SHOCK, Vol. 48, No. 1, pp.
1–4, 2017
Commentary
WHAT’S NEW IN SHOCK, JULY 2017?
Hiroyuki Hirasawa
Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine,
Eastern Chiba Medical Center, Chiba, Japan
The current issue of Shock contains six clinical studies (1–6),
10 basic studies (7–16), and one editorial comment (17).
Loftus et al. (1) from the University of Florida studied the
acute kidney injury (AKI) following the exploratory laparot-
omy and temporary abdominal closure. This is a very important
clinical study because the exploratory laparotomy and tempor-
ary abdominal closure using negative pressure wound therapy
are common procedures in the field of acute care surgery and
they sometimes complicate with AKI. The authors found that
AKI following exploratory laparotomy and temporary abdomi-
nal closure reached greatest prevalence 48 h after initial lapa-
rotomy, and that it was associated with increased mortality.
Furthermore, they found that fluid loss during temporary
abdominal closure using negative pressure wound therapy
was a risk factor for AKI. Thus, the results of the present
study suggest that the adequate body water management fol-
lowing exploratory laparotomy and temporary abdominal clo-
sure using negative pressure wound therapy might be very
important for the prevention of AKI.
As shown in the above study by Loftus et al. (1), AKI is one of
the serious complications in the field of critical care and it is
suggested that early diagnosis and early initiation of therapeutic
approach are the key for better outcomes. Therefore, many studies
have been investigated on the effective and useful biomarkers for
the early diagnosis of AKI. Hu et al. (2) from Southeast University,
Nanjing, China, investigated the usefulness of urinary mitochon-
drial DNA (UmtDNA) as a biomarker for the diagnosis of AKI on
surgical intensive care unit (ICU) patients. They employed the
quantitative polymerase chain reaction (PCR) for the measure-
ment of UmtDNA. And they found that elevated UmtDNA levels
could identify newly developed AKI and could predict renal
replacement therapy or hospital mortality in those patients. They
also suggested the involvement of mitochondrial injury in kidney
damage among surgical critical illness patients. This is a very
interesting study. Recently, mitochondrial DNA is paid much
attention not only as a mere biomarker, but also as one of the
very important damage-associated molecular patterns that initiate
inflammatory response following injury. Since UmtDNA levels in
the present study were measured with PCR which is not easily
available in clinical settings, easier measurement method of
UmtDNA is needed for UmtDNA to be widely measured as a
biomarker for the diagnosis of AKI in clinical settings.
E-mail: hhirasawa@faculty.chiba-u.jp
DOI: 10.1097/SHK.0000000000000876
Copyright ß 2017 by the Shock Society
1
Copyright © 2017 by the Shock Society. Unauthorized reproduction of this article is prohibited.
Selejan et al. (3) from Unversitat des Saarlandes, Germany,
investigated the matrix metalloproteinase-9 (MMP-9) activity
as a biomarker of condition of receptor for advanced glycation
end products (RAGE) and soluble RAGE in patients with
myocardial infarction-induced cardiogenic shock and in the
patients with acute myocardial infarction without cardiogenic
shock. They found serum MMP-9 activity was increased in
acute myocardial infarction, but that it was markedly sup-
pressed in cardiogenic shock following myocardial infarction.
Since s-RAGE in serum plays an opposite role against RAGE in
inflammation and since MMP-9 has been implied in RAGE
ectodomain cleavage and subsequent sRAGE shedding in vitro,
they suggested that maintaining MMP-9 activity could be a
therapeutic target to limit RAGE-induced deleterious inflam-
mation in cardiogenic shock.
As strongly recommended in Surviving Sepsis Campaign
guidelines 2016, as well as in Surviving Sepsis Campaign
guidelines 2012, early initiation of antibiotic administration,
even being empiric one is one of the key therapeutic approaches
for better survival on adult patients with sepsis and septic
shock. On the other hand, recently, much attention has been
paid for the poor long-term outcome of septic adult patients
who received intensive care and eventually survived in ICU.
However, no study concerning the effect of early initiation of
antibiotic administration in sepsis has been investigated on
pediatric patients. Therefore, Han et al. (4) from University of
Pennsylvania investigated the association of delayed antimi-
crobial therapy with 1-year mortality in pediatric patients with
sepsis. And their findings are very interesting. They found that
hourly delays up to 3 h were not associated with 1-year
mortality. However, they showed that increased 1-year
mortality was evident in patients who received antimicrobials
21 or >3 h compared with patients who received antimicro-
bials within 1 to 3 h from sepsis recognition. In other words,
they found that antibiotic administration, earlier than 1 hour
following recognition of sepsis in pediatric patients, was
resulted in poorer outcome. This finding is unexpected
even to the investigators of the present study. They could
not identify the reason for this result and they suggest that
this finding should be regarded as hypothesis-generating for
future studies.
Model for End Stage Liver (MELD) score is widely applied
as a predictor of pretransplant mortality on the patients with
liver diseases. However, as a predictor of postoperative out-
comes, recently developed MELD-Lactate model is reported to
be a better predictor of 30-day survival compared with the
2 SHOCK VOL. 48, No. 1
MELD and MELD-Sodium scores. Therefore, Kim et al. (5)
from Icahn School of Medicine at Mount Sinai in New York
investigated the comparison of the accuracy of postoperative
MELD-Lactate and isolated lactate values as outcome predic-
tors following orthotopic liver transplantation. The authors also
conclude that postoperative MELD-Lactate and isolated post-
operative lactate values are moderately predictive of 30-day
and in-hospital mortality following liver transplantation in this
patient cohort.
Acute Respiratory Distress Syndrome (ARDS) remains to
be one of the most serious pathological conditions to be treated
in ICU. There are many therapeutic approaches to ARDS, such
as so-called open lung strategy including positive end expir-
atory pressure and recruitment maneuvers during mechanical
ventilation. However, the efficacy of open lung strategy is not
clearly shown previously. Therefore, Lu et al. (6) from Nanjing
University of Traditional Chinese Medicine, China, performed
a systematic review and meta-analysis on this topic. After
extensive paper searches in several data bases, they identified
15 RCTs involving 1,563 patients in open lung strategy group
and 1,571 patients in control group, respectively. Poled
analysis showed that there were significantly better results
in hospital mortality, 28-day mortality, and ICU mortality in
open lung strategy group compared with those in control
group. However, they found no difference on ventilator-free
days at 28-day and ICU length of stay between the groups.
They also conclude that results from this systematic review and
meta-analysis suggest that open lung strategy during mech-
anical ventilation significantly reduces mortality among
patients with ARDS.
Lee et al. (7) from the University of South Alabama per-
formed a fundamental study concerning the importance of
oxidative mitochondrial DNA damage as an initiator of acute
lung injury (ALI) and multi-organ system failure using a rat
model of intra-tracheal Pseudomonas aeruginosa-induced ALI
and multi-organ system failure model. They found that the rats
given Pseudomonas aeruginosa showed increases in lung
vascular filtration coefficient accompanied by transient lung
tissue oxidative mtDNA damage and variable changes in
mtDNA copy number without evidence of nuclear DNA dam-
age. Furthermore, they examined the effect of a fusion protein
construct targeting the DNA glycosylase, Ogg1, to mitochon-
dria in this rat model and found that the active fusion protein,
but not a DNA repair-deficient mutant, prevented bacteria-
induced increases in lung tissue oxidative mtDNA damage,
failed to alter mtDNA copy number, and attenuated lung
endothelial barrier degradation. They also observed that these
changes were associated with suppression of liver, kidney, and
cardiovascular dysfunction and with decreased 24 h mortality.
They conclude that collectively, the present findings indicate
that oxidative mtDNA damage to lung tissue initiates Pseudo-
monas aeruginosa-induced ALI and MOSF in rats.
miR-155, a microRNA, is reported to have anti-inflammatory
effect through close linkage to transforming growth factor-b
activated kinase-1-binding protein 2 (TAB2) and autophagy.
Therefore, Liu et al. (8) from Nanchang University, Nanchang,
China hypothesized that miR-155 could reduce inflammation
after septic lung injury and induce autophagy by targeting
Copyright © 2017 by the Shock Society. Unauthorized reproduction of this article is prohibited.
HIRASAWA
TAB2. They utilized human bronchoalveolar lavage fluid
(BALF) samples, mouse model of septic lung injury, and
LPS-treated rat lung macrophage cell line as study models
to test their working hypothesis. They observed a higher level
of miR-155 in the BALF from sepsis patients with ARDS and
demonstrated that miR-155 alleviated inflammation in septic
lung injury in mouse and cell models by inducing autophagy
via inhibition of TAB2, and they suggested that miR-155 is a
potential candidate for anti-inflammation treatment during
septic lung injury.
It is now widely accepted that in accelerated endothelial
hyperpermeability plays an important role in the pathophysi-
ology of sepsis-induced multi-organ dysfunction syndrome. It
is also reported that diverging patterns of edema formation and
loss of function in organs, such as lung and kidney, suggest that
endothelial permeability-regulating molecular responses are
differentially regulated among those vital organs. Therefore,
Asian et al. (9) from University of Groningen, the Netherlands,
hypothesized that such regulation by endothelial cells in sepsis
took place in an organ-specific manner. Using mice model, they
showed that baseline endothelial expression of permeability-
related molecules differs in mouse kidney and lung. Moreover,
they showed differential regulation of these molecules after
LPS injection in the two mouse organs. In lung they found a
decrease in expression levels of molecules of the adherence and
tight junctions complex and related signaling systems, com-
patible with increased permeability. In contrast, in kidney they
found expression patterns of these molecules compatible with
decreased permeability. Furthermore, they partially corrobo-
rated their findings in mouse kidney in human kidneys from
septic patients. They conclude that these findings may help to
understand the clinical difference in the extent of edema
formation in kidney and lung in sepsis-associated organ failure.
The results of this interesting study suggest that we may need a
different therapeutic approach to sepsis-induced lung failure
and kidney failure, respectively.
In shock research, experimental study using small animals
such as rats and mice is very common. From the viewpoint of
humane handling of animals, it is very important to lessen pain
and stress of animals during the experimental procedure.
Nevertheless, very little is investigated on the influence of
anesthetic and analgesic on the physiological condition of
research animals. Therefore, Griffin et al. (10) from James
Cook University, Australia investigated the effect of buprenor-
phine analgesia recommended for post-surgical pain and
associated stress in small animals, on blood coagulation in
the rats using rotational thromboelastometry when it is used
with the combination of isoflurane. They observed that bupre-
norphine analgesia significantly increased clot strength without
affecting fibrinolysis, and increased plasma fibrinogen, imply-
ing that the drug increased liver fibrinogen synthesis and
release. The findings of the present study should be taken into
consideration when we use small animals in experimental study
under buprenorphine and isoflurane analgesia and anesthesia.
In the era of multidrug resistance-bacteria, search for some
therapeutic approach without the administration of antibiotics
being effective on sepsis is attractive. One such approach is
hydrogen-rich water, because it is reported that molecular
SHOCK JULY 2017
hydrogen (H2) acts as a therapeutic and preventive antioxidant.
Therefore, Iketani et al. (11) from Tokyo Metropolitan Institute
of Gerontology, Japan investigated the effect of pre-LPS chal-
lenge hydrogen water (HW) drinking in mouse model. They
found that drinking HW for 3 days before LPS injection
prolonged survival. The H2 concentration immediately
increased in the liver but not in the kidney after drinking
HW. The protective effects of the pre-administration of HW
on LPS-induced liver injury were due to reduction of the
increase in both apoptosis and oxidative stress, and enhanced
expression of heme oxygenase-1 and reduced endothelin-1
expression. These results indicate the therapeutic potential of
HW in preventing acute injury of the liver with attenuation of an
increase in oxidative stress. However, the pretreatment nature
of the present study suggests that further investigation is needed
before the clinical application of this effective and relatively
simple therapeutic approach.
Martire-Greco et al. (12) from Academia Nacional de
Medicina de Buenos Aires, Argentina studied whether all-
trans-retinoic acid (ATRA), a derivative of vitamin A with
antiproliferative properties, would be able to modulate
myeloid-derived suppressor cells (MDSC) generation by reg-
ulating myelopoiesis in murine hematopoietic organs, because
they have previously shown that ATRA reverses the immuno-
suppression state in sepsis by decreasing functional MDSC.
The authors found that administration of ATRA could over-
come the immunosuppressive state generated by sepsis that
often leads to opportunistic life-threatening infections. They
conclude that ATRA could be considered a complementary
treatment to enhance immune responses.
Complication of ALI following blunt chest trauma is a very
serious problem carrying high mortality. Therefore, Palmer
et al. (13) from the University of Ulm, Germany conducted
an experimental study on this pathological condition. It is
reported that blunt chest trauma induces severe local and
systemic inflammatory alterations and an accumulation of
apoptotic polymorphonuclear granulocytes (aPMN) in the
lungs, frequently followed by bacterial infection. Therefore,
the authors consider that elimination of both apoptotic cells and
bacteria is very important for the resolution of inflammation. It
is also reported that alveolar macrophages (AM) represent one
of the main actors for their clearance. AM as phagocytes of
immune system in the lung are able to clear apoptotic neu-
trophils, as well as bacteria by ingestion. Furthermore environ-
mental conditions appear to dictate AM development and
function. Therefore, they also investigated whether hypoxic
and hypercapnic condition developing in the lungs after blunt
chest trauma would affect the phagocytic activity as well as
cytokine release. They found that trauma significantly upregu-
lated the capacity of AM to ingest E coli starting 24 h after
trauma, whereas the aPMN uptake rate remained virtually
unchanged. They also observed that in vitro, AM reacted to
hypercapnic conditions by enhanced efferocytosis associated
with increased release of anti-inflammatory cytokines and that
phagocytosis and the pro-inflammatory reaction of AM after
trauma appeared to be impaired. However, they observed that
hypoxic conditions displayed no regulatory effect on AM. They
conclude that blunt chest trauma enhances phagocytic activity
Copyright © 2017 by the Shock Society. Unauthorized reproduction of this article is prohibited.
JULY COMMENTARY 3
of AM, but that on the other hand, hypercapnic conditions in the
lungs may significantly contribute to the clearance of aPMN.
The authors suggest that the application of CO2 as therapeutic
approach in clinical settings must be properly assessed, with the
benefits of CO2 balanced against the detrimental effects of
impaired bacterial clearance. This is a complicated experimen-
tal study that shows us a new aspect on the development of ALI
following blunt chest trauma.
Murata et al. (14) from Josai University, Japan investigated
the efficacy of low-dose sodium nitrite fluid resuscitation
following crush syndrome in a rat model. The authors reported
that effective rapid fluid resuscitation with a single injection of
sodium nitrite (NaNO2) improved survival by enhancing the
recovery of muscle tissue nitrite (NO2) levels and increasing
myeloperoxidase activity in both the muscle and the lung.
NaNO2 is thought to enhance kidney function and reduce
systemic inflammation by increasing nitric oxide (NO) recov-
ery. However, doses of 200 mmol/kg and 500 mmol/kg can also
induce vasodilation and methemoglobinemia. Therefore, they
hypothesized that side effects could be avoided by continuous
infusion of NaNO2-containing fluid. The results demonstrate
that intravenous administration of NO2 is an effective first-line
fluid therapy for treating crush syndrome. This experimental
study shows the possibility of clinical application of this unique
fluid therapy for crush syndrome.
Recently, growing evidence has indicated that macrophages
contribute to the resolution of lung inflammation with their
abilities to transition from proinflammatory to anti-inflammatory,
tissue-reparative phenotypes. Macrophages have diverse roles
in regulating inflammation and tissue repair in various dis-
eases. Based on their responses to environmental stimuli,
macrophages can be subdivided into two major populations
with distinct functions as generally termed proinflammatory
macrophages (M1) and anti-inflammatory macrophages (M2).
However, the role of M2 macrophages in the resolution and
fibroproliferation of ALI is poorly understood. Therefore,
Tang et al. (15) from Tong Ji University, China, investigated
the effects of two M2 macrophage subtypes, M2a induced by
interleukin (IL)-4/IL-13 and M2c induced by IL-10/transform-
ing growth factor-b, on the pathogenesis of ALI. They found
that M2c macrophages more effectively suppressed indices of
lung injury than M2a macrophages and that M2c macrophages
were also more effective than M2a in reduction of lung fibrosis.
In addition, they found that M2c but not M2a macrophages
increased IL-10 level in lung tissues of the recipient ALI mice
partially mediated by activating the JAK1/STAT3/suppressor
of cytokine signaling pathway. They suggest that M2c are
more potent than M2a macrophages in protecting against lung
injury and subsequent fibrosis due to their ability to produce
IL-10. They indicate that reprogramming macrophages to M2c
subset may be a novel treatment modality with transitional
potential.
Leptin belongs to the family of long-chain helical cytokines
and has structural similarity to IL-6. Leptin is thought to play an
important role in the regulation of the immune system. In
patients, leptin is inversely proportional to interleukin-6
(IL-6) level. Thus, Negrin et al. (16) from Technical University
of Munich, Germany evaluated a dose-dependent therapeutic
4 SHOCK VOL. 48, No. 1
impact of leptin with possible IL-6-dependency on immune
actions and outcome in a two-hit model of trauma/sepsis mice.
They conclude that due to the fact that leptin administration to
traumatized and septic mice seems to have a positive effect on
their outcome via IL-6 and does not negatively impact their
medical condition if applied preventively, leptin might be a
therapeutic agent for the prevention or treatment of sepsis-
related detrimental outcome after initial trauma.
The study by Negrin et al. (16) was followed by an editorial
comment by Kaplan (17), which pointed out two concerns
regarding Negrin’s study. One is that while there was a survival
benefit with leptin treatment, leptin treatment did not affect the
activity level in mice after trauma/sepsis. Kaplan was wonder-
ing how there is a survival benefit without a difference in
activity level between the groups. The other one is the lack of a
robust effect of leptin on systemic inflammation during trauma/
sepsis. Kaplan speculates that the reason of the lack of a robust
effect might be due to the fact that in the Negrin’s study leptin
was administered subcutaneously and that therefore, leptin
might not be sufficiently adsorbed to blood stream in septic
animals which had impaired perfusion of the skin, muscle, and
adipose tissue.
REFERENCES
1. Loftus TJ, Bihorac A, Ozrazgat-Baslanti T, Jordan JR, Croft CA, Smith RS,
Efron PA, Moore FA, Mohr AM, Brakenridge SC: Acute kidney injury following
exploratory laparotomy and temporary abdominal closure. Shock 48:5–10,
2017.
2. Hu Q, Ren J, Wu J, Li G, Wu X, Liu S, Wang G, Gu G, Ren H, Hong Z, et al.:
Urinary mitochondrial DNA levels identify acute kidney injury in surgical
critical illness patients. Shock 48:11–17, 2017.
3. Selejan S-R, Hewera L, Hohl M, Kazakov A, Ewen S, Kindermann I, Böhm M,
Link A: Suppressed MMP-9 activity in myocardial infarction-related cardio-
genic shock implies diminished rage degradation. Shock 48:18–28, 2017.
4. Han M, Fitzgerald JC, Balamuth F, Keele L, Alpern ER, Lavelle J, Chilutti M,
Grundmeier RW, Nadkarni VM, Thomas NJ, et al.: Association of delayed
antimicrobial therapy with one-year mortality in pediatric sepsis. Shock 48:29–
35, 2017.
Copyright © 2017 by the Shock Society. Unauthorized reproduction of this article is prohibited.
HIRASAWA
5. Kim S, Zerillo J, Tabrizian P, Wax D, Lin H-M, Evans A, Florman S, DeMaria S
Jr: Postoperative meld-lactate and isolated lactate values as outcome predictors
following orthotopic liver transplantation. Shock 48:36–42, 2017.
6. Lu J, Wang X, Chen M, Cheng L, Chen Q, Jiang H, Sun Z: An open lung strategy
in the management of acute respiratory distress syndrome: a systematic review
and meta-analysis. Shock 48:43–53, 2017.
7. Lee Y-L, Obiako B, Gorodnya OM, Ruchko MV, Kuck JL, Pastukh VM, Wilson
GL, Simmons JD, Gillespie MN: Mitochondrial DNA damage initiates acute
lung injury and multi-organ system failure evoked in rats by intra-tracheal
pseudomonas aeruginosa. Shock 48:54–60, 2017.
8. Liu F, Nie C, Zhao N, Wang Y, Liu Y, Li Y, Zeng Z, Ding C, Shao Q, Qing C,
et al.: miR-155 alleviates septic lung injury by inducing autophagy via inhibition
of transforming growth factor-b-activated binding protein 2. Shock 48:61–68,
2017.
9. Aslan A, van Meurs M, Moser J, Popa ER, Jongman RM, Zwiers PJ, Molema G,
Zijlstra JG: Organ-specific differences in endothelial permeability-regulating
molecular responses in mouse and human sepsis. Shock 48:69–77, 2017.
10. Griffin MJ, Letson HL, Dobson GP: Buprenorphine analgesia leads to coagul-
opathy and increased plasma fibrinogen in healthy rats: implications for small
animal research. Shock 48:78–84, 2017.
11. Iketani M, Ohshiro J, Urushibara T, Takahashi M, Arai T, Kawaguchi H, Ohsawa
I: Preadministration of hydrogen-rich water protects against lipopolysaccharide-
induced sepsis and attenuates liver injury. Shock 48:85–93, 2017.
12. Martire-Greco D, Rodriguez-Rodrigues N, Castillo LA, Vecchione MB, de
Campos-Nebel M, Moreno MC, Meiss R, Vermeulen M, Landoni VI, Fernandez
GC: Novel use of all-trans-retinoic acid in a model of lipopolysaccharide-
immunosuppression to decrease the generation of myeloid-derived suppressor
cells by reducing the proliferation of CD34þ precursor cells. Shock 48:94–103,
2017.
13. Palmer A, Eichner MSJ, Rittlinger A, Seitz DH, Gebhard F, Huber-Lang MS,
Niesler U: Hypercapnic conditions after experimental blunt chest trauma
increase efferocytosis of alveolar macrophages and reduce local inflammation.
Shock 48:104–111, 2017.
14. Murata I, Miyake Y, Takahashi N, Suzuki R, Fujiwara T, Sato Y, Inoue Y,
Kobayashi J, Kanamoto I: Low-dose sodium nitrite fluid resuscitation prevents
lethality from crush syndrome by improving nitric oxide consumption and
preventing myoglobin cytotoxicity in kidney in a rat model. Shock 48:112–118,
2017.
15. Tang L, Zhang H, Wang C, Li H, Zhang Q, Bai J: M2A and M2C macrophage
subsets ameliorate inflammation and fibroproliferation in acute lung injury
through interleukin 10 pathway. Shock 48:119–129, 2017.
16. Negrin LL, Jahn A, van Griensven M: Leptin protects against mortality and
organ dysfunction in a two-hit trauma/sepsis model and is IL-6-dependent.
Shock 48:130–137, 2017.
17. Kaplan J: Is leptin a key to metabolic inflammation in trauma and sepsis? Shock
48:138, 2017.