Evaluation of effectiveness of the PlasmaJet surgical device in the treatment of advanced stage ovarian cancer (PlaComOv-study): study protocol of a randomized controlled trial in the Netherlands.

BACKGROUND: The most important goal for survival benefit of advanced stage ovarian cancer is to surgically remove all visible tumour, because complete cytoreductive surgery (CCS) has been shown to be associated with prolonged survival. In a remarkable number of women, CCS is very challenging. Especially in women with many small metastases on the peritoneum and intestinal surface, conventional CCS with electrosurgery is not able to be "complete" in removing safely all visible tumour. In this randomized controlled trail (RCT) we investigate whether the use of the PlasmaJet Surgical Device increases the rate of CCS, and whether this indeed leads to a longer progression free and overall survival. The main research question is: does the use of the PlasmaJet Surgical Device in surgery for advanced stage ovarian cancer result in an increased number of complete cytoreductive surgeries when compared with conventional surgical techniques. Secondary study objectives are: 30-day morbidity, duration of surgery, blood loss, length of hospitalisation, Quality of Life, disease-free survival, overall survival, percentage colostomy, cost-effectiveness. METHODS: The study design is a multicentre single-blinded superiority RCT in two university and nine non-university hospitals in The Netherlands. Three hundred and thirty women undergoing cytoreductive surgery for advanced stage ovarian carcinoma (FIGO Stage IIIB-IV) will be randomized into two arms: use of the PlasmaJet (intervention group) versus the use of standard surgical instruments combined with electrocoagulation (control group). The primary outcome is the rate of complete cytoreductive surgery in both groups. Secondary study objectives are: 30-day morbidity, duration of surgery, blood loss, length of hospitalisation, Quality of Life, disease-free survival, overall survival, percentage colostomy, cost-effectiveness. Quality of life will be evaluated using validated questionnaires at baseline, at 1 and 6 months after surgery and at 1, 2, 3 and 4 years after surgery. DISCUSSION: We hypothesize the additional value of the use of the PlasmaJet in CCS for advanced stage epithelial ovarian cancer. More knowledge about efficacy, side effects, recurrence rates, cost effectiveness and pathology findings after using the PlasmaJet Device is advocated. This RCT may aid in this void. TRIAL REGISTRATION: Dutch Trial Register NTR6624 . Registered 18 August 2017. Medical Ethical Committee approval number: NL62035.078.17 (Medical Ethical Committee Erasmus Medical Centre Rotterdam).

The effect of maternal hypoxemia on the umbilical and femoral artery blood flow velocity waveforms and the relationship with mean arterial pressure in fetal sheep.

The relationship between the ratio femoral pulsatility index (PI)/umbilical PI and arterial oxygen content was examined in 8 fetal sheep at various stages of hypoxemia. This relationship was characterized by an inconsistent increase of the ratio femoral PI/umbilical PI at oxygen content levels beneath 1.0 mM. The correlation coefficient of the linear regression between both variables was only -0.54, indicating that prediction of fetal oxygenation on the basis of Doppler waveform measurements in peripheral fetal arteries might be invalid. The average correlation coefficient of the linear regressions between the femoral PI and fetal mean arterial pressure was 0.87 +/- 0.15 (SD), whereas the average correlation between the umbilical PI and fetal mean arterial pressure was 0.04 +/- 0.61. These data suggest that the degree of change in fetal mean arterial pressure considerably depends on the degree of change in vascular resistance in the fetal carcass.

Response of blood flow velocity waveforms in the abdominal aorta and cotyledonary artery to regional embolization of the umbilical circulation in fetal sheep.

Regional embolization of the placental circulation was performed in 3 anesthetized fetal sheep by retrograde administration of microspheres in a cotyledonary branch of one of the umbilical arteries. Registrations were made of blood velocity waveforms in the fetal abdominal aorta and in a major cotyledonary artery supplying the embolized placental region. Among the fetal lambs examined, a corresponding degree of regression was found between the decrease in umbilical blood flow and increase in the pulsatility index of the abdominal aorta waveforms (coefficient of variation: 0.19). In contrast, the degree of regression between the decrease in umbilical blood flow and increase in the pulsatility index of the cotyledonary artery waveforms varied per fetus (coefficient of variation: 0.79). It is suggested that in human fetuses, in the case of discordant umbilical artery blood flow velocity waveforms, the best information on fetoplacental circulatory competence is provided by the aorta blood velocity waveform.

Relationship between mean arterial pressure and parameters derived from blood flow velocity waveforms in the systemic circulation of fetal sheep.

In 8 fetal sheep under anesthesia, we examined the relationship between the fetal aorta blood flow velocity waveform and fetal mean arterial pressure after administration of norepinephrine and angiotensin II. It was hypothesized that the pulsatility index (PI) of the waveform would change during fetal hypertension. Measurements were performed using a 20-MHz Doppler transducer on the aorta directly beneath the diaphragm and a catheter inserted via the femoral artery into the abdominal aorta. Further instrumentation included a Doppler transducer and an electromagnetic flowmeter on the common umbilical artery and a catheter in the inferior vena cava. Fetal hypertension was induced by bolus administration of either norepinephrine or angiotensin II or by infusion of norepinephrine. With the Doppler transducer on the common umbilical artery, it was possible to study external iliac artery blood velocity waveforms in 4 fetal lambs, whereas aorta blood velocity waveforms were recorded in 7 fetal lambs. The measurements of external iliac artery PI and mean arterial pressure were characterized by a linear regression with a correlation coefficient of 0.72, whereas the measurements of aorta PI and mean arterial blood pressure were characterized by a linear regression with a correlation coefficient of 0.40. However, notable changes were observed in the aorta blood velocity waveform, which were not expressed by a substantial increase in the aorta PI. These changes can be described as a narrowing of the systolic peak and an earlier occurrence of the first dicrotic notch.(ABSTRACT TRUNCATED AT 250 WORDS)

The acute response of the umbilical artery pulsatility index to changes in blood volume in fetal sheep.

This experimental study was designed to test the effects of acute changes in fetal circulating blood volume on the umbilical artery pulsatility index (PI). Six fetal sheep were provided with an electromagnetic flow meter for measurement of umbilical venous blood flow, with catheters for determination of arterial blood pressure and umbilical venous pressure, and with a 5 MHz Doppler transducer around one umbilical artery for flow velocity waveform analysis. A catheter in the inferior vena cava was used to infuse 50 ml of maternal blood (hypervolemia) into the fetal circulation or to withdraw 50 ml of fetal blood (hypovolemia) after volume correction. Hypervolemia resulted in a rise in arterial pressure and umbilical venous pressure, without an effect on PI, umbilical blood flow or placental vascular resistance. Hypovolemia resulted in a decrease in fetal heart rate, arterial pressure, umbilical venous pressure and umbilical blood flow. Calculated placental vascular resistance was not changed, whereas the PI increased by 42%. We conclude that volume loading with 10-15% of fetal circulating volume does not affect the umbilical artery PI, whereas acute reduction of fetal blood volume with the same amount is associated with an increase in the umbilical artery PI, without changes in calculated placental vascular resistance.

Fetal hypertension induced by norepinephrine infusion and umbilical artery flow velocity waveforms in fetal sheep.

This study was designed to examine the effects of fetal hypertension on the umbilical artery pulsatility index. Fetal arterial blood pressure and umbilical venous pressure were measured in eight sheep, 3 to 5 days after surgery. Umbilical blood flow was measured with an electromagnetic flowmeter around the common umbilical vein. Umbilical artery flow velocity waveforms were obtained either by an indwelling 5 MHz pulsed Doppler device (n = 4) or transcutaneously by a 4 MHz continuous-wave Doppler device (n = 4). Fetal blood pressure was raised by intravenous infusion of norepinephrine 10 micrograms/min during 5 minutes. Norepinephrine infusion resulted in elevated arterial and umbilical venous pressures, accompanied by a bradycardia during the first 3 minutes. Umbilical blood flow, calculated placental vascular resistance, and umbilical artery pulsatility index did not change. After atropine administration, the norepinephrine-induced elevated arterial and umbilical venous pressures were accompanied by tachycardia, increased umbilical blood flow, and no change in placental vascular resistance and umbilical artery pulsatility index. It is concluded that fetal arterial hypertension provoked by norepinephrine infusion has no effect on placental vascular resistance, umbilical blood flow, and umbilical artery pulsatility index.

The effect of selective umbilical embolization on the common umbilical artery pulsatility index and umbilical vascular resistance in fetal sheep.

In eight anaesthesized fetal sheep (gestational age 112-127 days; term 147 days), embolization of the umbilical placental circulation was performed in order to evaluate the response of the umbilical artery pulsatility index to an exclusive increase in umbilical vascular resistance. Measurements were performed using a 20 MHz pulsed Doppler transducer and an electromagnetic flow meter mounted on the common umbilical artery and catheters at the aortic trifurcation and in one of the umbilical veins. Umbilical vascular resistance was calculated according the Poiseuille equation as the ratio of aortic to umbilical venous pressure gradient and umbilical blood flow. Microspheres were administered at 15-min intervals through a catheter in one of the cotyledonary arteries, until fetal heart rate had decreased beneath 100 beats/min or had become arrhythmic. The period of examination per fetus varied between 60 and 120 min, after which cardiac decompensation occurred. During this period, umbilical perfusion pressure increased from 20.3 +/- 4.9 to 28.1 +/- 4.7 mmHg (SD; P less than 0.01), umbilical blood flow (ml/min) decreased from 342 +/- 127 to 115 +/- 99 mmHg (SD; P less than 0.01), umbilical vascular resistance increased from 0.065 +/- 0.022 to 0.342 +/- 0.150 mmHg.min/ml (P less than 0.01) and common umbilical artery pulsatility index increased from 0.97 +/- 0.23 to 4.03 +/- 1.69 (P less than 0.01). Fetal heart rate did not change significantly (168 +/- 33 prior to cardiac decompensation versus 178 +/- 19 beats/min at baseline condition). The linear correlation between common umbilical artery pulsatility index and umbilical vascular resistance varied between 0.83 and 0.99 and the average correlation was 0.93 (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Umbilical artery pulsatility index and placental vascular resistance during acute hypoxemia in fetal lambs.

The effect of hypoxemia on the pulsatility index (PI) of the umbilical artery flow velocity waveform and placental vascular resistance was studied. Fetal hypoxemia was induced by maternal breathing of a low-oxygen gas mixture. Umbilical venous blood flow was measured with an electromagnetic flowmeter. Placental vascular resistance (PVR) was defined as the ratio perfusion pressure (mean arterial pressure minus umbilical venous pressure) and umbilical blood flow. Umbilical artery velocity waveforms were obtained by a 5-MHz pulsed Doppler device around one umbilical artery in 4 lambs and by a transcutaneous 4-MHz continuous wave Doppler transducer in 3 lambs. Fetal arterial oxygen content was lowered from 2.28 +/- 0.18 to 0.93 +/- 0.15 mM (p less than 0.05), while pCO2 and pH remained unchanged. Control values of the hemodynamic variables were compared with values during deepest hypoxemia. Fetal heart rate, mean arterial and umbilical venous pressure, PVR and the umbilical artery PI did not significantly change, whereas umbilical blood flow increased from 436 +/- 64.7 to 491 +/- 65.9 ml/min (p less than 0.05) during deepest hypoxemia. Individual regression analysis, however, showed a significant inverse correlation of umbilical venous pressure whereas PVR had a positive correlation with actual oxygen content. It is concluded that acute fetal hypoxemia slightly decreases PVR, but does not affect the umbilical artery PI in sheep. Decreasing fetal oxygenation is associated with an increase in pressure in the umbilical vein.

The response of the umbilical and femoral artery pulsatility indices in fetal sheep to progressively reduced uteroplacental blood flow.

Fetal artery Doppler velocimetry may provide noninvasive information on the state of fetal oxygenation. It was hypothesized that during decreasing fetal oxygenation, the pulsatility index in the femoral artery will increase, whereas the pulsatility index in the umbilical artery will not change. Decreasing fetal oxygenation was induced in ten chronically-instrumented fetal sheep by progressive occlusion of the maternal common internal iliac artery. The pulsatility index in the umbilical artery was serially measured in six fetuses (group I, n = 6) and the pulsatility index in the femoral artery was serially measured in four fetuses (group II, n = 4). Fetal arterial oxygen content decreased by 72% in group I (P less than 0.0001) and by 79% in group II (P less than 0.0001). Fetal heart rate did not change. Fetal blood pressure increased by 11% in group I (P less than 0.02) and by 15% in group II (P less than 0.005). The umbilical artery pulsatility index (group I) did not significantly change during decreasing fetal oxygenation, whereas the femoral artery pulsatility index (group II) increased by 150% (P less than 0.005). It is concluded that progressively reduced uteroplacental blood flow results in fetal hypoxaemia, which is associated with increased pulsatility index in the femoral artery, while the pulsatility index in the umbilical artery does not change.

The response of the umbilical artery pulsatility index in fetal sheep to acute and prolonged hypoxaemia and acidaemia induced by embolization of the uterine microcirculation.

In eight chronically-instrumented sheep, embolization of the uterine microcirculation was performed to evaluate the response of the umbilical artery pulsatility index to prolonged fetal hypoxaemia and acidaemia. From four days after surgery onwards, fetal arterial oxygen content [( O2]a) was progressively reduced by administration of microspheres into the uterine circulation. Measurements included fetal [O2]a, PO2, PCO2, pH, base excess, heart rate, blood pressure and umbilical artery pulsatility index. Fetal survival varied between less than 2 and less than 8 days, while mean fetal survival was less than 4 days. From baseline condition to the last evaluation preceding the diagnosis of fetal death, [O2]a decreased from 3.10 +/- 0.36 to 0.87 +/- 0.27 mM, pH decreased from 7.36 +/- 0.03 to 7.22 +/- 0.08, base excess decreased from -0.3 +/- 1.5 to -7.3 +/- 3.2 and blood pressure increased from 35.0 +/- 7.1 to 40.7 +/- 8.7 (means +/- SD). The umbilical artery pulsatility index (1.05 +/- 0.19 at baseline condition) did not significantly change (1.08 +/- 0.12 prior to fetal death). It is concluded that a condition of prolonged hypoxaemia and acidaemia in fetal sheep, induced by repeated embolizations of the uterine circulation, is not associated with consistent changes in the umbilical artery pulsatility index.

Umbilical artery flow velocity waveforms and placental vascular resistance during maternal placental outflow obstruction in sheep.

This study was designed to test the hypothesis that the pulsatility index (PI) of the umbilical artery flow velocity waveform varies as a function of placental vascular resistance. Placental vascular resistance was raised by a one-minute occlusion of the maternal inferior vena cava. Occlusion of the maternal inferior vena cava resulted in a decrease in fetal heart rate from 183 +/- 7.8 beats/min to 142 +/- 8.6 beats/min at the end of occlusion (P less than 0.05). Placental vascular resistance increased from 0.113 +/- 0.021 mmHg.ml-1.min during control to 0.151 +/- 0.033 mmHg.ml-1.min (P less than 0.05) during occlusion. The pulsatility index increased from 1.05 +/- 0.05 to 1.85 +/- 0.4 (P less than 0.05) during occlusion. After parasympathetic blockade with atropine fetal heart rate did not change during occlusion. Placental vascular resistance increased from 0.091 +/- 0.014 before to 0.121 +/- 0.021 mmHg.ml-1.min during occlusion (P less than 0.05). The pulsatility index increased from 0.98 +/- 0.1 before to 1.12 +/- 0.12 during occlusion (P less than 0.05). These results support the hypothesis that, in the fetal sheep, placental vascular resistance is one of the determinants of the pulsatility index of the umbilical artery.

Umbilical artery flow velocity waveforms during acute hypoxemia and the relationship with hemodynamic changes in the fetal lamb.

The contributions of the variables of the fetal circulation to changes in the pulsatility index of the umbilical artery flow velocity waveform have not been assessed. Acute fetal hypoxemia was induced by 60 to 90 seconds of total occlusion of the maternal common internal iliac artery in six sheep. Mean fetal PO2 levels decreased from 26.0 to 18.3 mm Hg (p less than 0.01) after occlusion of uterine blood flow. Fetal heart rate decreased from 188 to 121 beats per minute at the end of occlusion (p less than 0.05). Placental vascular resistance did not change during the heart rate deceleration. The pulsatility index increased from 0.86 during the control period to 1.27 at the end of occlusion (p less than 0.05). After fetal parasympathetic blockade with atropine, fetal heart rate and placental vascular resistance did not change during occlusion. The pulsatility index did not change during occlusion after parasympathetic blockade. It is concluded that the changes in the umbilical artery pulsatility index during late decelerations in the fetal heart rate pattern appear to be primarily associated with changes in fetal heart rate and bear no relationship with placental vascular resistance.