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P
ostpartum hemorrhage is an important and
Management of massive, life-threatening primary post- often preventable cause of maternal mortality
partum hemorrhage in the labor and delivery service is and morbidity worldwide.1,2 Primary postpar-
a challenge for the clinical team and hospital transfu- tum hemorrhage is defined as hemorrhage
sion service. Because severe postpartum obstetrical occurring within 24 hours of delivery. At term, the
hemorrhage is uncommon, its occurrence can result in uteroplacental circulation receives an estimated 700 mL
emergent but variable and nonstandard requests for of blood per minute, so it is not surprising that failure of
blood products. The implementation of a standardized the normal hemostatic mechanisms after delivery can
massive transfusion protocol for the labor and delivery result in life-threatening hemorrhage.3 Major causes of
department at our institution after a maternal death postpartum hemorrhage include uterine atony, patho-
caused by amniotic fluid embolism is described. This logic placental implantation, retained products of con-
guideline was modeled on a existing protocol used by ception, uterine rupture, birth trauma, and existing or
the trauma service mandating emergency release of acquired coagulopathy.
6 units of group O D– red cells (RBCs), 4 units of fresh In the modern era of fractionated blood component
frozen or liquid plasma, and 1 apheresis unit of plate- therapy, optimal management of massive hemorrhage is
lets (PLTs). The 6:4:1 fixed ratio of uncrossmatched an evolving concept. Resuscitation of a patient with post-
RBCs, plasma, and PLTs allows the transfusion service partum hemorrhage is conceptually similar to resuscita-
to quickly provide blood products during the acute tion after traumatic injury, where the goals are to establish
phase of resuscitation and allows the clinical team to rapid control of bleeding and restore systemic oxygen
anticipate and prevent dilutional coagulopathy. The suc- delivery. The trauma literature defines two phases of
cessful management of three cases of massive primary resuscitation: an immediate phase directly after injury
postpartum hemorrhage after the implementation of our with ongoing hemorrhage and a maintenance phase after
new massive transfusion protocol in the maternal and stabilization.4 Modern trauma resuscitation protocols
fetal medicine service is described. advocate sequential administration of therapeutic com-
ponents, beginning with colloid-crystalloid solutions in
fused to replace lost intravascular volume. Second, red
ABBREVIATIONS: D&C = dilatation and curettage;
blood cells (RBCs) are transfused to restore oxygen-
ICU = intensive care unit; MTP = massive transfusion protocol;
carrying capacity. Third, clotting factors and platelets
PT = prothrombin time; PTT = partial thromboplastin time.
(PLTs) are delivered to restore physiologic hemostasis.
From the Department of Pathology, Department of Anesthesiol- Rapid restoration of the components of the blood is essen-
ogy, and Department of Obstetrics and Gynecology, Stanford tial for ensuring adequate tissue perfusion and preventing
University Medical Center, Stanford, California. acidosis, coagulopathy, and hypothermia. Adequate
Address reprint requests to: Lawrence Tim Goodnough, MD, replacement of plasma components is particularly impor-
Department of Pathology, Stanford University Medical Center, tant for avoiding dilutional coagulopathy in the massively
300 Pasteur Drive, Room H-1402, Stanford, CA 94305-5626; bleeding patient.
e-mail: ltgoodno@stanford.edu. Massive transfusion protocols have been adopted by
Received for publication January 22, 2007; revision many hospitals with accredited trauma centers.5 The
received April 29, 2007, and accepted May 8, 2007. trauma center certification process administered by the
doi: 10.1111/j.1537-2995.2007.01404.x American College of Surgeons Committee on Trauma
TRANSFUSION 2007;47:1564-1572. (ACS-COT) stipulates that individual institutions address
Fig. 1. Massive transfusion protocol algorithm. Pt. = patient; DIC = disseminated intravascular coagulation; CBC = complete blood
count; ABG = arterial blood gas; INR = international normalized ratio.
the role of the transfusion service in support of the mas- rhage. Our massive transfusion protocol for the trauma
sively hemorrhaging patient.6 The clinical team is respon- service provides for emergency release of a “package” con-
sible for activating the massive transfusion protocol when sisting of 6 units of RBCs, 4 units of plasma (liquid or
a trauma patient presents with life-threatening hemor- fresh-frozen), and 1 apheresis PLT unit (Fig. 1). The entire
complement of blood products can be compiled, elec- 33 weeks’ gestation for persistent vaginal bleeding sec-
tronically issued, and delivered to the operating room, ondary to a presumed chronic placental abruption. At
delivery room, or emergency department in less than 35 weeks 6 days’ gestation she underwent induction of
15 minutes. labor for nonreassuring fetal heart tracings and intermit-
The 6:4:1 ratio of RBCs, plasma, and PLTs was tent vaginal bleeding. She failed to progress and pro-
designed to replace approximately 70 percent of the total ceeded to low transverse cesarean section. She delivered
RBC volume and 60 percent of the total circulating plasma twin A with Apgar scores of 7 and 8 at 1 and 5 minutes.
volume of a 70 kg individual. The 6:4:1 combination of Twin B was delivered with Apgar scores of 9 and 9. The
RBCs, plasma, and apheresis PLTs approximates a 60:40 patient tolerated the procedure well and was taken to the
volume-to-volume ratio of plasma to RBCs. Whole blood recovery room in good condition.
is theoretically the ideal replacement therapy for massive After 5 minutes in the postanesthesia recovery unit,
hemorrhage. The 6:4:1 ratio of blood products approxi- she developed increasing vaginal bleeding that was unre-
mates the composition of whole blood with a hematocrit sponsive to administration of multiple uterotonics. She
level of 40 percent. rapidly became hypotensive and was transferred to the
Blood draws for essential coagulation parameters are operating room for emergent dilatation and curettage
integrated into the massive transfusion protocol. Figure 1 (D&C). The patient suddenly went into cardiac arrest and
illustrates the massive transfusion protocol (MTP) flow- she was shocked into sinus rhythm. She was resuscitated
chart, where the obstetrical anesthesiologist sends initial with large volumes of crystalloid hetastarch solution,
laboratory tests to the clinical laboratory upon initiation followed by infusion of uncrossmatched RBCs. Because
of the massive transfusion protocol. The laboratories the patient was blood group B, and no group B FFP
include prothrombin time (PT), partial thromboplastin was immediately available, FFP was delivered 45 minutes
time (PTT), fibrinogen, D-dimer, and a complete blood after the request due to the time required for thawing
count. If a patient continues to hemorrhage or future this product. After initial resuscitation, the obstetrical
hemorrhage is anticipated, additional 6:4:1 packages can team performed a supracervical hysterectomy. Diffuse
be requested from the transfusion service provided that microvascular oozing from the uterus and pelvic side walls
additional coagulation laboratories are sent with each occurred throughout the procedure. Two sequential
request (Fig. 1). Importantly, the massive transfusion 4.8-mg bolus doses of recombinant factor (rF)VIIa were
guideline does not preclude customized ordering of other administered in succession approximately 30 minutes
blood products and pharmaceuticals. Later in resuscita- after her initial hemorrhage. Laboratory results showed
tion, abnormal laboratory values such as prolonged PT florid disseminated intravascular coagulation (Table 1).
and/or PTT, low PLT count, and low fibrinogen values can The patient became acidotic and hypothermic during the
be addressed individually as depicted in Fig. 1. hysterectomy procedure and suffered an estimated 10 L of
To provide rapid delivery of plasma in the MTP blood loss. The patient went into ventricular fibrillation
package, four units of thawed fresh-frozen plasma (FFP) and was again successfully defibrillated.
for blood groups A and O are continuously in inventory. After surgery, she was again returned to the intensive
For patients who are blood group B or AB, or whose blood care unit (ICU) where her abdomen became tense as blood
type is unknown, liquid plasma is initially substituted for reaccumulated. She became increasingly acidotic and
FFP. The RBCs and plasma units earmarked for the hypothermic. Nearly 13 hours after her cesarean section
massive transfusion protocol are checked daily for integ- she developed asystole and was pronounced dead after
rity and expiration dates. prolonged resuscitation attempts. Seventy-seven units of
We instituted our massive transfusion protocol in the RBCs, 37 units of FFP, 9 pools of cryoprecipitate (10 units
labor and delivery service to expedite and optimize deliv- each for each pool), and 10 apheresis PLT units were
ery of blood products during the acute, immediate phase administered during her cesarean section, D&C, hysterec-
of resuscitation for patients with uncontrolled, primary tomy, and resuscitation. Table 1 shows that despite resto-
postpartum hemorrhage. This guideline was initiated ration of blood pressure and RBC volume in this patient,
after the case of a woman with severe hemorrhage and she developed severe coagulopathy, hypothermia, and
coagulopathy after cesarean delivery of twins. tissue hypoxia that were refractory to replacement therapy.
Postmortem examination revealed cytokeratin-positive
fetal amniocytes within the pulmonary vasculature, con-
CASE 1
sistent with amniotic fluid embolism.
Patient 1 presented as a 49-year-old Asian woman gravida
9, para 4044 (9 pregnancies, 4 live births, 0 preterm births,
4 miscarriages and/or therapeutic abortions, and 4 living Comment
children). She was pregnant with diamniotic and/or The pathophysiology of amniotic fluid embolism is con-
dichorionic twins and was initially hospitalized at troversial.7,8 Maternal-fetal barriers can be compromised
Temperature
fluid into the maternal venous circulation. Patients with
34.3
34.3
34.5
34.7
34.4
33.5
(°C)
severe amniotic fluid embolism experience a biphasic
37
clinical course: immediate hyperacute cardiovascular col-
lapse followed by onset of profound disseminated intra-
vascular coagulation. If a patient survives initial
6.77
7.50
7.43
7.37
7.26
7.07
7.18
7.50
7.30
7.13
cardiopulmonary collapse, the thromboplastinlike sub-
pH
105
60
30
0
70
110
70
80
68
71
83
80
105
90
80
84
pathway culminating in disseminated intravascular
coagulation.9
TABLE 1. Cumulative transfusion products, laboratory values, and vital signs for Patient 1
D-dimer
(ng/mL)
>20K
>20K
>20K
9218
949
CASE 2
Patient 2 presented as an 18-year-old Caucasian
woman gravida 1, para 0102. She was pregnant with
Fibrinogen
(mg/dL)
<50
157
165
112
131
27
26
119
16
21
>300
>300
107
124
26.1
24.5
(sec)
>100
PT
8.9
6.5
8.2
7.1
7.5
12.4
7.7
12.1
6.4
7.2
3.7
Hb
0
0
0
0
1
1
1
4
6
6
6
6
6
8
9
10
number
Cryo-
(total
¥10)
Comment
0
0
0
0
0
0
0
3
4
5
7
7
7
8
8
9
Temperature
hysterectomy.
(°C)
37
CASE 3
Patient 3 presented as a 37-year-old Caucasian woman
7.32
gravida 2, para 1001. She was admitted at 38 weeks 2 days
pH
for a scheduled singleton cesarean delivery. She under-
went primary low transverse cesarean section and deliv-
155/100
(mmHg)
100/80
ered a liveborn male with Apgar scores of 7 and 9.
150/85
BP
D-dimer
(ng/mL)
357
311
189
137
140
31.9
32.4
PTT
8.7
10.9
PT
Comment
Abnormal placental implantation, including placenta
of units)
number
0
1
1
1
1
(total
¥10)
0
0
0
0
0
0
0
0
0
0
CASE 4
Patient 4 presented as a 30-year-old female gravida 2, para
BP = blood pressure.
of units)
number
RBCs
(total
13:30
20:25
11:00
Time
5:00
Temperature
marked atony of both uterine cornua. Administration of
35.2
36.2
36.2
36.7
37.2
(°C)
a series of uterotonic agents and continuous uterine
37
massage failed to ameliorate uterine atony and resultant
hemorrhage. Our massive transfusion guideline was acti-
vated. A bolus of 6 mg of rFVIIa was administered
7.21
7.42
7.26
7.36
7.40
40 minutes after her initial hemorrhage. Initial laborato-
pH
82
86
65
80
75
75
90
112
130
118
120
111
fibrinogen level of 78 mg per dL, PT of 16.6 seconds, PTT
of 131 seconds, and a PLT count of 60 ¥ 109 per L. She
TABLE 3. Cumulative transfusion products, laboratory values, and vital signs for Patient 3
hemorrhage.
>20K
>20K
>20K
>20K
192
287
158
121
100
79
150
137
158
39.0
31.4
29.7
PTT
Comment
(sec)
10.1
15.9
16.0
14.0
9.6
10.1
PT
13.6
13.8
Hb
0
0
1
1
3
3
5
5
5
5
5
5
DISCUSSION
Our index case and subsequent three cases illustrate the
precipitate
(total
¥10)
0
0
0
0
0
0
0
0
1
1
1
1
12:10
12:30
12:39
13:18
14:30
15:50
16:45
19:55
21:00
11:39
Time
8:10
Temperature
repletion.
36.2
33.3
34.3
35.1
35.3
36.4
(°C)
FFP requires up to 45 minutes to thaw, issue, and
transport to the labor and delivery ward. This delay is
problematic in the context of sudden, unexpected hemor-
rhage in an obstetrical patient. In contrast to trauma
7.14
7.34
7.39
pH patients, who arrive at the hospital with advance warning,
postpartum hemorrhage most often occurs suddenly and
unexpectedly.16,17 Risk factors for primary postpartum
(mmHg)
118
5584
Liquid plasma has distinct advantages over FFP.18
Liquid plasma is refrigerated and never frozen. Therefore,
it can be issued immediately for emergency release. A con-
Fibrinogen
78
110
186
145
117
56.6
29.9
(sec)
PTT
131
16.6
14.3
10.4
10.5
10.9
10.5
9.4
7.7
9.0
Hb
5
0
0
1
1
1
1
3
3
3
(total
¥10)
FV and FVIII.
In our experience, the results of laboratory coagula-
tion testing (PT, PTT, fibrinogen, and PLTs) are best used to
BP = blood pressure.
of units)
number
RBCs
(total
fractionated blood product therapy.26,27 Laboratory data, survival in massive postpartum hemorrhage.38,39 Rapid,
however, are usually unavailable during the immediate early, and definitive intervention is required to optimize
phase of resuscitation because of the time required for the patient outcomes for primary postpartum hemorrhage,
hospital laboratory to perform these tests. A stat blood achieved in part by implementation of a massive trans-
sample if sent to the clinical laboratory when a massive fusion protocol for the hospital labor and delivery
transfusion protocol is activated. Coagulation (PT, APTT, service.
fibrinogen, D-dimer) and hematology (complete blood
count) testing at our institution require that a blood
sample be sent to the laboratory via a pneumatic tube ACKNOWLEDGMENTS
system where the specimen is accessioned, aliquoted,
The authors thank Scott Boyd, MD, PhD, for his critical review
transported to instruments, and analyzed. The national
of the manuscript. We also thank Dorothy Nguyen, MD, at the
standard for turnaround of a stat laboratory test is 60 min-
Stanford Blood Center for information regarding liquid plasma.
utes.28 Even “super-stat” coagulation results are typically
available in 15 to 30 minutes.29 Thromboelastography,
although useful for monitoring coagulopathic patients, is
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