Influence of early goal-directed therapy using arterial waveform analysis on major complications after high-risk abdominal surgery: study protocol for a multicenter randomized controlled superiority trial

Both the extent of the surgical procedure and the presence of comorbidities increase the risk of an adverse outcome after surgery. Moreover, approximately 12.5% of all surgical patients are considered as ‘high-risk’ [1, 2]. The majority of perioperative complications and death occur in this minority of patients [1]. With increasing age and comorbidities in the general population, the number of high-risk surgical patients is expected to grow. Approximately 50% of these surgical patients develops one or more perioperative complications, and mortality in this specific patient group is around 5% [1‐6]. Major complications such as myocardial infarction, cardiac failure, stroke, pneumonia, renal failure, or sepsis, involve a significant burden to the patient and to hospital facilities during the hospitalization period [3]. After discharge, these complications may result in long-term disability, cognitive impairment and even death, significantly reducing quality of life and increasing healthcare consumption [3].

Surgical patients are subject to the effects of anesthesia, direct surgical trauma, inflammation, fluid shifts, and blood loss. In extensive surgical procedures these effects are enhanced, which may impair oxygen delivery to organs and tissues. Patients with significant comorbidities have limited cardiopulmonary reserve and are therefore more susceptible to the consequences of surgical stress [7]. An imbalance in tissue oxygen delivery and demand may occur, which promotes the incidence of complications [8‐10]. This emphasizes the need for appropriate hemodynamic monitoring and optimization therapy to maintain adequate tissue oxygen delivery in perioperative care for this high-risk group.

Cardiac output (CO) is the principal determinant of tissue oxygen delivery. Continuous monitoring of CO would therefore be valuable for each high-risk surgical patient. A number of CO measurement techniques are available. Pulmonary artery thermodilution remained the standard technique for a number of decades [11, 12]. This technique is, however, invasive and associated with potentially life-threatening complications which limits its use in clinical practice [11, 12]. Transesophageal echocardiography (TEE) can be used to measure CO, but is also rather invasive, does not provide CO continuously, and requires specific skills that are not included in the training of each anesthesiologist or intensive care physician [13]. Therefore, TEE is predominantly used in cardiac surgery. Esophageal Doppler probes for continuous CO measurement are easier to use but not readily tolerated by conscious patients. Other minimally invasive CO techniques such as bioimpedance are not yet sufficiently reliable for use in clinical practice [13].

Arterial waveform analysis (AWA) provides a less invasive and more practical alternative to conventional techniques of CO monitoring. CO is derived from the arterial pressure waveform and only requires an arterial line, which is almost routinely placed in high-risk surgical patients in the operating room (OR) and intensive care unit (ICU) [13, 14]. Moreover, the AWA technique enables dynamic preload assessment in mechanically ventilated patients. Assessment of cardiac preload or fluid responsiveness is the first step in optimizing CO [14, 15]. Both AWA-based CO measurement and dynamic preload assessment have been validated in a variety of clinical settings [14, 16]. The technique is therefore potentially valuable for advanced hemodynamic monitoring and fluid optimization of high-risk, non-cardiac surgical patients [17].

Adequate strategies to correct and improve hemodynamic variables should be available, since monitoring without therapeutic consequences is not enough. Early goal-directed therapy (EGDT) refers to the preemptive use of predefined target values for hemodynamic optimization in order to maintain tissue oxygen delivery. A target variable is continuously monitored and immediately corrected using a treatment algorithm if the value decreases below a predefined threshold. Especially CO or CO-derived variables have been used for this purpose. The treatment algorithms used in EGDT guide fluid therapy and inotropic support, in order to improve the patient’s hemodynamic status. With the emergence of AWA techniques, a new, promising CO measurement technique became available for EGDT [14, 18].

Before the start of the study we performed a systematic review of the literature to evaluate all available evidence on the use of EGDT in elective, high-risk, abdominal surgery (Additional file 1). The results indicated that EGDT is a promising strategy to reduce morbidity and even mortality in high-risk surgery. There are, however, several limitations to the previous literature which may explain why EGDT has never been widely implemented into routine practice [19]. First, the results from most studies are outdated and not applicable to the current standard of care. In studies from 1988 to 2000, morbidity and mortality are much higher in comparison with current practice, even in the intervention groups. The same applies for length of stay in the hospital. Second, pulmonary artery catheterization has been used for the purposes of EGDT at that time. As described before, this technique is limited to specific types of surgery and not broadly accepted for perioperative monitoring in non-cardiac surgery [11‐13, 20]. Two studies applying arterial waveform analysis for EGDT purposes were small and performed in a single center [4, 6]. Moreover, minor complications, such as short-lasting intraoperative hypotension or urinary tract infection, are included as an outcome measure. These complications are not associated with increased long-term morbidity and mortality and should be evaluated separately. One final but major limitation applies to all of the studies described. They lack information about the effect of EGDT on long-term outcome, quality of life, and utilization of healthcare resources. This hinders a cost-effectiveness analysis. EGDT requires the purchase of CO monitoring equipment which consists of specific patient monitors and arterial blood pressure sensors. Additional costs may be the result of an increased use of inotropic support or other therapeutic consequences of EGDT.

Since the start of the trial in May 2012, a number of interesting studies have been published which partially addressed the shortcomings mentioned above [5, 21‐23]. Two studies demonstrated that the implementation of a goal-directed strategy was cost-effective [21, 22]. In addition, two multicenter studies were performed in which a reduction in complications was shown [5, 23]. However, minor complications were included, and the number of patients was rather small in these studies.

The present study is a multicenter, randomized controlled trial in a relatively large group of patients and performed in both university and non-academic teaching hospitals. Patients scheduled for elective high-risk abdominal surgery are included. They represent an extensive group of patients at risk for adverse postoperative outcomes. The primary aim is to reduce the number of major complications that are associated with an increased short-term and long-term morbidity and mortality. These complications are expected to comprise a major burden to quality of life, healthcare costs, and long-term outcome, which are included as secondary outcome parameters. AWA-based CO monitoring techniques are used to assess tissue oxygen delivery, which are minimally invasive and easy-to-use. The treatment algorithm is straightforward and suitable for each anesthesiologist, ICU physician, and anesthesia or ICU nurse. The results of this study may therefore be useful in guiding evidence-based implementation of EGDT.

The primary objective of the study is to investigate the effect of perioperative EGDT using arterial waveform analysis on a composite endpoint of major complications, including mortality after high-ris, abdominal surgery, in comparison with standard care. Secondary endpoints are minor complications, length of stay in the hospital, length of stay in the ICU or post-anesthesia care unit (PACU), long-term outcome, quality of life (QOL), and cost-effectiveness. We hypothesize that perioperative EGDT using AWA reduces the number of major complications after high-risk abdominal surgery in comparison with standard care.

The EGDT trial is designed as a multicenter, randomized, controlled superiority trial with two parallel groups in a 1:1 allocation. The trial is unblinded for the clinicians involved, the patients, and the observers.

Currently, the study is performed in three hospitals in The Netherlands: Albert Schweitzer Hospital (Dordrecht, The Netherlands), University Medical Center Groningen (Groningen, The Netherlands), and University Medical Center Utrecht (Utrecht, The Netherlands). The Maastricht University Medical Center (Maastricht, The Netherlands) is preparing study participation. Additional participating centers may be added in the future.

Eligible are patients scheduled for elective high-risk abdominal surgery. Two groups of patients are considered high-risk: patients undergoing extensive procedures comprising a high risk for an adverse postoperative outcome, irrespective of the condition of the patient (group 1); patients undergoing moderately extensive procedures that suffer from significant comorbidity (group 2). These procedures comprise a moderately high-risk for an adverse postoperative outcome in healthy patients, but are considered high-risk for patients with significant comorbidity.

Inclusion criteria are:

Patients will be excluded if they meet one of the following criteria: patients with aortic insufficiency > grade 1, patients who are under 18 years-old, patients with cardiac arrhythmias (such as atrial fibrillation or flutter, or ventricular tachycardia), patients requiring emergency surgery, patients in which cardiac output measurement is mandatory for therapeutic decisions, or contraindication for passive leg raising in the entire postoperative period.

A randomization procedure is used to allocate patients to standard care (control group) or standard care with EGDT (intervention) in a 1:1 ratio. The randomization is stratified according to hospital and type of surgery. In each stratum, a block randomization with variable block size is applied using a computer.

Patients assigned to standard care will be treated according to local routine, with the following conditions: 1) after induction of anesthesia and tracheal intubation, patients are mechanically ventilated (volume control) with a fixed tidal volume of 8 ml/kg^-1 (ideal body weight, IBW) throughout the procedure, adjusting respiratory rate to maintain normocapnia; 2) an arterial line, central venous line, and urine catheter are placed, 3) hypotension after induction is treated preferably with crystalloids, eventually with colloids, with a maximum of 500 ml. Ongoing hypotension is treated with a continuous infusion of norepinephrine. Sudden, short-lasting hypotension is treated with phenylephrine or ephedrine depending on local routine and indication; and 4) transfusions with erythrocytes will be applied according to the 4-5-6 rule (Additional file 2).

Therapy is aimed at maintaining: S_pO₂ ≥ 95%, mean arterial blood pressure (MAP) ≥ 60 mmHg or ≤ 25% below baseline in cases of preexisting hypertension, and heart rate (HR) < 100/min or ≤ 25% above baseline.

The use of epidural analgesia, enhanced recovery after surgery (ERAS) protocols, corrections for preoperative fasting, and basic fluid regimes is allowed but not obligatory. Serum lactate, central venous oxygenation saturation, and other laboratory parameters may be used to the discretion of the attending anesthesiologist or ICU physician.

Patients assigned to EGDT are treated according to the same conditions as defined for the standard group. An EGDT algorithm is added to standard care in order to maintain tissue oxygen delivery in the perioperative period. After induction of anesthesia in the OR, an AWA technique is applied for continuous CO measurement and dynamic preload assessment. The choice of AWA technique depends on the institution in which the study is performed. CO values are indexed to the patients’ body surface area. For each patient, an age-dependent target cardiac index (CI) is determined with the following criteria: age < 60 years, target CI ≥ 2.8 l/min/m; age between 60 and 75 years, target CI ≥ 2.6 l/min/m; or age > 75 years, target CI ≥ 2.4 l/min/m.

If the CI drops below the target value, a treatment algorithm is used in order to restore the CI above the threshold (Figure 1). In this algorithm, the dynamic preload parameter stroke volume variation (SVV) is used to determine whether the patient should receive a fluid challenge (FC), or whether inotropic support should be started or increased. Continuous infusion of norepinephrine and/or dobutamine should be used as inotropic support. SVV cannot be used in the following circumstances: spontaneous breathing activity, tidal volume <8 ml/kg, and/or breathing frequency >16/min^-.

In these circumstances, a passive leg raising (PLR) test is used to guide fluid or inotropic support [24‐26]. The procedure is explained in Figure 2. If the CI increases 10% or more during PLR, a 500 ml FC is given. If not, inotropic support is started or increased. If both measurement of SVV and PLR testing are not possible, a small 250 ml FC is given. If the CI subsequently increases, another 250 ml FC is given. If the CI does not increase, inotropic support is started or increased. Treatment according to this EGDT algorithm starts after induction of anesthesia in the OR and is maintained until discharge from the ICU/PACU, with a maximum of 24 hours from induction of anesthesia.

In case of any newly developed arrhythmia in patients in the intervention group, CO and SVV measurements obtained with AWA are unreliable. Therefore, treatment according to the EGDT algorithm stops as long as the arrhythmia persists. If a patient in the intervention group develops unwanted tachycardia, arrhythmia, or (suspected) myocardial ischemia due to inotropic support applied within the EGDT algorithm, inotropic support needs to be reduced or stopped, irrespective of the CI. In addition, a FC should be withheld or stopped if pulmonary edema or cardiac decompensation is suspected, irrespective of the CI.

The EGDT algorithm is easy to use and rather straightforward, yet extensive training of nurses and physicians involved in the care of patients allocated to EGDT will be performed before the start of the study in each participating center. Moreover, a number of nurses and physicians from each institution have been involved in the trial from the beginning and are thoroughly informed about the procedures. These ‘trial experts’ can be consulted at any time and will monitor the appropriate application of the EGDT algorithm.

The primary outcome measure is the number of major complications per patient within the first 30 days after surgery, including mortality. An overview of all major complications can be found in Table 2. The complications within this composite endpoint are associated with increased long-term morbidity and mortality [3].

The following secondary outcome measures are considered: the grade of major complications occurring in the first 30 days after surgery according to the Accordion Severity Grading system [31]; the number of the following minor complications within the first 30 days after surgery: arrhythmia (requiring intervention), deep venous thrombosis (confirmed by ultrasonography), urinary tract infection (confirmed by urinalysis and treated with antibiotics), prolonged ileus (diagnose made and confirmed by surgeon), herniation or other prolonged wound healing (diagnosis made and confirmed by surgeon); the total amount of fluid administered in the first 24 hours after surgery (crystalloids, colloids, and blood products); inotropic support in the first 24 hours after surgery (amount and duration of infusion); hemodynamic (blood pressure, HR, CI, SVV, mean urine output) and laboratory (central venous oxygen saturation and pCO₂, serum lactate, troponin) variables in the first 24 hours after surgery; length of stay in the hospital and in the ICU/PACU; continuation of care at intermediate care units (level of care in between the ward and ICU/PACU); number and length of ICU/PACU or intermediate care readmissions; QOL; cost-effectiveness; long-term outcome: 3, 6, and 12 months complications and mortality.

Before the operation demographic data, ASA physical status, medical history, and drug usage are collected from the patient’s medical records.

A number of hemodynamic variables (blood pressure, HR, CI, and SVV if applicable) are recorded each hour during the first 24 hours after induction. In the EGDT group, these variables are also recorded before and after interventions to correct a drop in CI below the target value. Fluid balance in the first 24 hours is evaluated by recording the amount of fluids infused (crystalloid, colloid, and blood products) as well as urine output and blood loss. In addition, the use of inotropes is registered (type, amount, and duration of infusion). The following laboratory variables are determined after induction, during surgical closure, after admittance to the ICU/PACU, and the morning after surgery: serum hemoglobin, lactate, and full blood gas analysis (arterial and venous). After admittance to the ICU/PACU, the following additional blood values are determined in order to calculate the Sequential Organ Failure Assessment (SOFA) score [32]: serum creatinine, bilirubin, and platelet count. The morning after surgery, serum troponin and creatinine levels are measured. The Therapeutic Intervention Scoring System (TISS) is calculated after admittance to the ICU/PACU [33]. Variables are derived from the patient monitoring systems used in the operating room and ICU/PACU, or from the OR and ICU/PACU record systems.

The following information is obtained in the first 30 days after surgery: all-cause mortality, major and minor complications, if applicable; duration of postoperative mechanical ventilation (hours); length of stay in the in the hospital (days) and ICU/PACU (hours); length of stay in the in the hospital (days) and ICU/PACU (hours) according to fit-for-discharge criteria [5] (Additional file 3); continuation of care at intermediate care units (hours); number of readmissions to the ICU/PACU or intermediate care unit.

All information can be obtained from the patients’ medical records. Patient follow-up with respect to complications and length of stay is active.

QOL will be assessed with the EQ-5D and Short Form (SF) 36 questionnaires before surgery and 1, 3, 6, and 12 months after surgery. Depending on the patient’s preference, the questionnaires are sent to the patient by email or conventional mail, or the patient is called by an interviewer. Patients who do not respond will receive a maximum of two phone calls as a reminder. Before contacting or sending the questionnaires to the patient, confirmation will be obtained that the patient is still alive.

Both healthcare costs (treatment costs including equipment, hospital stay, and re-interventions) and non-healthcare costs (costs as a result of absence from work) will be analyzed. Additional equipment and staff costs associated with EGDT will be monitored to assess incremental costs associated with EGDT. Direct healthcare costs will be calculated by multiplying the volume of (healthcare) resources use with its cost, using standard reference prices for economic evaluation in healthcare whenever available. Information on the following direct costs will be collected from the medical records: blood sample measurements, cultures and other investigations (such as chest films, CT-scans, echography, and ECG), interventions (such as reoperation, catheterization, chest drainage, and antibiotic treatment), and discharge destination (home, nursing home, rehabilitation). Data on absenteeism from work will be collected using parts of the Short-Form Health and Labor Questionnaire (SF-HLQ). The following three questions are added to the SF-HLQ: how many times did you visit your general practitioner? How many times did you visit a doctor in the hospital? Have you been admitted to the hospital? These questions are included in the QOL questionnaire described above. Indirect costs associated with production losses will be estimated using the friction cost method.

Long-term outcome is determined with a letter to the general practitioner of the patient after 3, 6, and 12 months. In this way, mortality and morbidity in the period between 30 days and one year after the operation is determined.

A study of the hospital data of one of the participating centers revealed that the number of major complications embedded in the composite primary endpoint was 0.58 per patient, and that a Poisson distribution was applicable. We aim to reduce the number of major complications per patient by 30% (from 0.58 to 0.41). Using Poisson regression with an assumed two-sided error of 5%, we calculated that a sample size of 226 patients in each group will be needed to detect this reduction with a power of 80%. For the multicenter character of the study, a 20% correction was made, since the variance between the participating centers is unknown. This results in a total sample size of 542, or 271 patients in each group.

For the quality-of-life assessment, the mean EQ-5D score and the individual SF-36 subscale scores are determined, and a comparison will be made between the standard group and the EGDT group. In addition, mean change scores are determined and evaluated over time. For the economic evaluation, especially the EQ-5D, is of importance as utilities and consequently, quality-adjusted life years (QALY), can be elicited using this generic quality-of-life questionnaire. The incremental cost-effectiveness ratio (ICER) will be expressed as cost differences between groups divided by differences in numbers of serious complications between groups (cost per complication averted). The incremental cost-utility ratio (ICUR) will be expressed as cost differences between groups divided by differences in QALY’s gained between groups (cost per QALY). Confidence intervals will be determined using bootstrapping. A cost-effectiveness acceptability curve will be drawn using this bootstrap sample.

The trial has been reviewed and approved by the institutional review board (IRB) of the University Medical Center Utrecht (The Netherlands). Furthermore, local IRB approval has been obtained in the participating centers for the local applicability of the protocol. Details regarding the IRB approval are presented in Additional file 4. Written informed consent will be obtained from all patients.

The treatment algorithm introduced in the patients assigned to EGDT includes measurement of cardiac output, SVV, and PLR as a test. These measurements are performed using the arterial catheter, which is routinely placed in patients undergoing high-risk, non-cardiac surgery. Therefore, no additional catheters are placed in comparison with routine hemodynamic monitoring. EGDT involves fluid therapy and inotropic support, which are commonly used in patients undergoing high-risk surgery. Additional risk associated with its use in the treatment algorithm is therefore not likely in comparison with routine practice. The systematic review of the literature performed before this study (Additional file 1) reported adverse events due to the use of pulmonary artery catheters, which are not used in this study. Only one study reported myocardial ischemia due to use of inotropic support, which disappeared after stopping inotropic infusion [6]. In the other studies however, the results point to a lower incidence of myocardial ischemia, although significant reductions have not been reported. Adverse events with respect to fluid overload have not been described in the systematic review. Despite this, precautions have been taken in the EGDT algorithm to prevent the potentially harmful effects of excessive fluid and inotropic support.

Events that meet the criteria for ‘severe adverse events’ (SAE’s) are monitored and reported to the accredited IRB that approved the protocol and to a Data Safety Monitoring Board (DSMB). The major complications embedded in the primary outcome measure meet these criteria and are considered ‘expected SAE’s’. Cumulative data on these expected SAE’s are reported biannually. Mortality and all other ‘unexpected SAE’s’ are reported immediately. The DSMB has been created to assess the safety of the interventions and to monitor the overall conduct of the study. In addition, the DSMB assists and advises the investigators in protecting the validity and credibility of the trial. The members of the DSMB for this trial are an epidemiologist and biostatistician, an anesthesiologist and intensivist, and a gastrointestinal surgeon. The DSMB members will meet every six months in closed and open sessions. After each meeting the DSMB may decide the following: the trial is allowed to continue without further action, the trial is allowed to continue with recommendations which will be evaluated in the next meeting, or recruitment of patients is stopped since accumulating data points to an adverse effect in the intervention arm. The study will not stop if accumulating data points to a beneficial effect in the intervention arm. The roles and responsibilities of the DSMB are described in detail in a DSMB charter.

There is an urgent need for a multicenter, randomized controlled trial, evaluating the application of AWA-based hemodynamic monitoring in goal-directed strategies for high-risk surgical patients [14, 34, 35]. Ideally, the algorithm used for EGDT should be user-friendly and easily applicable in order to enhance the implementation in daily care. Moreover, this trial should include a large group of patients in order to have sufficient power to demonstrate differences in clinically relevant outcome parameters. Finally, long-term effects in terms of QOL and healthcare costs should be considered. So far, this ‘ideal’ trial has not been performed. The presented study protocol attempts to include the important features mentioned, however, a number of aspects of the trial design however need to be discussed in detail. First we try to elucidate the clinical choices made in the selection of patients, the EGDT algorithm, care in the control group, and safety. Next, we will discuss a number of methodological issues with respect to the study design, primary outcome measure, blinding, and discharge criteria.