Management of Hemorrhage

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MANAGEMENT OF HEMORRHAGE

One of the most crucial elements of obstetrical hemorrhage management is


recognition of its severity. As discussed on page 781, visual estimation of blood
loss, especially when excessive, is notoriously inaccurate, and true blood loss is
often two to three times the clinical estimates. Consider also that in obstetrics, part
and sometimes even all of the lost blood may be concealed. Estimation is further
compli- cated in that peripartum hemorrhage—when most severe cases are
encountered—also includes the pregnancy-induced increased blood volume. If
pregnancy hypervolemia is not a factor, then following blood loss of 1000 mL, the
hema- tocrit typically falls only 3 to 5 volume percent within an hour. The
hematocrit nadir depends on the speed of resusci- tation using infused intravenous
crystalloids. Recall that with abnormally increased acute blood loss, the real-time
hematocrit is at its maximum whenever measured in the delivery, operat- ing, or
recovery room.

A prudent rule is that any time blood loss is considered more than average by an
experienced team member, then the hema- tocrit is determined and plans are made
for close observation for physiological deterioration. Urine output is one of the
most important “vital signs” with which to monitor the woman with obstetrical
hemorrhage. Renal blood flow is especially sensitive to changes in blood volume.
Unless diuretic agents are given— and these are seldom indicated with active
bleeding—accurately measured urine flow reflects renal perfusion, which in turn
reflects perfusion of other vital organs. Urine flow of at least 30 mL, and
preferably 60 mL, per hour or more should be maintained. With potentially
serious hemorrhage, an indwelling bladder catheter is inserted to measure hourly
urine flow.

■ Hypovolemic Shock

Shock from hemorrhage evolves through several stages. Early in the course of
massive bleeding, there are decreases in mean arterial pressure, stroke volume,
cardiac output, central venous pressure, and pulmonary capillary wedge pressure.
Increases in arteriovenous oxygen content difference reflect a relative increase in
tissue oxygen extraction, although overall oxygen consumption falls.

Blood flow to capillary beds in various organs is controlled by arterioles. These


are resistance vessels that are partially con- trolled by the central nervous system.
However, approximately 70 percent of total blood volume is contained in venules,
which are passive resistance vessels controlled by humoral factors. Catecholamine
release during hemorrhage causes a general- ized increase in venular tone that
provides an autotransfusion from this capacitance reservoir (Barber, 1999). This is
accom- panied by compensatory increases in heart rate, systemic and pulmonary
vascular resistance, and myocardial contractility. In addition, there is
redistribution of cardiac output and blood volume by selective, centrally mediated
arteriolar constriction or relaxation—autoregulation. Thus, although perfusion to
the kidneys, splanchnic beds, muscles, skin, and uterus is dimin- ished, relatively
more blood flow is maintained to the heart, brain, and adrenal glands.

When the blood volume deficit exceeds approximately 25 percent, compensatory


mechanisms usually are inadequate to maintain cardiac output and blood pressure.
Importantly, additional small losses of blood will now cause rapid clini- cal
deterioration. Following an initial increased total oxy- gen extraction by maternal
tissue, maldistribution of blood flow results in local tissue hypoxia and metabolic
acidosis. This creates a vicious cycle of vasoconstriction, organ isch- emia, and
cellular death. Another important clinical effect of hemorrhage is activation of
lymphocytes and monocytes, which in turn cause endothelial cell activation and
platelet aggregation. These cause release of vasoactive mediators with small
vessel occlusion and further impairment of microcircu- latory perfusion. Other
common obstetrical syndromes—pre- eclampsia and sepsis—also lead to loss of
capillary endothelial integrity, additional loss of intravascular volume into the
extracellular space, and platelet aggregation (Chaps. 40, p. 734 and 47, p. 947).

The pathophysiological events just described lead to the important but often
overlooked extracellular fluid and electro- lyte shifts involved in both the genesis
and successful treatment of hypovolemic shock. These include changes in the
cellular transport of various ions such as sodium and water into skel- etal muscle
and potassium loss. Replacement of extracellular fluid and intravascular volume
are both necessary. Survival is enhanced in acute hemorrhagic shock if blood plus
crystalloid solu- tion is given compared with blood transfusions alone.

■ Immediate Management and Resuscitation

Whenever there is suggestion of excessive blood loss in a preg- nant woman, steps
are simultaneously taken to identify the source of bleeding and to begin
resuscitation. If she is undeliv- ered, restoration of blood volume is beneficial to
mother and fetus, and it also prepares for emergent delivery. If she is post-
partum, it is essential to immediately identify uterine atony, retained placental
fragments, or genital tract lacerations. At least one and preferably more large-bore
intravenous infusion systems are established promptly with rapid administration
of crystalloid solutions, while blood is made available. An operat- ing room,
surgical team, and anesthesia providers are assembled immediately. Specific
management of hemorrhage is further dependent on its etiology. For example,
antepartum bleeding from placenta previa is approached somewhat differently
than that from postpartum atony.

Fluid Resuscitation

It cannot be overemphasized that treatment of serious hem- orrhage demands


prompt and adequate refilling of the intra- vascular compartment with crystalloid
solutions. These rapidly equilibrate into the extravascular space, and only 20
percent of crystalloid remains intravascularly in critically ill patients after 1 hour
(Zuckerbraun, 2010). Because of this, initial fluid is infused in a volume three
times the estimated blood loss.

Resuscitation of hypovolemic shock with colloid versus crystalloid solutions is


debated. In a Cochrane review of resuscitation of nonpregnant critically ill
patients, Perel and Roberts (2007) found equivalent benefits but concluded that
colloid solutions were more expensive. Similar results were found in the Saline
versus Albumin Fluid Evaluation (SAFE) randomized trial of almost 7000
nonpregnant patients (Finfer, 2004). We concur with Zuckerbraun and colleagues
(2010) that acute volume resuscitation is preferably done with crystal- loid and
blood.

Blood Replacement
There is considerable debate regarding the hematocrit level or hemoglobin
concentration that mandates blood transfusion. Cardiac output does not
substantively decrease until the hemo- globin concentration falls to approximately
7 g/dL or hemato- crit of 20 volume percent. At this level the Society of Thoracic
Surgeons (2011) recommends consideration for red-cell trans- fusions. Also,
Military Combat Trauma Units in Iraq used a target hematocrit of 21 volume
percent (Barbieri, 2007). In general, with ongoing obstetrical hemorrhage, we
recommend rapid blood infusion when the hematocrit is 25 volume per- cent.
This decision is dependent on whether the fetus has been delivered, surgery is
imminent or ongoing operative blood loss is expected, or acute hypoxia, vascular
collapse, or other factors are present.

Scant clinical data elucidate these issues. In a study from the Canadian Critical
Care Trials Group, nonpregnant patients were randomly assigned to restrictive red
cell transfusions to maintain hemoglobin concentration 7 g/dL or to liberal
trans- fusions to maintain the hemoglobin level at 10 to 12 g/dL. The 30-day
mortality rate was similar—19 versus 23 percent in the restrictive versus liberal
groups, respectively (Hebert, 1999). In a subanalysis of patients who were less ill,
the 30-day mor- tality rate was significantly lower in the restrictive group—9
versus 26 percent. In a study of women who had suffered post- partum
hemorrhage and who were now isovolemic and not actively bleeding, there were
no benefits of red cell transfusions when the hematocrit was between 18 and 25
volume percent (Morrison, 1991). The number of units transfused in a given
woman to reach a target hematocrit depends on her body mass and on
expectations of additional blood loss.

Blood Component Products. Contents and effects of trans- fusion of various


blood components are shown in Table 41-8. Compatible whole blood is ideal for
treatment of hypovolemia from catastrophic hemorrhage. It has a shelf life of 40
days, and 70 percent of the transfused red cells function for at least 24 hours
following transfusion. One unit raises the hematocrit by 3 to 4 volume percent.
Whole blood replaces many coagulation factors—which is important in obstetrics
—especially fibrino- gen—and its plasma treats hypovolemia. A collateral
derivative is that women with severe hemorrhage are resuscitated with fewer
blood donor exposures than with packed red cells and components (Shaz, 2009).

There are reports that support the preferable use of whole blood for massive
hemorrhage, including our experiences at Parkland Hospital (Alexander, 2009;
Hernandez, 2012). Of more than 66,000 deliveries, women with obstetrical
hemor- rhage treated with whole blood had significantly decreased incidences of
renal failure, acute respiratory distress syndrome, pulmonary edema,
hypofibrinogenemia, ICU admissions, and maternal death compared with those
given packed red cells and component therapy. Freshly donated whole blood has
also been used successfully for life-threatening massive hemorrhage at combat
support hospitals in Iraq (Spinella, 2008).

It is problematic that in most institutions today, whole blood is rarely available.


Thus, most women with obstetrical hemorrhage and ongoing massive blood loss
are given packed red cells and crystalloid in 2:1 or 3:1 proportions. In these
instances, there are no data to support a 1:1 red cell:plasma transfusion ratio.
Many institutions use massive transfusion protocols designed to anticipate all
facets of obstetrical hemor- rhage defined as massive. These “recipes” commonly
contain a combination of red cells, plasma, cryoprecipitate, and platelets (Pacheco,
2011; Shields, 2011). If time permits, we usually prefer to await results of
emergently performed hematologi- cal laboratory assessments to treat deficiencies
of fibrinogen or platelets. If time does not permit this, however, the massive
transfusion protocol is activated.

Dilutional Coagulopathy. A major drawback of treatment for massive


hemorrhage with crystalloid solutions and packed red blood cells is depletion of
platelets and clotting factors. As discussed on page 808, this can lead to a
dilutional coagulopa- thy clinically indistinguishable from disseminated
intravascular coagulation (Hossain, 2013). In some cases, impaired hemosta- sis
further contributes to blood loss.

Thrombocytopenia is the most frequent coagulation defect found with blood loss
and multiple transfusions (Counts, 1979). In addition, packed red cells have very
small amounts of soluble clotting factors, and stored whole blood is deficient in
platelets and in factors V, VIII, and XI. Massive replacement with red cells only
and without factor replacement can also cause hypofibrinogenemia and
prolongation of the prothrom- bin and partial thromboplastin times. Because many
causes of obstetrical hemorrhage also cause consumptive coagulopathy, the
distinction between dilutional and consumptive coagulopa- thy can be confusing.
Fortunately, treatment for both is similar.

A few studies have assessed the relationship between massive transfusion and
resultant coagulopathy in civilian trauma units and military combat hospitals
(Bochicchio, 2008; Borgman, 2007; Gonzalez, 2007; Johansson, 2007). Patients
undergoing massive transfusion—defined as 10 or more units of blood—had
much higher survival rates as the ratio of plasma to red cell units was near 1.4,
that is, one unit of plasma given for each 1.4 units of packed red cells. By way of
contrast, the highest mortality group had a 1:8 ratio. Most of these studies found
that component replacement is rarely necessary with acute replacement of 5 to 10
units of packed red cells.

From the foregoing, when red cell replacement exceeds five units or so, a
reasonable practice is to evaluate the platelet count, clotting studies, and plasma
fibrinogen concentration. In the woman with obstetrical hemorrhage, the platelet
count should be maintained above 50,000/μL by the infusion of platelet con-
centrates. A fibrinogen level 100 mg/dL or a sufficiently pro- longed
prothrombin or partial thromboplastin time in a woman with surgical bleeding is
an indication for replacement. Fresh- frozen plasma is administered in doses of 10
to 15 mL/kg, or alternatively, cryoprecipitate is infused (see Table 41-8).

Type and Screen versus Crossmatch. A blood type and antibody screen should
be performed for any woman at sig- nificant risk for hemorrhage. Screening
involves mixing mater- nal serum with standard reagent red cells that carry
antigens to which most of the common clinically significant antibodies react.
Crossmatching involves the use of actual donor eryth- rocytes rather than the
standardized red cells. Clinical results show that the type-and-screen procedure is
amazingly efficient. Indeed, only 0.03 to 0.07 percent of patients identified to
have no antibodies are subsequently found to have antibod- ies by crossmatch
(Boral, 1979). Importantly, administration of screened blood rarely results in
adverse clinical sequelae.
Packed Red Blood Cells. One unit of packed erythrocytes is derived from one
unit of whole blood to have a hematocrit of 55 to 80 volume percent, depending
on the length of gen- tle centrifugation. Thus one unit contains the same volume
of erythrocytes as one whole blood unit. It will increase the hematocrit by 3 to 4
volume percent depending on patient size. Packed red blood cell and crystalloid
infusion are the mainstays of transfusion therapy for most cases of obstetrical
hemorrhage.

Platelets. With operative delivery or with lacerations, platelet transfusions are


considered with ongoing obstetrical hemorrhage when the platelet count falls
below 50,000/μL (Kenny, 2014). In the nonsurgical patient, bleeding is rarely
encountered if the platelet count is 10,000/μL or higher (Murphy, 2010). The
preferable source of platelets is a bag obtained by single-donor apheresis. This is
the equivalent of six units from six individual donors. Depending on maternal
size, each single-donor apher- esis bag raises the platelet count by approximately
20,000/μL (Schlicter, 2010). If these bags are not available, then individual- donor
platelet units are used. One unit contains about 5.5 1010 platelets, and six to
eight such units are generally transfused.

Importantly, the donor plasma in platelet units must be compatible with recipient
erythrocytes. Further, because some red blood cells are invariably transfused
along with the plate- lets, only units from D-negative donors should be given to
D-negative recipients. If necessary, however, adverse sequelae are unlikely. For
example, transfusion of ABO-nonidentical platelets in nonpregnant patients
undergoing cardiovascular surgery had no clinical effects (Lin, 2002).

Fresh-Frozen Plasma. This component is prepared by separating plasma from


whole blood and then freezing it. Approximately 30 minutes are required for
frozen plasma to thaw. It is a source of all stable and labile clotting factors,
including fibrinogen. Thus, it is often used for treatment of women with
consumptive or dilutional coagulopathy. Plasma is not appropriate for use as a
volume expander in the absence of specific clotting factor deficiencies. It should
be considered in a bleeding woman with a fibrinogen level 100 mg/dL or
with an abnormal prothrombin or partial thromboplastin time.
An alternative to frozen plasma is liquid plasma (LQP). This never-frozen plasma
is stored at 1 to 6oC for up to 26 days, and in vitro, it appears to be superior to
thawed plasma (Matijevic, 2013).

Cryoprecipitate and Fibrinogen Concentrate. Each unit of cryoprecipitate is


prepared from one unit of fresh-frozen plasma. Each 10- to 15-mL unit contains at
least 200 mg of fibrinogen, factor VIII:C, factor VIII:von Willebrand factor, factor
XIII, and fibronectin (American Association of Blood Banks, 2002). It is usually
given as a “pool” or “bag” using an aliquot of fibrinogen concentrate taken from 8
to 120 donors. Cryoprecipitate is an ideal source of fibrinogen when levels are
dangerously low and there is oozing from surgical incisions. Another alternative is
virus-inactivated fibrinogen concentrate. Each gram of this raises the plasma
fibrinogen level approxi- mately 40 mg/dL (Ahmed, 2012; Kikuchi, 2013). Either
is used to replace fibrinogen. However, there are no advantages to these compared
with fresh-frozen plasma for general clotting factor replacement. Exceptions are
general factor deficiency replacement for women in whom volume overload may
be a problem—an unusual situation in obstetrics—and for those with a specific
factor deficiency.

Recombinant Activated Factor VII (rFVIIa). This syn- thetic vitamin K-


dependent protein is available as NovoSeven. It binds to exposed tissue factor at
the site of injury to gen- erate thrombin that activates platelets and the coagulation
cascade. Since its introduction, rFVIIa has been used to help control hemorrhage
from surgery, trauma, and many other causes (Mannucci, 2007). More than three
fourths of Level I trauma centers include it in their massive transfusion protocols
(Pacheco, 2011). It is included in the massive transfusion pro- tocol at Parkland
Hospital.

One major concern with rFVIIa use is arterial—and to a lesser degree venous—
thrombosis. In a review of 35 random- ized trials with nearly 4500 subjects,
arterial thromboembolism developed in 55 percent (Levi, 2010a). A second
concern is that it was found to be only marginally effective in most of these
studies (Pacheco, 2011). In obstetrics, recombinant FVIIa has also been used to
control severe hemorrhage in women with and without hemophilia (Alfirevic,
2007; Franchini, 2007). It has been used with uterine atony, lacerations, and
placental abruption or previa. In approximately a third of cases, hysterec- tomy
was required. Importantly, rFVIIa will not be effective if the plasma fibrinogen
level is 50 mg/dL or the platelet count is 30,000/μL.

Topical Hemostatic Agents. Several agents can be used to control persistent


oozing. These were recently reviewed by dos Santos and Menzin (2012). In
general, these are rarely used in obstetrical hemorrhage.

Autologous Transfusion. Patient phlebotomy and autolo- gous blood storage for
transfusion has been disappointing. Exceptions are women with a rare blood type
or with unusual antibodies. In one report, three fourths of women who began such
a program in the third trimester donated only one unit (McVay, 1989). This is
further complicated in that the need for transfusion cannot be predicted (Reyal,
2004). For these and other reasons, most have concluded that autologous
transfusions are not cost effective (Etchason, 1995; Pacheco, 2011, 2013).

Cell Salvage. To accomplish autotransfusion, blood lost intra- operatively into the
surgical field is aspirated and filtered. The red cells are then collected into
containers with concentrations similar to packed red cells and are infused as such.
Intraoperative blood salvage with reinfusion is considered to be safe in obstetri-
cal patients (Pacheco, 2011; Rainaldi, 1998). That said, Allam and associates
(2008) reported the lack of prospective trials but also found no reports of serious
complications.

Complications with Transfusions. During the past sev- eral decades, substantial
advances have been achieved in blood transfusion safety. Although many risks are
avoided or miti- gated, the most serious known risks that remain include errors
leading to ABO-incompatible blood transfusion, transfusion- related acute lung
injury (TRALI), and bacterial and viral trans- mission (Lerner, 2010).

The transfusion of an incompatible blood component may result in acute


hemolysis. If severe, this can cause dis- seminated intravascular coagulation, acute
kidney injury, and death. Preventable errors responsible for most of such reactions

frequently include mislabeling of a specimen or transfusing an incorrect patient.


Although the rate of such errors in the United States has been estimated to be 1 in
14,000 units, these are likely underreported (Lerner, 2010; Linden, 2001). A
transfu- sion reaction is characterized by fever, hypotension, tachycardia, dyspnea,
chest or back pain, flushing, severe anxiety, and hemo- globinuria. Immediate
supportive measures include stopping the transfusion, treating hypotension and
hyperkalemia, provoking diuresis, and alkalinizing the urine. Assays for urine and
plasma hemoglobin concentration and an antibody screen help confirm the
diagnosis.

The syndrome of transfusion-related acute lung injury (TRALI) can be a life-


threatening complication. It is charac- terized by severe dyspnea, hypoxia, and
noncardiogenic pul- monary edema that develop within 6 hours of transfusion
(Triulzi, 2009). TRALI is estimated to complicate at least 1 in 5000 transfusions.
Although the pathogenesis is incom- pletely understood, injury to the pulmonary
capillaries may arise from anti-human leukocyte antigen (HLA) antibodies in
donor plasma (Lerner, 2010; Schubert, 2013). These antibod- ies bind to
leukocytes that aggregate in pulmonary capillaries and release inflammatory
mediators. A delayed form of TRALI syndrome has been reported to have an
onset 6 to 72 hours following transfusion (Marik, 2008). Management is with
supportive therapy that may include mechanical ventilation (Chap. 47, p. 944).

Bacterial infection from transfusion of a contaminated blood component is


unusual because bacterial growth is discouraged by refrigeration. The most often
implicated contaminant of red cells include Yersinia, Pseudomonas, Serratia,
Acinetobacter, and Escherichia species. The more important risk is from bacterial
con- tamination of platelets, which are stored at room temperature. Current
estimates are that 1 in 1000 to 2000 platelet units are con- taminated. Death from
transfusion-related sepsis is 1 per 17,000 for single-door platelets and 1 per 61,000
forapheresis-donor packs (Lerner, 2010).

Risks from many transfusion-related viral infections have been curtailed.


Fortunately, the most feared infection—HIV—is the least common. With current
screening methods using nucleic acid amplification, the risk of HIV or hepatitis C
virus infection in screened blood is estimated to be 1 case per 1 to 2 mil- lion units
transfused (Stramer, 2004). The risk for HIV-2 infection is less.
Other viral infections include hepatitis B transmission, which is estimated to be
1 per 100,000 transfused units (Jackson, 2003). Choosing donors who have
been vaccinated will lower this incidence. Because of its high prevalence,
cytomegalovirus-infected leukocytes are necessarily often transfused. Thus,
precautions are taken for immunosuppressed recipients, keeping in mind that this
includes the fetus (Chap. 15, p. 310). Finally, there are slight risks for transmitting
West Nile virus, human T-lymphotropic virus Type I, and par- vovirus B19
(American Association of Blood Banks, 2013).

Red Cell Substitutes. Use of these artificial carriers of oxy- gen has been
abandoned (Ness, 2007; Spiess, 2009). Three that have been studied include
perfluorocarbons, liposome-encapsu- lated hemoglobin, and hemoglobin-based
oxygen carriers.

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