Editorials 14. Pham H, Spigner C: Knowledge and opinions about organ donation and transplantation among Vietnamese Americans in Seattle, Washington: A pilot study, din Transpiant 2004; 18:707-715 15. Weaver M, Spigner C, Pineda M, et al: Knowledge and opinions about organ donation among urban high school students: Pilot
test of a health education program, din Transpiant 2000;14(4 Pt 1):292-303 16. Salim J, Ley EJ, Berry C, et al: Increasing organ donation in the Hispanic community; the role of media and community outreach efforts. JAMA Surg 2014; 149:71-76
C1 Esterase Inhibitor: A Biomarker for Amniotic Fluid Embolism?* István Kocsis, MD, PhD JánosGál, MD, PhD Department of Anaesthesiology and Intensive Therapy Semmelweis University Budapest, Hungary
A
mniotic fluid embolism (AEE) is a devastating condition in pregnancy. Its complications including circulatory and respiratory collapse, neurological symptoms, and intravascular coagulation make AEE one of the major causes of maternal mortality in developed countries and are also associated with a significant maternal and neonatal morbidity in the survivors. Recent large population-based studies, case series, and reviews provided data with a broad variation in prevalence and mortality of AEE ranging from 1 of 4,500 to 1 of 80,000 and 5% to 45%, respectively (1-6). The diagnosis is based on clinical symptoms and essentially one of exclusion or traditionally made at autopsy in fatal cases upon identification of fetal debris in the maternal pulmonary circulation. The precise diagnosis of AEE is hampered by the limited knowledge of clear pathophysiology leading to this condition. Eor several decades, amniotic fluid containing squamous cells, vernix, mucin, and lanugo was suspected to make a physical obstruction in the maternal pulmonary circulation as it is reflected by its name; however, the confounding clinical symptoms and several research data question whether this would be the main pathomechanism. Based on the clinical pattern sharing similarities with anaphylactic shock, a completely different theory was suggested as early as 1956 (7). According to this idea, fetal antigens in the amniotic fluid entering to maternal circulation would stimulate endogenous mediators of anaphylaxis (8). Recent data also highlighted the contribution of immune mechanisms including complement activation in
*Seealso p. 1392. Key Words: amniotic fluid embolism; C1 esterase inhibitor; disseminated intravascular coagulation The authors have disclosed that they do not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000359
1548
www.ccmjournal.org
AFE (9). Both serum C3 and C4 levels were found lower than normal in AEE patients in case series (10), raising the presence of complement activation. This notion was also supported by low C3a expression in a histological study (11). However, this concept is still to be verified. Despite that studies of specific fetal antigen (sialyl Tn), zinc coproporphyrin, or insulin-like growth factor binding protein-1 in maternal serum showed promise (6, 9, 12), one of the major problems that make difficult the investigation and early treatment of AFE is the absence of validated biomarkers. Identification of patients at risk or the early recognition of this condition would largely influence clinical decision making. In this issue of Critical Care Medicine, Tamura et al ( 13) publish their observations on Cl esterase inhibitor (ClINH) as a possible factor in AFE pathophysiology. They hypothesized that functions of ClINH other than the inhibition of Cl esterase activity, that is, the inhibition of EXIIa and kallikrein activities, might be responsible for AFE symptoms such as vasodilatation, hypotension, vascular permeability, and disseminated intravascular coagulopathy-type postpartum hemorrhage. Based on this assumption, the authors measured the ClINH activity in AFE patients. They concluded that low ClINH activity at the onset of symptoms would predict the risk and the outcome of this condition. They found higher ClINH activities in healthy age- and gestational age-matched controls without AEE than in those with AFE (62% vs 30% of the healthy nonpregnant reference values). They measured even lower ClINH activities in subjects with fatal AEE than in those with nonfatal AEE (22% vs 32%). Their results are seemingly supported by two cases when they used freshfi-ozenplasma (FFP) for AFE. During EEP therapy, ClINH activity normalized in the surviving patient, while it was constantly depressed in the fatal outcome. Although these results provide some base for enthusiasm, several limitations of the diagnostic suitability of ClINH activity should be considered. 1. No cutoff value supporting the differentiation between different subgroups was provided. 2. The ClINH activity is depressed even in healthy pregnancy and the detection of a further decrease may present methodological challenge. 3. There is no standard validated method for the ClINH activity measurements; hence, each laboratory should establish its own measurement conditions. June 2014 • Volume 42 • Number 6
Editorials
4. The preanalytical phase of ClINH activity measurements may be critical. Some assays include a step for immediate freeze that may be hard to be incorporated into routine clinical work. As some components are extremely labile, incorrect storage of samples for complement assay can result in decreased levels as well. The Berichrom Cl-inhibitor kit (Dade Behring, Marburg, Germany) provides reference data on sample stability stored at -20°C for 1 month according to the manufacturer's instruction. However, in this study, the storage temperature was set at -30°C, and the sample collection of AFE patients lasted for up to 24 months, whereas control samples were collected only for 6 months during the last part of the study period. As all samples were batch analyzed, this may provide unpredictable systemic bias. 5. ClINH activity assays are not performed on daily basis even in large centers. The longer turnaround times due to collection of samples prevent the use of this assay as a tool for the immediate detection of AFE risk. However, this limitation can be overcome by establishing a center laboratory specialized for AFE (such as that of Tamura et al [ 13] ) that collects samples and immediately performs the measurements. 6. There are still no definite and specific criteria for AFE diagnosis; this condition is still subject to the diagnosis of exclusion. Therefore, one cannot exclude that AFE patients form a heterogeneous population consisting of patients with different unidentified etiologies. In this case, one can assume that AFE patients with low ClINH activities present a specific subgroup of AFE patients. Again, the low patient number prevents the further conclusions. These limitations, however, can be resolved by further well-designed studies and the use of standard and generally accepted qualified tests for ClINH activities. For this purpose, establishment of biobanks containing large number of samples taken and stored at standardized conditions from well-defined patient groups is highly needed. Hopefully, the efforts to reach this goal are shortly under way.
Critical Care Medicine
In conclusion, the impairment of ClINH function in AFE provided a novel insight into the possible pathogenesis of this condition. The ClINH activity measurement may be a promising diagnostic or even a prognostic tool that may help the diagnosis and monitoring of AFE.
REFERENCES 1. Kramer MS, Rouleau J, Baskett TF, et al; Maternal Health Study Group of the Canadian Perinatal Surveillance System: Amniotic-fluid embolism and medical induction of labour: A retrospective, population-based cohort study. Lancet 2006; 368:1444-1448 2. Abenhaim HA, Azoulay L, Kramer MS, et al: Incidence and risk factors of amniotic fluid embolisms: A population-based study on 3 million births in the united States. Am J Obstet Gynecol 2008; 199:49. e1-49.e8 3. Roberts CL, Algert CS, Knight M, et ai: Amniotic fluid embolism in an Australian population-based cohort. SiOG2010; 117:1417-1421 4. Knight M, Berg C, Brocklehurst P, et al: Amniotic fiuid embolism incidence, risk factors and outcomes: A review and recommendations. BMC Pregnancy Childbirth 201 2; 1 2:7 5. Conde-Agudelo A, Romero R: Amniotic fluid embolism: An evidencebased review. Am J Obstet Gynecol 2009; 201:445.e1 -445.e13 6. Legrand M, Rossignol M, Dreux S, et al: Diagnostic accuracy of insulin-like growth factor binding protein-1 for amniotic fluid embolism. Crit Care Med 201 2; 40:2059-2063 7 Attwood HD: Fatal pulmonary embolism by amniotic fluid. J Clin Pathon 956; 9.38-46 8. Clark SL, Hankins GD, Dudley DA, et al: Amniotic fluid embolism: Analysis of the national registry. Am J Obstet Gynecol 1 995; 172:1158-1167; discussion 1167-1169 9. Benson MD: Current concepts of immunology and diagnosis in amniotic fluid embolism. Clin Dev Immunol 201 2; 201 2:946576 10. Benson MD, Kobayashi H, Silver RK, et al: Immunologie studies in presumed amniotic fluid embolism. Obstet Gynecol 2001 ; 97:510-514 11. Fineschi V, Riezzo I, Cantatore S, et al: Complement C3a expression and tryptase degranulation as promising histopathological tests for diagnosing fatal amniotic fluid embolism. Virchows Arch 2009; 454:283-290 12. Kanayama N, Yamazaki T, Naruse H, et al: Determining zinc coproporphyrin in maternal plasma—A new method for diagnosing amniotic fluid embolism. Clin Chem 1992; 38:526-529 13. Tamura N, Kimura S, Farhana M, et al: CI Esterase Inhibitor Activity in Amniotic Fluid Embolism. Crit Care Med 2014; 42:1392-1396
www.ccmjournal.org
1549
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
test of a health education program, din Transpiant 2000;14(4 Pt 1):292-303 16. Salim J, Ley EJ, Berry C, et al: Increasing organ donation in the Hispanic community; the role of media and community outreach efforts. JAMA Surg 2014; 149:71-76
C1 Esterase Inhibitor: A Biomarker for Amniotic Fluid Embolism?* István Kocsis, MD, PhD JánosGál, MD, PhD Department of Anaesthesiology and Intensive Therapy Semmelweis University Budapest, Hungary
A
mniotic fluid embolism (AEE) is a devastating condition in pregnancy. Its complications including circulatory and respiratory collapse, neurological symptoms, and intravascular coagulation make AEE one of the major causes of maternal mortality in developed countries and are also associated with a significant maternal and neonatal morbidity in the survivors. Recent large population-based studies, case series, and reviews provided data with a broad variation in prevalence and mortality of AEE ranging from 1 of 4,500 to 1 of 80,000 and 5% to 45%, respectively (1-6). The diagnosis is based on clinical symptoms and essentially one of exclusion or traditionally made at autopsy in fatal cases upon identification of fetal debris in the maternal pulmonary circulation. The precise diagnosis of AEE is hampered by the limited knowledge of clear pathophysiology leading to this condition. Eor several decades, amniotic fluid containing squamous cells, vernix, mucin, and lanugo was suspected to make a physical obstruction in the maternal pulmonary circulation as it is reflected by its name; however, the confounding clinical symptoms and several research data question whether this would be the main pathomechanism. Based on the clinical pattern sharing similarities with anaphylactic shock, a completely different theory was suggested as early as 1956 (7). According to this idea, fetal antigens in the amniotic fluid entering to maternal circulation would stimulate endogenous mediators of anaphylaxis (8). Recent data also highlighted the contribution of immune mechanisms including complement activation in
*Seealso p. 1392. Key Words: amniotic fluid embolism; C1 esterase inhibitor; disseminated intravascular coagulation The authors have disclosed that they do not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000359
1548
www.ccmjournal.org
AFE (9). Both serum C3 and C4 levels were found lower than normal in AEE patients in case series (10), raising the presence of complement activation. This notion was also supported by low C3a expression in a histological study (11). However, this concept is still to be verified. Despite that studies of specific fetal antigen (sialyl Tn), zinc coproporphyrin, or insulin-like growth factor binding protein-1 in maternal serum showed promise (6, 9, 12), one of the major problems that make difficult the investigation and early treatment of AFE is the absence of validated biomarkers. Identification of patients at risk or the early recognition of this condition would largely influence clinical decision making. In this issue of Critical Care Medicine, Tamura et al ( 13) publish their observations on Cl esterase inhibitor (ClINH) as a possible factor in AFE pathophysiology. They hypothesized that functions of ClINH other than the inhibition of Cl esterase activity, that is, the inhibition of EXIIa and kallikrein activities, might be responsible for AFE symptoms such as vasodilatation, hypotension, vascular permeability, and disseminated intravascular coagulopathy-type postpartum hemorrhage. Based on this assumption, the authors measured the ClINH activity in AFE patients. They concluded that low ClINH activity at the onset of symptoms would predict the risk and the outcome of this condition. They found higher ClINH activities in healthy age- and gestational age-matched controls without AEE than in those with AFE (62% vs 30% of the healthy nonpregnant reference values). They measured even lower ClINH activities in subjects with fatal AEE than in those with nonfatal AEE (22% vs 32%). Their results are seemingly supported by two cases when they used freshfi-ozenplasma (FFP) for AFE. During EEP therapy, ClINH activity normalized in the surviving patient, while it was constantly depressed in the fatal outcome. Although these results provide some base for enthusiasm, several limitations of the diagnostic suitability of ClINH activity should be considered. 1. No cutoff value supporting the differentiation between different subgroups was provided. 2. The ClINH activity is depressed even in healthy pregnancy and the detection of a further decrease may present methodological challenge. 3. There is no standard validated method for the ClINH activity measurements; hence, each laboratory should establish its own measurement conditions. June 2014 • Volume 42 • Number 6
Editorials
4. The preanalytical phase of ClINH activity measurements may be critical. Some assays include a step for immediate freeze that may be hard to be incorporated into routine clinical work. As some components are extremely labile, incorrect storage of samples for complement assay can result in decreased levels as well. The Berichrom Cl-inhibitor kit (Dade Behring, Marburg, Germany) provides reference data on sample stability stored at -20°C for 1 month according to the manufacturer's instruction. However, in this study, the storage temperature was set at -30°C, and the sample collection of AFE patients lasted for up to 24 months, whereas control samples were collected only for 6 months during the last part of the study period. As all samples were batch analyzed, this may provide unpredictable systemic bias. 5. ClINH activity assays are not performed on daily basis even in large centers. The longer turnaround times due to collection of samples prevent the use of this assay as a tool for the immediate detection of AFE risk. However, this limitation can be overcome by establishing a center laboratory specialized for AFE (such as that of Tamura et al [ 13] ) that collects samples and immediately performs the measurements. 6. There are still no definite and specific criteria for AFE diagnosis; this condition is still subject to the diagnosis of exclusion. Therefore, one cannot exclude that AFE patients form a heterogeneous population consisting of patients with different unidentified etiologies. In this case, one can assume that AFE patients with low ClINH activities present a specific subgroup of AFE patients. Again, the low patient number prevents the further conclusions. These limitations, however, can be resolved by further well-designed studies and the use of standard and generally accepted qualified tests for ClINH activities. For this purpose, establishment of biobanks containing large number of samples taken and stored at standardized conditions from well-defined patient groups is highly needed. Hopefully, the efforts to reach this goal are shortly under way.
Critical Care Medicine
In conclusion, the impairment of ClINH function in AFE provided a novel insight into the possible pathogenesis of this condition. The ClINH activity measurement may be a promising diagnostic or even a prognostic tool that may help the diagnosis and monitoring of AFE.
REFERENCES 1. Kramer MS, Rouleau J, Baskett TF, et al; Maternal Health Study Group of the Canadian Perinatal Surveillance System: Amniotic-fluid embolism and medical induction of labour: A retrospective, population-based cohort study. Lancet 2006; 368:1444-1448 2. Abenhaim HA, Azoulay L, Kramer MS, et al: Incidence and risk factors of amniotic fluid embolisms: A population-based study on 3 million births in the united States. Am J Obstet Gynecol 2008; 199:49. e1-49.e8 3. Roberts CL, Algert CS, Knight M, et ai: Amniotic fluid embolism in an Australian population-based cohort. SiOG2010; 117:1417-1421 4. Knight M, Berg C, Brocklehurst P, et al: Amniotic fiuid embolism incidence, risk factors and outcomes: A review and recommendations. BMC Pregnancy Childbirth 201 2; 1 2:7 5. Conde-Agudelo A, Romero R: Amniotic fluid embolism: An evidencebased review. Am J Obstet Gynecol 2009; 201:445.e1 -445.e13 6. Legrand M, Rossignol M, Dreux S, et al: Diagnostic accuracy of insulin-like growth factor binding protein-1 for amniotic fluid embolism. Crit Care Med 201 2; 40:2059-2063 7 Attwood HD: Fatal pulmonary embolism by amniotic fluid. J Clin Pathon 956; 9.38-46 8. Clark SL, Hankins GD, Dudley DA, et al: Amniotic fluid embolism: Analysis of the national registry. Am J Obstet Gynecol 1 995; 172:1158-1167; discussion 1167-1169 9. Benson MD: Current concepts of immunology and diagnosis in amniotic fluid embolism. Clin Dev Immunol 201 2; 201 2:946576 10. Benson MD, Kobayashi H, Silver RK, et al: Immunologie studies in presumed amniotic fluid embolism. Obstet Gynecol 2001 ; 97:510-514 11. Fineschi V, Riezzo I, Cantatore S, et al: Complement C3a expression and tryptase degranulation as promising histopathological tests for diagnosing fatal amniotic fluid embolism. Virchows Arch 2009; 454:283-290 12. Kanayama N, Yamazaki T, Naruse H, et al: Determining zinc coproporphyrin in maternal plasma—A new method for diagnosing amniotic fluid embolism. Clin Chem 1992; 38:526-529 13. Tamura N, Kimura S, Farhana M, et al: CI Esterase Inhibitor Activity in Amniotic Fluid Embolism. Crit Care Med 2014; 42:1392-1396
www.ccmjournal.org
1549
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
