Peripartum hemorrhage accounts for 8% of maternal deaths in the United States, and nearly 27% worldwide. A growing need exists for tactics to spare morbidity given a rise of abnormal placentation that contributes to excessive blood loss at the time of delivery. Approaches such as compression sutures, balloon tamponade, and pelvic artery embolization are not without side effects and potential implications for future fertility. The use of topical hemostatic agents has become widespread in gynecologic and obstetric surgery despite a paucity of distinct studies in the field, and may allow providers to increasingly avoid cesarean hysterectomy. A variety of topical hemostatic agents exist along a wide cost continuum, each characterized by specific efficacy, advantages, drawbacks, and often gaps in long-term data to support safety and impact on future fertility. Herein, we comprehensively review these agents and illustrate a nontraditional use of Monsel solution applied directly to the placental bed in a case of focal placenta accreta. This ultimately contributed to successful uterine preservation with no known adverse sequelae. Monsel solution may have a role in establishing hemostasis in the setting of abnormal placentation, and may be a particularly attractive alternative in resource-poor nations.
The use of topical hemostatic agents is widespread in gynecologic surgery despite a paucity of distinct studies in the field, and has increased by 10-21% from 2000 through 2010. This approach represents a very effective tool in the control of intraoperative bleeding, however, most data regarding topical hemostatic agents must be extrapolated from other specialties. Given the increasing incidence of abnormal placentation secondary to prior cesarean delivery, a critical role for topical hemostatic agents for obstetric indications has emerged. Placenta accreta now occurs in as many as 1:553 pregnancies. Hemorrhage at the time of cesarean delivery remains a leading cause of morbidity. In the United States, peripartum hemorrhage still accounts for 8% of maternal deaths ; worldwide it accounts for nearly 27% and resulted in 661,000 deaths from 2003 through 2009. The importance of this complication, risk factors, and therapeutic interventions has been the subject of multiple recent reports. Several strategies may be employed to control bleeding, including various surgical approaches (eg, oversewing of the site of hemorrhage; placement of B-lynch, Hayman, and Cho sutures), systemic uterotonics, restoration of coagulation pathways through activated factor VII, uterine or hypogastric artery ligation or embolization, and intrauterine tamponade. When conservative approaches fail, hysterectomy can be lifesaving. A case is presented below in which topical hemostatic agents, including Monsel solution, were applied directly on the endometrium to avoid cesarean hysterectomy.
Case
A 23-year-old gravida 3 para 0020 at 35 and 1/7 weeks’ gestational age presented to labor and delivery 2 hours after loss of fluid per vagina. Her history was significant for a posterior placenta previa diagnosed at 23 weeks’ gestational age and followed by ultrasound every 4 weeks during her pregnancy. An ultrasound performed 3 days prior to her presentation showed persistent marginal placenta previa with a leading edge <9 mm from the os. The patient was counseled at that time to undergo cesarean delivery. Her history was notable for 2 first-trimester terminations by dilation and curettage. The remainder of her prenatal course was uncomplicated.
On initial speculum examination, the patient was noted to have approximately 500 mL of blood in the vagina and on the surrounding perineum. The fetus was cephalic on ultrasound with an amniotic fluid index of 15 cm. External fetal monitoring revealed a category-1 tracing. Intravenous access was established. Preoperative hematocrit was 38.6%. Three units of blood were requested prior to proceeding to the operating room for cesarean delivery. Maternal vital signs remained stable with pulse 90-110 beats/min and blood pressure 110-116/65-80 mm Hg. Vaginal bleeding ceased spontaneously.
Nonemergent primary low transverse cesarean delivery was performed and a viable male infant was delivered with Apgar scores of 9/9 at 1 and 5 minutes, respectively. The placenta delivered spontaneously from the posterior endometrium. At this time, hemorrhage was noted arising from the bed of the placenta. Several 0-Vicryl (Ethicon, Blue Ash, OH) figure-of-8 sutures were placed in the bed with no resolution of bleeding. Pitocin (30 U) was given intravenously. Bleeding persisted heavily and an intraoperative consult to the gynecologic oncology service was requested. Severe additional stitches were placed in the endometrium without resolution of bleeding. The fundus was noted to be intermittently atonic. Intramuscular methylergonovine (200 μg) and intrauterine carboprost tromethamine (250 μg) were ordered; however, the patient’s blood pressure rose precipitously to 200/100 mm Hg and prevented administration of >75% of the proposed doses. With a total intraoperative estimated blood loss of 1700 mL, 3 U of packed red blood cells and 1 U of fresh frozen plasma were infused. Given the patient’s age and desire for future pregnancy, topical hemostatics were applied beginning with approximately 16 mL of Monsel solution impregnated in a uterine pack. Bleeding dramatically slowed after application for a few minutes of the pack on the placental bed. Surgicel SNoW (structure nonwoven material; Ethicon) and Evicel sealant (Ethicon) were subsequently prophylactically applied on the now hemostatic placental bed. The hysterotomy and abdomen were closed and the patient was transferred directly to the interventional radiology suite in preparation for potential arterial embolization. Angiography was performed immediately and was unremarkable for active bleeding ( Figure 1 ). The patient was transferred back to labor and delivery for further management, and ultimately discharged with her infant on postoperative day 4 without further bleeding. Hematocrit on discharge was stable and had equilibrated to 27.4%. She remained afebrile throughout her course.
Pathologic analysis revealed a 600-g placenta (>90th percentile for gestational age) with intervillous fibrin and calcification; there were increased syncytial knots within the chorionic villi but no evidence of inflammatory changes within the chorionic plate or amnion.
The patient began medroxyprogesterone acetate for contraception at 1 month postpartum. Computed tomography of the abdomen and pelvis at 4 months’ postpartum obtained for separate indications showed a normal-appearing uterine scar and no evidence of sequelae in the endometrium or peritoneal cavity ( Figure 2 ). A transabdominal and transvaginal ultrasound at 11 months’ postpartum was also unremarkable. The patient experienced no complications at 1 year from the procedure. The patient plans to delay future conception for >2 years from the time of her cesarean delivery.
Background and history
We report our experience with use of Monsel solution (20% aqueous ferric subsulfate) as the primary hemostatic to control hemorrhage during cesarean delivery secondary to marginal placenta previa and suspected focal placenta accreta. Leon Monsel, a French pharmacist, pioneered use of ferric subsulfate for its styptic qualities as early as 1852 during the Crimean War. Initially, Monsel solution was used primarily for disruptions of the epithelium, which were common in times of war. In 1859, Proctor published the formula for the solution in the American Journal of Pharmacology , which led to wider usage, though little research was conducted about its effects on tissue until the mid-twentieth century. In 1880, during a conference on postpartum hemorrhage, Dr Aug. F. Erich advocated “mopping the cavity with a styptic, the most effectual being Monsel solution…the uterus may be contracted to a considerable degree, and yet a vexatious oozing may continue…a sponge may be saturated with the styptic, carried into the uterus and the whole cavity thoroughly swabbed with it.” There is very little subsequent mention of ferric subsulfate in the medical literature until a study was published in the Archives of Dermatology , which compared it to ferrous chloride for hemostasis. The authors concluded that the hemostatic effect of Monsel solution was due to mechanical sealing of small vessels rather than the acidic background. Monsel solution subsequently gained popularity, and since that time has remained useful to gynecologists mostly during cervical biopsies and excisional procedures, and to dermatologists for punch biopsies. Modern intrauterine use of Monsel solution is not well documented, and to date only 1 case report regarding its application during hemorrhage following dilation and evacuation exists in the English-language literature.
Background and history
We report our experience with use of Monsel solution (20% aqueous ferric subsulfate) as the primary hemostatic to control hemorrhage during cesarean delivery secondary to marginal placenta previa and suspected focal placenta accreta. Leon Monsel, a French pharmacist, pioneered use of ferric subsulfate for its styptic qualities as early as 1852 during the Crimean War. Initially, Monsel solution was used primarily for disruptions of the epithelium, which were common in times of war. In 1859, Proctor published the formula for the solution in the American Journal of Pharmacology , which led to wider usage, though little research was conducted about its effects on tissue until the mid-twentieth century. In 1880, during a conference on postpartum hemorrhage, Dr Aug. F. Erich advocated “mopping the cavity with a styptic, the most effectual being Monsel solution…the uterus may be contracted to a considerable degree, and yet a vexatious oozing may continue…a sponge may be saturated with the styptic, carried into the uterus and the whole cavity thoroughly swabbed with it.” There is very little subsequent mention of ferric subsulfate in the medical literature until a study was published in the Archives of Dermatology , which compared it to ferrous chloride for hemostasis. The authors concluded that the hemostatic effect of Monsel solution was due to mechanical sealing of small vessels rather than the acidic background. Monsel solution subsequently gained popularity, and since that time has remained useful to gynecologists mostly during cervical biopsies and excisional procedures, and to dermatologists for punch biopsies. Modern intrauterine use of Monsel solution is not well documented, and to date only 1 case report regarding its application during hemorrhage following dilation and evacuation exists in the English-language literature.
Mechanism of action
Monsel solution Fe 4 (OH) 2 (SO 4 ) 5 is a brown fluid that is prepared by reacting ferric sulfate with sulfuric acid and nitric acid, and thus remains very acidic (pH approaching 1). Hemostasis as a result of Monsel solution is believed to be due to denaturation and agglutination of proteins such as fibrinogen by ferric ions, which is augmented by the low pH and subsulfate group. Uptake and tissue effects of Monsel solution have been studied extensively in the dermatologic and dermatopathology literature. Monsel solution may lead to deposition of ferric salts (ie, ferrugination) within fibrin, dermal collagen, and striated muscle, which may cause refractory pigmentation of skin following its usage and an inflammatory reaction that may persist for weeks at the site of damage. When Monsel solution is used on epithelium after dermatologic biopsies there is often evidence of a “tattoo” effect with extended pigmentation of tissue. Ferrugination can also be seen with trauma from an iron-coated instrument. In muscle, ferrugination may cause damage and inflammation, but cross-striations are preserved and sometimes accentuated.
Efficacy
Most evidence for the efficacy of Monsel solution is anecdotal. It is generally accepted that Monsel solution is an ideal hemostatic for small amounts of bleeding, particularly on the cervix or epithelium. No studies have determined its efficacy with larger amounts of hemorrhage, however, resultant coagulation may be so effective that some authors advocate application completely in lieu of sutures following cold-knife cone biopsy. Most commercial preparations achieve hemostasis in <20 seconds.
Concerns and complications
Critics have noted that Monsel solution can seep into tissues and lead to iron-protein precipitate formation, trapping calcium ions and causing denaturation of the sarcolemma in muscle, ultimately resulting in necrosis. Most practitioners agree that Monsel solution should be used with caution in the intraperitoneal setting given limited data. The histologic effect of Monsel solution may persist for up to 3 weeks in tissue. Monsel solution applied to biopsy sites specifically in the cervix has been associated with local tissue necrosis, impediment of reepithelialization, and formation of granulation tissue around the iron-containing solution, which can then persist in siderophages for up to 3 months. If Monsel solution is applied to a pathological specimen it is recommended that the physician inform the pathologist. In certain instances, atypical histiocytic reactions to Monsel solution in the skin have been confused with malignant melanoma, have obscured interpretation of depth of melanoma invasion, or have impaired interpretation of cone biopsy specimens if performed <3 weeks from use of Monsel at the time of cervical biopsy. Though not apparent in animal models, Armstrong et al (1986) found in human subjects that the agent caused less rapid wound healing and inferior cosmesis compared with collagen matrix product. Despite these pathological findings, most clinicians agree that cervical and vaginal tissue to which Monsel solution has been applied generally appears grossly normal within several weeks of application.
Several critics have proposed that Monsel solution may be a nidus of infection, particularly nosocomial microorganisms given its nonsterile usage in most clinics and storage over long periods of time with several uses across multiple patients. A study from Brigham and Women’s Hospital, however, failed to show growth in cultures after 5 days using Monsel solution inoculated with nosocomial bacteria, including Clostridium species and Pseudomonas aeruginosa . Furthermore, cultured Monsel solution from open clinic samples failed to grow bacterial colonies. Epidemiological literature and biochemical properties moreover suggest that Monsel solution may inhibit bacterial growth, thereby evoking its safety for usage in obstetrics.
In gynecologic literature, it has been reported that only 50% of operative reports correctly noted the usage of topical hemostatic agents when used intraoperatively. Inclusion of this information is essential when considering possible surgical complications and when interpreting postoperative imaging, as intraabdominal topical hemostatics may resemble abscesses.
Comparison to other topical hemostatic agents
Other topical hemostatic agents include chelating agents, polysaccharide matrices, exogenous coagulation pathway proteins (ie, fibrinogen, thrombin), and combination preparations ( Table ). Use of these agents for gynecologic and obstetric indications is underreported. There are no objective comparisons of Monsel solution to other available hemostatic agents.
- a.
Chelating agents: chitosan-covered gauze and aluminum silicate
| Substance | US trade name/manufacturer | Derivative | Predominant mechanisms | Disadvantages | Outcomes in intraabdominal/obstetrics and gynecology surgery | Time to absorption |
|---|---|---|---|---|---|---|
| Ferric subsulfate | Monsel solution (eg, Premier, Plymouth Meeting, PA, among others) | Chemical | Agglutination of coagulation factors; low pH may cause vasoconstriction |
| Present case | 3 wk |
| Chitosan (deacetylated chitin) | ChitoFlex (HemCon, Portland, OR) Celox (Medtrade Products, Cheshire, United Kingdom) | Shellfish exoskeleton | Positive charge attracts red blood cells and provides scaffold for clot formation |
| Must be removed within ∼48 h of application | |
| Kaolin (aluminum silicate) | QuikClot (Z-Medica, Wallingford, CT) | Mineral | Hydrophilic nature concentrates clotting factors and platelets |
| Not recommended by manufacturer for intrathoracic or intraabdominal use; reserved for external wounds or salvage of life-threatening penetrating trauma | Must be removed within ∼48 h of application |
| Microporous polysaccharide spheres | Arista (Bard Davol, Warwick, RI) | Plant | Osmotic nature concentrates clotting factors and platelets |
| 48 h via amylases | |
| Gelatin sponge/powder | Gelfilm (Pfizer, New York, NY) Surgifoam sponge and powder (Ethicon, Blue Ash, OH) | Porcine | Expansion by as much as 200% in vivo provides scaffold for clot; thromboplastin is also released from platelets after contact, which interacts with prothrombin and calcium to produce thrombin |
| 4-6 wk | |
| Oxidized regenerated cellulose | Surgicel family (Ethicon; Nu-Knit, Fibrillar, SNoW) | Plant | Provides scaffold for clot formation; low pH induces vasoconstriction ; may also prevent adhesion formation |
| 1-4 wk, though in rare instances material has been identified up to 15 mo postoperatively | |
| Collagen | Avitene/Actifoam (Bard Davol, Warwick, RI) Helistat/Helitene (Integra Lifesciences, Plainsboro, NJ) Ultrafoam (Bard Davol) | Bovine | Activation of intrinsic coagulation pathway |
| >8 wk | |
| Gelatin | Gelfoam (Pfizer) Surgifoam (Ethicon) Spongostan (Ethicon) | Porcine | Expansion by as much as 200% in vivo provides scaffold for clot; thromboplastin is also released from platelets after contact, which interacts with prothrombin and calcium to produce thrombin |
| 4-6 wk | |
| Thrombin | Thrombin-JMI (Pfizer) | Bovine | Augmentation of coagulation cascade; may promote uterine contractility |
| Immediate | |
| Evithrom (Ethicon) | Human | |||||
| Recothrom (Medicines Company, Parsippany, NJ) | Recombinant human | |||||
| Fibrin + thrombin | Artiss (Baxter Deerfield, IL) Tisseel (Baxter) Evicel (Ethicon) | Human | Augmentation of coagulation cascade |
| Immediate | |
| Gelatin + thrombin | FloSeal (Baxter) Surgiflo (Ethicon) | Bovine porcine | As above |
| 6-8 wk | |
| Collagen + fibrin + thrombin | TachoComb (Baxter) | Bovine | As above |
| <20 wk | |
| TachoSil (Baxter) | Human | |||||
| Collagen + thrombin + autologous plasma | CoStasis/Dynastat (Cohesion Technologies, Palo Alto, CA) | Bovine | As above |
| 4 wks |
Deacetylated chitin harvested from the exoskeletons of crustaceans exploits the electrostatic interaction of negatively charged erythrocyte membranes and positively charged carbohydrate to form clot. Chitosan (ChitoFlex, HemCon, Portland, OR; Celox, Medtrade Products, Cheshire, United Kingdom) is nontoxic, degradable, antimicrobial, and has even been considered as a mucoadhesive medium for vaginal drug delivery. Schmid et al (2013) used chitosan-impregnated gauze as uterine packing in 19 consecutive cases of postpartum hemorrhage following vaginal (n = 8) or cesarean (n = 11) delivery. Rate of hysterectomy was reduced by 75% relative to an equivalent time period prior to the introduction of the product, and no adverse side effects were noted. QuikClot (Z-Medica, Wallingford, CT) is a chelating agent consisting of aluminum silicate (kaolin) that concentrates clotting factors and platelets. This product was originally designed for external use in combat settings. Intraabdominal use should generally be reserved for life-threatening penetrating trauma given an exothermic reaction with blood that may cause local tissue damage. Accordingly, there are no reports of its use for obstetric or gynecologic indications.
In animal models, comparisons of these 2 products for external use show no superiority of either agent.
- b.
Nonflowable matrix: microporous polysaccharide spheres, gelatin, oxidized regenerated cellulose, collagen
Microporous polysaccharide spheres represent a proprietary preparation of potato starch granules irradiated for sterility (Arista; Bard Davol, Warwick, RI). Via osmosis, the carbohydrate spheres concentrate clotting factors and platelets. Microporous polysaccharide spheres have been shown to perform equivalently compared to other nonflowable hemostatic agents, but inferiorly to thrombin and gelatin combinations regardless of conditions of hypothermia, hypocoagulability, and hemodilution. Use in gynecologic/obstetric surgery is lacking, but good outcomes were achieved in robotic-assisted athermal nerve-sparing prostatectomy; mean decrease in postoperative hemoglobin was nearly double in patients who did not receive the agent (3.2 vs 1.2 g/dL).
Gelatin sponges (Gelfilm; Pfizer, New York, NY; Surgifoam-sponge; Ethicon) and powder (Surgifoam-powder; Ethicon) provide tamponade with expansion upon absorption of as much as 45 times their dry weight in fluid, as well as minor mechanical activation of the clotting cascade. Unfortunately, the neutral pH affords no antimicrobial properties, but the squares may be easily moldable for insertion through a laparoscopic port.
Oxidized regenerated cellulose serves as a scaffold for platelet adherence and thromboplastin release, and was introduced for surgical use in 1943. It is currently marketed as Sugicel, SNoW, Fibrillar, and Ni-Knit (Ethicon). Like Monsel solution, a low pH provides antimicrobial benefits and causes local vasoconstriction. Sharma and Malhotra (2006) employed it successfully across hysterotomy sites that exhibited persistent oozing despite oxytocin, ergometrine, intramyometrial prostaglandin, and local hemostatic sutures. This same group reported successful hemostasis with laparoscopic placement for uterine perforation during termination of pregnancy and tubal sterilization. In a cross-sectional study of 41 pregnant women who developed postpartum hemorrhage following cesarean delivery in 2006 through 2012 at a single institution, the rate of hysterectomy was 5% vs 66% in women who did and did not have application of 2-3 Fibrillar (Ethicon) gauzes to the lower uterine segment. Rates of transfusion, admission to the intensive care unit, and length of hospitalization were also reduced ( P < .001). Surgicel (Ethicon) has been used in combination with abdominal packing with good effect in cases of hemorrhage following cesarean hysterectomy or tumor debulking. No postmarketing contraindications have been identified for the use in obstetrics and gynecology. Though in most instances degradation occurs within 4 weeks, there have been reports of material discovered as many as 15 months from placement upon repeat laparotomy for gynecologic malignancy. Oxidized regenerated cellulose may also prevent formation of peritoneal adhesions, and is marketed under a separate entity (Gynecare Interceed; Ethicon) for this purpose and varies slightly by degree of oxidization and weave.
Collagen (eg, Avitene/Actifoam; Bard Davol; Helistat/Helitene; Integra Lifesciences, Plainsboro, NJ) attracts and aggregates platelets. Bovine collagen has been used laparoscopically to avoid laparotomy by controlling bleeding as a result of perforation during dilation and curettage. Karagiannis et al (2006) reported good outcomes with use of type-I collagen in 5 obstetric and 3 gynecologic cases. Use of microfibrillar collagen has shown to reduce blood loss more effectively relative to oxidized regenerated cellulose. One industry-sponsored porcine study found equal efficacy of collagen alone (Ultrafoam; Bard Davol) and gelatin matrix with thrombin (Gelfoam hemostasis kit; Baxter, Deerfield, IL). Though mostly innocuous, in rare instances patients may develop intense allergic reactions to this substance, as manifested by eosinophilia, fever, and hepatic dysfunction, and verified by skin testing. Occasionally, granulomas may form. After application during total abdominal hysterectomy and bilateral salpingo-oophorectomy for a mucinous cystadenoma, a patient experienced formation of a large granuloma that prompted reoperation 3 months postoperatively. In some cases, these granulomas have led to bowel obstruction requiring operative intervention.
- c.
Flowable matrix, biologic derivatives, and combination preparations: spray gelatin, thrombin, fibrinogen + thrombin, gelatin + thrombin, collagen + fibrin + thrombin, collagen + fibrin + autologous plasma
Exogenous biologic derivatives such as fibrinogen or thrombin augment the coagulation cascade ( Figure 3 ). Intraoperative use of fibrin sealants was conceptualized as early as 1909, with growing popularity after initial investigations during repair of peripheral nerves as early as 1940. Fibrin glue was utilized in conjunction with polyglycolic mesh by Jaraquemada et al (2004) in a protocol for uterine repair in the setting of placenta percreta. This was successful in 50 patients, though an additional 19 ultimately progressed to hysterectomy. Interestingly, thrombin may double as a potent uterotonic due to stimulation of membrane receptors, and thrombin-soaked uterine packs have been used to produce hemostasis of the lower uterine segment after 8 hours of tamponade.
