OPTIMIZING OUTCOME AND QUALITY OF LIFE FOR MESENTERIC ISCHEMIA PATIENTS BY IMPROVING DIAGNOSTIC AND TREATMENT STRATEGIES
The PhD defence of Juliëtte Blauw will take place (partly) online.
The PhD defence can be followed by a live stream.
Juliëtte Blauw is a PhD student in the research group Multi-Modality Medical Imaging (M3I). Supervisor is prof.dr. R.H. Geelkerken from the Faculty of Science & Technology (S&T).
The aim of this thesis was to make a significant contribution to the improvement of quality of life (QoL) and organ-sparing treatment for patients with mesenteric ischemia by providing more insight into contemporary diagnostic and therapeutic developments. Creating more awareness is the first step in abandoning old routines and beliefs.
Part I Developments in Diagnostics and the evolution of Treatment
First of all, it is important to improve the diagnostic process, because diagnostic delay is the number one contributing factor in the overall morbidity, mortality and societal burden of mesenteric ischemia, mainly for acute mesenteric ischemia (AMI) patients. Therefore, to start Part I, we focussed on the present status of diagnostic developments in occlusive AMI patients. Patients and their physicians are in desperate need of a more accurate, less invasive, rapidly and 24/7 available cost-effective diagnostic test. The gold standard now is a high index of suspicion combined with a 1-mm abdominal multislice multiphase computer tomography angiography (CTA) scan.(1) Although CTA has a 73% to 100% and 90% to 100% sensitivity and specificity for diagnosing acute superior mesenteric artery (SMA) occlusion, the possible presence of mesenteric ischemia must be recognized and acknowledged before the radiological images can and will be correctly assessed.(1) There has been an increasing interest in the possible use of biomarkers to shorten diagnostic delay. In Chapter 2 we have conducted a systemic review to define whether biomarkers have any potential diagnostic value for AMI. We included 49 suitable articles describing a total of 60 different biomarkers. However, we observed an enormous heterogeneity in the used inclusion and exclusion criteria, study populations and control groups, normal values and cut-off values, making it virtually impossible to compare the outcomes. Furthermore, the overall methodological quality of the articles was low. Primarily due to the high number of retrospective studies and the use of laparotomy as the reference test. Since diagnosis during a laparotomy often means that it is already too late. Based on this review we conclude that up to know no final decision can be made based on any biomarker or combination of biomarkers in the diagnostic process of AMI patients. This also accounts for leukocytes, lactate and D-dimer. The actual diagnosis of AMI can currently only be made on the basis of a high index of suspicion followed by a multislice CTA.
In order to be able to act in a truly organ-saving manner and to improve QoL, the outcome of treatment must of course improve. Therefore, we continued Part I with a focus on the evolution of treatment strategies and techniques that are now available. But also, on the additional and supportive measures we can offer our patients. Minimally invasive endovascular treatment options had been emerging since the 80s’, with the advantages of less in-hospital mortality and morbidity, shorter hospital stay and more availability in high-risk patients, but with lower primary patency and higher symptom recurrence rates then open surgical treatment.(2, 3) In 2006, percutaneous mesenteric artery stenting (PMAS) became the primary treatment option for mesenteric ischemia patients in Medisch Spectrum Twente (MST). To see whether there still was a place for open surgical mesenteric artery repair (OSMAR), we evaluated the outcome of OSMAR in chronic mesenteric ischemia (CMI) patients with coeliac artery (CA) or SMA stenosis treated between 1997 and 2014 in MST in Chapter 3. Patients were divided in a before 2006 group or a from 2006 group. Technical success was achieved in all patients, with more clinical failures in the historical group, 30.4% versus 34.1%. The only significant difference found was the superior primary patency of SMA reconstructions in the historical group (1-, 3- and 5 years follow-up). There were trends of less multivessel repairs, less antegrade situated bypasses, decreased clinical success but improved 30 days- and long-term survival after OSMAR. The most obvious explanations for this could be the more extensive mesenteric atherosclerosis and the severity of the patients' condition undergoing OSMAR in the “PMAS first” period from 2006. This study showed that elective OSMAR should only be used in patients with substantial physiologic reserve, with unfavourable mesenteric lesions, failed repeated PMAS or multiple recurrences of in-stent stenosis/occlusion. It strengthened our believe that PMAS is no longer a “bridge to surgery” for CMI patients, but a strong first choice treatment, with a side note of a “bridge to repeated PMAS”.
In Chapter 4 we went a step further, to show that OSMAR should not even be second choice in AMI patients, because we presented a better alternative which combines the advantages of open surgical and endovascular approaches, retrograde open mesenteric stenting (ROMS). It is a hybrid technique in which, via a small transverse upper abdominal laparotomy, retrograde stenting of the SMA can be performed with the direct possibility of assessing bowel vitality. Between January 2007 and September 2011, we included 15 consecutive patients undergoing ROMS for AMI. Technical success was achieved in 14 patients. Two patients had severely ischemic small bowel of which one needed a partial bowel resection due to irreversible transmural ischemia. Thirty days mortality rate was 20% and primary patency was 92%. Ten patients underwent unplanned relaparotomy of which one needed resection of a large part of the small bowel. Twelve months mortality rate was still 20%, with primary patency of 83%. Primary assisted patency was 91% and secondary patency was 100%. Clinical success at 30 days and 12 months was 73% and 67%, respectively. We were not the first to show the great outcome of ROMS, but we showed the biggest patient population until that time. And our results were part of the substantiation of Recommendation 26 in the ESVS 2017 Guideline that ROMS is the second-choice treatment option for AMI patients.(1)
And to finally make our statement on the advantages of PMAS for AMI patients we described the current insights in treatment options for mesenteric ischemia in Chapter 5. We also performed a small systematic review on articles between September 2013 and July 2016 comparing PMAS and OSMAR for mesenteric ischemia, leading to multiple practice points for clinicians to integrate in their daily practices. The most essential message in improving survival, QoL and intestinal salvage for AMI is to “Revascularize first, resect later” and that these patients need centers with 24/7 service and experience in both open and endovascular revascularization.(4-8) This statement paved the way for Recommendation 10 in the ESVS 2017 Guideline.(1) We also showed that PMAS is first choice treatment for AMI and CMI, with better short-term outcome, lower mortality and morbidity and reduced costs.(2, 3, 5, 6, 9-35) And that OSMAR should only be used in low-risk patients with unfavourable mesenteric lesions, failed repeated PMAS or ROMS or multiple recurrences of in-stent stenosis or occlusion.(4, 27) In case of on-going ischemia or inability to determine if additional resection is needed, a second look laparotomy after 18-36 hours is advised. Delayed reconstruction of bowel continuity is preferred as opposed to ostomies, due to the impact on morbidity and QoL.(5) Gradually and strictly monitored refeeding is crucial and all patients should be on lifelong anticoagulant therapy.(36)
Part II Life after mesenteric ischemia
Since 2017, 3 guidelines have been published that have come to the same conclusions as this thesis has described so far. The biggest gap in the current literature, however, is research into the impact of mesenteric ischemia and its treatment on our patients and their QoL. In other words, do we actually heal our patients and improve their QoL? This was discussed in Part II, for CMI and non-CMI patients.
The existence of the median arquate ligament syndrome (MALS), also known as Dunbar’s Syndrome or the coeliac artery compression syndrome (CACS), has been the subject of debate since its first description in the late 1950's early 1960's, leading to 'believers' and 'non-believers'. Many discussions have already taken place about the existence or non-existence of this disease and thus whether patients should be treated and whether that treatment is useful in improving QoL and reducing the burden of disease and lowering social and financial burdens on society. In Chapter 6 we performed a systematic review on the impact of surgical decompression of the median arcuate ligament (MAL) on symptoms and QoL in MALS patients. Overall quality of the articles was very low with great heterogeneity and most articles presented less than 10 patients. The treatment of MALS did improve QoL in 68% of patients supporting our believe of the existence of MALS and the possible positive effect of treatment with endoscopic coeliac artery release, (e)CAR. However, we showed a dire need for a good, prospective randomised controlled trial (RCT) to really show whether MALS exists and if (e)CAR is the answer for those who suffer from it. This review further showed that there is no reasonable support for a neurogenic origin of MALS and thus that there is no place for a plexus block in the treatment of these patients.
On behalf of the Dutch Mesenteric Ischemia Study Group (DMIS) we presented our application for the 'Promising care' project of the National Healthcare Institute for this double-blind prospective sham controlled RCT, the CARoSO study in Chapter 7. We hope that funding will be allocated in February of 2022, for us to publish the study protocol and start the study. Seventy patients will be randomised into a treatment group ((e)CAR) and a sham group to establish if retroperitoneal endovascular MAL release does relieve symptoms and improve QoL (measured with the EQ-5D-5L) in a two-year follow-up. The study will either demonstrate that (e)CAR is a (cost)effective minimally invasive treatment for MALS. Or it will prevent patients from being exposed to a futile intervention. If the effectiveness of (e)CAR is proven, it is estimated that up to 490 patients with chronically debilitating abdominal complaints in the Netherlands alone can be treated annually. Due to the relatively young age of between 20-40 years of this patient population, an average health gain of 6.05 Quality Adjusted Life Years (QALYs)/patient is expected. In addition, up to €4.3 million societal costs per year could be saved, due to a reduction of the substantial loss of productivity and healthcare consumption caused by MALS. As the necessity of conducting this study has been underlined by 2 recent international guidelines,(1, 37) the outcome of the CARoSO study will be translated into strong recommendations in the upcoming updates of all relevant (inter)national guidelines and, if effective, (e)CAR will become the standard treatment for MALS.
So, there is little known about the impact treatment has on the QoL of MALS patients, but do we know anything about the impact treatment has on the QoL of CMI patients in general? That is what we investigated in Chapter 8 and it turned out that we were the first to evaluate the impact of revascularization on quality of life in CMI patients. We compared pre- and post-intervention QoL data measured with the EuroQol-5D by analysing the minimum clinically important difference (MCID) to see if there was any clinical relevance. For this we used the MCID of irritable bowel syndrome (IBS) of 0.074, because there has not been a MCID established for CMI. We showed that the median EQ-index score increased significantly from 0.70 to 0.81 (p=0.02) with a mean difference of 0.162 which exceeds the MCID. Furthermore, patients had a significant reduction of symptoms in the domains usual activities (34.4%) and pain/discomfort (32.3%). Also, the overall current health condition expressed in the visual analogue scale (VAS) improvement significantly with 17% from 52 to 69 (p=0.001). These findings indicate that there is a clinically relevant improvement of QoL after revascularisation for CMI patients.
As the MST is a tertiary referral center for patients with chronic abdominal symptoms suspected of mesenteric ischemia, treating around 400 patients with mesenteric ischemia each year, the number of referred patients is higher, because naturally not all patients do have mesenteric ischemia. In Chapter 9 we performed a follow-up on patients diagnosed as not having CMI by the multidisciplinary expert panel to investigate whether the extensive diagnostic work up, including shared decision making, influenced their QoL. Six months after the assessment the QoL was clinically significantly improved without the patients actually undergoing treatment. However, this effect faded after two years to completely be gone after four years. The short-term increase in QoL may have been an effect of the attention and thorough evaluation at the expert centre for mesenteric ischemia. Consequently, the improvement in QoL in the first months after a thorough analyses of the symptoms as observed in the present study may occur without an objective change in underlying health state and should be interpreted with caution. In other words, this indicates that for assessment of the QoL improvement of an intervention, a six months period may be too short.
