A phase I pharmacokinetic study of hypoxic abdominal stop-flow perfusion with gemcitabine in patients with advanced pancreatic cancer and refractory malignant ascites

Purpose: As no curative treatment for advanced pancreatic and biliary cancer with malignant ascites exists, new modalities possibly improving the response to available chemotherapies must be explored. This phase I study assesses the feasibility, tolerability and pharmacokinetics of a regional treatment of gemcitabine administered in escalating doses by the stop-flow approach to patients with advanced abdominal malignancies (adenocarcinoma of the pancreas, n=8, and cholangiocarcinoma of the liver, n=1). Experimental design: Gemcitabine at 500, 750 and 1,125mg/m2 was administered to three patients at each dose level by loco-regional chemotherapy, using hypoxic abdominal stop-flow perfusion. This was achieved by an aorto-caval occlusion by balloon catheters connected to an extracorporeal circuit. Gemcitabine and its main metabolite 2′,2′-difluorodeoxyuridine (dFdU) concentrations were measured by high performance liquid chromatography with UV detection in the extracorporeal circuit during the 20min of stop-flow perfusion, and in peripheral plasma for 420min. Blood gases were monitored during the stop-flow perfusion and hypoxia was considered stringent if two of the following endpoints were met: pH≤7.2, pO2 nadir ratio ≤0.70 or pCO2 peak ratio ≥1.35. The tolerability of this procedure was also assessed. Results: Stringent hypoxia was achieved in four patients. Very high levels of gemcitabine were rapidly reached in the extracorporeal circuit during the 20min of stop-flow perfusion, with C max levels in the abdominal circuit of 246 (±37%), 2,039 (±77%) and 4,780 (±7.3%)μg/ml for the three dose levels 500, 750 and 1,125mg/m2, respectively. These C max were between 13 (±51%) and 290 (±12%) times higher than those measured in the peripheral plasma. Similarly, the abdominal exposure to gemcitabine, calculated as AUCt0-20, was between 5.5 (±43%) and 200 (±66%)-fold higher than the systemic exposure. Loco-regional exposure to gemcitabine was statistically higher in presence of stringent hypoxia (P<0.01 for C max and AUCt0-20, both normalised to the gemcitabine dose). Toxicities were acceptable considering the complexity of the procedure and were mostly hepatic; it was not possible to differentiate the respective contributions of systemic and regional exposures. A significant correlation (P<0.05) was found between systemic C max of gemcitabine and the nadir of both leucocytes and neutrophils. Conclusions: Regional exposure to gemcitabine—the current standard drug for advanced adenocarcinoma of the pancreas—can be markedly enhanced using an optimised hypoxic stop-flow perfusion technique, with acceptable toxicities up to a dose of 1,125mg/m2. However, the activity of gemcitabine under hypoxic conditions is not as firmly established as that of other drugs such as mitomycin C, melphalan or tirapazamine. Further studies of this investigational modality, but with bioreductive drugs, are therefore warranted first to evaluate the tolerance in a phase I study and later on to assess whether it does improve the response to chemotherap

Hemodynamics optimization during off-pump coronary artery bypass: the ‘no compression' technique

Objective: Heart manipulation during OPCAB may cause hemodynamical instability in particular for access to the posterior and lateral walls. The ‘no compression' technique involves enucleation of the heart without any compression on the cavities, and stabilization of the target area with a suction device. The impact of this technique on hemodynamics is assessed. Methods: In order to analyze a homogeneous group, 26 consecutive patients with triple grafts, one to each side of the heart in the same sequential order (posterior, lateral and anterior wall successively) were selected. Heart rate (HR), mean pulmonary arterial pressure (PAP, mmHg), pulmonary capillary wedge pressure (PCWP, mmHg), mean arterial pressure (MAP, mmHg), cardiac output index (COI, l/min per m2), and central venous saturation (SvO2,%) were monitored. A coronary shunt was used for all the anastomoses. Results: HR was stable with baseline value of 60±10 and the highest value for the anterior wall, 63.6±8 (P=0.23). PAP and PCWP exhibited their highest increase, when compared with baseline, for the lateral wall, 23.9±4.7 vs. 20.7±6.2 (P=0.06), and 17.2±4.7 vs. 14.9±5.6 (P=0.16), respectively. MAP, COI and SvO2, exhibited their largest drop, when compared with baseline, for the lateral wall too, 73.1±9.1 vs. 77.1±7.5 (P=0.12), 1.99±0.47 vs. 2.26±0.55 (P=0.09), and 70.5±8.4 vs. 74.8±9.3 (P=0.12), respectively. Conclusions: None of the hemodynamical parameter differed significantly from baseline value for all three territories. While hemodynamics was perfectly maintained during the posterior and anterior walls revascularization, exposure of the lateral wall led to marginal changes onl

Is our heart a well-designed pump? The heart along animal evolution

A carrier system for gases and nutrients became mandatory when primitive animals grew larger and developed different organs. The first circulatory systems are peristaltic tubes pushing slowly the haemolymph into an open vascular tree without capillaries (worms). Arthropods developed contractile bulges on the abdominal aorta assisted by accessory hearts for wings or legs and by abdominal respiratory motions. Two-chamber heart (atrium and ventricle) appeared among mollusks. Vertebrates have a multi-chamber heart and a closed circulation with capillaries. Their heart has two chambers in fishes, three chambers (two atria and one ventricle) in amphibians and reptiles, and four chambers in birds and mammals. The ventricle of reptiles is partially divided in two cavities by an interventricular septum, leaving only a communication of variable size leading to a variable shunt. Blood pressure increases progressively from 15 mmHg (worms) to 170/70 mmHg (birds) according to the increase in metabolic rate. When systemic pressure exceeds 50 mmHg, a lower pressure system appears for the circulation through gills or lungs in order to improve gas exchange. A four-chamber heart allows a complete separation of systemic and pulmonary circuits. This review describes the circulatory pumping systems used in the different classes of animals, their advantages and failures, and the way they have been modified with evolution

The weak heart: perioperative management

Heart failure (HF) is known to be a major risk factor in perioperative care. It should be subdivided into systolic or diastolic dysfunction as well as left or right ventricular failure. The perioperative management of HF patients is complex, consisting of prevention, diagnosis and therapy. The adequacy of the perioperative management determines the late postoperative outcome and will be presented in this review