Robot-assisted radical cystectomy with intracorporeal urinary diversion in patients with transitional cell carcinoma of the bladder.

BACKGROUND: Robot-assisted radical cystectomy (RARC) may reduce morbidity after cystectomy. Descriptions of the surgical techniques of RARC with intracorporeal orthotopic neobladder or ileal conduit are sparse and oncologic and functional outcome data have not been reported. OBJECTIVE: We present our technique with RARC and intracorporeal urinary diversion (neobladder or ileal conduit) and present oncologic and functional outcomes, as well as complication rates. DESIGN, SETTING, AND PARTICIPANTS: Single-hospital institution case-series from 2004 to 2009 including 45 selected patients (38 male, 7 female) with high-grade and/or muscle-invasive urothelial cancer of the bladder. SURGICAL PROCEDURE: We performed RARC; pelvic lymph node dissection using three different templates; and a totally intracorporeal urinary diversion, either orthotopic neobladder (n=36) or ileal conduit (n=9). MEASUREMENTS: Perioperative variables, pathology data, early and late complication rates, urinary continence, potency, and cancer-specific survival were evaluated as outcome measures. RESULTS AND LIMITATIONS: Median patient age, operative time, estimated blood loss, and lymph node yield were 62 yr (range: 37-79), 477 min (range: 325-760), 550 ml (range: 200-2200), and 19 (range: 10-52), respectively. Nine patients were diagnosed with positive lymph nodes. Surgical margins were clear in all but one patient. Early complications occurred in 18 patients (40%). Median postoperative stay was 9 d (range: 4-78), and median postoperative follow-up time was 25 mo. Four patients died due to metastatic disease. The study is limited by a relative small sample size and no comparative group. CONCLUSIONS: RARC with totally intracorporeal urinary diversion is technically feasible with good intermediate-term oncologic results. This is a nonrandomised study including a limited number of patients with a restricted follow-up time, however, and so precautions must be considered when interpreting the outcomes.

Formation of new bioactive organic nitrites and their identification with gas chromatography-mass spectrometry and liquid chromatography coupled to nitrite reduction.

Nitric oxide (NO) donors, notably organic nitrates and nitrites are used therapeutically but tolerance develops rapidly, making the use of e.g. nitroglycerin difficult. NO donation in the pulmonary vascular bed might be useful in critically ill patients. Organic nitrites are not associated with tachyphylaxis but may induce methaemoglobinemia and systemic hypotension which might hamper their use. We hypothesised that new lung-selective NO donors can be identified by utilizing exhaled NO as measure for pulmonary NO donation and systemic arterial pressure to monitor hypotension and tolerance development. Solutions of alcohols and carbohydrates were reacted with NO gas and administered to ventilated rabbits for evaluation of in vivo NO donation. Chemical characterization was made by liquid chromatography with on-line nitrite reduction (LC-NO) and by gas chromatography-mass spectrometry (GC-MS). In vivo experiments showed that the hydroxyl-containing compounds treated with NO gas yielded potent NO donors, via nitrosylation to organic nitrites. Analyses by LC-NO showed that the reaction products were able to release NO in vitro. In GC-MS the reaction products were determined to be the organic nitrites, where some are new chemical entities. Non-polar donors preferentially increased exhaled NO with less effect on systemic blood pressure whereas more polar molecules had larger effects on systemic blood pressure and less on exhaled NO. We conclude that new organic nitrites suitable for intravenous administration are produced by reacting NO gas and certain hydroxyl-containing compounds in aqueous solutions. Selectivity of different organic nitrites towards the pulmonary and systemic circulation, respectively, may be determined by molecular polarity.

Increased expired NO and roles of CO2 and endogenous NO after venous gas embolism in rabbits.

Venous gas embolism (VGE) is a feared complication in diving, aviation, surgery and trauma. We hypothesized that air emboli in the lung circulation might change expired nitric oxide (FeNO). A single intravenous infusion of air was given (100 mul kg(-1)) to three groups of anaesthetized mechanically ventilated rabbits: (A) one with intact NO production, (B) one with intact NO production and where end-tidal CO(2) was controlled, and (C) one with endogenous NO synthesis blockade (L: -NAME, 30 mg kg(-1)). Air infusions resulted in increased FeNO of the control group from 20 (4) [mean (SD)] ppb to a peak value of 39 (4) ppb within 5 min (P < 0.05), and FeNO was still significantly elevated [27 (2) ppb] after 20 min (P < 0.05). Parallel to the NO increase there were significant decreases in end-tidal CO(2 )(ETCO(2)) and mean arterial pressure and an increase in insufflation pressure. In group B, when CO(2) was supplemented after air infusion, NO was suppressed (P = 0.033), but was still significantly elevated compared with pre-infusion control (P < 0.05). In group C, all animals died within 40 min of air infusion whereas all animals in the other groups were still alive at this time point. We conclude that venous air embolization increases FeNO, and that a part of this effect is due to the concomitant decrease in ETCO(2). Furthermore, an intact NO production may be critical for the tolerance to VGE. Finally, FeNO might have a potential in the diagnosis and monitoring of pulmonary gas embolism.

Influence of oxygen, temperature and carbon dioxide on nitric oxide formation from nitrite as measured in expired gas from in situ perfused rabbit lungs.

In biological systems, nitric oxide (NO) may be generated non-enzymatically from nitrite (nitrite-derived NO), in addition to nitric oxide synthase-catalyzed (NOS-derived) L-arginine-dependent formation. Through recordings of expired NO, we studied the influence of temperature on NOS- and nitrite-derived NO in the perfused lung. We also studied the impact of other influencing factors (O(2), CO(2), and pH) on nitrite-derived NO in the same system. Both NO-generating systems exhibited biphasic temperature dependence with a positive correlation between temperature and NO generation that peaked between 42 and 44 degrees C. The nitrite-derived NO generation was enhanced by hypoxia alone (>20 x after 5 min) and further by concomitant increase in CO(2). The CO(2) effect could not be explained by changes in extracellular pH and was unaltered by acetazolamide. We conclude that the temperature dependence in the known enzyme-catalyzed NOS-derived NO and especially in the nitrite-derived NO strengthens the hypothesis that an enzyme could be involved in nitrite-derived NO formation. The enhancement of nitrite-derived NO by increases in CO(2) suggests that this system could be of importance to improve perfusion in ischemic tissues.

Direct gas measurements indicate that the novel cyclooxygenase inhibitor AZD3582 is an effective nitric oxide donor in vivo.

1. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is a COX-inhibiting nitric oxide donor that inhibits COX-1 and COX-2. It is as effective as naproxen in models of pain and inflammation, but causes less gastroduodenal damage. Nitric oxide (NO) is generated from AZD3582 in vitro, and this study sought to show that the drug donates NO in vivo. 2. In anaesthetised male New Zealand white rabbits, the endogenous NO concentration in exhaled air was reduced by N(G)-nitro-L-arginine methyl ester (L-NAME) (30 mg kg(- 1) i.v.) from 33.5+/-1.0 ppb (mean+/-s.e.m.; n=6 per group) to 3.0+/-1.0 ppb, while increasing blood pressure and reducing heart rate. AZD3582 (0.2, 0.6, 2.0 or 6.0 micromol kg(- 1) min(- 1)) given 30 min after L-NAME increased the concentration of NO in exhaled air (P<0.05), decreased blood pressure and increased heart rate in a dose-dependent manner versus L-NAME control values. The peak mean NO concentration obtained was 44+/-8.0 ppb. 3. In in situ-perfused rabbit lungs, L-NAME (185 micromol l(- 1)) reduced the NO concentration in exhaled air from 106+/-13 to 4.0+/-0.4 ppb (n=5). Addition of AZD3582 (6 micromol min(- 1)) to the perfusate produced an initial rapid increase in the NO concentration in exhaled air, followed by a sustained, but lower plateau. Infusion of L-NAME increased, and AZD3582 decreased, pulmonary arterial pressure. 4. In both anaesthetised rabbits and in the perfused lungs, brief periods of hypoxia increased NO concentrations generated by AZD3582. 5. We conclude that, in rabbits, AZD3582 donates NO in vivo with characteristics similar to those reported for nitroglycerin and isosorbide nitrates

Mechanisms of nitric oxide generation from nitroglycerin and endogenous sources during hypoxia in vivo.

Nitroglycerin (GTN), often used in conditions of cardiovascular ischaemia, acts through the liberation of nitric oxide (NO) and the local concentration of NO in the tissue is responsible for any biological effect. However, little is known about the way in which the concentration of NO from GTN and other NO-donors is influenced by low oxygen tension in the target tissues. To evaluate the impact of changes in oxygen tension in the metabolism of NO-donors we measured exhaled NO in anaesthetized rabbits in vivo and expired NO and perfusate nitrite (NO(2)(-)) in buffer-perfused lungs in situ. The impact of acute hypoxia on NO formation from GTN, isosorbide-5-mononitrate (ISMN), dissolved authentic NO, NO(2)(-) and NO generated from endogenous NO-synthase (NOS) was studied in either model. Acute hypoxia drastically increased exhaled NO concentrations from all NO-donors studied, both in vivo and in the perfused lung. During similar conditions endogenous NO generation from NOS was strongly inhibited. The effects were most pronounced at less than 3% inspired oxygen. The mechanisms for the increased NO-formation during hypoxia seems to differ between GTN- and NO(2)(-)-derived NO. The former phenomenon is likely due to diminished breakdown of NO. In conclusion, hypoxic conditions preserve very high local NO concentrations generated from organic nitrates in vivo and we suggest that this might benefit preferential vasodilation in ischaemic tissue regions. Our findings point out the necessity to consider the influence of oxygen tension when studying the action of NO-donors.