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\begin{document}

\title{Total cholesterol and Intensive Care survival in patients treated with
Veno-Arterial Extracorporeal Life Support; A preliminary single-centre
experience}



\author[1]{Maarten de Haan}%
\author[2]{Marco Haanschoten}%
\author[1]{Herman Kreeftenberg}%
\author[1]{Patrix Lanen}%
\author[1]{Saskia Houterman}%
\author[3]{Bart van Straten}%
\author[3]{Mohamed Soliman Hamad}%
\affil[1]{Catharina Hospital}%
\affil[2]{Catharina Hospital Department of Anesthesiology and Pain Medicine}%
\affil[3]{Catharina Ziekenhuis}%


\vspace{-1em}



  
  \date{May 21, 2024}


\begingroup
\let\center\flushleft
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\endgroup





\selectlanguage{english}
\begin{abstract}
Objective Veno-Arterial Extra Corporeal Life Support (VA ECLS) is widely
used as an effective device for patients in cardiogenic shock. The need
for predictive markers that daily guide physicians in the evaluation of
these patients could be of great value. Our aim was to investigate the
role of cholesterol value during VA ECLS in predicting the Intensive
Care Unit (ICU) survival. Methods Between January 2013 and November
2019, 67 patients with VA ECLS due to cardiogenic shock were included in
this study. Demographic data, laboratory values, ICU data and outcomes
were collected. Cholesterol was measured during morning routine blood
samples. The minimal cholesterol value during the ICU stay was
registered. Groups were stratified by minimal cholesterol cut-off point
of 2.0 mmol/L. Logistic regression analysis were performed to identify
variables associated with ICU survival. Results The ECLS duration was
not significantly different (p=0.36) between the non-survivors (median
5.0 (2.0-7.5) days) and survivors (median 6.0 (1.8-12.0) days). The
minimal cholesterol level was significantly lower (p=0.04) in
non-survivors group (1.54 (1.00-1.87) mmol/L) compared to survivors
(1.85 (1.38-2.24) mmol/L). By using logistic regression analysis,
minimal cholesterol level of [?]2.0 mmol/L was associated with a higher
ICU survival (p=0.02; OR 3.77; 95\% CI 1.20-11.81). Conclusion
Cholesterol level could be an additional marker for ICU survival of
patients with cardiogenic shock on VA ECLS. A larger cohort of patients
is necessary to determine total cholesterol as a specific risk factor
for survival in these patients.%
\end{abstract}%



\sloppy


\textbf{Total cholesterol and Intensive Care survival in patients
treated with Veno-Arterial Extracorporeal Life Support; A preliminary
single-centre experience}

M de Haan\textsuperscript{1}, MC Haanschoten, MD,
PhD\textsuperscript{2}, HG Kreeftenberg, MD\textsuperscript{2}, PWJ
Lanen\textsuperscript{1}, S Houterman, PhD\textsuperscript{3}, AHM van
Straten, MD, PhD\textsuperscript{4}, MA Soliman-Hamad, MD,
PhD\textsuperscript{4}

\textsuperscript{1} Department of Extra Corporeal Circulation, Catharina
Hospital Eindhoven, The Netherlands.

\textsuperscript{2} Department of Intensive Care Medicine, Catharina
Hospital Eindhoven, The Netherlands.

\textsuperscript{3} Department of Education and research, Catharina
Hospital Eindhoven, The Netherlands.

\textsuperscript{4} Department of Cardiothoracic surgery, Catharina
Hospital Eindhoven, The Netherlands.

\textbf{Corresponding Author:}

M. de Haan

Department of Extra Corporeal Circulation, Catharina Hospital

Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands.

\emph{Maartendehaan1@gmail.com}

Conflict of interest: None

Source of funding: None

The data generated and/or analyzed during this study are available from
the corresponding author on request.

\textbf{Abstract}

\textbf{Objective}

Veno-Arterial Extra Corporeal Life Support (VA ECLS) is widely used as
an effective device for patients in cardiogenic shock. The need for
predictive markers that daily guide physicians in the evaluation of
these patients could be of great value. Our aim was to investigate the
role of cholesterol value during VA ECLS in predicting the Intensive
Care Unit (ICU) survival.

\textbf{Methods}

Between January 2013 and November 2019, 67 patients with VA ECLS due to
cardiogenic shock were included in this study. Demographic data,
laboratory values, ICU data and outcomes were collected. Cholesterol was
measured during morning routine blood samples. The minimal cholesterol
value during the ICU stay was registered. Groups were stratified by
minimal cholesterol cut-off point of 2.0 mmol/L. Logistic regression
analysis were performed to identify variables associated with ICU
survival.

\textbf{Results}

The ECLS duration was not significantly different (p=0.36) between the
non-survivors (median 5.0 (2.0-7.5) days) and survivors (median 6.0
(1.8-12.0) days). The minimal cholesterol level was significantly lower
(p=0.04) in non-survivors group (1.54 (1.00-1.87) mmol/L) compared to
survivors (1.85 (1.38-2.24) mmol/L). By using logistic regression
analysis, minimal cholesterol level of [?]2.0 mmol/L was associated with a
higher ICU survival (p=0.02; OR 3.77; 95\% CI 1.20-11.81).

\textbf{Conclusion}

Cholesterol level could be an additional marker for ICU survival of
patients with cardiogenic shock on VA ECLS. A larger cohort of patients
is necessary to determine total cholesterol as a specific risk factor
for survival in these patients.

\textbf{Keywords:} VA ECLS; ECMO; Veno-Arterial Extracorporeal Life
Support; Cholesterol; ICU survival; Cardiogenic shock; Predictor

\emph{Introduction}

Veno-Arterial ExtraCorporeal Life Support (VA ECLS) is an effective
technique to support the circulation during cardiogenic
shock\textsuperscript{1, 2}. VA ECLS provides circulatory and pulmonary
support; therefore the perfusion to the organs is ensured during the
period of cardiogenic shock\textsuperscript{3}. VA ECLS can be used as a
bridge to myocardial recovery, a bridge to transplantation or a bridge
to long-term therapies\textsuperscript{4}. Earlier studies have shown
that survival rates of patients on VA ECLS due to cardiogenic shock are
60\% \textsuperscript{5}, and 50\% of the total patients were
transported to the ward\textsuperscript{6}. The outcome of patients with
cardiogenic shock on VA ECLS depends on several factors, including
comorbidities and organ dysfunction\textsuperscript{7}. Patient
selection, timely application of VA ECLS and well-trained users could
improve survival rates\textsuperscript{8}. Therefore, a
multidisciplinary approach is necessary to manage these patients in
daily practice\textsuperscript{9}. Physicians gather multiple markers to
monitor the hemodynamic status of the patient. Currently, there are
several predictive models that could inform the
physician\textsuperscript{10, 11}, but there are no specific markers
that daily inform the physician about the treatment and management of
patients on VA ECLS. This could be of great value in the initiated
therapy.

Low cholesterol levels are often seen in critically ill patients and are
correlated with an increased risk of sepsis\textsuperscript{12-14}.
Besides the increased risk of sepsis, low cholesterol level prior to
cardiac surgery is postoperatively associated with an increased risk of
sepsis\textsuperscript{15}. For patients who underwent cardiac surgery
cholesterol levels are described as prognostic factor for
outcome\textsuperscript{16}.

This study addresses the initial experience of our center in the
management of patients treated with VA ECLS. We sought to investigate
whether total cholesterol levels are a specific marker for ICU survival
of patients with cardiogenic shock treated with VA ECLS.

\emph{Methods}

\textbf{Study population}

Between January 2013 and November 2019, 81 patients were treated with VA
ECLS in the Intensive Care Unit (ICU) in our hospital. Sixty-seven
patients were included in the present retrospective observational study.
Fourteen patients were excluded from the analysis due to lack of
minimally three cholesterol determinations (n=9) or an ICU stay of
shorter than 48 hours (n=5). Out of the 67 included patients, 43
(64.2\%) were treated with VA ECLS after cardiac surgery of whom 11
patients (16.4\%) were emergency procedures. Other causes of severe
cardiogenic shock were encountered in 24 patients (35.8\%): 6 patients
(9.0\%) with ventricular septum rupture, 12 patients (17.9\%) with
in-hospital cardiac arrest following Percutaneous Coronary Intervention
(PCI) and 6 patients (9.0\%) with acute heart failure for other causes.

\textbf{Data collection}

The local medical ethical committee has approved the study and waived
the need for informed consent. The data were collected from the patient
data management system (HiX Chipsoft, Amsterdam, the Netherlands) in
the Catharina Hospital Eindhoven, The Netherlands. This included also
demographic data such as gender, age and other comorbidities.
Hypertension was defined conform the ESC/ESH
guidelines\textsuperscript{17}. Diabetes Mellitus (DM) was recorded when
the patients receive insulin or other oral anti-diabetic
medications\textsuperscript{18}. Chronic Obstructive Pulmonary Disease
(COPD) was defined when the patients use medication for chronic
pulmonary diseases. Peripheral Vascular Disease (PVD) was defined
according to the definition used by our department in the earlier study
of van Straten et al (2010)\textsuperscript{19}.

\textbf{ECLS system and cannulation}

The ECLS system is a closed system which consists of a centrifugal pump
with integrated oxygenator (Cardiohelp, Getinge GmbH, Rastatt, Germany)
and heater-cooler unit. Cannulation in the femoral artery (19-21fr.) and
femoral vein (23-25fr.) and were combined with a backflow catheter
(6fr.) to guarantee the distal perfusion of the cannulated leg.
Cannulation is performed by the cardiac surgeon either surgically or
percutaneously. The used approach depends on surgeons preference and the
patients habitus.

\textbf{Operative management}

All patients who underwent cardiac surgery were treated conform the
cardiac anesthesia protocol in the Catharina Hospital. Summarizing,
induction of anesthesia with fentanyl, etomidate, midazolam and
rocuronium. During surgery, the anesthesia was maintained with
continuous administration of propofol and alfentanil. Mechanical
ventilation with tidal volume based on 6 ml/kilogram ideal body weight
combined with end-tidal capnography of 35-40 mmHg. All patients received
a central venous catheter for infusion and radial artery catheter for
blood pressure monitoring. After inserting the cannulas for
non-pulsatile cardiopulmonary bypass (CPB), cardiac arrest was induced
with cold crystalloid cardioplegia or intermittent warm blood
cardioplegia according to the surgeon's preference. In all cases a cell
saver was intraoperatively used for blood management.

\textbf{ICU management}

The ICU management is a patient-dependent on-going process. In brief,
ICU management in our hospital includes the use of `FASTHUG' protocol.
Feeding of these critical care patients is executed with tube feeding.
Analgesia for patients with VA ECLS is performed with sufentanil.
Short-term sedation is achieved with propofol and long term VA ECLS with
midazolam. Thromboembolic prophylaxis is achieved with systemic
anticoagulation (heparin) and partially done with Low Molecular Weight
Heparin (LMWH). If possible, head position maximum 30 degrees and
rotation of the patients is always performed with assistance of the
clinical perfusionist. Ulcer (stress) prophylaxis is take care of with
proton pump inhibitors. Glycemic control was started when the patient
has diabetes or when glucose levels were too high. The standard ICU
monitoring includes arterial blood pressure, central venous pressure,
heart rate and saturation (SpO\textsuperscript{2}) combined with
cerebral Near-Infrared Spectroscopy (NIRS).

\textbf{Total cholesterol}

The minimal cholesterol value within the first five days after
implantation of the VA ECLS were retrieved. The total cholesterol
measurements were daily determined at the ICU department during the
morning routine check. A cut-off point of 2.0 mmol/L was used to
stratify the patients. This cut-off point is arbitrarily chosen to
investigate if total cholesterol levels are correlated with ICU survival
in this category of patients. Patients were divided into two groups
according to the outcome of ICU stay: group 1 (non-survivors) and group
2 (survivors).

\textbf{Statistical analysis}

The analysis started with the skewness- and kurtosis test with
boundaries -1 and +1 to determine the normal distribution in this data.
Continuous variables were presented as mean \selectlanguage{ngerman}± SD and compared using the
Student's t-test. Data with a non-normal distribution were presented
with median ± interquartile range (IQR) (25\%-75\%) and compared using
the Mann-Whitney test. Categorical variables were presented as numbers
and percentages and compared using the Fisher's Exact test. Univariate
regression analysis was performed and if significant at p
\textless{}0.1, confounders were entered into the multivariate
regressions analysis. Univariate regression analysis was used to test
for the potentially confounding effect of relevant biomedical and
demographic factors on outcome. Significance was considered at a p-value
of 0.1. This p-value was chosen because of the small group of patients.
Variables were entered in the multivariable analysis in case of being
significant in the univariable analysis. Odds Ratio (OR) with 95\%
Confidence Interval (CI) were reported. The statistical analysis has
been executed with SPSS version 25 (Chicago, IL, USA).

\emph{Results}

During the study period, 67 patients treated with VA ECLS were included
in the analysis. Patients were divided into two groups according the
outcome: 38 patients did not survive (group 1) the ICU period and 29
patients survived (group 2) their ICU stay. Table 1 shows the
demographic data of the two patient groups. The mean age was not
significantly different (p=0.80) between the two groups, with 59.5 ±
11.8 years in group 1 and 58.8 ± 10.1 years in group 2. Preoperative
hypertension was significantly different (p=0.07), 45\% in group 1 and
34\% in group 2. Besides, the ICU stay was significance between the two
groups, with 7.0 (2.9-13.0) days in group 1 and 16.0 (8.0-22.5) in group
2, respectively p=\textless{}0.01. There was no significant difference
regarding the ECLS duration between the groups, with 5.0 (2.0-7.5) days
in group 1 and 6.0 (1.8-12.0) days in group 2, respectively p=0.36.

In this study, there were 43 (64.2\%) patients who underwent cardiac
surgery (table 2); 25 patients in group 1 and 18 patients in group 2.
The median ExtraCorporeal Circulation (ECC) time reached no significant
difference between the two groups, with 258 (194-335) minutes in group 1
and 212 (165-270) minutes in group 2; p=0.18. The median aortic x-clamp
(AoX) time was not significantly different between the two groups, 124
(62-158) minutes in group 1 and 106 (79-155) minutes in group 2; p=0.83.

As shown in table 3, minimal cholesterol level during the first five
days of the VA ECLS period was significantly different between group 1
(1.54 (IQR 1.00-1.87) mmol/L) and group 2 (1.85 (1.38-2.24) mmol/L)
(p=0.04). In the group with a minimal cholesterol level of
\textless{}2.0 mmol/L the survival rate was 35\% and in the group with a
minimal cholesterol level of \selectlanguage{english}[?]2.0 mmol/L the survival rate was 67\%.
Using the univariate logistic regression analysis, minimal cholesterol
level \textless{}2.0 mmol/L was significantly associated with reduced
ICU survival (p=\textless{}0.01). After multivariable logistic
regression analysis (table 3), minimal cholesterol level was retrieved
as a significant factor associated with ICU survival (p=0.03; OR 3.81;
95\% CI 1.15-12.63).

All risk factors of univariate analysis and baseline characteristics
were entered into the multivariate analysis regression model (table 3).
This shows that a cut-off of \textless{}2.0 mmol/L was identified as
significant parameter (p=0.03; OR 3.81; 95\% CI 1.15-12.63) associated
with ICU survival in patients treated with VA ECLS. Figure 1 shows the
predicted probability of ICU survival according to the minimal
cholesterol levels during the first five days of the VA ECLS period.
This shows that a minimal cholesterol level of \textless{}2.0 mmol/L
indicates a poor prognosis.

During the VA ECLS period, one of the main complications was cardiac
tamponade. In group 1, there was one case with three times a
re-sternotomy, seven cases with twice a re-sternotomy and six cases with
a single re-sternotomy (n=14; 36.8\%). In group 2, there were three
cases with three times a re-sternotomy, two cases with twice a
re-sternotomy and six cases with a single re-sternotomy (n=11; 37.9\%).
All cases of re-sternotomy were due bleeding complications or cardiac
tamponade.

The peak creatinine levels during VA ECLS were significantly different
(p=0.03) between the two groups, with 216.5 (127.8-315.3) \selectlanguage{greek}µ\selectlanguage{english}mol/L in
group 1 and 222.0 (90.0-463.0) \selectlanguage{greek}µ\selectlanguage{english}mol/L in group 2. Transfusion of Red
Blood Cell (RBC) was not significantly different (p=0.86) between the
two groups. The median number of RBC units during the VA ECLS period was
13 (5-21) units in group 1 and 11 (4-21) in group 2. Transfusion of
Fresh Frozen Plasma (FFP) during VA ECLS was 4 (0-8) units in group 1
and 2 (0-4) in group 2, respectively p=0.11. Transfusion of Thrombocyte
Concentration (TC) during VA ECLS was 2 (1-5) units in group 1 and 2
(0-4) in group 2, respectively p=0.31.

\emph{Discussion}

The aim of this study was to investigate total cholesterol as predictive
marker of ICU survival in patients supported with VA ECLS due to
cardiogenic shock. According to our results, the minimal cholesterol
level during the first five days of the VA ECLS period was retrieved as
a significant variable associated with ICU survival. Besides, the median
total cholesterol was associated with ICU survival for these category of
patients.

Total cholesterol consists of Low Density Protein (LDL), High Density
Protein (HDL) and triglycerides. In this study, we used total
cholesterol as predictive marker for ICU survival. Low cholesterol
levels are mainly seen in patients who are critically ill, but it is
unknown if this is caused by deterioration or secondary to the
illness\textsuperscript{16}. Earlier studies have shown that low
cholesterol levels are correlated to sepsis\textsuperscript{20}.
Kreeftenberg et al wrote a case series of five patients in whom they
compared total cholesterol with procalcitonin and C-reactive protein as
indicators of success of treatment. They found that cholesterol could be
a parameter for disease progression or revival\textsuperscript{21}.
Haanschoten et al came with the same conclusion\textsuperscript{22}.
Total cholesterol is an independent risk factor for early mortality
(within 30 days) after cardiac surgery. Those two studies are in
agreement with the results of the current study.

Preoperative scoring systems have a high predictive value for operative
mortality in the standard cardiac surgery patient. However, due to
cardiac surgery with extracorporeal circulation and the need for
postoperative mechanical support by VA ECLS, the risk profile of the
patient changes completely. This means that the predictive score prior
to the surgical procedure is not specific and reliable anymore. Due to
this alteration of the patients' profile, we did not correct the results
for the preoperative comorbidities included in the EuroSCORE. Instead of
using the standard preoperative scoring, the SAVE-score could be a
reliable alternative for these patients. After external validation on
161 patients, the SAVE-score reached an area under the curve of 0.90
(0.85-0.95)\textsuperscript{11}. However, the SAVE-score is not a daily
score, whereas parameters of the patient combined with laboratorial
results are.

During the VA ECLS period, patients receive anticoagulation to prevent
thromboembolic oxygenator failure\textsuperscript{23}. Due to the
anticoagulation strategy, patients treated with VA ECLS has 30-60\%
bleeding complications\textsuperscript{24}. A study of Mazeffi and
colleagues showed similar results for transfusion frequencies and
numbers for RBC, FFP and TC\textsuperscript{25}. Frequent transfusions
have been shown to be an independent predictor of early
mortality\textsuperscript{26}. In our study, the ICU stay was
significantly different between the non-survivors and survivors. After
patients survived the VA ECLS period, the prolonged recovery at the ICU
starts. A major challenge is weaning from mechanical ventilation which
is complicated by critical illness polyneuropathy and general
weakness\textsuperscript{27, 28}.

In addition, patients treated with VA ECLS required substantial
financial and human resources. The combination of high mortality risk,
the large amounts of blood transfusions, the impact on hospital
resources and the prolonged ICU stay had a major impact on the patient
and on the hospital care\textsuperscript{29-31}. These patients should
be treated on an efficient manner with the daily guiding of reliable
markers.

\textbf{Strengths and limitations}

This analysis is an initial report since the start of our ECLS program
in our hospital in 2012. Due to the retrospective nature of this study,
it might have some limitations. Unknown confounding factors could have
influenced the results. On the other hand, the data are generated in a
very efficient, highly organized and protocolized centre which makes
interpretation of these data more viable. Despite the relatively small
number of included patients, this study could contribute to the
extension of predictive markers for patients with VA ECLS. The
preoperative cholesterol level was not determined and therefore this
study does not describe the complete overview of cholesterol during the
VA ECLS period. In our ICU department, cholesterol is used as daily
marker in combination with the standard markers. This could give the
physician a more complete insight in the status of the patient.

The effects of the heterogenous groups were corrected by performing a
multivariate regression analysis. Despite the heterogenous groups
cholesterol remains a variable who is associated with ICU survival. The
significant different ICU stay could be declared due to the prolonged
recovery at the ICU after the VA ECLS period. Several hurdles should be
conquered by the patient, like weaning of mechanical ventilation and
regaining strength and condition before transferred to the ward.
Sedation with propofol could influence the total cholesterol which could
results in a false positive measurement. This could be due to the lipid
concentration of 0.1 grams/ml in propofol. This effect was not within
the scope of this manuscript. The usage of cholesterol inhibitors
(statins) preoperatively or during the VA ECLS period was outside the
scope of this study.

\emph{Conclusion}

We can conclude that total cholesterol level is a significant marker
associated with ICU survival in patients with VA ECLS due to cardiogenic
shock.

\emph{Authors' contributions}

MdH 1. Made substantial contributions to conception and design study; 2.
Took part in data collection; 3. Drafting the manuscript. MH, HK, PL,
SH, AS, MSH were involved in revising the manuscript critically for
important intellectual content. MSH 1. Made substantial contributions to
conception and design study; 2. Was involved in revising the manuscript
critically for important intellectual content. All authors read and
approved the final manuscript.

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