Sufentanil and midazolam dosing and pharmacogenetic factors in pediatric analgosedation and withdrawal syndrome.

Our aim was to describe the effect of dosing and genetic factors on sufentanil- and midazolam-induced analgosedation and withdrawal syndrome (WS) in pediatric population. Analgosedation and withdrawal syndrome development were monitored using COMFORT-neo/-B scores and SOS score. Length of therapy, dosing of sufentanil and midazolam were recorded. Genotypes of selected candidate polymorphisms in CYP3A5, COMT, ABCB1, OPRM1 and PXR were analysed. In the group of 30 neonates and 18 children, longer treatment duration with midazolam of 141 h (2 - 625) vs. 88 h (7 - 232) and sufentanil of 326.5 h (136 - 885) vs. 92 h (22 - 211) (median; range) was found in the patients suffering from WS vs. non-WS group, respectively. Median midazolam cumulative doses were in the respective values of 18.22 mg/kg (6.93 - 51.25) vs. 9.94 mg/kg (2.12 - 49.83); P=0.03, and the respective values for sufentanil were 88.60 microg/kg (20.21 - 918.52) vs. 21.71 microg/kg (4.5 - 162.29); P<0.01. Cut off value of 177 hours for sufentanil treatment duration represented predictive factor for WS development with 81 % sensitivity and 94 % specificity. SNPs in the candidate genes COMT, PXR and ABCB1 affected the dosing of analgosedative drugs, but were not associated with depth of analgosedation or WS. Cumulative dose and length of analgosedative therapy with sufentanil significantly increases the risk of WS in critically ill neonates and children.

Carotid endarterectomy after ischemic stroke--is there a justification for delayed surgery?

PURPOSE: To assess the relationship between outcome of carotid surgery and wait after ischemic stroke. METHODS: We retrospectively analysed data from patients undergoing carotid endarterectomy after ischemic stroke. We investigated the time interval between the event and endarterectomy in relation to surgical results and complications. RESULTS: Between January 2000 and December 2003, 104 patients were scheduled to undergo carotid endarterectomy after a recent stroke. Endarterectomy was performed within 6 h in seven patients (6.7%); within 4 weeks in 29 (27.9%); 4 weeks or more in 62 (59.6%) and six (5.8%) patients received no further therapy. Perioperative complications among patients treated within 4 weeks were 3.4% and were comparable to those treated after 4 weeks (4.8%). However, more than 12% of the patients awaiting operation experienced a new cerebrovascular event (ischemic stroke or carotid occlusion), most of them occurred in the 3rd or 4th week after the initial event. CONCLUSION: Our data indicates, that carotid endarterectomy can be performed with a comparable risk within a short delay after stroke. In addition severe cerebrovascular events occurring within the waiting period may be avoided.

The axillocoronary bypass. Blood flow and short-term graft histology in a porcine model.

BACKGROUND: Bypass grafts arising from the axillary artery may be indicated for complications during minimally invasive direct coronary artery bypass grafting, for redo operations and for management of a severely atherosclerotic ascending aorta. As basic data research on this technique is scanty, we investigated intraoperative function and postoperative morphology of axillocoronary bypass grafts in a porcine model. METHODS: Thirteen German domestic pigs received an axillocoronary vein graft (Group I, n=7) or an aortocoronary vein graft (Group II, n=6) to the left anterior descending artery. In Group I the proximal anastomosis was performed to the left axillary artery, and after partial rib resection the graft was brought transpleurally to the target vessel. In both groups the coronary anastomosis was carried out on the beating heart without cardiopulmonary bypass. Graft flow was measured using transit time ultrasonic flow probes. RESULTS: Intraoperatively all grafts showed a typical diastolic flow profile. Stable graft flow was lower in axillocoronary bypass grafts: 47 (30-60 mL/min) in Group I and 65 (35-126 mL/min) in Group II (p=0.005). Flow given as percentage of cardiac output, however, did not differ between the two grafts: 0.9 (0.6-1.2%) in Group I and 1.2 (0.8-2.4%) in Group II (p=NS). At day 4 after surgery there was no clear histologic predilection site for microtrauma and early degenerative changes in the axillocoronary graft. CONCLUSIONS: Axillocoronary bypass flow compares well with flow in the aortocoronary graft. Microtrauma after implantation and early degenerative changes in the axillocoronary vein bypass are not particularly impacted by the thoracic entry site.

The subclavian and axillary arteries as inflow vessels for coronary artery bypass grafts--combined experience from three cardiac surgery centers.

BACKGROUND: The subclavian and axillary arteries represent reliable inflow vessels in peripheral vascular surgery. During recent years they have also been used for special situations in coronary artery bypass grafting. We report on a preliminary, triple center experience with subclavian/axillary artery to coronary artery bypass grafting. METHODS: Twenty-one patients (11 male, 10 female, median age 70 years) received subclavian artery/axillary artery to coronary artery bypass grafts. Indications for application of this bypass variation were internal mammary artery problems during minimally invasive coronary artery bypass grafting (n = 10), untouchable ascending aorta (n = 6), high risk reoperations (n = 3), severe chronic obstructive pulmonary disease (COPD) (n = 1) and right ventricular ischemia after ascending aortic replacement for acute aortic dissection type A (n = 1). Fourteen procedures were carried out via minithoracotomy, and seven via sternotomy. Inflow vessels were the left subclavian/axillary artery in 12 cases, the right subclavian/axillary artery in eight cases and bilateral subclavian/axillary artery in one case. Bypass conduits were the saphenous vein (n = 20 for revascularization of the left anterior descending artery, the right coronary artery and obtuse marginal branches) and the radial artery (n = 2 for revascularization of diagonal branches). RESULTS: The procedure was without major technical problems in all patients. Hospital mortality was 1/21. Neither brachial plexus injury nor arm ischemia occurred. Mean pre- and postoperative angina classification was 3.0 +/- 0.8 and 1.2 +/- 0.4 respectively (p < 0.001). After a mean follow-up period of seven months, one out of 14 axillocoronary vein grafts studied by ultrasonic duplex scan or angiography was found occluded. Graft patency could be demonstrated for an observation period of up to two years. CONCLUSION: Subclavian/axillary artery to coronary artery bypass is feasible and can be applied for complications in minimally invasive coronary artery bypass grafting, for redo operations and for management of the severely atherosclerotic ascending aorta. To reach the left anterior descending artery-system, the saphenous vein as well as the radial artery can be used. Complications concerning the infraclavicular incision seem to be no problem. Short-term patency rates are acceptable.

Beating heart axillocoronary bypass for management of the untouchable ascending aorta in coronary artery bypass grafting.

OBJECTIVES: Cannulation and clamping of a severely atherosclerotic ascending aorta during coronary artery bypass grafting (CABG) can lead to cerebral embolization of atheromatous debris and should therefore be avoided whenever possible. A variety of surgical techniques including performance of extraanatomical coronary bypass conduits has been described to solve this problem. We report on a preliminary series of four patients in whom the axillary artery was used as an inflow vessel for venous coronary artery bypass grafts which were performed on the beating heart in order to achieve an aortic no touch concept. METHODS: The axillary artery was exposed between the pectoralis major muscle and the deltoid muscle via an infraclavicular incision. A saphenous vein graft of at least 40 cm in length was sutured to the axillary artery and then brought into the pericardial cavity following an intercostal and transpleural route. The graft was anastomosed to the target vessel using local coronary occlusion. The procedure was carried out via sternotomy in three patients who also received additional internal mammary artery in situ grafts for adequate coronary revascularization. In one high risk patient an isolated axillocoronary bypass was performed in a minimally invasive fashion via anterolateral minithoracotomy. RESULTS: The procedure was completed without major technical difficulties in all four patients. The mean graft length required was 33.2 +/- 1.6 cm, postoperative ultrasonic duplex scans of the axillocoronary grafts revealed a mean flow of 62.5 +/- 23.6 ml/min. No stroke or brachial plexus injury occurred. Three patients are in angina class I (Canadian Cardiovascular Society Classification), one patient is in class II postoperatively. After a mean follow-up of 11.5 +/- 6.6 months postoperatively all grafts remain patent. CONCLUSION: Axillocoronary bypass grafting can be easily performed for management of the untouchable ascending aorta. Straightforward surgical technique and the accessibility to noninvasive diagnostics seem to offer advantages over other extraanatomical bypass grafts.

Synergistic enhancement of the antiproliferative activity of cis-diamminedichloroplatinum(II) by the ether lipid analogue BM41440, an inhibitor of protein kinase C.

The new phospholipid analogue 3-hexadecylmercapto-2-methoxy-methyl-propyl-1-phosphocholine inhibits the phospholipid-calcium-dependent protein kinase, partially purified from Walker carcinoma cells with a Ki value of 0.56 microM. The compound inhibits the phorbol ester stimulated phosphorylation of the ribosomal protein S6 indicating that the depression of Ca2+-phospholipid-dependent protein kinase by the alkyl phospholipid also occurs in intact cells. The dose effect curve for the inhibition of cell proliferation by 3-hexadecylmercapto-2-methoxy-methyl-propyl-1-phosphocholine in Walker cells exhibits a close correlation to the dose effect curve for the depression of Ca2+-phospholipid-dependent protein kinase activity. Although alternative mechanisms cannot be excluded, the data suggest that the growth inhibitory activity of 3-hexadecylmercapto-2-methoxy-methyl-propyl-1-phosphocholine correlates with the inhibition of Ca2+-phospholipid-dependent protein kinase. The antiproliferative activity of 3-hexadecylmercapto-2-methoxy-methyl-propyl-1-phosphocholine is synergistically enhanced by cis-diamminedichloroplatinum(II).

The phospholipid- and calcium-dependent protein kinase as a target in tumor chemotherapy.

Evidence for a constitutive activation of protein kinase C (EC 2.7.1.37) in Ha-ras transformed 3T3 cells is presented. Several compounds which inhibit protein kinase C in vitro have been studied with regard to their antiproliferative activity in cultured tumor cells. The following agents were investigated: 3-hexadecyl-mercapto-2-methoxy-methyl-propyl-1- phosphocholine (BM 41440); 1-octadecyl-2-methyl-sn-glycero-3-phosphocholine (ET-18-OCH3); quercetin, tamoxifen and staurosporine. All compounds decrease protein kinase C activity in vitro as well as in intact cells and inhibit cell multiplication within the same dose range. The results suggest a causal relation between the antiproliferative effects and the inhibition of protein kinase C. All inhibitors of protein kinase C synergistically enhance the antiproliferative activity of cis-diamminedichloroplatinum(II). Available data suggest that the effects of protein kinase C inhibitors should be exploitable for tumor chemotherapy.

Enhancement of the antiproliferative effect of cis-diamminedichloroplatinum(II) and nitrogen mustard by inhibitors of protein kinase C.

Quercetin (3,3',4',5,7-pentahydroxyflavone) has been shown to inhibit a variety of enzymes including the calcium- and phospholipid-dependent protein kinase (protein kinase C) in vivo and in vitro. We show that this compound synergistically enhances the antiproliferative activity of cis-diamminedichloroplatinum(II) (cis-DDP) and nitrogen mustard. Quercetin does not affect the repair of DNA interstrand cross-links introduced by cis-DDP. Long-term exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA), which reduces total protein kinase C activity, also amplifies the growth-inhibitory effect of cis-DDP and acts synergistically with quercetin. A synergism is also observed if tamoxifen or staurosporine are combined with cis-DDP. For both drugs the dose-effect curves for the inhibition of protein kinase C closely resemble the dose-effect curves for the antiproliferative activities. Although alternative mechanisms cannot be definitively excluded, the effects of quercetin, TPA, tamoxifen and staurosporine may result from the inhibition of protein kinase C.