Study Design: A randomized controlled trial
Ethics approval and consent to participate from the local ethics committee of the Faculty of Medicine at Menoufia University, Egypt (IRB, 0108/2018). Informed written consent was obtained from each patient. The trial registered at the South Africa Pan Cochrane Research Registry (PACTR201808140151322) (www.pactr.org). Consent for publication is “not applicable.” The study adheres to CONSORT guidelines. Sources of funding is none. Consecutive adult hepatitis C patients (18–60 years, Child classification A) with cirrhosis confirmed by ultrasonography and scheduled for elective liver resection surgery were included. Exclusion criteria included patients with pulmonary disease, contraindication for esophageal Doppler probe insertion, rupture hepatocellular carcinoma or inoperable, body mass index > 40 kg/m2, laparoscopic hepatic resection, and/or refusal to participate. Patients were randomized into two groups: TED or PVI groups. Intraoperative primary measurements include the FTc (msec) of TED, PVI (%), CVP (mmHg), and mean invasive blood pressure (IBP) (mmHg). Measurements were recorded at following times: T0, 10-min postanesthesia induction; T1, following abdominal fascia opening; T2, following retractor application; T3, first hour in dissection; T4, 2 h in dissection; T5, following resection completion; and T6, end of surgery. PVI values were blind to the anesthetist in TED group and vice versa. During dissection, the crystalloids were restricted to keep FTc < 330 msec in TED group or PVI > 14% in PVI group, otherwise infused at 6 ml/kg/h. Following resection, the hydroxyethyl starch (HES, Voluven, Fresenius Kabi, Bad Homberg, Germany) was infused only if FTc < 330 msec (maximum 1000 ml) or PVI > 14% despite above crystalloids infusion.
TED is a continuous, minimally invasive COP monitor measuring blood flow velocity in the descending aorta by esophageal Doppler technique. Continuous point-to-point measurement of stroke distance is performed by the calculation of stroke volume (mean of five cycles) using aortic diameter from a nomogram based on the patient’s age, weight, and height. CO (l.min−1) is calculated as the product of stroke volume and the heart rate. The time needed for blood to flow in a forward direction within the aorta is the systolic flow time. This was corrected for heart rate to give the corrected flow time (FTc). An esophageal Doppler probe (EDM™; Deltex Medical, Chichester, UK) greased with a lubricating gel and passed nasally into the mid-esophagus until aortic blood flow signals was best identified. TED parameters include FTc, normal range: 330–360 ms), stroke volume (SV, normal range: 50–100 cc/beat), cardiac output (COP, normal range: 4–8 l/min), and SVR, normal range: 1900–2400 dynes.sec/cm5). FTc values for normally hydrated resting healthy individuals are 330–360 msec (Sinclair et al., 1997).
PVI provides a continuous noninvasive measure of the relative variability in the photo plethysmography during respiratory cycles. PVI is used as a dynamic indicator of fluid responsiveness in select populations of mechanically ventilated adult patients. PVI is calculated by the Masimo set pulse oximeter (Masimo Co., Irvine, CA, USA) from the respiratory variations in the perfusion index (PI). The PI is the percentage amplitude difference between the pulsatile-infrared signal and the non-pulsatile infrared signal. The PVI is calculated by measuring changes in the PI during the respiratory cycle: PVI = [(PImax–PImin)/PImax] × 100. Cannesson et al. have demonstrated that the PVI predicts fluid responsiveness in the operating room. They showed that the cutoff value to distinguish responders from nonresponders to intravascular volume expansion (in terms of an increase of cardiac index) was a PVI > 14% (Cannesson et al., 2008). PVI was measured with a pulse oximetry probe placed on the finger of the patient. Normal range of PVI (9–13%) (Konur et al., 2016).
CVP indicates the circulatory volume and pressures in right atrium but affected by the intrathoracic pressure. CVP normal range varies between 8 and 12 cmH2O and can increase with mechanical ventilation. Multiple factors affect the CVP readings one of them is the positive end-expiratory pressure (PEEP) and mechanical ventilation, and both increase the intrathoracic pressure and hence the CVP. Yang et al. demonstrated that 0.38 cmH2O increase in PEEP increases the CVP by 1 cmH2O (Yang et al., 2012).
Monitoring includes 5-lead electrocardiography and continuous invasive (IBP, mmHg) and CVP (mmHg). The pulse oximetry, nerve stimulator, esophageal temperature, and anesthesia depth monitor (Bispectral index (BIS, Aspect, MA, USA) were also monitored as per anesthesia protocol. The noninvasive hemoglobin (SpHb) concentration (Radical 7, Masimo, Irvin, USA) and laboratory hemoglobin (Lab Hb) was monitored in surgery.
Anesthesia technique is for liver resection as per protocol (Kamel et al., 2012). All patients were on a fixed PEEP of 5 cmH2O during mechanical ventilation.
General anesthesia was induced with fentanyl 2–4 ug/kg, propofol 2 mg/kg (dose), and rocuronium 0.6 mg/kg dose. Two large-bore peripheral and a right internal jugular central venous catheter was placed. Anesthesia was maintained with a balanced anesthetic technique, consisting of a volatile agent (sevoflurane 0.7–1 MAC) and a mixture of air and oxygen (FiO2 0.4). For intraoperative analgesia, additional boluses of fentanyl were used. Anesthetic management includes the use of two forced air warming blankets for upper and lower extremities and an infusion blood warmer. The patient’s position was carefully checked before draping, and both arms were tucked by the patients’ side and well padded to prevent injury of the brachial plexus.
At the end of the procedure, all patients were extubated in the operating theater and admitted to the ICU immediately postoperatively (the intensive care suite is available close to the operating room. An early oral nutrition was encouraged. Standard deep vein thrombosis (DVT) prophylaxis with low-molecular-weight (LMW) heparin was implemented. Other prophylactic measures like intermittent calf compression during surgery and the first 24 h after surgery was always applied to reduce the risk of DVT. Chest physiotherapy and early mobilization is part of the routine immediate postoperative care. Postoperative medications included prophylactic perioperative antibiotic coverage of a third-generation antibiotic, ceftriaxone 1 g every 8 h intravenously as a prophylactic measure together with intravenous metronidazole 500 mg 8 h, and (explain) histamine H2 receptor antagonist as a prophylaxis for stress ulceration 50 mg intravenously every 8 h.
Intraoperative fluid management
During dissection, crystalloids (Ringer’s acetate) were restricted to keep FTc < 330 msec and PVI > 14%, but IBP > 60 mmHg and urine output (UOP) >0.5 ml/kg/h were kept at all times. Before and following resection, crystalloids were administered at a rate of 6 ml/kg/h to maintain FTc > 330 msec or PVI < 13% according to allocated group. Hydroxyethyl starch (HES, Voluven, Fresenius Kabi, Bad Homberg, Germany) was infused (6 ml/kg, max. 1000 ml) if the FTc < 350 msec or PVI > 14% despite crystalloids infusion. Hemoglobin > 10 g/dl was maintained with packed red blood cell transfusion if required.
Liver resection was performed with a J-shaped incision and with intraoperative cholangiography to identify bile duct anatomy. The same surgical team performed all the resections. A Cavitron Ultrasonic Surgical Aspirator (CUSA Excel, Valleylab Inc., Boulder, CO, USA) dissection device was used to perform hepatic anterior parenchymal transection with electrocautery and without temporary occlusion of vascular inflow or outflow (Pringle’s maneuver).
These are age (y), sex, weight (kg), and body mass index (BMI, kg/m2).
Type of resection, anesthesia duration (minute), total urine output (ml), crystalloids, and colloids (ml) are infused. Blood transfusion requirement (units) and blood loss (ml) were measured by the volume in the suction bottles and by weighing the surgical packs.
Intraoperative hemodynamic parameters include heart rate (HR) (bpm), mean IBP (mmHg), CVP (mmHg), and PVI (%) and TED data: FTc (msec), and SVR (dyn.sec.cm−5 and COP (l/min).
Sample size calculation
The minimal sample size was calculated based on a study. The study aims to assess the accuracy of PVI to predict preload responsiveness in perioperative and critically ill patients (Yin & Ho, 2012). A total sample size of 40 patients (sample size per group = 20) is the enough required sample for the condition of all individual, but one pair agrees with each other (k ≥ 1), as statistically significant with 80% power and a significance level of 95%. Sample size does not need to increase to control for attrition bias.
Method of randomization
The allocation sequence was generated using randomized (random number generator with sealed opaque envelopes). Allocation sequence/code concealed from the person allocating the participants to the intervention arms using sealed opaque envelopes.
Data are collected and entered to the computer using SPSS (Statistical Package for Social Science) program for statistical analysis (ver 21) as numerical or categorical, as appropriate. Kolmogorov-Smirnov test of normality revealed significance in the distribution of most of the variables, so nonparametric statistics is adopted. Data were described using median and interquartile range (IQR). Categorical variables were described using frequency and percentage. Comparisons were carried out using Mann-Whitney U-test. Comparisons were carried out among related samples by Friedman’s test. Pairwise comparison when Friedman’s test was significant was carried out using Dunn-Sidak method. Nonparametric Kendall’s tau correlation (τ) was used. Rule of thumb for interpreting the size of a correlation coefficient. Chi-square test was used to test association between qualitative variables. Box and Whiskers plot were used accordingly. An alpha level was set to 5% with a significance level of 95%, and a beta error is accepted up to 20% with a power of study of 80%.