the PMN with N-formyl-methionyl-leucyl-phenylalanine (0.5 nM) before filtration resulted in an increase of CD11b by both 5 (P < 0.05)- and 3-micron (P < 0.01) filtration. Neither 5- nor 3-micron filtration induced hydrogen peroxide production. We conclude that mechanical deformation of PMN, similar to what occurs in the pulmonary microvessels, induces both structural and functional changes in the cells, which might influence their passage through the pulmonary capillary bed.

Interleukin 8 (IL-8) and the release of leukocytes from the bone marrow.

Interleukin 8 (IL-8) is produced by various cells upon stimulation and influences a variety of functions of leukocytes in particular neutrophils. Systemic administration of IL-8 induces a rapid neutropenia associated by sequestration of neutrophils in the lung that is followed by a neutrophilia characterized by the rapid release of neutrophils from the bone marrow. These cells are released predominantly from the bone marrow venous sinusoids. In addition, several studies have shown the potential role of IL-8 in hematopoiesis and trafficking of hematopoietic stem cells. Systemic administration of IL-8 induces a rapid mobilization of progenitors from the bone marrow with long-term myelo-lymphoid repopulation capacity. It has been employed clinically to mobilize hematopoietic progenitor cells into the peripheral blood and used for autologous or allogeneic bone marrow transplantation. The mechanism for these effects of IL-8 is largely speculative. This report summarizes current ideas on the possible mechanisms how IL-8 influences cell trafficking in and from the bone marrow.

Circulating acute phase reactive proteins as indicators of infection in poorly controlled diabetes mellitus.

Serum levels of six acute phase proteins (APP)--C-reactive protein (CRP), serum amyloid A (SAA), alpha 1-antitrypsin, haptoglobin and complement fractions C3 and C4--were serially studied in 24 patients with poorly controlled diabetes mellitus, ten of whom had unequivocal evidence of an underlying infection. In diabetic patients without infection, no change in APP levels was noted suggesting that hyperglycaemia per se does not quantitatively influence the acute phase response. No correlation between the presence of infection, and fever, leukocytosis, a raised erythrocyte sedimentation rate, or serum levels of alpha 1-antitrypsin, haptoglobin or complement was apparent in these patients. However, serum CRP and SAA were initially increased 10-100 times above normal in diabetic patients with an underlying infection (P less than 0.01); during the following week circulating levels of CRP and SAA decreased steadily in response to the infection being brought under control. We conclude that serial measurement of CRP and/or SAA is a sensitive, albeit non-specific, parameter to detect and monitor the activity of infection in patients with diabetes.

Emphysematous pyelonephritis: case report and review of the literature.

Emphysematous pyelonephritis (EP), a rare necrotizing infection of the upper urinary tract, is a life-threatening complication of patients with diabetes mellitus. A case of EP is described where the diagnosis was delayed for 36 h and the patient died notwithstanding aggressive medical and surgical intervention. The demonstration of gas in the renal structures is pathognomonic of EP. Because early diagnosis and aggressive medical and surgical management is imperative for recovery, we recommend plain abdominal radiographs as a minimal screening tool for all diabetic patients who present to hospital with a presumptive pyelonephritis. The diagnosis should also be considered in patients who failed appropriate medical therapy.

Community-acquired pneumonia: evidence of functional inactivation of alpha 1 proteinase inhibitor.

Quantitative and qualitative elastase inhibitory capacity (EIC) alpha 1 proteinase inhibitor (alpha 1 PI) was measured in pulmonary arterial and systemic arterial blood of patients with community-acquired pneumonia (CAP). Eleven patients with uncomplicated CAP were compared with 16 patients with fulminating pneumonia requiring intensive care management. An appropriate increase in quantitative alpha 1 PI was demonstrated in all patients. A significant functional inactivation of alpha 1 PI was demonstrated in the ICU-treated patients that was not apparent in the uncomplicated CAP patients (p less than .01). This low EIC returned to normal 4 wk after hospital discharge in all survivors. A significant (p less than .02) difference in EIC between the pulmonary arterial and systemic arterial blood was found in the nonsurvivors on admission, which suggests that alpha 1 PI is inactivated in the lungs of patients with fulminating CAP. The present data demonstrate that alpha 1 PI is functionally inactivated in patients with fulminating CAP. This low serum functional alpha 1 PI may result in proteolytic lung damage and an unfavorable outcome.

Organophosphate poisoning: grading the severity and comparing treatment between atropine and glycopyrrolate.

Organophosphate poisoning occurs worldwide and often requires admission to an ICU. Grading of patients may be of value to identify high-risk cases but this has never been prospectively evaluated. Conventional treatment with atropine may lead to CNS toxicity, although control of secretions may still be inadequate. We conducted a randomized, controlled trial in 44 patients to compare atropine with glycopyrrolate, a drug that may provide better control of secretions and does not cross the blood-brain barrier. Grading was performed prospectively and compared to outcome. Thirty-nine cases were evaluated (atropine 22, glycopyrrolate 17); the treatment groups were comparable at baseline. No differences could be detected in outcome except for a trend to fewer respiratory infections in the glycopyrrolate group. Thus, treatment with atropine and glycopyrrolate was equally effective. A grading of serious was associated with ventilation, complications, and a prolonged ICU stay. A revised simplified grading is proposed.

The response of human bone marrow to chronic cigarette smoking.

Chronic cigarette smoking in humans causes leukocytosis. Animal studies show that chronic smoking shortens the transit time of polymorphonuclear leukocytes (PMNLs) through the bone marrow. The present study examines the response of human bone marrow to chronic cigarette smoking. Three characteristics of peripheral blood PMNLs that indicate active bone marrow release (band cell counts, surface L-selectin expression and myeloperoxidase (MPO) content), were measured in 38 healthy chronic smokers (23+/-5 pack-yrs) and 15 age- and sex-matched nonsmoking controls. The total white cell (6.8+/-0.3x10(9) versus 5.3+/-0.2x10(9) cells x L(-1), p<0.0001) and PMNL (4.2+/-0.18x10(9) versus 3.2+/-0.1x10(9) cells x L(-1), p<0.003) counts were higher in smokers as were the percentage (4.8+/-0.6 versus 1.1+/-0.2, p<0.0001) and total number (0.21+/-0.04x10(9) versus 0.03+/-0.001x10(9) cells x L(-1), p<0.01) of band cells. Flow cytometry showed that the mean fluorescence intensity (MFI) of L-selectin (3.2+/-0.2 versus 2.6+/-0.1, p<0.05) on PMNLs was higher in smokers. There was no difference in the baseline or N-formyl-methionyl-leucyl-phenylalanine-stimulated expression of CD63 or CD18/CD11b (surface markers of PMNL activation) between smokers and controls. The MPO content of PMNLs was higher in smokers (3.4+/-0.3 versus 1.7+/-0.2 MFI, p<0.05). Smokers with a low (<75% of the predicted value) diffusing capacity of the lung for carbon monoxide had higher PMNL MPO levels than smokers with a diffusing capacity of >75% pred (p<0.05). In conclusion, chronic smoking causes phenotypic changes in circulating polymorphonuclear leukocytes that are characteristic of chronic stimulation of the bone marrow and it is speculated that the increased number of immature polymorphonuclear leukocytes contributes to the chronic lung inflammation associated with cigarette smoking.