Amniotic fluid embolism (AFE) is a rare but catastrophic obstetric complication that can lead to profound coagulopathy and hemorrhage. The role of cell salvage and recombinant human Factor VIIa (rFVIIa) administration in such cases remains unclear. We present a case of AFE and describe our experience with the use of cell salvage and rFVIIa administration during the resuscitation. Cell salvage and transfusion through a leukocyte depletion filter was attempted after the diagnosis of AFE was made, but the attempted transfusion was immediately followed by hypotension and a worsening of hemodynamics. rFVIIa, on the contrary, was used with clinical improvement in coagulopathy and without apparent adverse thrombotic effect.
Published ahead of print June 7, 2013.
From the *Department of Anesthesiology, University of Wisconsin Hospital and Clinics; †Medical Scientist Training Program, University of Wisconsin School of Medicine and Public Health; ‡Department of Anesthesiology, Meriter Hospital; §Department of Obstetrics and Gynecology, University of Wisconsin School of Medicine and Public Health, Madison; and ‖Department of Anesthesiology, Gundersen Lutheran Health System, La Crosse, Wisconsin.
Accepted for publication February 27, 2013
Published ahead of print June 7, 2013.
The authors declare no conflicts of interest.
Reprints will not be available from the authors.
Address correspondence to William Kirke Rogers, MD, Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave., B6/319 CSC, Madison, WI 53792-3272. Address e-mail to firstname.lastname@example.org.
Amniotic fluid embolism (AFE) is a catastrophic obstetric condition characterized by cardiovascular and respiratory collapse, altered mental status, and disseminated intravascular coagulation. The diagnosis is often one of exclusion.1 Historically attributable to the presence of amniotic fluid and fetal cells in maternal circulation, current theories suggest that AFE occurs in response to inappropriate immune activation and is an anaphylactoid response.2 Management guidelines for AFE emphasize cardiovascular and respiratory support and establishment of hemostasis.3 Intraoperative cell salvage (ICS) and recombinant human Factor VIIa (rFVIIa) administration are recent additions to management schema in support of these goals.1 These recommendations are based on data from obstetric hemorrhage in general, but may or may not be applicable to hemorrhage caused by AFE. Here, we present a case of presumed AFE where use of ICS with leukocyte depletion was associated with profound hypotension and rFVIIa was used without apparent thrombotic complication. The patient provided written consent for publication of the report.
A healthy 27-year-old G6P2 female with monochorionic, diamniotic twin gestation presented for semielective cesarean delivery at 36 weeks and 3 days per a recommendation based on expert consensus guidelines for timing of delivery of monochorionic twin gestations. She reported 2 prior unremarkable cesarean deliveries. Her preoperative vital signs and laboratory studies, including a complete blood count and coagulation studies, were all within normal limits.
A subarachnoid block was performed for surgical anesthesia. Extensive adhesions of the lower uterine segment to the abdominal wall complicated the initial dissection, but vigorous and apparently healthy twins were ultimately delivered without incident. Between the deliveries of twin A and twin B, however, the patient complained of chest pressure before she suddenly became apneic, then unresponsive and cyanotic. The patient’s trachea was immediately intubated. The electrocardiogram monitor showed an organized cardiac rhythm but a noninvasive arterial blood pressure was no longer obtainable. An immediate diagnosis of probable AFE was made, and resuscitation commenced following Advanced Cardiac Life Support guidelines. IV epinephrine boluses and 30 to 45 seconds of chest compressions were initiated before spontaneous cardiac output returned. Epinephrine and vasopressin infusions were initiated; sedation amnesia was maintained with midazolam and fentanyl.
Clinical and laboratory evidence of profound coagulopathy was noted approximately 30 minutes after delivery of twin B (Fig. 1). There was a delay in obtaining cell-salvage equipment until an on-call perfusionist arrived, but empiric transfusion of allogenic blood products (red blood cells [RBCs], fresh frozen plasma, platelets, and cryoprecipitate) was initiated. A cesarean hysterectomy was ultimately performed after pharmacotherapy, and other less invasive surgical attempts at hemostasis failed to control bleeding. After the hysterectomy, the abdominal cavity was irrigated with 3 to 4 L warm saline and this fluid was suctioned and discarded.
The only attempt at transfusion of cell-salvaged blood occurred 1 hour after delivery of twin B, once an experienced perfusionist had arrived and set up cell-salvage equipment (Dideco Compact, Sorin Group, Milan, Italy). At this time, the patient was hemodynamically stable with an arterial oxygen saturation of 94% on minimal doses of pressors. Suctioned blood was washed in 2 L saline and filtered through a leukocyte depletion filter (LeukoGuard RS, Pall Corporation, Port Washington, NY). The first unit of salvaged blood was then given as a rapid bolus through a pressure bag, leukocyte depletion filter, and fluid warmer. Almost immediately after administration of the salvaged blood, the patient became profoundly hypotensive with another decrease in saturation of peripheral oxygen (Fig. 1). She required multiple epinephrine and vasopressin boluses with increased rates of pressor infusions. Pink frothy fluid was suctioned from the endotracheal tube. Further use of salvaged blood was not attempted, and the patient slowly achieved the prior level of cardiopulmonary stability.
Significant blood loss continued even after the cesarean hysterectomy, with continuous oozing from her denuded rectus muscle and other raw surfaces. When no obvious source of surgical bleeding could be identified, the patient was given rFVIIa (NovoSeven® RT, Novo Nordisk, Princeton, NJ) at a dose of 90 µg/kg. Clinical evidence of coagulopathy and the rate of hemorrhage decreased dramatically in the 10 to 15 minutes after administration of rFVIIa. No further blood product transfusion was necessary.
The patient was ultimately transferred to the intensive care unit in critical condition, not requiring vasopressors. She was started on pharmacologic antithrombosis prophylaxis with once-daily fondaparinux (rather than subcutaneous unfractionated heparin or a low molecular weight heparin due to a reported pork allergy with hives) on postoperative day 1. The patient’s postoperative recovery was prolonged, but she was discharged home from the hospital on postoperative day 16 without any apparent neurologic deficit other than slight short-term memory difficulties. Nine months postoperatively, she continues to do well.
This case is characterized by rapid cardiorespiratory collapse and subsequent coagulopathy after cesarean twin delivery, clinically consistent with the syndrome of AFE. The presumed etiology, pathophysiology, and typical clinical course of AFE have been well described elsewhere.1,3 In brief, current hypotheses characterize AFE as a massive immunologic response to a yet-unknown trigger. Some data suggest that complement activation and subsequent mast cell activation may underlie the pathogenesis.4 Because it is the apparent result of an immune-mediated response, the coagulopathy seen in AFE may be different from the coagulopathy seen in other forms of obstetric hemorrhage (i.e., it may be a primarily consumptive rather than dilutional process). Recommended treatment of AFE is targeted toward supportive measures with correction of hemorrhage and coagulopathy;3 the use of modalities such as ICS and rFVIIa to achieve these goals remains controversial.
Intraoperative Red Blood Cell Salvage
ICS technology anticoagulates, washes, and concentrates RBCs collected from the surgical field before their return to the circulation.5 Multiple reports have suggested that the routine use of ICS in obstetric surgery does not lead to “iatrogenic” AFE.6–8 Current literature is almost unanimous, therefore, in declaring that cell salvage with leukocyte depletion filtration may be valuable in cases of severe obstetric hemorrhage. Indeed, its use is advocated by both the American College of Obstetricians and Gynecologists and the British National Health Service.9,10
Previously published reports on the safety of ICS in obstetric hemorrhage have not discussed the use of ICS after a diagnosis of AFE, however. This may be a critical distinction because the exact immunologic triggers of AFE have not been definitively identified, and it is possible that cell-salvage technology inadequately clears the relevant inflammatory mediators in cases of AFE. In vitro studies have suggested that trophoblastic tissue and the protein elements of amniotic fluid, including α-fetoprotein, are effectively removed through standard cell-salvage techniques.11–14 Tissue factor, an initiator of coagulation proposed to contribute to coagulopathy12 and present in increased concentrations in patients with AFE,1 is also removed. The Dideco Compact Autotransfusion System, which was used in our case, has additionally been shown to effectively remove cytokines (>93%), complement, and inflammatory markers including interleukin (IL)-1β and IL-8, IL-6, tumor necrosis factor-α, myeloperoxidase, and elastase.15,16
However, cell-salvage filters do not completely remove fetal squamous cells.11,14 Additionally, cell-salvage filters cannot distinguish between fetal and maternal RBCs. Indeed, up to 19% of the RBCs in a cell saver filtered sample obtained after separate suctioning of the amniotic fluid may be fetal RBCs.13,14 While the presence of fetal RBCs in cell-salvaged blood may be relevant for ultimate dosing of anti-D immunoglobulin for prevention of rhesus immunization of rhesus-negative mothers,14,17 the presence of fetal RBCs or squamous cells are currently presumed unlikely to contribute to the clinical syndrome of AFE2,14,17 since such cells are routinely detected in the pulmonary circulation of normal obstetric patients.18 Indeed, the concentration of fetal RBCs in cell-salvaged blood may not be different than the concentrations found in maternal blood during normal pregnancy.19,20 While the presence of fetal RBCs and squamous cells in cell-salvaged blood may therefore be irrelevant, the presence of fetal leukocytes could be less benign.
Leukocyte Depletion Filters
Leukocyte depletion filtration appears effective in eliminating fetal and maternal leukocytes from a cell-salvaged sample14 and has been shown to further reduce the level of fetal squamous cells, phospholipids, and bacterial contamination from washed blood.13,21 The use of leukodepletion filters during the transfusion of cell-salvaged blood is therefore advised by expert authors and the British National Institute for Health and Clinical Excellence guidelines for ICS in obstetrics.10,21 However, at least 3 recent case reports,22–24 an alert from the Food and Drug Administration,25 and reports from the Serious Hazards of Transfusion (SHOT) group26 have provided circumstantial evidence that leukocyte depletion filters may contribute to significant hypotension during transfusion in obstetric surgery. Various mechanisms have been proposed for the cause of such hypotension, including the release of bradykinin by either Factor XII or platelets exposed to the negatively charged surface of a leukocyte depletion filter.22,27 We did not attempt retransfusion of cell-salvaged blood without the use of a leukocyte depletion filter, but in one of the previously published case reports, recommencing transfusion after removal of the filter allowed transfusion to proceed uneventfully without further hypotension.24 The authors of another case report recommended that at least an hour be allowed to pass before transfusing washed and filtered blood, because bradykinin has a short half-life.22 In our case, it is not clear whether the episode of hypotension immediately after transfusion of the cell-salvaged blood resulted from retransfusion of blood contaminated by fetal debris (and thus reexposure to whatever inflammatory mediators caused the syndrome of AFE in the first place) or the use of a leukocyte depletion filter.
Recombinant Human Factor VIIa
Some authors support the use of rFVIIa to treat profound coagulopathy associated with obstetric hemorrhage,28,29 but published data regarding its efficacy in cases of AFE specifically are very limited,30–35 with 1 recent review by Leighton et al.36 identifying <20 such case reports worldwide. This is relevant because rFVIIa works by combining with tissue factor to promote hemostasis and the deposition of fibrin at sites of vascular injury, and the clinical syndrome of AFE is characterized by abnormally high circulating tissue factor concentrations.1 This creates the possibility of widespread inappropriate fibrin deposition and an increased risk of thrombotic complications not necessarily seen with other types of obstetric hemorrhage. Indeed, the review of case reports by Leighton et al.36 suggested markedly worsened outcomes for those patients with AFE who were treated with rFVIIa compared with a cohort of patients who did not receive rFVIIa. Our patient did not show evidence of thrombotic complication after use of rFVIIa; our chosen dose of 90 mg/kg corresponds with the dose most commonly used in other published cases.29
In conclusion, we report a case of AFE in which the transfusion of cell-salvaged RBCs through a leukocyte depletion filter was accompanied by immediate and severe hypotension. Continued investigations are warranted to determine the usefulness and safety of ICS, with or without the use of a leukocyte depletion filter, in patients with presumed AFE. Additionally, we used rFVIIa with no apparent thrombotic complication.
Name: William Kirke Rogers, MD.
Contribution: This author participated in the case described and prepared the manuscript.
Affiliation: William Kirke Rogers approved the final manuscript.
Name: Sarah A. Wernimont, PhD.
Contribution: This author helped prepare the manuscript.
Affiliation: Sarah A. Wernimont approved the final manuscript.
Name: Girish C. Kumar, FRCA.
Contribution: This author participated in the case described and reviewed the manuscript.
Affiliation: Girish C. Kumar approved the final manuscript.
Name: Eliza Bennett, MD.
Contribution: This author participated in the case described and reviewed the manuscript.
Affiliation: Eliza Bennett approved the final manuscript.
Name: David H. Chestnut, MD.
Contribution: This author helped prepare the manuscript.
Affiliation: David H. Chestnut approved the final manuscript.
This manuscript was handled by: Cynthia A. Wong, MD.
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