The septic milieu triggers expression of spliced tissue factor mRNA in human platelets.

BACKGROUND: Activated platelets have previously-unrecognized mechanisms of post-transcriptional gene expression that may influence hemostasis and inflammation. A novel pathway involves splicing of pre-mRNAs in resting platelets to mature, translatable mRNAs in response to cellular activation. OBJECTIVES: We asked if bacterial products and host agonists present in the septic milieu induce tissue factor pre-mRNA splicing in platelets from healthy subjects. In parallel, we asked if spliced tissue factor (TF) mRNA is present in platelets from septic patients in a proof-of-principle analysis. PATIENTS/METHODS: TF pre-mRNA and mRNA expression patterns were characterized in platelets from septic patients and in platelets isolated from healthy subjects activated with bacteria, toxins and inflammatory agonists. Procoagulant activity was also measured. RESULTS AND CONCLUSIONS: Live bacteria, staphylococcal α-toxin and lipopolysaccharide (LPS) induced TF pre-mRNA splicing in platelets isolated from healthy subjects. Toxin-stimulated platelets accelerated plasma clotting, a response that was blocked by a previously-characterized splicing inhibitor and by an anti-tissue factor antibody. Platelets from septic patients expressed spliced TF mRNA, whereas it was absent from unselected and age-matched control subjects. Tissue factor-dependent procoagulant activity was elevated in platelets from a subset of septic patients. Thus, bacterial and host factors induce splicing of TF pre-mRNA, expression of TF mRNA and tissue factor-dependent clotting activity in human platelets. TF mRNA is present in platelets from some septic patients, indicating that it may be a marker of altered platelet phenotype and function in sepsis and that splicing pathways are induced in this syndrome.

Right and left heart failure in severe H1N1 influenza A infection.

Influenza infection can affect cardiac function. The recent pandemic of H1N1 influenza A provided an opportunity to study echocardiographic findings in critically ill infected patients. We hypothesised that critically ill patients with H1N1 infection would have a higher incidence of right and left heart failure than is seen in unselected populations of patients with septic shock and/or acute respiratory distress syndrome (ARDS). We retrospectively studied all patients admitted to four intensive care units at three hospitals in Salt Lake County, UT, USA, with laboratory-confirmed H1N1 infection in whom a clinical echocardiogram was available. 23 out of 48 patients had qualifying echocardiograms. Right ventricular (RV) dilatation (50-80%) and at least moderate systolic impairment (23%) were common, higher than the range described in general populations with ARDS. Left ventricular systolic dysfunction was present in 17% of patients. No single echocardiographic parameter was associated with 28-day mortality or ventilator-free days to 28 days. Critically ill patients with H1N1 infection frequently exhibit right heart dilatation and failure. RV basal dilatation was extremely common. These patients have less left heart failure than expected on the basis of prior descriptions of influenza myopericarditis or of general populations of septic patients.

A frame-based representation for a bedside ventilator weaning protocol.

We describe the use of a frame-based knowledge representation to construct an adequately-explicit bedside clinical decision support application for ventilator weaning. The application consists of a data entry form, a knowledge base, an inference engine, and a patient database. The knowledge base contains database queries, a data dictionary, and decision frames. A frame consists of a title, a list of findings necessary to make a decision or carry out an action, and a logic or mathematical statement to determine its output. Frames for knowledge representation are advantageous because they can be created, visualized, and conceptualized as self-contained entities that correspond to accepted medical constructs. They facilitate knowledge engineering and provide understandable explanations of protocol outputs for clinicians. Our frames are elements of a hierarchical decision process. In addition to running diagnostic and therapeutic logic, frames can run database queries, make changes to the user interface, and modify computer variables.

Normal oxygenation and ventilation during snow burial by the exclusion of exhaled carbon dioxide.

OBJECTIVE: To confirm that the accumulation of exhaled carbon dioxide (CO2) is the principal cause of nonmechanical asphyxiation during avalanche burial by demonstrating that complete exclusion of exhaled CO2 during experimental snow burial results in normal oxygenation and ventilation utilizing the air within the snowpack. METHODS: In the experimental group, 8 healthy volunteers (mean age 32 years, range 19-44 years) were fully buried up to 90 minutes in compacted snow with a density ranging from 300 to 680 kg/ m3 at an elevation of 2385 m. The 6 men and 2 women breathed directly from the snow utilizing a device containing no air pocket around the inhalation intake, in addition to an extended exhalation tube running completely out of the snowpack to remove all exhaled CO2. Continuous physiologic monitoring included oxygen saturation, end-tidal CO2, inspired CO2, electrocardiogram, rectal core temperature, and respiratory rate. As controls, 5 of the 8 subjects repeated the study protocol breathing directly into a small, fist-sized air pocket with no CO2 removal device. RESULTS: In the experimental group, the mean burial time was 88 minutes, despite the absence of an air pocket. No significant changes occurred in any physiologic parameters in this group compared to baseline values. In contrast, the controls remained buried for a mean of 10 minutes (P = .003) and became significantly hypercapnic (P < .01) and hypoxic (P < .02). CONCLUSIONS: There is sufficient oxygen contained within a densified snowpack comparable to avalanche debris to sustain normal oxygenation and ventilation for at least 90 minutes during snow burial if exhaled CO2 is removed. The prolonged oxygenation observed during CO2 exclusion is irrespective of the presence of an air pocket.

Respiration during snow burial using an artificial air pocket.

CONTEXT: Asphyxia is the most common cause of death after avalanche burial. A device that allows a person to breathe air contained in snow by diverting expired carbon dioxide (CO2) away from a 500-cm3 artificial inspiratory air pocket may improve chances of survival in avalanche burial. OBJECTIVE: To determine the duration of adequate oxygenation and ventilation during burial in dense snow while breathing with vs without the artificial air pocket device. DESIGN: Field study of physiologic respiratory measures during snow burial with and without the device from December 1998 to March 1999. Study burials were terminated at the subject's request, when oxygen saturation as measured by pulse oximetry (SpO2) dropped to less than 84%, or after 60 minutes elapsed. SETTING: Mountainous outdoor site at 2385 m elevation, with an average barometric pressure of 573 mm Hg. PARTICIPANTS: Six male and 2 female volunteers (mean age, 34.6 years; range, 28-39 years). MAIN OUTCOME MEASURES: Burial time, SpO2, partial pressure of end-tidal CO2 (ETCO2), partial pressure of inspiratory CO2 (PICO2), respiratory rate, and heart rate at baseline (in open atmosphere) and during snow burial while breathing with the device and without the device but with a 500-cm3 air pocket in the snow. RESULTS: Mean burial time was 58 minutes (range, 45-60 minutes) with the device and 10 minutes (range, 5-14 minutes) without it (P=.001). A mean baseline SpO2 of 96% (range, 90%-99%) decreased to 90% (range, 77%-96%) in those buried with the device (P=.01) and to 84% (range, 79%-92%) in the control burials (P=.02). Only 1 subject buried with the device, but 6 control subjects buried without the device, decreased SpO2 to less than 88% (P=.005). A mean baseline ETCO2 of 32 mm Hg (range, 27-38 mm Hg) increased to 45 mm Hg (range, 32-53 mm Hg) in the burials with the device (P=.02) and to 54 mm Hg (range, 44-63 mm Hg) in the control burials (P=.02). A mean baseline PICO2 of 2 mm Hg (range, 0-3 mm Hg) increased to 32 mm Hg (range, 20-44 mm Hg) in the burials with the device (P=.01) and to 44 mm Hg (range, 37-50 mm Hg) in the control burials (P=.02). Respiratory and heart rates did not change in burials with the device but significantly increased in control burials. CONCLUSIONS: In our study, although hypercapnia developed, breathing with the device during snow burial considerably extended duration of adequate oxygenation compared with breathing with an air pocket in the snow. Further study will be needed to determine whether the device improves survival during avalanche burial.

Alveolar haemorrhage in a case of high altitude pulmonary oedema.

A case of high altitude pulmonary oedema (HAPE) in a climber who made a rapid ascent on Mt McKinley (Denali), Alaska is described. The bronchoalveolar lavage (BAL) fluid contained increased numbers of red blood cells and an abundance of haemosiderin laden macrophages consistent with alveolar haemorrhage. The timing of this finding indicates that alveolar haemorrhage began early during the ascent, well before the onset of symptoms. Although evidence of alveolar haemorrhage has been reported at necropsy in individuals dying of HAPE, previous reports have not shown the same abundance of haemosiderin laden macrophages in the BAL fluid. These findings suggest that alveolar haemorrhage is an early event in HAPE.

Endothelial selectins in acute mountain sickness and high-altitude pulmonary edema.

STUDY OBJECTIVES: Mechanical or inflammatory injury to pulmonary endothelial cells may cause impaired pulmonary gas exchange in acute mountain sickness (AMS) and noncardiogenic pulmonary edema in high-altitude pulmonary edema (HAPE). This study was designed to determine whether markers of endothelial cell activation or injury, plasma E- and P-selectin, were increased after ascent to high altitude, in AMS or in HAPE. DESIGN: We collected clinical data and plasma specimens in control subjects at sea level and after ascent to 4,200 m, and in climbers with AMS or HAPE at 4,200 m. Data analysis was performed using standard nonparametric statistical methods, and results reported as mean+/-SD. SETTING: National Park Service medical camp at 4,200 m on Mt. McKinley (Denali), Alaska. PATIENTS: Blood samples and clinical data were collected from 17 healthy climbers at sea level and again after ascent to 4,200 m, and from a different group of 13 climbers with AMS and 8 climbers with HAPE at 4,200 m. Climbers with AMS were divided into normoxic (n=7) and hypoxemic (n=6) groups. MEASUREMENTS AND RESULTS: Using an enzyme immunoassay technique, plasma E-selectin concentrations were found to be increased in the 17 control subjects after ascent to 4,200 m (17.2+/-8.2 ng/mL) as compared to sea level (12.9+/-8.2 ng/mL) (p=0.001). Plasma E-selectin concentrations were also increased in subjects with hypoxemic AMS (30.6+/-13.4 ng/mL) and HAPE (23.3+/-9.1 ng/mL) compared to control subjects at sea level (p=0.009). Increased plasma E-selectin concentration significantly correlated with hypoxemia (p=0.006). Plasma P-selectin concentrations were unchanged after ascent to 4,200 m and in subjects with AMS and HAPE. CONCLUSION: Because E-selectin is produced only by endothelial cells, increased plasma E-selectin after ascent to high altitude and in hypoxemic climbers with AMS and HAPE provides evidence that endothelial cell activation or injury is a component of hypoxic altitude illness.

How well do older persons tolerate moderate altitude?

We studied the physiologic and clinical responses to moderate altitude in 97 older men and women (aged 59 to 83 years) over 5 days in Vail, Colorado, at an elevation of 2,500 m (8,200 ft). The incidence of acute mountain sickness was 16%, which is slightly lower than that reported for younger persons. The occurrence of symptoms of acute mountain sickness did not parallel arterial oxygen saturation or spirometric or blood pressure measurements. Chronic diseases were present in percentages typical for ambulatory elderly persons: 19 (20%) had coronary artery disease, 33 (34%) had hypertension, and 9 (9%) had lung disease. Despite this, no adverse signs or symptoms occurred in our subjects during their stay at this altitude. Our findings suggest that persons with preexisting, generally asymptomatic, cardiovascular or pulmonary disease can safely visit moderate altitudes.

Acetazolamide in the treatment of acute mountain sickness: clinical efficacy and effect on gas exchange.

OBJECTIVE: To determine the efficacy of acetazolamide in the treatment of patients with acute mountain sickness and the effect of the drug on pulmonary gas exchange in acute mountain sickness. DESIGN: A randomized, double-blind, placebo-controlled trial. SETTING: The Denali Medical Research Project high-altitude research station (4200 m) on Mt. McKinley, Alaska. PARTICIPANTS: Twelve climbers attempting an ascent of Mt. McKinley (summit, 6150 m) who presented to the medical research station with acute mountain sickness. INTERVENTION: Climbers were randomly assigned to receive acetazolamide, 250 mg orally, or placebo at 0 (baseline) and 8 hours after inclusion in the study. MAIN OUTCOME MEASURES: An assessment of acute mountain sickness using a symptom score and pulmonary gas exchange measurements was done at baseline and at 24 hours. MAIN RESULTS: After 24 hours, five of six climbers treated with acetazolamide were healthy, whereas all climbers who received placebo still had acute mountain sickness (P = 0.015). Arterial blood gas specimens were obtained from three of the six acetazolamide recipients and all of the placebo recipients. The alveolar to arterial oxygen pressure difference (PAO2-PaO2 difference) decreased slightly over 24 hours in the acetazolamide group (-0.8 +/- 1.2 mm Hg) but increased in the placebo group (+3.3 +/- 2.3 mm Hg) (P = 0.024). Acetazolamide improved PaO2 over 24 hours (+2.9 +/- 0.8 mm Hg) when compared with placebo (-1.3 +/- 2.8 mm Hg) (P = 0.045). CONCLUSION: In established cases of acute mountain sickness, treatment with acetazolamide relieves symptoms, improves arterial oxygenation, and prevents further impairment of pulmonary gas exchange.