General introduction

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3 Annually around patients in the Netherlands undergo major abdominal surgery for both benign and malignant disease 1. Major abdominal surgery may be defined as all digestive resections with reconstruction by means of anastomosis and/or stoma. Twenty percent of these patients will suffer a major complication in their postoperative course, requiring invasive treatment such as endoscopic treatment, percutaneous drainage, reoperation and intensive care management 2. Major complications cause patients to have to stay in hospital or in an intensive care unit for a longer period and these patients are at increased risk of morbidity and mortality 3. Moreover, an increased risk for long-term mortality and increased risk for cancer recurrence is reported 4-6. Finally, major complications are also associated with increased costs in a large cohort including general and vascular surgery 7. Research on the impact of major complications in patients who undergo major abdominal surgery is limited and should address important questions such as the longterm effects of major complications and impact on hospital costs. In order to decrease the amount of major complications and its consequences preventive measures start with an adequate indication for treatment, taking into account an optimal diagnostic workup and all personal aspects of the patient. Regarding surgical innovations two important advances have already been implemented in order to reduce the amount of trauma, such as increased use of minimally invasive techniques and fast track perioperative care. The introduction of minimally invasive surgical techniques has resulted in less perioperative blood loss, faster postoperative recovery and a shorter length of hospital stay in colorectal surgery 8, 9. In esophageal surgery the implementation of minimally invasive techniques has lead to a marked decrease in pulmonary complications 10. Alongside these minimally invasive surgical approaches, the implementation of fast track perioperative care has further improved postoperative recovery 8, 11, 12. With these perioperative measures and surgical innovations taken into account major complications still occur in up to 20% of patients 2. Studies have shown that early goal-directed treatment of complications improves outcomes regarding morbidity and mortality 13, 14. In order to facilitate early treatment for complications diagnostic quality control algorithms in the early postoperative phase are necessary. Early diagnosis of postoperative complications can be quite challenging, since clinical examination, biochemical testing and even additional imaging techniques can be rather non-specific due to effects of surgery itself. In the first days after surgery clinical risk assessment may have a low predictive value for major complications such as anastomotic leak 15. Therefore, biochemical markers are increasingly used to follow the postoperative period. Markers such as C-reactive protein, interleukins 6 and 8 and procalcitonin are 11

4 raised the first postoperative days due to surgical trauma. Currently the median time from surgery to diagnosis of complications is eight days 16, 17. Indicating room for improvement. Early postoperative computed tomography scans show a large overlap between uncomplicated patients and patients with anastomotic leak, with free air and fluid also seen often in uncomplicated postoperative patients 18. A standardized postoperative quality control algorithm, based on biochemical markers would further help the current Fast Track policy. Fast Track patients are often discharged as early as the fifth postoperative day if no postoperative complications are seen 8. With a median time from surgery to diagnosis of complications of eight days it is imperative that the risk of complications is assessed prior to discharge. These perspectives encouraged the initiative to research quality control algorithms in major abdominal surgery, aiming for both early diagnosis and treatment of complications as well as implementation of safe discharge criteria. Aim of the thesis The aim of this thesis was to assess the role of quality control in major abdominal surgery and to assess the optimal postoperative quality control algorithm in order to early diagnose and treat the postoperative complications and to allow for safe discharge. Outline of the thesis Part 1: Quality control in major abdominal surgery H1 H2 Quality control in major abdominal surgery Value of a step-up diagnosis plan by CRP and CT scan to diagnose and manage postoperative complications after major abdominal surgery The first part of this thesis explores quality control in digestive surgery. In chapter 1, all pre-, peri- and postoperative mechanisms are described that are of influence for optimal quality control in surgery. Ranging from an optimal diagnostic workup, adequate pre-assessment of patients before surgery, to a good indication for a personalized surgical treatment coordinated in a multidisciplinary meeting. Moreover perioperative and postoperative quality control mechanisms such as the use of markers are broadly discussed. This chapter further emphasizes the need for postoperative quality control algorithms in surgery. 12

5 Chapter 2 assesses which postoperative measurements and assessments should be implemented in a quality control algorithm after major abdominal surgery. In an observational cohort study the relationship between major complications and postoperative clinical and biochemical markers is explored. Interestingly clinical parameters can be rather non-specific, whereas C-reactive protein showed a strong association with major postoperative complications. Part 2: C-reactive protein and quality control H3 H4 H5 H6 H7 What is CRP; biochemical and clinical aspects C-Reactive protein in diagnosing postoperative complications after major abdominal surgery, proposal for a prediction model for early assessment of major complications Predictive value of C-reactive protein for major complications after major abdominal surgery: a systematic review and pooled-analysis Acute phase proteins in intra-peritoneal drain fluid: to drain or not to drain C-reactive protein and Interleukin-6 in perianastomotic exudate in diagnosis of major complications after major abdominal surgery Our observational study revealed C-reactive protein levels are highly correlated with major postoperative complications. The second part of the thesis further studies the use of C-reactive protein to predict postoperative complications. Chapter 3 describes the biochemical aspects of C-reactive protein with a historical overview. The inflammatory response, caused by surgical trauma, explains the physiological postoperative rise in C-reactive protein production in the liver. In the case of postoperative complications a further increase in CRP production is seen, caused by the increased inflammatory response. Postoperative CRP levels depict a wide range of values. In chapter 4 the relationship between CRP and major complications is further explored in a large cohort, aiming to determine a cut-off for CRP above which additional examination for complications should be performed. A CRP value above 140 mg/l on the third postoperative day has been calculated as a marker for major complications, indicating additional CT-scan examination of the patient. Chapter 5 consists of a systematic review of the literature for CRP as a marker for complications in order to obtain an optimal cut-off. Available studies are rather heterogeneous, limiting the possibility for a general conclusion. Raw data was obtained from seven separate studies, allowing for a pooled analysis of C-reactive protein levels in 1427 patients. Supporting the finding from our cohort study, the optimal cut-off was again found to be 140 mg/l on the third postoperative day. 13

6 Measured CRP levels depict information on the inflammatory state of the patient. As it is routinely measured in peripheral blood samples it is non-specific for location. In chapter 6 and 7 the measurement of CRP in peri-anastomotic drain fluid is explored, aiming to obtain local information on the inflammatory state around the anastomosis and in the intra-abdominal compartment, which may aid in narrowing the differential diagnosis in the assessment of patients at risk of major postoperative complications. Part 3: Quality control in specific patient groups H8 The effect of gender, age and BMI on postoperative C-reactive protein levels after major abdominal surgery. H9 C-reactive protein in predicting postoperative complications Are there differences in open and minimally invasive colorectal surgery. H10 C-reactive protein as a marker for postoperative complications. Are there differences in emergency and elective colorectal surgery? In this part the postoperative CRP levels in specific patient groups were studied, as well as the application of a cut-off for CRP and whether this should be adjusted in different patient groups. Factors as gender, age and BMI are evaluated in the context of postoperative major complications. Moreover differences in postoperative CRP levels are assessed in patients having major complications after laparoscopic or open colectomies, but also differences are assessed in elective or emergency colorectal interventions. Part 4: implications of major complications H11 Long-term survival after complications following major abdominal surgery H12 Major abdominal surgery in octogenarians: Should high age affect surgical decision-making? H13 Hospital cost-analysis of complications after major abdominal surgery. H14 The PRECious trial. PREdiction of Complications, A step-up approach, CRP first followed by CT-scan imaging to ensure quality control after major abdominal surgery: study protocol for a stepped-wedge trial The consequences of major complications are evaluated in two different perspectives; a) The effect of major complications on long-term survival of patients, and b) the effect of major complications in octogenerians is assessed. Finally, an evaluation is made of the direct costs of an uncomplicated and complicated patient. In the time of cost-efficiency adjustments this evaluation can help for determining the quality of surgical treatments. 14

7 All this information directs us to the design of a study protocol for a stepped-wedge trial, the PRECious trial in which a prospective stepped-wedge study is performed. In the case of CRP levels higher than 140 mg/l on the 3 th or 4 th postoperative day a CT scan is performed. Prospective evaluation of this data, gathered in different hospitals will indicate the value of this algorithm. 15

8 References 1. Centraal Bureau voor de Statistiek (CBS). Operaties in het ziekenhuis; soort opname, leeftijd en geslacht, http: //statlinecbsnl/statweb/publication/?vw=t&dm=slnl&pa=80386ne D&LA=NL. 2012; accessed 19 july Straatman J, Cuesta MA, Gisbertz SS, van der Peet DL. Value of a step-up diagnosis plan: CRP and CT-scan to diagnose and manage postoperative complications after major abdominal surgery. Rev Esp Enferm Dig. 2014; 106: Alves A, Panis YU, Mathieu P, Mantion G, Kwiatkowski F, Slim K. Postoperative mortality in French patients undergoing colorectal surgery. Arch Surg. 2005; 140: Khuri SF, Henderson WG, DePalma RG, Mosca C, Healey NA, Kumbhani DJ, Participants in the VANSQIP. Determinants of long-term survival after major surgery and the adverse effect of postoperative complications. Ann Surg. 2005; 242: ; discussion Elfstrom KM, Hatefi D, Kilgo PD, Puskas JD, Thourani VH, Guyton RA, Halkos ME. What happens after discharge? An analysis of long-term survival in cardiac surgical patients requiring prolonged intensive care. J Card Surg. 2012; 27: Rueth NM, Parsons HM, Habermann EB, Groth SS, Virnig BA, Tuttle TM, Andrade RS, Maddaus MA, D Cunha J. The long-term impact of surgical complications after resection of stage I nonsmall cell lung cancer: a population-based survival analysis. Ann Surg. 2011; 254: Dimick JB, Chen SL, Taheri PA, Henderson WG, Khuri SF, Campbell DA. Hospital costs associated with surgical complications: A reoprt from the Private-sector national surgical Quality Improvement Program. J Am Coll Surg. 2004; 4: Vlug MS, Wind J, Hollmann MW, Ubbink DT, Cense HA, Engel AF, Gerhards MF, van Wagensveld BA, van der Zaag ES, van Geloven AAW, Sprangers MAG, Cuesta MA, Bemelman WA. Laparoscopy in combination with Fast Track Multimodal Management is the best perioperative strategy in patients undergoing colonic surgery. (LAFA-study). Ann Surg. 2011; 254: MHGM van der Pas EH, MA Cuesta, A Fürst, AM Lacy, WCJ Hop, HJ Bonjer. Laparoscopic versus open surgery for rectal cancer (COLOR II): short-term outcomes of a randomised, phase 3 trial. Lancet. 2013; 14: Biere SS, van Berge Henegouwen MI, Maas KW, Bonavina L, Rosman C, Garcia JR, Gisbertz SS, Klinkenbijl JH, Hollmann MW, de Lange ES, Bonjer HJ, van der Peet DL, Cuesta MA. Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial. Lancet. 2012; 379: Grantcharov TP, Kehlet H. Laparoscopic gastric surgery in an enhanced recovery programme. The British journal of surgery. 2010; 97: Kisialeuski M, Pedziwiatr M, Matlok M, Major P, Migaczewski M, Kolodziej D, Zub-Pokrowiecka A, Pisarska M, Budzynski P, Budzynski A. Enhanced recovery after colorectal surgery in elderly patients. Wideochirurgia i inne techniki maloinwazyjne = Videosurgery and other miniinvasive techniques / kwartalnik pod patronatem Sekcji Wideochirurgii TChP oraz Sekcji Chirurgii Bariatrycznej TChP. 2015; 10: Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001; 345: Rivers EP, Coba V, Whitmill M. Early goal-directed therapy in severe sepsis and septic shock: a contemporary review of the literature. Curr Opin Anaesthesiol. 2008; 21:

9 15. Karliczek A, Harlaar, N.J., Zeebregts, C.J., Wiggers, T., van Dam, G.M. Surgeons lack predictive accuracy for anastomotic leakage in gastrointestinal surgery. Int J Colorectal Dis. 2009; 24: Alves A, Panis YU, Pocard M, Regimbeau J, P. V. Management of Anastomotic Leakage after Nondiverted Large Bowel Resection. JACS. 1999; 189: den Dulk M, Noter SL, Hendriks ER, Brouwers MAM, van der Vlies CH, Oostenbroek RJ, Menon AG, Steup WH, van de Velde CJH. Improved diagnosis and treatment of anastomotic leakage after colorectal surgery. EJSO. 2009; 35: Power N, Atri M, Ryan S, Haddad R, Smith A. CT assessment of anastomotic bowel leak. Clinical Radiology. 2007; 62: