Advertisement

Guidelines for Perioperative Care in Cytoreductive Surgery (CRS) with or without hyperthermic IntraPEritoneal chemotherapy (HIPEC): Enhanced recovery after surgery (ERAS®) Society Recommendations — Part I: Preoperative and intraoperative management

Open AccessPublished:August 24, 2020DOI:https://doi.org/10.1016/j.ejso.2020.07.041

      Abstract

      Background

      Enhanced recovery after surgery (ERAS) pathways have been shown to considerably reduce complications, length of stay and costs after most of surgical procedures by standardised application of best evidence-based perioperative care. The aim was to elaborate dedicated recommendations for cytoreductive surgery (CRS) ± hyperthermic intraperitoneal chemotherapy (HIPEC) in a two-part series of guidelines based on expert consensus. The present part I of the guidelines highlights preoperative and intraoperative management.

      Methods

      The core group assembled a multidisciplinary panel of 24 experts involved in peritoneal surface malignancy surgery representing the fields of general surgery (n = 12), gynaecological surgery (n = 6), and anaesthesia (n = 6). Experts systematically reviewed and summarized the available evidence on 72 identified perioperative care items, following the GRADE (grading of recommendations, assessment, development, evaluation) system. Final consensus (defined as ≥50%, or ≥70% of weak/strong recommendations combined) was reached by a standardised 2-round Delphi process, regarding the strength of recommendations.

      Results

      Response rates were 100% for both Delphi rounds. Quality of evidence was evaluated high, moderate low and very low, for 15 (21%), 26 (36%), 29 (40%) and 2 items, respectively. Consensus was reached for 71/72(98.6%) items. Strong recommendations were defined for 37 items, No consensus could be reached regarding the preemptive use of fresh frozen plasma.

      Conclusion

      The present ERAS recommendations for CRS±HIPEC are based on a standardised expert consensus process providing clinicians with valuable guidance. There is an urgent need to produce high quality studies for CRS±HIPEC and to prospectively evaluate recommendations in clinical practice.

      Keywords

      Abbreviations:

      ERAS (Enhanced recovery after surgery), CRS (Cytoreductive surgery), HIPEC (Hyperthermic intraperitoneal chemotherapy), GRADE (Grading of recommendations, assessment, development and evaluation), PICO (Population, Intervention, Comparator and Outcome)

      Introduction

      Enhanced recovery after surgery (ERAS) pathways aim to standardise and optimise perioperative care, and hence, modulate an exaggerated postoperative metabolic and inflammatory response that is linked with adverse outcomes after major surgery [
      • Ljungqvist O.
      • Scott M.
      • Fearon K.C.
      Enhanced recovery after surgery: a review.
      ]. The utilization of ERAS pathways combined with high degree of compliance has been shown to considerably decrease complications, length of hospital stay and costs. First demonstrated in colonic resection, ERAS protocols have since been applied to multiple types of digestive and other major surgical procedures with similar reproducible benefits [
      • Group E.C.
      The impact of enhanced recovery protocol compliance on elective colorectal cancer resection: results from an international registry.
      ,
      • Wijk L.
      • Udumyan R.
      • Pache B.
      • et al.
      International validation of Enhanced Recovery after Surgery Society guidelines on enhanced recovery for gynecologic surgery.
      ]. Due to increasing demand, dedicated ERAS guidelines have been issued and updated for multiple surgical subspecialties [
      • Gustafsson U.O.
      • Scott M.J.
      • Hubner M.
      • et al.
      Guidelines for perioperative care in elective colorectal surgery: enhanced recovery after surgery (ERAS((R))) society recommendations: 2018.
      ,
      • Nelson G.
      • Bakkum-Gamez J.
      • Kalogera E.
      • et al.
      Guidelines for perioperative care in gynecologic/oncology: enhanced Recovery after Surgery (ERAS) Society recommendations-2019 update.
      ,
      • Melloul E.
      • Hubner M.
      • Scott M.
      • et al.
      Guidelines for perioperative care for liver surgery: enhanced recovery after surgery (ERAS) society recommendations.
      ] and recommendations have been recently published to standardise and optimise the process and methodology of guideline development [
      • Brindle M.
      • Nelson G.
      • Lobo D.N.
      • Ljungqvist O.
      • Gustafsson U.O.
      Recommendations from the ERAS(R) Society for standards for the development of enhanced recovery after surgery guidelines.
      ].
      Cytoreductive surgery with or without the addition of hyperthermic intraperitoneal chemotherapy (CRS±HIPEC) has become a treatment standard for various subsets of peritoneal surface malignancies [
      • van Driel W.J.
      • Koole S.N.
      • Sikorska K.
      • et al.
      Hyperthermic intraperitoneal chemotherapy in ovarian cancer.
      ]. These extended procedures may cause excessive tissue trauma with subsequent inflammation that ultimately lead to potentially life-threatening side effects. Major complication rates have been reported to be as high as 51% [
      • Alyami M.
      • Kim B.J.
      • Villeneuve L.
      • et al.
      Ninety-day post-operative morbidity and mortality using the National Cancer Institute’s common terminology criteria for adverse events better describe post-operative outcome after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
      ], and advanced resuscitation and dedicated care protocols are warranted. Early reversal of this pathophysiological cascade by improvements of perioperative care is intriguing and forms the basis of ERAS interventions. Changing historical perioperative practice related to complex procedures, however, may involve risk especially when evidence is limited.
      The aim of this multidisciplinary effort was to develop ERAS guidelines for CRS±HIPEC by structured review of the most recent evidence and by use of a standardised Delphi approach and GRADE system for the definition of the quality of evidence and the strength of recommendations. A two-part series of guidelines was created based on the consensus of an expert panel. The present part I of the guidelines highlights preoperative and intraoperative management. Part II expands upon postoperative management and special considerations.

      Methods

      The process for ERAS guidelines for CRS±HIPEC was initiated in May 2019 but was planned in line with the recommendations for ERAS guidelines published in late 2019. The following briefly summarises the essential components, which are consistent with the standardised process for ERAS Guidelines [
      • Brindle M.
      • Nelson G.
      • Lobo D.N.
      • Ljungqvist O.
      • Gustafsson U.O.
      Recommendations from the ERAS(R) Society for standards for the development of enhanced recovery after surgery guidelines.
      ]:

      Forming the guideline core group, definition of timeline

      The 5 members of the core group (MH, SK, LV, JV, GN) were selected for having at least 2 of the following qualifications: being clinical specialists in the field of CRS±HIPEC (n = 5), ERAS experts (n = 3) or for their expertise/track record in guideline development (n = 4). A detailed timeline was elaborated to achieve completion of the guidelines within a 12-month period of time.

      Defining topics, items and delphi questions

      The core group defined the topics and identified individual items reflecting the essentials for pre-, intra- and postoperative care for CRS±HIPEC. This list included traditional ERAS items from previous relevant guidelines for other surgical procedures but also procedure-specific topics, which were added by the core group (Table 1). Finally, clinical questions were formulated for every perioperative care item: 21 for 9 topics in the preoperative phase, 23 for 8 topics in the intraoperative phase and 28 for 11 topics in the postoperative phase (overall 28 topics and 72 individual items).
      Table 1List of ERAS care items: Pre- and intraoperative.
      I Preoperative phaseII Intraoperative phase
      1. Preadmission information, education and counselling10. Antimicrobial prophylaxis and skin preparation
      2. Preoperative optimisation: alcohol, smoking, anemia A Preoperative antimicrobial prophylaxis
       A Intensive alcohol cessation program B Skin preparation by chlorhexidine
       B Intensive behavioral intervention for smokers C Additional SSI prevention measures
       C Preoperative anemia screening and treatment D Postoperative antibiotic prophylaxis
      3. Physical exercise/prehabilitation11. Standard anaesthetic protocol
      4. Nutritional care: Screening, supplementation (oral, enteral, parenteral), immunonutrition A Rapid sequence intubation
       A Preoperative nutritional screening B Epidural analgesia
       B Nutritional/Protein supplementation C Multimodal analgesia
       C Oral immunonutrition D Protective mechanical ventilation
      5. Preoperative anaesthetic assessment E Cardiac output monitoring
       A Assessment of cardiac risk F Use of neuromuscular antagonists
       B Screening for obstructive sleep apnea12. Intraoperative normothermia
       C Complete laboratory testing A Prevention of hypothermia
       D Frailty screening B Prevention of hyperthermia
      6. Post-Operative Nausea and Vomiting (PONV)13. Intraoperative normoglycemia
       A Use of antiemetic drugs14. Perioperative fluid management
       B Total-intravenous anaesthesia A Advanced monitoring to guide fluid therapy and catecholamines
      7. Pre-anaesthetic medication B Use of crystalloids
       A Preoperative multimodal analgesia C Limiting postoperative fluid-related weight gain
       B Preoperative use of sedative/anxiolytics15. Transfusion and management of coagulopathy
      8. Preoperative bowel preparation A Restrictive Blood transfusion policy
       A CRS and HIPEC including probable colectomy B Preemptive use of Fresh Frozen Plasma (FFP)
       B CRS and HIPEC including probable rectal resection C Tranexamic acid (TXA)
       C Oral antibiotic decontamination D Prothrombin Complex Concentrate (PCC)
      9. Preoperative fasting and carbohydrate treatment16. Abdominal and thoracic drains
       A Short preoperative fasting A Abdominal drains
       B Carbohydrate loading B Thoracic drains
      17. Early extubation

      Assembling expert panel

      Prominent active clinicians who are experts in the fields of general or gastrointestinal (GI) surgery (n = 12), gynaecologic oncology (n = 6) or anaesthesiology (m = 6) and who are also experts in peritoneal surface malignancies were invited to contribute to this guideline process and join the expert panel. Choice of experts was also guided by the endeavor to represent different countries/continents and garner well-balanced participation of different professionals, with female representation, from diverse disciplines.

      Systematic review and grading of the evidence

      Each expert was asked to work with another expert on 2–3 items. The goal was to systematically review and succinctly summarise the evidence for the different items related to each topic. Each item served as the basis to frame the clinical question using the PICO (population, intervention, comparator, outcome) framework. These questions successively were submitted to the expert panel to evaluate using the Delphi technique. The two experts assigned to each topic were asked in addition to apply the GRADE (grading of recommendations, assessment, development, evaluation) system (i) to assess the quality of underlying evidence (very low, low, moderate, high) and (ii) to propose the strength of recommendation (weak, strong). The evidence was carefully established after a systematic discussion involving the experts and members of the core group. The level of evidence was modulated according to risk of bias, imprecision, inconsistency, indirectness, and publication bias. Of note, level of evidence was not successively submitted to the panelists for voting due to its objective nature.
      Text and references for each topic were then scrutinised independently by three members of the core group in order to verify content and references, to avoid redundancy and enhance consistency between the sections, and to edit the chapter in a uniform format according to the predefined requirements.
      The final version for the manuscript was modified and approved together with the two experts for each section.

      Obtaining consensus by 2-round delphi process

      Text sections were presented to the entire expert panel (n = 24) together with interactive links to key references in the form of an online survey (SurveyMonkey Inc., San Mateo, CA). Each section ended with one or several closed-end questions to suggest a recommendation for a given care item on a two-sided scale (strong positive, weak positive, weak negative, strong negative). Results of the 1st Delphi round were provided to the expert panel for the 2nd round. Three weeks were given for completion of each round and every participant received at least three reminders.
      Consensus was defined as ≥50% of agreement for any of the four mentioned responses, or 2) those items in which 70% panelists voted on weak or strong recommendations, regardless of the direction (negative or positive).

      Statistics and presentation of results

      Descriptive statistics were used to summarise the results of the expert consensus. Figure presentation was preferred to allow for succinct and transparent presentation of the recommendations.

      Results

      Response rates for both Delphi rounds were 100%. Consensus was reached for 65 out of 72 care items in the 1st round (90.3%) and for 71 out of 72 care items in the 2nd round (98.6%). The clinical care items for pre-, intra- and postoperative phases are presented together with the experts’ voting in Fig. 1A–C.
      Fig. 1
      Fig. 1Experts′ voting for perioperative care items and clinical questions.
      Fig. 1
      Fig. 1Experts′ voting for perioperative care items and clinical questions.
      The available evidence for all 72 care items was systematically searched, discussed and presented to all panelists. Quality of evidence was estimated to be high, moderate, low and very low respectively, for 15, 26, 29, and 2 items. Specific evidence for the field of CRS±HIPEC was scarce or nonexistent for most clinical questions. In other words, indirectness was present in great majority of items (64/72) and downgraded the evidence in 37 out of 64 items.
      The following paragraphs summarise the resulting recommendations together with degree of consensus and grading of evidence. In summary, over half of recommendations (n = 37) were strong positive, while the remainder were either weak positive (n = 23) or weak negative (n = 11). There was no strong negative recommendation. Consensus was not reached in only one item after two Delphi rounds, specifically the preemptive use of fresh frozen plasma (low quality of evidence). While high quality of evidence resulted mostly (14/15) in strong recommendations, weak recommendations prevailed for items with moderate (15/26), low (17/29), and very low (1/2) quality of evidence. The panelists consensually delivered strong positive recommendations, even if the evidence was low, in 12 items. On the other hand, the recommendation was weak positive despite high evidence in 1 item (Table 2).
      Table 2Strength of recommendations according to the level of evidence (Grade system).
      Level of evidenceTotal
      Strength of recommendationHighModerateLowVery low
      Strong positive141112037
      Weak positive11011123
      Weak negative056112
      Strong negative00000
      Total152629272
      The following section details the explicit recommendations for preoperative and intraoperative care items along with grade of evidence and strength of consensus (% of expert votes) (Table 3).
      Table 3Preoperative and Intraoperative ERAS Recommendations for Cytoreductive Surgery (CRS) with or without Hyperthermic IntraPEritoneal Chemotherapy (HIPEC): Pre- and intraoperative items.
      ItemRecommendationEvidence LevelRecommendation Strength
      Preoperative phase
      Preoperative information educationand counsellingPreoperative counselling should be indicated routinelyLowStrong positive
      Preoperative optimisationSmoking and alcohol cessation (alcohol abusers)four weeks before surgery should be indicated routinelyModerate by indirectnessStrong positive
      Anemia identification and correction preoperatively should be indicated routinelyLow by indirectnessStrong positive
      Physical exercise/prehabilitationPrehab programme of physical exercise should be indicated routinelyModerate by indirectnessStrong positive
      Nutritional screening,supplementationPreop nutritional screening using a validated tool and measuring serum albumin should be indicated routinelLow by indirectnessStrong positive
      Nutritional and protein supplementation in cases of severe malnutrition should be indicated routinelyModerate by indirectnessStrong positive
      Oral immunonutrition could be indicatedModerate by indirectnessWeak positive
      Preoperative anaesthetic assessmentPreoperative anaesthetic assessment (including cardiac risk, obstructive sleep apnea and frailty screening)High despite indirectnessStrong positive
      PONV preventionAt least 2 antiemetic drugs should be indicated routinely to prevent PONVModerate by indirectnessStrong positive
      TIVA could be indicated to prevent PONVModerate by indirectnessWeak positive
      Pre-anaesthetic medicationPreoperative multimodal analgesia (including celecoxib, pregabalin, and tramadol) could be indicated

      Long-acting sedatives/anxiolytics to decrease anxiety preoperatively should not be indicated
      Low for CRS±HIPECWeak positive
      Low for CRS±HIPECWeak negative
      Preoperative bowel preparationMBP alone for patients undergoing CRS±HIPEC including probable colectomy should not be indicatedModerate by indirectnessWeak negative
      MBP alone for patients undergoing CRS±HIPEC including probable rectal resection could be indicatedModerate by indirectnessWeak positive
      In patients undergoing CRS±HIPEC, oral antibiotic decontamination with or without preoperative MBP could be indicatedModerate by indirectnessWeak positive
      Preoperative fasting and carbohydrate treatmentPreoperative fasting of 6 h for solids and 2 h for liquids should be indicated routinelyHigh despite indirectnessStrong positive
      Carbohydrate loading until 2 h before induction of anaesthesia could be indicatedModerate despite indirectnessWeak positive
      Intraoperative phase
      Antimicrobial prophylaxis and skin preparationProphylactic antibiotics within 1 h before incision should be indicated routinelyHigh despite indirectnessStrong positive
      Chlorhexidine-alcohol as skin disinfectant should be indicated routinelyHigh despite indirectnessStrong positive
      Antiseptic shower, shaving and adhesive drapes could be indicatedModerate by indirectnessWeak positive
      Antibiotic prophylaxis during the postoperative period should not be indicatedLow by indirectnessWeak positive
      Standard anaesthetic protocolCricoid pressure during rapid sequence intubation could be indicatedHigh despite indirectnessWeak positive
      Epidural analgesia should be indicated routinelyHigh despite indirectnessStrong positive
      Multimodal analgesia with one or several agents could be indicated routinelyModerate despite indirectnessWeak positive
      Protective ventilation should be indicated routinelyHigh despite indirectnessStrong positive
      Cardiac output monitoring should be indicated routinelyHigh despite indirectnessStrong positive
      Deep neuromuscular block and reversal by specific antagonists could be indicatedLow by indirectnessWeak positive
      Intraoperative normothermiaPrevention of intraoperative hypothermia by use of active warming devices should be indicated routinelyHigh despite indirectnessStrong positive
      Prevention of intraoperative hyperthermia by active measures could be performedLowWeak positive
      Intraoperative normoglycaemiaDiabetes screening and intraoperative glycaemic control should be indicated routinelyModerate despite indirectnessStrong positive
      Perioperative fluid managementUse of GDFT and catecholamines guided by advanced/invasive monitoring should be indicated routinelyHigh despite indirectnessStrong positive
      Substitution of losses (fluids and protein) by use of crystalloids could be indicatedModerate despite indirectnessWeak positive
      Limiting postop fluid-related weight gain is advisedModerate despite indirectnessWeak positive
      Transfusion and management of coagulopathyRestrictive transfusion should be performed routinelyModerate by indirectnessStrong positive
      Preemptive use of fresh frozen plasmaLow by indirectnessNo consensus
      TXA alone or with cryoprecipitate could be administeredModerate by indirectnessWeak negative
      Prothrombin complex concentrate could be administeredModerate by indirectnessWeak negative
      Abdominal and thoracic drainsProphylactic abdominal drains postop could be indicatedLow for CRS±HIPECWeak positive
      Prophylactic thoracostomy after CRS±HIPEC with diaphragmatic peritonectomy could be indicatedLowWeak positive
      Early extubationEarly extubation should be done routinelyLow by indirectnessStrong positive

      Preoperative phase

      Preadmission information, education and counselling

      Cytoreductive surgery with or without HIPEC (CRS±HIPEC) is one of the most complex, high-risk, abdominal surgeries offered for patients with advanced cancer. Decision-making around whether to proceed with CRS±HIPEC is often challenging for both patients and providers. Despite low quality of evidence, ERAS protocols for major cancer and/or abdominal surgeries have strongly recommended pre-operative counselling as a means to decrease anxiety, improve pain control and increase patient satisfaction [
      • Gustafsson U.O.
      • Scott M.J.
      • Hubner M.
      • et al.
      Guidelines for perioperative care in elective colorectal surgery: enhanced recovery after surgery (ERAS((R))) society recommendations: 2018.
      ,
      • Melloul E.
      • Hubner M.
      • Scott M.
      • et al.
      Guidelines for perioperative care for liver surgery: enhanced recovery after surgery (ERAS) society recommendations.
      ,
      • Lassen K.
      • Coolsen M.M.
      • Slim K.
      • et al.
      Guidelines for perioperative care for pancreaticoduodenectomy: enhanced recovery after surgery (ERAS(R)) society recommendations.
      ,
      • Mortensen K.
      • Nilsson M.
      • Slim K.
      • et al.
      Consensus guidelines for enhanced recovery after gastrectomy: enhanced Recovery after Surgery (ERAS(R)) Society recommendations.
      ]. A recent review has suggested that psychological prehabilitation prior to cancer surgery has the potential to improve patient-reported outcome measures, such as quality of life, somatic symptoms and psychological outcomes [
      • Tsimopoulou I.
      • Pasquali S.
      • Howard R.
      • et al.
      Psychological prehabilitation before cancer surgery: a systematic review.
      ].
      While the optimal form of preoperative counselling for CRS±HIPEC has not been determined, a recent study showed that patients preparing for CRS±HIPEC overwhelmingly requested audiovisual or mixed-type educational information, related to preoperative decision-making and the recovery process, as opposed to just written materials. The study also found that including caregivers as key members of the recovery process within the preoperative counselling programme is essential [
      • Francescutti V.A.
      • Maciver A.H.
      • Stewart E.
      • et al.
      Characterizing the patient experience of CS/HIPEC through in-depth interviews with patients: identification of key concepts in the development of a patient-centered program.
      ].
      Summary and recommendation: Before CRS±HIPEC, preoperative counselling, ideally by mixed-type educational information should be indicated routinely to improve quality of life, somatic symptoms and psychological outcomes.
      Evidence level: Low.
      Recommendation strength: Strong positive (95.8% agreement, consensus reached)

      Preoperative optimisation: alcohol, smoking and anaemia

      Moderate to heavy consumption of alcohol is associated with weakening of the immune system, cardiovascular events, infections, bleeding complications and impaired recovery as well as alcohol withdrawal in the postoperative period. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) in the United States defines a "standard drink" as 14 gm of ethanol (5 ounces of wine, 12 ounces of 5% alcohol beer, of 1.5 ounces of 80 proof spirit). "At-risk" or "heavy drinking" is defined as 4 drinks on any day or 14 per week for men and 3 drinks on any day or 7 per week for women. In a meta-analysis, patients who were high alcohol consumers (defined as 36 gm/day for men and 24 gm/day for women based on Danish guidelines for sensible drinking) were at increased risk for postoperative morbidity, general infections, wound complications, pulmonary complications, prolonged hospital length of stay, and admission to the intensive care unit [
      • Gronkjaer M.
      • Eliasen M.
      • Skov-Ettrup L.S.
      • et al.
      Preoperative smoking status and postoperative complications: a systematic review and meta-analysis.
      ]. A Cochrane Review assessed the evidence of 3 randomised controlled trials (RTCs) examining the effects of alcohol cessation interventions on postoperative complications in patients who were "risky drinkers." "Risky" alcohol consumption was defined as 3 alcoholic units (3 small glasses of wine) per day or 21 units per week. This systematic review found a decrease in occurrences of postoperative complications in the groups offered intensive alcohol cessation intervention for 4–8 weeks prior to orthopedic and colorectal surgery [
      • Egholm J.W.
      • Pedersen B.
      • Moller A.M.
      • Adami J.
      • Juhl C.B.
      • Tonnesen H.
      Perioperative alcohol cessation intervention for postoperative complications.
      ].
      Cigarette smoking is a risk factor for cardiovascular disease, neurologic disease, pulmonary disease, and cancer. Smoking is associated with increased morbidity, including wound complications, infections, pulmonary complications and admission to the intensive care unit [
      • Tonnesen H.
      • Nielsen P.R.
      • Lauritzen J.B.
      • Moller A.M.
      Smoking and alcohol intervention before surgery: evidence for best practice.
      ]. Cessation of smoking has been associated with risk reduction of pulmonary, cardiovascular and wound-related complications [
      • Warner D.O.
      Preoperative smoking cessation: the role of the primary care provider.
      ]. Optimal timing for smoking cessation is unknown, but most studies demonstrate that patients should be advised to stop smoking as soon as possible, with no harm noted for short duration abstinence, and that longer periods of cessation are associated with decreased complications [
      • Myers K.
      • Hajek P.
      • Hinds C.
      • McRobbie H.
      Stopping smoking shortly before surgery and postoperative complications: a systematic review and meta-analysis.
      ].
      Behavioural support and nicotine replacement therapy are mainstays of smoking cessation interventions. One meta-analysis concluded that the treatment effect of 4 weeks of smoking cessation had significantly larger treatment effect than shorter trials [
      • Mills E.
      • Eyawo O.
      • Lockhart I.
      • Kelly S.
      • Wu P.
      • Ebbert J.O.
      Smoking cessation reduces postoperative complications: a systematic review and meta-analysis.
      ]. Another meta-analysis concluded that cessation at 8 weeks was associated with even fewer respiratory complications than cessation at or less than 4 weeks. At least 4 weeks of abstinence was required to demonstrate reduction in respiratory complications, and at least 3–4 weeks was required for reduction in wound-healing complications. A Cochrane Review demonstrated that preoperative smoking interventions may reduce postoperative complications and that interventions beginning at 4–8 weeks prior to surgery that include weekly counselling and nicotine replacement therapy are more likely to impact postoperative complications and have a long-term effect on abstinence [
      • Thomsen T.
      • Villebro N.
      • Moller A.M.
      Interventions for preoperative smoking cessation.
      ].
      Alcohol and smoking cessation can be combined in a comprehensive multimodal prehabilitation programme designed to improve functional capacity and reduce postoperative complications, which may also include exercise, nutritional counselling, and anxiety reduction [
      • Iqbal U.
      • Green J.B.
      • Patel S.
      • et al.
      Preoperative patient preparation in enhanced recovery pathways.
      ,
      • Li C.
      • Carli F.
      • Lee L.
      • et al.
      Impact of a trimodal prehabilitation program on functional recovery after colorectal cancer surgery: a pilot study.
      ]. Prehabilitation is discussed elsewhere in this article.
      Anaemia is a common finding in up to 1/3 of preoperative patients and may be due to a variety of causes (iron, folate or vitamin B12 deficiency or chronic renal insufficiency) [
      • Shander A.
      • Knight K.
      • Thurer R.
      • Adamson J.
      • Spence R.
      Prevalence and outcomes of anemia in surgery: a systematic review of the literature.
      ]. The World Health Organization defines anaemia as haemoglobin 12 gm/dL for women and 13 gm/dL for men. Preoperative anaemia is associated with adverse outcomes in non-cardiac surgery, including cardiac events and death [
      • Wu W.C.
      • Schifftner T.L.
      • Henderson W.G.
      • et al.
      Preoperative hematocrit levels and postoperative outcomes in older patients undergoing noncardiac surgery.
      ,
      • Carson J.L.
      • Duff A.
      • Poses R.M.
      • et al.
      Effect of anaemia and cardiovascular disease on surgical mortality and morbidity.
      ,
      • Musallam K.M.
      • Tamim H.M.
      • Richards T.
      • et al.
      Preoperative anaemia and postoperative outcomes in non-cardiac surgery: a retrospective cohort study.
      ]. Appropriate correction of preoperative anaemia is contingent upon identifying its aetiology and the interval of time before the intended surgical procedure. Once anaemia is identified by complete blood count, additional labs may be considered: iron studies (ferritin, iron, total iron-binding capacity, transferrin saturation), B12, folate, reticulocyte count, glomerular filtration rate (on a basic metabolic panel). Patients should be screened for anaemia at least 30 days prior to surgery to allow enough time for intervention [
      • Goodnough L.T.
      • Shander A.
      Patient blood management.
      ]. Oral or intravenous iron should be considered for iron deficiency anaemia [
      • Froessler B.
      • Palm P.
      • Weber I.
      • Hodyl N.A.
      • Singh R.
      • Murphy E.M.
      The important role for intravenous iron in perioperative patient blood management in major abdominal surgery: a randomized controlled trial.
      ]; haemoglobin may improve by 0.5–1 gm/dL per week. In addition, referral to a gastroenterologist may be considered to rule out a source of occult malignancy unrelated to the indication for cytoreductive surgery. A low folate or vitamin B12 level is an indication for supplementation. Recombinant human erythropoietin may be considered in impaired erythropoiesis but carries the risk of perioperative thrombotic events. Rarely is preoperative blood transfusion indicated, except in cases of haemoglobinopathies such as sickle cell disease [
      • Kansagra A.J.
      • Stefan M.S.
      Preoperative anemia: evaluation and treatment.
      ,
      • Burton B.N.
      • A’Court A.M.
      • Brovman E.Y.
      • Scott M.J.
      • Urman R.D.
      • Gabriel R.A.
      Optimizing preoperative anemia to improve patient outcomes.
      ].

      Intensive alcohol cessation programme

      Summary and recommendation: In CRS±HIPEC patients at risk for heavy alcohol consumption, an intensive alcohol cessation programme, including pharmacological intervention ±counselling ±interviews, at least four weeks prior to surgery should be indicated routinely to reduce the risk of surgical complications.
      Evidence level: Moderate by indirectness.
      Recommendation strength: Strong positive (58.3% agreement, consensus reached)

      Intensive behavioural intervention for smokers

      Summary and recommendation: In cigarette smokers who are candidates for CRS±HIPEC, an intensive behavioural intervention associated with nicotine replacement, at least four weeks prior to surgery should be indicated routinely to reduce the risk of surgical complications.
      Evidence level: Moderate by indirectness.
      Recommendation strength: Strong positive (79.2% agreement, consensus reached)

      Preoperative anaemia screening and treatment

      Summary and recommendation: Anaemia screening at least 4 weeks prior to CRS±HIPEC, prompt medical therapy (oral/intravenous iron, folate/vitamin B12 replacement or erythropoietin treatment) and preoperative transfusions for severe refractory situations should be indicated routinely in order to reduce cardiac events and mortality.
      Evidence level: Low by indirectness.
      Recommendation strength: Strong positive (79.2% agreement, consensus reached)

      Physical exercise/prehabilitation

      Prehabilitation is a multimodal programme designed to optimise the state of the patient prior to surgery and focuses on nutrition, exercise, and psychology/anxiety. Several studies in colorectal cancer surgery have shown feasibility and improved outcomes with prehabilitation [
      • van Rooijen S.J.
      • Molenaar C.J.L.
      • Schep G.
      • et al.
      Making patients fit for surgery: introducing a four pillar multimodal prehabilitation program in colorectal cancer.
      ,
      • Trepanier M.
      • Minnella E.M.
      • Paradis T.
      • et al.
      Improved disease-free survival after prehabilitation for colorectal cancer surgery.
      ] however very little information is available in gynaecologic oncology [
      • Schneider S.
      • Armbrust R.
      • Spies C.
      • du Bois A.
      • Sehouli J.
      Prehabilitation programs and ERAS protocols in gynecological oncology: a comprehensive review.
      ].
      Poor preoperative nutrition has been assessed in multiple studies and is associated with impaired postoperative outcomes [
      • Ho J.W.
      • Wu A.H.
      • Lee M.W.
      • et al.
      Malnutrition risk predicts surgical outcomes in patients undergoing gastrointestinal operations: results of a prospective study.
      ,
      • Mignini E.V.
      • Scarpellini E.
      • Rinninella E.
      • et al.
      Impact of patients nutritional status on major surgery outcome.
      ]. A large systematic review of 9 trials with prehabilitation nutrition and exercise showed a reduction of hospital stay by 2 days [
      • Gillis C.
      • Buhler K.
      • Bresee L.
      • et al.
      Effects of nutritional prehabilitation, with and without exercise, on outcomes of patients who undergo colorectal surgery: a systematic review and meta-analysis.
      ].
      An important point of prehabilitation is to improve physical conditioning. Several randomised trials in preoperative exercise have shown improvements in preoperative oxygen uptake, quality of life, aerobic capacity and decreased complications [
      • Dunne D.F.
      • Jack S.
      • Jones R.P.
      • et al.
      Randomized clinical trial of prehabilitation before planned liver resection.
      ,
      • Barberan-Garcia A.
      • Ubre M.
      • Roca J.
      • et al.
      Personalised prehabilitation in high-risk patients undergoing elective major abdominal surgery: a randomized blinded controlled trial.
      ,
      • Gillis C.
      • Li C.
      • Lee L.
      • et al.
      Prehabilitation versus rehabilitation: a randomized control trial in patients undergoing colorectal resection for cancer.
      ]. Recommended tests to determine baseline physical condition include: “Six-minute walk test” with control of cardiac frequency and oxygen saturation and shallow assessment of respiratory status (respiratory pattern, thoracometry, modified MRI and Borg dyspnea scale). Training with an inspirometer to learn the breathing exercises and objectives for the postoperative period has been suggested [
      • Johnson M.J.
      • Close L.
      • Gillon S.C.
      • et al.
      Use of the modified Borg scale and numerical rating scale to measure chronic breathlessness: a pooled data analysis.
      ].
      Psychological support provides the tools to better manage anxiety related to the cancer process and surgery [
      • Devine E.C.
      Effects of psychoeducational care for adult surgical patients: a meta-analysis of 191 studies.
      ]. A large systematic review of 15 randomized trials in non-surgical patients, showed improvement in mild-moderate dementia with cognitive stimulation [
      • Woods B.
      • Aguirre E.
      • Spector A.E.
      • Orrell M.
      Cognitive stimulation to improve cognitive functioning in people with dementia.
      ]. One RCT in gastrointestinal surgery showed a decrease in postoperative cognitive decline with cognitive intervention [
      • Saleh A.J.
      • Tang G.X.
      • Hadi S.M.
      • et al.
      Preoperative cognitive intervention reduces cognitive dysfunction in elderly patients after gastrointestinal surgery: a randomized controlled trial.
      ]. A Cochrane review and meta-analysis have examined interventions for stress reduction and have found that psychological interventions may benefit postoperative pain, behavior, length of stay and poor affect, however the data remains heterogeneous [
      • Tsimopoulou I.
      • Pasquali S.
      • Howard R.
      • et al.
      Psychological prehabilitation before cancer surgery: a systematic review.
      ,
      • Powell R.
      • Scott N.W.
      • Manyande A.
      • et al.
      Psychological preparation and postoperative outcomes for adults undergoing surgery under general anaesthesia.
      ,
      • Freeman S.C.
      • Scott N.W.
      • Powell R.
      • Johnston M.
      • Sutton A.J.
      • Cooper N.J.
      Component network meta-analysis identifies the most effective components of psychological preparation for adults undergoing surgery under general anesthesia.
      ,
      • Treanor C.
      • Kyaw T.
      • Donnelly M.
      An international review and meta-analysis of prehabilitation compared to usual care for cancer patients.
      ].
      Summary and recommendation: In candidates for CRS±HIPEC, a prehabilitation programme of physical exercise, preferably integrated with other interventions (nutritional or anxiety control), should be indicated routinely.
      Evidence level: Moderate by indirectness.
      Recommendation strength: Strong positive (62.5% agreement, consensus reached)

      Nutritional care: screening, supplementation (oral, enteral, parenteral) and immunonutrition

      Preoperative malnutrition has been associated with increased postoperative morbidity and mortality and poor oncological outcomes in patients with gastrointestinal cancers [
      • Correia M.I.
      • Waitzberg D.L.
      The impact of malnutrition on morbidity, mortality, length of hospital stay and costs evaluated through a multivariate model analysis.
      ,
      • Norman K.
      • Pichard C.
      • Lochs H.
      • Pirlich M.
      Prognostic impact of disease-related malnutrition.
      ,
      • Pacelli F.
      • Bossola M.
      • Rosa F.
      • Tortorelli A.P.
      • Papa V.
      • Doglietto G.B.
      Is malnutrition still a risk factor of postoperative complications in gastric cancer surgery?.
      ,
      • Pressoir M.
      • Desne S.
      • Berchery D.
      • et al.
      Prevalence, risk factors and clinical implications of malnutrition in French Comprehensive Cancer Centres.
      ]. Routine preoperative nutritional screening is therefore strongly recommended (European Society for Clinical Nutrition and Metabolism [ESPEN] guidelines GI surgery 2017) [
      • Weimann A.
      • Braga M.
      • Carli F.
      • et al.
      ESPEN guideline: clinical nutrition in surgery.
      ]. Valuable screening tools include the Malnutrition Universal Screening Tool (MUST) [
      • Stratton R.J.
      • Hackston A.
      • Longmore D.
      • et al.
      Malnutrition in hospital outpatients and inpatients: prevalence, concurrent validity and ease of use of the ’malnutrition universal screening tool’ (’MUST’) for adults.
      ], the Nutritional Risk Screening score NRS-2002 [
      • Kondrup J.
      • Rasmussen H.H.
      • Hamberg O.
      • Stanga Z.
      • Ad Hoc E.W.G.
      Nutritional risk screening (NRS 2002): a new method based on an analysis of controlled clinical trials.
      ], the PreOperative Nutrition Score (PONS) [
      • Wischmeyer P.E.
      • Carli F.
      • Evans D.C.
      • et al.
      American society for enhanced recovery and perioperative quality initiative joint consensus statement on nutrition screening and therapy within a surgical enhanced recovery pathway.
      ]. Common criteria of all these tools include low body mass index (BMI <18.5), reduced food intake, older age (>65 or 70, respectively), recent unintentional weight loss (>10% over 3–6 months) and low serum albumin (<30 mg/l).
      Patients with malnutrition or at nutritional risk should document daily intake (diary) and benefit of oral nutritional supplements (≥7 days) containing at least 1.2–2.0 gm protein/kg per day [
      • McClave S.A.
      • Taylor B.E.
      • Martindale R.G.
      • et al.
      Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine (SCCM) and American society for parenteral and enteral nutrition (A.S.P.E.N.).
      ]. Preferentially enteral or parenteral nutrition (in non-functioning GI tract) should be initiated in patients with severe malnutrition or if sufficient oral intake is not achievable [
      • Jie B.
      • Jiang Z.M.
      • Nolan M.T.
      • Zhu S.N.
      • Yu K.
      • Kondrup J.
      Impact of preoperative nutritional support on clinical outcome in abdominal surgical patients at nutritional risk.
      ,
      • Waitzberg D.L.
      • Saito H.
      • Plank L.D.
      • et al.
      Postsurgical infections are reduced with specialized nutrition support.
      ]. Correction of malnutrition requires a minimal treatment of 7–14 days [
      • Weimann A.
      • Braga M.
      • Carli F.
      • et al.
      ESPEN guideline: clinical nutrition in surgery.
      ].
      Goals of preoperative evaluation are to assess the patient’s medical status and ability to tolerate anaesthesia, mitigate the risks of anaesthesia and surgery, and to prepare the patient for the procedure. The perioperative pathophysiological changes associated with CRS±HIPEC can cause major organ dysfunction. It is therefore imperative to perform a detailed and thorough preoperative evaluation as soon as this surgical procedure is considered [
      • De Hert S.
      • Staender S.
      • Fritsch G.
      • et al.
      Pre-operative evaluation of adults undergoing elective noncardiac surgery: updated guideline from the European Society of Anaesthesiology.
      ,
      • Sweitzer B.
      Preanesthesia evaluation for noncardiac surgery.
      ,
      • Schiff J.H.
      • Frankenhauser S.
      • Pritsch M.
      • et al.
      The Anesthesia Preoperative Evaluation Clinic (APEC): a prospective randomized controlled trial assessing impact on consultation time, direct costs, patient education and satisfaction with anesthesia care.
      ].

      Preoperative nutritional screening

      Summary and recommendation: In CRS±HIPEC patients, preoperative nutritional screening by use of a validated tool and by measuring serum albumin should be indicated routinely.
      Evidence level: Low by indirectness.
      Recommendation strength: Strong positive (95.8% agreement, consensus reached)

      Nutritional/protein supplementation

      Summary and recommendation: In patients with malnutrition or at risk for malnutrition, nutritional and protein (>1.2 g/kg/day) supplementation (oral>enteral>parenteral) for at least 5 days and up to 14 days in cases of severe malnutrition should be indicated routinely.
      Evidence level: Moderate by indirectness.
      Recommendation strength: Strong positive (91.7% agreement, consensus reached)

      Oral immunonutrition

      Summary and recommendation: Oral immunonutrition for 5–7 days prior to CRS±HIPEC could be indicated in an attempt to reduce postoperative (infectious) complications.
      Evidence level: Moderate by indirectness.
      Recommendation strength: Weak positive (66.7% agreement, consensus reached)

      Preoperative anaesthetic assessment

      Goals of preoperative evaluation are to assess the patient’s medical status and ability to tolerate anaesthesia, mitigate the risks of anaesthesia and surgery, and to prepare the patient for the procedure. The perioperative pathophysiological changes associated with CRS±HIPEC can cause major organ dysfunction. It is therefore imperative to perform a detailed and thorough preoperative evaluation as soon as this surgical procedure is considered [
      • De Hert S.
      • Staender S.
      • Fritsch G.
      • et al.
      Pre-operative evaluation of adults undergoing elective noncardiac surgery: updated guideline from the European Society of Anaesthesiology.
      ,
      • Sweitzer B.
      Preanesthesia evaluation for noncardiac surgery.
      ,
      • Schiff J.H.
      • Frankenhauser S.
      • Pritsch M.
      • et al.
      The Anesthesia Preoperative Evaluation Clinic (APEC): a prospective randomized controlled trial assessing impact on consultation time, direct costs, patient education and satisfaction with anesthesia care.
      ].
      The Revised Cardiac Risk Index and American College of Surgeons National Surgery Quality Improvement Program (ACS NSQIP) surgical risk calculator (https://riskcalculator.facs.org/RiskCalculator/) are useful for stratification of perioperative cardiac risk and provide a complementary prognostic value that can help clinicians in their decision-making process [
      • De Hert S.
      • Staender S.
      • Fritsch G.
      • et al.
      Pre-operative evaluation of adults undergoing elective noncardiac surgery: updated guideline from the European Society of Anaesthesiology.
      ]. Patients with reduced cardiac reserve and those with a previous history of heart failure or chemotherapy-induced cardiotoxicity may require echocardiogram and stress testing during the preoperative assessment.
      Ascites that is often associated with peritoneal carcinomatosis can result in basal atelectasis which places these patients at risk of perioperative hypoxia. The STOP-BANG (Snoring, Tiredness, Observed apnea, blood Pressure, Body mass index, Age, Neck circumference and Gender) score for obstructive sleep apnea (OSA) should also be calculated to anticipate a need for perioperative respiratory support such as continuous positive airway pressure (CPAP). In patients previously diagnosed with OSA, it is important to document the settings of positive airway pressure device used at home and to use CPAP preoperatively to reduce hypoxic events [
      • De Hert S.
      • Staender S.
      • Fritsch G.
      • et al.
      Pre-operative evaluation of adults undergoing elective noncardiac surgery: updated guideline from the European Society of Anaesthesiology.
      ,
      • Nagappa M.
      • Liao P.
      • Wong J.
      • et al.
      Validation of the STOP-bang questionnaire as a screening tool for obstructive sleep apnea among different populations: a systematic review and meta-analysis.
      ].
      Laboratory tests should include complete blood count, metabolic panel, and coagulation studies. Glomerular filtration rate (GFR) should be calculated as it has been shown to be a sensitive and reliable predictor of in-hospital mortality and morbidity [
      • Cywinski J.B.
      • Mascha E.J.
      • Kurz A.
      • Sessler D.I.
      Estimated glomerular filtration rate better predicts 30-day mortality after non-cardiac surgery than serum creatinine: a retrospective analysis of 92,888 patients.
      ].
      Frailty has been defined as a state of increased vulnerability and poor resolution of homeostasis after physiological stress. Frailty is also associated with worse outcomes after major surgery. The clinical frailty scale (CFS) is a global assessment that uses a nine-level scale that grades the patient’s overall condition from fit to terminally ill [
      • Rockwood K.
      • Song X.
      • MacKnight C.
      • et al.
      A global clinical measure of fitness and frailty in elderly people.
      ]. The CFS has been shown to independently predict readmission, disability, and death [
      • McIsaac D.I.
      • Taljaard M.
      • Bryson G.L.
      • et al.
      Frailty as a predictor of death or new disability after surgery: a prospective cohort study.
      ,
      • Watt J.
      • Tricco A.C.
      • Talbot-Hamon C.
      • et al.
      Identifying older adults at risk of harm following elective surgery: a systematic review and meta-analysis.
      ]. Patients with frailty score greater than 4, unless modifiable, may not be candidates for CRS±HIPEC.
      The Ovarian Consensus Panel considered the following as relative contraindications for CRS±HIPEC: heart failure (94%), pulmonary compromise (94%), previous pulmonary embolus 63%. This is not a definitive list and every case should be individualized [
      • Helm C.W.
      • Bristow R.E.
      • Kusamura S.
      • Baratti D.
      • Deraco M.
      Hyperthermic intraperitoneal chemotherapy with and without cytoreductive surgery for epithelial ovarian cancer.
      ,
      • Goodman M.
      Regional therapeutics for advanced malignancies: jaypee brothers.
      ].

      Assessment of cardiac risk and function

      Summary and recommendation: Preoperative anaesthetic work-up before CRS±HIPEC including assessment of cardiac risk and function should be indicated routinely.
      Evidence level: High despite indirectness.
      Recommendation strength: Strong positive (91.7% agreement, consensus reached)

      Screening for obstructive sleep apnea

      Summary and recommendation: Preoperative anaesthetic work-up before CRS±HIPEC including screening for obstructive sleep apnea should be indicated routinely.
      Evidence level: High despite indirectness.
      Recommendation strength: Strong positive (50.0% agreement, consensus reached)

      Complete laboratory testing

      Summary and recommendation: Preoperative anaesthetic work-up before CRS±HIPEC including complete laboratory testing (complete blood count, metabolic panel, renal function, coagulation tests) should be indicated routinely.
      Evidence level: High despite indirectness.
      Recommendation strength: Strong positive (100.0% agreement, consensus reached)

      Frailty screening

      Summary and recommendation: Preoperative anaesthetic work-up before CRS±HIPEC including frailty screening should be indicated routinely.
      Evidence level: High despite indirectness.
      Recommendation strength: Strong positive (91.7% agreement, consensus reached)

      Post-operative nausea and vomiting (PONV)

      Post-operative nausea and vomiting (PONV) is common after CRS±HIPEC. The aetiology of PONV can be classified into patient factors, anaesthetic factors and surgical factors. While the systemic uptake of chemotherapeutic agent during HIPEC is limited, chemotherapeutic agents often have an emetogenic effect (40–50% of nausea and vomiting) [
      • Escobar Y.
      • Cajaraville G.
      • Virizuela J.A.
      • et al.
      Incidence of chemotherapy-induced nausea and vomiting with moderately emetogenic chemotherapy: ADVICE (Actual Data of Vomiting Incidence by Chemotherapy Evaluation) study.
      ].
      The incidence of PONV is reported to be approximately 25–35% of all surgical patients, but the incidence varies depending on the type of surgery [
      • Apfel C.C.
      • Heidrich F.M.
      • Jukar-Rao S.
      • et al.
      Evidence-based analysis of risk factors for postoperative nausea and vomiting.
      ]. The incidence of PONV can be significantly reduced with a multifactorial, multimodal approach [
      • Dewinter G.
      • Staelens W.
      • Veef E.
      • Teunkens A.
      • Van de Velde M.
      • Rex S.
      Simplified algorithm for the prevention of postoperative nausea and vomiting: a before-and-after study.
      ,
      • Gan T.J.
      • Diemunsch P.
      • Habib A.S.
      • et al.
      Consensus guidelines for the management of postoperative nausea and vomiting.
      ]. Most PONV guidelines advocate risk stratification using well validated PONV scoring systems. These scoring systems classify patients into low, medium and high risk groups and allow individual tailoring of perioperative PONV prophylaxis [
      • Apfel C.C.
      • Laara E.
      • Koivuranta M.
      • Greim C.A.
      • Roewer N.
      A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers.
      ].
      Modifiable factors that are associated with an increased risk of PONV include opiate analgesics, nitrous oxide and inhalational anaesthesia [
      • Apfel C.C.
      • Heidrich F.M.
      • Jukar-Rao S.
      • et al.
      Evidence-based analysis of risk factors for postoperative nausea and vomiting.
      ,
      • Leslie K.
      • Myles P.S.
      • Chan M.T.
      • et al.
      Risk factors for severe postoperative nausea and vomiting in a randomized trial of nitrous oxide-based vs nitrous oxide-free anaesthesia.
      ]. Thoracic epidural or alternative regional anaesthetic technique can significantly reduce the incidence of PONV. The use of total intravenous anaesthesia has been shown to reduce the incidence of PONV in high risk groups when compared with inhalational anaesthesia, although this only seems to be true for the early post-operative phase [
      • Kumar G.
      • Stendall C.
      • Mistry R.
      • Gurusamy K.
      • Walker D.
      A comparison of total intravenous anaesthesia using propofol with sevoflurane or desflurane in ambulatory surgery: systematic review and meta-analysis.
      ].
      Many antiemetic medications are available, targeting different receptors. There is strong evidence confirming an enhanced antiemetic effect with the use of ≥2 anti-emetics with different mechanisms of action [
      • Apfel C.C.
      • Korttila K.
      • Abdalla M.
      • et al.
      A factorial trial of six interventions for the prevention of postoperative nausea and vomiting.
      ]. There is no recognized best combination of specific anti-emetic agents.

      Use of antiemetic drugs

      Summary and recommendation: In CRS±HIPEC candidates, a combination of at least 2 antiemetic drugs (ondansetron, dexamethasone, droperidol), should be indicated routinely to prevent PONV.
      Evidence level: Moderate by directness.
      Recommendation strength: Strong positive (75.0% agreement, consensus reached)

      Total intravenous anaesthesia

      Summary and recommendation: In CRS±HIPEC candidates, total intravenous anaesthesia as an alternative to inhalation anaesthesia, could be indicated to prevent PONV.
      Evidence level: Moderate by directness.
      Recommendation strength: Weak positive (95.8% agreement, consensus reached)

      Pre-anaesthetic medication

      Preoperative medications include multimodal pain medications and anxiolytics. Only one retrospective study has studied use of multimodal analgesia in 373 patients undergoing CRS with a combination of celecoxib 200–400 mg, pregabalin 75 mg and tramadol 100 mg [
      • Cata J.P.
      • Nguyen L.T.
      • Ifeanyi-Pillette I.C.
      • et al.
      An assessment of the survival impact of multimodal anesthesia/analgesia technique in adults undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: a propensity score matched analysis.
      ]. These medications in combination with intraoperative non-opioid analgesia like lidocaine infusions, ketamine and dexmedetomidine, reduced postoperative opioid consumption by almost 90% and length of hospital stay by 4–5 days. Reduced opioid consumption is likely to lead to improved bowel function and motility, leading to reduced length of stay, but was not associated with improved survival rates [
      • Cata J.P.
      • Nguyen L.T.
      • Ifeanyi-Pillette I.C.
      • et al.
      An assessment of the survival impact of multimodal anesthesia/analgesia technique in adults undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: a propensity score matched analysis.
      ].
      Preoperative anxiety may have a huge effect on the patient’s personal experience and postoperative pain [
      • Thompson T.
      • Keogh E.
      • French C.C.
      • Davis R.
      Anxiety sensitivity and pain: generalisability across noxious stimuli.
      ]. Classic preanaesthetic medication with anxiolytics is not encouraged. According to a randomized study, patients undergoing elective surgery under general anaesthesia, sedative premedication with lorazepam compared with placebo or no premedication did not improve the self-reported patient experience the day after surgery, but was associated with prolonged time to extubation and a lower rate of early cognitive recovery [
      • Maurice-Szamburski A.
      • Auquier P.
      • Viarre-Oreal V.
      • et al.
      Effect of sedative premedication on patient experience after general anesthesia: a randomized clinical trial.
      ]. Moreover, in other studies, premedication was associated with delays of oral resumption of liquids eliciting adverse effects in terms of optimal perioperative care [
      • Caumo W.
      • Hidalgo M.P.
      • Schmidt A.P.
      • et al.
      Effect of pre-operative anxiolysis on postoperative pain response in patients undergoing total abdominal hysterectomy.
      ].
      In the operative room, anxiolytics or opioids are often administered to increase patient’s comfort during the performance of venous cannulation or aid performing regional anaesthesia. Long-acting medications should be avoided as they defer postoperative recovery and have been linked to psychomotor disability, reduced mobilisation, and late refeeding. Short-acting drugs such as midazolam (0.04 mg/kg) are a better option. However, even midazolam has shown residual effects during longer evaluation time frames, and clinically, it has been associated to late discharge from the post-anaesthesia care unit and lower scores on psychomotor function, especially in older patients [
      • Vermeeren A.
      Residual effects of hypnotics: epidemiology and clinical implications.
      ,
      • Fredman B.
      • Lahav M.
      • Zohar E.
      • Golod M.
      • Paruta I.
      • Jedeikin R.
      The effect of midazolam premedication on mental and psychomotor recovery in geriatric patients undergoing brief surgical procedures.
      ,
      • Richardson M.G.
      • Wu C.L.
      • Hussain A.
      Midazolam premedication increases sedation but does not prolong discharge times after brief outpatient general anesthesia for laparoscopic tubal sterilization.
      ].

      Preoperative multimodal analgesia

      Summary and recommendation: Preoperative multimodal analgesia including celecoxib 200–400 mg, pregabalin 75 mg and tramadol 100 mg could be indicated to reduce postoperative opioid consumption, resumption of bowel function, and length of stay.
      Evidence level: Low for CRS±HIPEC.
      Recommendation strength: Weak positive (79.2% agreement, consensus reached)

      Preoperative use of sedative/anxiolytics

      Summary and recommendation: Considering the potential postoperative effects in terms of early cognitive recovery, time to extubation, time to discharge from the post anaesthesia care unit, refeeding, and mobilisation, the use of long-acting sedatives/anxiolytics before CRS±HIPEC to decrease anxiety should not be indicated (75.00% weak negative).
      Evidence level: Low for CRS±HIPEC.
      Recommendation strength: Weak negative (75.0% agreement, consensus reached)

      Preoperative bowel preparation

      For many years preoperative mechanical bowel preparation (MBP) was used with the assumption that this intervention decreased rates of infection and anastomotic leaks. Despite the perceived advantage, patients experienced discomfort, dehydration, electrolyte abnormalities and prolonged hospital admissions. Within the patient population undergoing peritoneal stripping and HIPEC, this becomes particularly important given that this group of patients will often have multiple bowel resections, anastomoses and pelvic en-bloc resections.
      Currently, there is a lack of high-level investigations examining bowel preparation within the CRS±HIPEC population, and therefore evidence must be derived from the colorectal literature, which has remained controversial. Multiple studies and meta-analyses have shown that the use of MBP alone is not associated with a decrease in overall mortality, surgical site infection (SSI) rate, anastomotic leak rate or reoperation compared to no MBP [
      • Cao F.
      • Li J.
      • Li F.
      Mechanical bowel preparation for elective colorectal surgery: updated systematic review and meta-analysis.
      ,
      • Dahabreh I.J.
      • Steele D.W.
      • Shah N.
      • Trikalinos T.A.
      Oral mechanical bowel preparation for colorectal surgery: systematic review and meta-analysis.
      ,
      • Pineda C.E.
      • Shelton A.A.
      • Hernandez-Boussard T.
      • Morton J.M.
      • Welton M.L.
      Mechanical bowel preparation in intestinal surgery: a meta-analysis and review of the literature.
      ,
      • Slim K.
      • Vicaut E.
      • Launay-Savary M.V.
      • Contant C.
      • Chipponi J.
      Updated systematic review and meta-analysis of randomized clinical trials on the role of mechanical bowel preparation before colorectal surgery.
      ]. Retrospective studies have re-opened the debate on preoperative use of oral antibiotics (OAB) with a potential decrease in hospital length of stay, SSI and readmissions after colorectal surgery [
      • Toneva G.D.
      • Deierhoi R.J.
      • Morris M.
      • et al.
      Oral antibiotic bowel preparation reduces length of stay and readmissions after colorectal surgery.
      ,
      • Morris M.S.
      • Graham L.A.
      • Chu D.I.
      • Cannon J.A.
      • Hawn M.T.
      Oral antibiotic bowel preparation significantly reduces surgical site infection rates and readmission rates in elective colorectal surgery.
      ]. Several meta-analyses of randomised controlled trials have since examined the role of OAB. Chen et al. [
      • Chen M.
      • Song X.
      • Chen L.Z.
      • Lin Z.D.
      • Zhang X.L.
      Comparing mechanical bowel preparation with both oral and systemic antibiotics versus mechanical bowel preparation and systemic antibiotics alone for the prevention of surgical site infection after elective colorectal surgery: a meta-analysis of randomized controlled clinical trials.
      ] showed that a combination of MBP+OAB was associated with a lower rate of SSI overall (7.2 vs. 16%, P < 0.001) and incisional SSI (4.6% vs. 12.1%, P < 0.001) when compared to MBP with intravenous antibiotics (IVA). Similarly, McSorely et al. [
      • McSorley S.T.
      • Steele C.W.
      • McMahon A.J.
      Meta-analysis of oral antibiotics, in combination with preoperative intravenous antibiotics and mechanical bowel preparation the day before surgery, compared with intravenous antibiotics and mechanical bowel preparation alone to reduce surgical-site infections in elective colorectal surgery.
      ] examined 22 studies with 57207 patients, and found that MBP+OAB+IVA were better than MB+IVA (Or0.45 CI 0.34–0.59). Toh et al. [
      • Toh J.W.T.
      • Phan K.
      • Hitos K.
      • et al.
      Association of mechanical bowel preparation and oral antibiotics before elective colorectal surgery with surgical site infection: a network meta-analysis.
      ] reviewed 38 randomized trials and showed that MBP+OAB had a lower rate of SSI compared to MBP alone (OR 0.7 CI 0.57–0.88); MBP alone was equivalent to no preparation and MBP+OAB was equivalent to OAB alone. The most recent Cochrane review on antibiotic prophylaxis also supports antibiotic use, both OAB and IVA, but finds this may increase the risk of Clostridium difficile [
      • Nelson R.L.
      • Gladman E.
      • Barbateskovic M.
      Antimicrobial prophylaxis for colorectal surgery.
      ]. The American College of Surgeons and Surgical Infection Society recommend using the combination of MBP+OAB [
      • Ban K.A.
      • Minei J.P.
      • Laronga C.
      • et al.
      American college of surgeons and surgical infection society: surgical site infection guidelines, 2016 update.
      ].
      Several retrospective trials have examined OAB versus MBP+OAB. These studies found no difference in outcomes for the two groups with respect to infectious morbidity, anastomotic leak, readmission or hospital stay [
      • Cannon J.A.
      • Altom L.K.
      • Deierhoi R.J.
      • et al.
      Preoperative oral antibiotics reduce surgical site infection following elective colorectal resections.
      ,
      • Garfinkle R.
      • Abou-Khalil J.
      • Morin N.
      • et al.
      Is there a role for oral antibiotic preparation alone before colorectal surgery? ACS-NSQIP analysis by coarsened exact matching.
      ,
      • Koller S.E.
      • Bauer K.W.
      • Egleston B.L.
      • et al.
      Comparative effectiveness and risks of bowel preparation before elective colorectal surgery.
      ]. These studies suggest that OAB is the crucial element in preoperative bowel preparation. This is further supported by the recent publication of the MOBILE (Mechanical and oral antibiotic bowel preparation versus no bowel preparation for elective colectomy) study in 2019, which compared MBP+OAB to no preparation [
      • Koskenvuo L.
      • Lehtonen T.
      • Koskensalo S.
      • et al.
      Mechanical and oral antibiotic bowel preparation versus no bowel preparation for elective colectomy (MOBILE): a multicentre, randomised, parallel, single-blinded trial.
      ]. This multicentre single blind trial showed no difference between SSI, anastomotic dehiscence or reoperation rate between rates. Several current RCTs are registered with clinicaltrials.gov that will be comparing OAB versus MBP+OAB including MECCA (#NCT03563586) and COLONPREP (#NCT03475680).

      For patients undergoing CRS±HIPEC including probable colectomy

      Summary and recommendation: Preoperative mechanical bowel preparation alone for patients undergoing CRS±HIPEC including probable colectomy should not be indicated to reduce the incidence of surgical site infection, and anastomostic leak.
      Evidence level: Moderate by indirectness.
      Recommendation strength: Weak negative (54.2%)

      For patients undergoing CRS±HIPEC including probable rectal resection

      Summary and recommendation: Preoperative mechanical bowel preparation alone for patients undergoing CRS±HIPEC including probable rectal resection could be indicated to reduce the incidence of morbidity and infectious complications.
      Evidence level: Moderate by indirectness.
      Recommendation strength: Weak positive (62.5% agreement, consensus reached)

      Oral antibiotic decontamination

      Summary and recommendation: In patients undergoing CRS±HIPEC, oral antibiotic decontamination with or without preoperative mechanical bowel preparation could be indicated to reduce the incidence of surgical site infection, and anastomotic leak.
      Evidence level: Moderate by indirectness.
      Recommendation strength: Weak positive (79.2% agreement, consensus reached)

      Preoperative fasting and carbohydrate treatment

      Traditionally, long fasting before elective surgery was considered the norm in order to avoid full stomach and thus the risk of pulmonary aspiration [
      • Sarin A.
      • Chen L.L.
      • Wick E.C.
      Enhanced recovery after surgery-Preoperative fasting and glucose loading-A review.
      ]. Ever since, several RCTs have proven that fasting from midnight does not reduce gastric content [
      • Brady M.
      • Kinn S.
      • Stuart P.
      Preoperative fasting for adults to prevent perioperative complications.
      ]. Consecutively, numerous anaesthesia societies recommended to allow a light meal up to 6 h and non-alcoholic clear fluids up to 2 h before surgery [
      Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: application to healthy patients undergoing elective procedures: an updated report by the American society of anesthesiologists task force on preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration.
      ].
      Risk factors for prolonging gastric emptying time for solids are smoking, functional dyspepsia, psychological stress, female hormones [
      • Sarin A.
      • Chen L.L.
      • Wick E.C.
      Enhanced recovery after surgery-Preoperative fasting and glucose loading-A review.
      ,
      • Scott A.M.
      • Kellow J.E.
      • Shuter B.
      • Nolan J.M.
      • Hoschl R.
      • Jones M.P.
      Effects of cigarette smoking on solid and liquid intragastric distribution and gastric emptying.
      ,
      • Hutson W.R.
      • Roehrkasse R.L.
      • Wald A.
      Influence of gender and menopause on gastric emptying and motility.
      ] but not obesity [
      • Maltby J.R.
      • Pytka S.
      • Watson N.C.
      • Cowan R.A.
      • Fick G.H.
      Drinking 300 mL of clear fluid two hours before surgery has no effect on gastric fluid volume and pH in fasting and non-fasting obese patients.
      ]. Some data show that diabetic patients with neuropathy may have delayed gastric emptying for solids but no conclusive data is available concerning fluids [
      • Gustafsson U.O.
      • Nygren J.
      • Thorell A.
      • et al.
      Pre-operative carbohydrate loading may be used in type 2 diabetes patients.
      ]. Patients with peritoneal metastases frequently suffer from abdominal pain, bloating, indigestion, abdominal distention or early satiety, but there is no evidence for longer gastric emptying [
      • Halkia E.
      • Spiliotis J.
      • Sugarbaker P.
      Diagnosis and management of peritoneal metastases from ovarian cancer.
      ,
      • Foster J.M.
      • Sleightholm R.
      • Smith L.
      • et al.
      The American Society of Peritoneal Surface Malignancies Multi-Institution evaluation of 1,051 advanced ovarian cancer patients undergoing cytoreductive surgery and HIPEC: an introduction of the peritoneal surface disease severity score.
      ,
      • Esquivel J.
      • Lowy A.M.
      • Markman M.
      • et al.
      The American society of peritoneal surface malignancies (ASPSM) multiinstitution evaluation of the peritoneal surface disease severity score (PSDSS) in 1,013 patients with colorectal cancer with peritoneal carcinomatosis.
      ].
      Preoperative administration of oral carbohydrates (CHO: maltodextrin 12.5%, 240–285 mOsm/kg, usually in 800 mL solution) was introduced to diminish the catabolic response induced by overnight fasting and surgery [
      • Nygren J.
      The metabolic effects of fasting and surgery.
      ,
      • Gianotti L.
      • Biffi R.
      • Sandini M.
      • et al.
      Preoperative oral carbohydrate load versus placebo in major elective abdominal surgery (PROCY): a randomized, placebo-controlled, multicenter, phase III trial.
      ]. A Cochrane review on CHO analyzed 27 trials and 1976 patients having different types of elective minor and major abdominal surgery, but also orthopaedic surgery, cardiac surgery, and thyroidectomy [
      • Smith M.D.
      • McCall J.
      • Plank L.
      • Herbison G.P.
      • Soop M.
      • Nygren J.
      Preoperative carbohydrate treatment for enhancing recovery after elective surgery.
      ]. CHO had no significant impact on complications but induced a moderate reduction of hospital stay in patients undergoing major abdominal surgery (reduction by 1.66 days, 95% CI - 2.97 to - 0.34) when compared to the placebo or fasting group.
      A more recent large RCT (PROCY) of 880 patients undergoing elective major abdominal surgery studied oral CHO administration versus placebo [
      • Gianotti L.
      • Biffi R.
      • Sandini M.
      • et al.
      Preoperative oral carbohydrate load versus placebo in major elective abdominal surgery (PROCY): a randomized, placebo-controlled, multicenter, phase III trial.
      ]. The RCT failed to show reduction of postoperative infections (primary end-point) but demonstrated improvement in insulin requirements and hyperglycaemia (≥180 mg/dL) which is consistent with previous data [
      • Awad S.
      • Varadhan K.K.
      • Ljungqvist O.
      • Lobo D.N.
      A meta-analysis of randomised controlled trials on preoperative oral carbohydrate treatment in elective surgery.
      ].
      Finally, several cohorts reported the use of ERAS protocols in CRS±HIPEC [
      • Cascales Campos P.A.
      • Gil Martinez J.
      • Galindo Fernandez P.J.
      • Gil Gomez E.
      • Martinez Frutos I.M.
      • Parrilla Paricio P.
      Perioperative fast track program in intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery in advanced ovarian cancer.
      ,
      • Cascales-Campos P.A.
      • Sanchez-Fuentes P.A.
      • Gil J.
      • et al.
      Effectiveness and failures of a fast track protocol after cytoreduction and hyperthermic intraoperative intraperitoneal chemotherapy in patients with peritoneal surface malignancies.
      ,
      • Agarwal R.
      • Rajanbabu A.
      • th P.V.N.
      • Goel G.
      • Madhusudanan L.
      • Gu U.
      A prospective study evaluating the impact of implementing the ERAS protocol on patients undergoing surgery for advanced ovarian cancer.
      ,
      • Meyer L.A.
      • Shi Q.
      • Lasala J.
      • et al.
      Comparison of patient reported symptom burden on an enhanced recovery after surgery (ERAS) care pathway in patients with ovarian cancer undergoing primary vs. interval tumor reductive surgery.
      ,
      • Meyer L.
      • Shi Q.
      • Iniesta M.
      • et al.
      Comparison of patient reported symptom burden in patients with ovarian cancer undergoing primary vs. interval tumor reductive surgery.
      ,
      • Webb C.
      • Day R.
      • Velazco C.S.
      • et al.
      Implementation of an enhanced recovery after surgery (ERAS) program is associated with improved outcomes in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
      ]. Some of these studies did not report duration of fasting or administration of CHO [
      • Cascales Campos P.A.
      • Gil Martinez J.
      • Galindo Fernandez P.J.
      • Gil Gomez E.
      • Martinez Frutos I.M.
      • Parrilla Paricio P.
      Perioperative fast track program in intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery in advanced ovarian cancer.
      ,
      • Cascales-Campos P.A.
      • Sanchez-Fuentes P.A.
      • Gil J.
      • et al.
      Effectiveness and failures of a fast track protocol after cytoreduction and hyperthermic intraoperative intraperitoneal chemotherapy in patients with peritoneal surface malignancies.
      ].

      Short preoperative fasting

      Summary and recommendation: Short preoperative fasting of 6 h for solids and 2 h for liquids before CRS±HIPEC should be indicated routinely.
      Evidence level: High despite indirectness.
      Recommendation strength: Strong positive (87.5% agreement, consensus reached))

      Carbohydrate loading

      Summary and recommendation: Carbohydrate loading until 2 h before induction of anaesthesia for CRS±HIPEC could be indicated to reduce postoperative insulin resistance and perioperative discomfort, including anxiety.
      Evidence level: Moderate despite indirectness.
      Recommendation strength: Weak positive (75% agreement, consensus reached)

      Intraoperative phase

      Antimicrobial prophylaxis and skin preparation

      Cytoreductive surgery with or without HIPEC can be clean contaminated or contaminated surgery depending on the absence or presence of bowel resection respectively. Incidence of postoperative SSI after CRS and HIPEC ranges from 11% to 46% [
      • Bartlett E.K.
      • Meise C.
      • Roses R.E.
      • Fraker D.L.
      • Kelz R.R.
      • Karakousis G.C.
      Morbidity and mortality of cytoreduction with intraperitoneal chemotherapy: outcomes from the ACS NSQIP database.
      ,
      • Haslinger M.
      • Francescutti V.
      • Attwood K.
      • et al.
      A contemporary analysis of morbidity and outcomes in cytoreduction/hyperthermic intraperitoneal chemoperfusion.
      ,
      • Mizumoto A.
      • Canbay E.
      • Hirano M.
      • et al.
      Morbidity and mortality outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy at a single institution in Japan.
      ,
      • Levine E.A.
      • Stewart JHt
      • Shen P.
      • Russell G.B.
      • Loggie B.L.
      • Votanopoulos K.I.
      Intraperitoneal chemotherapy for peritoneal surface malignancy: experience with 1,000 patients.
      ]. Parenteral antibiotics in the form of cephalosporins are the preferred for antimicrobial prophylaxis. Metronidazole is administered if there is involvement of bowel transaction (contaminated cases) [
      • Bratzler D.W.
      • Dellinger E.P.
      • Olsen K.M.
      • et al.
      Clinical practice guidelines for antimicrobial prophylaxis in surgery.
      ,
      • Alexander J.W.
      • Solomkin J.S.
      • Edwards M.J.
      Updated recommendations for control of surgical site infections.
      ]. Intravenous antibiotics are administered within 1 h of incision in order to obtain the highest drug serum levels at incision, and are repeated based on the pharmacokinetics of the drug [
      • Bratzler D.W.
      • Dellinger E.P.
      • Olsen K.M.
      • et al.
      Clinical practice guidelines for antimicrobial prophylaxis in surgery.
      ]. Additional prophylactic antimicrobial agent doses after the surgery are not indicated in clean contaminated cases [
      • Berrios-Torres S.I.
      • Umscheid C.A.
      • Bratzler D.W.
      • et al.
      Centers for disease control and prevention guideline for the prevention of surgical site infection.
      ]. However, around 51% surgeons practice the use of postoperative antibiotic [
      • Maciver A.H.
      • Al-Sukhni E.
      • Esquivel J.
      • Skitzki J.J.
      • Kane 3rd, J.M.
      • Francescutti V.A.
      Current delivery of hyperthermic intraperitoneal chemotherapy with cytoreductive surgery (CS/HIPEC) and perioperative practices: an international survey of high-volume surgeons.
      ] despite the absence of data in the literature regarding prolonged antibiotic prophylaxis.
      A prospective study has shown the reduction in rate of SSI by preoperative screening for superficial infections and directed therapy [
      • Valle M.
      • Federici O.
      • Carboni F.
      • et al.
      Postoperative infections after cytoreductive surgery and HIPEC for peritoneal carcinomatosis: proposal and results from a prospective protocol study of prevention, surveillance and treatment.
      ]. The Centres for Disease Control and Prevention (US) has recommended full body shower or bathing with soap (antimicrobial or non-antimicrobial) at least the night before the operative day [
      • Berrios-Torres S.I.
      • Umscheid C.A.
      • Bratzler D.W.
      • et al.
      Centers for disease control and prevention guideline for the prevention of surgical site infection.
      ]. Preoperative hair removal by the use of clippers has not shown to reduce SSI [
      • Tanner J.
      • Norrie P.
      • Melen K.
      Preoperative hair removal to reduce surgical site infection.
      ].
      Two of the most commonly used active components in preoperative skin antisepsis are chlorhexidine gluconate and povidone iodine. Chlorhexidine gluconate is the preferred agent in clean-contaminated surgery unless contraindicated [
      • Noorani A.
      • Rabey N.
      • Walsh S.R.
      • Davies R.J.
      Systematic review and meta-analysis of preoperative antisepsis with chlorhexidine versus povidone-iodine in clean-contaminated surgery.
      ,
      • Darouiche R.O.
      • Wall Jr., M.J.
      • Itani K.M.
      • et al.
      Chlorhexidine-alcohol versus povidone-iodine for surgical-site antisepsis.
      ,
      • Bratzler D.W.
      • Dellinger E.P.
      • Olsen K.M.
      • et al.
      Clinical practice guidelines for antimicrobial prophylaxis in surgery.
      ]. There is no evidence for use of preoperative antiseptic shower or adhesive incise drapes [
      • Ploegmakers I.B.
      • Olde Damink S.W.
      • Breukink S.O.
      Alternatives to antibiotics for prevention of surgical infection.
      ,
      • Webster J.
      • Alghamdi A.
      Use of plastic adhesive drapes during surgery for preventing surgical site infection.
      ].

      Preoperative antimicrobial prophylaxis

      Summary and recommendation: Prophylactic antibiotics within 1 h before incision for CRS±HIPEC without need for routine repeated administration should be indicated routinely to prevent surgical site infection.
      Evidence level: High despite indirectness.
      Recommendation strength: Strong positive (95.8% agreement, consensus reached)

      Skin preparation by chlorhexidine

      Summary and recommendation: Chlorhexidine-alcohol as skin disinfectant, in alternative to povidone-iodine should be indicated routinely to prevent surgical site infection.
      Evidence level: High despite indirectness.
      Recommendation strength: Strong positive (95.8% agreement, consensus reached)

      Additional surgical site infection prevention measures

      Summary and recommendation: Antiseptic shower, shaving and adhesive drapes could be indicated to prevent surgical site infection.
      Evidence level: Moderate by indirectness.
      Recommendation strength: Weak positive (87.5% agreement, consensus reached)

      Postoperative antibiotic prophylaxis

      Summary and recommendation: The antibiotic prophylaxis during the postoperative period should not be indicated to prevent surgical site infection.
      Evidence level: Low by indirectness.
      Recommendation strength: Weak negative (75% agreement, consensus reached)

      Standard anaesthetic protocol

      Anaesthesia for CRS±HIPEC is conducted using short acting anaesthetic agents (e.g. propofol 1.5–2.5 mg/kg) and neuromuscular blocking drugs (e.g. rocuronium 0.6 mg/kg). The latter should be titrated using neuromuscular monitoring; in addition, deep neuromuscular blockade may improve the surgical field during laparoscopic surgery [
      • Park S.K.
      • Son Y.G.
      • Yoo S.
      • Lim T.
      • Kim W.H.
      • Kim J.T.
      Deep vs. moderate neuromuscular blockade during laparoscopic surgery: a systematic review and meta-analysis.
      ], although if employed, adequate neuromuscular reversal must be confirmed prior to tracheal extubation. Maintenance of anaesthesia can be achieved either with a volatile based technique (e.g. sevoflurane or desflurane to an age-adjusted minimum alveolar concentration value of about 1.0) or total intravenous anaesthesia (TIVA) with propofol and remifentanil, using target controlled infusion pumps set to deliver approximately 3–6 mcg/mL, adjusted according to patient response and processed electroencephalographic monitoring. There is currently considerable interest as to which technique is preferable for patients undergoing major oncological resections, with some evidence supporting the use of TIVA for improved long term outcome in cancer surgeries [
      • Wigmore T.J.
      • Mohammed K.
      • Jhanji S.
      Long-term survival for patients undergoing volatile versus IV anesthesia for cancer surgery: a retrospective analysis.
      ] although no one anaesthetic technique to date has proven superiority for CRS±HIPEC. More recently, there is currently enthusiasm for multimodal anaesthesia, which includes agents such as dexmedetomidine, lidocaine, magnesium sulphate and ketamine to decrease perioperative opioid use with a lower risk of postoperative respiratory complications and faster return to gastrointestinal function [
      • Jessen Lundorf L.
      • Korvenius Nedergaard H.
      • Moller A.M.
      Perioperative dexmedetomidine for acute pain after abdominal surgery in adults.
      ,
      • Albrecht E.
      • Kirkham K.R.
      • Liu S.S.
      • Brull R.
      Peri-operative intravenous administration of magnesium sulphate and postoperative pain: a meta-analysis.
      ,
      • De Oliveira Jr., G.S.
      • Castro-Alves L.J.
      • Khan J.H.
      • McCarthy R.J.
      Perioperative systemic magnesium to minimize postoperative pain: a meta-analysis of randomized controlled trials.
      ,
      • Weibel S.
      • Jelting Y.
      • Pace N.L.
      • et al.
      Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery in adults.
      ,
      • Brinck E.C.
      • Tiippana E.
      • Heesen M.
      • et al.
      Perioperative intravenous ketamine for acute postoperative pain in adults.
      ]. Other key areas are the strategies to minimize postoperative nausea and vomiting (PONV) with multimodal antiemetic regimes, avoidance of nitrous oxide and the use of TIVA [
      • Feldheiser A.
      • Aziz O.
      • Baldini G.
      • et al.
      Enhanced Recovery after Surgery (ERAS) for gastrointestinal surgery, part 2: consensus statement for anaesthesia practice.
      ]. Epidural anaesthesia has the potential to provide excellent pain relief for large laparotomies [
      • Block B.M.
      • Liu S.S.
      • Rowlingson A.J.
      • Cowan A.R.
      • Cowan Jr., J.A.
      • Wu C.L.
      Efficacy of postoperative epidural analgesia: a meta-analysis.
      ,
      • Guay J.
      • Nishimori M.
      • Kopp S.L.
      Epidural local anesthetics versus opioid-based analgesic regimens for postoperative gastrointestinal paralysis, vomiting, and pain after abdominal surgery: a Cochrane review.
      ] and reduce pulmonary complications [
      • Popping D.M.
      • Elia N.
      • Marret E.
      • Remy C.
      • Tramer M.R.
      Protective effects of epidural analgesia on pulmonary complications after abdominal and thoracic surgery: a meta-analysis.
      ]. Prolonged thoracic epidural analgesia (over 72 h) is currently of interest as it may contribute to both an improved disease-free survival and overall survival [
      • Lorimier G.
      • Seegers V.
      • Coudert M.
      • et al.
      Prolonged perioperative thoracic epidural analgesia may improve survival after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: a comparative study.
      ]. Analgesia is described further in Section 21 of the Guidelines for Perioperative Care in Cytoreductive Surgery (CRS) with or without Hyperthermic IntraPEritoneal Chemotherapy (HIPEC): Enhanced Recovery After Surgery (ERAS®) Society Recommendations — Part II: Postoperative Management and Special Considerations.
      This patient group presents a wide range of specific physiologic challenges within the respiratory, cardiac, renal and coagulation systems. Abdominal distension from ascites will decrease the functional residual capacity of the lungs, thus increasing the likelihood of arterial oxygen desaturation with an increased PaO2/FiO2 ratio as well as an increased PaCO2. Pulmonary adverse events are common in this group of patients [
      • Arakelian E.
      • Torkzad M.R.
      • Bergman A.
      • Rubertsson S.
      • Mahteme H.
      Pulmonary influences on early post-operative recovery in patients after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy treatment: a retrospective study.
      ]. A number of interventions have been described to address these, including intraoperative protective mechanical ventilation, setting appropriate levels of fraction of inspired oxygen (FiO2) and positive end expiratory pressure (PEEP) with low tidal volumes (≤8 mL/kg of predicted body weight) [
      • Serpa Neto A.
      • Hemmes S.N.
      • Barbas C.S.
      • et al.
      Protective versus conventional ventilation for surgery: a systematic review and individual patient data meta-analysis.
      ] and avoid increased driving pressures [
      • Neto A.S.
      • Hemmes S.N.
      • Barbas C.S.
      • et al.
      Association between driving pressure and development of postoperative pulmonary complications in patients undergoing mechanical ventilation for general anaesthesia: a meta-analysis of individual patient data.
      ]. The avoidance of high intraoperative FiO2 concentrations recommended [
      • Feldheiser A.
      • Aziz O.
      • Baldini G.
      • et al.
      Enhanced Recovery after Surgery (ERAS) for gastrointestinal surgery, part 2: consensus statement for anaesthesia practice.
      ]. In addition, the abdominal distension will also cause a rise in intragastric pressure predisposing to aspiration of gastric contents during the induction of anaesthesia), and thus rapid sequence intubation should be considered in this patient group.
      Standard anaesthetic monitoring is recommended throughout [
      • Checketts M.R.
      • Alladi R.
      • Ferguson K.
      • et al.
      Recommendations for standards of monitoring during anaesthesia and recovery 2015: association of anaesthetists of great britain and Ireland.
      ]. In addition, since extensive fluid shifts occur during the cytoreductive phase, and hyperthermia leads to vasodilation and a hyperdynamic circulation with an increase in heart rate, close monitoring of central venous pressure and cardiac index during the HIPEC phase is required. Standard methods for haemodynamic monitoring of cardiac output and stroke volume variation (SVV) are recommended to guide goal directed fluid therapy [
      • Esteve-Perez N.
      • Ferrer-Robles A.
      • Gomez-Romero G.
      • et al.
      Goal-directed therapy in cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: a prospective observational study.
      ,
      • Mavroudis C.
      • Alevizos L.
      • Stamou K.M.
      • et al.
      Hemodynamic monitoring during heated intraoperative intraperitoneal chemotherapy using the FloTrac/vigileo system.
      ] and are described further in section 14. An arterial line is an important monitor to guide vasoactive drug use and arterial blood gas sampling. The latter is important to monitor and if necessary treat metabolic sequelae such as lactic acidosis developing from the hypermetabolic state. Temperature must be monitored continuously and reliably during the whole procedure with both intraperitoneal (subdiaphragmatic and pelvic) and core temperature monitoring (e.g. esophageal, tympanic probes or a zero heat-flux technique).
      In addition, close observation and management of coagulation status is recommended, both laboratory tests (e.g. INR) and point-of-care tests, such as thromboelastography (TEG) or rotational thromboelastometry (ROTEM), as coagulopathy is common and multifactorial [
      • Raspe C.
      • Piso P.
      • Wiesenack C.
      • Bucher M.
      Anesthetic management in patients undergoing hyperthermic chemotherapy.
      ,
      • Raspe C.
      • Flother L.
      • Schneider R.
      • Bucher M.
      • Piso P.
      Best practice for perioperative management of patients with cytoreductive surgery and HIPEC.
      ]. The use of tranexamic acid and cryoprecipitate has been recommended to reduce blood transfusion rate [
      • Sargant N.
      • Roy A.
      • Simpson S.
      • et al.
      A protocol for management of blood loss in surgical treatment of peritoneal malignancy by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
      ].

      Rapid sequence intubation

      Summary and recommendation: Cricoid pressure during rapid sequence intubation could be indicated to decrease risk of pulmonary aspiration in patients undergoing CRS±HIPEC.
      Evidence level: High despite indirectness.
      Recommendation strength: Weak positive (54.2% agreement, consensus reached)

      Epidural analgesia

      Summary and recommendation: Epidural analgesia (T5-T11, low dose of local anaesthetic and opioids) for ≥72 h after CRS/HIPEC should be indicated routinely to obtain pain relief, spare opioids and hasten the resumption of bowel function.
      Evidence level: High despite indirectness.
      Recommendation strength: Strong positive (75% agreement, consensus reached)

      Multimodal analgesia

      Summary and recommendation: Multimodal analgesia with integration of one or several agents (dexmedetomidine, magnesium sulphate, lidocaine and ketamine) could be indicated.
      Evidence level: Moderate despite indirectness.
      Recommendation strength: Weak positive (83.3% agreement, consensus reached)

      Protective mechanical ventilation

      Summary and recommendation: Protective mechanical ventilation with low tidal volumes, as compared to conventional ventilation should be indicated routinely to reduce the risk of postoperative pulmonary complications.
      Evidence level: High despite indirectness.
      Recommendation strength: Strong positive (100.0% agreement, consensus reached)

      Cardiac output monitoring

      Summary and recommendation: Minimally invasive cardiac output monitoring to guide goal-directed fluid therapy should be indicated routinely to reduce postoperative complications.
      Evidence level: High despite indirectness.
      Recommendation strength: Strong positive (83.3% agreement, consensus reached)

      Use of neuromuscular antagonists

      Summary and recommendation: Deep neuromuscular block and reversal by specific antagonists could be indicated to improve surgical exposure, decrease OR time and reduce the patient’s risk of residual blockade.
      Evidence level: Low by indirectness.
      Recommendation strength: Weak positive (83.3% agreement, consensus reached)

      Intraoperative normothermia

      Monitoring and maintenance of normothermia (36 °C) is a key component of fast track protocols in cytoreductive surgery [
      • Cascales Campos P.A.
      • Gil Martinez J.
      • Galindo Fernandez P.J.
      • Gil Gomez E.
      • Martinez Frutos I.M.
      • Parrilla Paricio P.
      Perioperative fast track program in intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery in advanced ovarian cancer.
      ,
      • Cascales-Campos P.A.
      • Sanchez-Fuentes P.A.
      • Gil J.
      • et al.
      Effectiveness and failures of a fast track protocol after cytoreduction and hyperthermic intraoperative intraperitoneal chemotherapy in patients with peritoneal surface malignancies.
      ]. Further, a survey with responses from 29 out of 41 centres noted active temperature monitoring usually with an esophageal temperature probe [
      • Cascales-Campos P.A.
      • Sanchez-Fuentes P.A.
      • Gil J.
      • et al.
      Effectiveness and failures of a fast track protocol after cytoreduction and hyperthermic intraoperative intraperitoneal chemotherapy in patients with peritoneal surface malignancies.
      ]. Prevention of hypothermia during cytoreductive surgery occurred usually with forced air warmers (79% of centres) and warming mattresses (41% of centres) [
      • Cascales-Campos P.A.
      • Sanchez-Fuentes P.A.
      • Gil J.
      • et al.
      Effectiveness and failures of a fast track protocol after cytoreduction and hyperthermic intraoperative intraperitoneal chemotherapy in patients with peritoneal surface malignancies.
      ]. For the HIPEC phase, 18 of 29 (62%) centres actively cooled patients using forced air blowers on cool or ambient settings. All centres allowed some increase in core temperature; range of 36–41 °C. With increased body temperature there is corresponding effects on metabolic rate including increased oxygen demand, heart rate, end tidal CO2 levels and metabolic acidosis/increased lactate values [
      • Schmidt C.
      • Moritz S.
      • Rath S.
      • et al.
      Perioperative management of patients with cytoreductive surgery for peritoneal carcinomatosis.
      ]. No studies have been published correlating increased core temperature during HIPEC and postoperative morbidity.
      There is a high level of evidence supporting intraoperative normothermia in elective colonic surgery and other areas including major gynecologic procedures, rectal resection, and gastric resection; all areas which may be included in cytoreductive surgical procedures with HIPEC [
      • Ljungqvist O.
      • Scott M.
      • Fearon K.C.
      Enhanced recovery after surgery: a review.
      ]. Several meta-analyses and randomised trials have demonstrated that the prevention of hypothermia during major abdominal surgery significantly reduces wound infections, cardiac complications, venous thromboembolic events and intraoperative bleeding and transfusion need [
      • Kurz A.
      • Sessler D.I.
      • Lenhardt R.
      Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. Study of Wound Infection and Temperature Group.
      ,
      • Frank S.M.
      • Fleisher L.A.
      • Breslow M.J.
      • et al.
      Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events. A randomized clinical trial.
      ,
      • Rajagopalan S.
      • Mascha E.
      • Na J.
      • Sessler D.I.
      The effects of mild perioperative hypothermia on blood loss and transfusion requirement.
      ,
      • Moslemi-Kebria M.
      • El-Nashar S.A.
      • Aletti G.D.
      • Cliby W.A.
      Intraoperative hypothermia during cytoreductive surgery for ovarian cancer and perioperative morbidity.
      ]. The majority of randomized controlled trials of enhanced recovery after surgery in colorectal surgery included prevention of hypothermia [
      • Greco M.
      • Capretti G.
      • Beretta L.
      • Gemma M.
      • Pecorelli N.
      • Braga M.
      Enhanced recovery program in colorectal surgery: a meta-analysis of randomized controlled trials.
      ]. Maintenance of intraoperative normothermia to prevent postoperative complications is well accepted and further trials are unlikely to be performed in this area.

      Prevention of hypothermia

      Summary and recommendation: Prevention of intraoperative hypothermia (<36 °C) by use of active warming devices, by maintaining an ambient temperature of ≥21 °C, and by warming of anaesthetic gases, intravenous and irrigation fluid should be performed routinely.
      Evidence level: High despite indirectness.
      Recommendation strength: Strong positive (100.0% agreement, consensus reached)

      Prevention of hyperthermia

      Summary and recommendation: Prevention of intraoperative hyperthermia (>41 °C) by active measures (forced air blowers, cool packs and ambient settings) could be performed.
      Evidence level: Low.
      Recommendation strength: Weak positive (75.0% agreement, consensus reached)

      Intraoperative normoglycaemia

      Intraoperative glycaemic control is recommended to minimize postoperative morbidity and mortality [
      • Ceelen W.
      • De Somer F.
      • Van Nieuwenhove Y.
      • Vande Putte D.
      • Pattyn P.
      Effect of perfusion temperature on glucose and electrolyte transport during hyperthermic intraperitoneal chemoperfusion (HIPEC) with oxaliplatin.
      ]. There are several glycaemia influencing factors for patients submitted to CRS and HIPEC related both to surgery itself (surgical stress, fasting, fluid administration) and to HIPEC (hyperthermia, chemotherapy, intraperitoneal carrier used) [
      • Mendonca F.T.
      • Guimaraes M.M.
      • de Matos S.H.
      • Dusi R.G.
      Anesthetic management of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC): the importance of hydro-electrolytic and acid-basic control.
      ].
      During surgery, insulin resistance is a common event. It is a physiological response induced by surgical trauma, and a catabolic response induced by fasting. It is frequently combined with electrolyte disorders following fluid administration during surgery [
      • Sheshadri D.B.
      • Chakravarthy M.R.
      Anaesthetic considerations in the perioperative management of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
      ]. During HIPEC, hyperthermia can cause higher lactate levels which may lead to metabolic acidosis, also worsened by tumorolysis induced by peritoneal chemotherapy [
      • Stewart C.L.
      • Gleisner A.
      • Halpern A.
      • et al.
      Implications of hyperthermic intraperitoneal chemotherapy perfusion-related hyperglycemia.
      ]. Moreover, some chemotherapeutic agents (i.e. oxaliplatin) are diluted in dextrose 5% solutions, due to their tendency to be converted in oxalate, which can cause an acute peripheral neuropathy [
      • Eto S.
      • Yamamoto K.
      • Shimazu K.
      • et al.
      [Formation of oxalate in oxaliplatin injection diluted with infusion solutions].
      ].
      The NICE-SUGAR study suggests keeping an intraoperative glucose target of 140–180 mg/dL, to avoid the major intraoperative risk of hypoglycaemia [
      • Van den Berghe G.
      • Schetz M.
      • Vlasselaers D.
      • et al.
      Clinical review: intensive insulin therapy in critically ill patients: NICE-SUGAR or Leuven blood glucose target?.
      ]. Indeed, avoiding perioperative hypoglycaemia is associated to a lower morbidity rate in both diabetic and non-diabetic patients [
      • van den Boom W.
      • Schroeder R.A.
      • Manning M.W.
      • Setji T.L.
      • Fiestan G.O.
      • Dunson D.B.
      Effect of A1C and glucose on postoperative mortality in noncardiac and cardiac surgeries.
      ].
      Conversely, perioperative hyperglycaemia leads to a higher surgical site infection rate [
      • Weiser M.R.
      • Gonen M.
      • Usiak S.
      • et al.
      Effectiveness of a multidisciplinary patient care bundle for reducing surgical-site infections.
      ] and patients with a misdiagnosed diabetes can develop worse post-operative outcomes with respect to diabetic patients [
      • Kotagal M.
      • Symons R.G.
      • Hirsch I.B.
      • et al.
      Perioperative hyperglycemia and risk of adverse events among patients with and without diabetes.
      ]. For this reason, surgical patients without diabetes but with risk factors such as age >45 and BMI >25 should be screened for hyperglycaemia and Hb1Ac levels [
      • Duggan E.W.
      • Carlson K.
      • Umpierrez G.E.
      Perioperative hyperglycemia management: an update.
      ].
      Since CRS and HIPEC are usually performed by laparotomy due to the complexity of surgery, these patients have a higher risk to develop wound infection, especially in presence of risk factors.
      All modifiable factors to preserve intraoperative normoglycaemia, including oral preoperative CHO loading, use of minimally invasive surgery when possible, thoracic epidural analgesia and early feeding [
      • Nelson G.
      • Bakkum-Gamez J.
      • Kalogera E.
      • et al.
      Guidelines for perioperative care in gynecologic/oncology: enhanced Recovery after Surgery (ERAS) Society recommendations-2019 update.
      ] should be pursued in case of CRS and HIPEC.
      Summary and recommendation: Diabetes screening and intraoperative glycaemic control (target: 140–180 mg/mL) should be indicated routinely to avoid intraoperative hyper- or hypoglycaemia and to reduce postoperative complications.
      Evidence level: Moderate despite indirectness.
      Recommendation strength: Strong positive (83.3% agreement, consensus reached)

      Perioperative fluid management

      Patients following CRS and HIPEC have a capillary leak with massive loss of fluid, blood and protein [
      • Kanakoudis F.
      • Petrou A.
      • Michaloudis D.
      • Chortaria G.
      • Konstantinidou A.
      Anaesthesia for intra-peritoneal perfusion of hyperthermic chemotherapy. Haemodynamic changes, oxygen consumption and delivery.
      ,
      • Kerscher C.
      • Ried M.
      • Hofmann H.S.
      • Graf B.M.
      • Zausig Y.A.
      Anaesthetic management of cytoreductive surgery followed by hyperthermic intrathoracic chemotherapy perfusion.
      ] causing substantial fluid shifts. Although parameters such as arterial blood pressure and urine output have been used to guide fluid therapy in the past, more recently goal-directed therapy is a recommended approach using stroke volume optimisation [
      • Colantonio L.
      • Claroni C.
      • Fabrizi L.
      • et al.
      A randomized trial of goal directed vs. standard fluid therapy in cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.
      ,
      • Kajdi M.E.
      • Beck-Schimmer B.
      • Held U.
      • Kofmehl R.
      • Lehmann K.
      • Ganter M.T.
      Anaesthesia in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: retrospective analysis of a single centre three-year experience.
      ,
      • Webb C.A.
      • Weyker P.D.
      • Moitra V.K.
      • Raker R.K.
      An overview of cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for the anesthesiologist.
      ,
      • Cafiero T.
      • Di Iorio C.
      • Di Minno R.M.
      • Sivolella G.
      • Confuorto G.
      Non-invasive cardiac monitoring by aortic blood flow determination in patients undergoing hyperthermic intraperitoneal intraoperative chemotherapy.
      ]. This will minimize the risks associated with both hypovolemia (e.g. renal dysfunction) and hypervolemia (e.g. tissue edema) [
      • Kanakoudis F.
      • Petrou A.
      • Michaloudis D.
      • Chortaria G.
      • Konstantinidou A.
      Anaesthesia for intra-peritoneal perfusion of hyperthermic chemotherapy. Haemodynamic changes, oxygen consumption and delivery.
      ,
      • Colantonio L.
      • Claroni C.
      • Fabrizi L.
      • et al.
      A randomized trial of goal directed vs. standard fluid therapy in cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.
      ,
      • Varadhan K.K.
      • Lobo D.N.
      A meta-analysis of randomised controlled trials of intravenous fluid therapy in major elective open abdominal surgery: getting the balance right.
      ,
      • Lees N.
      • Hamilton M.
      • Rhodes A.
      Clinical review: goal-directed therapy in high risk surgical patients.
      ,
      • Eng O.S.
      • Dumitra S.
      • O’Leary M.
      • et al.
      Association of fluid administration with morbidity in cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.
      ].
      Fluid administration of 9–12 mL/kg/h has been advocated, in particular if platinum derivatives are used to ensure a satisfactory urinary output (at least 1 mL/kg/h) [
      • Raspe C.
      • Flother L.
      • Schneider R.
      • Bucher M.
      • Piso P.
      Best practice for perioperative management of patients with cytoreductive surgery and HIPEC.
      ,
      • Raue W.
      • Tsilimparis N.
      • Bloch A.
      • Menenakos C.
      • Hartmann J.
      Volume therapy and cardiocircular function during hyperthermic intraperitoneal chemotherapy.
      ]. The use of furosemide, dopamine and mannitol for urinary output cannot be generally recommended [
      • Perez J.
      • Taura P.
      • Rueda J.
      • et al.
      Role of dopamine in renal dysfunction during laparoscopic surgery.
      ,
      • Yang B.
      • Xu J.
      • Xu F.
      • et al.
      Intravascular administration of mannitol for acute kidney injury prevention: a systematic review and meta-analysis.
      ].
      The preferred use of either crystalloid or colloid infusions is still a matter of debate. However, the need to substitute the protein loss of up 700 gm per day is recommended [
      • Raspe C.
      • Piso P.
      • Wiesenack C.
      • Bucher M.
      Anesthetic management in patients undergoing hyperthermic chemotherapy.
      ,
      • Patel A.
      • Laffan M.A.
      • Waheed U.
      • Brett S.J.
      Randomised trials of human albumin for adults with sepsis: systematic review and meta-analysis with trial sequential analysis of all-cause mortality.
      ,
      • Perel P.
      • Roberts I.
      • Ker K.
      Colloids versus crystalloids for fluid resuscitation in critically ill patients.
      ]. Transfusion of fresh frozen plasma should be restricted to patients with coagulation perturbations as the administration is associated with an increased risk of multi-organ failure and acute respiratory distress syndrome [
      • Watson G.A.
      • Sperry J.L.
      • Rosengart M.R.
      • et al.
      Fresh frozen plasma is independently associated with a higher risk of multiple organ failure and acute respiratory distress syndrome.
      ]. The use of crystalloids should be done in accordance with measured haemodynamic parameters as liberal use would increase interstitial edema with negative consequences not only for all vital organs but also for intestinal anastomoses with increased risk of leakage [
      • Colantonio L.
      • Claroni C.
      • Fabrizi L.
      • et al.
      A randomized trial of goal directed vs. standard fluid therapy in cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.
      ,
      • Jafari M.D.
      • Halabi W.J.
      • Stamos M.J.
      • et al.
      Surgical outcomes of hyperthermic intraperitoneal chemotherapy: analysis of the american college of surgeons national surgical quality improvement program.
      ].
      During surgery, as increased inflammatory mediators are released, patients will present with vasodilation and a hyperdynamic circulatory state. This will be counterbalanced not only by fluid administration but may also require catecholamines [
      • Raspe C.
      • Piso P.
      • Wiesenack C.
      • Bucher M.
      Anesthetic management in patients undergoing hyperthermic chemotherapy.
      ,
      • Cooksley T.J.
      • Haji-Michael P.
      Post-operative critical care management of patients undergoing cytoreductive surgery and heated intraperitoneal chemotherapy (HIPEC).
      ]. During the first 24 h after surgery, patients will lose up to 10 L of fluid per day, most of it via intraabdominal drains. Therefore, there is a need to substitute this loss, mostly with crystalloids and albumin.
      Great care is required to avoid excess perioperative intravenous fluids. This may lead to patients exceeding weight gain thresholds (>3.5 kg), which are associated with adverse postoperative outcomes, particularly in in open colorectal surgery [
      • Pache B.
      • Hubner M.
      • Sola J.
      • Hahnloser D.
      • Demartines N.
      • Grass F.
      Receiver operating characteristic analysis to determine optimal fluid management during open colorectal surgery.
      ].

      Advanced monitoring to guide fluid therapy and catecholamines

      Summary and recommendation: During CRS±HIPEC, use of goal-directed fluid therapy and catecholamines guided by advanced/invasive monitoring should be indicated routinely in order to maintain adequate urine output of >1 mL/kg/h.
      Evidence level: High despite indirectness.
      Recommendation strength: Strong positive (87.5% agreement, consensus reached)

      Use of crystalloids

      Summary and recommendation: During CRS±HIPEC, substitution of losses (fluids and protein) by use of crystalloids could be indicated.
      Evidence level: Moderate despite indirectness.
      Recommendation strength: Weak positive (70.8% agreement, consensus reached)

      Limiting postoperative fluid-related weight gain

      Summary and recommendation: Limiting postoperative fluid-related weight gain (target: < 3.5 kg on postoperative day 3) is advised to reduce morbidity, LOS, ICU LOS, and time to recovery of bowel function.
      Evidence level: Moderate despite indirectness.
      Recommendation strength: Weak positive (83.3% agreement, consensus reached)

      Transfusion and management of coagulopathy

      Coagulopathy may appear in 40% of patients in the perioperative period [
      • Pache B.
      • Hubner M.
      • Sola J.
      • Hahnloser D.
      • Demartines N.
      • Grass F.
      Receiver operating characteristic analysis to determine optimal fluid management during open colorectal surgery.
      ]. Transfusion of allogenic blood products is associated with increased morbidity and mortality with adverse effects on the prognosis due to immunosuppression [
      • Nakanishi K.
      • Kanda M.
      • Kodera Y.
      Long-lasting discussion: adverse effects of intraoperative blood loss and allogeneic transfusion on prognosis of patients with gastric cancer.
      ,
      • Baker L.
      • Park L.
      • Gilbert R.
      • et al.
      Guidelines on the intraoperative transfusion of red blood cells: a protocol for systematic review.
      ].
      Liberal (‘10/30’ approach: transfusion for haemoglobin <10 g/dL or haematocrit <30%) and restrictive (trigger of 7 g/dL in the asymptomatic patient without significant cardiac comorbidity) approaches for blood transfusion are common [
      • Baker L.
      • Park L.
      • Gilbert R.
      • et al.
      Guidelines on the intraoperative transfusion of red blood cells: a protocol for systematic review.
      ]. A meta-analysis has demonstrated that the restrictive strategy was non-inferior to the liberal strategy with respect to 30-day mortality and morbidity (pulmonary, infectious, renal, and cardiovascular) [
      • Chen Q.H.
      • Wang H.L.
      • Liu L.
      • Shao J.
      • Yu J.
      • Zheng R.Q.
      Effects of restrictive red blood cell transfusion on the prognoses of adult patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials.
      ]. A Cochrane Review of 31 trials involving 12,587 patients across multiple specialties provides good evidence that transfusions with allogenic packed red blood cells can be avoided in most patients with haemoglobin thresholds above 7 g/dL to 8 g/dL [
      • Carson J.L.
      • Guyatt G.
      • Heddle N.M.
      • et al.
      Clinical practice guidelines from the AABB: red blood cell transfusion thresholds and storage.
      ,
      • Carson J.L.
      • Stanworth S.J.
      • Roubinian N.
      • et al.
      Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion.
      ]. It is generally prudent to consider the clinical context, the patient’s willingness to accept blood products (e.g. Jehovah’s Witness) and alternative therapies before making the decision to recommend blood transfusion.
      In a recent meta-analysis, lower FFP: RBC ratio was associated with poorer 24-h and 30-day survival. High FFP: RBC ratio conferred survival benefits with the highest survival benefit at 1:1.5 [
      • Rahouma M.
      • Kamel M.
      • Jodeh D.
      • et al.
      Does a balanced transfusion ratio of plasma to packed red blood cells improve outcomes in both trauma and surgical patients? A meta-analysis of randomized controlled trials and observational studies.
      ].
      Tranexamic acid (TXA) is an anti-fibrinolytic agent that binds to lysine receptors on plasmin to fibrin and inhibiting fibrinolysis. A Cochrane Review looking at the effectiveness of TXA in reducing blood loss during cytoreductive surgery for advanced ovarian cancer demonstrated no difference in the number of transfused units between the TXA group vs the placebo/no treatment group [
      • Kietpeerakool C.
      • Supoken A.
      • Laopaiboon M.
      • Lumbiganon P.
      Effectiveness of tranexamic acid in reducing blood loss during cytoreductive surgery for advanced ovarian cancer.
      ].
      Prothrombin Complex Concentrate (PCC) is primarily indicated for the rapid reversal of the anticoagulant effects of vitamin K antagonists with certain advantages over FFP. The use of PCC has been advocated certain types of abdominal surgery (liver transplant), but there is little data for its use in CRS±HIPEC [
      • Srivastava P.
      • Agarwal A.
      • Jha A.
      • et al.
      Utility of prothrombin complex concentrate as first-line treatment modality of coagulopathy in patients undergoing liver transplantation: a propensity score-matched study.
      ].

      Restrictive blood transfusion policy

      Summary and recommendation: Restrictive intraoperative transfusion policy with a haemoglobin threshold level of 8 g/dL an as option to less stringent values should be performed routinely considering morbidity, mortality, and survival concerns.
      Evidence level: Moderate by indirectness.
      Recommendation strength: Strong positive (91.7% agreement, consensus reached)

      Preemptive use of fresh frozen plasma (FFP)

      Summary and recommendation: NO consensus was reached on the preemptive/prophylactic treatment of coagulopathy during CRS±HIPEC with fresh frozen plasma, as an option to the traditional reactive policy, in order to reduce the red blood cell transfusion requirements.
      Evidence level: Low by indirectness.
      Recommendation strength: No consensus.

      Tranexamic acid (TXA)

      Summary and recommendation: Tranexamic acid alone or associated with cryoprecipitate could be administered to reduce the risk of bleeding during CRS±HIPEC.
      Evidence level: Moderate by indirectness.
      Recommendation strength: Weak negative (79.2% agreement, consensus reached)

      Prothrombin complex concentrate (PCC)

      Summary and recommendation: Prothrombin complex concentrate, as an option to FFP, could be administered (66.67% weak negative) for the rapid reversal of the anticoagulant effects of vitamin K antagonists.
      Evidence level: Moderate by indirectness.
      Recommendation strength: Weak negative (66.7% agreement, consensus reached)

      Abdominal and thoracic drains

      Recently published systematic reviews and meta-analyses have demonstrated that short-term surgical outcomes in terms of fistula, wound infections, pulmonary complications, length of in-hospital stay and postoperative mortality are not favored by routine abdominal drains after gastric cancer surgery [
      • Liu H.P.
      • Zhang Y.C.
      • Zhang Y.L.
      • Yin L.N.
      • Wang J.
      Drain versus no-drain after gastrectomy for patients with advanced gastric cancer: systematic review and meta-analysis.
      ], colorectal surgery [
      • Karliczek A.
      • Jesus E.C.
      • Matos D.
      • Castro A.A.
      • Atallah A.N.
      • Wiggers T.
      Drainage or nondrainage in elective colorectal anastomosis: a systematic review and meta-analysis.
      ,
      • Urbach D.R.
      • Kennedy E.D.
      • Cohen M.M.
      Colon and rectal anastomoses do not require routine drainage: a systematic review and meta-analysis.
      ,
      • Zhang H.Y.
      • Zhao C.L.
      • Xie J.
      • et al.
      To drain or not to drain in colorectal anastomosis: a meta-analysis.
      ,
      • Podda M.
      • Di Saverio S.
      • Davies R.J.
      • et al.
      Prophylactic intra-abdominal drainage following colorectal anastomoses. A systematic review and meta-analysis of randomized controlled trials.
      ] pancreatic resection [
      • Villafane-Ferriol N.
      • Shah R.M.
      • Mohammed S.
      • et al.
      Evidence-based management of drains following pancreatic resection: a systematic review.
      ,
      • Schorn S.
      • Nitsche U.
      • Demir I.E.
      • et al.
      The impact of surgically placed, intraperitoneal drainage on morbidity and mortality after pancreas resection- A systematic review & meta-analysis.
      ] and liver surgery [
      • Gavriilidis P.
      • Hidalgo E.
      • de’Angelis N.
      • Lodge P.
      • Azoulay D.
      Re-appraisal of prophylactic drainage in uncomplicated liver resections: a systematic review and meta-analysis.
      ,
      • Gurusamy K.S.
      • Samraj K.
      • Davidson B.R.
      Routine abdominal drainage for uncomplicated liver resection.
      ]. There is no study addressing the actual role of abdominal drains in CRS±HIPEC. Data against prophylactic use of drains in conventional abdominal surgery are very consistent, but it is unclear if they can be extrapolated to CRS±HIPEC that represents a particular surgical setting.
      The occurrence of diaphragmatic procedures such as peritonectomy or full thickness muscle resection is quite frequent during CRS and there is no consensus regarding the prophylactic use of thoracostomy tubes to avoid postoperative pleural effusion or pneumothorax [
      • Preti V.
      • Chang D.
      • Sugarbaker P.H.
      Pulmonary complications following cytoreductive surgery and perioperative chemotherapy in 147 consecutive patients.
      ]. On the one hand, when thoracostomy tubes are not placed intraoperatively, a symptomatic pleural effusion may require thoracentesis or even postoperative placement of a chest drain. On the other hand, a prophylactic thoracostomy tube may result in malpositioning in up to 20% of cases, and in a minor proportion of cases, may lead to other complications like infection [
      • Vilkki V.A.
      • Gunn J.M.
      Complications related to tube thoracostomy in Southwest Finland hospital district between 2004 and 2014.
      ].
      Available data on prophylactic use of intraoperative thoracostomy in patients submitted to diaphragmatic manoeuvres during cytoreduction are of low level of evidence. One single retrospective comparative study favors its use claiming the reduction of subsequent severe or symptomatic pleural effusion that could require thoracentesis and/or postoperative chest tubes. The routine thoracostomy placement is not complication-free and may lead to problems of malfunctioning, requiring repositioning.

      Abdominal drains

      Summary and recommendation: Prophylactic abdominal drains after CRS±HIPEC could be indicated to lower the risk of gastrointestinal fistula, wound infection, pulmonary complications, length of stay and mortality.
      Evidence level: Low for CRS±HIPEC, high for other major abdominal surgeries.
      Recommendation strength: Weak positive (50.0% agreement, consensus reached)

      Thoracic drains

      Summary and recommendation: Prophylactic thoracostomy after CRS±HIPEC with diaphragmatic peritonectomy ± full thickness muscle resection could be indicated to lower the risk of severe subsequent pleural effusion or pneumothorax.
      Evidence level: Low.
      Recommendation strength: Weak positive (54.2% agreement, consensus reached)

      Early extubation

      The rate of extubation of patients undergoing CRS±HIPEC in the operating room differs in every institution and in different patient populations vary from 62 to 100% [
      • Cooksley T.J.
      • Haji-Michael P.
      Post-operative critical care management of patients undergoing cytoreductive surgery and heated intraperitoneal chemotherapy (HIPEC).
      ,
      • Thong S.Y.
      • Chia C.S.
      • Ng O.
      • et al.
      A review of 111 anaesthetic patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
      ,
      • Balakrishnan K.P.
      • Survesan S.
      Anaesthetic management and perioperative outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: a retrospective analysis.
      ]. Criteria for extubation in HIPEC patients have not been categorically defined and seem to vary with institutional practices and comfort of anaesthesiologist. A retrospective study observing reasons for increased morbidity and mortality in this patient population, associated ventilation more than 24 h with longer operative times, higher PCI, greater blood loss and higher needs for crystalloids, colloids and blood products with lower PaO2/FIO2 ratio [
      • Balakrishnan K.P.
      • Survesan S.
      Anaesthetic management and perioperative outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: a retrospective analysis.
      ]. High lactate levels during HIPEC was associated with prolonged ventilation [
      • Balakrishnan K.P.
      • Survesan S.
      Anaesthetic management and perioperative outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: a retrospective analysis.
      ]. Presence of metabolic acidosis is not considered a contraindication for extubation, as some degree of metabolic acidosis is observed in most of these patients [
      • Cooksley T.J.
      • Haji-Michael P.
      Post-operative critical care management of patients undergoing cytoreductive surgery and heated intraperitoneal chemotherapy (HIPEC).
      ]. Direct contact with authors suggested practice of early extubation on the OR table in nearly all patients in their practice after HIPEC surgery [
      • Cata J.P.
      • Nguyen L.T.
      • Ifeanyi-Pillette I.C.
      • et al.
      An assessment of the survival impact of multimodal anesthesia/analgesia technique in adults undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: a propensity score matched analysis.
      ]. Early extubation allows for early ambulation and reduced number of days on sedation, leading to earlier return of bowel function and early recovery. Presence of an epidural catheter and local anaesthetic infusion are likely to reduce opioid requirements in the intraoperative and immediate postoperative phase. This facilitates early extubation.
      Summary and recommendation: Early extubation should be done routinely after CRS±HIPEC in the absence of contra-indications, to reduce pulmonary complications, length of stay in ICU and hospital LOS.
      Evidence level: Low by indirectness.
      Recommendation strength: Strong positive (100.0% agreement, consensus reached)

      Discussion

      The ERAS guidelines for CRS±HIPEC represent a comprehensive set of recommendations regarding the performance of this complex and high-risk procedure. Unfortunately, the perioperative care of the combined procedure still lacks standardisation and is characterized by a wide variation in protocols across centres. The present evidence-based recommendations are timely and will enable a critical step forward in the evolution of perioperative management of patients affected by peritoneal surface malignancies.
      According to recent recommendations [
      • Brindle M.
      • Nelson G.
      • Lobo D.N.
      • Ljungqvist O.
      • Gustafsson U.O.
      Recommendations from the ERAS(R) Society for standards for the development of enhanced recovery after surgery guidelines.
      ,
      • Antoniou S.A.
      • Tsokani S.
      • Mavridis D.
      • et al.
      Guideline assessment project: filling the GAP in surgical guidelines: quality improvement initiative by an international working group.
      ], we adopted the GRADE methodology, which is a structured process for summarising evidence and for taking the steps required in developing recommendations. Following GRADE, we used the PICO approach to carefully frame questions, choose outcomes of interest, rate their importance and evaluate the evidence. The GRADE approach has the advantage of being transparent and including not only the evidence but also values and preferences of patients to arrive at recommendations.
      One of the main limitations of the present recommendations is the paucity of direct evidence and the lower quality of evidence from extrapolated studies. Direct evidence from studies conducted specifically in CRS±HIPEC was available in only 8/72 items. Therefore, evidence was extracted from studies carried out in the setting of other related procedures like colorectal or major abdominal surgeries. During the pre-voting phase, the panellists and the core team deemed upon review of the literature, that the magnitude of the effects of 64/72 care items would not be the same in the context of CRS±HIPEC setting, due to specifics of pathophysiology. Therefore, the evidence was rated down by indirectness in 37 out of 64 remaining items, following the GRADE methodology [
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • et al.
      GRADE guidelines: 8. Rating the quality of evidence--indirectness.
      ]. In 17 out of 64 items the evidence was kept as in other surgical fields, despite indirectness. Most of these are interventions directly or indirectly related to modulation of metabolic and inflammatory response to surgical trauma, which are deemed to be the same in all types of surgeries. For instance, preoperative anaesthetic management, preoperative fasting and carbohydrate load, perioperative pain management, perioperative glucose control, and pre/postoperative nutritional management are all items related the control of the stress, development of insulin resistance, hyperglycemia, metabolism, and postsurgical inflammation.
      Following the Delphi technique to achieve consensus, we conducted a well-structured two-round voting process that involved participants from diverse geographic locations with different areas of expertise that encompassed several disciplines. One of the main advantages of the Delphi technique is that we managed to avoid the situation where a specific expert might dominate the consensus process, ensuring quasi-anonymity in the process [
      • Keeney S.
      • Hasson F.
      • McKenna H.
      Consulting the oracle: ten lessons from using the Delphi technique in nursing research.
      ].
      One of shortcomings of the Delphi technique is the fact that criteria for “consensus” are not clearly defined in the literature [
      • Keeney S.
      • Hasson F.
      • McKenna H.
      Consulting the oracle: ten lessons from using the Delphi technique in nursing research.
      ]. Given the paucity and low quality of underlying evidence and anticipating a high number of controversial issues, the authors chose modest thresholds (≥50%). This cutoff was surpassed by far for most items. In fact, the panelists reached the consensus in 71 items, after the second round, with a mean rate of agreement of 78%. Moreover, consensus was so strong that it would have been reached in 74% of items, even if a far higher threshold of ≥75% were applied.
      High degree of consensus and strong recommendations were issued notably for extensive preoperative work-up and optimisation. The latter includes, among other items, very complex, work-intensive and costly interventions such as smoking and alcohol cessation programmes, screening for sleep apnea, frailty screening, and prehabilitation. It remains to be seen how successful the implementation and compliance to these ambitious interventions will be in the majority of centres, including centres of excellence.
      The recommendations for bowel preparation are controversial given the conflicting evidence that was generated recently. It is therefore consistent that only weak recommendations were found for the three related items: weak positive for bowel preparation for probable rectal resection, weak positive for oral antibiotic decontamination (even in the absence of mechanical bowel preparation) and weak negative against routine bowel preparation for probable colectomy in the context of CRS±HIPEC [
      • Rollins K.E.
      • Javanmard-Emamghissi H.
      • Acheson A.G.
      • Lobo D.N.
      The role of oral antibiotic preparation in elective colorectal surgery: a meta-analysis.
      ]
      One interesting finding worth discussing was the considerable number of strong positive recommendations that were supported by low level evidence (n = 12) (Table 1) The panellists issued strong recommendations, particularly in low risk interventions, as they perceived a clear balance in favour of benefit against undesirable effects, despite the absence of unbiased randomised controlled studies. This happened in the care items 1, 2A, 2B, 4, 17, 20, 22, 23, 24, 25, 26 and 27. The interpretation, according to GRADE, is that these recommendations may change when higher quality evidence becomes available, and therefore, they represent topics that deserve priority for further research.
      In summary, the best available evidence and a standardised expert consensus process were used to prepare ERAS recommendations for CRS±HIPEC. Clinicians are encouraged to use this guideline to optimise perioperative care for patients undergoing the high-risk combined procedure. Nonetheless, evidence in this field of surgery is lacking or weak and mostly based on indirectness. Therefore, it is prudent to implement these recommendations cautiously, while prospectively monitoring feasibility and results in routine clinical practice. Lastly, there is an urgent need to further investigate the different aspects of perioperative care for CRS±HIPEC to generate more and better primary evidence.

      Disclosures

      GN is Secretary of the ERAS® Society (no financial conflicts)

      Contribution Author(s)

      Study concepts: MH, JV, GN
      Study design: MH, SK, LV, JV, GN
      Data acquisition: ALL AUTHORS
      Quality control of data and algorithms: MH, SK, LV, JV, GN, AA, WF
      Data analysis and interpretation: MH, SK, LV, JV, GN
      Statistical analysis: MH, SK, LV
      Manuscript preparation: MH, SK, LV, JV, GN
      Manuscript editing: ALL AUTHORS
      Manuscript review: ALL AUTHORS

      Declaration of competing interest

      All other authors declare to have no disclosures.This information has been provided by all authors individually in their attached author forms with date and signatures.

      References

        • Ljungqvist O.
        • Scott M.
        • Fearon K.C.
        Enhanced recovery after surgery: a review.
        JAMA Surg. 2017; 152: 292-298
        • Group E.C.
        The impact of enhanced recovery protocol compliance on elective colorectal cancer resection: results from an international registry.
        Ann Surg. 2015; 261: 1153-1159
        • Wijk L.
        • Udumyan R.
        • Pache B.
        • et al.
        International validation of Enhanced Recovery after Surgery Society guidelines on enhanced recovery for gynecologic surgery.
        Am J Obstet Gynecol. 2019; 221: 237 e1-e11
        • Gustafsson U.O.
        • Scott M.J.
        • Hubner M.
        • et al.
        Guidelines for perioperative care in elective colorectal surgery: enhanced recovery after surgery (ERAS((R))) society recommendations: 2018.
        World J Surg. 2019; 43: 659-695
        • Nelson G.
        • Bakkum-Gamez J.
        • Kalogera E.
        • et al.
        Guidelines for perioperative care in gynecologic/oncology: enhanced Recovery after Surgery (ERAS) Society recommendations-2019 update.
        Int J Gynecol Canc. 2019; 29: 651-668
        • Melloul E.
        • Hubner M.
        • Scott M.
        • et al.
        Guidelines for perioperative care for liver surgery: enhanced recovery after surgery (ERAS) society recommendations.
        World J Surg. 2016; 40: 2425-2440
        • Brindle M.
        • Nelson G.
        • Lobo D.N.
        • Ljungqvist O.
        • Gustafsson U.O.
        Recommendations from the ERAS(R) Society for standards for the development of enhanced recovery after surgery guidelines.
        BJS Open. 2020; 4: 157-163
        • van Driel W.J.
        • Koole S.N.
        • Sikorska K.
        • et al.
        Hyperthermic intraperitoneal chemotherapy in ovarian cancer.
        N Engl J Med. 2018; 378: 230-240
        • Alyami M.
        • Kim B.J.
        • Villeneuve L.
        • et al.
        Ninety-day post-operative morbidity and mortality using the National Cancer Institute’s common terminology criteria for adverse events better describe post-operative outcome after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
        Int J Hyperther. 2018; 34: 532-537
        • Lassen K.
        • Coolsen M.M.
        • Slim K.
        • et al.
        Guidelines for perioperative care for pancreaticoduodenectomy: enhanced recovery after surgery (ERAS(R)) society recommendations.
        Clin Nutr. 2012; 31: 817-830
        • Mortensen K.
        • Nilsson M.
        • Slim K.
        • et al.
        Consensus guidelines for enhanced recovery after gastrectomy: enhanced Recovery after Surgery (ERAS(R)) Society recommendations.
        Br J Surg. 2014; 101: 1209-1229
        • Tsimopoulou I.
        • Pasquali S.
        • Howard R.
        • et al.
        Psychological prehabilitation before cancer surgery: a systematic review.
        Ann Surg Oncol. 2015; 22: 4117-4123
        • Francescutti V.A.
        • Maciver A.H.
        • Stewart E.
        • et al.
        Characterizing the patient experience of CS/HIPEC through in-depth interviews with patients: identification of key concepts in the development of a patient-centered program.
        Ann Surg Oncol. 2019; 26: 1063-1070
        • Gronkjaer M.
        • Eliasen M.
        • Skov-Ettrup L.S.
        • et al.
        Preoperative smoking status and postoperative complications: a systematic review and meta-analysis.
        Ann Surg. 2014; 259: 52-71
        • Egholm J.W.
        • Pedersen B.
        • Moller A.M.
        • Adami J.
        • Juhl C.B.
        • Tonnesen H.
        Perioperative alcohol cessation intervention for postoperative complications.
        Cochrane Database Syst Rev. 2018; 11: CD008343
        • Tonnesen H.
        • Nielsen P.R.
        • Lauritzen J.B.
        • Moller A.M.
        Smoking and alcohol intervention before surgery: evidence for best practice.
        Br J Anaesth. 2009; 102: 297-306
        • Warner D.O.
        Preoperative smoking cessation: the role of the primary care provider.
        Mayo Clin Proc. 2005; 80: 252-258
        • Myers K.
        • Hajek P.
        • Hinds C.
        • McRobbie H.
        Stopping smoking shortly before surgery and postoperative complications: a systematic review and meta-analysis.
        Arch Intern Med. 2011; 171: 983-989
        • Mills E.
        • Eyawo O.
        • Lockhart I.
        • Kelly S.
        • Wu P.
        • Ebbert J.O.
        Smoking cessation reduces postoperative complications: a systematic review and meta-analysis.
        Am J Med. 2011; 124: 144-154 e8
        • Thomsen T.
        • Villebro N.
        • Moller A.M.
        Interventions for preoperative smoking cessation.
        Cochrane Database Syst Rev. 2014; 3: CD002294
        • Iqbal U.
        • Green J.B.
        • Patel S.
        • et al.
        Preoperative patient preparation in enhanced recovery pathways.
        J Anaesthesiol Clin Pharmacol. 2019; 35: S14-S23
        • Li C.
        • Carli F.
        • Lee L.
        • et al.
        Impact of a trimodal prehabilitation program on functional recovery after colorectal cancer surgery: a pilot study.
        Surg Endosc. 2013; 27: 1072-1082
        • Shander A.
        • Knight K.
        • Thurer R.
        • Adamson J.
        • Spence R.
        Prevalence and outcomes of anemia in surgery: a systematic review of the literature.
        Am J Med. 2004; 116: 58S-69S
        • Wu W.C.
        • Schifftner T.L.
        • Henderson W.G.
        • et al.
        Preoperative hematocrit levels and postoperative outcomes in older patients undergoing noncardiac surgery.
        J Am Med Assoc. 2007; 297: 2481-2488
        • Carson J.L.
        • Duff A.
        • Poses R.M.
        • et al.
        Effect of anaemia and cardiovascular disease on surgical mortality and morbidity.
        Lancet. 1996; 348: 1055-1060
        • Musallam K.M.
        • Tamim H.M.
        • Richards T.
        • et al.
        Preoperative anaemia and postoperative outcomes in non-cardiac surgery: a retrospective cohort study.
        Lancet. 2011; 378: 1396-1407
        • Goodnough L.T.
        • Shander A.
        Patient blood management.
        Anesthesiology. 2012; 116: 1367-1376
        • Froessler B.
        • Palm P.
        • Weber I.
        • Hodyl N.A.
        • Singh R.
        • Murphy E.M.
        The important role for intravenous iron in perioperative patient blood management in major abdominal surgery: a randomized controlled trial.
        Ann Surg. 2016; 264: 41-46
        • Kansagra A.J.
        • Stefan M.S.
        Preoperative anemia: evaluation and treatment.
        Anesthesiol Clin. 2016; 34: 127-141
        • Burton B.N.
        • A’Court A.M.
        • Brovman E.Y.
        • Scott M.J.
        • Urman R.D.
        • Gabriel R.A.
        Optimizing preoperative anemia to improve patient outcomes.
        Anesthesiol Clin. 2018; 36: 701-713
        • van Rooijen S.J.
        • Molenaar C.J.L.
        • Schep G.
        • et al.
        Making patients fit for surgery: introducing a four pillar multimodal prehabilitation program in colorectal cancer.
        Am J Phys Med Rehabil. 2019; 98: 888-896
        • Trepanier M.
        • Minnella E.M.
        • Paradis T.
        • et al.
        Improved disease-free survival after prehabilitation for colorectal cancer surgery.
        Ann Surg. 2019; 270: 493-501
        • Schneider S.
        • Armbrust R.
        • Spies C.
        • du Bois A.
        • Sehouli J.
        Prehabilitation programs and ERAS protocols in gynecological oncology: a comprehensive review.
        Arch Gynecol Obstet. 2020; 301: 315-326
        • Ho J.W.
        • Wu A.H.
        • Lee M.W.
        • et al.
        Malnutrition risk predicts surgical outcomes in patients undergoing gastrointestinal operations: results of a prospective study.
        Clin Nutr. 2015; 34: 679-684
        • Mignini E.V.
        • Scarpellini E.
        • Rinninella E.
        • et al.
        Impact of patients nutritional status on major surgery outcome.
        Eur Rev Med Pharmacol Sci. 2018; 22: 3524-3533
        • Gillis C.
        • Buhler K.
        • Bresee L.
        • et al.
        Effects of nutritional prehabilitation, with and without exercise, on outcomes of patients who undergo colorectal surgery: a systematic review and meta-analysis.
        Gastroenterology. 2018; 155: 391-410 e4
        • Dunne D.F.
        • Jack S.
        • Jones R.P.
        • et al.
        Randomized clinical trial of prehabilitation before planned liver resection.
        Br J Surg. 2016; 103: 504-512
        • Barberan-Garcia A.
        • Ubre M.
        • Roca J.
        • et al.
        Personalised prehabilitation in high-risk patients undergoing elective major abdominal surgery: a randomized blinded controlled trial.
        Ann Surg. 2018; 267: 50-56
        • Gillis C.
        • Li C.
        • Lee L.
        • et al.
        Prehabilitation versus rehabilitation: a randomized control trial in patients undergoing colorectal resection for cancer.
        Anesthesiology. 2014; 121: 937-947
        • Johnson M.J.
        • Close L.
        • Gillon S.C.
        • et al.
        Use of the modified Borg scale and numerical rating scale to measure chronic breathlessness: a pooled data analysis.
        Eur Respir J. 2016; 47: 1861-1864
        • Devine E.C.
        Effects of psychoeducational care for adult surgical patients: a meta-analysis of 191 studies.
        Patient Educ Counsel. 1992; 19: 129-142
        • Woods B.
        • Aguirre E.
        • Spector A.E.
        • Orrell M.
        Cognitive stimulation to improve cognitive functioning in people with dementia.
        Cochrane Database Syst Rev. 2012; 2CD005562
        • Saleh A.J.
        • Tang G.X.
        • Hadi S.M.
        • et al.
        Preoperative cognitive intervention reduces cognitive dysfunction in elderly patients after gastrointestinal surgery: a randomized controlled trial.
        Med Sci Monit. 2015; 21: 798-805
        • Powell R.
        • Scott N.W.
        • Manyande A.
        • et al.
        Psychological preparation and postoperative outcomes for adults undergoing surgery under general anaesthesia.
        Cochrane Database Syst Rev. 2016; 5CD008646
        • Freeman S.C.
        • Scott N.W.
        • Powell R.
        • Johnston M.
        • Sutton A.J.
        • Cooper N.J.
        Component network meta-analysis identifies the most effective components of psychological preparation for adults undergoing surgery under general anesthesia.
        J Clin Epidemiol. 2018; 98: 105-116
        • Treanor C.
        • Kyaw T.
        • Donnelly M.
        An international review and meta-analysis of prehabilitation compared to usual care for cancer patients.
        J Cancer Surviv. 2018; 12: 64-73
        • Correia M.I.
        • Waitzberg D.L.
        The impact of malnutrition on morbidity, mortality, length of hospital stay and costs evaluated through a multivariate model analysis.
        Clin Nutr. 2003; 22: 235-239
        • Norman K.
        • Pichard C.
        • Lochs H.
        • Pirlich M.
        Prognostic impact of disease-related malnutrition.
        Clin Nutr. 2008; 27: 5-15
        • Pacelli F.
        • Bossola M.
        • Rosa F.
        • Tortorelli A.P.
        • Papa V.
        • Doglietto G.B.
        Is malnutrition still a risk factor of postoperative complications in gastric cancer surgery?.
        Clin Nutr. 2008; 27: 398-407
        • Pressoir M.
        • Desne S.
        • Berchery D.
        • et al.
        Prevalence, risk factors and clinical implications of malnutrition in French Comprehensive Cancer Centres.
        Br J Canc. 2010; 102: 966-971
        • Weimann A.
        • Braga M.
        • Carli F.
        • et al.
        ESPEN guideline: clinical nutrition in surgery.
        Clin Nutr. 2017; 36: 623-650
        • Stratton R.J.
        • Hackston A.
        • Longmore D.
        • et al.
        Malnutrition in hospital outpatients and inpatients: prevalence, concurrent validity and ease of use of the ’malnutrition universal screening tool’ (’MUST’) for adults.
        Br J Nutr. 2004; 92: 799-808
        • Kondrup J.
        • Rasmussen H.H.
        • Hamberg O.
        • Stanga Z.
        • Ad Hoc E.W.G.
        Nutritional risk screening (NRS 2002): a new method based on an analysis of controlled clinical trials.
        Clin Nutr. 2003; 22: 321-336
        • Wischmeyer P.E.
        • Carli F.
        • Evans D.C.
        • et al.
        American society for enhanced recovery and perioperative quality initiative joint consensus statement on nutrition screening and therapy within a surgical enhanced recovery pathway.
        Anesth Analg. 2018; 126: 1883-1895
        • McClave S.A.
        • Taylor B.E.
        • Martindale R.G.
        • et al.
        Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine (SCCM) and American society for parenteral and enteral nutrition (A.S.P.E.N.).
        JPEN - J Parenter Enter Nutr. 2016; 40: 159-211
        • Jie B.
        • Jiang Z.M.
        • Nolan M.T.
        • Zhu S.N.
        • Yu K.
        • Kondrup J.
        Impact of preoperative nutritional support on clinical outcome in abdominal surgical patients at nutritional risk.
        Nutrition. 2012; 28: 1022-1027
        • Waitzberg D.L.
        • Saito H.
        • Plank L.D.
        • et al.
        Postsurgical infections are reduced with specialized nutrition support.
        World J Surg. 2006; 30: 1592-1604
        • De Hert S.
        • Staender S.
        • Fritsch G.
        • et al.
        Pre-operative evaluation of adults undergoing elective noncardiac surgery: updated guideline from the European Society of Anaesthesiology.
        Eur J Anaesthesiol. 2018; 35: 407-465
        • Sweitzer B.
        Preanesthesia evaluation for noncardiac surgery.
        • Schiff J.H.
        • Frankenhauser S.
        • Pritsch M.
        • et al.
        The Anesthesia Preoperative Evaluation Clinic (APEC): a prospective randomized controlled trial assessing impact on consultation time, direct costs, patient education and satisfaction with anesthesia care.
        Minerva Anestesiol. 2010; 76: 491-499
        • Nagappa M.
        • Liao P.
        • Wong J.
        • et al.
        Validation of the STOP-bang questionnaire as a screening tool for obstructive sleep apnea among different populations: a systematic review and meta-analysis.
        PloS One. 2015; 10e0143697
        • Cywinski J.B.
        • Mascha E.J.
        • Kurz A.
        • Sessler D.I.
        Estimated glomerular filtration rate better predicts 30-day mortality after non-cardiac surgery than serum creatinine: a retrospective analysis of 92,888 patients.
        Can J Anaesth. 2015; 62: 745-752
        • Rockwood K.
        • Song X.
        • MacKnight C.
        • et al.
        A global clinical measure of fitness and frailty in elderly people.
        CMAJ. 2005; 173: 489-495
        • McIsaac D.I.
        • Taljaard M.
        • Bryson G.L.
        • et al.
        Frailty as a predictor of death or new disability after surgery: a prospective cohort study.
        Ann Surg. 2018;
        • Watt J.
        • Tricco A.C.
        • Talbot-Hamon C.
        • et al.
        Identifying older adults at risk of harm following elective surgery: a systematic review and meta-analysis.
        BMC Med. 2018; 16: 2
        • Helm C.W.
        • Bristow R.E.
        • Kusamura S.
        • Baratti D.
        • Deraco M.
        Hyperthermic intraperitoneal chemotherapy with and without cytoreductive surgery for epithelial ovarian cancer.
        J Surg Oncol. 2008; 98: 283-290
        • Goodman M.
        Regional therapeutics for advanced malignancies: jaypee brothers.
        Medical Publishe, 2012
        • Escobar Y.
        • Cajaraville G.
        • Virizuela J.A.
        • et al.
        Incidence of chemotherapy-induced nausea and vomiting with moderately emetogenic chemotherapy: ADVICE (Actual Data of Vomiting Incidence by Chemotherapy Evaluation) study.
        Support Care Canc. 2015; 23: 2833-2840
        • Apfel C.C.
        • Heidrich F.M.
        • Jukar-Rao S.
        • et al.