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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5524_Библиотеки_им_академика_М_И_Перельмана.pdf
358 F. M. Pieracci
Main Body
• The best treatment for ICU anemia is prevention. Each tube of blood adds up,
so think critically about the utility of every test that is ordered.
• In most cases, surgical ICU patients demonstrate a predictable, slow, regular
decline in hemoglobin of 0.2 g/dL – 0.5 g/dL per day. This pattern is due to
the aforementioned factors, is expected, and should not prompt an expensive
workup as to the etiology of worsening anemia.
• In the minority of cases in which anemia is either unexplained or refractory
to pRBCs transfusion, several laboratory tests may aid in the diagnosis.
These tests will help categorize the anemia into one of three broad etiologies:
(1) impaired erythropoiesis; (2) accelerated erythrocyte loss; or (3) both.
These laboratory tests include:
Complete blood count, including both mean corpuscular volume (MCV) and
mean corpuscular hemoglobin concentration. An elevated MCV (macrocytic
anemia) suggests either vitamin B12 or folate defi ciency. A depressed MCV
(microcytic anemia) suggests iron defi ciency (either absolute or functional).
Markers of hemolysis, including bilirubin (both direct and indirect), and
haptoglobin.
Reticulocyte count/reticulocyte index: a low reticulocyte index suggests
impaired erythropoiesis as opposed to accelerated erythrocyte loss.
Iron markers (discussed in Background section).
• The most common therapy for ICU anemia is pRBCs transfusion. Over the
last three decades, the use of pRBCs transfusion in the treatment of ICU anemia has decreased dramatically. This decrease is due to the recognition that:
(1) mild to moderate anemia is relatively well-tolerated by critically ill
patients; (2) pRBCs transfusion does not impact significantly oxygen consumption in stable cases of mild to moderate anemia; and (3) blood product
transfusion causes both inflammation and immunosuppression.
Theoretical basis for pRBCs transfusion
• Aerobic cellular metabolism may be characterized as a balance between
oxygen delivery and oxygen consumption [Chapter 5-(i)].
• Normally, oxygen delivery far exceeds oxygen consumption. In this case,
incremental increases in oxygen delivery are of no benefit. Conversely, when
oxygen needs exceed delivery, shock and eventual cell death ensue. In this
case, a prompt increase in oxygen delivery is necessary to preserve life.
• Oxygen delivery is the product of cardiac output and arterial oxygen content.
Intensive Care Unit Anemia and Packed Red Blood Cell Transfusion 359
• The great majority of arterial oxygen content is achieved through binding of
oxygen to hemoglobin within erythrocytes.
• The hemoglobin concentration is thus directly related to oxygen delivery.
• Accordingly, if one were to rely simply on mathematics, any increase in the
hemoglobin concentration via pRBCs transfusion should result in an increase
in oxygen delivery and ultimately oxygen consumption. However, this reasoning is flawed for several reasons:
It assumes that the patient’s oxygen consumption is dependent upon
oxygen delivery. This assumption is not true if either (1) the patient is not
in shock or (2) the etiology of the patient’s shock is not impaired oxygen
delivery (e.g., septic shock).
Increasing hemoglobin improves oxygen content at the price of an increase
in blood viscosity, which in turn decreases cardiac output. The net effect
on oxygen delivery is unpredictable.
Transfused pRBCs do not behave as endogenous pRBCs in vivo. Rather,
due to morphologic changes, as well as the accumulation of byproducts of
storage, these transfused cells are clumsy, sticky, and stingy with respect
to oxygen offl oading. These changes are exacerbated by storage time.
pRBCs are thrombogenic. They increase blood viscosity, platelet adhesion
and margination, and thrombin generation. These properties may be
particularly deleterious to patients with acute coronary syndromes (ACS)
secondary to atherosclerotic plaque disruption.
• Therefore, although the numeric calculation of oxygen delivery may increase
following pRBCs transfusion, the actual delivery at the capillary level, and
subsequent consumption by cells, is marginal.
• This hypothesis has been corroborated by several prospective studies, which
have reported no change in either oxygen delivery or consumption after
pRBCs transfusion.
• What, then, is a reasonable approach to pRBCs transfusion of critically ill
patients with ICU anemia? Currently, the most commonly applied approach
utilizes an absolute hemoglobin transfusion trigger of 7 g/dL (see Review of
Current Literature section for discussion of this literature).
• This transfusion trigger has been challenged in several specific clinical cir-
cumstances, the two most common of which will be discussed herein:
Acute coronary syndromes are defi ned as unstable angina, ST-elevation
myocardial infarction (MI), or non-ST-elevation MI.
These conditions share in common a reduction in myocardial oxygen delivery
due to an unstable atherosclerotic plaque within the coronary arteries.
360 F. M. Pieracci
It is argued that the hemoglobin transfusion trigger should be raised
in patients with ACS (anywhere from 8 g/dL to 12 g/dL) because:
(1) increased oxygen delivery is more important in this situation; and
(2) although oxygen delivery may not change with pRBCs transfusion,
increasing the arterial oxygen content will result in a decrease in cardiac
output to maintain the same level of oxygen delivery, thereby placing less
stress on the myocardium.
These theoretical concerns have not been borne out in clinical investigation.
There are many reasons for this disrecpancy, not the least of which is the
thrombogenic properties of pRBCs transfusion, which are particularly
dangerous in patients with ACS.
Currently, and based on two prospective studies, a reasonable hemoglobin
transfusion trigger for patients with ACS is 8 g/dL. There are no data to
support transfusing to a higher hemoglobin.
Traumatic brain injured patients are particularly vulnerable to secondary
brain injury, caused by hypotension, hypothermia, and hypoxia. Accordingly,
it has been argued that TBI patients should be transfused to a higher
hemoglobin concentration than 7 g/dL.
Approximately 50% of TBI patients receive at least one pRBCs trans-
fusion.
Studies of the effect of pRBCs transfusion on cerebral oxygen delivery
and consumption have reported a variable, unpredictable, transient
relationship.
A subgroup analysis of the TRICC trial (discussed in Review of Current
Literature section) limited to patients with moderate to severe TBI showed
equivalent outcomes between the liberal (transfuse for Hgb < 10 g/dL) and
restrictive (transfuse for Hgb < 7.0 g/dL) groups.
See Chapter 32 for discussion of hemoglobin transfusion trigger following
micro-vascular procedures.
• Treatment of ICU anemia with recombinant human erythropoietin has been
studied extensively, most notably in three large, multi-center, randomized
clinical trials by Corwin et al.
• In summary, these three trials showed a modest hemoglobin increase for the
erythropoietin group as compared to placebo group, on the order of 0.5 g/dL.
This increase in hemoglobin did not translate into a decrease in transfusion
requirement.
• Mortality between groups was unchanged, with the exception of a subgroup
analysis of trauma patients in the latest trial, in which erythropoietin therapy
Intensive Care Unit Anemia and Packed Red Blood Cell Transfusion 361
was associated with a significantly decreased mortality. This benefit is likely
non-hematologic and requires further investigation.
• One limitation of the erythropoietin trials involves inadequate documentation
of bone marrow iron delivery. Insufficient iron substrate may have hindered
the ability of erythropoietin to improve anemia.
• Standard dosing of iron supplements (either enteral or parenteral) are not
sufficient to overcome the functional iron deficiency associated with critical
illness.
• The optimal therapy for functional iron deficiency may involve a combina-
tion of higher, goal-directed dosing, and hepcidin antagonism. Studies are
ongoing.
• Standard dosing of iron supplements do not increase the risk of infection
during critical illness.
• Blood product transfusion (including pRBCs transfusion) is independently
associated with an increased likelihood of infection, organ failure, and
death.
• Many of the deleterious effect of blood product transfusion stem from immu-
nomodulation.
Passenger immune cells and cytokines attack recipient organ systems. In the
case of the lungs, this results in transfusion-associated lung injury (TRALI).
In the case of the immune system, this results in immunosuppression and
infection.
By contrast, recipient immune cells and cytokines attack transfused pRBCs,
resulting in the elaboration of further immune response, infl ammation,
and organ damage.
• Currently, no synthetic, hemoglobin-based oxygen carrier is FDA-approved
for use in the U.S.
362 F. M. Pieracci
Practical Algorithm(s)/Diagrams
Fig. 1. The packed red blood cell storage lesion.
Review of Current Literature with References
• The CRIT study reported that, among 4,892 critically ill patients, 44%
received at least one pRBCs transfusion while in the ICU. The number of
pRBCs transfusions was an independent predictor of worse outcome
(Corwin et al. Crit Care Med 2004;32:39–52).
• The transfusion requirements in critical care (TRICC) trial compared restrictive (hemoglobin <7.0 g/dL) and liberal (hemoglobin <9.0 g/dL) transfusion
triggers among 838 critically ill patients. Although inclusion criteria did not
specify ongoing resuscitation, 37% of patients were in shock at the time of
enrollment as evidenced by the need for vasoactive drugs. No difference in
30-day mortality was observed between groups. However, in-hospital mortality, as well as mortality among less severely ill patients (Acute Physiology and
Chronic Health Evaluation II Score <20) and younger patients (age <55 years)
was significantly lower in the restrictive transfusion group. It thus appears that
a hemoglobin concentration of >7g/dL is at least as well-tolerated, and perhaps
better tolerated, than a hemoglobin concentration of >9g/dL among critically
ill patients (Herbert et al. New Engl J Med 1999;340:409–417).
• The CRIT Randomized Pilot Study randomized 45 patients with acute myocardial infarction to liberal (transfuse when hematocrit <30%) or conservative
Intensive Care Unit Anemia and Packed Red Blood Cell Transfusion 363
(transfuse when hematocrit <24%) transfusion strategies. More patients in the
liberal than the conservative arm were transfused (100% vs. 54%, respectively, p < 0.01). The primary clinical safety measurement of in-hospital death,
recurrent myocardial infarction, or new or worsening congestive heart failure
occurred more commonly in the liberal arm as compared to the conservative
arm (38% vs. 13%, respectively, p = 0.05) (Cooper et al. Am J Cardiol 2011;
108:1108–1111).
• The third, large randomized clinical trial of recombinant erythropoietin
involved 1,460 critical ill patients. Comparing the erythropoietin and placebo
groups, there was no difference in either the transfusion requirement or the
number of patients transfused. Erythropoietin marginally increased the hemoglobin at day 29 as compared to placebo (1.6 g/dL vs. 1.2 g/dL, respectively,
p < 0.01) (Corwin et al. New Engl J Med 2007;357:965–976).
• We randomized 150 anemic, critically ill trauma patients to iron sucrose
100 mg IV thrice weekly or placebo for up to two weeks. Although ferritin
increased significantly for the iron as compared to the placebo group, there
was not discernable effect on iron-deficient erythropoiesis, anemia, pRBCs
transfusion requirement, or mortality (Pieracci et al. Crit Care Med 2014;42:
2048–2057).
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Chapter 9-(ii)
Diagnosis and Management
of Coagulopathy
Eduardo Gonzalez, MD* and Ernest E. Moore, MD
*Surgical Resident, University of Colorado School of Medicine
†
Professor of Surgery and Vice-Chair of Surgical Research, University of Colorado
School of Medicine
Take Home Points
• Appreciation of the underlying biologic mechanisms of hemostasis is central
to the diagnosis and management of patients with coagulopathic bleeding.
• An endogenous coagulopathy, present upon ED arrival, has been identified in
25% of trauma patients; hypothermia, acidosis, and on-going shock worsen
this already deranged hemostatic system.
• Hyper-fibrinolysis results in a 52–92% mortality rate, and should be identified promptly. Thrombelastography (TEG) is currently the best assay to
diagnose hyper-fibrinolysis.
• Optimal management of coagulopathy starts with its prompt identification, or
of those patients at risk of coagulopathy. Time is the main catalyst of coagulopathy, as the bloody vicious cycle perpetuates itself with every minute untreated.
†
Contact information: (Eduardo Gonzalez) 777 Bannock St. MC 0206, Denver, CO 80204;
(Ernest E. Moore) 655 Broadway, Ste. 365, Denver, CO 80203; Tel.: 303-602-182;
Emails: ernest.moore@dhha.org; Eduardo.Gonzalez@dhha.org
365
366 E. Gonzalez and E. E. Moore
• All bleeding patients should be initially approached with the universal A-B-C
(airway, breathing, circulation) assessment and management strategy, regardless of their coagulation status, as efforts to achieve hemostasis will be futile
if these principles are not addressed.
• Viscoelastic hemostasis assays such as TEG provide prompt information on
coagulation parameters that reflect all phases of clot formation; from the time
it takes to form the first strands of fibrin, to clot breakdown by fibrinolysis.
• Patients with coagulopathic hemorrhage should be resuscitated with blood
products when available, until bleeding has been controlled or coagulation
parameters corrected. In these patients, crystalloid and colloid can worsen
coagulopathy.
• Transfusion of blood products should be performed according to a massive
transfusion protocol, ideally goal directed.
• Factor replacement (e.g., factor VIIa, prothrombin complex concentrate) and
hemostatic medications should be used only as adjunct therapy to blood products and not as a substitute of them. They currently only have a role as salvage
therapy in those patients with bleeding secondary to excessive anticoagulation, particularly those with intracranial hemorrhage.
• Tranexamic acid is an anti-fibrinolytic medication that when used adequately,
can reduce mortality in trauma patients with documented hyper-fibrinolysis
(TEG-LY30 >3.0%).
Background
• Severe bleeding is a frequently encountered challenge in the surgical intensive care unit. Although the etiology is diverse, the management based on the
recent trauma experience is applicable to most bleeding scenarios.
• As much as 40% of injury-related mortality is attributable to hemorrhage.
In both the civilian and military settings, uncontrolled bleeding is the most
preventable cause of death.
In trauma patients, there is compelling evidence that 25% of seriously
injured patients have an endogenous coagulopathy, evidenced by deranged
coagulation assays upon emergency department (ED) arrival; now generally referred to as trauma induced coagulopathy (TIC).
• Hemostasis is the physiologic cessation of bleeding achieved by the fluid and
cellular components of the clotting system.
• The physiological mechanisms of hemostasis are complex. Our attempts to
manage coagulopathy have so far parted from our basic comprehension of
clot formation under homeostatic conditions; however unique mechanisms of
Diagnosis and Management of Coagulopathy 367
protein function and cell signaling exist under physiologic extremis, and
remain poorly understood.
• Cell-based model of hemostasis (Fig. 1).
The traditional division of the clotting cascade into the intrinsic, extrinsic,
and common pathways is medieval and has little in vivo validity.
Hoffman and Monroe advanced our conceptualization of in vivo hemostasis
with the cell-based model of hemostasis, emphasizing the key interactions of
the extravascular tissues, endothelium, platelets, and other blood cells, with
plasma coagulation proteins. This allows cells to regulate hemostasis through
receptors and signaling, and interact with other systems such as inflammation.
The cell-based model of hemostasis is conceptualized into three phases
(initiation, amplification, and propagation), with most enzymatic reactions
occurring on the phospholipid surfaces of cells.
Initiation
Exposed sub-endothelial collagen localizes circulating platelets by
binding to the platelet’s GP-VI receptor and α2β1 integrin, adhering
platelets to the site of injury (also referred to as primary hemostasis).
Ö At high shear rates (arterial circulation), circulating von-Willebrand
(vW) factor binds to exposed sub-endothelial collagen and platelet
adhesion is further re-enforced by binding of this collagen/
vonWillbrand factor complex to the platelet receptor GP Ib-IX-V.
With endothelial disruption, extra-vascular tissue factor (TF) binds
circulating factor VII. The TF/VIIa complex activates factor X, which
generates thrombin (factor IIa) from prothrombin.
Ö This initial amount of thrombin is insufficient to cleave fibrinogen
and form a clot, but capable of activating factors V and VIII, and
further activating adhered platelets via the protease activated
receptors 1 and 4 (PAR-1 and PAR-4).
Amplification
Ö Factors Va and Xa which were activated during the initiation phase
then form the pro-thrombinase complex (Va/Xa), and activated
factors VIIIa and IXa form the tenase complex (VIIIa/IXa). The
purpose of the tenase complex is to feed more Xa into the prothrombinase complex in order to yield a substantial amount of
thrombin during the propagation phase.
— Factor IXa can originate from activation either through the TF/
VIIa complex or through factor XIa. This represents an overlap