Perioperative application of L-alanyl-L-glutamine in cardiac surgery: effect on the polarized T cell cytokine expression.

At risk patients undergoing cardiac surgery with cardiopulmonary bypass have increased rates of postoperative infectious morbidity. Postoperatively, after cardiac surgery, an immunosuppression in the form of a polarization of T helper (Th) cells with a decreased Th1 response (IL-2 and IFN-gamma) and an increased Th2 response (IL-4 and IL-10) is recognized. Therapeutic strategies to modulate the immunological response include special key nutrients such as the amino acid glutamine favoring the Th2 response. There is no information available concerning its effect in patients undergoing cardiac surgery. The aim of this clinical study was to evaluate the effects of a perioperative infusion of glutamine on the polarized lymphocyte T cell cytokine expression and on infectious morbidity in cardiac surgery patients at risk of infection. Seventy-eight patients were included in the study undergoing elective cardiac surgery with a lymphopenia less than 1.2 giga/l. One or more of the following criteria had to be met: age older than 70 years, ejection fraction less than 40%, or mitral valve replacement. We randomly assigned patients to receive infusions of either high-dose L-alanyl-L-glutamine dipeptide [0.5 g/(kg day) glutamine] dissolved in an amino acid solution or an isonitrogeneous, isocaloric, isovolemic nutritional solution. An additional group with normal saline served as control to eliminate any nonspecific nutritional effect. We started the infusion after induction of anesthesia with 1,000 ml/24 h and continued it for 3 days. The primary endpoint was intracellular T cell cytokine expression (including the description in tertiles) on the first postoperative day (pod 1). Secondary endpoints were postoperative infection rate, mortality rate, cardiovascular circulation ventilation time, and renal function. A high-dose perioperative glutamine application leading to mean plasma levels of 1,177 microM had only a minor influence on the polarized intracellular T cell cytokine expression. On pod 1 there was a polarization of T cells, i.e., an augmented Th2 response with an increased number of IL-6 and IL-10 producing cells. On the other side the Th1 response with IL-2 and TNF-alpha declined on pods 1 and 2. Only the intracellular IL-2 response in the lower tertile of IL-2 production was improved with glutamine indicating a small influence. We did not observe any effects on the numbers of postoperative infections; on mortality rate; on cardiovascular circulation; on ventilation time or on renal function. The elevation of glutamine plasma levels by a perioperative intravenous infusion of L-alanyl-L-glutamine influenced the intracellular expression of IL-2 in the lower tertile only slightly. However, mean glutamine values in the other groups remained above or close 500 microM, thus suggesting that glutamine supply to the immune cells was still adequate in most patients, and that glutamine deficiency, if it occurred, was marginal. In the event of a severe glutamine deficiency the observed effect on cytokine production could be more pronounced. Furthermore, we could not observe any obvious clinical advantage in this at risk cardiac surgical patient population. A glutamine supplementation for patients undergoing cardiac surgery without a clear glutamine deficiency is not recommended.

Hypotension after spinal anesthesia for cesarean section: identification of risk factors using an anesthesia information management system.

OBJECTIVE: To determine risk factors for developing hypotension after spinal anesthesia for cesarean section to prevent obstetric patients from hypotensive episodes potentially resulting in intrauterine malperfusion and endangering the child. METHODS: The data from 503 women, having received spinal anesthesia for cesarean sections were investigated using online gathered vital signs and specially checked manual entries employing an anesthesia information management system. Blood pressure, heart rate, and oxygen saturation were measured throughout and hypotension was defined as either a drop in mean arterial blood pressure of >20% from baseline value or readings of <90 mmHg systolic arterial blood pressure. Thirty-two variables were studied for association with hypotensive episodes using univariate analysis and logistic regression employing a forward stepwise algorithm to identify independent variables (P < 0.05). RESULTS: Hypotension was found in 284 cases (56.5%). The univariate analysis identified the neonate's weight, mother's age, body mass index, and peak sensory block height associated with hypotension. Body mass index, age and sensory block height were detected as independent factors for hypotension (odds-ratio: 1.61 each). CONCLUSIONS: Knowledge of these risk factors should increase the anesthesiologist's attention to decide for the necessity to employ prophylactic or therapeutic techniques or drugs to prevent the neonate from any risk resulting of hypotension of the mother.

Critical appraisal of RCTs by 3rd year undergraduates after short courses in EBM compared to expert appraisal.

Introduction: An essential aim of courses in evidence-based medicine (EBM) is to improve the skills for reading and interpreting medical literature adequately. Regarding the conceptual framework, it is important to consider different educational levels. Aim: Our primary aim was to investigate the applicability of different instruments for the assessment of methodological study quality by 3rd grade students after short courses in EBM. Our secondary outcomes were agreement with expert assessments and student's knowledge and competences. Methods: We conducted four short courses in EBM of 90 minutes each for health care management and medical students focused on critical appraisal of the literature. At the end, the students assessed five publications about randomized controlled trials (RCTs) using five different instruments; the results were compared to expert assessments. Results: In total, 167 students participated in our EBM courses. Students' assessments showed a non-systematic over- and underestimation of risk of bias compared to expert assessments with no clear direction. Agreement with expert assessments ranged between 66% to over 80%. Across RCTs, evidence was found that the choice of instrument had an impact on agreement rates between expert and student assessments (p=0.0158). Three RCTs showed an influence of the instrument on the agreement rate (p<0.05 each). Discussion: Our results contrast sharply with those of many other comparable evaluations. Reasons may be a lack of students' motivation due to the compulsory courses, and the comparison to a reference standard in addition to self-ratings causing objectivity. Conclusion: Undergraduates should become familiar with the principles of EBM, including research methods, and the reading of scientific papers as soon as possible. For a deeper understanding, clinical experience seems to be an indispensable precondition. Based on our results, we would recommend an integration of lectures about EBM and critical appraisal at least twice during studies and with greater intensity shortly before graduation.

Expression, release, and biological activity of parathyroid hormone-related peptide from coronary endothelial cells.

Ventricular cardiomyocytes have previously been identified as potential target cells for parathyroid hormone-related peptide (PTHrP). Synthetic PTHrP peptides exert a positive contractile effect. Because systemic PTHrP levels are normally negligible, this suggests that PTHrP is expressed in the ventricle and acts as a paracrine mediator. We investigated the ventricular expression of PTHrP and its expression in cultured cells isolated from the ventricle, studied the release of PTHrP from hearts and cultures, and investigated whether this authentic PTHrP mimics the biological effects previously described for synthetic PTHrP on ventricular cardiomyocytes. We found PTHrP expressed in ventricles of neonatal and adult rat hearts. In cells isolated from adult hearts, we found PTHrP expression exclusively in coronary endothelial cells but not in cardiomyocytes. The latter, however, are target cells for PTHrP. PTHrP was released from isolated perfused hearts during hypoxic perfusion and from cultured coronary endothelial cells under energy-depleting conditions. This PTHrP was biologically active; ie, it exerted a positive contractile and lusitropic effect on cardiomyocytes. Authentic PTHrP was glycosylated and showed a slightly higher potency than synthetic PTHrP. These results suggest that PTHrP is an endothelium-derived modulator of ventricular function.

A N-terminal PTHrP peptide fragment void of a PTH/PTHrP-receptor binding domain activates cardiac ET(A) receptors.

1. Adult ventricular cardiomyocytes show an unusual structure-function relationship for cyclic AMP-dependent effects of PTHrP. We investigated whether PTHrP(1 - 16), void of biological activity on classical PTHrP target cells, is able to mimic the positive contractile effect of PTHrP(1 - 34), a fully biological agonist on cardiomyocytes. 2. Adult ventricular cardiomyocytes were paced at a constant frequency of 0.5 Hz and cell contraction was monitored using a cell-edge-detection system. Twitch amplitudes, expressed as per cent cell shortening of the diastolic cell length, and rate constants for maximal contraction and relaxation velocity were analysed. 3. PTHrP(1 - 16) (1 micromol l(-1)) mimicked the contractile effects of PTHrP(1 - 34) (1 micromol l(-1)). It increased the twitch amplitude from 5.33+/-0.72 to 8.95+/-1.10 (% dl l(-1)) without changing the kinetic of contraction. 4. PTH(1 - 34) (10 micromol l(-1)) affected the positive contractile effect of PTHrP(1 - 34), but not that of PTHrP(1 - 16). 5. RpcAMPS (10 micromol l(-1)) inhibited the positive contractile effect of PTHrP(1 - 34), but not that of PTHrP(1 - 16). 6. The positive contractile effect of PTHrP(1 - 16) was antagonized by the ET(A) receptor antagonist BQ123. 7. Sarafotoxin 6b and PTHrP(1 - 16), but not PTHrP(1 - 34), replaced (3)H-BQ123 from cardiac binding sites. 8. We conclude that N-terminal PTHrP peptides void of a PTH/PTHrP-receptor binding domain are able to bind to, and activate cardiac ET(A) receptors.