Perioperative Management of the Oncologic Patient Undergoing Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

  • Darline HurstEmail author
  • Pascal Owusu-Agyemang
Living reference work entry


The standard surgical treatment option for peritoneal carcinomatosis (PC) is cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). This is an aggressive and complex treatment that often involves multi-visceral resection including extensive peritonectomies, splenectomy, bowel resections, and removal of other major organs that are involved with tumor. Upon completion of surgical extirpation of tumor, heated chemotherapy is instilled into the peritoneal cavity, and the abdomen is agitated for 60–120 min. The extensive nature of these procedures is associated with longer and more complicated anesthetic administration.

There are many challenges for the anesthetic team related to blood loss, temperature shifts, extensive fluid loss, and toxicity related to chemotherapy. A basic knowledge of chemotherapy drugs that are used during the HIPEC phase is also needed. A thorough understanding of this multimodal treatment is necessary to keep the patients safe during all phases of perioperative care.


Cytoreductive surgery (CRS) Hyperthermic intraperitoneal chemotherapy (HIPEC) Peritoneal carcinomatosis (PC) Peritoneal carcinoma index (PCI) Appendix cancer (AC) Colorectal cancer (CRC) Ovarian cancer (OC) Peritoneal surface malignancy (PSM) 


Peritoneal surface malignancy (PSM), commonly known as peritoneal carcinomatosis (PC), is a group of diseases that arises from the gastrointestinal (GI) tract, from the ovaries, or from the peritoneal lining itself which then spreads throughout the peritoneal cavity. Traditionally, PC has been considered an incurable disease with a poor median survival of 6 months. Until recently, palliative systemic therapy was the only option and improved survival up to 12–20 months. The trimodality therapy of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) began in the 1980s and has since become the standard of care for many peritoneal-based tumors [12].

The CRS portion of the procedure attempts to remove all macroscopic disease. This may require extensive organ resection including the spleen, portions of the small bowel, liver, and pelvic organs along with extensive peritonectomies (removal of the peritoneal lining of the peritoneal cavity).

Once the surgical resection is completed, heated chemotherapy is introduced into the abdominal cavity, and the abdomen is manually shaken to allow the chemotherapy to bath all peritoneal surfaces. The instillation of intraperitoneal chemotherapy allows for a 10- to 100-fold increase in the concentration of the drug within the peritoneal cavity as compared to systemic therapy. The main goal of the chemotherapy is to treat small volume or microscopic disease that may remain after the CRS. The chemotherapy is heated to ~42 °C. The hyperthermia potentiates the action of the chemotherapy. Upon completion of the HIPEC portion of the procedure, the chemotherapy is removed and the abdomen irrigated.

Reconstruction of the GI tract is then performed, and any required drains and chest tubes are placed, and the patient’s abdomen is closed.

Complications from this surgery include wound infections, intra-abdominal abscess, anastomotic leak, renal failure, neutropenia, hypotension, pulmonary issues related to fluid replacement, and mechanical respiratory issues from chest tube insertion.

Etiology and Epidemiology

Peritoneal carcinomatosis may arise from primary tumors of the appendix, colon, stomach, pancreas, mesothelium, and the ovaries [2]. Other rare causes of PC include rare sarcomas such as the desmoplastic round cell tumors and hepatobiliary malignancies.


Surgical management: CRS targets macroscopic disease and consists of removing all visible tumor. This may require parietal peritonectomy and multi-visceral resection. HIPEC follows CRS and is directed at treating low volume or microscopic tumor that may remain after the cytoreduction. HIPEC consists of instilling heated chemotherapy for 60–120 min at between 41 and 42 °C. HIPEC achieves a higher peritoneal chemotherapy concentration than is possible with systemic therapy with the benefit of limited systemic absorption [3]. This procedure is time-consuming and complex with an average operating room time of 8 h.

Anesthetic management: CRS-HIPEC presents the anesthetist with numerous challenges. Optimal management of these patients requires an understanding of the details of both surgery and chemoperfusion [3]. Before the development of this technique, patients with this disease were considered inoperable, but now we find them routinely scheduled for surgery. The anesthesiologist requires knowledge of the physiology associated with wide temperature changes during CRS-HIPEC, tremendous fluid shifts, abdominal hypertension, electrolyte abnormalities, coagulopathies, increased cardiac index, oxygen consumption, and decreased systemic vascular resistance during the HIPEC phase. In addition, knowledge of toxicity related to the chemotherapy agent being used is important [3].

CRS and HIPEC may result in hemodynamic changes as a result of blood loss, peripheral vasodilatation, and massive fluid shift. The patient’s general condition and their respiratory, cardiovascular, and metabolic status and electrolyte balance are significantly altered [2]. In order to maintain adequate circulating volume and urine output, large amounts of intravenous fluids are typically administered during surgery (Arakelian et al.). However, similar to other areas of surgical practice, perioperative fluid management strategies have begun to shift toward a more restrictive approach. In a single-institution retrospective study performed at the University of Massachusetts Medical Center, a restrictive fluid approach (i.e., 4.4 vs. 8.0 L of crystalloid, 300 vs. 900 ml of colloid, and 0.04 vs. 0.26 units of blood) was associated with a decreased length of stay and decreased rate of postoperative complications [10]. In another retrospective study from the City of Hope National Medical Center, patients who received fluids at a rate higher than the mean rate of 15.7 ml/kg/h experienced a 43% increase in the rate of complications compared to patients who received less than the mean rate [7]. Colloids are helpful in stabilizing fluid status during periods of peripheral vasodilatation. However, their benefit in preventing acute kidney injury has not been demonstrated [17].

Goal-directed fluid therapy (see Table 1) is recommended during these procedures and can be used even in massive resections. The goal is to maintain effective circulating blood volume by careful fluid and transfusion management, vasopressors, and inotropes [11]. Goal-directed, aggressive treatment using algorithms and point-of-care testing is important. In a randomized control study of patients undergoing CRS-HIPEC, Colantonio et al. reported significantly less complications (10.5% vs. 38.1%) and length of stay (19 vs. 29 days) in patients who received goal-directed fluid therapy [6]. In their study, goal-directed fluid therapy was associated with significantly less crystalloid administration compared to standard therapy (3884 ± 1003 vs. 68,528 ± 1413 ml).
Table 1

HIPEC ERAS generalized protocol

Baseline ERAS protocol (HIPEC)






Day prior to surgery


Regular until evening meal


Bowel preparation



Antimicrobial prophylaxis

Chlorhexidine shower (evening)


Oral antibiotics


Discretion of surgeon


Day of surgery

Prehospital arrive


Clear carbohydrate drink

6 h before/at discretion of surgeon


Antimicrobial prophylaxis

Chlorhexidine shower (morning)


Hospital (preoperative holding)


Clear carbohydrate drink

2 h at discretion of surgeon



Alvimopan 12 mg



Acetaminophen 1.0 g

PO or IV

Hepatic disease


Celecoxib 100–200 mg




Ultram 100–300 mg



Scopolamine 1.5 mg



Lyrica 75 mg


Age over 60, consider omitting


Intraoperative phase

Regional anesthesia choices

Epidural (thoracic)

Free bupivacaine (maximum safe dose)


TAP block

Liposomal bupivacaine 266 mg



QL block

Liposomal bupivacaine 266 mg



ES block

Liposomal bupivacaine 266 mg





Lidocaine 1 mg/Kg



Propofol 1–2 mg/Kg



Ketamine 0.5 mg/Kg



Rocuronium 0.5–1.0 mg/Kg



Dexamethasone 4–10 mg



Not used at times

Magnesium 20–30 mg/Kg



Not used until end/omit if moderate EBL

Ketorolac 15–30 mg


Bleeding concerns


Heparin 5000 units


Bleeding concerns



Lidocaine 1–2 mg/min

IV infusion

Omit if exparel is used


Propofol 25–200 mg

IV infusion

Keep BIS 60–80


May need to adjust earlier

Ketamine 5–10 mg/H

IV infusion

Cut in half every 2 h until 1.25 mg/h

See below for dc times

Dexmedetomidine 0.3 mcg/Kg/H

IV infusion

Cut in half every 2 h until 0.075 mcg/kg/h

See below for dc times

Rocuronium 2–4 mcg/Kg/min

IV infusion

2–3/4 TOF


Acetaminophen 1.0 g

IV (q6h)


Goal-directed fluid therapy

Stroke volume variation (12–14 mmHg)

Albumin 5% 250 ml





Propofol 25–150 mcg/Kg/min

IV infusion

Discontinue 45–60 min prior to extubation


Ketamine 5–10 mg/H

IV infusion

May continue into recovery phase at 5 mg/H or less


Dexmedetomidine 0.3 mcg/Kg/H

IV infusion

Discontinue 60–90 min prior to extubation


Sugammadex 2 mg/Kg



Ondansetron 4–8 mg



Postoperative phase


Clear liquids




Only if needed

Ketamine 5–10 mg/H

IV infusion

May continue into recovery phase at 5 mg/H or less


Acetaminophen 1.0 g

PO (q6h)

Liver disease caution


Celecoxib 100–200 mg


Coronary artery disease


Gabapentin 200–700 mg


Renal disease


Rescue for pain breakthrough

Hydromorphone 0.5 mg



Alvimopan 12 mg



Not used routinely at my institution

Magnesium oxide 400 mg



AlBalawi et al. [1], Martin et al. [15], Martin et al. [16], Smith et al. [21], Thiele et al. [22], Thiele et al. [23]

The use of lidco or vigileo allows for stroke volume variation monitoring throughout case. Close monitoring of urine output also is a good indicator of volume status. Urine output of 2 cc per kg is recommended prior to the start of perfusion.

Maintaining adequate hydration in the immediate postoperative period is essential in preserving renal function. At our institution, a continuous infusion of lactated ringers (125 ml/h) is initiated postoperatively. Patients who received intraperitoneal cisplatin are maintained at a higher rate of 200 ml/h. Additional boluses of 5% albumin (500 ml) are administered for urine output less than 30 mL/h for two consecutive hours. Due to its nephrotoxic nature, a higher rate of urine output is maintained in patients who received intraperitoneal cisplatin, and additional boluses of 5% albumin are administered when the urine output falls below 200 ml/h.

Close monitoring of temperature by two different methods is recommended. Bladder temperature works well to correlate with abdominal temperature of chemotherapy infusion. Esophageal or nasopharyngeal temperature especially correlates to brain temperature during heated portion of case. Active methods of cooling such as cooling blanket on bed, bair huggers on ambient, and ice packs around head and face help to keep cerebral temp below 38 °C.

The pathophysiology of coagulopathy in patients undergoing CRS/HIPEC is not completely understood. Aside from bleeding, consumption, and dilution, patients are exposed to extreme changes in body temperature (both hypo- and hyperthermia). These factors along with metabolic acidosis and calcium depletion may play a role in the coagulopathy identified in these patients [11].

The use of thoracic epidural anesthesia has long been recommended for patients undergoing CRS/HIPEC secondary to the full midline incision and the need of potential multiorgan compartment resection. More recently, transversus abdominis plane (TAP) blocks are being utilized more frequently for these patients. The optimal postoperative pain management needs further study, and a number of institutions have randomized controlled trials trying to answer which postoperative pain management regimen is best.

Compared to volatile-opioid anesthesia, multimodal opioid-sparing anesthetic techniques have been associated with superior analgesia, reduced opioid consumption, shorter length of stay, and lower rates of complications in a variety of surgical procedures [8]. Multimodal analgesia is also an integral part of enhanced recovery protocols. At our institution, a multimodal opioid-sparing approach is typically initiated by the preoperative administration of pregabalin (75–150 mg), celecoxib (200–400 mg), and tramadol (300 mg). This is followed by the placement of an epidural catheter or TAP block and total intravenous anesthesia with propofol (50–150 mcg/kg/min), dexmedetomidine (0.3 mcg/kg/h), and ketamine (10 mg/h) (see Table 1). This combination may be altered depending on the preoperative status of each patient and the anesthesiologist or surgeon’s preferences (epidural catheter versus TAP block). The use of lidocaine infusions has been limited due to TAP blocks with exparel being administered frequently. Intravenous infusions are gradually titrated down and then discontinued before extubation (see Table 1).

Early postoperative pain management consists of epidural analgesia (bupivacaine 0.075% with hydromorphone 5–10 mcg/ml), intravenous acetaminophen, and opioid-based patient-controlled intravenous analgesia (IV PCA). As advances in diet are tolerated, oral opioids, gabapentinoids, and celecoxib are added to the analgesic regimen. Epidural catheters are usually discontinued after 5–7 days. In a retrospective review of 213 patients who had undergone CRS-HIPEC, a multimodal total intravenous anesthetic approach was associated with significantly less opioid consumption [18].


In a retrospective study done by Kajdi et al. in [11], the perioperative management of patient undergoing CRS/HIPEC was reviewed and analyzed. This study highlighted that maintaining renal function and prevention of renal injury is critical for the best operative outcome.

Acute kidney injury (AKI) is a postoperative complication associated with significant morbidity and mortality [5]. In a retrospective study done by Cata et al. in [5], the authors demonstrated several potential mechanisms explaining the AKI seen in this patient population. The authors note ischemia-reperfusion injury secondary to episodes of arterial hypotension, fluid redistribution, the direct effects of nephrotoxic drugs, and inflammation to be the key mediators of AKI.

The study by Cata et al. authors identified both modifiable and non-modifiable risk factors for AKI after CRS-HIPEC. The authors found that 21.3% of patients were identified as having developed an AKI stage I or higher injury. AKI was more frequent in older patients, males, and overweight/obese patients (84.1%), as well as those with moderate to severe baseline kidney disease.

In this same study, a higher percentage of patients with AKI had mesothelioma (17.82%) as the primary tumor. Many of these patients received systemic cisplatin prior to CRS/HIPEC and were at higher baseline risk of developing AKI. Nearly all of these patients had received cisplatin during the HIPEC which likely also contributed to the renal injury.

The authors also identified the type and doses of vasopressors administered during the surgery influenced AKI with cumulative doses of ephedrine (>32.61 mg) as having an increased risk of AKI but not for phenylephrine and dopamine. Interestingly, AKI was less frequent in patients who had splenectomies; however, the reason for this is unclear.

Finally, Cata et al. then went on to find that age, elevated BMI, administration of platinum-based agents, the use of pregabalin, placement of ureteral stents, and major blood loss are independent risk factors of AKI.

In an effort to mitigate the effects of HIPEC with cisplatin, many institutions will initiate a bolus of sodium thiosulfate 20 min prior to the start of HIPEC and continue a drip of the same medication for the next 12 h. This medication helps prevent precipitation of the drug within the kidney and markedly reduced AKI in this setting.

Brain natriuretic peptide (BNP) is a hormone secreted by cardiomyocytes in response to ventricle stretch. The blood level of BNP has previously been demonstrated to correlate with volume overload, readmission rates, cardiac-related morbidity and mortality, and overall mortality in both the inpatient and ambulatory medical settings [9]. In a 2-year study from 2014 to 2016, Fischer et al. evaluated BNP levels on POD1 in patients undergoing CRS/HIPEC in an effort to identify early factors associated with increased risk of complications. The authors identified elevated BNP as early as POD1 to be associated with a risk of major/cardiopulmonary complications (CP), which manifest later in the hospital course. This study also demonstrated that there may be a relationship between the rate of change of BNP and the development of major/CP complications, although this trend within the data requires further investigation.

In addition, those patients with early elevation of BNP demonstrated persistent diuretic requirements and were found to have higher rates of major/CP complications. Frequent diuretic requirements without improvement in BNP should alert the clinician to the possibility of a future complication [9].

Acute respiratory distress syndrome (ARDS) is a rapidly progressive disease which results in fluid leaking into the lungs, making respiration difficult. Although uncommon, this complication needs to be identified early to improve outcomes in patients with this disease process. The etiology of ARDS in these patients is thought to be attributed to systemic inflammatory response and possibly multiple transfusions during major surgery [2].

Pleural effusions are commonly seen in patients undergoing CRS/HIPEC. Many patients who have extensive peritonectomy of the diaphragmatic surfaces develop reactive pleural effusions which usually develop early in the postoperative course. Many surgeons who perform extensive peritonectomies of the diaphragmatic surfaces will prophylactically place thoracostomy tubes intraoperatively in an effort to avoid having to place these tubes postoperatively when the patient is awake. Other studies have demonstrated high peritoneal carcinomatosis index (PCI) (which is a surrogate for tumor burden) and ASA classification as risk factors for the development of postoperative pleural effusions. In spite of respiratory complications being common after this procedure, most have no effect on postoperative recovery [2].

In some hospitals, all patients undergoing CRS/HIPEC are admitted to the ICU postoperatively. In an effort to identify risks for prolonged ventilation requirements and ICU stay, a recent study evaluated 24 consecutive patients who underwent CRS and HIPEC with the primary endpoints of postoperative ventilation greater than 24 h and ICU stay over 5 days. The authors identified higher PCI; greater blood loss; higher requirements of crystalloids, colloids, and blood products; and lower PaO2/FiO2 ratio to be associated with the need for prolonged ventilation and ICU stay [3].

In another recent study of 136 patients who underwent 140 procedures, 8 patients (5.7%) developed delayed major complications. The most common major complications included pancreatic pseudocyst/pancreatitis (n = 3), abdominal wall dehiscence (n = 2), gastric perforation (n = 1), and ureteral stricture with associated hydronephrosis (n = 2). All of these patients had undergone multi-visceral resection. All patients eventually recovered following intervention without further morbidity or mortality [4].

One recent review article identified patient-specific factors such as hypoalbuminemia, performance status, age, and operative factors such as PCI, multiorgan resection, diaphragmatic involvement, and experience of the surgical team to be strongly associated with major morbidity [3].

A study by Lam evaluated CRS/HIPEC followed by early postoperative chemotherapy (EPIC) vs CRS/HIPEC alone. All patients had peritoneal carcinomatosis of either colorectal cancer or high-grade appendiceal cancer. There was no difference in overall survival and recurrence-free survival between the two groups. However in the group undergoing HIPEC followed by EPIC, patients suffered much greater morbidity, making HIPEC alone the preferable regimen [13] for many institutions.

A fistula occurs when there is an abnormal communication between two epithelialized surfaces, permitting loss of electrolytes and fluids and leading to a wide variety of pathophysiological complications including intra-abdominal abscess, wound infection, sepsis, malnutrition, and severe electrolyte imbalance [24]. Enterocutaneous fistula (ECF) is an abnormal connection between the bowel and the skin. This complication may occur in 2–23% of patients undergoing standard colorectal resections. The mortality rates from this complication vary from 6.5% to 39% [24]. Patients undergoing CRS/HIPEC have higher rates of this complication with some series demonstrating a doubling of the rate of ECF.

Many of the surgery-related major complications following CRS-HIPEC can occur late in the postoperative period even after discharge from the initial surgery [4]. Patients may be back at home far from the institution where the procedure was done. These patients need to be followed closely for longer periods and educated about the increased possibility of delayed complications.


PC by definition represents stage IV disease which was previously regarded as a rapidly terminal condition. In 2000 the EVOCAPE 1 group followed 370 patients with peritoneal carcinomatosis of non-gynecologic malignancies and demonstrated a mean and median overall survival after diagnosis of 6 and 3.1 months, respectively [4]. Over the last two decades with the application of complete CRS/HIPEC, the improvement in survival of lower GI malignancies, depending on the site of origin, now varies from 40 to 110 months, with the potential to cure a percentage of patients [4].

In all studies to date, the ability to remove all visible disease (complete cytoreductive surgery) is the strongest predictor of long-term outcome. Once again, this highlights the importance of multi-visceral resection in order to remove all disease from the peritoneal cavity.

Many studies have demonstrated that the PCI was found to be a predictor of both morbidity and long-term outcome in patients undergoing CRS-HIPEC.

Rodriguez et al. looked at both systematic and retrospective reviews in an effort to better understand the outcomes for patients with PC. The authors concluded that in appropriately selected patients with isolated peritoneal carcinomatosis, results with cytoreductive surgery and HIPEC are superior to those that can be achieved with modern combination chemotherapy regimens [19].

The most difficult aspect in the care of patients with PC remains selecting those patients who are most likely to benefit from this potentially morbid operation. The experience of the institution has been shown in many studies to best correlate with an increased ability to obtain complete resection and to decrease morbidity and mortality [20]. Multidisciplinary approaches to the care of these patients including input from medical oncologists, surgical oncologists, anesthetists, dieticians, and nursing and ancillary staff are all keys to proving excellent care for patients with PC both in and out of the operating room.


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Anesthesiology and Perioperative MedicineThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Critical CareThe University of Texas MD Anderson Cancer CenterHoustonUSA

Section editors and affiliations

  • Garry Brydges
    • 1
  1. 1.Department of Anesthesiology Division of Anesthesia, Critical Care and Pain MedicineThe University of Texas MD Anderson Cancer CenterHoustonUSA

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