Anesthesia for cytoreductive surgery with heated intraperitoneal chemotherapy

INTRODUCTION — Heated intraperitoneal chemotherapy (HIPEC) with cytoreduction is an increasingly used technique for treating isolated peritoneal dissemination of an intraabdominal malignancy. Cytoreductive surgery (CRS) is performed first through a traditional open or laparoscopic approach, after which chemotherapeutic agents heated to 40 to 41.5°C are infused for up to two hours. Thus, the procedure involves major abdominal surgery, thermal stress, and the deleterious effects of chemotherapeutic agents, with significant fluid shifts, electrolyte and acid base disturbances.

This topic will discuss the HIPEC process, preoperative evaluation, and anesthetic management for CRS with HIPEC procedures, focusing on the physiologic perturbations that may occur. Indications for HIPEC are discussed in topics that review the management of specific tumors.  

CYTOREDUCTIVE SURGERY — Cytoreductive surgery (CRS) is performed to maximize the effect of chemotherapy, since cytotoxic drugs instilled into the peritoneum can penetrate tissue only up to 3 millimeters [1]. CRS involves resection of the primary tumor, excision of any other visible tumor, peritonectomies, omentectomies, and bowel resections as necessary. This portion of the procedure may be extensive and prolonged, with significant fluid shifts and blood loss.

In a systematic review of the literature consisting of 24 observational and cohort studies of patients who underwent heated intraperitoneal chemotherapy (HIPEC) with cytoreduction, mean duration of the combined procedure was from 5 to 10.5 hours [2]. Blood loss varies widely with the extent of surgery and may be substantial; in one single institution review, the median blood loss was 3.5 liters, with a range of 0.4 to 30 liters [3].

HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY — Following cytoreductive surgery (CRS), a heated chemotherapy solution is infused into the abdomen. Infusion of chemotherapy immediately after CRS facilitates spread of the solution throughout the entire peritoneal cavity, avoiding compartmentalized spread that would occur after postoperative formation of adhesions.

Rationale for HIPEC — The benefits of heated intraperitoneal chemotherapy (HIPEC) derive from the high concentration of chemotherapy delivered directly to tumor cells without relying on blood supply and the fact that hyperthermia enhances the cytotoxic effect of chemotherapy agents.

●Local administration of chemotherapy – Intraperitoneal instillation of the commonly used chemotherapeutic agents achieves very high local doses, allowing diffusion into tumor nodules, while minimizing systemic absorption and toxicity [1]. The drugs with reduced systemic uptake are high molecular weight, hydrophilic, and ionized compounds. The agents most commonly used for HIPEC are mitomycin and the platinum-based drugs, oxaliplatin, cisplatin, and carboplatin, and less commonly, doxorubicin. These drugs are not cell cycle specific and act synergistically with heat [4]. They are sometimes used in combination. The characteristics of commonly used chemotherapeutic agents are shown in a table (table 1).

The rate of systemic absorption is higher for drugs that are lipophilic and penetrate deeply into tissue. Systemic absorption of chemotherapeutic agents does occur during HIPEC and is responsible for toxicity. Doses of chemotherapeutic agents and volume of the carrier are standardized based on body surface area [5]. (See 'Adverse effects of chemotherapeutic agents' below.)

●Benefit of heat – The benefits of heating chemotherapy agents are as follows [5-10]:

•Heat increases tissue penetration, with a preferential effect on tumor vasculature.

•Heat enhances cytotoxicity of chemotherapy by changing the drug's pharmacokinetics and excretion.

•Heat itself at 39 to 43°C preferentially alters tumor cell metabolism and results in inactivation of membrane receptors, altered enzyme activity, chromosome damage and misrepair, and altered tumor cellular structures.

Infusion procedure — Chemotherapy drugs are infused at a temperature from 41 to 43°C for 30 to 120 minutes in most HIPEC protocols. There is significant variation in the duration of HIPEC treatment depending on the characteristics of the infusate. The optimal duration of HIPEC has not been established [11]. After cytoreduction, HIPEC can be performed using a closed or open abdomen technique, or less commonly, a semi-open technique. Techniques for HIPEC with cytoreduction are not standardized, and practice varies significantly. A 2019 review of 168 studies of HIPEC found that approximately half of centers used the closed technique, 42 percent used the open technique, and 5 percent used alternatives, including laparoscopy [11].

●For the closed abdomen technique, infusion catheters and drains are strategically inserted to distribute the chemotherapy solution, after which the abdomen is closed. The surgeon manually agitates the abdomen during infusion to promote even distribution of the perfusate. After perfusion, the abdomen is reopened and the perfusate evacuated.

This technique minimizes heat loss during HIPEC and may reduce exposure of operating room personnel to hazardous drugs, but distribution of the drug solution may be uneven. A laparoscopic approach solves this last issue because it permits the surgeon to knead the abdomen frequently during infusion for even distribution in the abdominal cavity. In addition, the closed technique causes an increase in intra-abdominal pressure during infusion; this is less of an issue with the open technique. (See 'Physiologic effects of HIPEC' below.)

●For the open abdomen technique, the chemotherapy solution is infused into the abdomen without closing the wound, usually using what has been referred to as the Coliseum technique. The wound edges are sutured along with a plastic sheet to a self-retaining abdominal retractor to raise the edges of the wound and keep the drug solution in the abdomen. The surgeon inserts a hand into a slit in the plastic sheet to manipulate the solution throughout the infusion. A smoke evacuator is placed under the plastic sheet to reduce operating room exposure to aerosolized drug.

The open abdomen technique allows the even distribution of solution and heat, but may increase exposure of operating room personnel to aerosolized chemotherapeutic agents [12]. Regardless of the technique, several studies have found no signs of health risks for operating room staff when appropriate protective equipment is employed. (See 'Environmental safety' below.)  

Regardless of the technique, a heated chemotherapy solution (3 to 5 L) is circulated in the peritoneal cavity for 30 to 120 minutes using a roller pump and heating circuit [13,14]. The temperature of the peritoneal infusate is kept between 40 and 43°C.  

Anesthesia clinicians should be aware of the type of chemotherapy carrier solution and the volume and rate of infusion, all of which can cause major fluid shifts and electrolyte disturbances. Carrier solutions are chosen to provide enhanced exposure of the peritoneal surface, slow clearance from the peritoneal cavity and for absence of adverse effects on the peritoneal membranes [15]. Commonly used carrier solutions for HIPEC include isotonic saline solutions or dextrose-based peritoneal dialysis solutions. The majority of chemotherapy agents are administered with an isotonic carrier solution, but there are exceptions. Oxaliplatin is unstable in isotonic solutions and requires a hypertonic dextrose-based carrier, which can lead to hyponatremia, hyperglycemia, and major acid-base disturbances during infusion [16,17]. Mitomycin, doxorubicin, and paclitaxel may also be used with dextrose-based carrier solutions and may be associated with similar disturbances.

Adverse effects of chemotherapeutic agents — Intraperitoneal chemotherapy agents can cause adverse effects due to absorption of the drugs themselves, and absorption of their carrier solutions. Adverse effects may include postoperative nausea, effects on wound healing, bone marrow suppression, and organ toxicity. The adverse effects of chemotherapy agents used for HIPEC are shown in a table (table 1).

●Systemic absorption of chemotherapy agents – Concentrations of chemotherapy agents in the peritoneal cavity and the plasma are typically described by the area under the curve (AUC) created by plotting the drug concentration over time. The ratio of the peritoneal to plasma AUC is a measure of the degree to which a drug is absorbed, and a high AUC ratio is desirable in order to maximize cytotoxicity, while minimizing systemic toxicity (table 1). However, a high AUC ratio is only one factor that enters into the choice of intraperitoneal chemotherapy agent, along with efficacy of the drug for the tumor type.

●Renal toxicity – Acute kidney injury is one of the most common complications following CRS with HIPEC, particularly with administration of cisplatin [18]. Some HIPEC protocols include administration of sodium thiosulfate to reduce renal toxicity during HIPEC with cisplatin, a known nephrotoxin [18-20]. (See 'Renal function' below.)

Fluid management and management of urine output are discussed below. (See 'Fluid management' below.)

Physiologic effects of HIPEC — Cooling measures must be used during HIPEC, aiming to avoid severe hyperthermia. The target temperature varies among institutions and surgeons, and may be 39 to 39.5°C (see 'Temperature management' below). Hyperthermia induces a hypermetabolic response characterized by increases in metabolic rate, oxygen demand and consumption, carbon dioxide production, and serum lactate [21,22]. Systemic vascular resistance and mean arterial pressures tend to fall.  

The resulting hemodynamics may differ, depending on whether an open or a closed abdominal approach is used. The increase in intra-abdominal pressure that occurs with infusion in a closed abdomen causes increases in central venous pressure, intrathoracic pressure, and inspiratory pressures [23,24]. These changes are less significant with an open abdomen technique for HIPEC [25].

Heat-induced fluid losses and hyperdynamic hyperthermia may produce a hypermetabolic state with increased oxygen consumption and changes in tissue perfusion [24,26]. As the core temperature rises, damaged malignant cells increase the production of inflammatory cytokines and produce a change in pH in the microenvironment. Circulating inflammatory cytokines produce a significant drop in systemic vascular resistance, leading to a compensatory rise in heart rate and an increase in cardiac output [27]. These effects resemble the physiologic changes that occur in sepsis, with a rise in the inflammatory cytokine interleukin-6 within the peritoneum and decreases in systemic vascular resistance and effective circulatory volume [25,28,29]. In one study of 11 patients who underwent HIPEC with pulmonary artery catheter monitoring, mean arterial pressure decreased from a mean of 93.8 to 75.5 mmHg, systemic vascular resistance fell from 2214 to 1239 dynes × s/min⁵ × m^2, and cardiac index increased from 3.4 to 4.6 mL/min/m² [27]. Core temperature reached a mean of 39.2°C.

Environmental safety — The chemotherapy solutions used for HIPEC pose a risk to operating room personnel through direct or indirect skin contact (ie, contact with a contaminated surface), or less commonly, through inhalation of aerosols [30]. Heavy contamination with chemotherapy agents has been detected on surgeon's gloves, the floor near the operating room (OR) table, the OR table itself, and the surgeon's shoes after HIPEC [31,32].

Exposure to chemotherapy agents can be prevented by the use of appropriate protective equipment [30]. Recommended personal protective equipment (PPE) for OR staff during HIPEC includes airborne, droplet, and contact precautions (ie, properly fitted N95 masks; goggles or face shield; impermeable gown, gloves, and shoe covers) [33-35]. Specific environmental safety measures recommended when handling chemotherapy during HIPEC are shown in a table (table 2).

Multiple studies have found no quantifiable contamination of OR air and no measurable levels of chemotherapy agents in the blood or urine of OR personnel who used appropriate PPE and surgical precautions, with either an open or closed abdomen technique [36-39].

PREOPERATIVE EVALUATION — All patients should undergo preoperative evaluation and risk assessment before anesthesia. Cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC) must be considered a high risk procedure, and preoperative assessment and preparation must reflect this. (See "Preoperative evaluation for anesthesia for noncardiac surgery".).

Patient selection for HIPEC includes both tumor characteristics and the patient's fitness to tolerate a major procedure. Functional status and comorbidities are important determinants for patient selection in most centers and are discussed here. Tumor characteristics that determine eligibility for CRS with HIPEC are discussed in topic reviews of the management of specific tumors.

At the authors’ institution, preoperative interventions include written materials, emotional support, alcohol and smoking cessation programs, and incentive spirometry exercises prior to surgery. Prehabilitation programs may be beneficial for patients who undergo intraabdominal cancer surgery. The rationale for prehabilitation and components, interventions, and efficacy of prehabilitation are discussed separately. (See "Overview of prehabilitation for surgical patients".)

Risk factors for morbidity and mortality — CRS with HIPEC is associated with perioperative mortality of 0 to 4 percent and major complications as high as 30 to 40 percent in contemporary studies [2,40-45], similar to other major abdominal procedures. Risk factors for perioperative morbidity and mortality after HIPEC include poor performance status, older age, smoking history, cardiovascular disease, and diabetes [46-48].

In one retrospective review of 935 patients (91 with diabetes) who underwent CRS with HIPEC, diabetes was a strong independent predictor for major complications, including infection, thrombotic events, arrhythmias, renal insufficiency, and respiratory failure [46]. Diabetes was also associated with increased mortality at 30 and 90 days (8.8 versus 2.7 percent, and 13.2 versus 5.2 percent, respectively).

Anesthetic considerations for patients with diabetes are discussed separately. (See "Anesthesia for patients with diabetes mellitus and/ or hyperglycemia".)

Assessment of functional status — Most protocols limit HIPEC to patients with very good functional status. The Eastern Cooperative Oncology Group performance scale (range 0 to 5, 0 = full function), and the Karnofsky Performance Status scale (0 to 100, 100 = full function) are commonly used to assess cancer patients before HIPEC (table 3). Many protocols limit HIPEC to patients with Eastern Cooperative Oncology Group (ECOG) rating ≤2 or Karnofsky status >75 or 80 [33,49,50].

Some centers perform HIPEC with cytoreduction only in patients <75 years of age. In other centers, older age and comorbidities are considered together. As an example, the guidelines from the Canadian HIPEC Collaborative Group recommend that patients >65 years of age can be considered for HIPEC if they have no significant comorbidities [33].

Cardiac evaluation — We perform a preoperative electrocardiogram for all patients who undergo HIPEC with cytoreduction, and perform further testing based on usual indications. (See "Evaluation of cardiac risk prior to noncardiac surgery", section on 'Management based on risk'.)

Cardiac evaluation for HIPEC should be performed as it would be for all patients who are to undergo high risk procedures with expectations for significant blood loss, fluid shifts, and hemodynamic perturbations. Preoperative cardiac evaluation is discussed in detail separately. (See "Evaluation of cardiac risk prior to noncardiac surgery" and "Management of cardiac risk for noncardiac surgery".)

Cardiovascular disease is not in and of itself a contraindication to HIPEC in most centers, and there are case reports of anesthetic management of patients with significant disease [51]. Preoperative evaluation may suggest ways to optimize cardiac function, reduce risk, and determine the methods used for monitoring during anesthesia.

Pulmonary evaluation — We perform a preoperative chest radiographic before HIPEC, and base further evaluation and optimization on patient factors.

Patients with peritoneal tumors may have conditions that increase the risk of perioperative pulmonary complications, including ascites, pleural effusions, and related atelectasis, in addition to the risk factors that may be present in any patient. Preoperative evaluation of pulmonary risk and strategies to reduce postoperative pulmonary complications are discussed separately. (See "Evaluation of perioperative pulmonary risk" and "Strategies to reduce postoperative pulmonary complications in adults".)

Renal function — We order laboratory testing for baseline renal function (ie, blood urea nitrogen, creatinine, eGFR) and electrolytes as part of preoperative assessment for all patients who undergo HIPEC. We ask for preoperative nephrology consultation for patients with renal dysfunction.

Acute kidney injury (AKI) is one of the most common complications following HIPEC, with a reported incidence as high as 20 percent [18,52], and as high as 40 percent in patients who received cisplatin [53].

AKI after CRS with HIPEC is associated with a higher rate of major complications [18]. Suggested pathophysiologic mechanisms for AKI during HIPEC include hypotension or renal hypoperfusion related to intra-abdominal hypertension, major fluid shifts, nephrotoxic chemotherapy agents, and the inflammatory response [54]. Reported predictors of AKI in some but not all studies include older age, worse baseline renal function, higher body mass index, use of a platinum-based infusion, longer operative time, and a large estimated blood loss [18,52,53]. For patients with these predictors of AKI, we adjust fluid management to protect renal function. (See 'Restrictive fluid therapy' below.)

Hematologic assessment and preparation for transfusion — Patients undergoing CRS with HIPEC are at high risk of coagulopathy and anemia related to nutritional deficiency, hypoproteinemia, and the effects of prior chemotherapy. In addition, there is high likelihood of significant blood loss and transfusion during the procedure based on the extent of the cytoreductive surgery.

●We order a complete blood count and coagulation studies (ie, prothrombin time [PT] and international normalized ratio [INR], activated partial thromboplastin time [aPTT]), as part of preoperative assessment and correct abnormalities preoperatively.

●We also perform type and screen before surgery to assess for antibodies that would make cross match difficult. Given the low risk of transfusion we do not crossmatch blood preoperatively unless the surgeon requests it. In a single institution review of approximately 500 patients who underwent CRS with HIPEC, 74 percent of patients were transfused with a median of two units of PRBCs (range 0 to 37 units) [55].

●We do not order fresh frozen plasma or platelets in advance unless there is evidence of coagulopathy.

Plan for pain management — The plan for pain management should be discussed preoperatively with the patient. We and most other centers place a thoracic epidural for optimal opioid sparing postoperative pain control, and to facilitate extubation. Epidural analgesia may improve postoperative pulmonary function, speed recovery of bowel function, and decrease hospital length of stay [56-60]. (See "Continuous epidural analgesia for postoperative pain: Benefits, adverse effects, and outcomes".)

Preexisting coagulopathy or administration of antithrombotic or anticoagulant drugs may affect the decision to place an epidural, or affect the timing of placement or removal of the catheter, due to the risk of spinal epidural hematoma [61]. The potential for coagulopathy during the procedure is not a contraindication to the use of epidural anesthesia or analgesia. However, for patients who do develop coagulopathy, normal coagulation should be documented before removing or replacing the catheter postoperatively [62]. (See "Overview of neuraxial anesthesia", section on 'Preoperative evaluation'.)

If an epidural analgesia is contraindicated, alternative regional anesthesia techniques (ie, rectus sheath nerve block, transverse abdominal plane block) should be strongly considered. In a single institution trial, 68 patients who underwent CRS with HIPEC were randomly assigned to receive thoracic epidural analgesia versus a four quadrant transversus abdominis plane block (4Q-TAP; bilateral subcostal and lateral TAP blocks) in conjunction with multimodal anesthesia [63]. Postoperative opioid consumption was greater in the first two days postoperatively in patients who had TAP blocks, however opioid related adverse events, complications, hospital length of stay, and quality of recovery scores were similar in the two groups. (See "Transversus abdominis plane (TAP) blocks procedure guide".)

ERAS PROTOCOLS — Similar to other surgical procedures, enhanced recovery protocols have been developed for cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC), and may improve outcomes [40,64-66]. In one small study, implementation of an enhanced recovery after major surgery (ERAS) protocol was associated with reduced length of stay, 7 versus 11 days, and similar morbidity and mortality, compared with standard pre-ERAS care [64]. Further study is required to determine the relative benefits of specific components of ERAS protocols for CRS and HIPEC. ERAS is discussed in more detail separately. (See "Anesthetic management for enhanced recovery after major noncardiac surgery (ERAS)".)

ANESTHETIC MANAGEMENT — The goals of intraoperative management specific to cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC) are to minimize complications from chemotherapy agents and to maintain end-organ perfusion in the face of major fluid shifts. To achieve these goals, anesthesiologists must anticipate and manage the hemodynamic changes throughout HIPEC. We divide the anesthetic management into three major phases: pre-HIPEC, HIPEC, and post-HIPEC phases, and describe each of these phases in the following sections. Our protocol for CRS with HIPEC is shown in a table (table 4).

Premedication — We administer anxiolytics as we would for any patient who is to undergo a major surgical procedure, taking into account patient factors. We routinely administer prophylaxis for postoperative nausea and vomiting (PONV) that can result from anesthesia, or from chemotherapy. We administer triple drug prophylaxis: aprepitant 40 mg orally preoperatively, dexamethasone 4 to 8 mg intravenous (IV) prior to surgical incision, ondansetron 4 mg IV at the end of surgery. We administer amisulpride 10 mg IV as needed in the recovery room. These and other options for prophylaxis and treatment for PONV are discussed separately. (See "Postoperative nausea and vomiting".)

Venous access — We place two large bore (14 or 16 gauge) intravenous catheters. A central venous catheter (CVC) may be placed for patients with poor peripheral access, or for central administration of vasoactive drugs. We do not place CVCs for monitoring purposes, as central venous pressure (CVP) is an inaccurate surrogate for cardiac preload, and is a poor predictor of fluid responsiveness. In addition, patient positioning and infusion of the HIPEC solution make the CVP reading unreliable, as it is not reflective of preload in the setting of increased abdominal pressure. (See "Intraoperative fluid management", section on 'Traditional static parameters'.)

Monitoring — In addition to standard anesthesia physiologic monitors (ie, electrocardiogram, noninvasive blood pressure, pulse oximetry, end tidal carbon dioxide, core temperature), we place an arterial catheter for continuous blood pressure monitoring and access for blood sampling. We also place a urinary catheter to monitor urine output. We place additional cardiac monitors (eg, transesophageal echocardiography, pulmonary artery catheter) as indicated by patient factors.

We use a dynamic monitor of fluid responsiveness (ie, Flotrac or Lidco device) to help guide fluid therapy (see 'Restrictive fluid therapy' below). Use of these devices and their limitations are discussed separately. (See "Intraoperative fluid management", section on 'Dynamic parameters to assess volume responsiveness'.)

Induction of anesthesia — Induction and airway management techniques should be based on patient factors as they would be for any general anesthetic (see "Induction of general anesthesia: Overview"). Rapid sequence induction and intubation may be indicated for patients with large volume ascites, to minimize the risk of aspiration during induction.

Maintenance of anesthesia

Choice of maintenance technique — We base the choice of anesthetic agents for maintenance of anesthesia on patient factors, as we would be for any major abdominal surgery. There is no clear advantage of the use of inhalation anesthetics versus total intravenous anesthesia (TIVA) [67].  

We routinely place an epidural preoperatively for postoperative pain management. The decision to activate the epidural during surgery should be individualized, based on patient and surgical factors. Use of the epidural during surgery may reduce the need for other anesthetics, including intraoperative opioids. However, some clinicians may wait to activate the epidural until after HIPEC is complete. The rationale for waiting is to avoid complicating blood pressure support in the setting of restrictive fluid therapy, vasodilation due to hyperthermia, and possible significant blood loss, with the sympathectomy and vasodilation that result from the epidural [49,62]. (See 'Physiologic effects of HIPEC' above.)

There is intense interest in the possibility that anesthetic agents may affect cancer recurrence. However, there is insufficient evidence to suggest using or avoiding specific anesthetic agents to reduce the risk of recurrence. This is discussed in detail separately. (See "Anesthesia and cancer recurrence".)

Fluid management

Restrictive fluid therapy — We suggest using restrictive or goal directed fluid therapy rather than a liberal fluid administration strategy for CRS with HIPEC, to minimize complications related to fluid overload. We use goal directed fluid therapy based on stroke volume variation (SVV).

●We typically administer a Normosol crystalloid solution (our institution's preferred crystalloid), for maintenance IV fluid therapy at 4 mL/kg/hour.

●We aim for urine output between 0.5 and 1 mL/kg/hour during cytoreduction and 4 mL/kg/hour during HIPEC. (See 'Goal urine output' below.)

●If SVV exceeds 10 percent or urine output decreases to <0.5 mL/kg/hour, we administer a 250 mL bolus of albumin, up to a maximum of 1.5 L, and further boluses of Normosol 4 mL/kg as necessary thereafter.

●If the patient remains hypotensive and SVV and urine output thresholds have been reached, we start a vasopressor. Ongoing bleeding as a source of hypotension should be investigated, and laboratory studies used to determine whether blood product transfusions are needed.

Others use a bolus SVV threshold as high as 15 percent for goal directed therapy for HIPEC [41], while still others use restrictive fluid therapy without the use of dynamic parameters [42].

Restrictive or goal directed versus liberal fluid therapy — Early protocols for CRS with HIPEC included liberal fluid administration, particularly during HIPEC, to counteract fluid, blood, and protein loss, and to minimize the nephrotoxic effects of chemotherapy agents. However, practice has shifted towards more restrictive fluid therapy for all major abdominal procedures, including CRS with HIPEC. A number of institutional protocols include restrictive or goal directed fluid therapy, with low complication rates and low morbidity and low or no mortality [40-44].

Liberal perioperative fluid management for major abdominal surgery of other types has been associated with a higher incidence of perioperative morbidity, and possibly mortality, than restrictive or goal directed fluid therapy. This is discussed in detail separately. (See "Intraoperative fluid management", section on 'Major invasive surgery'.)

Similarly, liberal fluid administration during CRS with HIPEC has been associated with increased perioperative pulmonary and cardiac morbidity [41,43]. Examples of studies of this issue include the following:

●In a randomized trial of goal directed versus standard fluid therapy for 80 patients who underwent CRS with HIPEC, the incidence of major abdominal complications was lower (10.5 versus 38 percent) and the hospital length of stay shorter (19 versus 29 days) in the group who received goal directed therapy (GDT) [41]. Mortality was similar between groups. For standard fluid therapy, patients received crystalloid at a basal rate of 4 to 10 mL/kg/hour with the option to bolus colloid for low CVP, low mean arterial pressure, or a decline in urine output. For GDT, patients received crystalloid at 4 mL/kg/hour and colloid boluses in response to changes in dynamic indices (ie, cardiac index [CI], SVV, stroke volume index [SVI]) from the FloTrac/Vigileo system. All patients in both groups received one unit of fresh frozen plasma (FFP) every 15 minutes during HIPEC (total six units). Conclusions from this study are limited by the routine administration of FFP, the small sample size, and high length of hospital stay.

●In a single institution retrospective database study of 133 patients who underwent CRS with HIPEC with mitomycin or platinum based chemotherapy, administration of >15.7 mL/kg/hour was associated with a higher comprehensive complication index compared with patients who received less than this amount of fluid (31.5 versus 22) [43]. The comprehensive complication index uses a formula to combine perioperative complications and severity into a continuous variable with a range of 0 to 100.

●In a single institution retrospective review of 169 CRS with HIPEC cases (90 percent with mitomycin) before and after an institutional change from permissive (liberal) to restrictive fluid therapy, restrictive fluid therapy was associated with decreased 60 day complications and reduced hospital length of stay [42]. The rate of renal failure and peak creatinine were similar between groups. Permissive fluid therapy consisted of approximately 1000 mL/hour IV fluid. Restrictive fluid therapy consisted of approximately 500 mL/hour IV fluid, with more liberal use of vasopressors for blood pressure support.

Vasopressors — Vasopressors are commonly used during anesthesia to counteract the vasodilatory effects of anesthetics and are often required during HIPEC to reverse the fall in systemic vascular resistance that accompanies hyperthermia. The requirement for vasopressor support of blood pressure often extends into the postoperative period. (See 'Postoperative care' below.)

Goal urine output — We aim for urine output of ≥0.5 mL/kg/hour throughout CRS, and 4 mL/kg/hour during HIPEC infusion and perform laboratory studies every 30 minutes during HIPEC to monitor for and correct electrolyte abnormalities.

Urine output may trend down as a result of a nephrotoxic chemotherapy drug (ie, cisplatin), or reduced renal perfusion related to increased intra-abdominal pressure. Cisplatin has been associated in some studies with increased AKI. Other risk factors for AKI after CRS with HIPEC include pre-existing comorbidities, longer surgery time, increased blood loss, and pre-surgical exposure to nephrotoxic chemotherapy [41]. (See "Cisplatin nephrotoxicity", section on 'Prevention of nephrotoxicity'.)

●Some institutional protocols include a higher goal urine output and increased fluid administration during HIPEC with nephrotoxic chemotherapy agents [68].

●We do not routinely administer low dose dopamine to increase renal perfusion, as dopamine has not been shown to reduce renal insult during HIPEC [69,70].

●We do not routinely administer furosemide to increase urine output during HIPEC, though others do, particularly for platinum based chemotherapy agents [23,71]. The rationale for this practice is to enhance clearance of the chemotherapy, though a beneficial effect has not been shown. Importantly, fluid administration should be increased to maintain euvolemia and renal perfusion if diuretics are administered.

●Saline induced diuresis with magnesium and potassium supplementation are routinely used during systemic chemotherapy with cisplatin. Magnesium supplementation is used in some centers during HIPEC with cisplatin as well, though magnesium supplementation during HIPEC has not been well studied. (See "Cisplatin nephrotoxicity", section on 'Intravenous saline'.)

Blood products and coagulation — Blood loss may be substantial during cytoreductive surgery, and transfusion is often necessary. We use a hemoglobin transfusion threshold of 8 g/dL.

Antifibrinolytics (eg, tranexamic acid [TXA], epsilon aminocaproic acid) are increasingly used routinely for high blood loss surgery (eg, cardiac surgery, orthopedic and spine surgery). There is little literature on the use of TXA during CRS with HIPEC, and further study is required before recommending routine use. A small single institution study compared blood product usage and coagulation parameters before and after institution of a protocol for CRS with HIPEC including two doses of TXA and administration of cryoprecipitate early in blood loss [72]. The new protocol was associated with reduced transfusion of red blood cells (4.2 versus 1.8 units), fresh frozen plasma, and platelets.

Dilutional coagulopathy and coagulopathy related to hypothermia are possible during CRS (see "Perioperative temperature management", section on 'Coagulopathy'). Hyperthermia can also cause abnormal coagulation [73], though ex vivo data suggests that clinical impairment of coagulation is unlikely at the core temperatures that are maintained during HIPEC [74]. We send blood studies for hemoglobin, platelets, fibrinogen, and coagulation parameters as necessary based on blood loss, and correct abnormalities. We use thromboelastography to help diagnose coagulopathy.

Temperature management — We aim for normothermia throughout CRS and HIPEC, using warming measures during CRS (eg, fluid warmer, forced warm air blanket) and cooling techniques during HIPEC. We monitor core temperature continuously with a nasopharyngeal or esophageal temperature probe.

Patients are at high risk of hypothermia during CRS, due to the effects of anesthesia, wide abdominal exposure, and anesthetic-induced impaired thermoregulation. Effects of hypothermia and preventive/management measures are discussed separately. (See "Perioperative temperature management".)

We discontinue warming devices 15 to 30 minutes prior to HIPEC. During perfusion, we keep the core temperature below 39°C. During the infusion we set the forced air blanket to ambient or cool temperature, administer room temperature intravenous fluid, and reduce the operating room temperature to 64°F. If necessary, cooling blankets can be used, or ice packs applied to the neck and groin. If these measures fail, then the temperature of the hyperthermic instillate should be decreased [23,75]. In one study, 18 percent of patients had an increase in core temperature to >39° despite intensive cooling measures including ice packs under the axillae, at the sides of the neck, and the groin [23]. We continue cooling measures until the patient’s temperature drops to approximately 37°C.

Core body temperature can rise to 40.5°C during HIPEC. Maximum temperature is typically reached 60 minutes after initiation of HIPEC infusion and remains elevated throughout HIPEC infusion. Once HIPEC is discontinued, temperature usually normalizes within 30 minutes, but can remain elevated to 38°C well into the postoperative course.

In a single institution retrospective review of 24 CRS with HIPEC procedures, the difference in temperature between baseline and the peak during HIPEC was associated with the need for >24 hours of postoperative ventilation and increased intensive care unit (ICU) length of stay [21]. However, conclusions from this small study are limited by its retrospective methodology; other interrelated factors were also associated with longer ICU stay (ie, higher peritoneal cancer index, longer duration of surgery, higher blood loss, higher intraoperative fluid requirement, and lower mean arterial pressure).

Electrolyte and acid base balance — We check blood gases and electrolytes as necessary during CRS, and every 30 minutes during HIPEC and during the two hours after infusion is complete.

Electrolyte abnormalities commonly occur as chemotherapy is infused during HIPEC, often associated with combined respiratory and metabolic acidosis [24,76]. The metabolic acidosis is multifactorial.

●Hyperthermia generated in the peritoneal cavity leads to massive fluids shifts and electrolyte disturbances.

●Hyperthermia induced vasodilation and systemic hypotension lead to increased lactic acid production.

●Lysis of tumor cells releases organic acids.

Respiratory acidosis occurs during the HIPEC phase, related to decreased gas exchange due to increased intra-abdominal pressure, increased airway pressure and decreased functional residual capacity. This resolves in the post-HIPEC phase and most patients are able to be extubated at the end of surgery [23].

[77-79].

Infusion of dextrose containing carrier solutions can cause hyperglycemia and hyponatremia [16] (see 'Physiologic effects of HIPEC' above). Intravenous insulin infusion is usually required to correct hyperglycemia (see "Perioperative management of blood glucose in adults with diabetes mellitus", section on 'Long and complex procedures'). Hypomagnesemia, hypokalemia, and hypocalcemia also commonly occur.

Emergence and extubation — Most patients can be extubated at the end of the procedure, before transfer to the ICU or post-anesthesia care unit (PACU).

POSTOPERATIVE CARE — In our experience, most patients can recover from anesthesia in the post-anesthesia care unit (PACU) and are discharged to the hospital floor. The decision to transfer the patient to the intensive care unit (ICU) is individualized, and is often related to comorbidities. Patients may require intensive care after surgery, for hemodynamic support, fluid and electrolyte management, and if necessary ventilatory support. Length of ICU stay in contemporary studies is typically 24 to 48 hours [43,80]. Considerations during the immediate postoperative period include:

●Hemodynamic support – We continue goal directed therapy in the postoperative period, adding vasopressors as necessary to maintain hemodynamic stability. We aim for urine output of >0.5 mL/hour. In a single center retrospective review of the intensive care of 69 patients who underwent cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC), 26 percent of patients required norepinephrine for a mean duration of approximately 14 hours [81].

●Electrolyte abnormalities – Postoperative electrolyte disturbances are common, related to large intraoperative fluid shifts, intravenous fluids administered, and absorption of carrier solutions used for HIPEC. Hyperglycemia after administration of dextrose containing carriers can be ongoing into the postoperative period.

●Renal dysfunction – Renal dysfunction is usually transient, occurs in up to 20 percent of patients after HIPEC, and is more common with platinum based chemotherapy [52].

●Coagulopathy – Alterations in coagulation parameters and platelet counts are relatively common after HIPEC with CRS and may affect the timing of removal of the epidural catheter. Etiology of coagulopathy in this setting is likely multifactorial, including dilution related to blood loss, effects of chemotherapy, and perhaps other factors. In one retrospective review of 170 patients who underwent CRS with HIPEC, coagulopathy (defined as platelet count <100, international normalized ratio [INR] ≥1.5) occurred in 38 percent of patients, and was severe (ie, platelet count <50, INR ≥2) in 4.7 percent, with return to normal by postoperative day 6 [82].

●Postoperative respiratory care – Whereas early studies reported a high incidence of delayed extubation, current practice in most reports is to extubate most patients at the end of surgery [41,44,80]. Epidural analgesia rather than systemic opioids, and restrictive or goal directed fluid therapy may facilitate early extubation [59,83].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ovarian, fallopian tube, and peritoneal cancer" and "Society guideline links: Peritoneal mesothelioma" and "Society guideline links: Enhanced recovery after surgery".)

SUMMARY AND RECOMMENDATIONS

●Cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC) procedure

•CRS with HIPEC is a major abdominal procedure, associated with significant fluid shifts, thermal stress, the deleterious effects of chemotherapeutic agents, and electrolyte and acid base disturbances. (See 'Introduction' above.)

•Cytoreduction is performed first, followed by intraperitoneal infusion of chemotherapy solution heated to 40 to 41.5°C. The cytotoxic benefit derives from the high local concentration of chemotherapy, enhanced by the effects of heat. (See 'Hyperthermic intraperitoneal chemotherapy' above.)

●Preoperative evaluation – Preoperative evaluation is similar to evaluation for any patient who undergoes a high-risk procedure, including assessment of functional status and comorbidities. Risk factors for perioperative morbidity and mortality after HIPEC include poor performance status, older age, smoking history, cardiovascular disease, and diabetes. (See 'Preoperative evaluation' above.)

●Anesthetic management – Our protocol for anesthetic management for CRS with HIPEC is shown in a table (table 4). (See 'Anesthetic management' above.)

•We suggest using restrictive or goal directed intravenous (IV) fluid therapy rather than a liberal fluid strategy for CRS with HIPEC, to minimize complications related to fluid overload (Grade 2C). We use goal directed fluid therapy based on stroke volume variation, with crystalloid for maintenance fluid, and boluses of colloid for stroke volume variation >10 percent.  

•We aim for a urine output of ≥0.5 mL/kg/hour during CRS and 4 mL/kg/hour during HIPEC. (See 'Goal urine output' above.)

•Blood loss can be substantial during CRS. Coagulopathy can occur due to hypothermia or hemodilution during CRS. (See 'Blood products and coagulation' above.)

•We aim for normothermia throughout CRS and HIPEC, using warming measures during CRS and cooling techniques during HIPEC. During HIPEC we aim for a core temperature <39°C. (See 'Temperature management' above.)

•We check blood gases and electrolytes as necessary during CRS, and every 30 minutes during HIPEC and during the two hours after infusion is complete. (See 'Electrolyte and acid base balance' above.)

●Emergence and postoperative care – We extubate most patients at the end of the procedure and transfer to the intensive care unit. (See 'Emergence and extubation' above and 'Postoperative care' above.)