Varenicline in the routine treatment of tobacco dependence: a pre-post comparison with nicotine replacement therapy and an evaluation in those with mental illness.

AIMS: To compare the effectiveness of varenicline with nicotine replacement for smoking cessation and to evaluate the safety and effectiveness of varenicline in people with mental illness. DESIGN: Evaluation of consecutive routine cases before and after the introduction of varenicline. SETTING: National Health Service (NHS) tobacco dependence clinic in London, UK. PARTICIPANTS: A total of 412 cases receiving routine care. INTERVENTION: Seven group support sessions over 6 weeks with either nicotine replacement therapy (NRT) (n = 204) or varenicline (n = 208). MEASUREMENTS: Verified abstinence 4 weeks after quit day, severity of withdrawal symptoms, incidence and severity of adverse drug symptoms, cost per patient treated and cost per successful short-term quitter. FINDINGS: Short-term cessation rates were higher with varenicline than NRT (odds ratio = 1.70, 95% confidence interval = 1.09-2.67). Varenicline was equally effective in those with and without mental illness. Craving to smoke, but not adverse mood, was less severe with varenicline than NRT. The cost per quitter was similar for varenicline and NRT. There was a higher incidence of adverse drug symptoms among those taking varenicline, but these were tolerated by most smokers. There was no evidence that varenicline exacerbated mental illness. CONCLUSIONS: In this setting and with group support varenicline appears to improve success rates over those achieved with NRT, and is equally effective and safe in those with and without a mental illness.     

A human yeast artificial chromosome containing the multiple endocrine neoplasia type 2B Ret mutation does not induce medullary thyroid carcinoma but does support the growth of kidneys and partially rescues enteric nervous system development in Ret-deficient mice

We generated a line of transgenic mice using a yeast artificial chromosome containing the Ret mutation responsible for the multiple endocrine neoplasia type 2B syndrome (MEN 2B). The resulting animals did not develop any of the expected neoplasms associated with MEN 2B. Transgenic animals were then bred with animals lacking murine Ret (Ret(M)) to further evaluate the function of human mutated Ret (Ret(H)(2B)) in the murine context. Whereas mice lacking Ret(M) exhibit intestinal aganglionosis and the absence of kidneys with other genitourinary anomalies, expression of the Ret(H)(2B) transgene in Ret(M)-deficient mice allowed significant renal development with a partial rescue of the enteric nervous system. These Ret(H)(2B)-positive/Ret(M)-deficient mice exhibit normal Ret expression and survive longer than Ret(M)-deficient mice, but still die at 3 to 5 days of age with evidence of enterocolitis. We conclude that the normal expression of a human Ret proto-oncogene with the MEN 2B mutation does not cause any features of MEN 2B in mice. Although the gene is normally expressed in the appropriate target tissues, there is incomplete phenotypic rescue in mice lacking murine Ret. These results suggest important interspecies differences between humans and mice in the function of the Ret oncogene.     

Early growth response gene 1-mediated apoptosis is essential for transforming growth factor beta1-induced pulmonary fibrosis

Fibrosis and apoptosis are juxtaposed in pulmonary disorders such as asthma and the interstitial diseases, and transforming growth factor (TGF)-beta(1) has been implicated in the pathogenesis of these responses. However, the in vivo effector functions of TGF-beta(1) in the lung and its roles in the pathogenesis of these responses are not completely understood. In addition, the relationships between apoptosis and other TGF-beta(1)-induced responses have not been defined. To address these issues, we targeted bioactive TGF-beta(1) to the murine lung using a novel externally regulatable, triple transgenic system. TGF-beta(1) produced a transient wave of epithelial apoptosis that was followed by mononuclear-rich inflammation, tissue fibrosis, myofibroblast and myocyte hyperplasia, and septal rupture with honeycombing. Studies of these mice highlighted the reversibility of this fibrotic response. They also demonstrated that a null mutation of early growth response gene (Egr)-1 or caspase inhibition blocked TGF-beta(1)-induced apoptosis. Interestingly, both interventions markedly ameliorated TGF-beta(1)-induced fibrosis and alveolar remodeling. These studies illustrate the complex effects of TGF-beta(1) in vivo and define the critical role of Egr-1 in the TGF-beta(1) phenotype. They also demonstrate that Egr-1-mediated apoptosis is a prerequisite for TGF-beta(1)-induced fibrosis and remodeling.     

Procalcitonin-guided antibiotics in severe sepsis

Citation

Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J: Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. Am J Respir Crit Care Med 2008, 177: 498–505 [1].

Background

The duration of antibiotic therapy in critically ill patients with sepsis can result in antibiotic overuse, increasing the risk of developing bacterial resistance. Procalcitonin (PCT)-guided antibiotic use reduces antibiotic exposure in community-acquired pneumonia. Whether it might also reduce antibiotic exposure in severe sepsis is unknown.

Methods

Objective

To test the hypothesis that an algorithm based on serial measurements of PCT allows reduction in the duration of antibiotic therapy compared with empirical rules, and does not result in more adverse outcomes in patients with severe sepsis and septic shock.

Design

Single-center, non-blinded randomized controlled trial.

Setting

Mixed medical and surgical ICU at a university teaching hospital.

Subjects

79 adult patients with suspected severe sepsis or septic shock.

Intervention

All patients had circulating PCT levels drawn daily. In patients randomly assigned to the intervention group, antibiotics were stopped when PCT levels had decreased 90% or more from the initial value (if clinicians agreed) but not before Day 3 (if baseline PCT levels were <1 mg/L) or Day 5 (if baseline PCT levels were >1 mg/L). In control patients, clinicians decided on the duration of antibiotic therapy based on empirical rules.

Outcome

Systemic antibiotic exposure, measured using three variables: 1) duration of antibiotic treatment, 2) antibiotic exposure days per 1000 inpatient days, and 3) days alive without antibiotics within the 28-day follow-up period.

Results

Patients assigned to the PCT group had 3.5-day shorter median duration of antibiotic therapy for the first episode of infection than control subjects (intention-to-treat, n = 79, P = 0.15). In patients in whom a decision could be taken based on serial PCT measurements, PCT guidance resulted in a 4-day reduction in the duration of antibiotic therapy (per protocol, n = 68, P = 0.003) and a smaller overall antibiotic exposure (P = 0.0002). A similar mortality and recurrence of the primary infection were observed in PCT and control groups. A 2-day shorter intensive care unit stay was also observed in patients assigned to the PCT group (P = 0.03).

Conclusion

Our results suggest that a protocol based on serial PCT measurement allows reducing antibiotic treatment duration and exposure in patients with severe sepsis and septic shock without apparent harm.     

Black Hawk Down: The evolution of resuscitation strategies in massive traumatic hemorrhage

Citation

Borgman MA, Spinella PC, Perkins JG, Grathwohl KW, Repine T, Beekley AC, Sebesta J, Jenkins D, Wade CE, Holcomb JB: The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma 2007, 63: 805–813 [1].

Background

Patients with severe traumatic injuries often present with coagulopathy and require massive transfusion. The risk of death from hemorrhagic shock increases in this population. To treat the coagulopathy of trauma, some have suggested early, aggressive correction using a 1:1 ratio of plasma to red blood cell (RBC) units.

Methods

Objective

To determine whether the ratio of plasma to RBCs transfused would affect survival by decreasing death from hemorrhage.

Design

Retrospective chart review.

Setting

United States Army combat support hospital in Iraq.

Subjects

246 patients who received a massive transfusion (≥10 units of RBCs in 24 hours) from November 2003 to September 2005. Three groups of patients were constructed according to the plasma to RBC ratio transfused during massive transfusion.

Intervention

None.

Outcome

Hospital mortality rates and the cause of death were compared among groups. Multivariable logistic regression was used to determine the independent association between plasma to RBC ratio and hospital mortality.

Results

For the low ratio group the plasma to RBC median ratio was 1:8 (interquartile range (IQR), 0:12–1:5), for the medium ratio group, 1:2.5 (IQR, 1:3.0–1:2.3), and for the high ratio group, 1:1.4 (IQR, 1:1.7–1:1.2) (p < 0.001). Median Injury Severity Score (ISS) was 18 for all groups (IQR, 14–25). For low, medium, and high plasma to RBC ratios, overall mortality rates were 65%, 34%, and 19%, (p < 0.001); and hemorrhage mortality rates were 92.5%, 78%, and 37%, respectively (p < 0.001). Upon logistic regression, plasma to RBC ratio was independently associated with survival (odds ratio 8.6, 95% confidence interval 2.1–35.2).

Conclusion

In patients with combat-related trauma requiring massive transfusion, a high 1:1.4 plasma to RBC ratio is independently associated with improved survival to hospital discharge, primarily by decreasing death from hemorrhage. For practical purposes, massive transfusion protocols should utilize a 1:1 ratio of plasma to RBCs for all patients who are hypocoagulable with traumatic injuries.     

Anxiety and agitation in mechanically ventilated patients

During an ethnography conducted in an intensive care unit (ICU), we found that anxiety and agitation occurred frequently and were important considerations in the care of 30 patients weaning from prolonged mechanical ventilation. We conducted a secondary analysis to (a) describe characteristics of anxiety and agitation experienced by mechanically ventilated patients, (b) explore how clinicians recognized and interpreted anxiety and agitation, and (c) describe strategies and interventions used to manage anxiety and agitation with mechanically ventilated patients. We constructed the Anxiety/Agitation in Mechanical Ventilation Model to illustrate the multidimensional features of symptom recognition and management. Patients' ability to interact with the environment served as a basis for identification and management of anxiety or agitation. Clinicians' attributions about anxiety or agitation, and "knowing the patient," contributed to their assessment of patient responses. Clinicians chose strategies to overcome either the stimulus or the patient's appraisal of risk of the stimulus. This article contributes to the body of knowledge about symptom recognition and management in the ICU by providing a comprehensive model to guide future research and practice.