1041 e2 Vascular smooth muscle Erythrocyte Sickle erythrocyte Endothelial cells Monocyte CapillaryArteriole Hemoglobin Neutrophil NETs Venule Vasoocclusion αVβ3 integrin ADMA Activated platelet Adenin[.]
1041.e2 Vascular smooth muscle Erythrocyte Endothelial cells Hemoglobin Neutrophil Sickle erythrocyte NETs Vasoocclusion Monocyte Capillary Arteriole Hemolysis Fe2+ Venule PGF VEGFR1 Cell adhesion ROS Hb TLR2 AE1 ↓ Catalytic antioxidants ↓ GSH HMGB1 LPS Phagocytosis and extravascular hemolysis L-Arg TLR4 Ornithine Inflammatory cytokines • IL-1β • IL-6 • IL-8 • PGE2 • TNF Activated endothelial cell Hb Subendothelial basement membrane Innate immune system Polyamine Vascular remodeling Activation of platelets and coagulation factors NOS NO IL-1β IL-6 TNF NO depletion NO–3 • eFig 88.4 Mechanisms Vasoconstriction LDH Microparticle Oxidized membrane lipids Oxidized membrane protein Phosphatidylserine P-selectin Resting platelet Thrombospondin VCAM1 in sickle cell disease Damage and dysfunction of the erythrocyte membrane caused by sickle hemoglobin (HbS) polymerization lead to hemolysis Oxidized membrane proteins reveal antigens that bind to existing antibodies, and membranes expose phosphatidylserine Both mechanisms promote phagocytosis of erythrocytes by macrophages, a pathway of extravascular hemolysis Intravascular hemolysis releases the contents of erythrocytes into the plasma Hb scavenges nitric oxide (NO), arginase depletes the l-arginine (L-Arg) substrate of NO synthase (NOS), and asymmetric dimethylarginine (ADMA) inhibits NOS Reactive oxygen species (ROS) further deplete NO, leading to vasoconstriction and vascular remodeling, especially in the lung Adenine nucleotides and NO deficiency promote platelet activation and activation of blood-clotting proteins Heme and other danger-associated molecular pattern (DAMP) molecules activate the innate immune system Ligand-bound toll-like receptor (TLR4) and TLR2 activate monocytes and macrophages to release inflammatory cytokines, which promote an inflammatory state and activation of endothelial cells TLR4 activation on platelets promotes their adhesion to neutrophils, which, in turn, form neutrophil extracellular traps (NETs) Circulating blood cells adhere to each other and to the activated endothelium, contributing and potentially even initiating vasoocclusion In postcapillary venules, activated endothelial cells that express P-selectin and E-selectin can bind rolling neutrophils Activated platelets and adhesive sickle erythrocytes can adhere to circulating or endothelium-bound neutrophils and form aggregates Sickle erythrocytes might also bind directly to the activated endothelium The figure shows only some examples of the complex and redundant receptor–ligand interactions involved in the adhesion of circulating cells to the damaged endothelium and exposed subendothelium AE1, Band anion transport protein; BCAM, basal cell adhesion molecule; Fe21, ferrous ion; GSH, glutathione; HMGB1, high-mobility group protein B1; ICAM1, intercellular adhesion molecule 1; IL, interleukin; LDH, lactate dehydrogenase; LPS, lipopolysaccharide; PGE2, prostaglandin E2; PGF, placenta growth factor; TNF, tumor necrosis factor; VCAM1, vascular cell adhesion protein 1; VEGFR1, vascular endothelial growth factor receptor (From Kato GJ et al Sickle cell disease Nat Rev Dis Primers 2018;4:18010.) αVβ3 integrin ADMA Activated platelet Adenine nucleotide Arginase BCAM CD36 CD47 E-selectin Heem ICAM1 1041.e3 eTABLE Hematologic Characteristics of Sickle Hemoglobinopathies 88.1 HEMATOLOGIC STUDIES AFTER AGE YEARD Diagnosisa Predominant Hemoglobins After Age Yearb Phenotypec Hb A A nl Hgb MCVe HbA2 (%)f nl nl nl Hb A/S (trait) A Sg nl nl nl nl or h Hb S/S S Hemolysis and anemia by age 6–12 mo gg nl nl Hb S/b0-thalassemia S Hemolysis and anemia by age 6–12 mo gg gg nl or h Hb S/b1-thalassemia S.A Milder hemolysis and anemia g g nl or h Hb S/C SC Milder hemolysis and anemia g nl or g nl Hb S/E S.E Milder hemolysis and anemiai g g nlj h Table shows typical results; exceptions occur a The b-thalassemias are divided into b1-thalassemia, in which reduced levels of normal b-globin chains are produced, and b0-thalassemia, in which there is no b-globin chain synthesis b Hemoglobins are reported in order of quantity Only the most prominent hemoglobins are listed c Overview of phenotype d Values vary during the first year of life Some patients’ values continue to change after age year e Must use age-specific values MCV can be lowered by a-thalassemia trait and increased by hydroxyurea f HbA2 results vary depending on laboratory method g In sickle trait, HbS is ,40% of total hemoglobins h Although patients not have severe sequelae, patients may have subtle abnormalities i Although patients have hemolysis and anemia, the severity of sickle cell–related complications tends to be less than Hb S/C j Although HbA2 is typically normal, this is often difficult to discern, as HbE and HbA2 comigrate in some assays Hb, hemoglobin type; Hgb, hemoglobin concentration; nl, normal; h, increased; g, decreased; gg, significantly decreased From Bender MA Sickle cell disease GeneReviews at GeneTests: Medical Genetics Information Resource Seattle: University of Washington; 2017 1042 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology 24 h 48 h 55 h 70 h • Fig 88.5 Rapid progression of acute chest syndrome Serial chest radiographs of a 13-year-old male with homozygous sickle cell disease admitted for pain Hours from admission are noted Notably, acute chest syndrome typically presents to days into an admission for a vasoocclusive event membrane proteins, generation of reactive oxygen species, increased cellular rigidity, and alteration of the red cell membrane lipid bilayer These derangements, in turn, promote coagulation, platelet activation, and activation of neutrophils, increasing adherence and triggering the oxidative burst Damage to the endothelium exposes tissue factor and von Willebrand factor (vWF), leading to further coagulation and platelet aggregation, respectively Selectins and integrins on activated endothelium interact with tolllike receptor (TLR2) and TLR4 on activated neutrophils, leading to adhesion and capture of sickled cells, increasing CTT and promoting occlusion Bound white cells release cytokines, increasing inflammatory cell recruitment and adhesion, perpetuating the process Simultaneously, these changes within red cells lead to hemolysis and the release of arginase and heme that result in the decreased production and increased destruction of NO, respectively This, in turn, leads to decreased ability to vasodilate and increased vascular remodeling Free heme and adenine nucleotides also activate platelets, further increasing CTT Heme induces expression of a multitude of inflammatory cytokines and adhesion molecules capturing red blood cells (RBCs), platelets, invariant natural killer T (iNKT) cells and monocytes, and induces neutrophil extracellular traps, further attenuating blood flow This inflammatory component of SCD is often underappreciated Thus, SCD represents an activated inflammatory state in which the CTT is prolonged, propagating the cycle of HbS polymerization The activation and integration of multiple pathways explains the tremendous clinical heterogeneity observed in people with the same Hb genotype as well as why patients can show rapid clinical decline (Fig 88.5) Further, it explains why an elevated white blood cell (WBC) count is a risk factor for vasoocclusive complications such as pain, acute chest syndrome (ACS), and early death.15,16 Therapeutically, this points to the benefits of nonsteroidal antiinflammatory drugs (NSAIDs) in affecting the underlying pathophysiology and providing analgesia and why clinical response to hydroxyurea is correlated with a decrease in WBC count.17–19 In contrast to vasoocclusive complications, a subset of complications—including pulmonary hypertension, skin ulcers, and priapism—were found to correlate with increased lactate dehydrogenase, bilirubin, and reticulocyte counts, which can be thought of as hemolytic complications resulting from disturbances in NO hemostasis.12,14 Despite sharing a common genotype, there is a high degree of phenotypic variability observed in people with SCD, the attribution of which is dependent on the extent to which they experience vasoocclusive versus hemolytic pathophysiology Clinical Manifestations Although a summary of clinical problems and management is provided in the following section, the reader is referred to the National Heart Lung and Blood Institute Evidence-Based Management of Sickle Cell Disease standard of care guidelines for more details.20,21 Pain See eFig 88.6 for a detailed care plan and eFigs 88.7 and 88.8 for overviews of pain management.22,23 Pain management in SCD is 1042.e1 Diagnosis Vasoocclusive pain in a child with sickle cell disease Monitoring Vital signs q hr Record I&O, daily weight Continuous pulse ox if any respiratory symptoms present, or if on parenteral opiates Consider CR monitor Diagnostic (if not previously obtained) CBC, diff., plt count and retic count initially (compare with patient’s baseline data); consider a hold tube for the blood center (for later type and cross) if severe anemia suspected or transfusion anticipated CXR: low threshold if cough or any respiratory signs or symptoms are present, or develop after admission; encourage incentive spirometry prior to CXR Blood culture if ≥38.3°C; urinalysis, urine culture and other cultures (e.g., CSF) as indicated Consider diagnostic tests to evaluate possible nonsickle causes of pain (e.g., abdominal ultrasound, liver function tests for RUQ to R/O cholelithiasis and cholecystitis) Fluids, nutrition, general care IV + PO 1.25 × maintenance Increased fluids only if patient is dehydrated and/or insensible losses are increased (e.g., persistent fever); avoid excessive fluids, which may worsen respiratory status Avoid IV fluid bolus unless clinically dehydrated or clinically indicated (not for pain alone) Incentive spirometry−10 breaths q hr from 0800-2200 and while awake Encourage ambulation and activity Medications/treatments Discharge criteria Follow patient-specific care plan if available; if not, follow generic steps below Offer heat pads, imagery, relaxation methods or other comfort measures as adjunct to pharmaceuticals A parenteral or oral nonsteroidal antiinflammatory agent if no contraindication (i.e., gastritis, ulcer, or renal impairment) If no established pain plan: Morphine sulfate 0.1 mg/kg/ dose IV q hr or 0.01-0.1 mg/ kg/hr Continuous infusion or via PCA (doses above 0.1 mg/kg/hr may be required but should be used with caution); alternative analgesics may be used in individual cases* Reassess pain control at least twice daily and after every intervention; analgesics may be weaned as tolerated by decreasing dose, not by prolonging interval between doses; discuss analgesic changes with patient/family Start oral opiates as soon as tolerated from a gastrointestinal standpoint, even if requiring IV opiates Consider pain team consultation Ceftriaxone 75 mg/kg q 24 hr (maximum dose g/d) if febrile (prophylactic penicillin may be discontinued while on broad-spectrum antibiotics) Continue prophylactic folic acid, if applicable 10 O2 by nasal cannula as needed to keep O2 saturation > 93% 11 Colace or laxative to prevent narcotic-induced constipation 12 See other Clinical Care Paths for acute chest syndrome, acute anemia crisis, stroke, priapism, if present 13 Avoid use of ice or cold packs Taking oral fluids well and able to take all PO meds (e.g., prophylactic penicillin) if applicable Adequate pain relief on oral analgesics Afebrile >24 hr and negative cultures >24 hours if applicable Resolution of any pulmonary symptoms or documentation of adequate oxygenation on room air • eFig 88.6 Clinical guidelines for sickle cell pain management CBC, Complete blood count; diff, differential; CR, cardiorespiratory; CSF, cerebrospinal fluid; CXR, chest x-ray; I&O, intake and output; IV, intravenous; PCA, patient-controlled analgesia; plt, platelet; retic, reticulocyte; R/O, rule out; RUQ, right upper quadrant (From Center for Children with Special Needs Sickle Cell Disease—Critical Elements of Care, ed Seattle: Seattle Children’s Hospital; 2012.) 1042.e2 Identify appropriate intervention based on comprehensive assessment Pharmacological Behavioral Psychological Physical Acetaminophen or NSAIDs Relaxation Cognitive therapies Hydration Deep breathing Hypnotherapy Heat Behavior modification Imagery Massage Distraction Hydrotherapy Biofeedback Social support Opioids Adjuvants Exercise Ultrasound Acupuncture/acupressure Physical therapy Identify patient/family educational needs Formulate treatment plan • eFig 88.7 Multimodal approach to sickle cell pain management NSAIDs, Nonsteroidal antiinflammatory drugs (From Center for Children with Special Needs Sickle Cell Disease—Critical Elements of Care 5th ed Seattle: Seattle Children’s Hospital; 2012.) ... Simultaneously, these changes within red cells lead to hemolysis and the release of arginase and heme that result in the decreased production and increased destruction of NO, respectively This, in turn, leads... sickle cell–related complications tends to be less than Hb S/C j Although HbA2 is typically normal, this is often difficult to discern, as HbE and HbA2 comigrate in some assays Hb, hemoglobin type;...1041.e3 eTABLE Hematologic Characteristics of Sickle Hemoglobinopathies 88.1 HEMATOLOGIC STUDIES AFTER AGE YEARD Diagnosisa Predominant Hemoglobins After Age Yearb