Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of sickle cell disease in general and sickle cell anemia in particular. The disease itself is chronic in nature but many of its complications are acute such as the recurrent acute painful crises , acute chest syndrome, and priapism. These complications vary considerably among patients, in the same patient with time, among countries and with age and sex. To date, there is no well-established consensus among providers on the management of the complications of sickle cell disease due in part to lack of evidence and in part to differences in the experience of providers. It is the aim of this paper to review available current approaches to manage the major complications of sickle cell disease. We hope that this will establish another preliminary forum among providers that may eventually lead the way to better outcomes.The sickle hemoglobin is an abnormal hemoglobin due to point mutation (GAG → GTG) in exon 1 of the  Although gene therapy for sickle cell anemia, the ultimate goal of cure, is not feasible at the present, significant strides have been made at the basic level to achieve the genetic correction of hemoglobinopathies . The molde chain , 3. Thisde chain , 3. The de chain  thus creThe purpose of this paper is to briefly update the definitions by including newly described complications and review the accepted approaches for the management and treatment of the major complications of sickle cell disease. These will be based on published evidence if available and on the experience of experts in the field. To that end management of pain syndromes, hematological, neurological, ophthalmological, pulmonary, hepatobiliary, splenic, renal, genitourinary, musculoskeletal, and dermatological complications will be addressed. Recently, there has been increasing evidence that asthma predisposes to certain complications of sickle cell disease including acute painful crises, acute chest syndrome, pulmonary hypertension and stroke . ManagemNeurocognitive impairment , 6 is anA controlled cross-sectional multicenter study  comparedAnother uncontrolled study from a single institution  showed t2-weighted abnormality from the stroke develops and persists indefinitely as a remote SCI. It is not clear how long it takes before the permanent abnormality appears.The term “Acute Silent” seems paradoxical since acuity is usually associated with overt signs and symptoms whereas silence is associated with covert findings. Nevertheless, in an observational study  pediatriThe complications of SCD are divided into three major types: (1) pain syndromes and related issues; (2) anemia and its sequelae; (3) organ or tissues damage. Management of these complications will be described below. Management of SCD in general and its complications in particular follow five major approaches . These iβ+ thalassemia generally have less severe anemia than hemoglobin SS and sickle β0 thalassemia. Certain SCD-related complications, such as splenic sequestration, aplastic crisis, and hyperhemolytic crisis, can lead to acute exacerbation of anemia [The majority of patients with sickle cell disease (SCD) have some degree of baseline anemia due to ongoing hemolysis. Although there is interpatient variability, individuals with hemoglobin SC and sickle f anemia . Below, β+ thalassemia at risk due to occasional persistent splenomegaly into adulthood [The spleen undergoes variations in size during childhood in SCD. It may be initially enlarged in children with SCD but may become dysfunctional as early as in first year of life. More than 90% of children with sickle cell anemia (SCA) may have total loss of functional splenic tissue by early childhood , 14. Chidulthood . Early pdulthood .Acute splenic sequestration in SCD results from the trapping of red cells in the splenic sinuses which leads to a sudden rapid enlargement of the spleen which could be massive. These episodes are generally associated with viral or bacterial infections. Patients present with pallor, tachycardia, tachypnea, weakness, abdominal pain and distension, and shock due to hypovolemia and acute decline in hemoglobin level. Mild thrombocytopenia may also be present. The cooperative study of sickle cell disease (CSSCD) defined acute splenic sequestration as decrease of hemoglobin or packed cell volume (PCV) of at least 20% from the baseline along with increase in palpable spleen size of at least 2 centimeters from baseline . HoweverAcute splenic sequestration should be managed with urgency due to its potential life-threatening nature. Immediate treatment of acute splenic sequestration includes the correction of hypovolemia to avoid hypovolemic shock and the transfusion of packed red cells to maintain oxygen-carrying capacity. Once the cardiovascular status is restored, the patient improves rapidly and the spleen shrinks in few days releasing the trapped red cell back into circulation. Hemoglobin level increases often to a greater extent than the predicted based on the red cell volume administered. Therefore, to avoid hyperviscosity and related complications, patients should not be transfused to achieve baseline hemoglobin levels.The rate of recurrence of an acute life-threatening episode of splenic sequestration is high, occurring in approximately 50% of those who survive first episode . To elimIn a steady state of health in SCD, shortened lifespan of red cells remains compensated by an increased production of erythroid cells by the bone marrow. Thus even a temporary cessation of erythropoiesis in SCD can lead to acute exacerbation of anemia. Suppression of erythropoiesis can be caused by many infections, including the classic example of parvovirus B19, which preferentially attack erythroid precursors due to P-antigen of erythrocyte being its receptor. Destruction of erythroid precursors leads to severe anemia and reticulocytopenia .The clinical course following Parvovirus B19 infection is variable, and not all patients develop severe anemia. Episodes of aplastic crisis are generally preceded by febrile illness. Patients present with fatigue, pallor, and weakness along with laboratory evidence of anemia and reticulocytopenia  , 12. RecHyperhemolytic crisis is defined as the presence of acute anemia along with the evidence of accelerated hemolysis. It presents with acute reduction in hemoglobin level often associated with reticulocyte count that is higher than the baseline. Several subphenotypes have been described including hyperhemolysis during an episode of acute vasoocclusive painful crises  or as anHyperhemolysis associated with painful crises can often be managed conservatively, but transfusion of red cells can be considered if clinically indicated. A high index of suspicion is needed in case of transfusion-related hyperhemolysis, because symptoms may be similar to painful crises including bone pain and fever making the identification difficult. It is a serious and potentially life-threatening complication of red cell transfusion. The laboratory evaluation in delayed hemolytic transfusion reaction (DHTR) may reveal low hemoglobin, elevated serum lactate dehydrogenase, and bilirubin above the patient's baseline. Serial hemoglobin levels, reticulocyte counts, and hemoglobin electrophoresis may be helpful in making a diagnosis of hyperhemolysis in the posttransfusion setting. DHTR is often associated with a positive antiglobulin test (DAT) . The manSickle cell disease affects the hepatobiliary system in different ways at different ages. Intrinsic disease results from recurrent ischemia and bilirubin stones. These result from the vascular obstruction and red cell hemolysis of sickle cell. Biliary sludge is a common finding that is often clinically unimportant. Viral infections that affect the liver may be independent of or secondary to red cell transfusions. The iron overload that accompanies red cell transfusions can lead to liver dysfunction and fibrosis. Many medications taken by sickle cell patients may cause or worsen hepatobiliary disease. The dysfunction of the liver can affect the lungs, kidneys, and coagulation systems. Treatment is directed at the etiology of the dysfunction as well as the underlying sickle cell disease.The natural consequences of any hemolytic condition affect both the gallbladder  and the The challenge physicians caring for sickle cell patients is recognizing the life-threatening course from the more frequent, similar appearing milder, recurrent syndromes. A useful way to consider the protean effects of hepatobiliary issues in sickle cell is to consider the disorders of the presentation and evaluation of abdominal complaints of sickle cell followed by a review of the major disorders. Although hepatobiliary conditions are intimately linked, the embryology of the biliary system and the hepatic system shows these two organs to be histologically and functionally separate . This exAcute pain in the right upper quadrant is common in sickle cell patients –67. The The liver is often increased in size throughout the life of the patient . If the If right upper quadrant pain is severe, then acute swelling or inflammation may be involved. Murphy's sign is often lost in the general pains but, if present, may point to the gallbladder. If the serum bilirubin concentration is over 4 mg/dL, then checking whether the fraction of direct bilirubin exceeds 10% would point to the gallbladder as the source of the increase , 71. SomInitial evaluation is for conditions that need emergent transfusions or treatments.Pain patterns that differ from a patient's usual pattern need close evaluation.Having sickle cell does not protect a patient from any other condition.Liver involvement may be part of a multiorgan failure syndrome , 75.With any severe sickle cell complication, exchange transfusions are often the treatment of choice –79.Hepatic crisis is often used as a general term to describe right upper quadrant pain in a sickle cell patient [ patient , 81. How patient . The defBacteroides species were found in one report [If the condition is from typical sickle vaso-occlusion and inflammation, then the elevation of ALT decreases after a few days. Severe, persistent elevations may relate to hepatic infarct, characterized by a wedge-shaped, hypointense CT lesions . Hepatice report . BilirubHepatic sequestration is best diagnosed by a rapid enlargement of the liver with a concurrent drop in hemoglobin concentration [ntration –91. The ntration –91. Smalntration , 75.Chronic hepatic sequestration has been reported in a 17-year old with SS hemoglobin . After eOne report of “reverse sequestration” occurred following simple transfusions. This syndrome comprises a sudden increase in hemoglobin concentration, sudden onset of hypertension, acute congestive heart failure, neurologic signs of infarct or hemorrhage .Autoimmune hepatitis is reported in sickle cell patients [patients , 95. IntViral hepatitis occurs at least as frequently as in the general population [pulation . Hepatitpulation . Liver tpulation –101.Hepatic siderosis is a growing area of concern and research [research . As red research , 104. Thresearch , 105, deresearch , or deferesearch , 108. Onresearch –111.Hepatic effects on kidneys and lungs are increasingly recognized. Although there are few publications concerning sickle cell patients, such effects are well known in other conditions where the liver is cirrhotic or dysfunctional. The hepatorenal syndrome [syndrome , hepatopsyndrome , and thesyndrome  syndromeSickle cell intrahepatic cholestasis or sickle cell hepatopathy is a condition with marked hyperbilirubinemia (>50 mg/dL) and a high fraction of direct (conjugated) bilirubin (about 50%) [out 50%) , 115–118out 50%) . Some auout 50%) . Ischemiout 50%) .Early reports indicate that sickle cell intrahepatic cholestasis was a life-threatening condition that mandated exchange transfusions. As clinicians were more aware of the condition, series were reported that had a less severe course . Given tCholelithiasis occurs as early as two years old [α-thalassemia may reduce the incidence of stones since it may lessen the degree of hemolysis that is thought to drive stone formation [ears old . About 3ears old , 124. Thears old . The coiormation . The cauormation . Some reormation . Howeverormation , 68, 123ormation , 124. Laormation , 129. Thormation , 131. Stormation .Biliary sludge is a common finding in sickle cell patients [patients , 50. Bilpatients . Most aupatients .Choledocholithiasis also occurs in sickle cell disease [ disease . Even in disease . After c disease .Acute cholecystitis presents as it does in patients without sickle cell disease [ disease , 136. Ri disease .Chronic cholecystitis may be related to persistent gallstones or persistent biliary sludge. Recurrent symptoms consistent with colic warrant screening with blood work and imaging. If the blood work shows increases in conjugated (direct) bilirubin during the attacks, and there are ultrasonographic signs of a thickened gallbladder wall, then cholecystectomy may decrease these symptoms. However, just as in chronic cholecystitis in the general population, the symptoms may recur several months after surgery.Disorders of the hepatobiliary symptoms are common in sickle cell disease. Besides the conditions found in the general population, several conditions occur that are specific to sickle cell disease. These conditions include the prevalence of pigmented stones, intrahepatic cholestasis, hepatic sequestration, and recurrent hepatic ischemia and necrosis. A directed history and physical examination will suggest needed further evaluations. Laboratory values and imaging will often establish the diagnosis. Cholecystectomy is best reserved for symptomatic patients. Biliary sludge should be followed for the development of symptoms. For any severe or multiorgan dysfunction in sickle cell patients, red cell transfusions or exchange transfusions will stabilize the underlying sickle cell disease and may reverse the pathologic process.P > 0.0001) [Dactylitis is usually the earliest musculoskeletal manifestation of SCD and occurs in infants and very young children with a peak incidence during the first 6–12 months of life . Prevale 0.0001) .Osteoporosis (OP) and low bone mineral density (BMD) or osteopenia is now being recognized as a common bone complication in both children and adults with SCD. The prevalence of low BMD in SCD ranges from 30 to 80% –151 withThe specific etiology of osteoporosis in SCD is multifactorial with many similarities to the OP found in thalassemia syndromes albeit less well studied , 158. HyAccording to the World Health Organization (WHO) to be diagnosed with osteoporosis, one must have a bone mineral density (BMD or bone mass) of at least 2.5 standard deviations (T score) below the peak bone mass typically achieved by a healthy adult between the ages of 18–30 years of age of the same sex and ethnicity   and myoglobin in serum may be suggestive; however it is not present in all cases. Elevated CRP may suggest concurrent infection and warrants empiric antibiotic therapy. Confirmation is made by evidence of muscle inflammation and necrosis by MRI or on muscle biopsy showing inflammation, edema, and necrosis of muscle fibers with collagen deposition and fibrosis [Acute vaso-occlusion involving muscles, tendons, and fascia can occur in SCD . It is sfibrosis , 192.κB inhibitor and IVIG [Although myositis, myonecrosis, and fasciitis are difficult to distinguish clinically, initial treatment modalities are the same and include bed rest, short-term immobilization, intravenous fluid hydration, anti-inflammatory agents, and opioid analgesics for pain relief . There iand IVIG . Sulfasaand IVIG , 197. FuThe complete disruption of vascular supply to the articular surfaces and ends of long bones, particularly the femoral and humeral head and spine, results in avascular necrosis or AVN , 199. ScRecent studies in SCD suggest a 26% prevalence of AVN among children with hemoglobin SS (mean age 9.8 years), and in adults it is 48.6% with a mean age of 26.7 years with a four-year progression rate of 67% , 212. InEarly diagnosis of AVN is of critical importance as outcomes of conservative management are dependent on disease severity. A multidisciplinary approach preferably in a specialized center with expertise in SCD is needed to achieve optimal treatment outcomes and should involve orthopedics, hematology, physiotherapy, and nutritional expertise . TreatmeThe use of core decompression although established as an effective treatment for stage 1 AVN was showed to have no superiority over intensive physiotherapy in a randomized controlled trial  , 230. NoThe treatment of stage 4 disease is more complex, and depending on size and location of the necrotic zone and the pathology of the adjacent bone, resurfacing or short-stem hip arthroplasty can be performed. Conventional total joint replacement (TJR) is still however the gold standard. This poses a challenge for the younger patient before the second decade of life who continues to have longitudinal bone growth in the unaffected limb and is more active resulting in length discrepancies, prosthesis instability, and muscle imbalance. There have been conflicting reports on the success of joint replacement surgery for severe AVN in SCD, and prosthesis failure is especially common in these patients. The typical lifespan of a replaced joint is 5–10 years with individuals suffering loosening of the prosthesis over time. Patients may continue to have continued pain and limitations of mobility even after arthroplasty. A recent review reported a revision rate of 31–63% with less than ten years of followup compared to 10% in nonsickle patients , 234–236The use of chronic hypertransfusion (CHT) and hydroxycarbamide (HU) to modulate disease severity and prevent sickle vaso-occlusive complications has not been shown to conclusively reduce the risk of AVN in SCD . On the Ulcerations of the skin and underlying tissues may occur in SCD most commonly involving the medial and lateral aspects of the ankle. Delayed healing leading to skin ulceration may also occur at postsurgical sites of after mild trauma. Risk factors associated with the development of leg ulcers in SCD include trauma, infection, severe anemia, high hemolytic rate , geographic location, socioeconomic status, and venous incompetence –244. RecThe epidemiology of leg ulcers in SCD is not well defined as the clinical impact on patients is often underestimated by clinicians since it is not immediately life-threatening complications. Environmental factors and geography influence the prevalence of leg ulcers, and in the Unites States approximately 2.5%  of persoThe pathogenesis of chronic leg ulcers in SCD is poorly understood and quite complex. Factors that predispose to chronic ulceration in SCD include poor skin perfusion , increased local edema from venous incompetence, abnormal autonomic vascular control  , microvaPrimary prevention is the main focus of the management of leg ulcers in SCD. A detailed review of prevention strategies and the treatment of leg ulcers by Eckman provides practical management insights . All patOnce an ulcer is established, treatment can be very frustrating for both patient and medical team. A multipronged approach that provides for gentle debridement , prevention and control of local edema, control of infection, provision of a local healing environment with topical agents, and systemic treatment of the disease and other identified micronutrient deficiencies has provided the best treatment outcomes. Zinc is a trace element that plays an important role in immune function and wound healing. Small but randomized studies have shown efficacy of oral zinc sulfate 220 mg three times a day in promoting rapid healing of leg ulcers . This maChronic leg ulcers will recur between 25 and 50% of the time, and retreatment will be needed. There are several anecdotal  reports Staphylococcus aureus and enteric gram-negative bacilli [Bacterial infections involving the cortical bone (osteomyelitis) and joint space (septic arthritis) have been commonly reported in SCD, particularly in association with avascular necrosis and bone infarcts , 258. Th bacilli , 261. Th bacilli . It is i bacilli . The utiEarly changes on plan radiography are nonspecific and include periosteal reactions, osteopenia, and lucent areas within bone. Ultrasonography is a rapid noninvasive way of showing extra osseous pathology associated with OM; however it has only 74% sensitivity, and findings are nonspecific , 265. CoSeptic arthritis (SA) is estimated to occur in 0.2 to 5.4% of individuals with SCD and usually occurs in an osteonecrotic joint and is caused by similar organisms to OM –272. SepThe mainstay of treatment for both OM and OA is a prolonged course of antibiotics. Initial use of parenteral antibiotics against salmonella, staph, and enteric gram-negative organisms is prudent to achieve rapid bactericidal blood levels. A six-week course of antibiotics is recommended for confirmed cases. Physical therapy to improve joint function and avoid muscle wasting should be encouraged once pain improves.Data from the Cooperative Study of Sickle Cell Disease (CSSCD) revealed that stroke occurred in 11% of children with hemoglobin SS (HbSS) below the age of 20 years and 24% of adults by age 45 . HoweverThe acute management of overt stroke has not changed substantially in the past three decades. Patients presenting with clinical evidence of acute cerebral ischemia receive an immediate CT scan of the brain to rule out intracranial hemorrhage and are initially managed in an ICU where they receive simple or exchange transfusion to lower circulating HbS levels to ≤30% and correct anemia to a hemoglobin level of approximately 11 g/dL. Subsequent management requires chronic simple transfusion or erythrocytapheresis to maintain HbS at ≤30% (or a community standard level of ≤45% ). Of majIn contrast, primary prevention of ischemic stroke using TCD screening and prophylactic chronic transfusion of persons at high risk for stroke indicated by abnormal velocities (>200 cm/sec) has dramatically lowered the overall incidence of stroke –276, 287Silent infarcts occur in approximately 20% of children with sickle cell anemia and are associated with significant compromise of neurocognitive performance as well as an increased risk for subsequent overt stroke , 293. ChAlthough neurocognitive deficits are usually associated with overt stroke in sickle cell disease, compromise is almost as significant in persons with silent infarcts and also occurs in those who have no apparent lesions on cerebral MRI , 299. EvCerebral blood flow (CBF) has also been shown to influence neurocognitive function. Children with sickle cell anemia and abnormal CBF velocity, measured by TCD, perform more poorly on tests of verbal intelligence and executive function . CerebraNo treatment has been demonstrated to improve neurocognitive dysfunction in this population, but results of a multicenter controlled randomized trial of short-term (6-month) transfusion intervention are pending . In addition, there is suggestive evidence from a report of 15 children treated with hydroxyurea, who scored higher on tests of verbal comprehension, fluid reasoning, and general cognitive ability than children not on the drug . BenefitMoya-moya syndrome has been increasingly recognized following stroke in children with sickle cell anemia and has been associated with intellectual decline, particularly in performance IQ , as wellVaso-occlusion can affect any vascular bed in the eye, including the conjunctiva, anterior segment, retina, choroid, or optic nerve with potentially blinding consequences . Little Although rare, orbital compression syndrome (OCS) has been reported as an ocular manifestation of sickle cell disease –315. In One of the early vaso-occlusive features in SCD may be seen in the conjunctival vasculature. Abnormalities take the form of transient saccular and sausage-like dilations packed with red cells, resulting in dark red, comma-shaped vessel segments, most notably in the inferior bulbar conjunctiva . Paton rConjunctival blood flow improves following transfusion. The comma signs are also noted to diminish under heat from slit lamp beam illumination, which probably induces vasodilation. Abnormalities increase with pharmacologic agents inducing vasoconstriction, and these effects are reported to be more apparent in the pediatric patient group , 320. Hi2 and lactic acid leading to acidosis, even sickle trait red cells become sickled. They then become trapped, since deformed and less pliable sickle cells are unable to pass through the 0.3–2 μm pores of the aqueous outflow apparatus, namely, the trabecular meshwork and intraocular pressure increases [The anterior chamber of the eye, normally filled with aqueous humor, has low oxygen tension, low pH, and high ascorbate concentration (a reducing agent) and may be filled with red blood cells following trauma or surgery, resulting in a condition called hyphema. When erythrocytes and leukocytes consume oxygen and liberate COncreases , 323. Onncreases . The prencreases , 326. Anncreases . Paracenncreases , by convPosterior segment findings include retinal hemorrhages and exudates, angioid streaks, chorioretinal infarctions, vitreous hemorrhage, central or branch retinal artery occlusion, and proliferative sickle cell retinopathy (PSR).Salmon patch hemorrhage represents a well-defined area of hemorrhage located within the superficial retina, between the sensory retina and its internal limiting membrane. It usually occurs in the midperipheral retina adjacent to an intermediate-sized arteriole . AlthougIntraretinal hemorrhages may track into the subretinal space, dissecting between the neurosensory retina and the retinal pigment epithelium (RPE), resulting in RPE migration into the site and forming the stellate and spiculate hyperpigmented lesion known as a black sunburst. The black sunburst lesion appears as a flat, round-to-oval, black patch about 0.5–2 mm in size Figures . GlistenVaso-occlusions may occur in the retina or less commonly in the choroid of patients with sickle cell disease. In the retina, the initial vaso-occlusions typically occur in the peripheral retinal vasculature and mainly involve capillaries and precapillary arterioles. In more advanced retinopathy, occlusions can occur in any vessel within the peripheral retinal vasculature and can result in new vascular formations characteristic of sickle cell disease, such as sea fan neovascularization and hairpin loops  Figures. OcclusiSeveral case reports suggest that vascular occlusions also occur in the choroid , 335. ChAngioid streaks are small breaks in Bruch's membrane, which separates retina from choroid. Angioid streaks resemble blood vessels, thus their name, and typically emanate radially from the optic nerve. These streaks are thought to be due to calcification and fragility of Bruch's membrane . They arThe macular findings in patients with sickle cell disease include abnormal perfusion and an enlarged foveal avascular zone (FAZ) due to vaso-occlusive episodes. Epiretinal membranes, schisis, holes, and neovascularization may also occur. The “retinal depression sign” was first described by Goldbaum as an abnormality in the reflection from the internal limiting membrane due to depression of the inner surface resulting from a small retinal infarct and subsequent atrophy . These cThe presence of multifocal perifoveal occlusions was suggested to result possibly from a central retinal artery occlusion with migration of microemboli downstream in a 9-year-old boy with SS hemoglobinopathy . In the Fluorescein angiography and automated perimetry of the central 30 degrees are more sensitive tests for detection of ischemic macular disease than visual acuity, and macular ischemia can be quantified by these two techniques . Since mAlthough infrequent, macular holes can also be seen in association with proliferative sickle cell retinopathy. The occurrence of fibroglial proliferation around the disc, with subsequent nasal traction on the macula, along with temporal traction resulting from vasoproliferative tissues near the temporal equator, has been suggested to play an important role in the formation of macular holes by stretching of the retina. The occlusion of perifoveal capillaries may be another possible mechanism, because it causes retinal atrophy, thinning, and possible hole formation .Retinoschisis is a rare complication of sickle cell retinopathy that is related to chronic low-grade ischemia of the inner nuclear layer . It is cThe disc sign in sickling hemoglobinopathies is the appearance of isolated comma or hyphen-shaped small vascular segments on the surface of the optic nerve head. It is most likely due to piling up and subsequent deoxygenation of sickled erythrocytes caught at bifurcations in the capillary bed or precapillary arterioles and is most commonly seen in patients with HbSS disease. These transient plugs do not seem to result in any visual changes or loss . They arβ-thalassemia; about 14% of patients with this genotype have PSR [Arteriolar occlusion and loss of capillary perfusion in the peripheral retina are the most striking features of sickle cell retinopathy. They are generally more prominent in the temporal peripheral retina, especially superotemporally. The ischemic areas caused by these occlusions release substances that can stimulate angiogenesis . The inihave PSR . PSR canhave PSR . The peahave PSR .Goldberg and colleagues developed a widely accepted grading system detailing the stages of proliferative sickle retinopathy  320, 35.Recent studies investigating the pathogenesis of retinal angiogenesis have focused on the balance between pigment epithelium-derived factor (PEDF), an anti-angiogenic factor, and vascular endothelial growth factor (VEGF), an angiogenic factor . PEDF is°  of the circumference, therapy is usually implemented.Observations in a Jamaican cohort study showed that spontaneous regression occurred in 32% of eyes with PSR. Permanent vision loss was rare among the subjects followed for 20 years until the age of 26 years . Given tThe goal is to induce regression of stage III lesions prior to a substantial hemorrhage and/or retinal detachment. With an early, successful treatment, the need for pars plana vitrectomy and/or scleral buckling, and their associated potential surgical complications, can be avoided –358. VarPrior to demonstration of the indirect effect of peripheral retinal destructive therapy on proliferating capillaries by suppression of vascular growth factors, laser treatment was used to occlude feeding vessels. Direct, heavy laser treatment was applied to the feeding arterioles and then to the draining venules. The sea fans were closed in 88% of eyes studied in a controlled clinical trial . AlthougThe preferred therapy by many clinicians is either localized or widespread scatter photocoagulation because of its low rate of complications. It is performed similar to its use in proliferative diabetic retinopathy. The goal is to destroy nonperfused retina that is responsible for production of the angiogenic factors initially triggered by ischemia . The lasThe new Optos P200MA Ophthalmic Imaging System may offer a distinct advantage over the traditional angiographic imaging in evaluating patients with sickle cell disease. The technology provides ultrawide field, high-resolution angiography, red-free, and full-color imaging, captured via a noncontact and nonmontage acquisition process, with up to a 200° internal view of the retina at one time. The images in Figures The P200MA uses low-powered laser wavelengths that scan simultaneously. While the red (633 nm) and green (532 nm) lasers are used to image the retina and the choroid, the blue (488 nm) laser permits the addition of fluorescein angiography with the ability to image almost the entire retina. Photocoagulation is now guided by findings on the wide-field angiography and is applied to areas of nonperfusion noted in these images adjacent to sea fans Figures . The seaThere are two retinal ablation techniques suggested for patients with PSR: sectoral and circumferential. Sectoral ablation is scatter photocoagulation only in the area around neovascularization. It has shown a reduction in vitreous hemorrhage and visual loss, without numerous complications . HoweverRegular followup is critical to assess progression of neovascular disease or treatment response following local, sectoral scatter photocoagulation. Despite scatter treatment, new neovascular fronds may develop in up to 34% of eyes .A 360-degree peripheral scatter photocoagulation may be considered for an unreliable patient. In one series, peripheral circumferential retinal scatter photocoagulation to the peripheral zones of retinal capillary nonperfusion was shown to result in complete regression of 33% of preexisting sea fans . As yet,This technique was shown to be effective and safe in a case of PSR with vitreous hemorrhage and can be considered an alternative method in eyes when transpupillary laser application is not possible due to clouding of the media .For successful photocoagulation, the media must be sufficiently clear overlying the vasoproliferative tissue to allow the photocoagulation beam to form a sharp image on the retina. Vitreous hemorrhage or lenticular opacities can interfere with an adequate view of the retina and prevent successful photocoagulation. In such cases, the single freeze-thaw technique has been successful in approximately 70% of treated sea fans . The vitThe neodymium: yttrium-aluminum-garnet (Nd : YAG) laser has been used in patients with PSR to reduce vitreoretinal traction by lysing localized, taut vitreous bands or to clear the media in front of the macula . Safety PSR may cause vitreous hemorrhage that occasionally is severe or persistent and that requires surgical intervention. Patients with new vitreous hemorrhages may be followed for at least 6 months to allow spontaneous clearing of the media when there is no associated retinal detachment , 356. EaFull-thickness macular hole is another indication for vitrectomy surgery in patients with PSR. The surgical approach usually includes vitrectomy and removal of epiretinal membranes , 375.Vitrectomy and scleral buckling surgery carry significantly higher risks of intraoperative and postoperative complications in patients with sickle hemoglobinopathies. There has been, however, considerable advancement of vitreoretinal surgical techniques and instrumentation in the course of recent years, making this type of surgery much safer than ever before. The introduction of endolaser photocoagulation, intraocular diathermy, endoillumination, and, most recently, small gauge, microincisional surgery is one of the advances that has improved the rate of surgical success in patients with sickle cell disease.Vitrectomy is often combined with scleral buckling in patients with enlarged or progressive tractional detachments or with a notable tractional component in association with proliferative disease. The success rate, however, for visual acuity improvement in a series of eyes with tractional retinal detachment with or without a rhegmatogenous component, requiring vitrectomy plus a scleral buckling procedure, was only 50% . ComplicAnterior segment ischemia was reported to occur in 71% of patients undergoing a scleral buckling procedure . It was in vitro and in vivo assay systems. It is approved for the systemic treatment of metastatic colorectal cancer. However, studies reporting off-label use of intravitreal bevacizumab in patients with neovascular age-related macular degeneration have shown promising results. It has also been shown that the intravitreal injection of bevacizumab resulted in regression of retinal neovascularization in patients with sickle cell disease in an anecdotal report [Recent studies showed that the balance of PEDF and VEGF changes as the disease progresses to the proliferative stage . This wal report . Controlα and IL-1α, upregulate leukocyte adhesion molecule expression by vascular endothelial cells [α4β1 (VLA-4) on their surface [α, was demonstrated in a rat model of sickle-cell-mediated retinal vascular occlusion. Blocking VLA-4 with a cyclic peptide or monoclonal antibody has been shown to prevent sickled RBC retention in the retina in this model [α stimulated retention of the SS red cells in choroid appears to be mediated by VLA-4, and this retention was inhibited by a VLA-4 antagonist (TBC772), a cyclic peptide, or by blocking one of the VLA-4's ligands, the CS-1 portion of fibronectin [Although it has been assumed that sickled erythrocytes solely contribute to the vaso-occlusive processes seen in sickle cell disease, there is evidence that neutrophils may also contribute to the process . The adhal cells . Both ofal cells . Several surface , 384. This model . The mecronectin .P < 0.01) compared with pre- and posttreatment crisis rates of 7.6 and 7.1 per year in five others taking the same doses of olive oil as placebo (P > 0.4) [Recurrent vaso-occlusion and tissue infarction cause a repetitive inflammatory reaction in patients with sickle cell disease (SCD). The importance of inflammation is highlighted by observations that anti-inflammatory agents ameliorate SCD in humans and in animal models , 387. OmP > 0.4) .Recent studies have, therefore, shed light onto the pathogenesis of SCD and may permit identification of new treatment modalities in these patients.Many early studies of SCD in infants and young children concentrated on the initial manifestations of SCD that might be a hint to early diagnosis of this disorder, while subsequent studies after the advent of newborn screening have focused on factors associated with specific clinical events, such as pain, which did not suffer the ascertainment bias that was common in early studies. Bainbridge et al. described the experience from Jamaica of 314 children with SS identified over an 8-year period from 6/73–12/81 . OccurreGill et al. reported the experience of the Cooperative Study of Sickle Cell Disease (CSSCD) which enrolled 694 infants identified with SCD by newborn screening prior to 6 months of age and followed them prospectively up to age 10 years, from 10/78 to 10/88 . DactyliThe most comprehensive study of pain frequency in this age group comes from the Cooperative Study of Sickle Cell Disease (CSSCD), which examined a 10-year longitudinal cohort of about 4000 adults and children . Rates oHealth-related quality of life and its relationship to pain have been studied QOL using the PedsQL version 4.0 generic core and fatigue scales in 1772 subjects (53% boys) with a mean age of 9.6 years (SD 4.7) from the Collaborative Data (C-Data) Project of the Comprehensive Sickle Cell Centers (CSCC) Clinical Trial Consortium . MultiplA substantial literature exists that describes pain characteristics in school-age children (>6 years) and adolescents, and recommendations have been made for appropriate pediatric assessment instruments , 402. PaP < .0001, by ANOVA with hospital day as independent variable and VAS as dependent variable). A similar temporal trend for pain relief was also seen, with generally very poor pain relief early in the painful episode and good pain relief by the time of discharge. Patients reported a mean of  3 ± 2  (mean ± SD) painful sites on day 1 of hospitalization, with spine, sternum, both knees, and both ankles being the four most common sites. Subsequent studies have documented similar findings [Initial studies of hospitalized children and adolescents with sickle pain examined 17 adolescent and young adult patients who were hospitalized for treatment of severe pain with parenteral morphine using the Varni-Thompson PPQ . Pain infindings , 407.A number of studies have described the characteristics of vaso-occlusive pain in the home setting , 408. InVaso-occlusive pain experienced during these episodes was of mild-to-moderate intensity on the majority of reported days with pain, but severe pain, rated as 7 or higher on a 10-point intensity scale, was reported on 12% of days. Gender or hemoglobinopathy did not significantly influence pain intensity, while younger children on average reported less intense pain than did older children. Pain was localized to one or two distinct sites on 65% days with vaso-occlusive pain. While age and hemoglobinopathy did not influence the number of sites, female gender was associated with a higher number of reported painful sites.n = 37; aged 13 to 17 years), who completed daily diaries assessing pain, stress, mood, activity, and health-care use for up to 6 months, showed that daily increases in stress and negative mood were associated with increases in same-day pain, health-care use, and reductions in school and social activity using multilevel regression modeling [A number of personal factors can also contribute to the sickle pain experience. For example, a study of adolescents with SCD (modeling . Increasmodeling . At medimodeling . CurrentAnother evolving area of pain assessment is the development of assessment tools to characterize the impact of pain on daily activities. The NIH-sponsored Patient Reported Outcomes Measurement Information System (PROMIS) has developed validated pediatric assessment tools for a number of relevant domains including physical functioning and pain interference . Other iPain management in children with SCD presents unique challenges and opportunities. A recurrent pain condition with unpredictable occurrence and severity with variable response to pharmacologic therapies represents the fundamental challenge. The opportunity afforded by SCD is to provide anticipatory and concurrent guidance to children and their families while the child is asymptomatic to encourage and support the use of a variety of cognitive-behavioral therapies, positive coping skills, and an acceptance of lifelong pain disorder.Pharmacologic therapies for acute pain in childhood are similar to that of other acute pain disorders in children. Much of the pain experienced and treated at home is of mild-to-moderate intensity and responses well to acetaminophen or nonsteroidal anti-inflammatory agents (NSAIDs) , while mManagement of severe vaso-occlusive pain in the acute care or hospital setting is somewhat more problematic. Parenteral opioids given on a time-contingent basis, often in combination with parenteral NSAIDs, is the most common pharmacologic therapy in this situation, but few large controlled trials are available to guide dosing. Frequent dose titration to adequate pain relief in specialized day hospital units has been quite effective in children , as it hAlthough there are few studies documenting the prevalence of persistent or “chronic” pain in children with SCD, most clinical experience suggests that condition is infrequent in children, but does occur in adolescents. However, there are no controlled trials of pharmacologic therapies for adolescents with SCD and persistent pain. There is experience with cognitive-behavioral therapies for other persistent pain conditions in adolescents , and cogPain dominates the clinical picture of SCD in general and sickle cell anemia in particular. Many of the complications of sickle cell disease are associated with either acute or chronic pain. Acute chest syndrome and hepatic cholestasis, for example, are associated with acute pain. Leg ulcers and avascular necrosis, on the other hand, are often associated with chronic pain. Management of these types of pain is associated with the management of the complication in question as will be discussed below under specific organ/tissue damage. This section will address sickle cell pain that is not associated with complications of the disease but itself is a major complication of SCD.Sickle cell pain is often classified as either acute or chronic. The acute type is the recurrent painful crisis that often requires treatment in the emergency room, day unit, or hospital with parenteral analgesics, mostly opioids. Pain that occurs between the acute episodes is usually milder and treated at home with oral analgesics and is often referred to as chronic pain. Although this classification is somewhat arbitrary, nevertheless management of sickle pain is based on these assumptions as will be discussed below.The acute sickle cell painful crisis  is the hallmark of sickle cell disease in both children and adults. It is the number one cause of hospital admissions in adults with 95% of admissions due to acute painful crises . The paiThe frequency of acute pain crises in patients varies within and between individuals from rare occurrences during a lifetime to many times a month . About 3There are at least three sets of known predisposing events that seem to predict the frequency and severity of the acute sickle cell painful crisis. These are genetic, cellular, and environmental/epigenetic factors.+ thalassemia, and Hb C decreases the frequency of crises. The Senegalese beta haplotype seems to be associated with less crises than the Benin or the CAR haplotypes [Genetic factors include Hb F level, the coinheritance of thalassemia , the coinheritance of other hemoglobin variants (such as Hb C), beta haplotypes, epistatic gene modifiers, and gender. The higher the level of Hb F the milder is the disease and the less frequent are the painful crises –435. Theplotypes . Femalesplotypes , 437.Cellular factors associated with decreased RBC deformability and increased number of dense cells in the steady state have salutary effect, most likely because these are associated with more severe anemia and, hence, relatively decreased whole blood viscosity , 439. PaNocturnal hypoxia, sleep apnea, and nutritional factors such as vitamin A deficiency are environmental factors amenable to preventative therapy , 442.Patients relate onset of pain to emotional stress, changes in weather, exposure to cold, dehydration, infection, fatigue, and overexertion. Major reported factors that seem to precipitate acute painful crises include dehydration, stress of any kind , infection, asthma, acidosis, sleep apnea, climate, and pregnancy , 444. NeAnecdotally, many patients report that sudden changes in temperature seem to precipitate acute painful episodes. Several studies have found an increased incidence of pain episodes during cold and rainy weather –448. OthPain of the acute crisis is often described as throbbing, sharp dull, or stabbing in decreasing order of frequency. Anatomic sites most affected include the back, legs, knees, arms, chest, and abdomen in decreasing order of frequency . The intChronic pain is pain that does not go away and lasts for months and even years throughout the lifespan of the patient. It is usually described as deep, nagging, and achy in nature that is there all the time. It could be in the chest, back, abdomen, extremities, neck, or headache. It resides there without invitation and resists any trial for its resolution. It usually follows frequent recurrent and severe acute painful crises. Early and aggressive interventions in treating acute sickle cell pain may be successful in reducing the development of chronic pain. The principles of treating chronic pain are different than those of acute pain. The goal of managing acute pain is to heel the acute injury or precipitating factor(s). The goal of treating chronic pain is to restore function. In a sense chronic sickle cell pain is a spin off the recurrent acute painful episodes. As such it becomes a disease by itself due to neuroplasticity of the central nervous system and central sensitization. To that end, ambient environmental stimuli that are normally innocuous become painful to the sensitized patient with chronic pain.Once chronic pain sets in it is joined by other maladies that enhance its chronicity. These include depression, anxiety, suffering, despair, insomnia, loneliness, helplessness, and dependence on pain medications. With the onset of chronic pain there seems to be a process of “re-wiring” the brain where the threshold for pain perception is lowered so that ambient environmental stimuli that are normally painless or mildly painful induce the perception of severe pain. Hyperalgesia in this context is the perception of severe pain generated by stimuli that are normally mildly painful, and allodynia is the perception of severe pain by stimuli that are normally painless , 457.It is usually described as numb, tingling, lancinating, shooting, or paroxysmal in nature associated with a sensation of pins and needles. Its severity is also enhanced by exposure to either cold or heat. This pain was believed to be secondary to nerve injury whether peripherally or centrally. This definition has recently been modified by the International Association for the Study of Pain (IASP) to include injury and dysfunction of nerves as causes. Persistent chronic pain and/or its management seem to cause the perception of neuropathic pain. The pathophysiologic events leading to this transformation are not well understood also. Activation of the glia seems to be a possible pathophysiologic mechanism leading to neuropathic pain .It is another kind of pain often referred to by care providers following patients with SCD. Literally this term means the act of breaking through pain relief. Originally this term was introduced for patients with cancer pain  and was They include postoperative pain and iatrogenic pain due to therapeutic interventions. These are not unique to SCD and, hence, will not be discussed in this paper.Effective management of acute pain in the emergency room, day unit, or in the hospital depends on systematically following certain sequential steps  that staAssessment is the basis of effective pain management. It should be done before and periodically after the initiation of analgesic therapy , 461. ThThe intensity of pain can be assessed by any of several available scales, such as the visual analogue scale, verbal scale, numerical scale, or Wong-Baker faces scale for children. It is important, however, to stick to one scale and use it routinely, so that both the patient and provider become familiar with it and with its significance to a particular patient. Nociceptive sickle cell pain typically is sharp or throbbing in nature. Pain that is burning, shooting, lancinating, or tingling suggests the presence of a neuropathic component that entails the use of certain adjuvants mentioned below , 460.Pharmacologic management of pain includes three major classes of compounds: nonopioids, opioids, and adjuvants , 461. A These compounds have fewer systemic adverse effects than NSAIDs , but theμ-, κ-, and, to a lesser extent, δ-receptors [Opioid agonists are most often used in the management of sickle cell pain. They decrease or modify the perception of pain at the level of the central nervous system. They exert their effect by binding to eceptors , 464. OpAdverse effects of opioid analgesics include itching, nausea, vomiting, sedation, and respiratory depression. Seizures may be associated with opioids, especially with the prolonged use of meperidine (pethidine) and the consequent accumulation of its major metabolite, normeperidine, in some patients. The effects of meperidine and normeperidine on seizure induction are more pronounced in the presence of renal disease. Tolerance and physical dependence occur in some patients, but addiction is rare . MethadoOpioid analgesics have no ceiling effect (with the possible exception of codeine); hence the only limiting factor on their dose is adverse effects. Severe sedation and respiratory depression are the most important adverse effects. Hospitalized patients receiving opioid analgesics on a regular basis should be monitored for their respiratory rate and sedation level. A respiratory rate of less than ten per minute or severe sedation justifies skipping, decreasing, or delaying the dose or discontinuing the opioid in question until the depressive effects disappear. Opioid analgesics should be used carefully in patients with impaired ventilation, asthma, increased intracranial pressure, and liver failure. The presence of acetaminophen in combination with codeine or oxycodone limits the daily dose that may be safely used so that the maximum allowable dose of acetaminophen is not exceeded. The FDA has recently decreased the maximum allowable daily dose of acetaminophen to 3000 mg/day instead of the previous 4000 mg/day .Providers who prescribe opioids for patients with sickle cell pain must be cognizant of the current legal requirements. Specifically and besides prescribing enough opioids to optimize pain relief, providers must institute measures to minimize the risk of misuse, abuse, or diversion of the prescribed opioids. Specific approaches to these recommendations have been published by the American Pain Society in collaboration with the American Academy of Pain Medicine , 468. MoThey include antihistamines, antidepressants, benzodiazepines, and anticonvulsants. These are heterogeneous compounds that potentiate the analgesic effect of opioids, ameliorate their side effects, and have their own mild analgesic effect. The role of selective serotonin reuptake inhibitors in sickle cell anemia is not clear at present. Adjuvants must be used with care, and patients should be monitored carefully when receiving them. Adjuvants also have adverse effects, some of which precipitate or worsen manifestations of sickle cell anemia .Acute painful episodes of mild or moderate severity are usually treated at home using a combination of nonpharmacologic and pharmacologic modalities. Home treatment of pain usually follows the three-step analgesic ladder proposed by the World Health Organization . Mild paPatients with chronic sickle cell pain are best managed with a combination of long-acting opioids and a short-acting opioid for breakthrough pain. Again, anecdotal reports suggest that this approach decreases the frequency of admissions to the emergency department or hospital, but data to confirm this finding are not available to date. Oxycodone CR appears to be unique in that it has both an immediate analgesic effect and a delayed long-acting one. These properties have made oxycodone CR popular among drug abusers who have learned to remove the mesh and release a high dose of pure oxycodone that has an immediate “euphoric” effect . Care prβ0-thalassemia, results of the recently described Baby HUG trial justify its use in children as well [Measures to reduce the morbidity and mortality of sickle cell anemia include prophylactic penicillin therapy in infants and children  and hydr as well . Patient as well , 476. Thsine qua non for the diagnosis. The presence of new infiltrates with some of the other signs and symptoms is usually enough to make the diagnosis. An infiltrate is new when compared to a previous radiograph with no infiltrate. If a previous radiograph is not available, the infiltrate in question is considered as new. It is obvious from this description that there are gaps in making an accurate diagnosis. For example, there is no agreement on the number and nature of the accompanying signs and symptoms to make the diagnosis. Moreover, an occasional patient may have all the signs and symptoms mentioned above with no new infiltrate on chest radiograph thus generating a dilemma for the provider. Suffice to say is that the ACS, like other syndromes, is a spectrum of clinical manifestations that vary from the mild to the very severe. Observation and careful monitoring on a daily basis or more often if needed are most important in ruling the diagnosis in or out.The clinical manifestations of acute chest syndrome (ACS) complicating SCD include chest pain, tachypnea, fever, hypoxia, dyspnea, cough, leukocytosis, decreasing Hb level, and new infiltrates on chest X-ray –479. Notβ0-thalassemia, Hb SC disease and S-β+-thalassemia in decreasing order of frequency. Coexistent α gene deletion, the platelet count, and the mean corpuscular volume (MCV) of RBC do not seem to affect the incidence of ACS [The incidence of ACS is age and genotype dependent with no difference between the sexes. It is about three times more common in young children than in adults but more severe in adults , 479. ACe of ACS . The ince of ACS . ACS is e of ACS , 481. Abe of ACS . Moreovee of ACS –485.in situ sickling, rib/sternal infarction, infection, and pulmonary embolism [S. aureus, S. pneumonia, Mycoplasma hominis, parvovirus and rhinovirus in decreasing order of frequency [In situ sickling leading to in situ thrombosis/pulmonary infarct is different from the usually known PE due to emboli from the lower extremities or pelvis. The prevalence of apparent PE in patients with SCD is higher than in non-SCD African-American patients with the same age despite the fact that the prevalence of DVT was comparable in both groups [in situ thrombosis. This differentiation is important in deciding whether long-term anticoagulation is indicated or not.Causes of ACS include pneumonia, bone marrow fat embolism, pulmonary infarct due to embolism , 486–488embolism . Rib or embolism . Infectirequency . In situh groups . This diProspective multicenter study of ACS in SCD showed that bone marrow/fat embolism is more common than previously thought . Severe Management of ACS utilizes multiple modalities in order to prevent possible catastrophic outcomes. The most important aspect of management is to maintain adequate ventilation. In mild cases incentive spirometry may be sufficient to achieve this. In severe cases, however, mechanical ventilation in the intensive care unit is essential. Once adequate ventilation is maintained, specific treatment includes oxygen, antibiotics, simple blood transfusion or exchange transfusion, judicious use of analgesics, bronchodilators, careful hydration, and possible vasodilators. Incentive spirometry prevents splinting and atelectasis and may actually prevent ACS in patients who have rib infarction . Intravein situ thrombosis is unknown.Although intravenous steroids in children with ACS may be beneficial , their uExcessive opioid analgesics may precipitate acute chest syndrome due to their depressive effect on respiration. This recommendation should be considered carefully. Opioids have a few systemic side effects, and careful monitoring of their use ensures their safety. They should be discontinued if the respiratory rate is ≤10/minute and their adverse effects can be quickly reversed with opioid antagonists. NSAIDSs, on the other hand, have considerable systemic side effects that may not be readily obvious. NSAIDSs decrease the levels of prostaglandins, prostacyclin, and prostanoids that are essential in modulating the vascular tone of smooth muscle and renal blood flow. Thus, NSAIDSs may worsen the clinical picture of ACS due to their vasoconstrictive effects and bronchospasm. NSAIDSs are contraindicated in asthma for the same reasons.The use of nitric oxide, a vasodilator, in patients with SCD supports a possible role of this agent in the management of ACS . Other vThe role of vasodilators in the management of SCD in general and ACS in particular is not finalized. Nitric oxide (NO) had a beneficial effect on painful crises in children  and in amean pulmonary artery pressure (PAP) of 25 mm Hg, determined by right heart catheterization (RHC), is one of the leading causes of mortality and morbidity in adults with sickle cell disease (SCD). Interestingly, elevated systolic PAP, derived from echocardiography-based tricuspid jet velocity (TRJV), if present in adult patients with SCD, also portends a poor prognosis.Pulmonary hypertension (PHT), which is defined as Castro and colleagues were amongst the first to study sickle PHT and determine the relationship of PHT (determined by RHC) to patient survival. They studied 34 adult patients with SCD and showed that mean PAP had a significant inverse relationship with survival, with each increase of 10 mm Hg in mean PAP associated with a 1.7-fold increase in the rate of death; the median survival for patients with PHT was 25.6 months, whereas for patients without PHT, the survival was >70% at the end of the 119-month observation period, showing that onset of PHT in patients with SCD significantly shortens their survival . GladwinFollowing the report by Gladwin et al. , TRJV >2That said, elevated TRJV in adults with SCD, regardless of whether they have RHC-proven PHT or not, predicts a poor survival. Hence high TRJV is likely indicative of other underlying cardiac pathologies, such as ventricular diastolic dysfunction, vasculopathy/endothelial dysfunction, or perhaps a sickle cardiomyopathy resulting from the chronic hypoxic stress on the myocardium. Recently, Knight-Perry et al. found cardiac structural and functional abnormalities in patients with high peak systolic PAP (TRJV >2.5 m/s). They assessed RV and LV structure and function via echocardiography in adults with SCD. Patients who had high TRJV (>2.5 m/s) had higher left atrial volumes, LV and RV filling pressures, and reduced LV and RV compliance [PHT has been reported to be present in 6–33% of adult patients with SCD in different studies, with most studies using echocardiography-based TRJV to predict PHT. It is becoming increasingly clear that echocardiography-based studies  overestimate the prevalence of PHT in nearly two-thirds of adults with SCD , while Rmpliance . More rempliance . TherefoIn children, TRJV defined of systolic PHT is more controversial, where high TRJV ≥2.5 m/s is not reproducible . PashankThe last six years have seen an upsurge of studies on the pathophysiology of PHT in SCD. In clinical studies, high TRJV is associated with a higher rate of hemolysis, renal insufficiency, leg ulcers, increasing age, low exercise capacity and high levels of N-terminal probrain natriuretic peptide or vascular cell adhesion molecule-1, and a hypercoagulable state , 515–522The hemodynamic etiology of PHT is multifactorial; studies show that elevated systolic PAP is associated with either pulmonary arterial hypertension, pulmonary venous hypertension, and PHT secondary to a hyperdynamic state associated with right and/or left ventricular hypertrophy and diastolic dysfunction , 523–525Reduced nitric oxide bioavailability has been implicated in the pathophysiology of PHT in SCD and other hemolytic anemias , 531. Thα [α). HIF-1α then induces expression of the potent pulmonary vasoconstrictor endothelin-1 (ET-1) [ET-1, a potent pulmonary vasoconstrictor, is elevated in SCA patients with PHT , 524. ETα . ET-1 reα , have beα , indicat1 (ET-1) , and a p1 (ET-1) . Indeed,1 (ET-1) , 536. Th1 (ET-1) . Hence, β, insulin, and lipopolysaccharide [A hypercoagulable state and microthrombi have been shown to contribute to PHT in other diseases. SCD is a hypercoagulable state. Studies show that SCD patients have elevated steady-state plasma levels of circulating tissue factor  and PAI-ccharide –537. Ourccharide .Recently, albuminuria in SCA has been associated with high TRJV , an assoCurrently, there are limited data on the effects of any specific treatment modality for PH in patients with SCA. Endothelin-1 receptor antagonists have been tried, are safely tolerated, and show some hemodynamic and functional improvement , 539. InA multicenter trial of sildenafil was initiated to improve NO bioavailability  , 541. HeOral arginine supplementation was attempted in a multicenter trial to improve NO bioavailability, but the results of this trial were inconclusive (unpublished data). Chronic transfusions and hydroxyurea are currently being tried for patients with high TRJV/PHT, and the results of these trials are eagerly awaited. Currently, there is no targeted therapy available for patients with SCD that develop PHT. Therefore, newer therapies for sickle PHT are desperately needed.PHT is one of the leading causes of morbidity and mortality in adult patients with SCD. However, there are significant gaps in knowledge in the predictors, accurate screening modalities, pathophysiology, and treatment of sickle PHT. PHT is defined as a mean pulmonary arterial pressure (PAP) of ≥25 mm Hg by RHC, but the invasive nature of this modality is prohibitive to using RHC as a screening tool. There is lack of an accurate noninvasive screening test for PHT in SCD. In children, where RHC is rarely performed, data on PHT is much more limited and restricted to echocardiography-based projections, which are less predictive of the prognosis than similar estimations in adults. Echocardiography-obtained tricuspid regurgitation jet velocity (TRJV) is used to estimate peak/systolic pulmonary artery pressure. Recent studies show that high TRJV/Peak PAP only predicts PHT in 25–33% of adult patients with SCD. Nevertheless, high TRJV is associated with poor prognosis in multiple studies, suggesting that additional cardiac/endothelial pathology leads to increased systolic PAP in SCD and portends a poor prognosis. The prognosis of PHT in SCD is poor, with the development of PHT associated with a 40–50% risk of death within 2-3 years (odds ratio of 8–15) , 543. SeThe kidney appears to get affected in several different ways in sickle cell disease (SCD). Children, and even infants with SCD have hyposthenuria/urine concentrating defect (UCD), supranormal glomerular filtration rate (GFR) and proximal tubular function, and an impaired ability to acidify urine or excrete potassium (reviewed in references –547). A The renal plasma flow and increased GFR are increased in SCA, possibly from the compensatory hypersecretion of vasodilator prostaglandins in response to hypoxia-induced sickling . GFR dec2 35–40 mm Hg), hyperosmolar medullary environment promotes sickling. The vasa recta become congested, tortuous, occluded, and hemorrhage, resulting in painless hematuria. They eventually undergo fibrosis, resulting in infarctive papillary damage and necrosis. Hematuria is often from the left kidney, occurs at any age, and is even seen in persons with sickle trait. Renal papillary necrosis is observed in as many as 40–50% of patients with SCA. Painful hematuria in patients with sickle trait has been associated with renal medullary carcinoma, a very aggressive malignancy characteristically seen in this group of young adults. Damage to the juxtamedullary nephrons and collecting ducts also occurs and contributes to the UCD and to tubular defects.Vascular obstruction from sickled RBCs leads to microscopic-to-gross painless hematuria, occurring from medullary congestion and renal papillary necrosis. The hypoxic , supranormal proximal tubular function is present in SCD, as evident by increased reabsorption of sodium, phosphorus, and increased excretion of creatinine and uric acid in the urine . HGlomeruli, especially the juxtamedullary glomeruli in young SCA patients, are enlarged and congested, reaching a size that is 60–80% larger than normal glomeruli . Glomeruβ+ thalassemia [Standard renal function tests like serum creatinine and GFR become subnormal in this disease only when renal damage has become extensive and largely irreversible. Therefore, good biomarkers that predict early SN need to be identified. Microalbuminuria is the most studied biomarker of SN in cross-sectional studies. We and others have shown that prevalence of albuminuria in SCD increases with age –575; alblassemia . Guasch lassemia ; microallassemia . Albuminlassemia , and notlassemia . Whetherlassemia , suggestSN has remained relatively underdiagnosed and understudied despite its onset early on in life: classic biomarkers of renal damage are normal even in the face of existing chronic sickle kidney disease, until extensive renal damage has occurred. Supranormal creatinine excretion in the urine results in lower than normal serum creatinine; therefore serum creatinine rises only in late stages of SN. Patients also have higher than normal renal blood flow and GFR; therefore urinary creatinine clearance is high from the resulting hyperfiltration, and subnormal GFR develops only when significant proteinuria and glomerular damage has developed and is largely irreversible . Hence tPriapism is a persistent unwanted and recurrent painful erectile erection that may last from hours to days. It is diagnosed by the provider based on patient self-report. During an episode, priapism can be confirmed by physical examination of finding a fully erect penis and complaint of pain in the penis and/or scrotum. There are no controlled studies on this complication of SCD. Most reports in the literature are case reports or observational studies –585. PatAbout 75% of priapism occurs between midnight and 6 AM and after sexual intercourse , 590. AcThrombocytosis, low level of Hb F, and severity of hemolysis are reported risk factors of priapism , 598. RePriapism has been classified in a number of ways . EtiologMajor goals of management of priapism include pain relief and prevention of impotence. Minor episodes of priapism and stuttering priapism usually last less than 4 hours and are often treated at home with analgesics, benzodiazepines, or pseudoephedrine and do not require treatment in the emergency department (ED) or hospital. Patients are advised to report to the emergency department if an episode lasts longer than 4 hours. Initial treatment in the ED should include hydration and opioid analgesics. Catheterization of the urinary bladder may be indicated to promote emptying. If these measures fail to cause detumescence, penile aspiration and epinephrine irrigation should be utilized. Mantadakis et al.  recommenThe role of hydroxyurea, etilefrine, leuprolide, sildenafil, and pseudoephedrine in preventing priapism is not well defined at the present . AnecdotBlood transfusion is one of the three current major approaches for the effective and promising therapeutic approaches for SCD in general and SS in particular. The other two include hydroxycarbamide (HCD), also known as hydroxyurea (HU), and stem cell transplantation. Moreover blood transfusion could be symptomatic management of severe anemia or preventative management to prevent the occurrence of primary and secondary strokes in children with SS and the recurrence of acute chest syndrome in some patients. Historically blood transfusion was second to analgesia as a nonsurgical therapeutic approach for SS as far back as to the 1930s and 1940s even before the pathophysiology of the disease was well understood , 608. ItBecause Hb S has decreased oxygen affinity and, hence, is efficient in delivering oxygen to tissues, most patients tolerate chronic anemia with an average Hb level of 7-8 g/dL well without the need for blood transfusion in the steady state , 610. NeThe transfusion of blood from normal donors to patients with sickle cell disease achieves the following two major goals: (1) improvement of the oxygen-carrying capacity of blood and its delivery to tissues and (2) dilution of circulating sickled red cells in order to improve microvascular perfusion. The achievement of these goals, however, is best if Hb S is decreased to <30% and the total Hb level is not >10 g/dL , 618. HiThe availability of safe blood due to advances in donor selection, the utilization of phenotype matching, the availability of oral iron chelators, and the reported efficacy of blood transfusion in preventing strokes and acute chest syndrome encouraged providers to use blood transfusion more frequently in managing the acute and chronic complications of SCD. Thus one study from a single institution found that about 50% of the patients with SS admitted to the hospital over 12-year period (1987–1998) received blood transfusion . AnotherThe indications for blood transfusion have been classified in a number of ways. Moreover blood transfusions could be episodic or chronic, and the transfusion method could be simple transfusion or exchange transfusion –623. In Blood selected for transfusion to patients with SCD should be sickle cell negative, ABO and Rh compatible, phenotypically matched for C, E, and K antigens, leuko-reduced and irradiated for selected patients . MoreoveComplications of blood transfusion in patients with SCD include the transmission of infectious disease, alloimmunization, hemolytic transfusion reactions (acute or delayed), allergic reactions, febrile reactions, volume overload, and iron overload. Multiply transfused patients before 1992, when a screening test for hepatitis C was introduced in blood banks, were at risk for the transmission of hepatitis C virus (HCV). In one study  antibodyOn a brighter note chronic transfusion therapy is associated with a number of unintended benefits. These include decrease in the number of hospitalizations per year, decrease in the frequency of painful crises, and decrease in the frequency of acute chest syndrome .Patients with SCD who receive blood transfusion chronically are at risk to develop iron overload. An observational study reported increased frequency of painful crises, organ damage and mortality in patients with SS and iron overload . For bilμg/L and transferrin saturation >50% in the steady state are suggestive of iron overload. To further confirm the diagnosis of iron overload, a liver biopsy may be indicated. Hepatic iron concentration >7 mg/g liver dry weight is diagnostic of iron overload and is an indication for iron chelation therapy [The diagnosis of iron overload entails documentation of history of transfusion of ≥20 units of RBC in adults or ≥200 mL of RBC/kg in children and confirmation of iron overload by certain blood tests. These tests include serum ferritin level, liver biopsy to measure the amount of iron per g of liver dry weight and Ferriscan . Other s therapy . FerriscThree iron chelators are available for the therapeutic management of transfusional hemosiderosis , 628. Th


A chronic pain condition may result in altered autonomic nervous system regulation in various patient populations. We evaluated whether autonomic regulation differs between sciatica patients referred to spine surgery and age-matched healthy controls analyzed with heart rate variability techniques (HRV).1 as indices of sympathovagal balance were analyzed. Pain intensity was assessed on a Visual Analog Scale (VAS) and perceived disability with Oswestry Disability Index.HRV of patients (n = 201) and healthy controls (n = 138) were measured in standing conditions (5 min). High frequency (HF) power as an index of cardiac vagal modulation and the low-to-high-frequency (LF/HF) ratio and short-term fractal scaling exponent α1 were higher in the patients than in the controls (p < 0.01 for both). After adjusting for sex, smoking, BMI, and leisure-time physical activity, HF power (p = 0.011) and α1 (p = 0.012) still differed between the groups. Among the patients, HF power was slightly associated with the duration of chronic pain .The Oswestry and VAS scores were higher in the patients than in the controls (p < 0.0001 for both). HF power was markedly lower for the patients compared to the controls (p < 0.0001). The LF/HF ratio and αSciatica patients referred to spine surgery had altered cardiac autonomic regulation expressed as decreased vagal activity and an increased sympathovagal balance toward sympathetic dominance when compared with age-matched healthy controls. Low back disorders, including low back pain (LBP) and sciatica, are common health problems among adults and represent a significant burden on health care systems globally. A population-based survey showed that 19% of the subjects had chronic pain, and LBP was the main reason in almost half of these patients . FurtherVarious states of chronic pain are associated with altered autonomic nervous system function, assessed with the heart rate variability (HRV) indices, e.g. patients with fibromyalgia have shown lower HRV  and blunDepressed HRV has been shown to be associated with an adverse prognosis in general populations as well as in different patient groups -16. The The study population consisted of voluntary consecutive patients  referred to evaluation of spine surgery because of radicular symptoms in the Departments of Orthopedic Surgery and Neurosurgery at the Oulu University Hospital between June 2007 and January 2011. A neurosurgeon or orthopedic surgeon investigated the patients and a lumbar magnetic resonance imaging (MRI) was performed to all. Altogether 88% (n = 176) of patients had MRI-verified disc herniation (HNP)-induced nerve root impingement and major part of these patients were operated consequently. Twelve percent (n = 25) of patients did not have HNP-induced sciatica; about one half of them had radicular pain but in MRI only disc degeneration with or without bulge at the suspected level, while the rest had spondylolisthesis, nerve root canal narrowing or ligamentum flavum thickening. Patients with symptomatic spinal stenosis or spondylolisthesis on basis of the referral were excluded. The control subjects  were healthy volunteers without low back pain, back disease, or back surgery and they were recruited to the study by the local occupational health care center . All the subjects were asked not to eat or to drink coffee for 3 h before the tests. In addition, strenuous physical activity and alcohol consumption were prohibited on the day of the test and the preceding day. MRI of the lumbar spine was performed for both groups with 1.5-T equipment . A routine spine MRI protocol was used, including sagittal T1- and T2-weighted images of the entire lumbar spine. The subjects’ place of residence was mainly the city of Oulu  or the neighboring municipalities, but the enrollment area was comprised of the two northernmost provinces of Finland (Oulu and Lapland). All the subjects filled out a baseline questionnaire. Potential confounders or modifying factors including comorbidities, leisure-time physical activity (LTPA), and smoking status were collected with the questionnaire. The demographics and clinical characteristics of the study cohort are presented in Table All the subjects reported the duration of LBP during the past year. The diagnoses for surgical referral were obtained from hospital records. Back-related disability was assessed using the Oswestry Disability Index . A 10-cmA heart rate (HR) monitor  was used to record R-R intervals with a timing accuracy of 1 ms during 5 minutes (min) in a supine position followed by 5 min of standing in a quiet room after 5 min of rest in a supine position. The recordings were saved on a computer for further analysis of HRV with HEARTS software . To exclude all undesirable beats, which accounted for <1% of the data for each subject, the R-R intervals were edited by visual inspection. HRV indices were calculated separately for the 5-min supine and standing conditions.1) fractal scaling exponent. The fractal analysis method differs from traditional measures of HRV because it does not measure the magnitude of variability, but rather the qualitative characteristics and correlation features of HR behavior. Briefly, in the fractal analysis, the root-mean-square fluctuations of integrated and detrended data are measured in observation windows of different sizes and then plotted against the size of the window on a log-log scale. In this study, short-term (from 4 to 11 beats) α1 was calculated on the basis of previous experiments [Mean HR and the standard deviation of normal-to-normal R-R intervals (SDNN) were used as time-domain measures of HRV. An autoregressive model (model 18) was used to estimate the power spectrum densities of R-R interval variability. Vagally mediated HF power (0.15 to 0.4 Hz), both sympathetically and vagally mediated low frequency power , and the low-to-high-frequency ratio (LF/HF ratio) as an index of sympathovagal balance were calculated . A Poinceriments ,22. Detaeriments .The normal Gaussian distribution of the data was verified with the Kolmogorov-Smirnov goodness-of-fit test. Because the spectral components of HRV had a non-Gaussian distribution, a natural logarithmic transformation was performed on both. Analysis of variance (ANOVA) was used to compare if the demographics and clinical characteristics and the mean values of HRV differed between the patients and the controls. A chi-square test was also used to compare categorical parameters. Analysis of covariance (ANCOVA) with 95% confidence intervals (CI) was performed to compare the differences in HRV between the groups, with gender, body mass index (BMI), smoking status, and high LTPA used as covariates. Pearson correlation analysis and ANOVA were applied to study the associations between HRV and demographics, disability, and pain-related parameters among the patients. Since underlying co-morbidities may be associated with altered HRV, we excluded patients with hypertension, diabetes, coronary artery disease, hypercholesterolemia, asthma and arthritis or fibromyalgia from both patient and control populations and reperformed the statistical analyses. Furthermore, we performed separately a sub-analysis by comparing patients with and without HNP-induced sciatica. The SPSS statistical software package  was used for the analyses. A P-value <0.05 was considered statistically significant.The patients and controls did not differ with respect to age, co-morbidities, or moderate or low LTPA Table . However1 . Furthermore, when comparing patients with and without HNP-induced sciatica, patients without HNP-induced sciatica were older  and the duration of pain was longer  compared to patients with HNP-induced sciatica. The two patient groups differed also in HRV; e.g. HF power in standing position was 5.63 ± 1.36 in HNP-induced sciatica patients and 4.99 ± 1.36 (p = 0.002) in patients without HNP-induced sciatica. However, after adjustment with age and pain duration the difference disappeared in all HRV parameters (e.g. in HF power in standing position p = 0.211).The differences in HRV between the patients referred to spine surgery and the controls are presented in Table 1 Table . When un1 . Similar results were found when underlying co-morbidities were taken into consideration; e.g. pain duration correlated with standing HF power . Age and BMI were negatively associated with standing HF power . In a subgroup analysis according to smoking status or LTPA among the patients, standing HR, HF power, SD1, or α1 did not differ from each other .The Oswestry and VAS scores did not correlate with HRV, e.g. the correlation values between HF power and the Oswestry score and HF power and the VAS score in a standing position were −0.036 and −0.094, respectively. Pain duration was inversely associated with standing HF power  but not with HR, SD1, or α1, indicating sympathovagal balance, was higher in the patients than in the controls after adjusting for potential confounders. Impaired functional capacity caused by pain or pain intensity was not associated with HRV among the patients, but HF power correlated negatively with LBP duration. Since altered HRV has been shown to have a prognostic value in both healthy subjects and various patient groups, the present results may provide important clues for understanding and considering the contribution of autonomic nervous system function in sciatica patients referred to spine surgery.We have shown that autonomic nervous system function assessed with the HRV method differs between sciatica patients referred to spine surgery and healthy controls. Vagally mediated HF power and SD1 were significantly lower in the patients than in the healthy controls, whereas the short-term fractal scaling exponent αIt is well documented that gender, BMI, smoking, and physical activity affects HRV -27. Althper se.In a previous study, higher HF power was observed among patients with chronic LBP whose Oswestry score was less than 20% compared with patients whose score was 20–40%, but HF power did not differ between patients whose VAS score was 0–5 vs. 6–10 [It has been evidenced for a long time that various states of chronic pain, including LBP, are associated with signs of altered autonomic nervous system function, but the physiological mechanisms remain unclear. A recent study showed that HRV was reduced in complex regional pain syndrome (CRPS) patients compared with controls . During Recent studies have shown that the production of proinflammatory markers within the nucleus pulposus may be an important mediator in discogenic pain. Elevated levels of serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in patients with a herniated lumbar intervertebral disc  or elevaIn the present study, we assessed HRV in a supine position and also during orthostatic stress in a standing position. It is well documented that HRV is susceptible to saturation when measured at a low HR ,35, whic1 as an index of sympathovagal balance, because this index has been shown to provide information on autonomic interactions during various interventions and is less sensitive than spectral measures to trends and non-stationarities in HR behavior [1 between the groups remained evident (p = 0.012) after adjusting for the above-mentioned covariates, indicating the role of both reduced vagal and increased sympathetic outflow among the patients.It is also noteworthy that we measured the fractal scaling exponent αbehavior ,39-41. IUncontrolled factors such as the night-time sleep or other psychological and physiological stressors may contribute to daily HRV. Our subjects were voluntary consecutive patients or healthy controls scheduled to daily hospital routine, and we were not able to control the above-mentioned factors. In addition, we could not control the use of pain medications, which may have an effect on HRV. Even though we may be able to evaluate pain medications according to hospital databases, we do not know the quality and amount of over-the-counter pain medication. However, we believe that most of the patients used pain medication at least to some extent while control population did not. This should “dilute” the results as pain medication is supposed to alleviate pain symptoms. Unfortunately, we do not have knowledge about use of physical therapy but we do not regard it an important confounder as it (if it works) has similar effect as pain medication. However, we analysed the data when underlying co-morbidities were excluded and the results were the same. Obviously, subjects with co-morbidities use more likely medication than subjects without co-morbidities. Therefore, we feel that, at least to some extent, medication is taken into consideration.Reduced HRV has been shown to be associated with the occurrence of various clinical events. Our results indicate that sciatica patients referred to spine surgery had autonomic dysregulation with decreased vagal activity and an increased sympathovagal balance compared with age-matched healthy controls. Therefore, it seems important to consider monitoring of the autonomic nervous system in addition to pain management in sciatica patients. We did not observe a significant relationship between impaired functional capacity caused by pain or pain intensity and HRV. In this respect, it can be suggested that HRV may reflect an independent intrinsic regulatory system of the autonomic nervous system that may be affected by the severity of the sciatic disease.These data suggest that sciatica patients referred to spine surgery have decreased HRV when compared with healthy subjects, and this may reflect a predisposition to impaired autonomic cardiovascular regulation.BMI: Body mass index; CAD: Coronary artery disease; CRPS: Complex regional pain syndrome; CWP: Chronic widespread pain; HF: High frequency; HNP: Disc herniation induced nerve root impingement; HR: Heart rate; HRV: Heart rate variability; IL-6: Interleukin-6; LBP: Low back pain; LF: Low frequency; LF/HF: Low-to-high-frequency ratio; LTPA: Leisure-time physical activity; MRI: Magnetic resonance imaging; Oswestry: Low back pain disability index; SDNN: Standard deviation of all R-R intervals; SD1: Beat to beat R-R interval fluctuation; TNF-α: Tumor necrosis factor-α; VAS: Visual analog scale; α1=: Short-term fractal scaling exponent.The authors declare that they have no financial or non-financial competing interests.JK, AJH and JS conceived the study and participated in its design. JK, AJH and JS had also full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analyses and final version of the manuscript. JK, JP and EK coordinated and carried out the clinical data of the patients, participated the data analysis and drafted the manuscript. AMK and MPT participated in the analysis and interpretation of data and helped to draft the manuscript. AJH performed the statistical analysis together with AMK and MPT. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/14/149/prepub