Feasibility of Profound Hypothermia as Part of Extracorporeal Life Support in A Pig Model

Abstract

Objective:
To investigate the feasibility of a refined aortic flush catheter and pump system to induce emergency preservation and resuscitation before extracorporeal cardiopulmonary resuscitation in a normovolemic cardiac arrest swine model simulating near real size/weight conditions of adults.

Methods:
In this feasibility study, 8 female Large White breed pigs weighing 70 to 80 kg underwent ventricular fibrillation cardiac arrest for 15 minutes, followed by 4°C aortic flush (150 mL/kg for the brain; 50 mL/kg for the spine) via a new hardware ensued by resuscitation with extracorporeal cardiopulmonary resuscitation.

Results:
Brain temperature was lowered from 39.9°C (interquartile range [IQR] 39.6-40.3) to 24.0°C (IQR 20.8-28.9) in 12 minutes (IQR 11-16) with a median cooling rate of 1.3°C (IQR 0.7-1.6) per minute. A median of 776 mL (IQR 673-840) per minute with a median pump pressure of 1487 mm Hg (IQR 1324-1545) were pumped to the brain.

Conclusions:
With the new hardware, we were able to cool the brain within a few minutes in a large pig cardiac arrest model. The exact position; the design, diameter, and length of the flush catheter; and the brain perfusion pressure seem to be critical to effectively reduce brain temperature. Redistribution of peripheral blood could lead to sterile inflammation again and might be avoided.

Full text

Feasibility of profound hypothermia as part of extracorporeal
life support in a pig model
Christoph Weiser, MD,
a
Wolfgang Weihs, DVM,
a
Michael Holzer, MD,
a
Christoph Testori, MD,
a
Anne-Margarethe Kramer, DVM,
b
Christoph Kment, DI,
c
Martin Stoiber, DI,
d
Michael Poppe,
a
Christian Wallm€
uller, MD,
a
Peter Stratil, MD,
a
Michael Hoschitz, DSc,
e
Anton Laggner, MD,
a
and
Fritz Sterz, MD
a
ABSTRACT
Objective: To investigate the feasibility of a refined aortic flush catheter and
pump system to induce emergency preservation and resuscitation before extracor-
poreal cardiopulmonary resuscitation in a normovolemic cardiac arrest swine
model simulating near real size/weight conditions of adults.
Methods: In this feasibility study, 8 female Large White breed pigs weighing 70
to 80 kg underwent ventricular fibrillation cardiac arrest for 15 minutes, followed
by 4C aortic flush (150 mL/kg for the brain; 50 mL/kg for the spine) via a new
hardware ensued by resuscitation with extracorporeal cardiopulmonary resuscita-
tion.
Results: Brain temperature was lowered from 39.9C (interquartile range [IQR]
39.6-40.3) to 24.0C (IQR 20.8-28.9) in 12 minutes (IQR 11-16) with a median
cooling rate of 1.3C (IQR 0.7-1.6) per minute. A median of 776 mL (IQR
673-840) per minute with a median pump pressure of 1487 mm Hg (IQR
1324-1545) were pumped to the brain.
Conclusions: With the new hardware, we were able to cool the brain within a few
minutes in a large pig cardiac arrest model. The exact position; the design, diam-
eter, and length of the flush catheter; and the brain perfusion pressure seem to be
critical to effectively reduce brain temperature. Redistribution of peripheral blood
could lead to sterile inflammation again and might be avoided. (J Thorac Cardi-
ovasc Surg 2017;-:1-8)
Future chain of survival with emergency preservation
and resuscitation (EPR).
Central Message
One step further toward emergency preserva-
tion and resuscitation with a refined aortic flush
catheter and pump system showing that it is still
worthwhile to go the long pathway to daily
clinical use.
Perspective
The developed emergency preservation and
resuscitation hardware demonstrated its feasi-
bility in near real size/weight conditions of
adults. We were able to cool the brain within
a few minutes. The information about the exact
position, design, diameter, length of the flush
catheter, and the brain perfusion pressure
gained will serve as a valuable source for
refining the flush hardware.
Although there have been advances in the treatment of pa-
tients with cardiac arrest (CA) in the past decades, survival
and good neurologic recovery after CA is still a rare event.
1
There is growing evidence that extracorporeal cardiopul-
monary resuscitation (ECPR) could be a promising tool
for surviving out-of-hospital (OOH) CA if an experienced
team is readily available (Figure 1).
2-6
At the moment,
From the Departments of
a
Emergency Medicine and
b
Biomedical Research,
e
Tech-
nology Transfer Office, and
d
Center for Medical Physics and Biomedical Engineer-
ing, Medical University of Vienna, Vienna; and
c
Austrian Center for Medical
Innovation and Technology, Wiener Neustadt, Austria.
This study was funded by the AWS–P1308407 fund (Austria Wirtschaftsservice). The
study sponsors had no influence on the study design; on the collection, analysis, and
interpretation of data; in the writing of the manuscript; and in the decision to submit
the manuscript for publication. International patent application pending.
Received for publication Sept 1, 2016; revisions received Feb 2, 2017; accepted for
publication March 4, 2017.
Address for reprints: Fritz Sterz, MD, Universit€
atsklinik f€
ur Notfallmedizin am
Allgemeinen Krankenhaus der Stadt Wien, Medizinische Universit€
at Wien,
W€
ahringer G€
urtel 18-20/6D, 1090 Wien, Austria (E-mail: fritz.sterz@
meduniwien.ac.at).
0022-5223
Copyright Ó2017 by The American Association for Thoracic Surgery. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
http://dx.doi.org/10.1016/j.jtcvs.2017.03.055
Scanning this QR code will take
you to a supplemental video for
the article.
The Journal of Thoracic and Cardiovascular Surgery cVolume -, Number -1
MCS
Weiser et al Mechanical Circulatory Support

only a few patients have the chance to benefit from
ECPR.
2,7
The concept of emergency preservation and
resuscitation (EPR) aims to increase the number of
potential patients benefiting from ECPR.
8-10
In 1990, a
study on therapeutic deep hypothermic circulatory arrest
showed that 60 to 90 minutes of circulatory arrest can be
survived with good neurologic recovery.
11
In 1999, a cold
flush applied by a catheter in the aortic arch could success-
fully resuscitate dogs after exsanguination CA up to a no-
flow time of 120 minutes with good neurologic outcome.
12
Between 2006 and 2012 in a series of experiments, EPR and
ECPR has shown after ventricular fibrillation (VF) CA up to
a no-flow time of 13 minutes to be superior to conventional
resuscitation and ECPR alone.
13-17
There is currently a
human clinical trial of aortic flush under way (https://
clinicaltrials.gov/ct2/show/NCT01042015). Therefore, the
necessity existed to further develop the EPR hardware.
The aim of this study was to investigate in near real
size/weight conditions of adults the feasibility and
performance of a newly developed and refined flush
hardware (Video 1).
METHODS
The experiments were approved by the animal investigation committee
(Ethik-Kommission der Medizinischen Universit€
at Wien zur Beratung und
Begutachtung von Forschungsprojekten am Tier; 1488/155-1997/98; 2014/
15) and performed by qualified personnel and supervised by veterinarians.
18
In this feasibility trial, 8 female Large White breed pigs weighing 70 to
80 kg were brought to the laboratory stable 7 days before the experiment.
After 15 minutes of VFCA, the brain was cooled as low as possible with a
flush solution injected via a newly developed flush pump and an aortic flush
balloon catheter (AFBC) followed by ECPR. The primary goal of this
feasibility study was the achievable brain-cooling rate and attainable mini-
mal brain temperature (not fixing a target temperature), and measurement of
flow and pressure regarding to the AFBC and the Flush pump.
Aortic Flush Balloon Catheter
The AFBC (Bavaria Medical Technology, Wessling, Germany) is a
2-balloon 16-F catheter, 90 cm long with 5 separated lumina. Two lumina
were used to inflate/deflate the balloons with NaCl 0.9%, the other 3
lumina for applying the flush solution. The main lumen, for the brain flush,
ended at the tip of the catheter. The other 2 lumina ended in 6holes on both
sides between the balloons to flush the arteries supplying the spinal cord. To
guarantee these 2 separated streams, 2 balloons were necessary: one to
occlude the aorta distal to the brain outflow and a second to prevent the
flush solution from trickling away into visceral and distal vessels. The first
balloon was located near the tip of the catheter with a length of 2 cm and the
second balloon within 20 cm distal from the first balloon with a length of
4 cm. The balloons were designed to stabilize the catheter and to fully
occlude the aorta during the flush procedure. Preliminary in vitro tests
were undertaken to prove the catheters’ stability and balloon occlusion
with the maximum amounts of flush-fluids (1000 mL/min at the tip [brain]
and 500 mL/min at the side holes [spine]) administered.
VIDEO 1. Drs Weiser and Sterz explain the setup to induce profound
hypothermia in cardiac arrest as part of extracorporeal life support
(ECLS). The aortic catheter is inserted via the femoral artery and advanced
into the descending thoracic aorta. The tip lies in the distal arch with a
balloon in the proximal descending aorta to isolate the cerebral circulation.
There is also a second balloon that sits in the distal descending aorta.
Additional infusion ports between the 2 balloons rapidly infuse cold saline
to cool the spinal cord. After completion of the predetermined cerebral and
spinal flush infusion, the balloons were deflated, the catheter was removed,
and ECLS was initiated. Video available at: http://www.jtcvs.org.
FIGURE 1. Future chain of survival with emergency preservation and
resuscitation (EPR).
Abbreviations and Acronyms
AFBC ¼aortic flush balloon catheter
CA ¼cardiac arrest
ECG ¼electrocardiogram
ECLS ¼extracorporeal life support
ECPR ¼extracorporeal cardiopulmonary
resuscitation
EPR ¼Emergency Preservation and
Resuscitation
IQR ¼interquartile range
OOHCA ¼out-of-hospital cardiac arrest
PEEP ¼positive end-expiratory pressure
ROSC ¼restoration of spontaneous circulation
VF ¼ventricular fibrillation
Mechanical Circulatory Support Weiser et al
2 The Journal of Thoracic and Cardiovascular Surgery c-2017
MCS

Flush Pump
To administer these amounts of fluids in a short time, we developed a
pump that allowed us to have control over and monitor data on applied pres-
sure and volume. The flush pump had 2 separate units: each unit consisted
of a roller pump, with its own controller to regulate the speed of the pump, a
mechanical pressure measure unit, an ultrasound-guided flow measure-
ment, and a temperature measurement unit.
Animal Preparation
The animals were fasted 12 hours before the experiment with free access
to water. After premedication in the stable with ketamine (25 mg/kg) and
acepromazine (1.75 mg/kg), anesthesia was induced in the operating the-
ater with a bolus of propofol 2%(10 mL), fentanyl (0.2 mg), and rocuro-
nium (20 mg). Animals were intubated with a conventional endotracheal
tube and mechanically ventilated (Servo 300; Maquet Critical Care, Solna,
Sweden) with tidal volumes of 10 mL/kg, positive end-expiratory pressure
(PEEP) of 5 cm H
2
O, FIO
2
of 0.3, and a ratio of inspiration to expiration
(I:E) of 1:2. The respiratory rate was adjusted to a PaCO
2
of 35 to
40 mm Hg. During preparation, propofol 2%(20 mg/kg/h), fentanyl
(10 mg/kg/h), and rocuronium (2 mg/kg/h) were given.
Electrocardiogram (ECG) electrodes and a pulse-oximeter probe were
attached; arterial catheters (brachial artery left and right) and a pulmonary
artery catheter were placed. Temperature probes (Neurodur-Temp; Rau-
medic, Helmbrechts, Germany) were inserted into the right and left frontal
brain lobes (1 cm right and left of the sagittal suture and 1 cm in front of the
coronal suture) via boreholes to a depth of 2.5 cm (animals 1 to 4 had only
the left-brain temperature probe). Additional temperature probes were in-
serted through the brachial arteries on both sides (animals 5-8) and in the
esophagus and bladder for 39.0C0.2C baseline levels.
The AFBC was inserted into the left femoral artery via cut-down and
advanced into the thoracic aorta until the tip of the catheter was placed right
at the beginning of the descending aorta (correct position confirmed via
radiograph). A venous bypass cannula (23 F) and arterial bypass cannula
(14 F) (Bio-Medicus; Medtronic, Inc., Minneapolis, Minn) were inserted
into the right femoral vein (advanced into the right atrium) and into the
right femoral artery.
Cardiac Arrest
After cardiopulmonary parameters stabilized and baseline measure-
ments, heating devices, intravenous (IV) fluids, and anesthesia were discon-
tinued, heparin (50 IU/kg IV) was given to avoid tube clotting during CA.
Two needle electrodes were placed into the pectoral muscles for induction
of VFCA via an external current impulse of 90 Vand 60 Hz of 2-seconds’
duration. Drop of blood pressure and ECG readings confirmed CA.
Flush Solution
At 14 minutes of VFCA, the brain lumen of the AFBC was primed
with NaCl 0.9%50 mL containing epinephrine 0.04 mg/kg and
vasopressin 0.6 IU/kg. At 15 minutes of VFCA, a 4C flush solution was
administered via the AFBC (brain: NaCl 0.9%150 mL/kg with
epinephrine 0.06 mg/kg, vasopressin 0.9 IU/kg and heparin 37.5 IU/kg;
spine: 50 mL/kg NaCl 0.9%with epinephrine 0.02 mg/kg, vasopressin
0.3 IU/kg and heparin 40 IU/kg). The basis for choosing the perfusion
compositions and rates were experiences from former experiments.
13,16
During the flush procedure, the venous bypass cannula was opened to
drain blood and fluids from the right heart (150 mL/kg).
13
The first
1000 mL of drained blood was collected in citrate bags to be returned as
blood transfusion during extracorporal life support (ECLS). After the entire
flush volume was administered, the AFBCs were immediately deflated and
the catheter was removed.
Extracorporeal Cardiopulmonary Resuscitation
Immediately after the flush, ECPR was started with a centrifugal pump
(Bio-Pump; Medtronic, Inc.), a hollow-fiber oxygenator with a plasma-
resistant fiber (Minimax-Plus; Medtronic, Inc), and a heater-cooler
system (Heater-Cooler-System; Stoeckert Instruments, Munich,
Germany). Target continuous flow rate was 60 to 100 mL/kg/min to keep
mean arterial pressure >65 mm Hg and pigs were rewarmed to 33C.
Ventilation was restarted with ECPR beginning with tidal volumes of
4 mL/kg, PEEP of 10 cm H
2
O, FIO
2
of 0.4, and an I:E of 1:2. Oxygen
and air flow were adjusted to achieve a paCO
2
of 35 to 40 mm Hg and a
paO
2
of 80 to 120 mm Hg. Even though restoration of spontaneous circula-
tion (ROSC) was no study goal, we tried to achieve ROSC while a maximal
ECPR duration of 60 minutes. If the rhythm was shockable, 3 shocks (150 J
each) were applied when the esophageal temperature (T
es
) reached 28C.
Every 2 minutes, 1 biphasic shock with 200 J was repeated if still shockable.
Epinephrine (0.04 mg/kg) and vasopressin (0.4 IU/kg) were administered at
the start of ECPR followed by epinephrine every 4 minutes and vasopressin
every 8 minutes. If ROSC was achieved, the experiment was terminated
with 7 mL/kg propofol 2%and 40 mmol potassium.
Additional Measurements
To gather further information on local flow and catheter position,
contrast agencies (Iomeron iodine 400 mg/mL) with NaCl 0.9%500 mL
was given via the distal lumen of the AFBC during the 15 minutes of
CA. Flush volume distribution was imaged with digital subtraction
angiography.
Behavior of the aortic valve, the ascending aorta, and the left ventricle
during the flush procedure at the onset of heart muscle contractions during
ECPR was observed with transesophageal echocardiography.
RESULTS
In this VFCA model, 8 pigs with a median weight of
73 kg (interquartile range [IQR] 72.0-76.5) received
150 mL/kg flush within 12 minutes (IQR 11-16) and
ECPR was started 27 minutes (IQR 26-31) after CA
(Table 1).
TABLE 1. Blood laboratory results
Baseline
(before preparation)
Baseline
(after preparation)
Cardiac arrest
(þ13 min) ECLS (start) ECLS (þ12 min) ECLS (þ30 min)
pH 7.45 (7.41-1.47) 7.5 (7.49-7.51) 7.24 (7.15-7.27) 6.6 (6.49-6.89) 6.93 (6.85-7.23) 6.89 (6.85-7.08)
pCO2, mm Hg 39 (37-42) 35 (25-39) 62 (57-69) 28 (14-29) 58 (29-69) 48 (38-69)
pO2, mm Hg 146 (130-171) 132 (121-140) 32 (21-34) 110 (63-196) 78 (74-135) 89 (84-103)
Hemoglobin, g/dL 8.8 (8.8-9.1) 8.3 (8.0-8.5) 4 (2.9-6.8) 0.13 (0.1-0.4) 5.3 (4.5-6.1) 5.5 (5-7.2)
Potassium, mmol/L 3.6 (3.5-3.9) 4.3 (4.2-4.7) 4.3 (3.5-4.6) 1.1 (1.0-2.1) 4.2 (4.0-4.4) 3.8 (3.5-3.8)
Glucose, mg/dL 90 (85-103) 105 (99-114) 76 (57-97) 70 (35-92) 216 (138-269) 170 (141-236)
Lactate, mmol/L 3.2 (2.7-3.5) 1.6 (1.4-1.9) 4.0 (2.8-4.9) 0.9 (0.2-1.5) 10.5 (6.2-11.9) 8.4 (6.7-12.1)
Data are presented as median (interquartile range). ECLS, Extracorporeal life support.
Weiser et al Mechanical Circulatory Support
The Journal of Thoracic and Cardiovascular Surgery cVolume -, Number -3
MCS

Temperature
Brain temperature (T
br
) was lowered from 39.9C (IQR
39.6-40.3) to 24.0C (IQR 20.8-28.9) with a median cooling
rate of 1.3C/min (IQR 0.7-1.6). During ECPR. the median
T
br
was 25.9C (IQR 20.2-33.4) and returned to 33.0C
within 31 minutes (IQR 24-37) (Figure 2).
Hemoglobin Fall and Rise
Because of venting the right heart, the central measured
(pulmonary artery) hemoglobin at the end of the flush
procedure was nearly zero. During the flush, a lot of blood
pooled in the peripheral veins and arteries, which we were
not able to flush out with the AFBC (Figure 3). This and
the first liter of saved venting blood, which was
retransfused, was the reason for the hemoglobin rise over
time during concomitant ECPR.
Flush Volumes
As presented in Table 2, the median flush volumes for the
brain were 10,907 mL (IQR 8911-12,390) and for the spine
were 4912 mL (IQR 4813-5106). The vented volume
during flush was 10,950 mL (IQR 10,800-11,475). Overall,
FIGURE 2. Brain temperature during flush and bypass.
FIGURE 3. Fall and rise of hemoglobin during flush and bypass. ECPR, Extracorporeal cardiopulmonary resuscitation.
Mechanical Circulatory Support Weiser et al
4 The Journal of Thoracic and Cardiovascular Surgery c-2017
MCS

the procedure caused þ5867 mL (IQR 3924-7021) of
additional intracorporeal fluids.
Flush Pump
A median of 776 mL/min (IQR 673-840) was pumped to
the brain with a median pump pressure of 1487 mm Hg
(IQR 1324-1545) to reach a median subclavian artery
pressure of 52 mm Hg (IQR 42-67) (Figure 4).
Transesophageal Echocardiography and Observed
ROSC
Before CA, as well as during the experiment, none of the
animals had aortic valve insufficiency. Even though ROSC
was no study goal, during ECPR when T
br
came back to
28C, we observed that the right heart started to beat again,
with acceptable pressures and stroke volumes measured via
the pulmonary artery catheter. At the same time, the left
ventricle started to fibrillate. Sustained ROSC could be
achieved in 2 animals (25%); the remaining animals stayed
in VF.
DISCUSSION
In this feasibility study, a new unique novel multilumen
catheter and perfusion apparatus were used to rapidly
induce profound cerebral hypothermia for potential
preservation of the brain and heart after CA with a
no-flow time of 15 minutes in human-sized animals. We
could show that the developed hardware was able to cool
the brain within a few minutes. The experiments described
provide initial data on how effectively this approach can
cool the brain in a CA state. The main findings of our study
are the necessity of the exact intra-aortic AFBC placement,
a missing relationship between generated aortic pressure
and cooling effectiveness, and a substantial auto redistribu-
tion of the hemoglobin levels despite high flush volumes.
Furthermore, during rewarming and VF of the left ventricle,
we found a return of spontaneous contractions in the right
heart with increasing temperatures.
TABLE 2. Flush procedure data
Animal weight, kg 73 (72-77)
Flush duration, min 12 (11-16)
Bypass start after cardiac arrest, min 27 (26-31)
Bran temperature delta, C/min 1.3 (0.9-1.6)
Vented venous volume, mL 10,950 (10,800-11,475)
Brain flush volume, mL 10,906 (8911-12,390)
Spine flush volume, mL 4911 (4813-5106)
Brain perfusion pump pressure, mm Hg 1487 (1324-1544)
Spine perfusion pump pressure, mm Hg 1510 (1444-1579)
Data are presented as median (interquartile range).
FIGURE 4. Lowest brain temperature versus cumulated left subclavian artery pressure during flush procedure.
Weiser et al Mechanical Circulatory Support
The Journal of Thoracic and Cardiovascular Surgery cVolume -, Number -5
MCS

Cooling Speed
Janata and colleagues
13
achieved a median cooling rate
of 4.7C/min by using the same procedure but with a
different cooling catheter and pump. Even the best cooling
rate of our study with 3.2C/min did not accomplish
their median rate. This might be explained by some
differences between the trials: Janata and colleagues
13
used small 31- to 42-kg pigs, and a 14-F single lumen
catheter oriented to the brain. They used 100 mL/kg of
the NaCl 0.9%plus vasopressin flush solution in their phase
II model. No-flow time was 10 minutes in comparison to
our 15-minute model. Their flush time on average was
180 seconds; our setup had a median flush time of
720 seconds. Therefore, Janata and colleagues
13
had a bet-
ter brain-cooling rate in a shorter time. We suppose the main
difference between the studies is the animal size/weight. As
presented in Figure 4, we could not find a relationship
between measured pressure in the subclavian artery and
cooling effectiveness in the brain. This suggests a nonlinear
relationship between aortic pressure and brain blood flow,
with a plateau at higher pressures. Unfortunately, we are
not able to report about the cooling effect on the spinal
cord because of technical problems in placing temperature
probes.
There are 2 possibilities to solve this problem. First, more
powerful pumps might reach the same flow rates during the
EPR procedure. Janata and colleagues
13,14
and Weihs and
colleagues
19
reported approximately 1.2 L/min in their
trials differing from our measured median brain flush of
776 mL/min: 35%less volume per minute. Even
though we used a 16-F (5.33-mm) catheter (5 lumina)
instead of a 14-F catheter (single lumen) by Janata and
colleagues
13,14
and Weihs and colleagues,
19
our brain flush
lumen had just as effective diameter of 7.8 F (2.6 mm).
Other studies did not report information on the inside
diameter.
11,13,15,16,20-23
Following the Hagen-Poiseuille
equation, the diameter of the catheter is most important
for the transported fluid over time. This means that a
diameter reduction of 10%leads to a flow reduction of
34%, which can be compensated by 52%more pressure
difference. But the assumptions for the Hagen-Poiseuille
equation are that the fluid is incompressible and the flow
is laminar. These are the limitations of the equation in our
setting: blood is not Newtonian and we do not know if the
flow in the catheter was laminar or turbulent. As the flow
rates through the catheter increase, it is more likely to
generate turbulent flow, which increases flow resistance.
One additional factor could be the material of the cathe-
ters used. Because of the experience of unstable bending
catheters in former experiments of our group, we decided
to use a catheter material that is as stiff as possible to be still
introduced into the femoral artery and to be moved forward
into its final position. By contrast, the Foley catheter, which
was used in some studies, is a flexible tube.
13,14,16
We
hypothesize that this flexible tube is not able to stay in an
exact position, but has the possibility to expand in
diameter if fluids are pumped with high pressure through
the catheter. However, as the vascular access is the
limitation, larger catheter diameters are limited.
Volume Overload
After the flush application was finished, there was a
median additional intracorporeal volume of 5687 mL.
This applies to our clinical experience with ECPR patients
who need a large amount of additional volume during the
first hours on bypass.
24
This is caused by a volume demand
of the extracorporeal bypass circuit and second by the
capillary leakage caused by a sterile inflammatory
sepsislike response.
25
Therefore, we do not consider the
6%to 7%additional volume per body weight as harmful
during this initial time on bypass. However, we are
convinced that this additional volume must be removed as
soon as the patient is stabilized.
26
In our earlier studies,
we showed that there was superiority in neurologic outcome
by using this technique with a high-volume flush
comparing conventional cardiopulmonary resuscitation
(CPR)/ECLS.
14
These volume overloads would not be
necessary if we could cool down blood during the extracor-
poreal ECLS circuit to 4C, but by now we are technically
not able to solve this condition. More studies are necessary
to design the perfect reperfusion fluid. This reperfusion
fluid should be a cocktail that refers for reduction of the
response inflammatory syndrome and cooling of the tissue.
There is need to further discuss this important limitation in
FIGURE 5. Labeled digital subtraction angiography during flush of the
brain (the tip of the catheter in this picture is slightly too high: in the
descending part of the aortic root).
Mechanical Circulatory Support Weiser et al
6 The Journal of Thoracic and Cardiovascular Surgery c-2017
MCS

our strategy creating an ideal resuscitation fluid, but this
would be the topic of a different project and extends the
bounds of this article.
Precise Catheter Placement
The necessity for the precise catheter placement below
the separation of the truncus brachiocephalicus in the aorta
(Figure 5) has never before been reported and seems to be
critical for effective cooling of the brain. Although we
positioned the catheter under radiographic control, we
experienced substantial differences in T
br
curves, indicating
large influences by small and nondetectable differences of
position of the catheter in relation to the truncus brachioce-
phalicus. To overcome this problem, we used multilumen
central venous catheters with a length of 8 cm (Arrow
International, Reading, Pa) to measure arterial pressures
in both brachial arteries and to introduce very small
temperature probes on both sides. This, however, did not
substantially improve cerebral cooling effectivity. It might
be necessary to introduce the flush catheter directly into
the truncus bicaroticus to achieve maximum effectivity.
But this approach could then not be directly transferred to
the different human aortic anatomy. In the human clinical
setting, or even preclinical setting, ultrasound can deliver
the necessary information, with an epigastric view on the
upper abdominal aorta where the catheter and the placement
of the lower balloons can be identified.
27-29
ROSC of the Right Heart
During the flush and ECPR procedure, we observed with
continuous transesophageal echo isolated ROSC of the right
heart while the left heart was still fibrillating. One
explanation might be that reperfusion of the smaller right
ventricle muscle might be initially better than of the larger
left ventricle. Echo also has proven the aortic valve during
the EPR procedure being closed and tight. Distension of the
left ventricle can be a problem in prolonged CA and
resuscitation efforts. Maybe the use of an Impella or
intra-aortic balloon pump device could help to overcome
this problem by left ventricular unloading.
30,31
Additional Limitations
The bore holes for the T
br
probes were exactly positioned
as planned, but the intracerebral placement of the probes
was done blind. We did placement control by radiograph,
but we cannot distinguish if the probe was placed near a
brain artery or not. This could partly explain the difference
between temperatures monitored as presented in Figure 2.
Because of technical problems with data monitoring of sub-
clavian artery pressures in 2 experiments, we can present
subclavian artery pressure data of only 6 animals. Further-
more, we had technical problems with the blood gas device
on animal 4. As ROSC was no study goal, we did not use the
whole 60 minutes of ECPR in all animals, but because of the
interesting observations of right heart ROSC, we reported
these results. The ‘‘missing relationship between generated
aortic pressure and cooling effectiveness’’ is not completely
clear from this small set of experiments, but it raises impor-
tant questions about the relationship among blood pressure,
vascular resistance, and actual perfusion when using an
invasive perfusion technique for resuscitation. In addition,
it was not the goal to conduct sophisticated investigations
of organ injury, postmortem procedures, and outcome,
such as the comparison with the standard CPR control
group.
CONCLUSIONS
With the new AFBC and flush pump for EPR, we were
able to cool the brain within a few minutes in a large pig
CA model. The catheter performed as desired; however,
the exact position; the design, diameter, and length of the
flush catheter; and the brain perfusion pressure seems still
to be critical to effectively reduce T
br
and, therefore, will
have no impact on daily clinical practice jet. Additionally,
the redistribution of peripheral blood could lead to sterile
inflammation again and might be avoided by the develop-
ment of specific blocking flush-solutions. The next steps
are designated to simplify the procedure even more, to
reduce the technical effort, and to develop the optimal
‘‘flush cocktail’’ to improve effectiveness.
Conflict of Interest Statement
Authors have nothing to disclose with regard to commercial
support.
The authors thank the team of the Vienna Resuscitation Group
as the team of the Department for Biomedical Research for their
support during the project.
References
1. Berdowski J, Berg RA, Tijssen JG, Koster RW. Global incidences of out-of-
hospital cardiac arrest and survival rates: systematic review of 67 prospective
studies. Resuscitation. 2010;81:1479-87.
2. Lazzeri C, Valente S, Peris A, Gensini GF. Extracorporeal life support for out-of-
hospital cardiac arrest: part of a treatment bundle. Eur Heart J Acute Cardiovasc
Care. 2016;5:512-21.
3. Poppe M, Weiser C, Holzer M, Sulzgruber P, Datler P, Keferb€
ock M, et al. The
incidence of ‘‘load&go’’ out-of-hospital cardiac arrest candidates for emergency
department utilization of emergency extracorporeal life support: a one-year re-
view. Resuscitation. 2015;91:131-6.
4. Anselmi A, Fl
echer E, Corbineau H, Langanay T, Le Bouquin V, Bedossa M,
et al. Survival and quality of life after extracorporeal life support for refractory
cardiac arrest: a case series. J Thorac Cardiovasc Surg. 2015;150:947-54.
5. Singal RK, Arora RC. Use of extracorporeal membrane oxygenation in
cardiac arrest: developing a new frontier. J Thorac Cardiovasc Surg. 2015;150:
1350-1.
6. Spangenberg T, Meincke F, Brooks S, Frerker C, Kreidel F, Thielsen T, et al.
‘‘Shock and Go?’’ extracorporeal cardio-pulmonary resuscitation in the
golden-hour of ROSC. Catheter Cardiovasc Interv. 2016;88:691-6.
7. Peigh G, Cavarocchi N, Hirose H. Saving life and brain with extracorporeal
cardiopulmonary resuscitation: a single-center analysis of in-hospital cardiac
arrests. J Thorac Cardiovasc Surg. 2015;150:1344-9.
8. Wu X, Drabek T, Tisherman SA, Henchir J, Stezoski SW, Culver S, et al. Emer-
gency preservation and resuscitation with profound hypothermia, oxygen, and
Weiser et al Mechanical Circulatory Support
The Journal of Thoracic and Cardiovascular Surgery cVolume -, Number -7
MCS

glucose allows reliable neurological recovery after 3 h of cardiac arrest from
rapid exsanguination in dogs. J Cereb Blood Flow Metab. 2008;28:302-11.
9. Buckberg GD. Controlled reperfusion after ischemia may be the unifying recov-
ery denominator. J Thorac Cardiovasc Surg. 2010;140:12-8. 18.e1-2.
10. Athanasuleas CL, Buckberg GD, Allen BS, Beyersdorf F, Kirsh MM. Sudden
cardiac death: directing the scope of resuscitation towards the heart and brain.
Resuscitation. 2006;70:44-51.
11. Tisherman SA, Safar P, Radovsky A, Peitzman A, Sterz F, Kuboyama K. Thera-
peutic deep hypothermic circulatory arrest in dogs: a resuscitation modality for
hemorrhagic shock with ‘irreparable’ injury. J Trauma. 1990;30:836-47.
12. Behringer W, Prueckner S, Safar P, Radovsky A, Kentner R, Stezoski SW, et al.
Rapid induction of mild cerebral hypothermia by cold aortic flush achieves
normal recovery in a dog outcome model with 20-minute exsanguination cardiac
arrest. Acad Emerg Med. 2000;7:1341-8.
13. Janata A, Holzer M, Bayegan K, Frossard M, Sterz F, Losert UM, et al. Rapid
induction of cerebral hypothermia by aortic flush during normovolemic cardiac
arrest in pigs. Crit Care Med. 2006;34:1769-74.
14. Janata A, Weihs W, Schratter A, Bayegan K, Holzer M, Frossard M, et al. Cold
aortic flush and chest compressions enable good neurologic outcome after 15
mins of ventricular fibrillation in cardiac arrest in pigs. Crit Care Med. 2010;
38:1637-43.
15. Weihs W, Krizanac D, Sterz F, Sipos W, H€
ogler S, Janata A, et al. Outcome after
resuscitation using controlled rapid extracorporeal cooling to a brain temperature
of 30 degrees C, 24 degrees C and 18 degrees C during cardiac arrest in pigs.
Resuscitation. 2010;81:242-7.
16. Janata A, Bayegan K, Weihs W, Schratter A, Holzer M, Frossard M, et al. Emer-
gency preservation and resuscitation improve survival after 15 minutes of normo-
volemic cardiac arrest in pigs. Crit Care Med. 2007;35:2785-91.
17. Janata A, Bayegan K, Sterz F, Weihs W, Holzer M, Sipos W, et al. Limits of con-
ventional therapies after prolonged normovolemic cardiac arrest in swine. Resus-
citation. 2008;79:133-8.
18. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving
bioscience research reporting: the ARRIVE guidelines for reporting animal
research. PLoS Biol. 2010;8:e1000412.
19. Weihs W, Krizanac D, Sterz F, Hlavin G, Janata A, Sipos W, et al. Rapid induc-
tion of hypothermia with a small volume aortic flush during cardiac arrest in pigs.
Am J Emerg Med. 2012;30:643-50.
20. Woods RJ, Prueckner S, Safar P, Radovsky A, Takasu A, Stezoski SW, et al.
Hypothermic aortic arch flush for preservation during exsanguination cardiac ar-
rest of 15 minutes in dogs. J Trauma. 1999;47:1028-36.
21. Behringer W, Prueckner S, Kentner R, TishermanSA, Radovsky A, Clark R, et al.
Rapid hypothermic aortic flush can achieve survival without brain damage after
30 minutes cardiac arrest in dogs. Anesthesiology. 2000;93:1491-9.
22. Behringer W, Safar P, Wu X, Kentner R, Radovsky A, Kochanek PM, et al.
Survival without brain damage after clinical death of 60-120 mins in dogs using
suspended animation by profound hypothermia. Crit Care Med. 2003;31:
1523-31.
23. Wu X. Induction of profound hypothermia for emergency preservation and resus-
citation allows intact survival after cardiac arrest resulting from prolonged lethal
hemorrhage and trauma in dogs. Circulation. 2006;113:1974-82.
24. Wallmuller C, Sterz F, Testori C, Schober A, Stratil P, H€
orburger D, et al.
Emergency cardio-pulmonary bypass in cardiac arrest: seventeen years of
experience. Resuscitation. 2013;84:326-30.
25. Rock KL, Latz E, Ontiveros F, Kono H. The sterile inflammatory response. Annu
Rev Immunol. 2010;28:321-42.
26. Schmidt M, Bailey M, Kelly J, Hodgson C, Cooper DJ, Scheinkestel C, et al.
Impact of fluid balance on outcome of adult patients treated with extracorporeal
membrane oxygenation. Intensive Care Med. 2014;40:1256-66.
27. Anselmi A, Flecher E. Extracorporeal cardiopulmonary resuscitation for out-of-
hospital refractory cardiac arrest: a word of caution. J Thorac Cardiovasc Surg.
2016;151:1217-8.
28. Hamada SR, Delhaye N, Kerever S, Harrois A, Duranteau J. Integrating eFASTin
the initial management of stable trauma patients: the end of plain film radiog-
raphy. Ann Intensive Care. 2016;6:62.
29. Cebicci H, Salt O, Gurbuz S, Koyuncu S, Bol O. Benefit of cardiac sonography
for estimating the early term survival of the cardiopulmonary arrest patients. Hip-
pokratia. 2014;18:125-9.
30. Vase H, Christensen S, Christiansen A, Therkelsen CJ, Christiansen EH,
Eiskjær H, et al. The Impella CP device for acute mechanical circulatory support
in refractory cardiac arrest. Resuscitation. 2017;112:70-4.
31. Ouweneel DM, Schotborgh JV, Limpens J, Sjauw KD, Engstr€
om AE,
Lagrand WK, et al. Extracorporeal life support during cardiac arrest and cardio-
genic shock: a systematic review and meta-analysis. Intensive Care Med. 2016;
42:1922-34.
Key Words: resuscitation, cardiac arrest, ECLS, extracor-
poreal life support, eCPR, EPR, preservation, target temper-
ature management, hypothermia
Mechanical Circulatory Support Weiser et al
8 The Journal of Thoracic and Cardiovascular Surgery c-2017
MCS

000 Feasibility of profound hypothermia as part of extracorporeal life support in a
pig model
Christoph Weiser, MD, Wolfgang Weihs, DVM, Michael Holzer, MD, Christoph Testori, MD,
Anne-Margarethe Kramer, DVM, Christoph Kment, DI, Martin Stoiber, DI, Michael Poppe,
Christian Wallm€
uller, MD, Peter Stratil, MD, Michael Hoschitz, DSc, Anton Laggner, MD, and
Fritz Sterz, MD, Vienna and Wiener Neustadt, Austria
One step further toward emergency preservation and resuscitation with a refined aortic flush
catheter and pump system showing that it is still worthwhile to go the long pathway to daily clinical
use.
Weiser et al Mechanical Circulatory Support
The Journal of Thoracic and Cardiovascular Surgery cVolume -, Number -
MCS