Critical Care Obstetrics part 41 pdf

Acute Fatty Liver of Pregnancy 389 2 Ibdah JA . Acute fatty liver of pregnancy: an update on pathogenesis and clinical implications . World J Gastroenterol 2006 ; 12 ( 46 ): 7397 – 7404 . 3 Reyes H , Sandoval L , Wainstein A , et al. Acute fatty liver of pregnancy: a clinical study of 12 episodes in 11 patients . Gut 1994 ; 35 : 101 – 106 . 4 Kaplan MM . Acute fatty liver of pregnancy . N Engl J Med 1985 ; 313 : 367 . 5 Usta IM , Barton JR , Amon EA , Gonzalez A , Sibai BM . Acute fatty live of pregnancy: an experience in the diagnosis and management of fourteen cases . Am J Obstet Gynecol 1994 ; 171 : 1342 – 1347 . 6 Pockros PJ , Peters RL , Reynolds TB . Idiopathic fatty liver of pregnancy: fi ndings in ten cases . Medicine 1984 ; 63 : 1 . 7 Bacq Y . Acute fatty liver of pregnancy . Semin Perinatol 1998 ; 22 ( 2 ): 134 – 140 . 8 Monga M , Katz AR . Acute fatty liver in the second trimester . Obstet Gynecol 1999 ; 93 ( 5 Pt 2 ): 811 – 813 . 9 Suzuki S , Watanabe S , Araki T . Acute fatty liver of pregnancy at 23 weeks of gestation . Br J Obstet Gynaecol 2001 ; 108 : 223 – 224 . 10 Barton JR , Sibai BM , Mabie WC , Shanklin DR . Recurrent acute fatty liver of pregnancy . Am J Obstet Gynecol 1990 ; 163 : 534 – 538 . 11 Schoeman MN , Batey RG , Wilcken B . Recurrent acute fatty liver of pregnancy associated with a fatty - acid oxidation defect in the offspring . Gastroenterology 1991 ; 100 : 544 – 548 . 12 Wilcken B , Leung KC , Hammond J , Kamath R , Leonard JV . Pregnancy and fetal long - chain 3 - hydroxyacyl coenzyme A dehydrogenase defi - ciency . Lancet 1993 ; 341 : 407 – 408 . 13 Burroughs AK , Seong NGJ , Dojcinov DM , et al. Idiopathic acute fatty liver of pregnancy in twelve patients . Q J Med 1982 ; 204 : 481 . 14 Davidson KM , Simpson LL , Knox TA , d ’ Alton ME . Acute fatty liver of pregnancy in triplet gestation . Obstet Gynecol 1998 ; 91 ( 5 Pt 2 ): 806 – 808 . 15 Ibdah JA , Bennett MJ , Rinaldo P , et al. A fetal fatty - acid oxidation disorder as a cause of liver disease in pregnant women . N Engl J Med 1999 ; 340 ( 22 ): 1723 – 1731 . 16 Rinaldo P , Raymond K , al - Odaib A , Bennett MJ . Clinical and bio- chemical features of fatty acid oxidation disorders . Curr Opin Pediatr 1998 ; 10 : 615 – 621 . 17 Pons R , Roig M , Riudor E , et al. The clinical spectrum of long - chain 3 - hydroxyacyl - CoA dehydrogenase defi ciency . Pediatr Neurol 1996 ; 14 : 236 – 243 . 18 Ibdah JA , Tein I , Dionisi - Vici C , et al. Mild trifunctional protein defi ciency is associated with progressive neuropathy and myopathy and suggests a novel genotype - phenotype correlation . J Clin Invest 1998 ; 102 : 1193 – 1199 . 19 Treem WR , Rinaldo P , Hale DE , et al. Acute fatty liver of pregnancy and long - chain 3 - hydroxyacyl - coenzyme A dehydrogenase defi - ciency . Hepatology 1994 ; 19 : 339 – 345 . 20 Sims HF , Brackett JC , Powell CK , et al. The molecular basis of pediatric long chain 3 - hydroxyacyl - CoA dehydrogenase defi ciency associated with maternal acute fatty liver of pregnancy . Proc Natl Acad Sci USA 1995 ; 92 : 841 – 845 . 21 Isaacs JD Jr , Sims HF , Powell CK , et al. Maternal acute fatty liver of pregnancy associated with fetal trifunctional protein defi ciency: molecular characterization of a novel maternal mutant allele . Pediatr Res 1996 ; 40 : 393 – 398 . 22 Matern D , Hart P , Murtha AP , et al. Acute fatty liver of pregnancy associated with short - chain acyl - coenzyme A dehydrogenase defi - ciency . J Pediatr 2001 ; 138 ( 4 ): 585 – 588 . gastric tube. Nitrogenous waste production can be reduced further by exclusion of protein intake during the acute phase of the illness. Once clinical improvement is evident, protein intake should gradually be restored. With rare exceptions, any drug that requires hepatic metabolism should be withheld from the patient. Colonic emptying should be facilitated through the use of enemas and/or magnesium citrate; ammonia production by intestinal bacteria may be diminished by the administration of neomycin, 6 – 12 g orally per day. Exchange transfusion, hemodialysis, plasmapheresis, extracor- poreal perfusion, and corticosteroids have all been used to treat fulminant hepatic failure [39] and should be considered in cases unresponsive to traditional management. Successful liver transplantation has also been reported in women with AFLP who continue to deteriorate in spite of delivery and appropriate supportive care [40 – 42] . However, because the pathophysiologic changes associated with AFLP are reversible, transplantation is inappropriate in all but the most extreme cases [1,43] . Successful temporary auxiliary liver transplant has also been reported [41] . Mild coagulation abnormalities need not be corrected if delivery can be accomplished atraumatically and there is no evidence of clinical bleeding. However, in the presence of hemorrhagic complications or if surgery is contemplated, the coagulation abnormalities should be corrected with platelet, fresh frozen plasma, or cryoprecipitate transfusion based on the results of laboratory evaluation. The successful use of antithrombin [1,43] and factor VII [44] concentrations have also been reported. Morbidity from other potential complications may be prevented by prophylactic treatment and careful surveillance. The liberal use of broad - spectrum antibiotics may decrease the incidence of concomitant infection [1] . Prophylactic administration of antacid solutions and H 2 blocking agents may decrease the risk of gastrointestinal bleeding. Summary Acute fatty liver of pregnancy is fortunately uncommon but when it occurs, results in serious morbidity and even mortality in the worst cases. Early diagnosis and prompt treatment remain the best strategy for managing patients with AFLP. Defects in long - chain fatty acid oxidation play a role in the development of AFLP and genetic testing may useful in preventing neonatal morbidity as well as future pregnancy morbidity. Delivery is the treatment of choice and supportive care and treatment of systemic manifestations of AFLP improve both maternal and perinatal survival. References 1 Castro MA , Fassett MJ , Reynolds TB , Shaw KJ , Goodwin TM . Reversible peripartum liver failure: a new perspective on the diagnosis, treatment, and cause of acute fatty liver of pregnancy, based on 28 consecutive cases . Am J Obstet Gynecol 1999 ; 181 ( 2 ): 389 – 395 . Chapter 29 390 34 Clements D , Young WT , Thornton JG , Rhodes J , Howard C , Hibbard B . Imaging in acute fatty liver of pregnancy. Case report . Br J Obstet Gynaecol 1990 ; 97 : 631 – 633 . 35 Farine D , Newhouse J , Owen J , Fox HE . Magnetic resonance imaging and computed tomography scan for the diagnosis of acute fatty liver of pregnancy . Am J Perinatol 1990 ; 7 : 316 – 318 . 36 Goldfarb G , Debaene B , Ang ET , Roulot D , Jolis P , Lebrec D . Hepatic blood fl ow in humans during isofl urane N 2 O and halothane - N 2 O anesthesia . Anesth Analg 1990 ; 71 : 349 – 353 . 37 Holzman RS , Riley LE , Aron E , Fetherston J . Perioperative care of a patient with acute fatty liver of pregnancy . Anesth Analg 2001 ; 92 ( 5 ): 1268 – 1270 . 38 Antognini JF , Andrews S . Anaesthesia for caesarean section in a patient with acute fatty liver of pregnancy . Can J Anaesth 1991 ; 38 : 904 – 907 . 39 Katelaris PH , Jones DB . Fulminant hepatic failure . Med Clin North Am 1989 ; 73 : 955 – 970 . 40 Amon E , Allen SR , Petrie RH , Belew JE . Acute fatty liver or pregnancy associated with pre - eclampsia: management of hepatic failure with postpartum live transplantation . Am J Perinatol 1991 ; 8 : 278 – 279 . 41 Franco J , Newcomer J , Adams M , Saeian K . Auxiliary liver transplant in acute fatty liver of pregnancy . Obstet Gynecol 2000 ; 95 ( 6 Pt 2 ): 1042 . 42 Ockner SA , Brunt E , Cohn SM , Krul ES , Hanto DW , Peters MG . Fulminant hepatic failure caused by acute fatty liver of pregnancy by orthotopic liver transplantation . Hepatology 1990 ; 11 : 59 – 64 . 43 Doepel M , Backas HN , Taskinen EI , Isoniemi HM , Hockerstedt KA . Spontaneous recovery of post partus liver necrosis in a patient listed for transplantation . Hepatogastroenterology 1996 ; 43 ( 10 ): 1084 – 1087 . 44 Gowers CJ , Parr MJ . Recombinant activated factor VIIa use in massive transfusion and coagulopathy unresponsive to conventional therapy . Anaesth Intens Care 2005 ; 33 ( 2 ): 196 – 120 . 23 Treem WR . Mitochondrial fatty acid oxidation and acute fatty liver of pregnancy . Semin Gastrointest Dis 2002 ; 13 : 55 – 66 . 24 Yang Z , Zhao Y , Bennett MJ , Strauss AW , Ibdah JA . Fetal genotypes and pregnancy outcomes in 35 families with mitochondrial trifunctional protein mutations . Am J Obstet Gynecol 2002 ; 187 : 715 – 720 . 25 Yang Z , Yamada J , Zhao Y , Strauss AW , Ibdah JA . Prospective screening for pediatric mitochondrial trifunctional protein defects in pregnancies complicated by liver disease . JAMA 2002 ; 288 : 2163 – 2166 . 26 Ibdah JA , Zhao Y , Viola J , Gibson B , Bennett MJ , Strauss AW . Molecular prenatal diagnosis in families with fetal mitochondrial trifunctional protein mutations . J Pediatr 2001 ; 138 : 396 – 399 . 27 Kennedy SK , Hall PM , Seymore AE , Hague WM . Transient diabetes insipidus and acute fatty liver of pregnancy . Br J Obstet Gynaecol 1994 ; 101 : 387 – 391 . 28 Tucker ED , Calhoun BC , Thorneycroft IH , Edwards MS . Diabetes insipidus and acute fatty liver: a case report . J Reprod Med 1993 ; 38 : 835 – 838 . 29 Purdie JM , Waters BNJ . Acute fatty liver of pregnancy. Clinical features and diagnosis . Aust NZ J Obstet Gynaecol 1988 ; 28 : 62 – 67 . 30 Castro MA , Ouzounian JG , Colletti PM , Shaw KJ , Stein SM , Goodwin TM . Radiologic studies in acute fatty liver of pregnancy. A review of the literature and 19 new cases . J Reprod Med 1996 ; 41 ( 11 ): 839 – 843 . 31 Liebman HA , McGhee WG , Patch MJ , Feinstein DI . Severe depression of antithrombin III associated with disseminated intravascular coagulation in women with fatty liver of pregnancy . Ann Intern Med 1983 ; 98 : 330 – 333 . 32 Lauersen B , Frost B , Mortensen JZ . Acute fatty liver of pregnancy with complicating disseminated intravascular coagulation . Acta Obstet Gynecol Scand 1983 ; 62 : 403 . 33 Duma RJ , Dowling EA , Alexander HC , et al. Acute fatty liver of pregnancy: report of a surviving patient with serial liver biopsies . Ann Intern Med 1965 ; 63 : 851 . 391 Critical Care Obstetrics, 5th edition. Edited by M. Belfort, G. Saade, M. Foley, J. Phelan and G. Dildy. © 2010 Blackwell Publishing Ltd. 30 Sickle Cell Crisis Michelle Y. Owens & James N. Martin Department of Obstetrics and Gynecology, Division of Maternal - Fetal Medicine, University of Mississippi Medical Center, Jackson, MS, USA Introduction Sickle cell disease represents a spectrum of heritable disorders of hemoglobin synthesis that result in the production of abnormal hemoglobin molecules (hemoglobin S). Included in this group are sickle cell anemia (Hgb β S β S ), SC disease (Hgb β S β C ), and sickle β - thalassemia (Hgb β + β 0 ). In sickle cell trait (Hgb β A β S ) only one β - chain is abnormal. As such, sickle trait is considered to be an essentially benign disease, except under extremely stress- ful physiologic conditions. In sickle cell disease, the production of abnormal hemoglobin causes deformities of the red cell membrane which result in hemolytic anemia, tissue ischemia, organ failure, and episodic vaso - occlusive pain crises. Other sequelae include chronic pain from long - term or repeated ischemic events, and altered immunity leading to an increased susceptibility to infections. When compared with unaffected pregnancies, sickle cell disease in pregnancy is associated with an increased incidence of pre - eclampsia, preterm labor, spontaneous abortion, and still- birth compared to unaffected pregnancies [1,2] . Over the past few decades, much has been learned about this particular class of hemoglobinopathies. In one generation, survival for individuals with sickle cell disease has increased from 14 years to almost 50 years, and 50% survive beyond the fourth decade [3] . With the advent of widespread screening, prophylactic antibiotic therapy, vaccine use, and the application of novel technologies such as transcranial Doppler, morbidity and mortality from sickle cell disease have diminished greatly and signifi cant increases in quality of life have occurred. Epidemiology The sickle cell mutation arose, independently, in fi ve geographic locations worldwide [4] . The mutations are identifi ed by their association with different β - globin gene haplotypes (Tables 30.1 & 30.2 ). Four occurred in Africa (Senegal, Bantu, Benin, and Cameroon types), and one originated in Southern India (Indian/ Saudi Arabian type). The high prevalence of such a deleterious gene among some ethnic groups has been attributed to selective pressure from falciparum malaria. Heterozygotes (sickle cell trait) are usually asymptomatic and have partial protection against the malarial parasite. Sickle cell anemia is the most common heritable hemoglobin- opathy. It is the most common single gene disorder in the United States, with 1 in 400 African Americans affected and 1 in 12 being carriers of the trait. The disorder is also common among other ethnic groups around the world, including Asian Indians, those of Mediterranean descent, and inhabitants of the Arabian Peninsula. Hemoglobin SC disease has an approximate frequency of 1 in 1250 and the sickle β - thalassemias occur in approximately 1 in 24 000 African Americans [5] . However, because American society is made up of immigrants from many countries, it is useful to be aware that the sickle hemoglobin gene has a prevalence of 25% in some parts of Saudi Arabia and 30% among some Indian populations. The gene has also been identifi ed in parts of the former Soviet Union, in Arabs living in Israel, in Central and South America, and in the Mediterranean countries of Greece, Italy, and Spain [4,6] . Similarly, the β - thalassemia mutations are common in Africa, some parts of India and around the Mediterranean and in Southeast Asia. Fertility is not impaired in women with sickle cell disease. Although no statistics are available on the number of births to affected women, the high prevalence of the disease makes it very likely that a clinician will at some time be responsible for the care of a pregnant sickle cell patient. Molecular b asis of the s ickle h emoglobinopathies The sickle hemoglobinopathies are inherited as autosomal reces- sive traits. Individuals with sickle cell disease possess at least one Chapter 30 392 gene which precludes any production of β - chains. Sickle β + - thalassemia is the mildest variant of sickle cell disease, followed in order of increasing severity by doubly heterozygous sickle hemoglobin C (SC), sickle β 0 - thalassemia, and homozygous sickle cell disease. Diagnosis The diagnosis of sickle cell disease cannot and must not be made from either a sickle cell preparation or a solubility test. While these are adequate screening tools, neither of these tests will reliably distinguish sickle cell trait from sickle cell disease. Cellulose acetate electrophoresis or an isoelectric focusing test can be used for diagnostic purposes [9] . Preimplantation genetic diagnosis is also available for use with assisted reproductive technologies. Pathophysiology Under conditions of normal oxygenation, sickle hemoglobin has normal form and function. Under conditions that cause reduced oxygen concentrations, the sickle β - globin demonstrates a high affi nity for other Hgb S chains. This process is facilitated by the neutrally charged valine which is substituted for glutamic acid. Tetramers of deoxyhemoglobin polymerize to form longer deoxyhemoglobin strands within the erythrocyte [10,11] . These rigid polymers deform the erythrocyte membrane, causing occlusion of the smaller - caliber blood vessels. Fully oxygenated hemoglobin is sterically prevented from polymerization. Additionally, sickled cells adhere to the vascular endothelium and precipitate intimal hyperplasia and the release of infl ammatory cytokines which accelerate endothelial injury. Most importantly, there is a delay between the deoxygenation and the formation of the hemoglobin polymer that is inversely dependent upon the concentration of sickle hemoglobin [12] . Thus, the higher the intracellular hemoglobin concentration, the more readily polymerization will occur. It is this polymerization that is responsible for the distor- tion of the red cell membrane. This process remains cyclical throughout the life of the red blood cell, and is also responsible for alterations in cellular membrane permeability leading to the overall egress of water from the erythrocyte [13] . While polymerization is a reversible process, the dehydration process is not. Over time, the net effect of multiple episodes of polymerization and dehydration is an irreversibly sickled cell. It has been shown that the presence of fetal hemoglobin (Hgb F) decreases the severity of sickle cell anemia. Fetal hemoglobin has a higher affi nity for oxygen and does not polymerize. Individuals with higher percentages (20 – 30%) of hemoglobin F rarely experience crises because the speed of the sickling is reduced and the presence of the alternate globin chain inhibits the polymerization process [6] . gene for sickle hemoglobin in addition to another abnormal hemoglobin gene. Those with sickle cell trait possess one gene for sickle hemoglobin and another for normal adult hemoglobin. The offspring of parents with sickle cell trait have a 25% chance of being homozygous for sickle cell anemia, a 25% chance of having normal hemoglobin, and a 50% chance of being a carrier. Clinical manifestations of sickle cell disease vary according to the type of abnormal hemoglobin produced as well as the amount of abnormal hemoglobin present. The β - globin chain is coded on the short arm of chromosome 11. Sickle cell anemia was the fi rst disease determined to have a molecular basis [7] . Though the fi rst clinical description of sickle cell anemia was published by Herrick in 1910 [8] , it was not until 1949 that Pauling and colleagues [7] discovered the underlying mechanism of disease. They determined that sickle cell anemia was the result of a point mutation in the gene coding for the β - chain of the hemoglobin molecule which resulted in the substitu- tion of a single amino acid (valine for glutamic acid) in the sixth position of the β - globin chain. When present on both chromo- somes in a patient, the result was sickle cell hemoglobin (Hgb S) [7] . It was later discovered that another abnormal hemoglobin, hemoglobin C, was also the result of a missense mutation at the sixth position causing lysine to replace glutamic acid. In addition to the more common point mutations, double mutations also sometimes occur. These resultant hemoglobin variants still exhibit the characteristic sickling tendencies, but when electrophoresed, they demonstrate different migration pat- terns. There are six known double mutation variants, which result in abnormalities of the tertiary structure of the resulting globin chain [4] . Unlike the sickle gene which is responsible for the production of a dysfunctional globin chain, the thalassemia genes result in an abnormal amount of globin produced. The β - thalassemia mutations are subdivided into two categories, β + and β 0 , based on globin gene production. In β + , there is reduced production of β - chains, while β 0 is the result of a gene deletion or abnormal Table 30.1 Mutations that cause sickle cell disease. β 6glu → val β 6glu → val Sickle cell anemia β 6glu → val β 6glu → lys SC disease β 6glu → val β 0 or β + Sickle β - thalassemia β 6glu → val β A Sickle trait Table 30.2 Known double mutations. β 6glu → val 121glu → lys β 6glu → val 73asp → asn β 6glu → val 142ala → val β 6glu → val 23val → ile β 6glu → val 82lys → asn β 6glu → val 58pro → arg Sickle Cell Crisis 393 Additionally, parturients with sickle cell disease are at increased risk for gestational hypertension, pre - eclampsia, and growth restriction. The reasons why this occurs is unknown. The authors recommend screening for hypertensive disorders at the time of registration which includes a 24 - or 12 - hour urine collection for urine protein and creatinine, liver function tests, uric acid, and a complete blood count to establish a baseline from which to evaluate these patients if and when symptoms occur. Furthermore, close monitoring of maternal weight, blood pressure, clinical symptoms, and urine protein is essential. In sickle cell disease, blood pressures tend to be lower than that with normal hemoglobin. Part of our routine care also includes serial ultrasonogra- phy to evaluate the fetal rate of growth. The authors typically follow these patients serially (4 – 6 weeks) if fetal growth rate is normal and every 3 weeks in the presence of growth restriction. However, alterations in the timing of such examinations may be necessary as clinical indications arise. Respiratory Another common site for sickle cell involvement is the lung. The degree of involvement is variable, and comprises both acute and chronic processes. Pulmonary complications are the second leading cause of hospitalization, and represent the leading cause of death in the patient with sickle cell disease [18] . Pulmonary mortality has declined with the initiation of penicillin prophylaxis and widespread vaccination protocols in childhood sicklers, but pneumonia remains a serious complication of sickle cell anemia. Pneumonia is the third leading cause of death in pregnancy complicated by sickle cell disease. Though Streptococcus pneumoniae is most common, atypical organisms such as Chlamydia species should also be considered in this population [9] . It is also recommended that these patients receive the infl uenza vaccine annually and the polyvalent pneumococcal vaccine. In cases of asplenia, vaccination against Haemophilus infl uenzae type B and the meningococcus is also recommended [19] . Acute chest syndrome (ACS) is an acute life - threatening illness that can occur in sickle cell disease. It will be discussed in further detail later in this chapter. Chronic pulmonary changes such as pulmonary hypertension and pulmonary fi brosis are the respiratory sequelae of recurrent episodes of ACS and the widespread endothelial injury that occurs in sickle cell disease. In one study, 90% of adults with sickle cell disease were found to have abnormal pulmonary function tests, the majority of which demonstrated a restrictive physi- ology (76%) [20] . It is estimated that approximately one - third of patients with sickle cell disease will develop pulmonary hypertension. The maternal mortality rate associated with pregnancy and pulmonary hypertension ranges from 30 to 50%, and in severe cases, termination of pregnancy is recommended for maternal benefi t. In the event that pregnancy is continued, management should include frequent visits, serial cardiopulmonary evaluation (including transthoracic Doppler echocardiography), and a mul- tidisciplinary approach to care. Successful medical management has been reported in some cases with the utilization of sildenafi l, Sickling can be precipitated by a number of physiologic and environmental factors. Among the more common aggravating factors are acidosis, dehydration, extremes of temperature (hot or cold), hypoxia, elevation, and infection. In the initial stages, the sickling process is reversible with oxygenation. However, with repeated episodes of deoxygenation, the red blood cell membrane becomes rigid and irreversibly sickled [10] . The alterations in the molecular structure of sickled cells signifi cantly reduce the lifespan of the erythrocyte. While the lifespan of a normal red blood cell is approximately 120 days, the life span of a sickled cell ranges from 10 to 20 days. These damaged cells are cleared by the reticu- loendothelial system (largely the spleen and liver) where the majority of the hemolysis occurs, with approximately one - third of hemolysis occurring intravascularly. A chronic compensated anemia results via the bone marrow and extramedullary hematopoiesis. Vaso - occlusive crises occur fi rst as a result of occlusion of the microvasculature. Unlike the more pliable normal red blood cells, sickled cells lack the fl exibility to maneuver through the smaller diameters of the microcapillary beds. These rigid cells become entrapped within the capillaries, producing a vicious cycle of local hypoxia, deoxygenation, and more sickling. Secondary o rgan s ystem e ffects Sickle cell disease effects may be seen in multiple organ systems. As a result of the wide variety of systemic effects, the pregnant sickle cell patient is at increased risk for more frequent pain crises, hypertensive disorders of pregnancy, intrauterine growth restriction, preterm labor, and infections. Maternal mortality is reported to be 1% in this population, but is continuing to decline [14] . Though the effects of chronic sickling may be numerous, we have decided to focus on those organ systems most commonly affected in the gravid adult with sickle cell disease. Cardiovascular Cardiac abnormalities are almost ubiquitous in this patient population. Cardiac output is increased to compensate for the reduced oxygen - carrying capacity of the blood caused by anemia. This increase in output occurs without an elevation in heart rate and thus must be accomplished by increasing stroke volume. Cardiomegaly is found in 80 – 100% of adults with sickle cell disease. The right and left ventricles and left atrium are usually enlarged and the interventricular septum is thickened, though contractility appears to remain normal [15,16] . On an ECG, 10% of sicklers have prolongation of PR interval and 50% have some evidence of left ventricular hypertrophy [17] . Fortunately, despite the known effects of sickle cell disease on the cardiovascular system, it is uncommon for women with sickle cell anemia to die of cardiac disease. However, the physiologic adaptations to chronic anemia combined with the volume changes of pregnancy put the pregnant sickle cell patient at an increased risk of heart failure should volume overload occur. Chapter 30 394 sis (12 – 17 000 cells/ µ L) usually occurs even in the absence of infection and is most likely a reaction to tissue ischemia. In the presence of infection the white blood cell count can exceed 20 000 with an associated bandemia. Serum lactate dehydrogenase values (LDH), especially isoenzymes 1 and 2, are elevated in sickle pain crises most likely due to marrow infarction [17] . Levels of LDH rise in proportion to the severity of systemic vaso - occlusion. C - reactive protein is elevated within 1 – 2 days of onset of a crisis and the erythrocyte sedimentation rate is decreased. Approximately, one - third of pain crises are associated with infection. The most common infections during pregnancy are pneumonia, urinary tract infections, endomyometritis and osteomyelitis. Standard management of sickle pain crises is supportive: rest, hydration, oxygenation, and pain control. The majority of patients will be dehydrated due to an inability to concentrate urine. Fluid resuscitation should be initiated with normal saline. Fluid therapy probably has no effect on irreversibly sickled cells but euvolemia will decrease blood viscosity and thereby decrease the predisposition to ongoing vaso - occlusion. Input and output should be followed closely to limit the occurrence of pulmonary edema, though Foley catheterization should be avoided, if possible, to decrease the risk of infection. If infection is suspected, blood and urine cultures and a chest radiograph should be taken and broad - spectrum antibiotic coverage should be started empirically. Fetal a ssessment During and immediately after a vaso - occlusive crisis, there is signifi cant risk for fetal distress, premature labor, and fetal loss. Continuous electronic fetal monitoring should be initiated for fetuses at the age of viability, and continued until the patient is stable. A non - reactive fetal heart tracing is common during vaso - occlusive crises. One - third of fetuses will have a biophysical profi le score of 6 or less [29] . Fetal assessments typically improve as the sickle crisis resolves. The maternal condition should be stabilized and intrauterine resuscitation initiated before emergent operative delivery is considered. Once the patient is well hydrated, oxygenation optimized, her vital signs stabilized, there is no evidence of major organ involvement or severe infection, and her pain is well controlled, continuous fetal monitoring can be replaced by intermittent fetal assessments such as daily or twice weekly non - stress testing or biophysical profi les for fetuses 26 weeks and older. As with most pregnancy complications, antena- tal assessments should be individualized to the patient and her clinical situation. Chest s yndrome Acute chest syndrome (ACS) or pulmonary crisis is a potentially fatal complication of sickle cell disease characterized by fever, pleuritic chest pain, tachypnea and pulmonary infi ltrates. If a cough is present it is usually non - productive. The syndrome results from infarction of the pulmonary vasculature or pulmonary infection or a combination of these. The inhaled nitric oxide, and L - arginine therapy [21 – 24] . Though data are limited regarding pulmonary fi brosis in pregnancy, scat- tered case reports demonstrate that successful outcomes are possible with close follow - up [25,26] . Renal Sickle cell anemia is also associated with alterations in renal morphology and function. Light microscopy has demonstrated sickled blood cells in glomerular capillaries and afferent arteri- oles. The glomerulus is prone to glomerulosclerosis, which may lead to proteinuria, nephritic syndrome, or renal failure [27] . In sickle cell disease, destruction of the vasa recta through exposure to the hypertonic interstitium of the medulla leads to hyposthe- nuria, the inability to maximally concentrate the urine, further potentiating sickling and dehydration. Hemorrhage from sur- rounding medullary veins is thought to be responsible for occa- sional self - limited bouts of hematuria which are commonly seen in patients with sickle cell disease [28] . As pregnant patients with sickle cell disease are at an increased risk for urinary tract infections, it is recommended that they undergo routine urinary screening. The authors use urine dip- sticks at each visit, with serial urine cultures at least every trimester. Sickle cell disease affects almost every organ system. From cerebrovascular accidents, Moya - Moya disease (chronic cerebrovascular disease characterized by severe bilateral stenosis or occlusion of the arteries around the circle of Willis with promi- nent collateral circulation), and sensorineural hearing loss, to proliferative retinopathy and acute retinal artery occlusion with resultant vision loss, the complications are many. A high index of suspicion and a low threshold for further investigation is imperative. Sickle c risis m anagement (Figure 30.1 ) Uncomplicated a cute p ain c risis Pain crises without major organ involvement are the most common types of crises during pregnancy. Clinical features of acute pain crises vary with age and sex and frequently recur in a pattern, which is stereotypical for each individual. Pregnancy and the puerperium are associated with an increased frequency of painful episodes. Musculoskeletal pain, limited motion and swollen tender joints with effusions may be present. Dark urine is a common complaint refl ecting excretion of urinary porphyrin. The diagnosis of pain crisis is a diagnosis of exclusion because objective laboratory and physical fi ndings are lacking. Approximately 50% of patients with pain crises have alterations in vital signs including mild to moderate fever (37.8 ° C or higher), elevations of blood pressure, tachycardia and tachypnea. Fever can occur in the absence of infection due to release of endogenous pyrogens by ischemic tissue. Nonetheless, when fever is encoun- tered, an infectious cause should be sought. Moderate leukocyto- Sickle Cell Crisis 395 keep arterial oxygen tension above 70 mmHg. Hypoventilation due to pleuritic chest pain can worsen hypoxia. Likewise, narcotics should be used cautiously to prevent respiratory depression. Use of an incentive spirometer may minimize atelectasis and infi ltrates [31] . Empiric antibiotic coverage for community - acquired pneumonia should be started. In a multicenter trial with 538 patients, the most frequent organisms identifi ed in sputum were Chlamydia pneumoniae , Mycoplasma pneumoniae , and respiratory syncytial virus [30] . Transfusion to increase the level of hemoglobin A to 30 – 50% without exceeding a hematocrit of differential diagnosis of chest syndrome includes pulmonary embolus, fat embolus from bone marrow infarction, and amni- otic fl uid embolus [30] . The ventilation – perfusion scan may be abnormal due to recurrent episodes of pulmonary infarction. It is important to realize that chest syndrome is often a secondary diagnosis, developing in hospitalized sicklers or in the immediate postoperative period. Treatment is supportive. The goals of therapy are adequate oxygenation, hydration, treatment of infection, and pain relief. An arterial blood gas should be obtained and oxygen provided to Admit to hospital Continuous fetal monitoring if fetus viable CBC with differential and platelets, reticulocyte count, LDH, type and screen, urinalysis Hgb electrophoresis Blood and sputum cultures if indicated Pleuritic chest pain, tachypnea, cough Bone and joint pain, swelling, limitation of motion Right upper quadrant pain, N/V, elevated transaminases Chest crisis Bone crisis Cholelithiasis vs HELLP vs hepatic crisis ABG, EKG Chest X-ray with abdominal shielding IV hydration Pain management Radiograph of affected area Consider simple transfusion or partial exchange transfusion IV hydration Antibiotics Pain management 12 or 24 hour urine collection for protein and creatinine clearance Serial liver function tests, uric acid, CBC with platelets Oxygen Cautious IV hydration* Incentive spirometer Empiric antibiotics Pain management** Partial exchange transfusion *** * ** *** Avoid fluid overload and pulmonary edema Assess for respiratory depression that can worsen hypoxia Partial exchange transfusion may be life saving in severe cases Consider ICU admission Figure 30.1 Proposed clinical management approach for the patient in sickle cell crisis. Chapter 30 396 morphine is the preferred opioid, the type of opioid used should be based on the type and expected duration of the pain. Demerol should be avoided if possible, because of the increased potential for dependency and abuse. Morphine should be given in a loading dose to provide pain relief. The loading dose should be based on the patient ’ s previous use of narcotics. A possible starting dose is 4 mg of morphine sulfate IV or 8 – 10 mg IM. After the loading dose, subsequent doses are titrated with the goal of providing quick and sustained relief of the pain. The patient should be reassessed frequently for amount of pain and sedation. One - fourth of the initial loading dose should be given at each reassessment until the pain is relieved or there is concern about sedation. Once relief of pain is achieved, maintenance dosing should be started either at scheduled inter- vals or by patient - controlled pump. Sickle cell patients with pain crises who are given patient - controlled analgesia use less medication, develop less respiratory depression, and report better pain control than those receiving bolus injections on demand [36] . The maintenance dose can be calculated as the medication required during the titration phase divided by the number of hours over which it was given. An alternative to morphine, for those patients who report morphine allergies, is butorphanol. An intramuscular injection of 2 mg of butorphanol has equivalent analgesic effect to 10 mg of IM morphine or 80 mg of IM meperidine. It is a mixed ago- nist – antagonist and can precipitate withdrawal in addicted patients. In a study comparing butorphanol to morphine for the control of pain due to sickle cell crisis, no difference was found in pain relief or level of alertness [37] . Butorphanol can be given as 2 mg IM or 1 mg IV with assessment of the patient in 30 minutes and repeated doses until pain is relieved. Maintenance dosing should be the initial dose given at schedule times every 2 – 4 hours. Adjuvant analgesics are often added to improve the effect of the opioids and minimize side effects. The most commonly used adjuvants are antihistamines [12] . They counteract the opioid - induced release of histamines that cause pruritus, reduce nausea, and have a mild sedative effect. In the event that sedatives and anxiolytics are needed, they should always be used in combination with analgesics and not alone in the management of pain, as they may mask the behavioral response to pain without providing analgesia [35] . Once consistent pain control has been achieved, the parenteral opioids should be tapered over several days while maintaining pain control with oral opioids. Once pain control is achieved, the patient may be followed in the outpatient setting, with oral analgesia for home use. Of note, long - term opioid use produces opioid tolerance and physical dependence. This should be expected to develop over time, and should not be confused with psychologic dependence [35] . The authors have also experienced great success in the outpatient population with fentanyl patches, which provide a more steady level of analgesia over time, and may also be utilized in patients who suffer from chronic pain as a result of their disease process. 30% has been shown to reverse acute respiratory distress during pulmonary crisis [30,32] . Davies [33] recommended exchange transfusion for worsening hypoxia, continuing fever and tachycardia, or worsening chest radiograph. Atz [34] reported the successful use of inhaled nitric oxide in two patients with chest syndrome. Inhaled nitric oxide selectively dilates the pulmonary vasculature, increases oxygenation, and potentially alleviates the vaso - occlusive process. Hepatic c risis Hepatic crisis due to disseminated vaso - occlusion of the hepatic microvasculature with sickled red cells simulates acute cholecystitis with fever, right upper quadrant pain, leukocytosis, and elevations in transaminases and bilirubin. Differentiating this syndrome from cholecystitis or the syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP) can be a diagnostic challenge. It is reasonable to manage such patients with parenteral hydration, broad - spectrum antibiotics, pain control, and serial laboratory assessments of liver function, uric acid, and complete blood count with platelets. Pain m anagement The management of pain (Figure 30.2 ) in the sickle cell population presents diffi culties to the clinician for multiple reasons. Sickle cell patients are often economically disadvantaged and sometimes non - compliant. There are no objective criteria for identifying a pain crisis or for quantifying the pain. The patient ’ s self - report of her level of pain is the only assessment tool available. Factitious disorder and Munchausen ’ s syndrome are well documented among sickle patients. On the other hand, patients who require large doses of narcotics to control their pain may be incorrectly labeled as drug seeking. In an effort to optimize the management of pain associated with sickle cell, the American Pain Society released the fi rst evidence - based guideline for acute and chronic pain management in sickle cell disease. This guideline includes a comprehensive initial pain assessment which includes the patient ’ s treatment history, physical factors, demo- graphic and psychosocial factors, dimensions of pain, and the impact of pain on functioning [35] . The initial dose of pain medicine should be individualized based on the patient ’ s prior use of analgesia, including the type, route and frequency of dosage. Traditional therapy includes non - opioid and opioid analgesics with analgesic adjuvants. For mild pain, peripherally acting oral analgesia, such as acetaminophen, may be suffi cient, combined with aggressive oral hydration. Acetaminophen provides analgesia and antipyresis. The recommended adult dosage should not exceed 6 g in a 24 - hour period. Mild to moderate pain can be managed by the addition of codeine. Hospitalization is recommended for greater than mild to moderate pain, as severe pain should be considered a medical emer- gency, with timely and aggressive management provided until the pain becomes tolerable [35] . Opioids combined with non - opioids and adjuvant analgesics are the mainstay of treatment. Though Sickle Cell Crisis 397 been shown to improve both maternal and fetal outcomes in one study [39] . In contrast, no improvement in pregnancy outcome was found in a retrospective review of matched patients who received prophylactic exchange during pregnancy compared to those who did not [40] . The major disadvantage is the potential for isosensitization. Patients can become so severely sensitized that cross - matching becomes nearly impossible. During an emer- gency requiring transfusion, inability to fi nd compatible blood can be fatal. During pain crises, exchange transfusion has been shown to provide symptomatic relief within 1 hour of initiation of the procedure [41] . This procedure rapidly decreases the amount of hemoglobin S and increases hemoglobin A, thereby improving oxygenation and decreasing the risk of sickling and associated complications. The goal is to achieve a hemoglobin A concentration of at least 60 – 70% with a hematocrit of 30 – 35%. Tables are available to calculate the required volume of transfusion given a target percentage of hemoglobin A, the hematocrit of the transfused blood, and the patient ’ s weight in kilograms. Therapeutic o ptions Oxygen t herapy The benefi t of oxygen therapy in non - hypoxic patients is uncer- tain. Although oxygen has been shown to reduce the number of reversibly sickled cells in vitro , clinical trials of such therapy have not produced a reduction in the duration of pain, analgesic administration, or length of hospitalization [38] . The therapeutic goal is to maintain a normal P a O 2 . If oxygen therapy is needed, 3 L supplied by nasal cannula is usually suffi cient. In severe oxygenation failure refractory to supplemental oxygen, continuous positive airway pressure or positive end - expiratory pressure may be necessary. Exchange t ransfusion Prophylactic partial exchange transfusion during pregnancy, before the onset of a vaso - occlusive crisis, is controversial. It has Mild pain Moderate pain Moderate to severe pain Admit to hospital Loading dose of morphine 4 mg IV or 8–10 mg IM * plus antihistamine (vistaril 50 mg IM or benadryl 25–50 mg IV) Assess patient for pain and level of sedation, every 30 min Pain not controlled Pain controlled 1 mg morphine IV or 2 mg morphine IM Scheduled doses of morphine or PCA ** Taper parenteral drugs over 3–5 days; add oral opioids * Butorphanol may also be used (see text) Maintenance dose is medication required to control pain divided by the time over which it was given ** Acetaminophen Oral hydration Acetaminophen, add codeine, oral hydration Figure 30.2 Pain management approach for patients with sickle cell crisis. Chapter 30 398 and the United States [50] have reported on a total of 116 patients with sickle cell disease. Though cure rates are reported at 80 – 85% in both studies, the mortality ranges from 5 to 10%. Complications are high, with 25% neurologic morbidity (including intracranial hemorrhage) and 10% incidence of graft - versus - host disease. The transplants have been predominantly performed in children and young adults [49,50] . There are no reports of bone marrow transplantation during pregnancy, and the procedure remains unproven in adults. Due to concerns over safety, bone marrow transplantation has been reserved for only the most severe cases of sickle cell disease. It is hoped that further advances may someday make bone marrow transplantation a more plausible treatment option for a greater majority of patients. References 1 Seoud MAF , Cantwell C , Nobles G , Lerry DL . Outcome of pregnancies complicated by sickle cell and sickle - C hemoglobinopathies . Am J Perinatol 1994 ; 11 : 187 . 2 Sun PM , Wilburn W , Raynor BD , Jamieson D . Sickle cell disease in pregnancy: twenty years of experience at Grady Memorial Hospital, Atlanta, Georgia . Am J Obstet Gynecol 2001 ; 184 ( 6 ): 1127 – 1130 . 3 Mehta SR , Afenyi - Annan A , Byrns P , Lottenberg R . Opportunities to improve outcomes in sickle cell disease . J Am Fam Pract 2006 ; 74 ( 2 ): 303 – 310 . 4 Bain BJ . Haemoglobinopathy Diagnosis . London : Blackwell Science , 2001 : 113 – 117 . 5 Whitten CF , Whitten - Shurney W . Sickle cell . Clin Perinatol 2001 ; 28 ( 2 ): 435 – 448 . 6 Sergeant GR , Sergeant BE . Sickle Cell Disease , 3rd edn. Oxford : Oxford University Press , 2001 . 7 Pauling L , Itano HA , Singer SJ , Wells IC . Sickle cell anemia: a molecular disease . Science 1949 ; 110 : 543 – 549 . 8 Herrick JB . Peculiar elongated and sickle - shaped red blood corpuscles in a case of severe anemia . Arch Intern Med 1910 ; 6 : 517 – 521 . 9 Dauphin - McKenzie N , Gilles JM , Jacques E , Harrington T . Sickle cell anemia and the female patient . Obstet Gynecol Surv 2006 ; 61 ( 5 ): 343 – 352 . 10 Bunn HF . Pathogenesis and treatment of sickle cell disease . N Engl J Med 1997 ; 337 ( 11 ): 762 – 769 . 11 Rust OA , Perry KG Jr . Pregnancy complicated by sickle hemoglobin- opathy . Clin Obstet Gynecol 1995 ; 38 ( 3 ): 472 – 484 . 12 Steinberg MH , Rodgers GP . Pathophysiology of sickle cell disease: role of cellular and genetic modifi ers . Semin Hematol 2001 ; 38 ( 4 ): 299 – 306 . 13 Lonergan GJ , Cline DB , Abbondanzo SL . Sickle cell anemia . Radiographics 2001 ; 21 ( 4 ): 971 – 994 . 14 Howard RJ , Tuck SM . Sickle cell disease and pregnancy . Curr Obstet Gynaecol 1995 ; 5 ( 1 ): 36 – 40 . 15 Covitz W , Espeland M , Gallagher D , Hellenbrand W , Leff S , Talner N . The heart in sickle cell anemia: the Cooperative Study of Sickle Cell Disease (CSSCD) . Chest 1995 ; 108 : 1214 – 1219 . 16 James TN , Riddick L , Massing GK . Sickle cells and sudden death: morphologic abnormalities of the cardiac conduction system . J Lab Clin Med 1994 ; 124 : 507 – 520 . Patients usually require placement of a double - lumen central catheter before the procedure and should be premedicated as for any blood transfusion. We have found that a standard exchange of 6 units of washed packed red blood cells results in approximately 70% of hemoglobin A. Simple t ransfusion Simple transfusion of packed red cells is indicated for hematocrit less than 15% or hemoglobin less than 6 g/dL. A hematocrit of 30 – 35% is considered optimal. This should not be exceeded due to the increased viscosity of sickled cells which can precipitate a crisis when the hematocrit is elevated. Hydroxyurea Hydroxyurea is an antineoplastic agent that has been shown to induce production of hemoglobin F. It is commonly used in non - pregnant sicklers and has been shown to decrease the frequency of pain crises, acute chest syndrome, and the necessity of transfu- sions [42 – 44] . Hydroxyurea works by selectively killing cells in the bone marrow thus increasing the number of erythroblasts producing hemoglobin F [43,44] . Because it is cytotoxic, the risk of teratogenesis when used during the fi rst trimester, its long - term effect, and the risk of carcinogenesis are a concern. No randomized studies exist on its use in pregnancy. There are case reports reporting favorable outcomes even in the fi rst trimester of pregnancy. Diav - Citrin [45] reported a case of hydroxyurea use during the fi rst 9 weeks of pregnancy and additionally reviewed case reports of 15 other exposures to the drug during pregnancy. Nine cases had fi rst - trimester exposure. All of those pregnancies had phenotypically normal children. However, there is no long - term follow - up on those children. Though the available data suggest that use of hydroxyurea during pregnancy is not commonly associated with adverse short - term outcomes, at this time, use of hydroxyurea in pregnancy cannot be advocated [46] . However, for patients with unplanned exposure to the drug during pregnancy, the prognosis may not be as grim as expected. There are no human data available regarding reproductive toxic- ity of hydroxyurea in the female patient. Erythropoietin Erythropoietin is a hormone that stimulates red blood cell production. It has been shown to increase the number of reticulo- cytes containing fetal hemoglobin in humans [47] . It has been used alone and in alternating doses with hydroxyurea to increase the amount of hemoglobin F [43,47] . Studies have produced confl icting results about its effi cacy in either augmenting the effect of hydroxyurea or of enhancing production of fetal hemoglobin [47,48] . Erythropoietin is currently not used for induction of fetal hemoglobin in sickle cell patients, but may be useful in sickle patients with renal insuffi ciency. Bone m arrow t ransplant Bone marrow transplantation has emerged as the only cure for the patient with sickle cell disease. Two large trials in Europe [49] . a surviving patient with serial liver biopsies . Ann Intern Med 1965 ; 63 : 851 . 391 Critical Care Obstetrics, 5th edition. Edited by M. Belfort, G. Saade, M. Foley, J. Phelan and G. Dildy with pre - eclampsia: management of hepatic failure with postpartum live transplantation . Am J Perinatol 1991 ; 8 : 278 – 279 . 41 Franco J , Newcomer J , Adams M , Saeian K . Auxiliary liver. Blackwell Publishing Ltd. 30 Sickle Cell Crisis Michelle Y. Owens & James N. Martin Department of Obstetrics and Gynecology, Division of Maternal - Fetal Medicine, University of Mississippi