Ann Surg Oncol (2012) 19:4244–4251 DOI 10.1245/s10434-012-2496-y

ORIGINAL ARTICLE – GASTROINTESTINAL ONCOLOGY

Perioperative Management of Patients Undergoing Cytoreductive Surgery Combined with Heated Intraperitoneal Chemotherapy for Peritoneal Surface Malignancy: A Multi-Institutional Experience John C. Bell, FRCA, FFICM, Barnaby G. Rylah, FRCA, MRCP, Robert W. Chambers, FRCA, Helen Peet, FRCA, MRCP, Faheez Mohamed, MD, FRCS, and Brendan J. Moran, MCH, FRCS National Centre for Pseudomyxoma Surgery, Basingstoke and North Hampshire Hospitals NHS Foundation Trust, Basingstoke, UK

ABSTRACT Background. Cytoreductive surgery (CRS) combined with heated intraperitoneal chemotherapy (HIPEC) is an established treatment for patients with pseudomyxoma peritonei. There is now increasing evidence for the use of CRS and HIPEC in the treatment of other peritoneal surface malignancies. There is currently no consensus on the perioperative management of this patient group. Methods. An international survey of practice was conducted using an online survey tool. Centers were identified from the list of delegates attending the Seventh International Workshop on Peritoneal Surface malignancy held in Uppsala, Sweden, in September 2010. Results. Fully completed surveys were received from 29 of 41 identified centers (71 %). The survey covers the combined experience amassed by anesthesiologists caring for 8,467 patients undergoing cytoreductive surgery. Intraoperative fluid management, management of coagulopathy, management of the HIPEC phase of the operation, and postoperative analgesia caused the greatest difficulties for the anesthesia team with variation in management identified between different institutions. The incidence of

Electronic supplementary material The online version of this article (doi:10.1245/s10434-012-2496-y) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2012 First Received: 6 February 2012; Published Online: 18 July 2012 J. C. Bell, FRCA, FFICM e-mail: [email protected]

epidural abscess in this patient group was found to be 1:2,139. Conclusions. Optimal preoperative, intraoperative, and postoperative care is crucial to diminish the complications in this complex treatment strategy. Multicenter collaboration is suggested to gain evidence on the best strategies for perioperative management. Further data collection needs to be undertaken to assess the safety of epidural anesthesia in this patient group.

Cytoreductive surgery (CRS) combined with heated intraperitoneal chemotherapy (HIPEC) is now an established treatment for patients with pseudomyxoma peritonei.1,2 In addition, increasing evidence supports the benefits in the treatment of selected patients with peritoneal carcinomatosis of colorectal and ovarian origin and in peritoneal mesothelioma.3,4 This will necessitate an increase in both the number of procedures performed in established centers and the number of centers offering this type of surgery. Cytoreductive surgery is a complex intervention with the potential for significant morbidity and mortality. The ‘‘global learning curve’’ has provided the opportunity for emerging and less experienced centers to optimize their treatment strategies for peritoneal malignancy with acceptable morbidity and mortality.5–8 There are major difficulties in establishing evidence on best practice for rare cancers, and randomized controlled trials are either impractical or cannot address important issues.9,10 As the number of centers performing CRS and HIPEC increases, it is important to reach a consensus regarding optimal perioperative care. The small, or relatively small, number of cases performed by individual

Management of Patients Undergoing CRS and HIPEC

centers poses difficulties in demonstrating procedural safety and efficacy. A multi-institutional survey was conducted (registry was established) to identify current approaches to the perioperative management of patients undergoing CRS and HIPEC. The purpose was to highlight challenges in the anesthetic management of this patient group and to provide some guidelines for centers setting up a CRS and HIPEC service. PATIENTS AND METHODS Worldwide centers conducting CRS combined with HIPEC were contacted, based on a mailing list of attendees at the Seventh International Workshop on Peritoneal Surface malignancy held in Uppsala, Sweden, in September 2010. Additional centers were sought and identified using web and literature searches. Each center was asked to identify an anesthesiologist regularly involved in the perioperative management of patients undergoing CRS and HIPEC. The anesthesiologist was then invited to complete an online survey covering the perioperative management of patients at their institution. The survey was conducted using the online survey service provided by SurveyMonkey. The local research ethics committee considered this study to be a service evaluation and so deemed that no ethical approval was required. In total, 152 surgeons who attended the Seventh International Workshop on Peritoneal Surface Malignancy were contacted. Surgeons from 41 centers replied confirming that they performed CRS and provided contact details for their lead anesthesiologist. Many of the surgeons approached had yet to commence a CRS service. Fully completed survey responses were received from anesthesiologists in 29 centers (29 of 41, 71 %). These responses included 8 centers in the United States, 18 centers in Europe, 1 center in Argentina, 1 in South Korea, and 1 in Australia (Table 1). The data in the survey covers the combined experience amassed by anesthesiologists caring for 8,467 patients undergoing CRS.

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patient age over 70, and 1 center using 80 years as the upper limit above which surgery was not considered. Other reported exclusion criteria included ASA grade 4 or greater, significant cardiac or pulmonary disease, and preoperative renal impairment Preoperative Testing Preoperative testing was normally organized on an individual patient basis; however, some centers routinely organized specific preoperative tests for their patients. All centers used laboratory blood tests, a routine electrocardiogram (ECG) in 27 of 29 centers (93 %) and an echocardiogram in 7 of 29 centers (24 %). Pulmonary function tests (PFTs) were routine in 8 of 29 centers (28 %). Anesthetic Setup

RESULTS

The anesthetic setup for patients undergoing CRS combined with HIPEC was similar to the setup for patients having a major laparotomy for colorectal surgery. All patients were intubated and ventilated throughout with vascular access by large bore peripheral cannulae. All centers used arterial lines for intraoperative blood pressure measurement and blood sampling. Central venous lines for all patients were used in 26 of 29 centers (90 %), and 13 of 29 (45 %) used some form of cardiac output monitoring to guide perioperative fluid management. Intraoperative transesophageal echocardiography was used routinely in 2 of 29 centers (7 %). Various methods were used to monitor cardiac output intraoperatively. Of the centers regularly using cardiac output monitoring 15 of 29 (52 %) used some form of pulse contour analysis (e.g., Lidco, Picco, or Vigileo), 5 of 29 (17 %) used esophageal Doppler, 5 of 29 (17 %) used pulmonary artery catheters, and the remainder used transesophageal echocardiography. Thoracic epidurals were commonly cited for use both intraoperatively and in the management of postoperative pain. Of the 29 centers, 21 (72 %) regularly used epidural anesthesia.

Patient Selection

Fluid Management

Patients were selected for CRS and HIPEC by the surgical team in most centers. Anesthetic involvement in the assessment of fitness for surgery occurred in only 6 of 29 centers (21 %). Most centers had no specific exclusion criteria, but assessed patients on an individual basis. Exclusion criteria existed in 7 of 29 centers (24 %) with 3 centers using

Central venous pressure and cardiac output monitoring were used in 19 of 29 centers (66 %) and 16 of 29 centers (55 %), respectively. Trigger levels for blood transfusion were used in 18 of 29 centers (62 %), varying from less than 4 g/dL to greater than 10 g/dL with the majority opting for 7–8 g/dL. Human albumin solution was part of the fluid regime in 16 of 29 centers (55 %).

4246 TABLE 1 Centers and cases

J. C. Bell et al.

Country

Years of experience

Annual case load

Total case load

Anesthetists

Surgeons

Belgium

10

60

500

3

2

Denmark

4

40

Unknown

3

2

Finland

3

25

43

2

3

France

15

50

700

10

3

10

100

750

7

3

7

15

100

3

2

5

25

100

5

3

Europe

Germany Italy Netherlands

10

50

600

5

6

15

40

407

2

3

15

70

1,000

8

3

3

45

120

6

2

4

50

Unknown

?

?

Spain

1

12

12

4

2

Sweden Switzerland

7 2

80 25

468 50

6 3

1 3

Turkey

14

20

200

3

3

UK

8

50

300

6

4

14

90

620

3

3

4

10

50

3

5

Americas Argentina United States

15

80

400

12

4

10

30

500

50

3 6

20

60

350

10–15

6

130

500

2

2

1

10

10

4

2

5

50

200

6

2

1

22

22

8

1

5

40

170

6

1

7 2

25 12

100 15

1 3

1 2

Rest of the world South Korea Australia Total

Management of Coagulopathy In 27 of 29 centers (93 %), management of coagulopathy was guided by standard laboratory testing, such as APTT, PT, or INR. In some centers, coagulation parameters were tested in the operating suite. The techniques included bedside thromboelastography (TEG or ROTEM) in 6 of 29 centers (21 %) and bedside activated coagulation time (ACT testing) in 1 center. The median interval for coagulation testing was once every 2–4 h. In 18 of 29 centers (62 %), preemptive treatment was given before coagulopathy developed. Routine fresh frozen plasma (FFP) prior to the development of a coagulopathy was administered in 14 of 29 centers (48 %), while in 4 of 29 (14 %) tranexamic acid was used. In established

8,467

coagulopathy, FFP was the first-line treatment in 26 of 29 centers (90 %). A small number of centers used coagulation factor concentrates, or cryoprecipitate as first-line treatment. Management of HIPEC Phase Temperature Management Intraoperatively, 23 of 29 centers (79 %) used forced air warmers and 12 of 29 centers (41 %) used a warming mattress. Most centers also actively warmed all infused fluids. All centers monitored the patients’ temperature intraoperatively. Most commonly this was achieved with esophageal temperature probes (25 of 29 centers), although vesical (2 of 29), tympanic (1 of 29), and rectal probes (1 of 29) were also used. Of the 29 centers, 18 (62 %) actively cooled patients during HIPEC.

Management of Patients Undergoing CRS and HIPEC

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Techniques used included forced air blowers on cool/ ambient settings, ice packs, or cooling mattresses. All centers allowed an increase in core temperature with a mean accepted core temperature of 39.2 °C (range 36–41 °C). Of the 29 centers, 22 (76 %) rarely, or never, had to reduce the temperature of HIPEC to control core temperature.

Staffing

Renal Protection In total, 18 of 29 centers (62 %) used some technique to avoid nephrotoxicity intraoperatively. While the majority of centers advocated aggressive fluid management as the most important factor, 8 of 29 (28 %) used a dose of loop diuretic (furosemide) during the HIPEC phase to increase urinary output, 5 of 29 (17 %) used mannitol, and 6 of 29 (21 %) used a dopamine infusion. Of the 29 centers, 12 (41 %) reported renal dysfunction with an incidence ranging between 1 and 10 %.

DISCUSSION

Postoperative Management All centers transferred all, or a proportion, of patients to a critical care unit (CCU) in the immediate postoperative period (mean 93 %, range 20–100 %). A mean of 42 % (range 0–100 %) of patients were extubated at the end of surgery prior to transfer to CCU. Of those patients transferred to CCU intubated, the mean duration of ventilation was 9 h (range 2–24 h). The mean overall duration of time spent in the CCU was 2.4 days (range 1–5 days). Pain Control Most centers used a combination of epidural anesthesia and patient controlled systemic analgesics (PCAs). Of the 29 centers, 21 (72 %) used epidurals routinely for postoperative analgesia, with 20 of 29 (69 %) using opiatebased PCAs often supplemented by the addition of regular paracetamol and/or other adjunctive analgesic agents. No epidural hematomas were reported in 4,277 patients. Epidural abscesses were reported in 3 patients. In 1 patient the abscess formed following the insertion of a second epidural at reoperation 1 week after initial surgery following a complicated postoperative period. If this patient is excluded, the incidence of epidural abscess for primary epidural insertion is 1:2,139 (2 of 4,277 epidurals). Epidural catheters were left in place for a mean of 4.8 days (range 2–8 days). Despite the use of epidurals and PCAs, only 8 of 29 centers (28 %) reported postoperative pain control as excellent. Common problems reported included difficulty in providing adequate analgesia to both the thoracic and pelvic regions, and the high incidence of hallucinations.

The mean duration of surgery was 8.8 h (range 4–12 h). Most centers did not change anesthetic staff during a case. In 21 of 29 (72 %) the lead member of the anesthetic team was present from the beginning of the case up until transfer to the Critical Care Unit.

Cytoreductive surgery combined with HIPEC is a major surgical procedure that is being used increasingly frequently in the treatment of peritoneal malignancy. The perioperative management of this patient group is complex and challenging. Currently, little has been published on the anesthetic management of these patients, and many questions remain unanswered. As with other major surgical procedures, one would expect the perioperative management to have an impact on postoperative morbidity and mortality. Assessment of Volume Status Optimizing organ perfusion and reducing morbidity through adequate fluid therapy is a significant challenge during CRS with HIPEC. Inadequate fluid therapy leading to hypovolemia results in impaired perfusion of major organs (kidneys, gastrointestinal tract, and skin) with subsequent postoperative morbidity.11 Ascitic drainage, prolonged surgery, exposed raw viscera combined with the cardiovascular effects of HIPEC result in large fluid requirements, often greater than 12 mL/kg per hour.12 Morbidity with CRS is high (up to 56 %), and strategies to avoid perioperative hypovolemia are essential to minimize complications.13 Central venous pressure measurements were used in the majority of centers despite being a poor guide to volemic status and an inaccurate predictor of response to fluid resuscitation.14,15 Prescriptive strategies using liberal and restrictive fluid regimes have both demonstrated improved outcome in major bowel surgery, suggesting that the ideal regime may have to be tailored on an individual patient basis.16–18 Using hemodynamic variables such as stroke volume variation and cardiac output to assess patient’s response to fluid allows an individualized prescription aimed at optimizing oxygen delivery. When compared with prescriptive strategies this ‘‘goal directed therapy’’ has been shown to reduce morbidity and hospital stay when used in abdominal, cardiac and orthopedic surgery.19–23 Recent consensus guidelines on intravenous fluid therapy for adult surgical patients recommended the use of flow guided fluid therapy.24 In our unit, this is achieved using LIDCO rapid (LiDCO Ltd, Cambridge, UK) where fluid

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therapy is titrated to stoke volume variation, which has been shown to predict fluid responsiveness in mechanically ventilated patients undergoing general anesthesia.25 Blood loss during CRS is often substantial with around half of patients requiring blood transfusion intraoperatively.26 As indicated in many replies the trigger to transfuse will depend on many factors including patient comorbidity. The popularity of the 7–8 g/dL range probably results from extrapolation from the transfusion requirements in a critical care study, which showed a reduction in 30-day mortality in young, less severely unwell adults when a restrictive (less than 7.0 g/dL) trigger was used.25 Hypoalbuminemia due to a combination of ascitic drainage, debulking surgery, and increased capillary leakage is common with mean levels falling from 42.6 to 15.7 g/L during CRS reported in 1 retrospective review.26 While hypoalbuminemia is a predictor of increased morbidity in surgical and critically ill patients, the use of albumin in this setting is still debated.27 Following on from an earlier meta-analysis suggesting increased harm from the use of albumin, the saline versus albumin fluid evaluation study (SAFE) showed albumin was as safe as saline when used for resuscitation.28 When used to correct hypoalbuminemia, some studies show improved organ function and others either no benefit or reduced survival.29,30 Further research is needed to assess if giving albumin to patients having CRS improves organ function. Coagulation Patients undergoing CRS, combined with HIPEC, will usually develop deranged hemostasis and coagulation, and unless this is monitored closely, and treated aggressively, it can have a significant impact on intraoperative blood loss and ongoing postoperative coagulopathy. The cause of this coagulopathy remains poorly understood. Large fluid shifts, high protein losses, a tumor burden effect, and the hyperthermic chemotherapy may be contributory. Fibrinogen, APTT, and INR are most commonly deranged, and further abnormalities in other unmeasured factors are likely.26,31 The early activation of protein C and factor X is a recognized problem in the coagulopathy of trauma, even without massive hemorrhage, and this may be a contributory factor during CRS.32 Dynamic, point-of-care testing of clot formation such as TEG and platelet function analysis would allow goaldirected therapy in the intraoperative and immediate postoperative phase. Hemodynamic Effects of HIPEC The major advantage of HIPEC is regional dose intensity.33 Following intracavitary drug administration, the peritoneal cavity is exposed to higher concentrations than the rest of the body. The concentration differential arises because drug

J. C. Bell et al.

movement from peritoneal cavity to plasma (peritoneal clearance) is generally slow relative to the body drug clearance. The penetration of intraperitoneal chemotherapy into peritoneal carcinomatosis nodules is limited to between 2 and 5 mm, even when combined with heat.34–36 HIPEC can either be administered using an open abdomen technique (coliseum), or a closed abdominal technique with variation in physiology as outlined later. Even before the administration of HIPEC, the large surface area exposed, and the use of high-powered diathermy can result in large fluid shifts. This creates significant fluid requirements intraoperatively and a need for accurate intravascular volume control before HIPEC. A large number of cardiovascular physiological parameters change during HIPEC, although not to statistically significant degrees in published studies.37,38 Increasing heart rate raises cardiac output by up to 18 % with increasing temperature with a corresponding change in cardiac index. Aortic peak velocity (representing contractility) measured with Doppler techniques also increases during HIPEC with an increase in stroke volume and flow time. As the patient’s temperature increases, there is a reduction in systemic vascular resistance, which continues throughout the period of HIPEC. Lowest systemic vascular resistance correlates with the greatest cardiac output.39 Differences in hemodynamic variables depend on how intraperitoneal chemotherapy is administered. The closed technique initially causes an increase in intra-abdominal pressure and afterload as the chemotherapeutic perfusate is added, resulting in an initial fall in cardiac output/index. These changes are short-lived and hemodynamic parameters are similar overall for both closed and open abdomen HIPEC techniques. With the large fluid shifts precipitated by surgery and the additive effect of low serum albumin concentrations, intravenous fluid replacement commonly requires in excess of 10 L intraoperatively. Cardiac output monitoring is recommended as an aid to management to help avoid noncardiogenic pulmonary edema.31 Electrolyte Imbalances and Renal Function During the intraoperative period, a number of electrolyte abnormalities can develop from the physiological insult of surgery, chemotherapy, and elevated temperature during HIPEC. When 5 % dextrose is used as the intraperitoneal chemotherapy carrier solution, significant hyperglycemia necessitating insulin therapy can ensue. Dilutional hyponatremia may develop as absorption of water across the remaining peritoneum can be significant. Mortality associated with cerebral edema has been reported.40 Lactic acidosis develops frequently. Hyperglycemia in association with lactic acidosis may lead to an accelerated diuresis secondary to osmosis, exacerbating any preexisting hyponatremia.41

Management of Patients Undergoing CRS and HIPEC

The incidence of renal dysfunction postoperatively has been reported to be as high as 5 % and has been linked to nephrotoxicity of chemotherapy used for HIPEC.42 The majority of reports of renal injury have been with the use of cisplatinum for HIPEC. The optimal dose of this anticancer drug for HIPEC is still unknown and should be defined in a phase I–II study. Many centers use diuretics or a dopamine infusion during HIPEC to minimize renal dysfunction, although there is no published evidence to support this practice.

4249 TABLE 2 Recommendations for perioperative care Preoperative

Patient selection Anesthesiology input into patient selection, assessment of fitness for surgery, and listing

Intraoperative Monitoring/fluid administration Arterial line with continuous invasive blood pressure monitoring Central venous line with continuous CVP monitoring Cardiac output monitoring to optimize fluid administration Management of coagulopathy

Epidural Analgesia The extent of CRS can make adequate postoperative pain control challenging. Patients often have stripping of diaphragmatic peritoneum with insertion of chest drains as well as extensive pelvic dissection requiring analgesia from approximately T4 down to low lumbar or sacral nerve roots. Controversy exists regarding the safety of epidural analgesia in this patient group.43,44 The high incidence of perioperative coagulopathy may increase the incidence of epidural hematomas and make timing of safe removal of the catheter problematic. There were no reports of epidural hematomas in our study, but the epidural site abscess rate of 1:2,139 was much higher than the 1:47,000 reported in a large national study.45 HIPEC may increase the risk of epidural site abscesses through some form of immunosuppression.

Preemptive treatment with FFP or cryoprecipitate in patients having major cytoreductive procedures

Staffing and Fatigue The mean operating time at our center is 10.5 h.46 This does not include the anesthetic setup time or the time required to transfer the patient to the critical care unit postoperatively. It is not uncommon for the total procedure time (anesthetic plus surgical time) to exceed 15 h so that safe, alert staffing levels are critical. In Europe the maximum working shift as guided by the European Working Time Directive is 13 h, so anesthetizing for these cases will frequently lead to a breach of that directive.47 Research into fatigue in anesthetists focuses on the impact of night shifts rather than long day shifts.48,49 There is inherent risk in the handing over of patients from 1 anesthetic team to another during a major operation. The question of whether the presence of 1 lead anesthetist throughout such a lengthy case is safer than handing over of care between anesthetic teams needs to be addressed. Our approach has been to involve a second senior trainee for both educational and service support roles in these cases. In conclusion, the relatively low number of cases being undertaken in most individual centers, combined with the variation in extent of disease at the time of presentation, means that research into management of these cases is best conducted in a multicenter setting. Our experience in Basingstoke (JB, FM, and BJM) has developed over the last 20 years with our most recently published results

Staffing

Frequent bedside/laboratory testing of coagulation (approximately once every 2 h intraoperatively) Active management of evolving coagulopathy aiming for normal laboratory coagulation results Management of HIPEC phase—special considerations Temperature control with ambient room temperature air via forced air unit/cooling unit Reduction in temperature of intraperitoneal chemotherapy fluid if the patient’s core temperature exceeds 39 °C Optimization of intravascular volume and hemodynamics with fluids and inotropes/ vasopressors to minimize risk of renal injury Close monitoring of electrolytes, especially if dextrose is being used as the chemotherapy carrier solution Staffing should be adequate to allow staff to have rest breaks. Comprehensive midcase patient handover if necessary Postoperative Critical care Postoperative critical care bed should be available Decision regarding the suitability for early extubation should be taken on an individual patient basis Analgesia Epidural and/or patient-controlled analgesia as dictated by local protocols and patient specific factors Frequent assessment of patients with epidural catheters with high index of suspicion for epidural abscess/hematoma

demonstrating an in-hospital mortality of 1.6 % and morbidity of 7 % for 456 patients who underwent CRS.50 In light of the data from this cumulative experience of a large number of centers conducting this type of surgery we make the following recommendations for optimizing outcomes in patients undergoing CRS and HIPEC (Table 2). All centers who took part in this study will be included in a new register of anesthetists involved in cytoreductive surgery to optimize the perioperative care of patients undergoing these complex procedures.

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Management of Patients Undergoing CRS and HIPEC

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