CARbon Dioxide Flooding to Reduce Postoperative Neurological Injury Following Surgery for Acute Type A Aortic Dissection - A Prospective, Randomized, Blinded, Controlled Clinical Trial
Phase: NA
Conditions: D000784, D020521
Sponsor: Region Skane

 
CARbon dioxide flooding for reduction of neurological injury following 
surgery for acute Type A aortic dissection. A prospective, randomized, 
blinded, controlled clinical trial. 
 
 
 
The CARTA trial 
 
 
 
 
 
NCT ID: 2021-02039 
 
 
ORIGINAL DOCUMENT 
SEPTEMBER 1st 2021 
 
LAST UPDATE 
OCTOBER 31st 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

BACKGROUND 
 
Aortic dissection is a life-threatening condition and a consequence of a tear of the innermost of 
the three aortic layers- the intima. When a tear occurs, blood surges through the tear and causes 
the flow of blood between the aortic layers, causing a “false lumen”. This causes a weakening 
of the aortic wall and hinders the blood from reaching its target organs.  
Type A aortic dissection affects the portion of aorta closest to the heart- the ascending aorta, 
and up to half of all afflicted patients die before reaching hospital care (1). This mainly occurs 
due to aortic rupture or bleeding into the pericardium, preventing venous return to the heart and 
thereby causing cardiac tamponade. An acute type A aortic dissection (ATAAD) requires 
immediate surgical treatment and patients are generally transferred to the operating room as 
soon as the diagnosis has been confirmed. Despite urgent surgical treatment, 15-20% of patients 
die during the operation or within the first 30 days after surgery (2). 
The clinical symptoms associated with ATAAD may vary depending on which end organ is 
affected by circulatory compromise. Extremity malperfusion can lead to limb ischaemia or 
altered blood pressure measurements, gastrointestinal malperfusion may lead to intestinal 
ischaemia or necrosis and if the spinal circulation is compromised, patients may present with 
paraplegia.  
In cases where patients are in hypotensive shock or if the carotid arteries are dissected, the 
patient may present with unconsciousness or hemiparesis. It has been demonstrated that 10-
20% of the patients with ATAAD have neurological symptoms at initial assessment (3) and 
misdiagnosis is associated with increased risk of postoperative complications (2, 4, 5). In 
addition, we have previously shown that postoperative neurological injuries account for 10-
15% of in-hospital deaths (6). 
Several mechanisms may explain cerebral injuries following ATAAD surgery, the first being 
the patients' preoperative state. Preoperative neurological symptoms due to hypotensive shock 
or cerebral malperfusion related to carotid artery dissection are associated with a two-fold 
increase in risk of postoperative neurological injury (7). 
Furthermore, the surgical procedure by itself includes several technical aspects that may cause 
cerebral injury. The foundation for all cardiac surgery is the use of cardiopulmonary bypass, 
which enables the re-routing of the circulation to enable cardiac arrest during surgery. Almost 
all ATAAD surgery is carried out in deep hypothermia (18-20C) with complete circulatory 
arrest. This allows the surgeon to open the aorta and inspect the aortic arch for intimal tears. 
For the majority of patients, a short period of circulatory arrest (<30 min) is considered safe 
from a neurological standpoint, but a recent meta-analysis showed that cerebral injuries may be 
reduced by the use of retrograde cerebral perfusion (RCP), where the cerebral circulation is 
“flushed” by blood flowing retrogradely from the superior vena cava (8). It has been speculated 
that the protective effect of RCP is a result of the retrograde blood flow flushing out air that has 
been trapped in the aortic arch branch vessels during the circulatory arrest.  
In association with other cardiac procedures where the left side of the heart is opened and air 
may be trapped within the arterial circulation, carbon dioxide flooding is used to displace open 
air from the surgical wound. In comparison to air, carbon dioxide is significantly more soluble 
in blood and may therefore decrease the risk of air embolism. In cardiac surgery, carbon dioxide 
flooding has been demonstrated to reduce levels of biomarkers of cerebral injury (9, 10), but 
carbon dioxide is not routinely employed in ATAAD surgery and has not been studied in 
association with these procedures.  
Several biomarkers have been used to predict neurological injury, of which S100B and neuron-
specific enolase (NSE) are the most commonly used in cardiac surgery. S100B has been shown 
to predict stroke after cardiac surgery but the usefulness of NSE has not been properly assessed 
(11). Furthermore, none of these biomarkers has been evaluated in the setting of ATAAD 

surgery, and therefore, we do not have adequate information on the utility of these biomarkers 
in association with ATAAD surgery. Other biomarkers, including Neurofilament (NFL), Glial 
fibrillary acid protein (GFAP) and Tau-protein (TAU) have all showed to be valuable for 
predicting cerebral injury, but there is limited data on these biomarkers in cardiac surgery and 
none at all in association with ATAAD. 
Although much effort has been put into describing the long term outcomes of ATAAD few 
studies have addressed the late neurological effects of ATAAD repair and its impact om 
postoperative quality of life and cognitive function.  
In summary, our hypothesis is that carbon dioxide flooding reduces cerebral air embolism and 
the aim of thos project is to evaluate whether carbon dioxide flooding may reduce neurological 
injuries following ATAAD surgery. 
 
MATERIAL AND METHODS 
 
Study design: 
This is a prospective, randomized, controlled, patient- and reviewer blinded interventional 
study. Patients over the age of 18, presenting with ATAAD with symptom duration <14 days 
and are offered open heart surgery will be screened for inclusion. Those patients that have 
undergone previous open heart surgery or those who present with neurological symptoms will 
be excluded from the study. 
 
Ethical approval for this study has been granted by the Swedish Ethical Review Agency (ref: 
2021-02039, date: 5th of May 2021).  
 
Endpoints: 
Primary outcomes: Presence, number and volume of ischaemic lesions observed using 
magnetic resonance imaging (MRI) after ATAAD surgery.  
Secondary outcomes: Clinical signs of neurological injury. Levels of biomarkers of 
neurological injury (S100B, NSE, NFL, GFAP, UCH-L1 and TAU) before and after surgery. 
Quality of life, postoperative recovery and neurological function after ATAAD surgery. 
Primary outcomes in relation to retrograde cerebral perfusion.  
 
MRI: 
”MRI Stroke” will be carried out within the first seven days of surgery, but as soon as the 
external pacemaker wires have been extracted. Daily assessment of the need for external 
pacemaker from postoperative day three and onward. If pacemaker wires cannot be extracted 
by postoperative day seven, the imaging will be carried out as soon as the wires are removed.  
”MRI Stroke” includes diffusion weighted imaging “DWI”, Apparent diffusion coefficient 
(ADC) and a Flair-sequence. 
A neuro-radiologist blinded to the randomisation arms and the clinical outcomes following 
surgery will analyse the images and quantify the ischaemic lesions with regard to number and 
volume of the lesions. Furthermore, the lesions will be described as focal- related to 
embolism, water-shed- related to hypoperfusion and its anatomical location. The volume of 
ischaemic lesions will be calculated using the formula (AxBxC)/2. 

 
Biomarker analyses:  
10ml of blood will be collected before surgery, immediately after surgery, four days and three 
months after the procedure. S100B, NSE, NFL, GFAP, UCH-L1 and TAU will be analysed. 
S100B and NSE will be analysed as routine analyses while remaining biomarkers will be 
analysed using the Simoa 4-plex analysis kit (NFL, T-tau, GFAP, UCH-L1). The analyses 
require  <0.2mL of blood per analysis and will be analysed at the Biomedical centre (BMC) at 
Lund university. The samples drawn will be centrifuged at 2000g for 10 minutes and stored in 
a biobank until batch analysis.  
 
Clinical follow-up: 
Patients will be assessed using the NIH Stroke Scale (NIHSS), Modified Rankin scale for 
neurologic disability (mRS) and the Glasgow Outcome Scale Extended (GOSE) prior to 
hospital discharge. Three months after surgery, patients will be re-evaluated with regard to 
postoperative recovery and quality of life using the WHO-5 Well-being index, Postoperative 
recovery profile, Satisfaction with life scale and EQ5D-5L.Neurological function will be re-
assesed using the Montereal cognitive assesment (MoCA) test, SDMT (Symbol digit 
modalities test), NIHSS, mRS and GOSE. 
 
Power calculation:  
To date, there are no studies to indicate the effect of carbon dioxide flooding on postoperative 
neurological outcomes following ATAAD surgery. However, Leshnower et al. recently 
published a study showing that RCP in conjunction with aortic surgery reduces the occurrence 
of lesions from 100% to 45% and the number of ischaemic lesions by 70% compared 
antegrade cerebral perfusion (12). Previous studies have shown that 61% of patients that have 
underwent routine aortic valve replacement have postoperative ischaemic lesions visualised 
by MRI (13). Provided that the beneficial effect of RCP showed by Leshnower et al. is due to 
a reduction of air-embolism, that data may be used as a basis for our power calculation. If one 
would use the finding by Leshnower et al. that the number of ischaemic lesions is reduced 
from 4 3.5 to 1.2 2.1, then a study sample of 25 patients in each arm would give a power of 
80% to detect a significant difference between the groups with a 0.05 significance level 
(alpha). If instead, the calculation is based on a 50% reduction of presence of ischaemic 
lesions from a baseline prevalence of 70% (as in the study by Leshnower and colleagues), 
then 31 patients in each arm will be required to achieve similar statistical power. Given that 5-
10% of patients die during or immediately after the surgical procedure, and therefore will not 
be eligible for postoperative assessment, we aim to include 40 patients in each arm. With an 
annual case volume of 30 patients, we expect an inclusion period over three years.  
An interim analysis will be performed once 20 patients have been included in each arm. Apart 
from the primary endpoints, the safety arm including intraoperative mortality, 30-day 
mortality, reoperation for bleeding, stroke, myocardial infarction and other thromboembolic 
events will be analysed by a statistician that has previously not been involved in the study. 
The external statistician and the PI will hereafter decide for the study to proceed or be 
terminated due to harms, effect or futility.  
 
Statistical analysis: 

Groups will be compared using independent sample t-test and Mann-Whitney U-test 
depending on distribution of the data. Chi-squared test will be used for categorical data or 
Fisher's exact test in samples with fewer than 5 observations. Subgroup analyses will be 
performed comparing patients operated using RCP versus those undergoing surgery under 
straight hypothermic circulatory arrest. 
 
Time plan:  
Study design, acquisition of ethical approval and registration during 2021. Start of inclusion 
Jan 1st, 2022 or earlier if possible. We aim to start the writing of a manuscript describing the 
study methods and study objectives in 2021 and our ambition is to write the final manuscript 
during 2025.  
 
IMPACT 
 
Acute type A aortic dissection is one of the most devastating conditions that we face in 
clinical practice. Even if the patient arrives safely to the hospital and is treated surgically, 
mortality is significant and often associated with chronical neurological impairment. 
Neurological injuries can occur preoperatively, but it is clear that the surgical techniques 
employed and clinical decisions during surgery have a major impact on the development of 
cerebral injuries. Despite intensive research, our local database shows that approximately 25% 
of patients develop neurological , and that up to 15% of the early mortality is caused by 
cerebral injury. Thus, neurological injuries account for a significant portion of morbidity and 
mortality associated with ATAAD surgery and apart from its effects on the patients’ 
neurological function and quality of life, it is associated with a significant consumption of 
health care resources. Postoperative stroke is associated with prolonged stay both in the 
intensive care unit and in the postoperative ward (14). This in turn causes crowding-out 
effects and thus poorer availability for other types of cardiac surgical care. 
 
When analysing our data in association to a previous study, we observed that the vast majority 
of patients who suffered a postoperative stroke had ischaemic lesions in the right cerebral 
hemisphere. This implies that the lesions observed are the consequence of air-embolism, since 
there are no calcifications or thrombi to explain other types of embolic material. Therefore, 
we believe that air-embolism is a significant cause of neurological morbidity following 
ATAAD surgery. This has previously not been studied in detail and if our hypothesis is 
correct, our findings would contribute to a significant change of the surgical technique in 
ATAAD repair.  
 
In the field of cardiovascular surgery, neurological injuries are a hot topic. Intensive research 
is addressing how modifications in surgical management may reduce the frequency of 
neurological injury, but the main focus is aimed towards cannulation strategies and selective 
cerebral perfusion. To the best of our knowledge, the effects of carbon dioxide have not been 
studied in ATAAD patients and therefore, any positive findings from our study would have a 
major impact within the cardiac surgical community. Furthermore, a positive finding could 
confirm our hypothesis of air-embolism being a significant cause of cerebral injury, and thus 
serve as a basis for new studies on how to reduce air-embolism during ATAAD surgery.  
 
 
BUDGET 

 
 
MRI scans 
 
 
 
229 600 SEK(2870 SEK/scan) 
Salary for personnel conducting clinical follow-up 
81 360 SEK 
(339 SEK/h, 3h per patient) 
  
Biomarker analyses 
 
 
360 000 SEK 
Simoa 4-plex analysis kit (1000 SEK per patient) 
Processing and storage of blood samples 
100 000 SEK 
 
Medical freezer 
 
 
110 000 SEK 
Disposable material for sample collection 
20 000 SEK 
Statistical services 
 
 
100 000 SEK 
Conference expenses 
 
 
100 000 SEK 
Hardware 
 
 
 
80 000 SE 
Software and licensing 
 
 
20 000 SEK 
Sum 
 
 
 
1 200 960 SEK 
 
Overhead (Lund University 21%) 
 
252 200 SEK 
Total 
 
 
 
1 453 160 SEK 
 
 
 
 
 

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