In our study, we prospectively described the physiological changes during open abdominal cytoreductive surgery with HIPEC. To the best of our knowledge, the present study is the first trial to examine the cardiopulmonary and intravascular volume status with a new thermodilution measurement approach using the VolumeViewTM system in cytoreductive surgery with HIPEC.
A previous systemic review of patients treated with cytoreductive surgery and HIPEC due to pseudomyxoma peritonei reported that the median survival duration ranged from 51 to 156 months and that the 5-year survival rate ranged from 52% to 96% depending on the severity of disease at the time of treatment [18, 19]. Moreover, Verwaal et al. showed that patients with peritoneal carcinomatosis secondary to colorectal cancer treated with cytoreductive surgery and HIPEC demonstrated a significant increase of median survival (22 months) when compared with systemic chemotherapy alone (12 months) [20]. Consequently, cytoreductive surgery with HIPEC is currently identified as the standard method for treating peritoneal carcinomatosis secondary to colorectal cancer and appendiceal neoplasm [8].
Despite constant enhancement in surgical and anesthetic techniques, cytoreductive surgery with HIPEC is necessarily related with disturbances in hemodynamics, coagulation, gas exchange, and nutrition [7, 21]. Consequently, understanding the pathophysiological alterations accompanying with cytoreductive surgery with HIPEC is crucial and helpful for patients undergoing anesthesia. There were 3 studies systemically evaluated additional hemodynamic parameters, such as cardiac output and vascular resistance, assessed using either esophageal Doppler or transpulmonary thermodilution (TPTD) and pulse contour analysis [22, 23]. Although the results of the variation of systemic vascular resistance and cardiac output were not consistent and significant [24], a decrease in the SVRI and an increase in the CI were only measured in patients during the open coliseum technique of HIPEC [24], which is consistent with our results.
Considering the wide extent and duration of surgery, the large amount of fluid shifting, the necessity of vasopressor support, and intraoperative pathophysiologic changes need persistent attention, although they are transient in nature. Intraoperative hemodynamic monitoring is multilateral, and across studies on cytoreductive surgery with HIPEC, the monitoring approaches used include at least an invasive central venous and arterial pressure line, and hourly fluid administration and urine amount assessment [26, 27]. However, the CVP and amount of urine are not accurate indices of fluid responsiveness and only help to detect a patient’s intravascular volume status [28–30]. In addition, both pulse pressure variation and SVV, which may exhibit faster responses to sudden changes in volume responsiveness, are calculated using an arterial pressure waveform analysis method. However, some studies have reported clinically unacceptable accuracy for these systems in patients with vasodilation or impaired systolic function during a hypovolemic state [31, 32].
To surmount the shortcoming of existing hemodynamic monitoring, a novel TPTD system has been introduced and employed in clinical practice recently. It has a specific thermistor-tipped arterial catheter, the VolumeViewTM catheter, and the EV 1000 monitoring platform [16]. After injection of cold saline in the superior vena cava, TPTD allows the calculation of cardiac output from a TPTD curve recorded using a thermistor-tipped femoral arterial catheter [33]. Additional physiological data, such as the GEDI and ELWI, can be derived from the dilution curve. Volumetric preload indicators, such as the GEDI [34–36], have been reported to be reliable indicators of cardiac preload and have been successfully implemented in therapeutic strategies that may improve outcomes. The GEDI ranged from 715.4 to 809.7 in the present study, and this level steadily increased during the HIPEC period because of fluid resuscitation for compensating a decreased SVRI and increased SVV and HR. The ELWI, measured with single indicator dilution, is a reliable measure of pulmonary edema that has been validated against postmortem gravimetric measurement in animals [37–39]. Moreover, ELWI and PVPI may be used as criteria indicating the risk of fluid administration [40]. Especially, ELWI ≥10 mL/kg was defined as pulmonary edema, although no definitive quantitative criteria for ELWI associated with pulmonary edema have been established. A previous human autopsy study reported that the normal ELWI value is approximately 7.4 (SD 3.3) mL/kg, and this value can distinguish between healthy and pathological lungs [41]. Because ELWI ranged from 6.9 to 7.3 (peak value during HIPEC) in our study, the risk of occurrence of intraoperative pulmonary edema related to the cytoreductive surgery with HIPEC was lower more than anticipated.
During HIPEC, the circulation support with inotropes/vasopressors does not have definite recommendations [28]. The common practice in the setting of vasodilation was the use of noradrenaline and methoxamine, and it usually depends on institutional protocols. We almost selected and administered phenylephrine to our patients as a vasopressor because of increased HR and decreased SVRI. As a compensatory mechanism for the fallen SVRI, increased CO up to and HR up to were measured using VigileoTM during HIPEC, which is consistent with previous reports [42, 43]. Especially, the SVRI remained low not only during HIPEC but also postoperatively. In 6 cases, the vasopressor was maintained when leaving the operating room.
The choice of intraoperative fluid infusion involves balanced infusion therapy to maintain preload, colloid oncotic pressure, end-organ perfusion (urinary output), and electrolyte homeostasis [10]. To prevent hemodynamic imbalance and reductions in end-organ perfusion, the main aim of the anesthesiologist should be adequate fluid replacement and blood loss adjustment and maintenance of euvolemia. Moreover, in surgery with HIPEC, AKI usually occurs because of a decrease in blood pressure and insufficiency of intravascular volume. With just maintenance of normovolemia and adequate urine output, no change in creatinine values occurred during cytoreductive surgery and HIPEC [12, 44], and in our study, only 1 patient experienced AKI. It would be helpful to perform comprehensive evaluation of a patient’s intravascular volume status with closed monitoring involving various approaches, including the use of the VolumeViewTM system [7].
The severity of metabolic imbalances observed during HIPEC rely on the type of carrier solution and degree of hyperthermia. The carrier solution used in this study was a fluid containing 5% dextrose. Metabolic disturbances occur when both glucose and free water are absorbed into the plasma causing increased temperature and dilutional hyponatremia [1]. In our study, body temperature increased up to 38°C for 2 hours during the HIPEC period. Hyperthermia has been shown to increase metabolic activity, HR, carbon dioxide production, and ultimately oxygen consumption [7]. Additionally, a previous study reported increases in the lactate level of 2 to 4 mmol/L [45]. Although the results of this study also showed elevated glucose and lactic acid levels, the levels of electrolytes, such as sodium, were almost in the normal range. This result may be associated with closed monitoring and adequate fluid management made possible by the new TPTD system.
After HIPEC, patients are mostly admitted to the ICU for monitoring of organ function, management of postoperative complications, and correction of electrolytes and coagulopathy. Physiological perturbations during the perioperative period affect the duration of ICU stay and may precipitate multisystem organ failure [1]. Although the length of ICU stay (1.4 days) in our study was similar to the length reported in other studies, postoperative complications after surgery were unavoidable in our study. Regarding postoperative outcomes, there are many debates about the ideal postoperative nutrition strategies. According to a retrospective study by Arakelian et al., postoperative ileus is a common problem after surgery [46]. Although there are no prospective studies, most patients were tolerable oral feeding between 7 and 11 days postoperatively. To promote healing and improve intestinal transit, early enteral feeding is well known for both safe and beneficial for patients [47–49]. In our study, the recovery time of bowel movement was about 6 days, and the water and soft diet feeding times were lower than the gas passing time.
Some limitations must be acknowledged. This was a prospective observational study and the number of enrolled patients was relatively low. Consequently, it is slightly unreasonable to generalize the results of our study. In addition, it may be more critical to investigate the course of pathophysiologic changes, including fluid redistribution, after HIPEC surgery compared with intraoperative conditions. However, our findings will be a valuable source of information for further studies that address the anesthetic management of patients who are scheduled to undergo major surgery accompanied with severe hemodynamic changes, such as those associated with HIPEC.