Heme oxygenase-1-dependent central cardiorespiratory adaptations to chronic hypoxia in mice.

Adaptations to chronic hypoxia (CH) could reflect cellular changes within the cardiorespiratory regions of the rostral ventrolateral medulla (RVLM), the C1 region, and the pre-Bötzinger complex (pre-BötC). Previous studies have shown that the hypoxic chemosensitivity of these regions are heme oxygenase (HO) dependent and that CH induces HO-1. To determine the time course of HO-1 induction within these regions and explore its relevance to the respiratory and sympathetic responses during CH, the expression of HO-1 mRNA and protein in the RVLM and measures of respiration, sigh frequency, and sympathetic activity (spectral analysis of heart rate) were examined during 10 days of CH. Respiratory and sympathetic responses to acute hypoxia were obtained in chronically instrumented awake wild-type (WT) and HO-1 null mice. After 4 days of CH, there was a significant induction of HO-1 within the C1 region and pre-BötC. WT mice acclimated to CH by increasing peak diaphragm EMG after 10 days of CH but had no change in the respiratory response to acute hypoxia. There were no significant differences between WT and HO-1 null mice. In WT mice, hypoxic sigh frequency and hypoxic sensitivity of sympathetic activity initially declined before returning toward baseline after 5 days of CH, correlating with the induction of HO-1. In contrast, HO-1 null mice had a persistent decline in hypoxic sigh frequency and hypoxic sensitivity of sympathetic activity. We conclude that induction of HO-1 in these RVLM cardiorespiratory regions may be important for the hypoxic sensitivity of sighs and sympathetic activity during CH.

Use of drotrecogin alfa (activated) for severe sepsis in New Jersey acute care hospitals.

PURPOSE: The use of drotrecogin alfa (activated) for the treatment of severe sepsis in acute care hospitals in New Jersey was evaluated. SUMMARY: An observational study was conducted to determine the prevalence of severe sepsis and drotrecogin alfa use in hospitalized patients in New Jersey. In November 2003, a survey was mailed to the pharmacy directors of 84 acute care hospitals (teaching, major teaching, nonteaching) in New Jersey to collect information about the monthly use of drotrecogin alfa in 2002 and 2003. Health Care Financing Administration Uniform Bill of 1992 patient discharge data from New Jersey for the same period were analyzed to identify patients with severe sepsis and calculate the rate of drug use for their treatment. The survey received a total response rate of 55%. Among 7292 patients with severe sepsis who were treated in 2002 in participating hospitals, 137 received drotrecogin alfa. From January 2003 to October 2003, the average rate of drotrecogin alfa use in the same hospitals was identical. Drug use in teaching and major teaching hospitals was greater than in nonteaching hospitals. An increase in drotrecogin alfa use in 2003 compared with 2002 was expected; however, a comparison of its use in 2002 and 2003 in New Jersey acute care hospitals found that the rate of drug use remained the same. One tenth of responding hospitals never used drotrecogin alfa during the study period. CONCLUSION: An observational study showed an apparent underutilization of drotrecogin alfa (activated) for treatment of severe sepsis in acute care hospitals in New Jersey.

Oxygen-sensing neurons in the central nervous system.

This mini-review summarizes the present knowledge regarding central oxygen-chemosensitive sites with special emphasis on their function in regulating changes in cardiovascular and respiratory responses. These oxygen-chemosensitive sites are distributed throughout the brain stem from the thalamus to the medulla and may form an oxygen-chemosensitive network. The ultimate effect on respiratory or sympathetic activity presumably depends on the specific neural projections from each of these brain stem oxygen-sensitive regions as well as on the developmental age of the animal. Little is known regarding the cellular mechanisms involved in the chemotransduction process of the central oxygen sensors. The limited information available suggests some conservation of mechanisms used by other oxygen-sensing systems, e.g., carotid body glomus cells and pulmonary vascular smooth muscle cells. However, major gaps exist in our understanding of the specific ion channels and oxygen sensors required for transducing central hypoxia by these central oxygen-sensitive neurons. Adaptation of these central oxygen-sensitive neurons during chronic or intermittent hypoxia likely contributes to responses in both physiological conditions (ascent to high altitude, hypoxic conditioning) and clinical conditions (heart failure, chronic obstructive pulmonary disease, obstructive sleep apnea syndrome, hypoventilation syndromes). This review underscores the lack of knowledge about central oxygen chemosensors and highlights real opportunities for future research.

Occurrence and outcomes of sepsis: influence of race.

OBJECTIVE: To evaluate premorbid conditions and sociodemographic characteristics associated with differences in hospitalization and mortality rates of sepsis in blacks and whites. DESIGN: Secondary data analysis of the publicly available New Jersey State Inpatient Database for 2002. SETTING: Acute care hospitals in New Jersey. PATIENTS: All black and white adult patients with sepsis hospitalized in 2002. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 5,466 black and 19,373 white adult patients with sepsis were identified with the International Classification of Diseases, Ninth Revision, Clinical Modification codes for septicemia. Blacks were significantly younger than whites (61.6 +/- 0.25 and 72.8 +/- 0.11 yrs, respectively, p < .0001). Blacks had greater hospitalization rates than whites, with the greatest disparity between the ages of 35 and 44 yrs (relative risk, 4.35; 95% confidence interval, 3.93-4.82). Compared with whites, blacks had higher age-adjusted rates for hospitalization and mortality but similar case fatality rates. They were more likely than whites to be admitted to the hospital through the emergency room (odds ratio, 1.4; 95% confidence interval, 1.27-1.50) and to the intensive care unit (odds ratio, 1.14; 95% confidence interval, 1.07-1.21), and they were 3.96 times (95% confidence interval, 3.44-4.56) more likely to be uninsured. Black patients with sepsis had a greater likelihood of human immunodeficiency virus infection, diabetes, obesity, burns, and chronic renal failure than white patients and had a smaller likelihood of cancer, trauma, and urinary tract infection. CONCLUSIONS: In this study, age-adjusted case fatality rates for hospitalized white and black patients with sepsis were similar. These data are not suggestive of systematic disparities in the quality of treatment of sepsis between blacks and whites. However, blacks had higher rates of hospitalization and population-based mortality for sepsis. We speculate that disparities in disease prevention and care of preexisting conditions before sepsis onset may explain these differences.

Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003.

OBJECTIVE: To determine recent trends in rates of hospitalization, mortality, and hospital case fatality for severe sepsis in the United States. DESIGN: Trend analysis for the period from 1993 to 2003. SETTING: U.S. community hospitals from the Nationwide Inpatient Sample that is a 20% stratified sample of all U.S. community hospitals. PATIENTS: Subjects of any age with sepsis including severe sepsis who were hospitalized in the United States during the study period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Utilizing International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for septicemia and major organ dysfunction, we identified 8,403,766 patients with sepsis, including 2,857,476 patients with severe sepsis, who were hospitalized in the United States from 1993 to 2003. The percentage of severe sepsis cases among all sepsis cases increased continuously from 25.6% in 1993 to 43.8% in 2003 (p < .001). Age-adjusted rate of hospitalization for severe sepsis grew from 66.8 +/- 0.16 to 132.0 +/- 0.21 per 100,000 population (p < .001). Age-adjusted, population-based mortality rate within these years increased from 30.3 +/- 0.11 to 49.7 +/- 0.13 per 100,000 population (p < .001), whereas hospital case fatality rate fell from 45.8% +/- 0.17% to 37.8% +/- 0.10% (p < .001). During each study year, the rates of hospitalization, mortality, and case fatality increased with age. Hospitalization and mortality rates in males exceeded those in females, but case fatality rate was greater in females. From 1993 to 2003, age-adjusted rates for severe sepsis hospitalization and mortality increased annually by 8.2% (p < .001) and 5.6% (p < .001), respectively, whereas case fatality rate decreased by 1.4% (p < .001). CONCLUSIONS: The rate of severe sepsis hospitalization almost doubled during the 11-yr period studied and is considerably greater than has been previously predicted. Mortality from severe sepsis also increased significantly. However, case fatality rates decreased during the same study period.

Neuroleptic malignant syndrome and serotonin syndrome in the critical care setting: case analysis.

BACKGROUND: Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are medical emergencies associated with psychotropic administration. Differentiation and treatment can be complex, especially when features of both syndromes are present and the patient has taken both serotonergic and neuroleptic agents. METHOD: Case analysis of a poly-drug overdose (venlafaxine, topiramate, divalproex sodium, risperidone, and carbamazepine) presenting with mixed SS/NMS features and whose clinical management suggests a practical algorithm for treatment of undifferentiated SS/NMS in critical care settings. RESULTS: The suggested algorithm includes: 1) Supportive care and withdrawal of all potentially offending agents; 2) Laboratory evaluation with prompt initiation of treatment for both disorders--cyproheptadine for SS and dantrolene for NMS; 3) Do not use bromocriptine (contraindicated in SS) or chlorpromazine (contraindicated in NMS) initially; 4) Add bromocriptine when clinical presentation becomes consistent with NMS (SS can be prolonged if serotonergic agent has long half-life). CONCLUSIONS: Prompt and appropriate identification and intervention are essential for successful management of SS and NMS. The suggested treatment algorithm allows for specific treatment of both disorders and avoids potentially exacerbating either one. The algorithm derived from this case could serve as both a practical guideline and impetus for further investigation in light of increasing psychotropic co-administration.

Facing the challenge: decreasing case fatality rates in severe sepsis despite increasing hospitalizations.

OBJECTIVE: To determine recent trends in severe sepsis-related rates of hospitalization, mortality, and hospital case fatality in a large geographic area and to determine the impact of age, race, and gender on these outcomes. DESIGN: Trend analysis for the period of 1995 to 2002. SETTING: Acute care hospitals in New Jersey. PATIENTS: Subjects > or = 18 yrs of age with severe sepsis who were hospitalized in New Jersey during the period of 1995 to 2002. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed data from the 1995-2002 New Jersey State Inpatient Databases (SID) developed as part of the Healthcare Cost and Utilization Project (HCUP), covering all acute care hospitals in the state. On the basis of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for septicemia and organ dysfunction, we identified 87,675 patients with severe sepsis. The percentage of patients with severe sepsis among all hospitalized patients with sepsis grew steadily, from 32.7% to 44.7% (p < .0001), during these years. The crude rate of hospitalization with severe sepsis increased 54.2%, from 135.0/100,000 population in 1995 to 208.2/100,000 population in 2002 (p < .0001). Over time, the crude mortality rate rose by 35.8% (p < .0001), whereas the crude case fatality rate (number of deaths/number of cases) fell from 51.0% to 45.0% (p < .0001). For any given year, the rates of hospitalization and mortality were greater among older patients. After adjustment by age, the rates among blacks were greater than among whites, and they were greater among males than females. At the same time, there was no significant difference in the age-adjusted hospital case fatality rates with regard to gender and race. There was a significant increase in age-adjusted gender- and race-specific rates for hospitalization and mortality from 1995 to 2002. Blacks were more likely than whites to be admitted to the intensive care unit: for males, odds ratio = 1.19 (95% confidence interval, 1.13-1.26), and for females, odds ratio = 1.35 (95% confidence interval, 1.29-1.42). However, although case fatality rate was increased among patients admitted to the intensive care unit, this was not reflected in an increased case fatality among blacks. In addition, age-adjusted gender- and race-specific case fatality rates declined during 1995-2002. CONCLUSIONS: In spite of increasing rates of hospitalization and mortality, there is a decreasing case fatality rate for severe sepsis. These data suggest that advances in critical care practice before and during the study period have resulted in improved outcomes for this population.