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\begin{document}

\title{Liver-type fatty acid-binding protein: A hemodynamic index during
extracorporeal membrane oxygenation}



\author[1]{Ryo Ichibayashi}%
\author[1]{Saki Yamamoto}%
\author[1]{Yoshimi Nakamichi}%
\author[1]{Yuka Masuyama}%
\author[1]{Hibiki Serizawa}%
\author[1]{Masayuki Watanabe}%
\author[1]{Takayuki Yabe}%
\author[1]{Mitsuru Honda}%
\affil[1]{Toho University Omori Medical Center}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\selectlanguage{english}
\begin{abstract}
Herein, we discuss a case in which L-FABP measurements were used to
manage a 46-year-old male patient receiving VA-ECMO support. His mean
blood pressure was [?] 75 mmHg for the first 24 h after the initiation of
VA-ECMO, and he experienced a rapid decrease in L-FABP.%
\end{abstract}%



\sloppy


\textbf{Title}

Liver-type fatty acid-binding protein: A hemodynamic index during
extracorporeal membrane oxygenation

\textbf{Authors}

Ryo Ichibayashi, Saki Yamamoto, Yoshimi Nakamichi, Yuka Masuyama, Hibiki
Serizawa, Masayuki Watanabe, Takayuki Yabe, Mitsuru Honda

\textbf{Affiliation}

Department of Critical Care Center, Toho University Medical Center Omori
Hospital, 6-11-1 Omori-Nishi, Ota-ku, Tokyo 143-8541, Japan

\textbf{Corresponding Author}

Ryo Ichibayashi, MD, PhD

ORCID iD https://orcid.org/0000-0002-1273-4875

Department of Critical Care Center

Toho University Medical Center Omori Hospital

6-11-1 Omori-Nishi

Ota-ku, Tokyo 143-8541, Japan

Phone: +81-3-3762-4151

Fax: +81-3-3-3765-6518

e-mail: ryou.ichibayashi@med.toho-u.ac.jp

KEY CLINICAL MESSAGE

Measurement of L-FABP levels can aid in indicators of circulation and
management of VA-ECMO. L-FABP levels can be measured in approximately 10
minutes, the advantage over lactate is the non-invasive results from the
urine test.

ABSTRACT

Herein, we discuss a case in which L-FABP measurements were used to
manage a 46-year-old male patient receiving VA-ECMO support. His mean
blood pressure was [?] 75 mmHg for the first 24 h after the initiation of
VA-ECMO, and he experienced a rapid decrease in L-FABP.

KEYWORDS

Liver-type fatty acid-binding protein, extracorporeal membrane
oxygenation, lactate, circulation index

1 INTRODUCTION

Veno-arterial~extracorporeal membrane oxygenation~(VA-ECMO) is applied
in circulatory failure cases such as cardiogenic shock, cardiac arrest,
and refractory ventricular fibrillation. VA-ECMO management includes
echocardiographic assessments of cardiac function and evaluations of
peripheral circulation based on venous oxygen saturation, lactate
levels, regional cerebral oxygen saturation, and central venous
pressure. ECMO flow rates exceeding cardiac output result in low pulse
pressure, leading to low mean blood pressure. Thus, the mean blood
pressure is also used to manage organ perfusion and peripheral
circulation during ECMO support.

Urinary liver-type fatty acid-binding protein (L-FABP)---a biomarker of
renal ischemia---has also been considered to reflect acute systemic
ischemic injury and to be effective in the assessment of sepsis
treatment {[}1,2{]}. However, no reports have discussed L-FABP use
during VA-ECMO management in severe ischemic injury after cardiac arrest
cases.

Herein, we discuss a case in which L-FABP measurements were used during
VA-ECMO management.

2 CASE HISTORY

The patient was a 46-year-old man who had collapsed at home, following
which a witnessing family member called for an ambulance and performed
chest compressions until the emergency medical team's arrival. Monitor
waveforms at the time of their arrival indicated ventricular
fibrillation. The team performed cardiac massage, secured the airway
with a laryngeal tube, and defibrillated the patient three times,
following which he was transported to our hospital. Extracorporeal
cardiopulmonary resuscitation was performed on arrival, given the
persistence of ventricular fibrillation. The interval from cardiac
arrest to resuscitation with VA-ECMO cannulation was 45 minutes.

Based on the increase in creatine kinase-muscle/brain (CK-MB) levels and
electrocardiographic changes, acute myocardial infarction was suggested,
and emergency coronary angiography was performed (Table 1). Coronary
angiography revealed significant stenosis in branch \#6 of the left
anterior descending artery, which led to a diagnosis of acute myocardial
infarction. Percutaneous coronary intervention (PCI) was performed,
following which an intra-aortic balloon pump (IABP) was inserted. The
patient was admitted to the intensive care unit (ICU), where targeted
temperature management (TTM) was performed at 34\selectlanguage{ngerman}°C for 24 h. Thereafter,
the patient's body temperature was gradually restored to 36°C over 2
days.

Figure 1 shows changes in L-FABP levels, lactate levels, mean blood
pressure, daily fluid balance, flow rate, and other parameters during
ICU admission. Values measured from urine collected before ECMO
cannulation on arrival were regarded as baseline values, and urine
L-FABP and serum lactate levels were measured every 6 h. L-FABP levels
were also measured every 24 h after weaning. On arrival, the patient's
L-FABP level was 74,100 \selectlanguage{greek}μ\selectlanguage{english}g/gCr, which decreased to 816 \selectlanguage{greek}μ\selectlanguage{english}g/gCr at 24 h
after admission, at which time the lactate level, which had also been
high, decreased to 2.4 mmol/L. Twenty-four hours after arrival, the ECMO
flow rate was 2.6--3.6 L/min; mean blood pressure, 76--97 mmHg; and
pulse pressure, 42--60 mmHg. On and after hospital day 2, the patient's
lactate levels remained at 0.9--1.0 mmol/L. However, his mean blood
pressure increased, while L-FABP levels decreased.

On hospital day 5, the patient was weaned off VA-ECMO without
deterioration of L-FABP levels, lactate levels, or mean blood pressure.
On hospital day 6, he was weaned off IABP without changes in mean blood
pressure or lactate levels. Thereafter, although the mean blood pressure
remained unchanged, L-FABP levels temporarily increased, following which
they decreased again. During the same period, the daily fluid balance
was negative on consecutive days. On hospital day 8, he could follow
instructions and was weaned off mechanical ventilation and extubated on
hospital day 10. On hospital day 13, he was discharged from the ICU and
transferred to the general ward. On hospital day 24, no neurological
sequelae were noted, and he was discharged from our hospital with
independent gait.

3 DISCUSSIONS

Lactate levels increase owing to tissue hypoxia resulting from
circulatory failure or insufficient oxygen supply. Therefore, improving
circulation or oxygenation should decrease lactate levels. However, some
patients with normal hemodynamics and oxygenation exhibit elevated
lactate levels due to the influence of underlying diseases such as
sepsis and malignant tumors {[}3{]}. Such elevation may be attributed to
increased lactate production, decreased lactate consumption, or both in
various organs such as the muscles, skin, and brain. Contrastingly,
FABPs are specifically distributed in various tissues {[}4{]}. For
example, urinary L-FABP, which is released from proximal tubule cells,
has been highlighted as a strong biomarker of acute ischemic injury
{[}1{]}. Given that L-FABP is unlikely to be affected by other factors,
it may represent a more sensitive hemodynamic indicator than lactate.

During ECMO, the mean blood pressure is often maintained at [?] 65 mmHg.
However, there are no clear criteria for the index value, and the target
value varies across institutions. Although one report suggested a higher
survival rate among patients managed with a target mean blood pressure
of 70--80 mmHg {[}5{]}, the optimal mean blood pressure is considered to
differ for each patient. L-FABP levels should decrease if patients are
managed with optimal mean blood pressure, suggesting they can aid in
blood pressure management.

Our patient's mean blood pressure was [?] 75 mmHg for the first 24 h after
VA-ECMO initiation, and he experienced rapid decreases in both L-FABP
and lactate levels. In this case, the target mean blood pressure was 70
mmHg, and weaning from VA-ECMO was eventually successful. Since both
L-FABP and lactate levels were low during weaning, L-FABP also appeared
to be an appropriate hemodynamic index for VA-ECMO management.

In patients managed with a mean blood pressure of [?] 70 mmHg who exhibit
normal lactate levels, temporary increases in L-FABP may occur following
extubation, as observed in our patient. During this period, the daily
fluid balance is adjusted between --500 and --5,000 mL to achieve
successful extubation or improve systemic edema. Therefore, the volume
of fluid replacement is maintained at the minimum level to ensure a
relatively higher urinary output. Thus, L-FABP levels may reflect a
slight shortage of intravascular volume that is not reflected by lactate
levels.

Our findings suggest that L-FABP can be used as a hemodynamic indicator
for managing patients receiving VA-ECMO support and it can be used
equivalently to conventional hemodynamic indicators such as lactate and
mean blood pressure. Thus, Measurement of L-FABP levels appears to be
useful for determining whether to increase or decrease the flow rate of
VA-ECMO, and determining whether weaning from VA-ECMO is appropriate.
Unfortunately, LFABP failed to prove to be more sensitive than
traditional hemodynamic indicators such as lactate and mean blood
pressure. However, this study is suggested that L-FABP may be more
sensitive than lactate in controlling intravascular water balance.
Therefore, it is necessary to accumulate and investigate cases in the
future. L FABP measurement has a Limitation. Since L-FABP levels are
measured from urine samples, they cannot be used for patients undergoing
dialysis or those with anuria in the early stage of shock. As strong
point of test, L-FABP levels can be measured in approximately 10
minutes, and the results can be obtained more non-invasively than blood
tests.

CONFLICT OF INTEREST

None declared.

AUTHOR CONTRIBUTIONS

RI: wrote and drafted the manuscript

SY: measured L-FABP and lactate levels

YN: drafted the manuscript

YM: measured L-FABP and lactate levels

HS: drafted the manuscript

MW: drafted the manuscript

TY: drafted the manuscript

MH: drafted the manuscript

All authors read and approved the final manuscript

ETHICAL APPROVAL

The present study was approved by the Toho University Medical Center
Omori Hospital Ethics Committee. Informed consent was obtained from
participants or their family members prior to enrollment and after
receiving written explanations about the aims and procedures used in the
study (Approval No. M19141).

\par\null

CONSENT

Written informed consent was obtained from the patient for publication
of this case report.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the
corresponding author upon reasonable request.

\textbf{REFERENCES}

1. Yamamoto T, Noiri E, Ono Y, Doi K, Negishi K, Kamijo A, et al.~Renal
L-type fatty acid--binding protein in acute ischemic injury.~J Am Soc
Nephrol~2007;18:2894--902.\emph{https://doi.org/10.1681/ASN.2007010097}

2. Nakamura T, Sugaya T, Koide H. Urinary liver-type fatty acid-binding
protein in septic shock: effect of polymyxin B-immobilized fiber
hemoperfusion. Shock
2009;31:454--9.\emph{https://doi.org/10.1097/SHK.0b013e3181891131}

3. Garcia-Alvarez M, Marik P, Bellomo R. Sepsis-associated
hyperlactatemia. Crit Care
2014;18:503.\emph{https://doi.org/10.1186/s13054-014-0503-3}

4. Tan NS, Shaw NS, Vinckenbosch N, Liu P, Yasmin R, Desvergne B, et al.
Selective cooperation between fatty acid binding proteins and peroxisome
proliferator-activated receptors in regulating transcription. Mol Cell
Biol
2022;22:5114--27.\emph{https://doi.org/10.1128/MCB.22.14.5114-5127.2002}

5. Tanaka D, Shimada S, Mullin M, Kreitler K, Cavarocchi N, Hirose H.
What is the optimal blood pressure on veno-arterial extracorporeal
membrane oxygenation? Impact of mean arterial pressure on survival.
ASAIO J
2019;65:336--41.\emph{https://doi.org/10.1097/MAT.0000000000000824}

TABLES AND FIGURES

Table 1.\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}Laboratory results on admission\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\emph{Biochemical} & \emph{Biochemical} & \emph{Biochemical} &
\emph{Coagulation} & \emph{Coagulation} &
\emph{Coagulation}\tabularnewline
TP & 6.4 & g/dL & APTT & 35.3 & s\tabularnewline
Alb & 3.6 & g/dL & PT & 14.1 & s\tabularnewline
CK & 139 & U/L & PT-INR & 1.1 &\tabularnewline
CK-MB & 77 & U/L & PT\% & 81 & \%\tabularnewline
AST & 119 & U/L & FDP & 31 & \selectlanguage{greek}µ\selectlanguage{english}g/mL\tabularnewline
ALT & 70 & U/L & & &\tabularnewline
LD & 450 & U/L & \emph{Venous blood gas} & \emph{Venous blood gas} &
\emph{Venous blood gas}\tabularnewline
ALP & 238 & U/L & pH & 7.034 &\tabularnewline
\selectlanguage{greek}γ-\selectlanguage{english}GT & 70 & U/L & PCO\textsubscript{2} & 84.5 & Torr\tabularnewline
Cre & 1.01 & mg/dL & PO\textsubscript{2} & 15.1 & Torr\tabularnewline
UN & 23 & mg/dL & Lac & 11.1 & mmol/L\tabularnewline
eGFR & 64 & mL/min/1.73 m\textsuperscript{2} & & &\tabularnewline
NH\textsubscript{3} & 179 & \selectlanguage{greek}µ\selectlanguage{english}g/dL & \emph{Immunological} &
\emph{Immunological} & \emph{Immunological}\tabularnewline
Glu & 307 & mg/dL & CRP & 0.1 & mg/dL\tabularnewline
HbA1c & 5.1 & \% & TnI & 0.03 & or less pg/mL\tabularnewline
Na & 136 & mEq / L & & &\tabularnewline
K & 4.7 & mEq / L & \emph{Urinalysis} & &\tabularnewline
Cl & 100 & mEq/ L & L-FABP & 74100 & \selectlanguage{greek}μ\selectlanguage{english}g/gCr\tabularnewline
\emph{Hematology} & \emph{Hematology} & \emph{Hematology} & &
&\tabularnewline
WBC & 9,800 & /\selectlanguage{greek}µ\selectlanguage{english}L & & &\tabularnewline
Hb & 17.5 & g/dL & & &\tabularnewline
Plt & 26.1 & \selectlanguage{ngerman}×10\textsuperscript{4}/\selectlanguage{greek}µ\selectlanguage{english}L & & &\tabularnewline
\bottomrule
\end{longtable}

TP: total protein; Alb: albumin; CK: creatine kinase; AST: aspartate
aminotransferase; ALT: alanine aminotransferase; LD: lactate
dehydrogenase; ALP: alkaline phosphatase; \selectlanguage{greek}γ-\selectlanguage{english}GT:
gamma-glutamyltransferase; Cre: creatinine; UN: urea nitrogen; eGFR:
estimated glomerular filtration rate; Glu: glucose; APTT: activated
partial thromboplastin time; PT: prothrombin time; INR: international
normalized ratio; FDP: fibrinogen degradation product; Lac: lactate;
CRP: C-reactive protein; TnI: troponin I; WBC: white blood cell; Hb;
hemoglobin; Plt: platelet; L-FABP: liver-type fatty acid-binding protein

Figure 1. Clinical course

Lactate and L-FABP levels decreased with stabilization of hemodynamics.
While the daily fluid balance was negative, L-FABP levels remained
mildly elevated.

TTM: targeted temperature management; MBP: mean blood pressure; VA-ECMO:
veno-arterial extracorporeal membrane oxygenation, L-FABP: liver-type
fatty-acid binding protein, IABP: intra-aortic balloon pumping, Lac:
lactate\selectlanguage{english}
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