A prospective study of the impact of air pollution on respiratory symptoms and infections in infants

Rationale: There is increasing evidence that short-term exposure to air pollution has a detrimental effect on respiratory health, but data from healthy populations, particularly infants, are scarce. Objectives: To assess the association of air pollution with frequency and severity of respiratory symptoms and infections measured weekly in healthy infants. Methods: In a prospective birth cohort of 366 infants of unselected mothers, respiratory health was assessed weekly by telephone interviews during the first year of life (19,106 total observations). Daily mean levels of particulate matter (PM10), nitrogen dioxide (NO2), and ozone (O3) were obtained from local monitoring stations. We determined the association of the preceding week's pollutant levels with symptom scores and respiratory tract infections using a generalized additive mixed model with an autoregressive component. In addition, we assessed whether neonatal lung function influences this association and whether duration of infectious episodes differed between weeks with normal PM10 and weeks with elevated levels. Measurements and Main Results: We found a significant association between air pollution and respiratory symptoms, particularly in the week after respiratory tract infections (risk ratio, 1.13 [1.02-1.24] per 10 μg/m(3) PM10 levels) and in infants with premorbid lung function. During times of elevated PM10 (>33.3 μg/m(3)), duration of respiratory tract infections increased by 20% (95% confidence interval, 2-42%). Conclusions: Exposure to even moderate levels of air pollution was associated with increased respiratory symptoms in healthy infants. Particularly in infants with premorbid lung function and inflammation, air pollution contributed to longer duration of infectious episodes with a potentially large socioeconomic impact.

Effects of prolonged endotoxemia on liver, skeletal muscle and kidney mitochondrial function

INTRODUCTION: Sepsis may impair mitochondrial utilization of oxygen. Since hepatic dysfunction is a hallmark of sepsis, we hypothesized that the liver is more susceptible to mitochondrial dysfunction than the peripheral tissues, such as the skeletal muscle. We studied the effect of prolonged endotoxin infusion on liver, muscle and kidney mitochondrial respiration and on hepatosplanchnic oxygen transport and microcirculation in pigs. METHODS: 20 anesthetized pigs were randomized to receive endotoxin or saline infusion for 24 hours. Muscle, liver and kidney mitochondrial respiration was assessed. Cardiac output (thermodilution), carotid, superior mesenteric and kidney arterial, portal venous (ultrasound Doppler) and microcirculatory blood flow (laser Doppler) were measured, and systemic and regional oxygen transport and lactate exchange were calculated. RESULTS: Endotoxin infusion induced hyperdynamic shock and impaired the glutamate- and succinate-dependent mitochondrial respiratory control ratio (RCR) in the liver (glutamate: endotoxemia: median [range] 2.8 [2.3-3.8] vs. controls: 5.3 [3.8-7.0]; p<0.001; succinate: endotoxemia: 2.9 [1.9-4.3] vs. controls: 3.9 [2.6-6.3] p=0.003). While the ADP:O ratio was reduced with both substrates, maximal ATP production was impaired only in the succinate-dependent respiration. Hepatic oxygen consumption and extraction, and liver surface laser Doppler blood flow remained unchanged. Glutamate-dependent respiration in the muscle and kidney was unaffected. CONCLUSIONS: Endotoxemia reduces the efficiency of hepatic but neither skeletal muscle nor kidney mitochondrial respiration, independent of regional and microcirculatory blood flow changes.

Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency

RATIONALE: ABCA3 mutations are known to cause fatal surfactant deficiency. OBJECTIVE: We studied ABCA3 protein expression in full-term newborns with unexplained respiratory distress syndrome (URDS) as well as the relevance of ABCA3 mutations for surfactant homeostasis. METHODS: Lung tissue of infants with URDS was analyzed for the expression of ABCA3 in type II pneumocytes. Coding exons of the ABCA3 gene were sequenced. Surfactant protein expression was studied by immunohistochemistry, immunoelectron microscopy, and Western blotting. RESULTS: ABCA3 protein expression was found to be greatly reduced or absent in 10 of 14 infants with URDS. Direct sequencing revealed distinct ABCA3 mutations clustering within vulnerable domains of the ABCA3 protein. A strong expression of precursors of surfactant protein B (pro-SP-B) but only low levels and aggregates of mature surfactant protein B (SP-B) within electron-dense bodies in type II pneumocytes were found. Within the matrix of electron-dense bodies, we detected precursors of SP-C (pro-SP-C) and cathepsin D. SP-A was localized in small intracellular vesicles, but not in electron-dense bodies. SP-A and pro-SP-B were shown to accumulate in the intraalveolar space, whereas mature SP-B and SP-C were reduced or absent, respectively. CONCLUSION: Our data provide evidence that ABCA3 mutations are associated not only with a deficiency of ABCA3 but also with an abnormal processing and routing of SP-B and SP-C, leading to severe alterations of surfactant homeostasis and respiratory distress syndrome. To identify infants with hereditary ABCA3 deficiency, we suggest a combined diagnostic approach including immunohistochemical, ultrastructural, and mutation analysis.

Decreasing gut wall glucose as an early marker of impaired intestinal perfusion

OBJECTIVE: The aim of this study was to assess the microcirculatory and metabolic consequences of reduced mesenteric blood flow. DESIGN: Prospective, controlled animal study. SETTING: The surgical research unit of a university hospital. SUBJECTS: A total of 13 anesthetized and mechanically ventilated pigs. INTERVENTIONS: Pigs were subjected to stepwise mesenteric blood flow reduction (15% in each step, n = 8) or served as controls (n = 5). Superior mesenteric arterial blood flow was measured with ultrasonic transit time flowmetry, and mucosal and muscularis microcirculatory perfusion in the small bowel were each measured with three laser Doppler flow probes. Small-bowel intramucosal Pco2 was measured by tonometry, and glucose, lactate (L), and pyruvate (P) were measured by microdialysis. MEASUREMENTS AND MAIN RESULTS: In control animals, superior mesenteric arterial blood flow, mucosal microcirculatory blood flow, intramucosal Pco2, and the lactate/pyruvate ratio remained unchanged. In both groups, mucosal blood flow was better preserved than muscularis blood flow. During stepwise mesenteric blood flow reduction, heterogeneous microcirculatory blood flow remained a prominent feature (coefficient of variation, approximately 45%). A 30% flow reduction from baseline was associated with a decrease in microdialysis glucose concentration from 2.37 (2.10-2.70) mmol/L to 0.57 (0.22-1.60) mmol/L (p < .05). After 75% flow reduction, the microdialysis lactate/pyruvate ratio increased from 8.6 (8.0-14.1) to 27.6 (15.5-37.4, p < .05), and arterial-intramucosal Pco2 gradients increased from 1.3 (0.4-3.5) kPa to 10.8 (8.0-16.0) kPa (p < .05). CONCLUSIONS: Blood flow redistribution and heterogeneous microcirculatory perfusion can explain apparently maintained regional oxidative metabolism during mesenteric hypoperfusion, despite local signs of anaerobic metabolism. Early decreasing glucose concentrations suggest that substrate supply may become crucial before oxygen consumption decreases.

Effects of epinephrine, norepinephrine, and phenylephrine on microcirculatory blood flow in the gastrointestinal tract in sepsis

OBJECTIVE: The use of vasopressors for treatment of hypotension in sepsis may have adverse effects on microcirculatory blood flow in the gastrointestinal tract. The aim of this study was to measure the effects of three vasopressors, commonly used in clinical practice, on microcirculatory blood flow in multiple abdominal organs in sepsis. DESIGN: Random order, cross-over design. SETTING: University laboratory. SUBJECTS: Eight sedated and mechanically ventilated pigs. INTERVENTIONS: Pigs were exposed to fecal peritonitis-induced septic shock. Mesenteric artery flow was measured using ultrasound transit time flowmetry. Microcirculatory flow was measured in gastric, jejunal, and colon mucosa; jejunal muscularis; and pancreas, liver, and kidney using multiple-channel laser Doppler flowmetry. Each animal received a continuous intravenous infusion of epinephrine, norepinephrine, and phenylephrine in a dose increasing mean arterial pressure by 20%. The animals were allowed to recover for 60 mins after each drug before the next was started. MEASUREMENTS AND MAIN RESULTS: During infusion of epinephrine (0.8 +/- 0.2 mug/kg/hr), mean arterial pressure increased from 66 +/- 5 to 83 +/- 5 mm Hg and cardiac index increased by 43 +/- 9%. Norepinephrine (0.7 +/- 0.3 mug/kg/hr) increased mean arterial pressure from 70 +/- 4 to 87 +/- 5 mm Hg and cardiac index by 41 +/- 8%. Both agents caused a significant reduction in superior mesenteric artery flow (11 +/- 4%, p < .05, and 26 +/- 6%, p < .01, respectively) and in microcirculatory blood flow in the jejunal mucosa (21 +/- 5%, p < .01, and 23 +/- 3%, p < .01, respectively) and in the pancreas (16 +/- 3%, p < .05, and 8 +/- 3%, not significant, respectively). Infusion of phenylephrine (3.1 +/- 1.0 mug/kg/min) increased mean arterial pressure from 69 +/- 5 to 85 +/- 6 mm Hg but had no effects on systemic, regional, or microcirculatory flow except for a 30% increase in jejunal muscularis flow (p < .01). CONCLUSIONS: Administration of the vasopressors phenylephrine, epinephrine, and norepinephrine failed to increase microcirculatory blood flow in most abdominal organs despite increased perfusion pressure and-in the case of epinephrine and norepinephrine-increased systemic blood flow. In fact, norepinephrine and epinephrine appeared to divert blood flow away from the mesenteric circulation and decrease microcirculatory blood flow in the jejunal mucosa and pancreas. Phenylephrine, on the other hand, appeared to increase blood pressure without affecting quantitative blood flow or distribution of blood flow.

Pilot study on the comprehensive economic costs of major trauma: Consequential costs are well in excess of medical costs

BACKGROUND: Trauma care is expensive. However, reliable data on the exact lifelong costs incurred by a major trauma patient are lacking. Discussion usually focuses on direct medical costs--underestimating consequential costs resulting from absence from work and permanent disability. METHODS: Direct medical costs and consequential costs of 63 major trauma survivors (ISS >13) at a Swiss trauma center from 1995 to 1996 were assessed 5 years posttrauma. The following cost evaluation methods were used: correction cost method (direct cost of restoring an original state), human capital method (indirect cost of lost productivity), contingent valuation method (human cost as the lost quality of life), and macroeconomic estimates. RESULTS: Mean ISS (Injury Severity Score) was 26.8 +/- 9.5 (mean +/- SD). In all, 22 patients (35%) were disabled, causing discounted average lifelong total costs of USD 1,293,800, compared with 41 patients (65%) who recovered without any disabilities with incurred costs of USD 147,200 (average of both groups USD 547,800). Two thirds of these costs were attributable to a loss of production whereas only one third was a result of the cost of correction. Primary hospital treatment (USD 27,800 +/- 37,800) was only a minor fraction of the total cost--less than the estimated cost of police and the judiciary. Loss of quality of life led to considerable intangible human costs similar to real costs. CONCLUSIONS: Trauma costs are commonly underestimated. Direct medical costs make up only a small part of the total costs. Consequential costs, such as lost productivity, are well in excess of the usual medical costs. Mere cost averages give a false estimate of the costs incurred by patients with/without disabilities.

Membrane microdialysis: Evaluation of a new method to assess splanchnic tissue metabolism

OBJECTIVE: Measuring peritoneal lactate concentrations could be useful for detecting splanchnic hypoperfusion. The aims of this study were to evaluate the properties of a new membrane-based microdialyzer in vitro and to assess the ability of the dialyzer to detect a clinically relevant decrease in splanchnic blood flow in vivo. DESIGN: A membrane-based microdialyzer was first validated in vitro. The same device was tested afterward in a randomized, controlled animal experiment. SETTING: University experimental research laboratory. SUBJECTS: Twenty-four Landrace pigs of both genders. INTERVENTIONS: In vitro: Membrane microdialyzers were kept in warmed sodium lactate baths with lactate concentrations between 2 and 8 mmol/L for 10-120 mins, and microdialysis lactate concentrations were measured repeatedly (210 measurements). In vivo: An extracorporeal shunt with blood reservoir and roller pump was inserted between the proximal and distal abdominal aorta, and a microdialyzer was inserted intraperitoneally. In 12 animals, total splanchnic blood flow (measured by transit time ultrasound) was reduced by a median 43% (range, 13% to 72%) by activating the shunt; 12 animals served as controls. MEASUREMENTS AND MAIN RESULTS: In vitro: The fractional lactate recovery was 0.59 (0.32-0.83) after 60 mins and 0.82 (0.71-0.87) after 90 mins, with no further increase thereafter. At 60 and 90 mins, the fractional recovery was independent of the lactate concentration. In vivo: Abdominal blood flow reduction resulted in an increase in peritoneal microdialysis lactate concentration from 1.7 (0.3-3.8) mmol/L to 2.8 (1.3-6.2) mmol/L (p = .006). At the same time, mesenteric venous-arterial lactate gradient increased from 0.1 (-0.2-0.8) mmol/L to 0.3 (-0.3 -1.8) mmol/L (p = .032), and mesenteric venous-arterial Pco2 gradients increased from 12 (8-19) torr to 21 (11-54) torr (p = .005). CONCLUSIONS: Peritoneal membrane microdialysis provides a method for the assessment of splanchnic ischemia, with potential for clinical application.

The pulmonary artery catheter: the tool versus treatments based on the tool

The pulmonary artery catheter (PAC) is a powerful tool that has been used extensively in the assessment and monitoring of cardiovascular physiology. Gross misinterpretation of data gathered by the PAC is common, and its routine use without any specific interventions has not been shown to influence outcome. However, there currently is no evidence from randomized, controlled trials that any diagnostic or monitoring tool used in intensive care patients improves outcome. Studies evaluating the use of the PAC have included numerous potential confounding factors, and should be interpreted with caution. The information obtained with the PAC should be used to find better treatment strategies, and these strategies, instead of the tool itself, should be tested in clinical trials.

Aortic rupture in high-speed skiing crashes

BACKGROUND: New equipment and techniques in winter sports, such as carving skis and snowboards, have brought up new trauma patterns into the spectrum of leisure trauma. The injuries resemble high-energy trauma known from road crashes. The aim of the present study was to assess the incidence of acute traumatic descending aortic rupture in recreational skiing-crashes. MATERIAL: Between January 1995 and December 2004, 22 patients were admitted to our hospital for aortic rupture. Four patients had skiing crashes (18.2%). Mean age was 31 years, all patients were male. In two cases, aortic rupture was associated with fractures of the upper and lower extremities. One patient additionally had a cerebral contusion with an initial Glasgow Coma Scale score of 13. In two patients, isolated aortic rupture was diagnosed. RESULTS: Two patients were treated by graft interposition, and one by endograft. One patient arrived under mechanical resuscitation without blood pressure. He died at admission. He had been observed for 5 hours in another hospital, complaining of severe intrascapular back pain, before transport to our trauma unit for unknown bleeding. In the other three cases, treatment was successful. CONCLUSION: Rescue services and paramedics should be aware of this new type of injury. Acute aortic rupture has to be considered as possible injury in high velocity skiing crashes.

Elevated exhaled nitric oxide in newborns of atopic mothers precedes respiratory symptoms

RATIONALE: Exhaled nitric oxide (NO) is a well-known marker of established airway inflammation in asthma. Its role in the disease process before the onset of respiratory symptoms remains unclear. Objectives: To examine whether elevated NO in newborns with clinically naive airways is associated with subsequent respiratory symptoms in infancy. METHODS: We measured exhaled NO concentration and output after birth and prospectively assessed respiratory symptoms during infancy in a birth cohort of 164 unselected healthy neonates. We examined a possible association between NO and respiratory symptoms using Poisson regression analysis. RESULTS: In infants of atopic mothers, elevated NO levels after birth were associated with increased risk of subsequent respiratory symptoms (risk ratio [RR], 7.5; 95% confidence interval [CI], 1.7-32.4 for each nl/s increase in NO output; p = 0.007). Similarly, a positive association between NO and symptoms was seen in infants of smoking mothers (RR, 6.6; 95% CI, 2.3-19.3; p = 0.001), with the strongest association in infants whose mothers had both risk factors (RR, 21.8; 95% CI, 5.8-81.3; p < 0.001). CONCLUSIONS: The interaction of NO with maternal atopy and smoking on subsequent respiratory symptoms is present early in life. Clinically, noninvasive NO measurements in newborns may prove useful as a new means to identify high-risk infants. Future confirmation of a role for NO metabolism in the evolution of respiratory disease may provide an avenue for preventative strategies.

Chemokines indicate allergic bronchopulmonary aspergillosis in patients with cystic fibrosis

RATIONALE: Allergic bronchopulmonary aspergillosis (ABPA) is characterized by a Th2 immune response. Mouse models suggest a critical role for the Th2 chemokines thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) in ABPA. OBJECTIVES: To determine whether serum levels of TARC and MDC characterize ABPA in patients with cystic fibrosis (CF) and to examine longitudinally if levels of TARC and MDC indicate ABPA exacerbations in patients with CF. METHODS: Levels of TARC and MDC and levels of Th1 (IL-12 and IFN-gamma) and Th2 (IL-4, IL-5, and IL-13) cytokines were analyzed in serum of 16 patients with CF with ABPA, six non-CF patients with asthma with ABPA, 13 patients with CF colonized with Aspergillus fumigatus, six patients with CF sensitized to A. fumigatus, 12 atopic patients with CF, and 13 non-CF atopic control subjects by ELISA. The longitudinal course of TARC, MDC, and IgE levels was assessed during ABPA episodes. RESULTS: Patients with ABPA had significantly higher serum levels of TARC compared with the other patient groups. Cytokine levels did not differ among the patient groups. Longitudinally, levels of TARC indicated ABPA exacerbations in patients with CF more clearly than IgE levels. In patients with CF and ABPA, levels of TARC correlated positively with specific IgE to A. fumigatus and rAsp f4. CONCLUSIONS: Serum levels of TARC differentiate patients with CF or patients with asthma with ABPA from patients with CF colonized with or sensitized to A. fumigatus, atopic patients with CF, and atopic control subjects. Longitudinally, levels of TARC indicate ABPA exacerbations, suggesting TARC as a marker for identification and monitoring of ABPA in patients with CF.

Chronic rhinoviral infection in lung transplant recipients

RATIONALE: Lung transplant recipients are particularly at risk of complications from rhinovirus, the most frequent respiratory virus circulating in the community. OBJECTIVES: To determine whether lung transplant recipients can be chronically infected by rhinovirus and the potential clinical impact. METHODS: We first identified an index case, in which rhinovirus was isolated repeatedly, and conducted detailed molecular analysis to determine whether this was related to a unique strain or to re-infection episodes. Transbronchial biopsies were used to assess the presence of rhinovirus in the lung parenchyma. The incidence of chronic rhinoviral infections and potential clinical impact was assessed prospectively in a cohort of 68 lung transplant recipients during 19 mo by screening of bronchoalveolar lavages. MEASUREMENTS AND MAIN RESULTS: We describe 3 lung transplant recipients with graft dysfunctions in whom rhinovirus was identified by reverse transcriptase-polymerase chain reaction in upper and lower respiratory specimens over a 12-mo period. In two cases, rhinovirus was repeatedly isolated in culture. The persistence of a unique strain in each case was confirmed by sequence analysis of the 5'NCR and VP1 gene. In the index case, rhinovirus was detected in the lower respiratory parenchyma. In the cohort of lung transplant recipients, rhinoviral infections were documented in bronchoalveolar lavage specimens of 10 recipients, and 2 presented with a persistent infection. CONCLUSIONS: Rhinoviral infection can be persistent in lung transplant recipients with graft dysfunction, and the virus can be detected in the lung parenchyma. Given the potential clinical impact, chronic rhinoviral infection needs to be considered in lung transplant recipients.

Multicentre study on peri- and postoperative central venous oxygen saturation in high-risk surgical patients

Introduction Low central venous oxygen saturation (ScvO2) has been associated with increased risk of postoperative complications in high-risk surgery. Whether this association is centre-specific or more generalisable is not known. The aim of this study was to assess the association between peri- and postoperative ScvO2 and outcome in high-risk surgical patients in a multicentre setting. Methods Three large European university hospitals (two in Finland, one in Switzerland) participated. In 60 patients with intra-abdominal surgery lasting more than 90 minutes, the presence of at least two of Shoemaker's criteria, and ASA (American Society of Anesthesiologists) class greater than 2, ScvO2 was determined preoperatively and at two hour intervals during the operation until 12 hours postoperatively. Hospital length of stay (LOS) mortality, and predefined postoperative complications were recorded. Results The age of the patients was 72 ± 10 years (mean ± standard deviation), and simplified acute physiology score (SAPS II) was 32 ± 12. Hospital LOS was 10.5 (8 to 14) days, and 28-day hospital mortality was 10.0%. Preoperative ScvO2 decreased from 77% ± 10% to 70% ± 11% (p < 0.001) immediately after surgery and remained unchanged 12 hours later. A total of 67 postoperative complications were recorded in 32 patients. After multivariate analysis, mean ScvO2 value (odds ratio [OR] 1.23 [95% confidence interval (CI) 1.01 to 1.50], p = 0.037), hospital LOS (OR 0.75 [95% CI 0.59 to 0.94], p = 0.012), and SAPS II (OR 0.90 [95% CI 0.82 to 0.99], p = 0.029) were independently associated with postoperative complications. The optimal value of mean ScvO2 to discriminate between patients who did or did not develop complications was 73% (sensitivity 72%, specificity 61%). Conclusion Low ScvO2 perioperatively is related to increased risk of postoperative complications in high-risk surgery. This warrants trials with goal-directed therapy using ScvO2 as a target in high-risk surgery patients.