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Preconditions of Hemostasis in Trauma: A Review. The Influence of Acidosis, Hypocalcemia, Anemia, and Hypothermia on Functional Hemostasis in Trauma


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Beside the often discussed topics of consumption and dilution coagulopathy, additional perioperative impairments of coagulation are caused by acidosis, hypocalcemia, anemia, hypothermia, and combinations. Reviewing current literature, cutoff values of these parameters become obvious at which therapy should commence. A notable impairment of hemostasis arises at a pH < or = 7.1. Similar effects are caused by a BE of -12.5 or less. Thus, in case of severe bleeding, buffering toward physiologic pH values is recommended, especially with massive transfusions of older RBCCs displaying exhausted red blood cell buffer systems. It completes the optimization of the volume homeostasis to ensure an adequate tissue perfusion. Combining beneficial cardiovascular and coagulation effects, the level for ionized calcium concentration should be held > or = 0.9 mmol/L. From the hemostatic point of view, the optimal Hct is higher than the one required for oxygenation. Even without a "classical" transfusion trigger, the therapy of acute, persistent bleeding should aim at reaching an Hct > or = 30%. A core temperature of < or = 34 degrees C causes a decisive impairment of hemostasis. A controlled hypotensive fluid resuscitation should aim at reaching a mean arterial pressure of > or = 65 mm Hg (possibly higher for cerebral trauma). Prevention and later aggressive therapy of hypothermia by exclusive infusion of warmed fluids and the use of warming devices are prerequisites for the cure of traumatic coagulopathy. Combined appearance of single preconditions cause additive impairments of the coagulation system. The prevention and timely correction, especially of the combination acidosis plus hypothermia, is crucial for the treatment of hemorrhagic coagulopathy.
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Preconditions of Hemostasis in Trauma: A Review.
The Influence of Acidosis, Hypocalcemia, Anemia,
and Hypothermia on Functional Hemostasis in Trauma
Heiko Lier, MD, Henning Krep, MD, PhD, Stefan Schroeder, MD, PhD, and Frank Stuber, MD, PhD
Beside the often dis-
cussed topics of consumption and dilution
coagulopathy, additional perioperative im-
pairments of coagulation are caused by acido-
sis, hypocalcemia, anemia, hypothermia, and
Reviewing current literature,
cutoff values of these parameters become ob-
vious at which therapy should commence.
A notable impairment of he-
mostasis arises at a pH <7.1. Similar ef-
fects are caused by a BE of 12.5 or less.
Thus, in case of severe bleeding, buffering
toward physiologic pH values is recom-
mended, especially with massive transfu-
sions of older RBCCs displaying exhausted
red blood cell buffer systems. It completes
the optimization of the volume homeostasis
to ensure an adequate tissue perfusion.
Combining beneficial cardiovascular
and coagulation effects, the level for ion-
ized calcium concentration should be held
>0.9 mmol/L.
From the hemostatic point of view,
the optimal Hct is higher than the one
required for oxygenation. Even without a
“classical” transfusion trigger, the ther-
apy of acute, persistent bleeding should
aim at reaching an Hct >30%.
A core temperature of <34°C causes
a decisive impairment of hemostasis. A
controlled hypotensive fluid resuscitation
should aim at reaching a mean arterial
pressure of >65 mm Hg (possibly higher
for cerebral trauma). Prevention and later
aggressive therapy of hypothermia by ex-
clusive infusion of warmed fluids and the
use of warming devices are prerequisites
for the cure of traumatic coagulopathy.
Combined appearance of single pre-
conditions cause additive impairments of
the coagulation system.
The prevention and
timely correction, especially of the combi-
nation acidosis plus hypothermia, is cru-
cial for the treatment of hemorrhagic
Key Words:
Blood coagulation, Co-
agulopathy, Acidosis, Hypocalcemia, Ane-
mia, Hypothermia.
J Trauma. 2008;65:951–960.
In the first four decades of life, trauma is the leading cause
of death and remains a significant cause in later life.
Exsanguination accounts for 40% to 45% of total fatalities
in the trauma setting.
It is the second most common reason
for acute and early deaths within the first days in hospitals,
only central nervous system injuries are more frequent.
than 80% of trauma deaths that occur in the operating room
do so as a result of hemorrhage.
Traumatic hemorrhage may
occur as a result of direct injury to blood vessels, with
massive bleeding, or as a result of diffuse bleeding secondary
to coagulopathy in vessels too small and too numerous for
surgical management. Impaired hemostasis in these patients
is often caused by a combination of dilution and consumption
of clotting factors and hyperfibrinolysis. The goal of therapy
lies in the stabilization of the clotting process.
However, despite the application of apparently sufficient
quantities of fresh frozen plasma, coagulation factors and plate-
lets, this goal is not met in many instances. The major reason for
inefficacy of this therapy is given by the fact that optimal
coagulation requires specific preconditions concerning acid-
base-balance, calcium, hematocrit (Hct), and temperature. In
case these prerequisites are not fulfilled, all procoagulants may
have been applied in vain as stable clotting does not occur.
The standard clinical clotting assays, i.e., activated partial
thromboplastin time and prothrombin time (PT) are performed
in buffered plasma or serum with calcium excess but without
any erythrocytes and at 37°C. These tests are not sensitive
indices of coagulation function in clinical practice,
neither can
prolonged PT or elevated international normalized ratio predict
excessive bleeding in patients undergoing invasive procedures at
Thus, routine coagulation tests are not reliable in cases of
impaired preconditions of traumatic hemostasis.
Awareness of perioperative impairments of coagula-
tion’s preconditions is essential for their prevention and a
reduction in perioperative morbidity and mortality. Parame-
ters to be considered are:
A. Acidosis: Decreased tissue perfusion represents the main
reason for blood acidosis. Lactic acidosis directly reduces
the activity of the coagulation.
Nevertheless, the serum
Submitted for publication September 24, 2007.
Accepted for publication July 24, 2008.
Copyright © 2008 by Lippincott Williams & Wilkins
From the Department of Anaesthesiology and Intensive Care Medicine
(H.L., H.K.), University of Cologne, Cologne, Germany; Department of
Anaesthesiology and Intensive Care Medicine (S.S.), Westkuestenklinikum
Heide, Heide, Germany; and Department of Anaesthesiology and Pain Ther-
apy (F.S.), University of Bern, Bern, Switzerland.
Address for reprints: Dr. Heiko Lier, Department of Anaesthesiology
and Intensive Care Medicine, University of Cologne, Kerpener Street 62,
D-50924 Ko¨ln, Germany; email:
DOI: 10.1097/TA.0b013e318187e15b
Review Article The Journal of TRAUMAInjury, Infection, and Critical Care
Volume 65 Number 4 951
pH does not necessarily reflect the pH in hypoxic, injured
tissue. It may remain acidotic although the blood pH is in
the normal range.
Most of the coagulation proteases
have an optimum pH value between 8.0 and 8.5.
B. Hypocalcemia: In extracellular plasma, Calcium
Factor [F] IV) is in a free ionized state as well
as bound to other molecules. About 55% are biologically
inert and bound to proteins. The majority of protein-
bound Ca
associates with albumin (80%). Therefore,
changes in albumin alter total calcium concentrations sig-
nificantly. Forty-five percent of the total Ca
is biolog-
ically active and exists in the ionized form (Ca
), with
a normal concentration of 1.1 mmol/L to 1.3 mmol/L.
There is an inverse relation between Ca
and the
blood’s pH: an increase in pH of 0.1 will decrease Ca
by 0.036 mmol/L
to 0.05 mmol/L.
In states of hy-
pocalcemia, it is also important to anticipate decreased
magnesium serum concentrations.
C. Hemoglobin/Hematocrit: Platelets play a major role in
localizing clotting reactions to the site of injury because
they adhere and aggregate at the sites of injury where
tissue factor is exposed.
They flow primarily at the
vascular margin.
The number and size of the red blood
cells, the Hct, are the determining factors of platelets’
radial transport and their adhesion to damaged sites of the
D. Hypothermia: According to the equations of van’t Hoff
and Arrhenius, a decrease in temperature of 1°C or 1°K
will theoretically cause a decrease in the coagulation
proteases’ activity of 4% to 10%.
The standard coag-
ulation tests, PT and activated partial thromboplastin
time, are prolonged by hypothermia when they are per-
formed at the patient’s actual core temperature.
even then, these assays still underestimate the magnitude
of the coagulopathy as they do not reflect the in vivo
process occurring on cell membranes.
Reviewing current literature, cutoff values of these
parameters become obvious at which therapy should
Nonsurvivors of trauma are more likely to have a lower
pH than survivors.
Acidosis impairs almost all essential
parts of the coagulation process: At a pH lower than 7.4,
normal human platelets change their internal structure and
their shape, becoming spheres deprived of pseudopodia.
Different coagulation factors are differently influenced by
Additionally, the factors’ Ca
-binding sites
have a unique pH-dependent affinity that is reduced consid-
erably under acidic conditions.
Impaired thrombin generation is the main cause of co-
agulopathic bleeding.
In Martini’s experiments thrombin
generation in the propagation phase was inhibited by a pH of
7.1 by as much as 50%, with no changes in the initiation
phase. A pH of 7.1 caused a 35% reduction of fibrinogen
most likely caused by altered sequestration or degradation.
Additionally, the platelet count was reduced to 50%.
A thrombelastographic (TEG) survey
found a pH of
7.1 to significantly affect each platelet receptor examined.
Such a low pH seemed to have a more deleterious effect on
coagulation than hypothermia which is consistent with other
Another TEG study showed that the rate at
which the clot is formed and polymerized is impaired in a
progressive manner by acidosis.
The base excess (BE) was characterized as an expedient
and sensitive measure of both the degree and the duration of
inadequate perfusion
and correlated with mortality.
the BE refers to the amount of acid required to return the
blood pH of an individual to normal (pH 7.4, assuming
normal physiologic values of PaO
, and temperature),
there is also an influence of BE on coagulation factors,
ing a BE above 12.5.
Transforming Meng’s findings
pH values to negative BE (postulating a nonrespiratory aci-
dosis) shows: a BE of 15 mmol/L reduces the activity of
different coagulation factors by 50%
(Fig. 1).
Even in industrialized countries, more than 30% of red
blood cell concentrates (RBCCs) are stored longer than 3
Although the storage’s effect on oxygen capacity is
still discussed controversially, a massive transfusion of older
RBCCs can boost a patient’s acidosis.
Hyperkaliemia is
increased when blood is held in storage, as 2,3-diphospho-
glycerate levels decrease, pH is reduced, supernatant potas-
sium levels increase, and intracellular potassium levels
Fresh RBCCs have a BE of 20 mmol/L, after 6
weeks it is 50 mmol/L.
These findings indicate the adverse effects of acidosis
lower than 7.1 on the activity of coagulation factors and
platelets. High concentrations of hydrogen lead to an im-
paired ionic interaction between the coagulation factors and
negatively charged phospholipids.
For this reason, correc-
tion of acidosis using sodium bicarbonate (NaHCO
) or trishy-
droxymethylaminomethane (THAM) should be beneficial.
Other findings suggest that NaHCO
may inhibit the conversion
of fibrinogen to fibrin.
Although bicarbonate infusion suc-
Fig. 1. Conclusive correlation between the activity respectively ac-
tivation of different coagulation factors and a negative base excess
(BE) (postulating a nonrespiratoric acidosis): generation of FXa,
generation of FIIa, Eactivation of FVIIa (data according to
, adapted from Zander
, with kind permission).
The Journal of TRAUMAInjury, Infection, and Critical Care
952 October 2008
cessfully reversed pH and BE, neither the reduced fibrinogen
concentration nor the impaired thrombin generation were
reversed by buffering.
Albeit, NaHCO
buffering effect is
dependent on normal respiratory function.
the neutralization of arterial pH did not alter the
loss of fibrinogen, but the inhibition in thrombin generation
was not observed and thrombin generation kinetics returned
to baseline levels. The addition of the buffer THAM also
reversed the coagulation’s impairment at lower pH values in
TEG studies.
Like Martinowitz demanded for rFVIIa,
rection of the pH to 7.2 is recommended before the adminis-
tration of any hemotherapeutics.
Future studies will need to
address the question which buffering agent should be used.
Because conversion of fibrin to thrombin will only be
accomplished if enough platelets and fibrinogen are avail-
able, data support a possible need for fibrinogen and platelets
supplementation in treating acute trauma patients with aci-
dotic coagulopathy.
A notable impairment of hemostasis arises at a pH 7.1.
Similar effects are caused by a BE of 12.5 or less. Thus, in
case of severe bleeding, buffering toward physiologic pH
values is recommended, especially with massive transfusions
of older RBCCs displaying exhausted red blood cell buffer
systems. It completes the optimization of the volume ho-
meostasis to ensure an adequate tissue perfusion.
Ionized hypocalcemia is common among critically ill
adults and is associated with increased mortality. Hazard
ratios of 5.1 for severe (0.90 mmol/L) and 1.8 for mild
ionized hypocalcemia (0.90 –1.15 mmol/L) at admission on
the intensive care unit were published.
Adverse cardiac
effects of hypocalcemia have been reported to commence at
or below 0.8 mmol/L to 0.9 mmol/L.
In a cohort of 212
consecutive severe trauma patients admitted to a trauma cen-
ter, significant correlations between Ca
within 77 minutes
after trauma and the amount of infused colloid and arterial pH
but not with the amount of infused crystalloid were noted.
Analyzing severely traumatized patients with a hypocalcemia
0.9 mmol/L
strongly suggested that colloid-induced he-
modilution is an important causative factor of early hypocal-
cemia in severe trauma patients and is further amplified by
shock and ischemia-reperfusion.
The vitamin K-dependent factors FII, FVII, FIX, and FX
as well as protein C and S are negatively charged. The same
is true for the phospholipids. Positively charged Ca
acts as
a “bridge” between these surfaces and serves the enhance-
ment of coagulation factors at the damaged endothelium. Its
role in the conversion of fibrin to thrombin was noted as early
as 1892.
The binding of Ca
to fibrinogen exerts a pro-
tective effect on the molecule, decreasing its susceptibility to
denaturation by heat, acids, or plasmin proteolysis.
It is
essential for the timely formation and stabilization of fibrin
polymerization sites at all successive stages of the fibrin
A reduction of cytosolic calcium concen-
tration causes a decrease in all platelet-related activities
the modification of their shape during activation.
lular Ca
mobilization is required for stable platelet incor-
poration into the developing thrombus.
This mobilization
acts on the platelets via the same surface ADP-receptors that
are responsible for the platelets’ morphologic changes and the
beginning of their aggregation.
Inhibitory pathways, partic-
ularly the activation of protein C
and fibrinolysis
are also
calcium dependent.
Infusions of the citrate anticoagulant in blood compo-
nents may worsen hypocalcemia.
Excess amounts of citrate
anticoagulant are present in fresh frozen plasma.
The more
rapid the infusion is, the stronger the temporary decrease of
will be
(Fig. 2).
Very few studies analyze the dose-response effects of
calcium on coagulation. The search for this relationship
of calcium and thrombin generation identified an upper limit
of 0.5 mmol/L above which thrombin generation was not
further enhanced.
By using heparinized blood, the authors
may have underestimated the true Ca
by up to 9%.
Accordingly, coagulation defects can be attributed to hy-
pocalcemia if the Ca
is 0.6 mmol/L to 0.7 mmol/L.
Two distinct pharmacologic compounds are usable for
substitution of Ca
: One milliliter of calcium gluconate
provides 9.3 mg of elemental calcium whereas 1 mL of
calcium chloride yields 27 mg.
Combining beneficial cardiovascular and coagulation ef-
fects, the level for ionized calcium concentration should be
held 0.9 mmol/L.
Platelets are expelled toward the red blood cell-depleted
marginal layer near the tube wall by mutual interaction with
erythrocytes: the near-wall concentration of platelets is sig-
nificantly enhanced up to about seven times the average
concentration, practically independent of the tube diameter in
the range of 100
Therefore, rheologic
displacement of platelets toward the vessel’s area with max-
imum shear-stress
is dependent on the amount of red blood
cells and is called margination.
The number and size of the
red blood cells, the Hct, are the determining factors of plate-
lets’ radial transport and their adhesion to endothelial
: Under flow conditions platelet adhesion increases
fivefold as Hct values increase from 10% to 40% but under-
goes no further increase from 40% to 70%, implying a satu-
ration of the transport-enhancing capabilities of red cells. For
flow conditions in which platelet-surface reactivity is more
dominant, platelet adhesion and thrombus formation increase
monotonically as Hct values increase from 10% to 70%.
Activation of platelets is dependent on red blood cells’
provision of ADP.
The presence of erythrocytes induced a
Preconditions of Hemostasis in Trauma
Volume 65 Number 4 953
twofold increase in platelet thromboxane B2 synthesis upon
collagen stimulation, indicating that erythrocytes modulated
platelet eicosanoid formation. Stimulated platelet-erythrocyte
suspensions contained 6.9-fold more ADP and 4.9-fold more
ATP than stimulated platelets alone. Metabolically active
erythrocytes amplify platelet reactivity as expressed by in-
creased recruiting capacity, production of thromboxane B2,
and release of ADP and P-thromboglobulin.
promoted significant increases in cyclo-oxygenase and li-
poxygenase metabolites upon platelet stimulation with colla-
gen or thrombin.
Thromboxane A2 and arachidonic acid
derived from activated platelets, induce a prothrombotic phe-
notype on erythrocytes in proximity. So, erythrocytes can
actively contribute to platelet-driven thrombogenesis and mi-
crovascular occlusion.
Normal RBC participate in the he-
mostatic process of thrombin generation through exposure of
procoagulant phospholipids.
A significant inverse correlation was noted between the
bleeding time and Hct
and an inverse correlation of Hct
and platelet count.
This fact must be taken into account in
the assessment of anemic patients, particularly those who
may have an associated hemostatic disorder.
A normaliza-
tion of both platelet count and Hct are required to achieve
optimum hemostasis. A reduced Hct inhibits the platelet
aggregation and adhesion.
Significant abnormalities in laboratory measures of
blood clotting develop before compromise of tissue oxygen-
ation (assessed by mixed venous oxygen saturation and total
body oxygen consumption) in swine and in healthy
Especially, in patients with severe trauma who
received large volumes of colloids, the hemodilution had
important effects on Hct levels and hemostasis.
Removal of
two units of RBCs in healthy volunteers produced a 60%
increase in the bleeding time associated with a 15% reduction
in the peripheral venous Hct and a 9% reduction in the
platelet count. The platelet dysfunction observed with the
reduction in Hct was due in part to a reduction in shed blood
thromboxane B2.
A decrease of the platelet count by
L could be compensated for by a 10% increase in
The endogenous thrombin potential increased as the
Fig. 2. Present model of “cell-based” coagulation according to Hoffman
and the target location of ionized calcium. The coagulation
factors are characterized by their Latin numbers. Ca
: ionized calcium; GP: glycoprotein receptor on the platelets’ surface; PAR14:
protease-activated receptor 1 and 4 thrombin’s bonding side on platelets, essential for the activation of platelets; TF: tissue factor; TFPI:
tissue factor pathway inhibitor blocks (like ATIII) Xa, if Xa is not on the surface of TF-bearing cells; vWF: von Willebrand factor.
The Journal of TRAUMAInjury, Infection, and Critical Care
954 October 2008
Hct was elevated from 10% to 40%; the maximal thrombin
concentration achieved increased linearly over the range from
0% to 60%. The effect of red cells on thrombin generation is
probably due to the presence of exposed phosphatidylserine
on their membranes.
Initial therapy of traumatic blood loss is the replacement
of the lost volume by crystalloid and colloidal solutions.
Volume replacement, and not oxygen-carrying capacity,
plays the most important role in initial treatment of hemor-
rhagic shock.
Yet concerning the preconditions of hemo-
stasis, current military experience in Iraq and Afghanistan
point to a possible usefulness of damage control resuscitation
with minimal colloid use and early application of thawed
plasma and RBCC.
Nevertheless, sole compensation of the
lost blood by crystalloids and colloids and later by RBCCs
will worsen the consumption coagulopathy by adding a dilu-
tion effect.
The decrease of almost all procoagulant and
anticoagulant factors will closely follow that of the Hct.
The formation of fibrin from its precursor fibrinogen is
the essence of the coagulation process.
Only 10 g of
fibrinogen exist in the normal circulation at any given time.
The decline of fibrinogen levels have been considered as one
of the two most sensitive measures of clinical coagulopathy
(the other being platelet counts).
Maintaining fibrinogen
concentrations is essential when continuing blood loss is
bridged by colloid infusion until transfusion triggers are
reached, especially in patients already exhibiting borderline
fibrinogen levels at baseline.
In diluted blood, “primary”
hemostasis, i.e., the interaction of platelets and the damaged
endothelium seems to be influenced by lower blood viscosity
and altered rheology. Hydroxy-ethyl-starch (HES) caused
changes which mainly corresponded to hypocoagulability:
TEG parameters, which predominantly are influenced by
platelet function (
-angle, maximal amplitude) were always
reduced with HES.
The reduction of fibrinogen levels was
significantly worse in patients substituted with HES.
So, the
first coagulation factor decreasing to pathologically low lev-
els in trauma and hemodilution is usually fibrinogen.
apparently is the factor most closely linked to the clot’s
quality in normal individuals.
This drop cannot be ex-
plained solely by blood loss and resuscitation fluids
often is reached earlier than expected.
Fries et al. withdrew
60% of the estimated total blood volume from pigs and
replaced the loss with gelatin solution. Compensation exclu-
sively with fibrinogen concentrate normalized the impaired
clot strength and led to statistically significant less blood loss
after a liver stab wound.
Even moderate dilution with col-
loids reduced the clot’s firmness and impaired especially the
polymerization of FI.
In fact, this interference also held true
for low molecular weight HES (6% HES 130/0.4).
Therefore, optimal hemostasis in severely bleeding
trauma patients requires a fairly high Hct
which exceeds
Hct values needed for adequate oxygenation
: Depending on
the patient’s clinical status, RBC transfusion is recommended
if acute anemia reduces hemoglobin (Hb)-values to 6 g/dL
and 9 g/dL.
A liberal transfusion strategy even seems to
have possible negative effects on patients’ survival.
ertheless, these values are not sufficient for the improvement
of hemostasis in persistent hemorrhage requiring massive
: sometimes continued massive bleeding re-
quires a increase in Hct possibly as high as 35%
to 10 g/dL to 11 g/dL.
From the hemostatic point of view, the optimal Hct is
higher than the one required for oxygenation. Even without a
“classical” transfusion trigger, the therapy of acute, persistent
bleeding should aim at reaching an Hct 30%.
The impact of body core hypothermia on outcome in 71
adult trauma patients with Injury Severity Scores (ISS)
greater than or equal to 25 was analyzed
: Although mor-
tality was 7% if body core temperature was 34°C, it was
40% at 34°C, 69% at 33°C, and 100% at 32°C. Within
each subgroup (i.e., greater ISS, massive fluid administration,
shock) the mortality of hypothermic patients was signifi-
cantly higher than those who remained warm.
more than 38,000 patients of the Pennsylvania Trauma Out-
come Study registry, admission hypothermia defined as
35°C measured within 30 minutes after arrival in the
trauma center noted a threefold-increased odds of death, even
when adjusted for the confounding effects of age, injury
severity and mechanism, admission systolic blood pressure,
and temperature measurement route.
High risk for persis-
tent coagulopathy was qualified as temperature 35°C in the
patient with medical bleeding.
A strong correlation between
perioperative temperature and blood loss independent of de-
gree of physiologic or anatomic injury was also noted.
hypothermic (35.0°C 0.5°C) patients intraoperative and
postoperative blood loss were significantly greater.
Temperature-related coagulation disorders are caused by
clotting factor enzyme function, platelet function, and fi-
brinolytic activity.
The series of enzymatic reactions of the
coagulation cascade are strongly inhibited by hypothermia.
Thirty-four degree celsius was the critical point at which
enzyme activity in trauma patients slowed significantly, and
at which significant alteration in platelet activity was seen.
It has been recommended to quickly obtain a temperature of
or 36°C,
respectively. Clotting time prolongation
appeared proportional to the number of enzymatic steps
: clotting time correlated significantly with assay
temperature in a negative exponential fashion. This data
showed that hypothermia-induced coagulopathy is, at least in
part, independent of the clotting factor levels. In a follow-up
study the same group suggested that clotting times were more
severely prolonged when test temperatures were hypothermic
than when body temperatures were hypothermic.
Despite the
presence of normal clotting factor levels, at temperatures
below 33°C hypothermia produces a coagulopathy that is
Preconditions of Hemostasis in Trauma
Volume 65 Number 4 955
functionally equivalent to significant, i.e., 50% of nor-
mal activity, factor-deficiency states under normothermic
So the avoidance or correction of hypothermia
may be critical in preventing or correcting coagulopathy in
the patient receiving massive transfusion.
Therefore, the
appropriate treatment for hypothermia-induced coagulopathy
is rewarming rather than administration of clotting factors.
Interestingly, in Martinowitz’ study the recombinant FVIIa
retained its activity at the patients’ mean temperature of
34.1°C 2.5°C.
Nonetheless, the authors recommended that
body temperature should be restored to physiologic values.
In addition to the negative influence of hypothermia on
clotting factors, there is also an impairment of platelets’
function. Hypothermia has been shown to induce morpho-
logic changes in the platelet structure during activation
results in coagulopathy by reducing the availability of platelet
In vitro, hypothermia inhibited thrombin- and
up-regulation of GMP-140 complex, down-regulation of the
GPIb-IX complex, platelet aggregation, thromboxane B2
generation and in vivo platelet activation. These inhibitory
effects of hypothermia were all completely reversed by re-
warming the blood.
Measuring local skin temperature of the
forearm cooled with ice, isolated local hypothermia produced
an increased bleeding time and a significant reduction in the
thromboxane B2 level at the bleeding time site.
Each 1°C
decrease in temperature resulted in a 15% decrease in the
rate of thromboxane B2 production and thus in platelet
In platelets, the intracellular concentration of
and the three catalytic steps of the metabolism of
arachidonic acid to thromboxane A2 by the cyclo-oxygenase
pathway are strongly temperature dependent.
Thus, hypo-
thermia acts on platelet activation and adhesion by inhibiting
the interaction between vonWillebrand factor with the plate-
let GPIb-IX-V complex.
Measured with TEG, core temperature 34°C caused a
significant slowing of enzyme activity of about 10% per
degree celsius and decreased platelet activity without signif-
icantly altered fibrinolysis.
A systematic evaluation of the
effect of temperature on coagulation enzyme activity and
platelet function showed
: Factor Xa generation was re-
duced by 13% at 33°C compared with 37°C, which is almost
consistent with an expected twofold increase in rate for every
10°C increase in reaction temperature for a typical enzyme.
Prothrombinase (FXa/Va) activity decreased in a temperature-
dependent fashion from 37°C to 33°C and thrombin genera-
tion was reduced by 25% at 33°C. At that temperature,
platelet aggregation and adhesion are significantly impaired.
Below 33°C reduced enzymatic reaction rate significantly
blocked the factors’ activity.
Thus, between 37°C and 33°C hemostatic defects
primary result from a defect in platelet adhesion and aggre-
gation, but below 33°C altered enzymatic activity is an ad-
ditional factor. In a porcine model, hypothermia of 32°C
resulted in decreased platelet count but increased receptor
Systemic hypothermia between 31°C and 34°C
accelerated microvascular thrombosis, which was mediated
by increased GPIIb-IIIa activation on platelets.
The au-
thors speculated, fibrinogen may possibly “bridge” the acti-
vated GPIIb-IIIa receptors, so the consumption of fibrinogen
may cause the coagulopathy. Additionally, another reason
seems to be a reduction in the availability of platelet activa-
tors, like the observed reduction in thrombin generation.
So, the net result of hypothermia in vivo is still considered to
be anticoagulant, even a superficial cooling of an arm with
preserved core temperature resulted in a significantly pro-
longed bleeding time.
Perioperative heat loss in the trauma setting is primarily
caused by fluid resuscitation and is proportional to the mass
of fluid used and the temperature gradient from the patient to
the fluid.
The energy needed by the body to warm2Lof
colloidal fluids infused at room temperature of 25°C within 1
hour exceeds the energy that can be delivered by conven-
tional warming methods in 1 hour.
Therefore, the amount
of infused fluids should be limited to ensure the delicate
balance between oxygen delivery and the tissue’s metabolic
demands. As proposed by the concept of “low-volume fluid
and “goal-directed therapy”,
this equilib-
rium should be reached with an mean arterial pressure of 65
mm Hg
or systolic pressure at approximately 90 mm
The effects of hypothermia-induced coagulopathy
can be limited by early and sole infusion of warmed fluids,
use of warm fluids via rapid infusion systems,
more effec-
tive, efficient, possibly aggressive and invasive (i.e., contin-
uous arteriovenous)
rewarming techniques,
the use of
adjunctive warming devices
such as warm air blankets,
and an increased ambient or operation room temperature.
A core temperature of 34°C causes a decisive impair-
ment of hemostasis. A controlled hypotensive fluid resusci-
tation should aim at reaching a mean arterial pressure of 65
mm Hg (possibly higher for cerebral trauma). Prevention and
later aggressive therapy of hypothermia by exclusive infusion
of warmed fluids and the use of warming devices are prereq-
uisites for the cure of traumatic coagulopathy.
Although studies determining the influences of single
preconditions to traumatic coagulopathy are interesting for
scientific purposes, in the clinical setting, the deterioration of
hemostasis in trauma is always caused by multiple and con-
curring ones.
The terms “lethal triad ” or “bloody vicious circle” are
used by many authors for the combination of hypothermia,
acidosis, and coagulopathy.
Of 45 trauma patients re-
quiring massive transfusions with a mean ISS of 55 6, a
mean transfusion of 22.5 5 units of blood, and a mortality
of 33%, nonsurvivors had a higher incidence of clinical
coagulopathy (73% vs. 23%), had lower pH (pH 7.04 0.06
vs. 7.18 0.02), received more transfusions (26.5 9 vs.
The Journal of TRAUMAInjury, Infection, and Critical Care
956 October 2008
18.6 1), and had lower core temperature (31 1°C vs.
34 1°C).
Despite adequate blood, plasma, and platelet
replacement, patients who were hypothermic and acidotic
developed clinically significant bleeding. Hypothermia
35°C and dilution acted additively on coagulation times and
platelet function.
Analyzing 58 injured patients without
severe head injury and preexisting coagulation dysfunction
who received 10 units RBCC per 24 hour, a model was
developed to identify patients at risk for early life-threatening
The four risk factors were: pH 7.1, core
temperature 34°C, ISS 25, and systolic blood pressure
70 mm Hg. With all four risk factors the incidence of
coagulopathy was 98%. Comparing hypothermia and acidosis
regarding the development of coagulopathy found the effects
of lowering pH from 7.4 to 7.15 to be almost identical to the
effects of decreasing the temperature from 36°C to 32°C.
In a porcine model of hemorrhagic shock when shock and
hypothermia occurred simultaneously, their deleterious ef-
fect on hemodynamic and coagulation parameters were
The effects of hypothermia persisted despite the
arrest of hemorrhage and volume replacement. In 212 severe
trauma patients, a study showed hemodilution by colloids and
acidosis are highly correlated with hypocalcemia.
plus hypothermia led to a 72% increase in splenic bleeding
time in a pig model.
Both acidosis and hypothermia altered
circulating platelet status in swine.
In the same setting, pH
of 7.1 and temperature of 32°C led to significantly delayed
thrombin generation and platelet granule release, and reduced
thromboxane B production rate.
Although in this model
the effects of 32°C on clot initiation (r time) suggested re-
duced enzymatic rates, the pH of 7.1 slowed clot initiation
primarily by altered cellular response. Nevertheless, the com-
bined effects of acidosis plus hypothermia were greater than
the individual ones.
The fact that high infusion rates of blood
products containing citrate will decrease Ca
is particularly
true in combination with hypothermia.
As proven by Martini
et al.,
the kinetics of fibrinogen activation and thrombin gen-
eration are inhibited by acidosis and hypothermia via different
mechanisms: thrombin generation is impaired by hypothermia in
the initiation phase and by acidosis in the propagation phase.
Although fibrinogen generation is reduced by hypothermia,
acidosis impairs its degradation.
Recently, in a rabbit model
employing 50% hemodilution and 4°C temperature reduction,
all the clotting proteins as well as RBC and platelets were diluted
by at least 40%.
The excessive bleeding was caused by a slow
clotting process and a decrease in platelet count and fibrinogen
concentration in the blood.
Combined appearance of single preconditions cause ad-
ditive impairments of the coagulation system. The prevention
and timely correction, especially of the combination acidosis
plus hypothermia, is crucial for the treatment of hemorrhagic
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112. Rossaint R, Cerny V, Coats TJ, et al. Key issues in advanced
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In the article, “Blunt Abdominal Trauma Leading to Traumatic Transection of the Liver Without Massive Hemorrhage,”
which appeared as an online only article in volume 65, number 2 of The Journal of Trauma, two author’s names were
misspelled. The author listing should have read: Martijn Hommes, MD, J. Carel Goslings, MD, and Thomas M. van
Gulik, MD.
This error has been corrected in the online version of the article available at
Hommes M, Goslings C, van Gulik TM. Blunt abdominal trauma leading to traumatic transaction of the liver without massive hemorrhage.
J Trauma 2008;65:E21–3.
In volume 65, number 2 of The Journal of Trauma, the Letters to the Editor from Dr. Dirnhofer and Dr. Rutty were
incorrectly published under the heading of “The Authors’ Reply.” These letters should have appeared under the heading
“To the Editor.”
These errors have been corrected in the online version of the article available at
Dirnhofer R, Ranner G, Yen K. CT scanning as a detection tool for forensic pathologists. J Trauma 2008;65:494.
Rutty GN, Morgan B, O’Donnell C, Leth PM, Thali M. Forensic institutes across the world place CT or MRI scanners or both into their
mortuaries. J Trauma 2008;65:493– 4.
The Journal of TRAUMAInjury, Infection, and Critical Care
960 October 2008
... Calcium plays an essential role in physiologic processes; calcium derangement is linked to complications of severe trauma, including hypothermia, coagulopathy, and acidosis. [1][2][3][4][5][6][7][8] Inadequate serum calcium in trauma patients is associated with the exacerbation of hemorrhagic shock secondary to traumatic injury and subsequently poorer outcomes than those with adequate calcium levels. Hemorrhagic shock continues to be a significant cause of death after traumatic injury in both military and civilian settings. ...
... Calcium-dependent pathways are key in vasomotor tone, platelet function, intrinsic and extrinsic pathway-mediated coagulation, and therefore play a crucial role in hemorrhagic shock and resuscitation (Table 1). 5,11,12 Both trauma and transfusion procedures lead to worsening hypocalcemia. 3 The role of hypocalcemia in trauma patients has been a recent area of study, with goals to optimize resuscitation and understand the link between calcium derangements, risk of death, and need for transfusion. ...
... In addition, patients in the iCa <0.90 mmol/L group received more blood products (34 [23-58] vs. 22 [18][19][20][21][22][23][24][25][26][27][28][29][30] units, p < .001) and calcium chloride (4 [2][3][4][5][6][7] vs. 3 [1][2][3][4] g, p = .002), possibly showing a bias by indication in this study. ...
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Background: Calcium plays an essential role in physiologic processes, including trauma's "Lethal Diamond." Thus, inadequate serum calcium in trauma patients exacerbates the effects of hemorrhagic shock secondary to traumatic injury and subsequently poorer outcomes compared to those with adequate calcium levels. Evidence to date supports the consideration of calcium derangements when assessing the risk of mortality and the need for blood product transfusion in trauma patients. This review aims to further elucidate the predictive strength of this association for future treatment guidelines and clinical trials. Methods: Publications were collected on the relationship between i-Ca and the outcomes of traumatic injuries from PubMed, Web of Science, and CINAHL. Manuscripts were reviewed to select for English language studies. Hypocalcemia was defined as i-Ca <1.2 mmol/L. Results: Using PRISMA guidelines, we reviewed 300 studies, 7 of which met our inclusion criteria. Five papers showed an association between hypocalcemia and mortality. Conclusions: In adult trauma patients, there has been an association seen between hypocalcemia, mortality, and the need for increased blood product transfusions. It is possible we are now seeing an association between low calcium levels prior to blood product administration and an increased risk for mortality and need for transfusion. Hypocalcemia may serve as a biomarker to show these needs. Therefore, hypocalcemia could potentially be used as an independent predictor for multiple transfusions such that ionized calcium measurements could be used predictively, allowing faster administration of blood products.
... The patient must be normothermic [13]. Hypothermia, acidosis and hypocalcaemia cause impaired haemostasis and increase the blood loss and transfusion requirements [14]. Tranexamic acid is also included in the Initial care recommendation [15,16]. ...
... Finally, for normal haemostasis, the patient must also have normal pH, normothermia and normal calcium levels [14]. However, when the patient stops bleeding, one can accept impaired values. ...
Postpartum haemorrhage (PPH) is one of the most common causes of maternal mortality worldwide. Management of PPH depends on the severity of bleeding. If the bleeding is severe, aorta compression can reduce bleeding. It should be followed by insertion of two coarse needles for intravenous access and blood sampling for haemoglobin and haemostasis. Further on, monitoring of vital parameters, as well as provision of extra oxygen and warm crystalloids, should be performed. Uterine atony is the most common cause of PPH and local guidelines for uterotonic drug selection should be followed. Patients with ongoing bleeding should immediately receive surgical care for bleeding control. During severe ongoing bleeding, haemostasis care includes early tranexamic acid, transfusion in ratio 4:4:1 (blood:plasma:platelets), and extra fibrinogen intravenously. If not severe PPH, use goal-directed therapy. During general anaesthesia and uterine atony, stop volatile anaesthesia and change to intravenous anaesthesia.
... This condition also contributes to alteration of hemostatic process. 5 Another complication of transfusion also including transfusionrelated acute lung injury, allergic reaction and transfusionassociated circulatory overload. 6 Thus, the transfusion treatment must be decided carefully to achieve the purpose and minimize the complication. ...
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Background and aims: Critically ill children with anemia often requires blood transfusion, which can cause several complications. It is important to decide when to start the red blood cell (RBC) transfusion; however, the guidelines is still lacking. The aim of this study was to compare restrictive and liberal transfusion strategy. Methods: This is an observational retrospective study of critically-ill children who receive RBC transfusion. Subjects categorized into two groups by initial hemoglobin (Hb), that is, restrictive (Hb ≤ 7 g/dl) and liberal (Hb ≤ 9.5 g/dl) strategy. In each group, subjects categorized based on: (1) Hb increment: high (increased ≥2.5 g/dl) and low (increase <2.5 g/dl) and (2) final Hb level: low (<7.0 mg/dl), moderate (7.0-10.0 mg/dl), and high (>10.0 mg/dl). Patient with hematologic or congenital disorder, severe malnutrition, chronic infection-related anemia, and transfusion in Hb level ≥9.5 g/dl were exclude. Each patients were evaluated for the clinical outcome, which is: intensive care length of stay (IC-LOS), length of mechanical ventilation (LoMV), and mortality rate. Results: Clinical outcome and mortality rates of both transfusion strategies are similar. The mortality rates were lower in higher Hb increment and final Hb level (p = 0.04 and p = 0.01, respectively). Multivariate analysis in all groups revealed mortality rate had moderate correlation with Hb increment (odds ratio [OR] = 0.694, 95% confidence interval [CI] 0.549-0.878; p = 0.002) and moderate correlation (OR = 0.642, 95% CI 0.519-0.795; p = 0.000) with final Hb level. The similar results was found after categorization based on transfusion strategy. Conclusion: We conclude the restrictive and liberal transfusion strategy have a similar effect to IC-LOS, LoMV, and mortality rate. High Hb increment (≥2.5 g/dl) and moderate-high final Hb (≥7.0 g/dl) after transfusion reduce the mortality rate.
... Physiological conditions include a body temperature more than 358C, a physiological pH more than 7.2 and ionised calcium more than 1.0 mmol l -1 . 49 In case hyperfibrinolysis is the cause of major bleeding, administration of tranexamic acid (TXA) is recommended. TXA does not only reduce bleeding in patients undergoing elective surgery, but also has been especially recommended in trauma patients. ...
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The majority of ICU patients are anaemic. Anaemia is associated with worse outcomes and a necessity for red blood cell transfusions. ICU patients are a heterogeneous patient group with a broad spectrum of main diagnoses and comorbidities. Evidence-based transfusion trigger guidelines have been established that are dependent on comorbidities. Special attention has been given to blood saving measures and point-of-care diagnosis of coagulation disorders in ICU patients. The administration of intravenous iron and erythropoiesis-stimulating agents can provide useful and individualised alternatives to the administration of red blood cell concentrates in treatment of iron deficiency anaemia. In presence of inflammation and infection, it is challenging to identify the cause of anaemia. The hepcidin-ferroportin pathway may facilitate the diagnosis of anaemia in ICU patients and indicate novel targets in anaemia treatment. This review article presents patient blood management measures and summarises the current literature on transfusion thresholds and alternative therapeutic options using intravenous iron and erythropoiesis-stimulating agents with a key focus on the ICU.
Introduction: Thromboelastography (TEG)-derived maximum amplitude-reaction time (MA-R) ratio that accounts for both hypocoagulable and hypercoagulable changes in coagulation is associated with poor outcomes in adults. The relationship between these TEG values and outcomes has not been studied in children. Methods: In a retrospective cohort study, a level I pediatric trauma center database was queried for children younger than 18 years who had a TEG assay on admission between 2016 and 2020. Demographics, injury characteristics, and admission TEG values were recorded. The MA-R ratio was calculated and divided into quartiles. Main outcomes included mortality, transfusion within 24 hours of admission, and thromboembolism. A logistic regression model was generated adjusting for age, Injury Severity Score, injury mechanism, admission shock, and Glasgow Coma Scale. Results: In total, 657 children were included, of which 70% were male and 75% had blunt mechanism injury. The median (interquartile range) age was 11 (4-14) years, the median (interquartile range) Injury Severity Score was10 (5-22), and in-hospital mortality was 7% (n = 45). Of these patients, 17% (n = 112) required transfusion. Most R and MA values were within normal limits. On unadjusted analysis, the lowest MA-R ratio quartile was associated with increased mortality (15% vs. 4%, 5%, and 4%, respectively; p < 0.001) and increased transfusion need (26% vs. 12%, 16%, and 13%, respectively; p = 0.002) compared with higher quartiles. In the logistic regression models, a low MA-R ratio was independently associated with increased in-hospital mortality (odds ratio [95% confidence interval], 4.4 [1.9-10.2]) and increased need for transfusion within 24 hours of admission (odds ratio [95% confidence interval], 2.0 [1.2-3.4]) compared with higher MA-R ratio. There was no association between MA-R ratio and venous thromboembolic events (venous thromboembolic event rate by quartile: 4%, 2%, 1%, and 3%). Conclusion: Although individual admission TEG values are not commonly substantially deranged in injured children, the MA-R ratio is an independent predictor of poor outcome. Maximum amplitude-reaction time ratio may be a useful prognostic tool in pediatric trauma; validation is necessary. Level of evidence: Therapeutic/Care Management; Level III.
Skin is highly susceptible to foreign pathogens when damaged. Infections usually lead to serious damage to wounds and hinder wound healing, which results in nonhealing and inflammation of the wounds. Herein, a kind of fibrous membrane incorporated with calcium peroxide nanoparticles (n‐CaO2) is fabricated by electrospinning the polymer blend solution of polycaprolactone and gelatin. The obtained membranes show a randomly distributed nanofibrous structure with n‐CaO2 particles embedded in each fiber. Such a structure endows the membranes with medium hydrophilicity and improves blood clotting in comparison with the commonly used gauze, while the loading of n‐CaO2 achieves the in situ generation and rapid release of hydrogen peroxide (H2O2), enabling FM‐10 to display a robust bacteria inhibition of over 90% elimination to E. coli. The in vitro cytocompatibility experiment on the fibrous membranes demonstrates low cytotoxicity to L929 fibroblasts. The in vivo assessment indicates that the fibrous membranes can distinctly accelerate the wound healing, of which FM‐5 exhibits the highest wound closure rate (>95%) after 14 days. This study provides a versatile approach, simply by varying the loading dosage of n‐CaO2 into fiber matrix, to fulfill different functions to meet the multiple needs of wound care. The novel polycaprolactone (PCL)‐gelatin ultrafine fibers are fabricated by electrospinning, in which the nano‐CaO2 is utilized as functional constituent, for the acceleration of wound healing. The PCL and gelation in the fiber matrix provide robust structure support and biocompatibility, while the embedded n‐CaO2 particles give rise to the in situ release of H2O2, aiming at the fast antibacterial property.
Importance: Postpartum hemorrhage (PPH) is a common complication of childbirth and the leading cause of maternal deaths worldwide, also associated with important secondary sequelae. Objective: The aim of this study was to review and compare the most recently published influential guidelines on evaluation, management, and prevention of this severe, life-threatening obstetric complication. Evidence acquisition: A descriptive review of guidelines from the American College of Obstetricians and Gynecologists, the Royal College of Obstetricians and Gynecologists, the Royal Australian and New Zealand College of Obstetricians and Gynecologists, the Society of Obstetricians and Gynecologists of Canada, the Network for the Advancement of Patient Blood Management, Hemostasis and Thrombosis in collaboration with the International Federation of Gynecology and Obstetrics, the European Board and College of Obstetrics and Gynecology and the European Society of Anaesthesiology, and the World Health Organization on PPH was carried out. Results: There is a consensus among the reviewed guidelines that once PPH occurs, it is important to identify the underlying cause (4 T's), estimate the blood loss, and immediately initiate a resuscitation protocol with fluid replacement, blood transfusion, and close monitoring of the woman. In case of uterine atony, all the reviewed medical societies recommend uterine massage, bimanual uterine compression, and administration of uterotonics, although minor discrepancies are observed regarding the optimal regimens. If these measures fail, the use of intrauterine balloon tamponade or other surgical interventions is unanimously recommended. There is also agreement regarding the management of PPH due to retained placenta, placenta accreta, obstetric trauma, uterine rupture or inversion, and acute coagulopathy. Massive transfusion protocols are not consistent in the reviewed guidelines. Finally, all guidelines highlight the importance of the active management of the third stage of labor for the prevention of PPH, suggesting several interventions, with the administration of oxytocin being the criterion standard. Conclusions: Postpartum hemorrhage is a significant contributor of maternal morbidity and mortality. Thus, the development of consistent international practice protocols for the effective management and prevention of this major complication seems of paramount importance and will hopefully improve obstetric outcomes and especially maternal mortality rate.
Background: Blood clot formation or hemostasis is vital to minimize blood loss and mitigate the risk of death from severe bleeding. This study investigates the characteristics of a novel hemostatic composite containing chemically modified chitosan and starch for emergency bleeding control. The performance of this novel hemostatic powder was compared with commercially available starch-based (Arista AH) and chitosan-based (Celox) hemostats. Methods: Hemostatic composite was prepared according to the patent registered by the authors (Patent No. 100865, Iranian Intellectual Property Organization) in Bani Zist Baspar Healda, Inc. (Shiraz, Iran). The properties of the product were surveyed by Fourier-transform infrared spectroscopy and compared with Arista-AH and Celox as commercial counterparts. The cytocompatibility, hemolysis, platelet and red blood cells (RBCs) adhesion, biocompatibility, and biodegradability attributes were evaluated in in vivo and in vitro studies. Hemostatic efficacy was evaluated in 24 healthy 6-month-old male New Zealand white rabbits in lethal and sublethal injuries of femoral artery and veins, respectively. Results: Modification and composition led to a fundamental development in physicochemical characteristics including swelling properties, water absorption, and platelet and RBC adhesion due to improved electrostatic and hydrophilic attributes. The significant superiority in clotting efficiency was confirmed after the application of the composite in 2 models of venous and arterial injury in comparison with common commercial hemostats. Conclusion: Simultaneous use of water-absorbing compounds and introducing positively charged functional groups to hemostatic material led to a considerable control of femoral bleeding in emergency conditions. The introduced composite was biodegradable and biocompatible and prompts RBC aggregation and platelet adhesion.
Background: Trauma-induced hypocalcemia is an underappreciated complication of severe injury but is well known to result in the derangement of an array of physiological regulatory mechanisms. Existing literature provides a compelling link between hypocalcemia and worse trauma-induced coagulopathy and increased mortality after injury. Study design and methods: This narrative review evaluates available data related to the risk factors, mechanisms, and treatment of hypocalcemia after severe injury. The authors did not perform a systemic review or meta-analysis. Results and discussion: The interplay of acidosis, hypothermia, and coagulopathy with hypocalcemia potentiates the bloody vicious cycle of hemorrhagic shock which has been the paradigm of trauma resuscitation for over half a century. However, current screening and treatment of postinjury hypocalcemia are relegated to a secondary consideration in trauma resuscitation. We conclude calcium supplementation should be a primary tier intervention for life-threatening injury.
The neurosurgical patient is exposed to high blood loss due to the lesions to be operated on and the duration of the surgeries. Reducing anemia and perioperative bleeding avoids complications, improves outcomes, and reduces costs. To achieve this objective, in addition to the strategies of increasing the hemoglobin level with iron and erythropoietin, and blood saving with PABD, acute normovolemic and hypervolemic hemodilution, cell salvage (cell saver), there are additional therapies and strategies that can be performed by the anesthesiologist and surgeon during the perioperative process. Conditions that may increase the risk of intraoperative and postoperative bleeding such as comorbidities, medications, and herbal medicine are detected and corrected preoperatively; the anesthetic management with the correct position of the patient, temperature adequacy, acid-base and electrolyte status, choice of anesthetic technique, hemodynamic and ventilation management; strategies with antifibrinolytics and hemostatics such as tranexamic acid, desmopressin, factor concentrates and sealants; and the rationalization of blood sampling and patient-side coagulation analysis methods, points of care (POCs), such as viscoelastic methods (VHAs) with rapid information for timely decision making make perioperative bleeding less. On the other hand, the surgical preparation of the patient, the number of surgeons, experience, and the decisions, devices, and techniques to be used are also determining factors that together with the others described try to achieve the goal of minimizing perioperative bleeding and thus better outcomes.KeywordsPatient blood management (PBM)Acute normovolemic hemodilution (ANH)Preoperative autologous blood donation (PABD)Cell saver (CS) Direct oral anticoagulants (DOACs) Tranexamic acid (TXA) AntifibrinolyticsTopical hemostatic agentsViscoelastic hemostatic assays (VHAs)Points of care (POC)Removal bloodEmbolizationProne positionSpinal surgeryBrain surgery
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Erythrocytes promoted platelet reactivity in a plasma medium, as demonstrated in an in vitro system that independently evaluated the biochemistry of platelet activation and recruitment. The prothrombotic erythrocyte effects were metabolically regulated, as evidenced by lack of activity of ATP-depleted or glutaraldehyde-fixed erythrocytes. They occurred in the absence of cell lysis as verified by lactate dehydrogenase assays, and had an absolute requirement for platelet activation. The presence of erythrocytes induced a twofold increase in platelet thromboxane B2 (TXB2) synthesis upon collagen stimulation, indicating that erythrocytes modulated platelet eicosanoid formation. Cell-free releasates from stimulated platelet-erythrocyte suspensions, which exhibited increased recruiting capacity, contained 6.9-fold more ADP and 4.9-fold more ATP than releasates from stimulated platelets alone. Following aspirin ingestion, TXB2 formation was blocked, but erythrocyte promotion of platelet reactivity persisted at those doses of collagen that reinduced platelet activation. Moreover, when platelet mixtures consisted of as little as 10% obtained before aspirin plus 90% obtained post-aspirin ingestion, significant erythrocyte enhancement of platelet reactivity occurred, even at low agonist concentrations. These erythrocyte effects would decrease the therapeutic potential of inhibition of platelet cyclooxygenase by aspirin. The erythrocyte- induced modulation of platelet biochemistry and function emphasizes the importance of cell-cell interactions in stimulus-response coupling.
Context.—It is well known that the concentration of ionized calcium in blood is affected by the pH of the specimen, since hydrogen ions compete with calcium for binding sites on albumin and other proteins. However, the relationship between pH and ionized magnesium concentration is not as well characterized. Objective.—To determine the effects of pH on ionized magnesium concentration over a wide range of pH values in serum or plasma. Design.—Both ionized calcium and ionized magnesium concentrations were measured in 3 sets of samples. (1) Pools of serum or whole blood at different pH values (7.20–7.60) achieved by adding a constant volume of acid or base (diluted solutions of either hydrochloric acid or sodium hydroxide) plus saline. These pools consisted of 2 serum and 3 heparinized whole blood pools collected from leftover blood remaining in clinical specimens in the Clinical Chemistry and Blood Gas Laboratories, respectively, at Duke University Medical Center. (2) Five whole blood specimens obtained from apparently healthy individual donors. (3) Twenty-six whole blood specimens obtained from individual patients (leftover blood from the Blood Gas Laboratory) in which pH was varied by in vitro loss or gain of carbon dioxide. Results.—Both ionized calcium and ionized magnesium concentrations decreased as the pH in the specimen increased, indicating the stronger binding of these ions with proteins in the more alkaline environment. Conclusion.—We conclude that the rate of change of ionized magnesium concentration with pH change (0.12 mmol/L per pH unit) is significantly less than that of ionized calcium (0.36 mmol/L per pH unit). Furthermore, our findings indicate that if adjustment to pH 7.40 is necessary, the ionized magnesium test results need to be adjusted when pH is markedly abnormal, as is sometimes done for ionized calcium.
A hypothermia-induced hemorrhagic diathesis is associated with cardiopulmonary bypass, major surgery, and multiple trauma, but its pathophysiological basis is not well understood. We examined the hypothesis that hypothermia reversibly inhibits human platelet activation in vitro and in vivo. Platelet activation was studied in normal volunteers by whole blood flow cytometric analysis of modulation of platelet surface GMP-140 and the glycoprotein (GP) Ib-IX complex in: a) shed blood emerging from a standardized in vivo bleeding time wound; b) peripheral blood activated in vitro with either thrombin (in the presence of gly-pro-arg-pro, an inhibitor of fibrin polymerization) or the stable thromboxane (TX) A2 analogue U46619. Platelets in peripheral whole blood were activated at temperatures between 22° C and 37° C. the forearm skin temperature was maintained at temperatures between 22° C and 37° C prior to and during the bleeding time incision. Platelet aggregation was studied in shed blood by flow cytometry and in peripheral blood by aggregometry. Generation of TXB 2 (the stable metabolite of TXA 2) was determined by radioimmunoassay. In vitro, hypothermia inhibited both thrombin- and U46619-induced upregulation of GMP-140, downregulation of the GPIb-IX complex, platelet aggregation, and TXB2 generation. These inhibitory effects of hypothermia were all completely reversed by rewarming the blood to 37° C. In vivo, platelet activation was inhibited by hypothermia as shown by 5 independent assays of shed blood: upregulation of GMP-140, downregulation of the GPIb-IX complex, platelet aggregate formation, TXB 2 ggeneration, and the bleeding time. In summary, by a combination of immunologic, biochemical, and functional assays, we demonstrate that hypothermia inhibits human platelet activation in whole blood in vitro and in vivo. Rewarming hypothermic blood completely reverses the activation defect. These results suggest that maintaining normothermia or rewarming a hypothermic bleeding patient may reduce the need for platelet transfusions.
The management of acute massive blood loss is considered and a template guideline is formulated, supported by a review of the key literature and current evidence. It is emphasized that, if avoidable deaths are to be prevented, surgeons, anaesthetists, haematologists and blood-bank staff need to communicate closely in order to achieve the goals of secure haemostasis, restoration of circulating volume, and effective management of blood component replacement.
Massive transfusion may cause abnormalities of electrolytes, clotting factors, pH, and temperature and may occur in a scenario of refractory coagulopathy and irreversible shock. Identification of correctable variables to improve survival is complicated by the interplay of this pathophysiology. Temperature may be an under-appreciated problem in the genesis of coagulopathy. In vitro studies have demonstrated that platelet function and vascular response are critically temperature-dependent. We reviewed the records of 45 trauma patients without head injury or co-morbid medical illness who required massive transfusions. The mean Injury Severity Score was 55 +/- 6, a mean of 22.5 +/- 5 units of blood was transfused, and mortality was 33%. Nonsurvivors were more likely to have had penetrating injury (88% versus 55%), received more transfusions (26.5 +/- 9 versus 18.6 +/- 1, p less than 0.05), had lower pH (pH 7.04 +/- 0.06 versus 7.18 +/- 0.02, p less than 0.05), had lower core temperature (31 +/- 1 degree C versus 34 +/- 1 degree C, p less than 0.01), and had a higher incidence of clinical coagulopathy (73% versus 23%). Severe hypothermia (temperature less than 34 degrees C) occurred in 80% of the nonsurvivors and in 36% of survivors. Patients who were hypothermic and acidotic developed clinically significant bleeding despite adequate blood, plasma, and platelet replacement. Avoidance or correction of hypothermia may be critical in preventing or correcting coagulopathy in the patient receiving massive transfusion.
In surgical intensive care medicine, the conditions most frequently associated with abnormalities in coagulation are sepsis, severe trauma and the operative procedure involving substantial blood loss itself. Possible coagulation disorders include coagulopathy related to dilution, disseminated intravascular coagulation and hyperfibrinolysis. These disturbances often occur in combination and may be exacerbated by current or incipient impairment of hepatic and renal function. This article reviews the pathophysiology, diagnostic procedures and therapy of complex coagulation disorders in critically ill patients.