Terlipressin dose response in healthy and endotoxemic sheep: impact on cardiopulmonary performance and global oxygen transport

OBJECTIVE: To determine whether a goal-directed terlipressin infusion increases mean arterial pressure without causing a pulmonary vasopressive effect and whether this response impacts on key parameters of oxygen transport in healthy and endotoxemic sheep. DESIGN AND SETTING: Prospective controlled trial in a university research laboratory. ANIMALS AND INTERVENTIONS: Six conscious adult ewes instrumented for chronic study received terlipressin as titrated infusion started with 10 microg x kg(-1) x h(-1) and increased by 5 microg x kg(-1) x h(-1) every 15 min, either until mean arterial pressure was increased by 15 mmHg from baseline, or a maximum of 40 microg x kg(-1) x h(-1) was given. Following 24 h of recovery sepsis was induced and maintained in the same ewes by a continuous infusion of endotoxin ( Salmonella typhosa, 10 ng x kg(-1) min(-1)). After 16 h of endotoxemia the sheep were again treated with terlipressin. MEASUREMENTS AND RESULTS: Systemic oxygen delivery and consumption were calculated before and after the titration period; hemodynamic parameters were measured every 15 min. The increase in mean arterial pressure was greater during endotoxemia than in healthy controls. In both states terlipressin administration decreased cardiac index and diminished oxygen delivery and consumption. While mean pulmonary arterial pressure remained constant, terlipressin increased the pulmonary vascular resistance index in endotoxemic sheep. CONCLUSIONS: During ovine endotoxemia titrated terlipressin reversed hypotension but impaired the pulmonary circulation. The observed decrease in oxygen delivery may carry the risk of tissue hypoxia especially in sepsis, where oxygen demand is typically increased.     

Evidence-based guidelines for the prevention of ventilator-associated pneumonia: results of a knowledge test among intensive care nurses

Objective To determine intensive care nurses' knowledge of evidence-based guidelines for the prevention of ventilator-associated pneumonia (VAP). Design A survey using a validated multiple-choice questionnaire, developed to evaluate nurses' knowledge of VAP prevention. The questionnaire was distributed and collected during the annual congress of the Flemish Society for Critical Care Nurses (Ghent, November 2005). Demographic data included were gender, years of intensive care experience, number of critical beds, and whether respondents hold a special degree in emergency and intensive care. Main results We collected 638 questionnaires (response rate 74.6%). Nineteen percent of the respondents recognized the oral route as the recommended way for intubation. It was known by 49% of respondents that ventilator circuits should be changed for each new patient. Heat and moisture exchangers were checked as the recommended type of humidifier by 55% of respondents, but only 13% knew that it is recommended to change them once weekly. Closed suctioning systems were identified as recommended by 17% of respondents, and 20% knew that these must be changed for each new patient only. Sixty percent and 49%, respectively, recognized subglottic drainage and kinetic beds to reduce the incidence of VAP. Semi-recumbent positioning is well known to prevent VAP (90%). The average knowledge level was higher among more experienced nurses (> 1 year experience) and those holding a special degree in emergency and intensive care. Conclusion Nurses lack knowledge regarding recommendations for VAP prevention. Nurses' schooling and continuing education should include support from current evidence-based guidelines. The authors have written this article on behalf of the Executive Board of the Flemish Society for Critical Care Nurses. Stijn I. Blot and Sonia Labeau are the joint primary authors.     

The effect of a reduced sodium intake on post-renal transplantation hypertension in rats

In an experimental model of post-renal transplantation hypertension in rats, we studied the effect of a reduction of sodium intake on the development of this type of hypertension. Systolic blood pressure, plasma renin concentration and renal function were measured regularly in recipients of an allogeneic kidney transplant that had previously undergone active immunological enhancement. Transplant recipients on a normal diet showed a rise in systolic blood pressure during the second week after transplantation. The systolic blood pressure of recipients on a low sodium diet remained normotensive throughout the 15 weeks follow-up period. The plasma renin concentration was low in the hypertensive recipients on a normal diet, as compared with unilaterally nephrectomized controls. Although the plasma renin concentration of recipients on a low sodium diet fell below that of unilaterally nephrectomized controls on a low sodium diet, it was higher than that of recipients on a normal diet. The renal function of transplant recipients was greatly reduced compared with that of control rats. The glomerular filtration rate was reduced to a greater extent than the effective renal plasma flow. In a separate experiment it was revealed that a similar reduction in the glomerular filtration rate of kidneys permanently damaged by temporary ischaemia did not result in an increase in the systolic blood pressure. Survival up to 6 weeks after transplantation was the same for both groups of recipients. Recipients on a low sodium diet, however, showed a better 15 weeks survival, probably owing to the absence of hypertension in this group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mortality in patients treated for Cushing's disease is increased, compared with patients treated for nonfunctioning pituitary macroadenoma

CONTEXT: Increased mortality in patients with pituitary tumors after surgical treatment has been reported. However, it is unknown to what extent excess mortality is caused by pituitary tumors and their treatment in general and to what extent by previous exposure to hormonal overproduction. OBJECTIVE: The aim of the study was to compare mortality between patients treated for Cushing's disease and nonfunctioning pituitary macroadenomas (NFMAs). DESIGN: This was a follow-up study. PATIENTS: We included 248 consecutive patients with pituitary adenomas treated by transsphenoidal surgery in our hospital for NFMAs (n = 174) and ACTH-producing adenomas (n = 74). The mean duration of follow-up after surgery was 10.1 +/- 7.2 yr for the whole cohort. OUTCOME MEASURES: The standardized mortality ratio (SMR) was calculated for the whole cohort and also for the two diseases separately. Cox regression analysis was used to compare mortality in patients with Cushing's disease with NFMA patients. RESULTS: Patients with Cushing's disease (39.1 +/- 16.1 yr) were significantly younger at time of operation than NFMA patients (55.3 +/- 13.4 yr). The SMR for the whole cohort was 1.41 [95% confidence interval (CI), 1.05-1.86]. The SMR in NFMA patients was 1.24 (95% CI, 0.85-1.74) vs. 2.39 (95% CI, 1.22-3.9) in patients with Cushing's disease. In patients with Cushing's disease, compared with NFMAs, the age-adjusted mortality was significantly increased: hazard ratio 2.35 (95% CI, 1.13-4.09, P = 0.008). CONCLUSIONS: Mortality in patients previously treated for Cushing's disease is increased, compared with patients treated for NFMAs. This implies that previous, transient overexposure to cortisol is associated with increased mortality.     

A helix-breaking mutation in TRPML3 leads to constitutive activity underlying deafness in the varitint-waddler mouse

Homozygote varitint-waddler (Va) mice, expressing a mutant isoform (A419P) of TRPML3 (mucolipin 3), are profoundly deaf and display vestibular and pigmentation deficiencies, sterility, and perinatal lethality. Here we show that the varitint-waddler isoform of TRPML3 carrying an A419P mutation represents a constitutively active cation channel that can also be identified in native varitint-waddler hair cells as a distinct inwardly rectifying current. We hypothesize that the constitutive activation of TRPML3 occurs as a result of a helix-breaking proline substitution in transmembrane-spanning domain 5 (TM5). A proline substitution scan demonstrated that the inner third of TRPML3's TM5 is highly susceptible to proline-based kinks. Proline substitutions in TM5 of other TRP channels revealed that TRPML1, TRPML2, TRPV5, and TRPV6 display a similar susceptibility at comparable positions, whereas other TRP channels were not affected. We conclude that the molecular basis for deafness in the varitint-waddler mouse is the result of hair cell death caused by constitutive TRPML3 activity. To our knowledge, our study provides the first direct mechanistic link of a mutation in a TRP ion channel with mammalian hearing loss.     

Diagnostic imaging of dopamine receptors in pituitary adenomas

Dopamine D2 receptor scintigraphy of pituitary adenomas is feasible by single-photon emission computed tomography using (123)I-S-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-3-iodo-6-methoxybenzamide ((123)I-IBZM) and (123)I-epidepride. (123)I-epidepride is generally superior to (123)I-IBZM for the visualization of D2 receptors on pituitary macroadenomas. However, (123)I-IBZM and (123)I-epidepride scintigraphy are generally not useful to predict the response to dopaminergic treatment in pituitary tumour patients. These techniques might allow discrimination of non-functioning pituitary macroadenomas from other non-tumour pathologies in the sellar region. Dopamine D2 receptors on pituitary tumours can also be studied using positron emission tomography with (11)C-N-raclopride and (11)C-N-methylspiperone.     

Peptide receptor radionuclide therapy with <Superscript>177</Superscript>Lu-octreotate in patients with foregut carcinoid tumours of bronchial,gastric and thymic origin

Purpose Foregut carcinoid tumours have a different embryological origin than other gastroenteropancreatic neuroendocrine tumours (GEP NETs). In the total group of GEP NETs (n = 131), treatment with ¹⁷⁷Lu-octreotate resulted in tumour remission in 47% of patients, with a median time to progression (TTP) of >36 months. As patients with foregut carcinoids may respond differently, we here present the effects of this treatment in a subgroup of patients with foregut carcinoids of bronchial, gastric or thymic origin. Methods Nine patients with bronchial, five with gastric and two with thymic carcinoids were treated. All patients had metastasised disease. The intended cumulative dose of ¹⁷⁷Lu-octreotate was 22.2–29.6 GBq. Southwest Oncology Group criteria were used for response evaluation. Results Bronchial carcinoids: Five patients had partial remission, one had minor response (MR, tumour size reduction: ≥25%, <50%), two had stable disease (SD) and one had progressive disease (PD). Median TTP was 31 months. Gastric carcinoids: One patient had complete remission, one had MR and two had SD, including one with PD at baseline. One patient developed PD. Thymic carcinoids: One patient had SD. In the other patient, disease remained progressive. All patients: Overall remission rate was 50%, including MR. Conclusion ¹⁷⁷Lu-octreotate treatment can be effective in patients with bronchial and gastric carcinoids. Its role in thymic carcinoids cannot be determined yet because of the limited number of patients. The overall remission rate of 50% in patients with the studied foregut carcinoids is comparable to that in the total group of GEP NETs.