Comparison of the Effects of Norepinephrine and Phenylephrine on Tissue Oxygenation and Hemodynamic Stability During an SVV Fluid Guided Therapy in Elderly Undergoing Radical Resection of Colon Cancer Surgery
Phase: PHASE3
Conditions: Hypotension, Fluid Therapy
Sponsor: The Second Affiliated Hospital of Dalian Medical University

 
 
 
Study Protocol with SAP 
 
 
 
 
Comparison of the effects of Norepinephrine and Phenylephrine on tissue 
oxygenation and hemodynamic stability during an SVV fluid guided therapy in 
elderly undergoing radical resection of colorectal carcinoma 
 
 
 
 
 
 
 
NCT03215797 
 
2018.1.21 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Introduction 
 
Fluids management is crucial during the operation, it is a part of integrated and 
life-saving treatment. Different strategy of fluids management introperative has great 
influence on patient’s outcome and overall morbidity and mortality. Conventional 
liberal fluid management often cause fluid overload, resulting in tissue swelling and 
cellular edema, and then patients will occure gastrointestinal tract and pulmonary 
complications, including nausea, vomiting, paralytic ileus and pulmonary edema or 
pneumonia, Even prolonged the hospitalization time and ICU stays, increasing 
medical costs; However, Restrictive fluid management leads to reduced of effective 
circulating blood volume, it also caused different problems such as circulatory 
abnormalities, resulting in an imbalance between systemic oxygen delivery and oxygen 
consumption, and even leads to global tissue hypoxia or shock. Therefore, the fluid 
overload or insufficient are not benefit to patients, “The right amount” of fluid to be 
infused remains a question. 
 Following the indicators monitored by esophageal ultrasound or other invasive 
monitoring techniques are widely used in clinically work, including cardiac 
output(CO)、stroke volume(SV)、stroke volume variation(SVV)、Pulse pressure 
variation(PVV) and pulse perfusion variation index (PVI ), which can dynamically 
reflect volume responsiveness, the goal-directed fluid therapy(GDFT) in perioperative 
gradually caught our attention. GDFT is a individualized fluid treatment that based on 
the Frank-Starling law, the aim is to stabilize the indicators (SVV、PVV、PVI、CO) in 
the certain range through suppliment capacity, to achieve the ideal of intravascular 
volume, then the cardiopulmonary function of patients is optimized and the optimal 
oxygen supply for tissue organs. The SVV is one of the commonly used indicators in 
GDFT, which based on the variations of stroke volume during the respiratory cycle.  
 Many studies have proved the effectiveness of GDT in guiding fluid therapy and 
better outcome mostly in critically ill and septic patients, rarely in elderly patients. In 
fact, people older than 65 years represent the fastest-growing segment of the population. 
Exponentially, the percentage of elderly presenting for Gastrointestinal surgery is 
enlarging. Due to the long periods of fasting, bowel preparation, surgical stress and 
pre-existing omorbidities, especially in addition to the role of peripheral vasodilation 
caused by anesthetic drugs, elderly are more prone to dehydration and to perioperative 
hypotension. SVV GDT and colloid alone might not be able to correct hypotension for 
this group of patients, Thus it is imperative need for vasoconstrictors. 

 Phenylephring and norepinephrine are commonly used in clinical prictice to 
countract arterial hypotension. Phenylephrine is a pure α1 adrenoceptor agonist, 
predominantly resulting in vasoconstriction, whereas norepinephrine has both α1 and 
β 1 adrenoceptor agonist properties, with additional positive inotropic and 
chronotropic effects. Although both agents are equally effective in restoring a desired 
blood pressure, their individual working mechanisms may have different consequences 
for the macro and microcirculation. Norepinephrine was more described in literature 
and preferred by clinicians while Phenylephrine was less talked about and was used in 
specific clinical settings.  
Our impression was that phenylephrine might be as effective as norepinephrine in 
improving Hemodynamic variables and tissue oxygenation. The aim of this study was 
to test the hypothesis that phenylephrine could be as effective as norepinephrine in 
treating hypotension in elderly undergoing radical resection of colorectal carcinoma. 
 
 
Materials and methods 
 
Ethical approval for this study ( Reference: 2016068) was provided by the Ethical 
committee of the Second Hospital of Dalian Medical University, Dalian, China on the 
4th of August,2016). The trial was registered with the U.S.National Institutes of Health 
National Clinical Trials (NCT03215797). 
Patients selection 
Eighty (80) elderly aged over 65 years old undergoing radical resection of 
colorectal carcinoma surgery were planed to enrolled in this study. So far, we have 
enrolled 68 patients from July 18, 2017 to January 18,2018. 35 patients in 
norepinephrine group and 33 patients in phenylephrine group. 
 Inclusion criteria were: Radical resection of colorectal carcinoma surgery; Age 
over 65 years old; Surgery time >2 hours; ASA II or III(the American Society of 
Anesthesiologists, ASA); Exclusion criteria were: Clear arrhythmia; Severe 
cardiovascular disease; Need to use positive end-pressure ventilation (PEEP); 
Peripheral vascular disease; Arterial catheterization contraindications.Patients were 
randomily divided into two groups: Group N (Norepinephrine 5ug/ml) and Group P 
(Phenylephrine 20ug/ml). The concentration of norepinephrine and phenylephrine 
were based on the efficiency of two drugs. 
Preparation for anesthesia and hemodynamic monitoring  
When patients arival in the operation room, standard monitoring equipment was 
connected to them, including ECG, pulse oximeter and noninvasive blood pressure 

monitor on the right upper arm. Then, the arterial puncture needle was inserted in left 
radial artery under local anesthesia and connected to the Flo Trac Viligleo, We can get 
the parameters, such as CI, CO, SVV, SV, and the nvasive artery blood pressure.  
After intubation, A central venous catheter was inserted via the right internal jugular 
vein, it is allows us to pump drugs and monitor central venous pressure.  
Anesthetic Management 
In both groups, standard general anesthesia was induced after 5 min mask 
oxygenation with 100% O2, then i.v. fentanyl 4-7μg/kg, etomidate 0.15-0.3mg/kg, 
cisatracurium 0.15mg /kg. After tracheal intubation, the lungs were ventilated at 8 
ml/kg of tidal volume in a volume-controlled mode with 0-3 mm Hg positive 
end-expiratory pressure. The respiratory rate was set to maintain the end-tidal carbon 
dioxide at 35-40 mm Hg. The ventilator settings were unchanged during this study. 
Anesthesia was maintained with dexmedetomidine given at a dose of 0.2-0.4ug/kg.h 
propofol 4-6mg / kg.h , 1-1.5 % sevoflurane and remifentanil 0.25-0.5mcg / kg.h 
adjusted to maintain a bispectral index of 40-60. The body temperature was 
maintained at >36°C by a fluid warmer. 
Experimental Protocol 
Blood pressure should be maintained to be not less than 20 % of the basic values 
in intraoperative period. if the blood pressure was in normal range and SVV was less 
than 9(measured by the FloTrac/Vigileo 3.0), patients was given a continuous infusion 
of 5 ml/kg/h crystalloid solution (Ringer's acetate); However, when hypotension 
occurred and SVV was greater than 13, a bolus of 200cc colloid ( Voluven 130/0.4; 
6%) was fastly administered, if the blood pressure was not elevated to normal after 
5mins, then norepinephrine or phenylephrine was injected through central catheter. 
When SVV was between 9-13, a bolus of crystalloid of 8ml/kg was administered. 
According to the provious study, the effective ratio of norapinephrine and 
phenylephrine is 1:20, so the concentration of norepinephrine and phenylephrine is 
5ug/ml and 100ug/ml repectively. Heart rate was maintained not less than 20% of the 
baseline value, urine output maintained at 0.5 mL/kg/h, and CVP between 4 - 12 
mmHg, if these value were exceed normal range, the correspondind rdmedies was 
given, such as artopine, diuretic. And dobutamine was infused in case this 
hypotension was accompanied with a decrease incardiac output to less than 2.0L/min. 
Parameters Investigated 
Intraoperative observation index. Systematic hemodynamic parameters: MAP, 
HR, CO, CI, SV were recorded at some specified time points；the indicators that 
reflecting tissue oxygenation and perfusion, including DO2I、VO2I、ERO2, Which 
were calculated based on the Fick equation, besides the ScvO2 and Lac also were 
recorded at the beginning of operating and operating finished respectively; Morever, 

we also recorded the crystalloid, colloid , urine output, blood loss and the doses of 
dobutamine, vasoactive drugs, diuretics and atropine, which were used in surgery. 
Postoperative observation index. When patients left the operating room, we 
counted the APACHE II scores of the first day after surgery and recorded the ICU 
stays, mechanical ventilation time, exhaust time, hospitalization time and expenses. 
we also compared the preoperative liver and renal function with postoperative 12 
hours. In addition to recording the complications and the rate of death at 28 days.  
Data registration and statistical analysis 
Data were analyzed by SPSS 20.0 software. Normal distribution was assessed 
with mean ± standard deviation. Within arms, data were assessed by using two-factor 
repeated measures analysis of variance. All two tailed tests were performed and 
statistical significance was defined as P value less than0.05 in all cases. Data was 
imported into Microsoft Excel 2016 for synchronization and analysis.