Elizabeth R. Jacobs

Nationwide Trends of Severe Sepsis in the 21st Century (2000–2007)

BACKGROUND Severe sepsis is common and often fatal. The expanding armamentarium of evidence-based therapies has improved the outcomes of persons with this disease. However, the existing national estimates of the frequency and outcomes of severe sepsis were made before many of the recent therapeutic advances. Therefore, it is important to study the outcomes of this disease in an aging US population with rising comorbidities. METHODS We used the Healthcare Costs and Utilization Projects Nationwide Inpatient Sample (NIS) to estimate the frequency and outcomes of severe sepsis hospitalizations between 2000 and 2007. We identified hospitalizations for severe sepsis using International Classification of Diseases, Ninth Revision, Clinical Modification codes indicating the presence of sepsis and organ system failure. Using weights from NIS, we estimated the number of hospitalizations for severe sepsis in each year. We combined these with census data to determine the number of severe sepsis hospitalizations per 100,000 persons. We used discharge status to identify in-hospital mortality and compared mortality rates in 2000 with those in 2007 after adjusting for demographics, number of organ systems failing, and presence of comorbid conditions. RESULTS The number of severe sepsis hospitalizations per 100,000 persons increased from 143 in 2000 to 343 in 2007. The mean number of organ system failures during admission increased from 1.6 to 1.9 (P < .001). The mean length of hospital stay decreased from 17.3 to 14.9 days. The mortality rate decreased from 39% to 27%. However, more admissions ended with discharge to a long-term care facility in 2007 than in 2000 (35% vs 27%, P < .001). CONCLUSIONS An increasing number of admissions for severe sepsis combined with declining mortality rates contribute to more individuals surviving to hospital discharge. Importantly, this leads to more survivors being discharged to skilled nursing facilities and home with in-home care. Increased attention to this phenomenon is warranted.

Chronic exposure to everyday discrimination and coronary artery calcification in African-American women: the SWAN Heart Study.

Background: Emerging evidence suggests that exposure to discrimination may be associated with atherosclerosis in African-American women, although research in this area focused on short-term rather than chronic exposure to discriminatory events. Methods: We examined the relationship between chronic exposure to multiple types of discrimination (self-reported and averaged over 5 years) and coronary artery calcification (CAC) in a sample of 181 middle-aged African-American women. Discrimination was assessed at each time point, and the presence/absence of CAC was assessed at the fifth annual follow-up examination by electron beam tomography. We hypothesized that chronic discrimination would be more strongly associated with CAC than recent discrimination and that racial/ethnic discrimination would be more strongly associated with CAC than other types of discrimination. Results: Chronic exposure to discrimination was significantly associated with the presence of CAC in unadjusted logistic regression analyses (p = .007) and after adjustment for demographics (p = .01), standard cardiovascular risk factors (p = .02), and Body Mass Index (BMI) (p = .05). In contrast, recent discrimination was only marginally associated with the presence of CAC in both unadjusted (p = .06) and fully adjusted logistic regression models (p = .08). Persistent exposure to racial/ethnic discrimination was not more strongly associated with CAC compared with other types of discrimination in either unadjusted or adjusted models. Conclusion: Chronic exposure to discrimination may be an important risk factor for early coronary calcification in African-American women. This association appears to be driven by exposure to discrimination from multiple sources, rather than exposure to racial/ethnic discrimination alone. CVD = cardiovascular disease; CAC = coronary artery calcification; SWAN = Study of Women’s Health Across the Nation; EBT = electron beam tomographic; CES-D = Center for Epidemiological Studies Depression; BMI = body mass index; FRS = Framingham Risk score; HDL-c = high density lipoprotein cholesterol; CRP = C-reactive protein; OR = odds ratio; CI = confidence interval; IMT = intima-media thickness.

Cat cerebral arterial smooth muscle cells express cytochrome P450 4A2 enzyme and produce the vasoconstrictor 20-HETE which enhances L-type Ca2+ current

1 Cerebral arteries express cytochrome P450 4A enzymes (P450 4A) and produce 20‐ hydroxyeicosatetraenoic acid (20‐HETE), a potent constrictor of pial arterioles. It is not known which cell type in the vessel wall is responsible for the formation of 20‐HETE. We examined whether freshly isolated cerebral arterial muscle cells (VSMCs) express P450 4A and produce 20‐HETE. We also studied the effect of 20‐HETE on pressurized cerebral arteries and on whole‐cell L‐type Ca2+current (ICa) recorded in cat cerebral VSMCs. 2 Cat cerebral VSMCs incubated with [14C]arachidonic acid ([14C]AA) produced 20‐HETE (3.9 ± 1.1 pmol min−1 (mg protein)−1). 3 Reverse transcription‐polymerase chain reaction studies revealed that cat cerebral VSMCs express mRNA for P450 4A which metabolizes AA to 20‐HETE. Cloning and sequencing of the cDNA amplified from mRNA isolated from VSMCs showed > 96 % amino acid homology to the rat and human P450 4A2 and 4A3. 4 20‐HETE (1–300 nM) induced a concentration‐dependent constriction of cat cerebral arteries, which was inhibited by nifedipine. 5 Addition of 10 and 100 nM 20‐HETE to the bath increased peak ICa by 50 ± 3 and 100 ± 10 %, respectively. This effect was not influenced by altering the frequency of depolarization. 20‐HETE (100 nM) failed to increase ICa in the presence of nifedipine. 6 These results demonstrate that cat cerebral VSMCs express P450 4A enzyme, and produce 20‐HETE which activates L‐type Ca2+ channel current to promote cerebral vasoconstriction.

Chronic Hypoxia Activates Lung 15-Lipoxygenase, Which Catalyzes Production of 15-HETE and Enhances Constriction in Neonatal Rabbit Pulmonary Arteries

Abstract— Hypoxia causes localized pulmonary arterial (PA) constriction to divert blood flow to optimally ventilated regions of the lung. The biochemical mechanisms for this have remained elusive, especially during prolonged exposures to reduced Po2. We have evidence that subacute hypoxia activates 15-lipoxygenase (15-LO) in small PAs of neonatal rabbits maintained for 9 days in hypoxic environments (Fio2=0.12) compared with siblings raised under normoxia. PA microsomal products of 15-LO, 15-hydroxyeicosatetraenoic acid (HETE), 11,14,15-trihydroxyeicosatrienoic acid (THETA), and 11,12,15-THETA were identified by gas chromatography/mass spectrometry. Increased amounts of these products are synthesized in vivo and in vitro by the lungs of animal raised in hypoxic versus normoxic environments. 15-HETE formation is attenuated by lipoxygenase, but not cytochrome P450 or cyclooxygenase inhibitors. Activation of 15-LO is associated with translocation of the enzyme from the cytosol to membrane as seen by Western immunoblotting. Immunohistochemical analysis demonstrates that 15-LO expression is clearly localized in vascular cells in lungs from normoxic and hypoxic kits. 15-HETE causes concentration-dependent constriction of PA rings from animals exposed to hypoxic but not normoxic environments. In addition, lipoxygenase inhibitors reduce phenylephrine-induced constriction of PA rings. Therefore, subacute hypoxia increases expression of and activates 15-LO, and enhances sensitivity of pulmonary arteries to its product, 15-HETE. Because 15-HETE is a constrictor in this vascular bed, it may play an important role in hypoxia-induced pulmonary vasoconstriction in rabbit kits. Although a clear causal relationship remains to be demonstrated, these data suggest a previously unrecognized role for 15-LO in hypoxic vasoconstriction in neonatal mammals.

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.

Shear activated channels in cell-attached patches of cultured bovine aortic endothelial cells.

We investigated the response of inward rectifier K+ (IRK) currents in bovine aortic endothelial cells (BAECs) to shear stress. Shear evoked reversible hyperpolarization in current clamped BAECs. Voltage clamped BAECs exhibited large inward and small outward whole cell K+ currents blocked by cesium and increased in amplitude by exposure to shear stress. The open state probability of IRK channels in cell-attached membrane patches was increased within minutes of exposure to shear stress. IRK channels in inside-out patches were activated by increases in [Ca2+]i from 10−7 to 10−6 mM. We demonstrate that shear stress induces hyperpolarization and gating of single channel and whole cell IRK currents in BAECs.

Renin-Angiotensin System Suppression Mitigates Experimental Radiation Pneumonitis

PURPOSE To find the mitigators of pneumonitis induced by moderate doses of thoracic radiation (10-15 Gy). METHODS AND MATERIALS Unanesthetized WAG/RijCmcr female rats received a single dose of X-irradiation (10, 12, or 15 Gy at 1.615 Gy/min) to the thorax. Captopril (an angiotensin-converting enzyme inhibitor) or losartan (an angiotensin receptor blocker) was administered in the drinking water after irradiation. Pulmonary structure and function were assessed after 8 weeks in randomly selected rats by evaluating the breathing rate, ex vivo vascular reactivity, and histopathologic findings. Survival analysis was undertaken on all animals, except those scheduled for death. RESULTS Survival after a dose of 10 Gy to the thorax was not different from that of unirradiated rats for <or=1 year. Survival decreased to <50% by 45 weeks after 12 Gy and by 8-9 weeks after 15 Gy. Captopril (17-56 mg/kg/d) improved survival and reduced radiation-induced increases in breathing rate, changes in vascular reactivity, and histopathologic evidence of injury. Radiation-induced increases in the breathing rate were prevented even if captopril was started 1 week after irradiation or if it was discontinued after 5 weeks. Losartan, although effective in reducing mortality, was not as efficacious as captopril in mitigating radiation-induced increases in the breathing rate or altered vasoreactivity. CONCLUSION In rats, a moderate thoracic radiation dose induced pneumonitis and morbidity. These injuries were mitigated by captopril even when it was begun 1 week after radiation or if discontinued 5 weeks after exposure. Losartan was less effective in protecting against radiation-induced changes in vascular reactivity or tachypnea.

20-HETE increases superoxide production and activates NAPDH oxidase in pulmonary artery endothelial cells.

Reactive oxygen species (ROS) signal vital physiological processes including cell growth, angiogenesis, contraction, and relaxation of vascular smooth muscle. Because cytochrome P-450 family 4 (CYP4)/20-hydroxyeicosatetraenoic acid (20-HETE) has been reported to enhance angiogenesis, pulmonary vascular tone, and endothelial nitric oxide synthase function, we explored the potential of this system to stimulate bovine pulmonary artery endothelial cell (BPAEC) ROS production. Our data are the first to demonstrate that 20-HETE increases ROS in BPAECs in a time- and concentration-dependent manner as detected by enhanced fluorescence of oxidation products of dihydroethidium (DHE) and dichlorofluorescein diacetate. An analog of 20-HETE elicits no increase in ROS and blocks 20-HETE-evoked increments in DHE fluorescence, supporting its function as an antagonist. Endothelial cells derived from bovine aortas exhibit enhanced ROS production to 20-HETE quantitatively similar to that of BPAECs. 20-HETE-induced ROS production in BPAECs is blunted by pretreatment with polyethylene-glycolated SOD, apocynin, inhibition of Rac1, and a peptide-based inhibitor of NADPH oxidase subunit p47(phox) association with gp91. These data support 20-HETE-stimulated, NADPH oxidase-derived, and Rac1/2-dependent ROS production in BPAECs. 20-HETE promotes translocation of p47(phox) and tyrosine phosphorylation of p47(phox) in a time-dependent manner as well as increased activated Rac1/2, providing at least three mechanisms through which 20-HETE activates NADPH oxidase. These observations suggest that 20-HETE stimulates ROS production in BPAECs at least in part through activation of NADPH oxidase within minutes of application of the lipid.

Pulmonary Embolism: The Weekend Effect

BACKGROUND Pulmonary embolism is a common, often fatal condition that requires timely recognition and rapid institution of therapy. Previous studies have documented worse outcomes for weekend admissions for a variety of time-sensitive medical conditions. This phenomenon has not been clearly demonstrated for pulmonary embolism. METHODS We used the Healthcare Cost and Utilization Project Nationwide Inpatient Sample for the years 2000 to 2008 to identify people with a principal discharge diagnosis of pulmonary embolism. We classified admissions as weekend if they occurred between midnight Friday and midnight Sunday. We compared all-cause in-hospital mortality between weekend and weekday admissions and investigated the timing of inferior vena cava (IVC) filter placement and thrombolytic infusion as potential explanations for differences in mortality. RESULTS Unadjusted mortality was higher for weekend admissions than weekday admissions (OR, 1.19; 95% CI, 1.13-1.24). This increase in mortality remained statistically significant after controlling for potential confounding variables (OR, 1.17; 95% CI, 1.11-1.22). Among patients who received an IVC filter, a larger proportion of those admitted on a weekday than on the weekend received it on their first hospital day (38% vs 29%, P < .001). The timing of thrombolytic therapy did not differ between weekday and weekend admissions. CONCLUSIONS Weekend admissions for pulmonary embolism were associated with higher mortality than weekday admissions. Our finding that IVC filter placement occurred later in the hospital course for patients admitted on weekends with pulmonary embolism suggests differences in the timeliness of diagnosis and treatment between weekday and weekend admissions. Regardless of cause, physicians should be aware that weekend admissions for pulmonary embolism have a 20% increased risk of death and warrant closer attention than provided during the week.

Radiation damage to the lung: mitigation by angiotensin converting enzyme (ACE) inhibitors

Concern regarding accidental overexposure to radiation has been raised after the devastating Tohuku earthquake and tsunami which initiated the Fukushima Daiichi nuclear disaster in Japan in March 2011. Radiation exposure is toxic and can be fatal depending on the dose received. Injury to the lung is often reported as part of multi‐organ failure in victims of accidental exposures. Doses of radiation >8 Gray to the chest can induce pneumonitis with right ventricular hypertrophy starting after ∼2 months. Higher doses may be followed by pulmonary fibrosis that presents months to years after exposure. Though the exact mechanisms of radiation lung damage are not known, experimental animal models have been widely used to study this injury. Rodent models for pneumonitis and fibrosis exhibit vascular, parenchymal and pleural injuries to the lung. Inflammation is a part of the injuries suggesting involvement of the immune system. Researchers worldwide have tested a number of interventions to prevent or mitigate radiation lung injury. One of the first and most successful class of mitigators are inhibitors of angiotensin‐converting enzyme (ACE), an enzyme that is abundant in the lung. These results offer hope that lung injury from radiation accidents may be mitigated, since the ACE inhibitor captopril was effective when started up to 1 week after irradiation.