Haemodynamic optimisation in Whipple’s surgery

A randomised controlled outcome study evaluating the effect of peri-
operative haemodynamic optimisation on mortality, morbidity and length of
hospital stay in Whipple’s operations

 

 

ABSTRACT

Background
Patients undergoing Whipple’s surgery perhaps represent the ultimate discriminator in
terms of the efficacy of goal-directed therapy (GDT). We aimed to compare the outcomes of
patients with a perioperative GDT algorithm using ProAQT technology with those receiving
standard care.
Methods
100 patients listed for Whipple’s surgery were randomised to three groups. Group one
received standard intra-operative care without GDT. Group two had their pre-operative
cardiac index (CI) maintained intra-operatively. Group three had their pre-operative CI
maintained intra-operatively, with a post-operative oxygen delivery index (DO2I) target of
600ml/min/m2 for 8 hours. In the GDT groups patients if stroke volume variation (SVV) was
>12.5 per cent, then a bolus of Gelofusine® was administered. Post-induction MAP was maintained
≥60mmHg and systemic vascular resistance index (SVRI) >1000 with phenylephrine infusion.
If CI fell by 10 per cent from the baseline value, a dopexamine infusion was commenced. Length of
hospital stay was the primary endpoint and complication rate the secondary endpoint.
Results
Of the 100 patients recruited, 73 subsequently underwent Whipple’s surgery. Mean P-
POSSUM score was similar between groups one to three, but predicted morbidity (%) was
not (24.9 ±13.5 vs 33.1 ±18.7 vs 41.1 ±20.3; p=0.018). When comparing median length of
hospital stay (11 days [9.5-16.5] vs 10 days [9.5-15.5] vs 13 days [10-25]) a significant
difference could not be demonstrated (p=0.265). There was no statistical difference
between the three groups when comparing volumes of intravenous fluid administered or
postoperative complications.
Conclusions
This study indicates that implementing a GDT algorithm guided by a minimally invasive
cardiac output monitor was not associated with a decrease in length of stay or the incidence
of overall complications in patients undergoing pancreaticoduodenectomy. It is possible
that these findings may have been confounded by the allocation of patients with higher
predicted morbidity to the GDT groups despite randomisation.

 

 

INTRODUCTION

High risk surgery in a high risk patient carries high morbidity and mortality rates. Pancreaticoduodenectomy (Whipples procedure) is usually performed for pancreatic cancer
in patients with multiple co-morbidities. Mortality rates range from 3-20 per cent, and major
complications are not infrequent.
All patients undergoing major (high risk) surgical procedures are at risk from inadequate intra-operative oxygen delivery leading to a build-up of oxygen debt which needs to be re-paid in the post-operative period. Shoemaker et al considered that the pre-operative oxygen consumption (VO2) could be used as a baseline for quantifying this debt using invasive monitoring together with repeated intra-operative and post-operative VO2, DO2 and cardiac output measurements. If the debt exceeded a specific value, this led to complications and death as well as the detrimental effects of both hypovolaemia or else fluid overload. [1,2] At present, there is a substantial evidence base to provide guidance on peri-operative fluid therapy and haemodynamic optimisation, although much of it is conflicting. The challenge is to provide the right amount of the right type of fluid at the right time. [3,4]
Fluid optimisation underpins principles outlined in the ‘Enhanced Recovery Programme’, which refers specifically to colorectal patients and recommendations made in the GIFTASUP (Guidelines on Intravenous Fluid Therapy for Adult Surgical Patients). In addition to fluid optimisation, a number of authors have proposed that goal directed therapy – measuring and targeting supranormal oxygen delivery – can improve outcome in high risk surgical patients. [4] The normal physiological response to surgery includes an increased cardiac output, and an increased oxygen delivery. Shoemaker et al demonstrated that those who were unable to increase their peri-operative oxygen delivery in response to intra-operative oxygen debt were at increased risk of complications. The median haemodynamic parameters of those surviving surgery included CI >4.5 l/min/m2, DO2I >600ml/min/m2 and VO2 of >170ml/min/m2. Shoemaker demonstrated that augmenting these parameters with fluids and inotropes led to a substantial decrease in mortality. [5,6]
Optimisation and maintenance of normal DO2 during surgery is readily achieved by maintenance of haemoglobin levels and cardiac output. Technologies currently available for measuring cardiac output peri-operatively include the pulmonary-artery catheters (PAC), PiCCO™ /ProAQT, esophageal dopler monitoring (EDM), LiDCO™ /PulseCO, Vigileo™ /Flotrac™, ultrasonic cardiac output monitor (USCOM) and noninvasive cardiac output monitoring (NICOM). All methods attempt to ensure adequate tissue oxygen delivery. However, practice which targets central venous pressure (CVP) to guide fluid therapy often does not achieve these aims. [7]
The aim of this study was to determine the effect of optimisation and goal directed therapy applied in a reproducible, minimally invasive and resource-efficient fashion through the peri-operative course. Measures of outcome would include length of hospital stay as a primary endpoint and complication rate as a secondary endpoint.

 

METHODS

Patients listed for Whipple’s surgery were randomised using sequentially numbered sealed envelopes to one of three groups over a three year period from Oct 2011. Demographic data was collected for all patients, including age, gender, height, weight, body mass index and co-morbidity. P-POSSUM score, pre-operative serum electrolytes, renal indices, albumin and intestinal alkaline phosphatase were recorded. [8]
Table 1. Patient demographic characteristics of the three groups. Values are absolute (%) or mean ± SD. BMI, Body Mass Index, NET, neuroendocrine tumour, IPMN, intraductal papillary mucinous neoplasm, P-POSSUM, Portsmouth Physiologic and Operative Severity Score for the enUmeration of Mortality and morbidity.

GROUP 1 – Standard intra-operative care without GDT

GROUP 2 – Pre-operative CI maintained intra-operatively (Fig.1), with no post-operative target

GROUP 3 – Pre-operative CI maintained intra-operatively, with a post-operative DO2I target of 600ml/min/m² for 8 hours

Exclusion criteria: Age <18 years, permanent arrhythmia, unstable angina, infection, severely immunocompromised patients (AIDS) or patients receiving immunosuprressive therapy (bone marrow or stem cell transplantation or chemotherapy ) and combined surgical procedures.

Pre-operatively, patients were fasted according to RCOA/AAGBI guidelines. Clear fluids were permitted until two hours pre-operatively.

The study was carried out in accordance with Declaration of Helsinki. Full ethical and R&D approval was obtained at Kings College Hospital and authorized by National Research Ethics Service(NRES) Committee SouthEast Coast ,Brighton (REC Reference:11/LO/1189).

All subjects participating in this study provided written informed consent .

Clinicians involved in the study were trained appropriately with the study guide and continuously evaluated and monitored by the lead author.

 

 

Monitoring and Management

In all groups, a determination of cardiac index and stroke volume index was made by a minimally invasive technique ProAQT (Pulsion, Munich) with internal calibration. The control group was then blinded to the physiological data and the patient proceeded to surgery in the usual manner.

All patients had an arterial line sited and a baseline CI calculated with internal calibration.

In the protocol, Groups 2 and 3 received supplemental oxygen to achieve SpO2>94 per cent and standard monitoring for a level 2 patient was applied.

The intervention groups received Hartmann’s solution at 4ml/kg/hr. If SVV>12.5%, then 250ml Gelofusine bolus was administered. Post-induction MAP was maintained ≥60mmHg and SVRI >1000 with phenylephrine infusion. If CI fell by 10 per cent from the baseline value, a dopexamine infusion 0.25-1 mcg/kg/min was commenced.

 

Intraoperative

Anaesthetic techniques were standardised as far as possible, using fentanyl 1-2 μg/kg, propofol 1.5-2 mg/kg and atracrurium 0.5 mg/kg for induction of standard general anaesthesia. After intubation, the lungs were ventilated to maintain normocapnia (as judged by arterial blood gas analysis and capnography) using a constant fresh gas flow of 1 l/min. Maintenance of anaesthesia was performed with desflurane +/-remifentanil to maintain BIS™ (Bispectral index, Medtronic UK) monitoring between 40-60. Further increments of atracurium were given at the discretion of the anaesthetist. Standard monitoring for both groups included electrocardiogram, invasive arterial blood pressure via right or left radial artery, CVP, pulse oximetry, temperature and inspiratory and expiratory gas concentrations. All groups were given standard antibiotic therapy and received a low/mid thoracic epidural at the discretion of the anaesthetist. A haemoglobin level of ≤ 8g/dl served as a transfusion trigger for each group intraoperatively. Although it was anticipated that there will be a degree of haemodilution, the Whipple’s procedure is not normally associated with large volume blood loss.

In the control group, the administration of fluids, pressors and inotropes was at the discretion of the anaesthetist, judged by CVP 8-12 (or a rise >2mmHg following fluid challenge), MAP ≥ 60 mmHg, lactate <2, and clinical parameters.

Given that patients in all groups might have received a thoracic (interspaces T8-T12) epidural, it was anticipated that ‘rescue’ bolus of phenylephrine might have been required to maintain an adequate MAP following loading of the epidural with bupivicaine 0.25 – 0.5 per cent).

In the protocol groups fluids, pressors and inotropes were administered according to measured indices thus:

• 4ml/kg intra-operative intravenous maintenance fluid (Hartmann’s solution)
• Post-induction MAP maintained ≥60mmHg and SVRI >1000 with phenylephrine infusion.
• If DO2I↓ by 10 per cent from baseline, and SVV>12 per cent, then fluid bolus of 250ml colloid, repeated if SVI↑ by ≥10 per cent and SVV>12 per cent.
• If DO2I<pre-operative value, dopexamine infusion; incremental increase (max dose 1ug/kg/min)

Physiological data routinely obtained during the course of the procedure was electronically captured for later analysis. Although not used in the protocol, data was also obtained from CeVOX- device measurement (central venous oxygen saturation (SCVO2) and VO2) where available.

 

Postoperative

Postoperatively, all patients were extubated in theatre/recovery and admitted to Todd Ward HDU at King’s College Hospital. All groups received 1.5ml/kg/hr intravenous fluid therapy (standardised to 100ml/hr for body weights within ‘normal’ range). All groups received standard care and interventions, aiming for SpO2 ≥ 94 per cent, Temp 37ºC, HR <100 and MAP 60-100 mmHg.

Group 1 and group 2 received fluids/pressors/inotropes as deemed necessary by the attending physicians, and judged by a CVP of 8-12mmHg (or a rise in CVP of >2 mmHg following fluid challenge), urine output, MAP, lactate <2, and clinical examination.

Group 3 received fluids, pressors and inotropes according to a standard post-operative goal-directed protocol (cf Pearse et al 2005) for eight hours post-operatively.

In addition to the above, the first 30 patients had indocyanine green (ICG) plasma decrement rate (as a surrogate marker of hepato-splanchnic blood flow) measured pre-induction, intra-operatively at the time of first anastamosis, one-hour post-op and eight hours post-op using LiMON-Technology (Pulsion, Munich).

 

Endpoints

Length of hospital stay (LOS) was the primary endpoint and complication rate the secondary endpoint, which included the duration of the ICU stay, the amount and type of fluids used intraoperatively, and the amount and type of vasoactive and positive inotropic support used intraoperatively.

 

STATISTICAL ANALYSIS

The results are presented as median with the Kruskal-Wallis Test for unpaired data used to determine differences between the three groups.

Retrospective data capture and the results of similar studies allowed us to make a preliminary power calculation. Assuming that a minimum clinically important endpoint is a 15 per cent reduction in the primary endpoint, then with an assumed α error of 0.05 (two-sided) and type II error of 0.15, in terms of length of stay, this equates to a 2-3 day reduction based on a range of 10-15 days in hospital for this procedure. For the St Georges post-op GDT study, the mean LoS fell by 12 days, though the median fell by only 3.[9]

Assuming roughly equal standard deviations (SD) for each group of say +/- 4 days on the mean, and looking for a difference of just 2 days between Arm 1 and 2 would require 60 patients per group. Drop-out would not be expected given that the study is applied in the immediate peri-operative period. Interim analysis was to be performed after data for 30 and 45 patients in each group was examined. Statistical analyses were performed using SPSS statistics version 25 (IBM,Chicago ,IL ,USA).

 

RESULTS

Of the 100 patients, 73 underwent a standard Whipple’s operation, 10 exploratory laparotomy/laparoscopy, 9 palliative bypass, 3 duodenotomy and 5 other non-Whipple’s operations.

Group comparison of patient characteristics, clinical management and LOS are shown in Table 2. Post-operative complications were not significantly different between groups (Figure 2).

 

Table 2. Results for patients who underwent Whipple’s surgery. 

Data presented as No. (%), Mean (±SD) and Median [25th-75th] percentile.

Mean P-POSSUM score was similar between groups, but predicted morbidity (%) was not (24.9 ±13.5 vs 33.1 ±18.7 vs 41.1 ±20.3; p=0.018). Dopexamine was used in 44 per cent (intra-operatively), 23 per cent (post-operatively) in the GDT groups versus 0 per cent in the control group (p = <0.0001). When comparing median length of hospital stay between the standard care vs intra-op GDT vs intra and post-operative GDT (11 days [9.5-16.5] vs 10 days [9.5-15.5] vs 13 days [10-25]) a significant difference could not be demonstrated (p=0.265). There was no statistical difference between the three groups when comparing volumes of intravenous fluid administered or post-operative complications during length of hospital stay. 

In addition, the first 30 patients recruited had an indocyanine green plasma disappearance rate (ICG PDR) as a surrogate marker of hepato-splanchnic blood flow measured pre-induction (Figure 3), intra-operatively at the time of first anastomosis, 1 hour post-op and 8 hours post-op via a transcutaneous system. ICG PDR appears to be inversely related to the pre-operative bilirubin level.

 

DISCUSSION

The results of this pragmatic study indicate that implementing a GDT algorithm guided by a minimally invasive cardiac output monitor was not associated with a decrease in length of stay or the incidence of overall complications in patients undergoing Whipple’s surgery compared to good standard clinical care.

When comparing volume and type of fluid administered between the three groups a statistically significant difference was not demonstrated.

The question of whether GDT improves postoperative outcome is still under debate, just as the discussion about the best method of monitoring. The results of three recent randomised trials also failed to demonstrate a treatment benefit.[10-12]

The principal advantage of this study was that outcomes were compared for a single major operation (pancreaticoduodenectomy). It also used individual baseline CI as the basis for administering intra-operative dopexamine. This may be the first study to take this approach instead of using fixed values.

Patients in the intervention groups demonstrated a higher predicted morbidity (P-POSSUM) despite randomisation which may have been a significant confounding factor. On multiple regression P POSSUM and post-operative lactate were associated with increased hospital length of stay. Risk of having a major complication was affected by group, but risk of one-year mortality was unaffected. ICG PDR appears to be inversely related to the pre-operative bilirubin level.

The impact of epidural analgesia on the efficacy of GDT is not clear. In this study we attempted to compensate for the reduction in systemic vascular resistance induced by effective epidural block using a phenylephrine infusion. Despite this it is possible that the use a GDT algorithm in conjunction with an epidural may result in excessive fluid administration

The complexity and individual variability of human physiology and pre-surgical morbidities, makes it easy to understand why a one-size-fits-all fluid protocol is unlikely to provide benefit. Perioperative fluid choice and therapy should be individualised as a single GDT algorithm may not be suitable for all patients. A prospective observational study of stroke volume responsiveness to a passive leg raise manoeuvre in healthy volunteers as assessed by transthoracic echocardiography demonstrated a wide variation in baseline stroke volume and response, suggesting greater heterogeneity in the normal population than previously recognised.[13] Sinus arrhythmia can result in raised SVV and potential fluid administration if following a GDT algorithm. This common intra-operative finding should be taken into account as with patients in atrial fibrillation

The interpretation of SVV may not always be consistent by different attending anaesthetists. It is a fluctuant variable that can rise transiently and then fall again. Perhaps a time period at a particular value should be specified before the administration of fluid. Also consistency of training may be an important factor.[14]

A treatment benefit at this single centre may have have been hard to demonstrate as standard care was already of high quality.

Slow rate of recruitment and 27 out of 100 selected patients undergoing a procedure other than standard Whipple operation resulted in interim analysis being brought forward.

The trial was stopped because at interim analysis it was apparent that the groups were skewed in terms of perioperative risk. Higher risk patients had been randomised to the intervention groups. Although not statistically significant it was also apparent that complications were higher in these groups.

It was also clear that the standard deviation of ±4 days used in the original power calculation in terms of length of stay was an underestimate. Based on actual length of stay standard deviation a higher recruitment of 200 patients per group would be required to achieve adequate power.

Publication of the Optimise trial during recruitment also made it apparent that higher numbers of patients would be needed to demonstrate a treatment benefit from perioperative goal directed therapy.[15]

Recruitment of patients was slower than expected due limited resources and a significant proportion of recruited patients underwent a non-Whipple’s surgical procedure, often due to disease progression. Other GDT studies have been stopped due to slow inclusion rate.[16]

In view of the above it was decided to stop the study at interim analysis stage after recruiting one hundred patients.

The principal limitation of this study is that is underpowered. Just the presence of a covered PulsioFlex (Pulsion Medical Systems, Munich, Germany) monitor could have influenced the attending anaesthetist’s haemodynamic management in the control group resulting in more considerate fluid administration. The minimally invasive cardiac output monitor used was non-calibrated and the algorithm at the radial arterial was not clearly validated. Failure of arterial lines during the perioperative period including a damped trace can make interpretation of haemodynamic values unreliable and difficult.

The majority of the evidence supporting the use of GDT is derived from studies using oesophageal doppler monitoring.[17-21] It is not clear how transferable this evidence is to pulse contour analysis based techniques and inferring cardiac output from the arterial wave form is dependent on a multitude of factors.[22]

Dopexamine was the drug chosen to augment cardiac output in this study, but it is possible that dobutamine or even adrenaline have a role in this setting.[23,24]

It may be the case that fluid administration practice may have changed over the three year study period at this single centre. In general there has been a move away from the use of colloids in the ICU and the adoption of more restrictive fluid practice in the operating theatre. It is possible this may have had a beneficial effect to the control group. A recent study has shown that more restrictive fluid administration may improve postoperative outcomes after Whipple’s surgery.[25]

Significantly higher patient recruitment would be required to ensure equal patient demographics and to enable adequate power to determine clinically important endpoints.

Further work should consider using propensity score matching to ensure that groups are evenly matched and patients with equal perioperative risk are compared.

 

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Authors: Timothy Hughes 1 , Krushna Patel 2 , Shyam Laxman 3 , Andreas Prachalias 4 ,
Nigel Heaton 4 , William Bernal 5 , Mark McPhail 5 , Christopher Willars 5
Abbreviated names: Hughes T, Patel K, Laxman S, Prachalias A, Heaton N, Bernal
W, McPhail M, Willars C

1- Consultant Anaesthetist, King’s College Hospital, London UK
2- Foundation doctor, King’s College Hospital, London UK
3- Senior Anaesthetic Registrar, King’s College Hospital, London UK
4- Consultants Hepatobiliary &amp; Liver Transplant Surgeon, King’s College
Hospital, London UK
5- Liver Intensive Care Consultant, King’s College Hospital, London UK

Corresponding Author: Dr Timothy Hughes
Email address: t.hughes1@nhs.net
Consultant Anaesthetist, King’s College Hospital, London, UK SE5 9RS

Ethical approval: This study was approved by the Ethics Committee of King’s
College Hospital and authorised by National Research Ethics Service (NRES)
Committee South East Coast, Brighton (REC Reference:11/LO/1189).
Competing interest: No benefits in any form have been received or will be received
from a commercial party related directly or indirectly to the subject of this article.