Hemoglobinopathies









  • The pathophysiology of sickle cell disease is multifactorial, involving hemoglobin polymerization, oxidative damage to cell membrane proteins, white blood cell activation and inflammation, activation of the clotting cascade, and chronic hemolysis, resulting in disturbances in nitric oxide metabolism.



  • Acute chest syndrome is responsible for up to 25% of deaths in sickle cell disease. Its management should include antibiotic therapy with both a cephalosporin and a macrolide, oxygen to maintain saturations greater than 94%, prevention of atelectasis with incentive spirometry and potential biphasic positive airway pressure, diligent fluid management, adequate pain control, bronchodilators, and, in severe cases, transfusion.



  • The default should always be to trust a patient’s self-assessment of sickle cell pain.



  • Up to 30% of patients with sickle cell disease have pulmonary hypertension. The threshold to treat must be lower than for other etiologies, as even mild elevations in pulmonary arterial pressure (>25 mm Hg) correlate with a significantly increased risk of death.



  • A major cause of death in thalassemia major is cardiac failure secondary to iron overload; therefore, a thalassemic patient presenting with cardiac failure must be assessed for cardiac iron content and, if present, undergo continuous chelation therapy.



The evolution of animals is dependent on high concentrations of hemoglobin (Hb) in red cells, which relies on the extraordinarily robust and coordinated synthesis of the α- and β-like globin polypeptide chains and iron-containing heme rings. Each has a highly evolved structure essential for optimal pairing of α- and β-like chains, as unpaired peptides are unstable and initiate cellular damage. The resultant α 2 β 2 Hb plays a critical role in the transport and regulation of carbon dioxide, pH, and nitric oxide (NO) in addition to oxygen (O 2 ). Thus, Hb synthesis is a high-stakes process in which any mutation may affect Hb production, stability, or function, or result in unpaired globin chains, leading to devastating downstream effects. The approach to any Hb alterations must consider the qualitative effects (how the plethora of Hb’s functions are altered) and quantitative effects (the amount of Hb and unpaired globin chains).


Globin gene loci


The α- and β-like genes reside within multigene loci and are transcribed at unparalleled levels in both tightly tissue-specific and developmentally specific patterns. This and their involvement in human disease has made these loci paradigms for gene regulation and pathophysiology. The five genes of the β-globin locus reside in a cluster on chromosome 11. The genes are expressed in an erythroid and developmentally stage-specific manor, the ε, Aγ and Gγ, and δ and β genes being expressed primarily during the embryonic, fetal, and postnatal periods, respectively. At birth, the majority of β-like chains are γ and the rest are β. This ratio inverts during the first year of life, explaining why phenotypes limited to the β-globin gene, such as sickle cell and most β-thalassemias, usually do not manifest until several months of age. Expression of the chromosome 16–based α-like genes differs; the embryonic ζ-gene parallels the expression of ε, but the twin α-genes are expressed from the fetal period onward. Thus, α abnormalities manifest in utero, potentially with devastating consequences (e.g., hydrops fetalis). The resultant Hb α-chain 2 , β-chain 2 heterotetramers are developmentally expressed ( eFig. 88.1 ).




• eFig. 88.1


Hemoglobin (Hb) changes through development. Expression patterns of individual α-like (ζ and α) and β-like (ε, γ, δ, and β) chains are plotted through development. The resultant Hb present at various developmental stages; a rough estimate of their abundances are shown.

(From Hoffman R, et al. Pathobiology of the human erythrocyte and its hemoglobins. In: Silberstein LE, Anastasi J, Hoffman R, et al, eds. Hematology: Basic Principles and Practice . 5th ed. Philadelphia: Elsevier; 2008:90.)


Sickle cell disease


Molecular description and epidemiology


Sickle cell disease (SCD) refers to a group of single-gene, autosomal recessive disorders most commonly observed in people originating from specific regions of Africa or India and in those of Hispanic descent; however, it can be seen in any background. SCD encompasses a group of disorders characterized by the presence of the sickle mutation (substitution of an adenine [A] for a thymidine [T] in codon 6) and a second abnormal allele permissive for sickle Hb polymerization. The sickle mutation results in replacement of a hydrophilic glutamic acid residue with a hydrophobic valine residue. With deoxygenation, allosteric changes in Hb expose a destabilizing valine-containing pocket that aligns with others, leading to polymerization of Hb, the transition of the red cell into the classic sickle cell morphology ( Fig. 88.2 ), and the initiation of downstream events leading to pain and end-organ damage ( eFigs. 88.3 and 88.4 ). In the United States, approximately 1 in 12 and 1 in 360 African Americans have sickle trait and SCD, respectively, with approximately 100,000 cases and approximately 2000 new birth cases per year (in contrast to approximately 300,000 birth cases per year in Africa). With increased ethnic mixing, compound heterozygous forms of SCD are increasingly being observed (e.g., S/β-thalassemia or HbS/E).




• Fig. 88.2


Morphology of sickled cells. Note that although a subset of cells has a high degree of polymerized HbS and has taken on the classic sickle shape, the majority of cells maintain normal morphology.

(Courtesy Kresta Austin and Leslie Nakagawa, Seattle Children’s Hospital.)



• eFig. 88.3


HbS polymerization and erythrocyte deformation. Long polymers of sickle hemoglobin (HbS) align into fibers, which then align into parallel rods. The polymer has a helical structure, with 14 HbS molecules in each section. The polymerization of HbS depends on many factors, including the HbS concentration, partial pressure of oxygen (P o 2 ), temperature, pH, 2,3-diphosphoglycerate (2,3-DPG) concentration, and the presence of different Hb molecules. The basic concept of HbS polymerization kinetics is the double nucleation mechanism. Before any polymer is detected, there is a latency period (delay time) in which deoxygenated HbS molecules form a small nucleus, which is followed by rapid polymer growth and formation. Free cytoplasmic heme can increase the attraction of the HbS molecules and the speed of nucleation and polymer formation. Cation homeostasis is abnormal in sickle erythrocytes, leading to the dehydration of cells. Potassium loss occurs via the intermediate conductance calcium-activated potassium channel protein 4 (also known as the putative Gardos channel ) and K-Cl (potassium chloride) cotransporter 1 (KCC1), KCC3, and/or KCC4. Plasma adenosine can also reprogram the metabolism of the erythrocyte, altering sphingosine-1-phosphate (S1P). ADORA2B, Adenosine receptor A2b; AE1, band 3 anion transport protein; HbA, hemoglobin A; HbF, fetal hemoglobin; H 2 O, water; K + , potassium ion; O 2 , oxygen.

(From Kato GJ et al . Sickle cell disease. Nat Rev Dis Primers . 2018;4:18010.)



• eFig. 88.4


Mechanisms 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 1 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 4 (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 3 anion transport protein; BCAM, basal cell adhesion molecule; Fe 2+ , 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 1.

(From Kato GJ et al . Sickle cell disease. Nat Rev Dis Primers . 2018;4:18010.)


Sickle cell trait


Sickle cell trait (SCT) is a condition whereby an individual has one normal β-globin allele along with a β-globin allele that contains the sickle mutation. Hb electrophoresis demonstrates a HbA level of approximately 60% and a HbS level of approximately 40% ( eTable 88.1 ). SCT does not result in the classic spectrum of sickle-related complications or alter red cell indices. However, it can, albeit rarely, lead to clinical abnormalities reviewed elsewhere. , Perhaps most notable among the potential complications of SCT is the concern that extremes of aerobic physical exertion, when coupled with dehydration and humidity, may induce sudden death in athletes with SCT. Individuals with SCT are at an increased risk of exertional rhabdomyolysis. Athletes with SCT should be counseled about these potential risks prior to engaging in vigorous exercise and counseled that these risks can be significantly reduced by maintaining adequate hydration, avoiding exercise when febrile, and ensuring adequate periods of rest during exercise.



eTABLE 88.1

Hematologic Characteristics of Sickle Hemoglobinopathies

From Bender MA. Sickle cell disease GeneReviews at GeneTests: Medical Genetics Information Resource . Seattle: University of Washington; 2017.































































Diagnosis a Predominant Hemoglobins After Age 1 Year b Phenotype c HEMATOLOGIC STUDIES AFTER AGE 1 YEAR d
Hgb MCV e HbA 2 (%) f
Hb A A nl nl nl nl
Hb A/S (trait) A > S g nl h nl nl nl or ↑
Hb S/S S Hemolysis and anemia by age 6–12 mo ↓↓ nl nl
Hb S/β 0 -thalassemia S Hemolysis and anemia by age 6–12 mo ↓↓ ↓↓ nl or ↑
Hb S/β + -thalassemia S > A Milder hemolysis and anemia nl or ↑
Hb S/C S ≅ C Milder hemolysis and anemia nl or ↓ nl
Hb S/E S > E Milder hemolysis and anemia i nl j

Table shows typical results; exceptions occur.

Hb, hemoglobin type; Hgb, hemoglobin concentration; nl, normal; ↑ , increased; ↓ , decreased; ↓↓, significantly decreased.

a The β-thalassemias are divided into β + -thalassemia, in which reduced levels of normal β-globin chains are produced, and β 0 -thalassemia, in which there is no β-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 1 year.


e Must use age-specific values. MCV can be lowered by α-thalassemia trait and increased by hydroxyurea.


f HbA 2 results vary depending on laboratory method.


g In sickle trait, HbS is ∼40% of total hemoglobins.


h Although patients do 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 HbA 2 is typically normal, this is often difficult to discern, as HbE and HbA2 comigrate in some assays.



Spectrum of sickle cell disease genotypes and natural history


The clinical manifestations of SCD result from intermittent episodes of vascular occlusion leading to tissue ischemia/reperfusion injury and variable degrees of hemolysis, both of which contribute to multiorgan dysfunction. Although homozygous sickle cell (Hb S/S, often called sickle cell anemia ) is most common, it is essential to be aware of additional genotypes that result in a spectrum of disease severity (see eTable 88.1 ) and that the spectrum of manifestations change with age.


Laboratory and diagnostics


The prominence of HbS in conjunction with diminished or absent HbA defines SCD. With universal newborn screening in the United States, all pediatric cases of SCD should be identified at birth and diagnostics are rarely indicated. For immigrant families and international adoptions, several forms of electrophoresis or high-pressure liquid chromatography can be used diagnostically but are rarely available on an emergent basis, though new point-of-care tests are in development. , HbS screening tests (e.g., Sickledex, Sickleprep, Sicklequick) are available emergently; however, results must be interpreted with extreme caution as they lack sensitivity and specificity. Although imperfect, screening tests in conjunction with a complete blood count (CBC) and smear will help distinguish between clinically severe forms of SCD and SCT. Thus, when there is significant clinical suspicion of a new sickle cell hemoglobinopathy, consultation with laboratory medicine and hematology is recommended.


Pathophysiology


The polymerization of HbS and resultant red cell sickling are the central pathophysiologic steps that drive the pathobiology of SCD. A multitude of pathophysiologic pathways downstream from Hb polymerization, including hemolysis, inflammation, oxidative stress, coagulation, and altered endothelial adhesion, contribute to the complex pathobiology observed in SCD. These complex downstream pathways inform approaches to prevention and treatment of SCD-related complications. See the Key References and eFigs. 88.3 and 88.4 for more detail. ,


Hemoglobin polymerization


The polymerization of sickle Hb is triggered by hypoxemia. Polymerization is enhanced by a high Hb concentration (mean corpuscular Hb concentration [MCHC]) and thus by higher osmolarity as well as low pH and low temperature, and attenuated by high levels of HbA and/or HbF. A key determinant of sickling is the capillary transit time (CTT). The longer a red cell is exposed to the relatively deoxygenated, cold, and acidotic environment of the capillary and postcapillary venule, the more likely HbS polymerization is to occur. This drives the basic tenets of patient education, prevention, and medical management, which include the importance of hydration, warmth, avoiding acidosis and vasoconstriction (including judicious use of drugs that cause vasoconstriction), ambulation, and ensuring oxygenation. It also is the rationale for the preventive and interventional use of medications that induce HbF, agents that prevent cell dehydration, and agents that modify the adhesion of cells to the endothelium.


Red cells, inflammation, hemolysis, and the endothelium


The pathophysiology after polymerization is complex, with many parallel pathways convening on the same common end points of vasoocclusion, hemolysis, and inflammation. , Polymerization leads to deformation of erythrocytes, oxidative damage to 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 toll-like receptor 2 (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. , 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. 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. , 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.




• 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 2 to 3 days into an admission for a vasoocclusive event.


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. ,


Pain


See eFig. 88.6 for a detailed care plan and eFigs. 88.7 and 88.8 for overviews of pain management. , Pain management in SCD is particularly difficult, as there are numerous etiologies (e.g., vasoocclusive events [VOEs], dactylitis, avascular necrosis, ACS, priapism, splenic sequestration and infarctions, hepatic crisis, gallstones, and leg ulcers) and pathways involved (e.g., vasoocclusion, inflammation, and alterations in pain processing) leading to acute and chronic pain. VOEs, defined as the acute onset of severe pain due to ischemia and reperfusion injury, are a hallmark of SCD. The complexities of SCD pain are best summarized by Shapiro and Ballas: “Vasoocclusion is a physiologic process, but the resultant pain is a biopsychosocial phenomenon. Psychosocial issues such as coping skills, social context, personality, mood, and interactions with the health care system mingle with the biologic factors and contribute to the expression of the illness.” In the intensive care unit (ICU), there must be an awareness of potential alterations in pain processing as well as awareness of the acute, neuropathic, inflammatory, psychologic, and sociocultural components of pain. Pain can be acute, recurrent, or chronic, and it is complicated by coexisting chronic disease and racial overlays. , Too often, racial attitudes and concerns of drug seeking prevent sufficient medication delivery to patients in excruciating pain. , The need for aggressive and rapid treatment is critical and well documented in guidelines of the American Pain Society and British Society of Hematology and is essential for humane care and physiologic improvements (e.g., improving respiratory mechanics when having rib infarction pain). ,




• 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 5. Seattle: Seattle Children’s Hospital; 2012.)



• 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.)



• eFig. 88.8


Pain assessment approach to sickle cell pain. ED, Emergency department; SCD, sickle cell disease.

(From Center for Children with Special Needs. Sickle Cell Disease—Critical Elements of Care . 5th ed. Seattle: Seattle Children’s Hospital; 2012.)


Pathophysiology, diagnosis, and presentation


Individual risk factors for VOE pain include a higher WBC count, lower HbF, coexisting α-thalassemia, and older age. Physiologic factors that may lead to VOE include Hb polymerization, rheology of RBCs, cellular dehydration, RBC deformability and fragility, whole blood viscosity, WBC activation, endothelial factors, adhesion of RBCs to the endothelium, hemostatic factors, altered NO metabolism, and vascular factors. , , , Vessel occlusion results in ischemic/reperfusion injury and the release of multiple inflammatory mediators that activate nociceptors, evoking a pain response. Recurrent episodes lead to altered pain processing, making assessment and management more complex. Diagnosis is based on a detailed qualitative description (typically, two components: a deep fatiguing, unrelenting ache with a component of biting, gnawing, or throbbing) and location ( eFig. 88.9 ). The description is essential to help rule out other etiologies of pain, as there is no definitive test to differentiate sickle cell pain from other sources of pain. Physical findings can include swelling, warmth, erythema, and tenderness. However, most commonly, examination of the involved area may be entirely normal and, despite excruciating pain, patients can appear in no apparent distress. There is no laboratory or radiologic study that can validate the existence or absence of a VOE. Therefore, one must trust the patient’s report of pain. It is essential to perform pain assessments every several hours using a developmentally appropriate pain scale, adjusting the pain plan as necessary to provide adequate analgesia. As pain becomes more chronic, goals of treatment should shift toward maintaining function and maximizing quality of life.




• eFig. 88.9


Self-depiction of a 6-year-old’s sickle cell pain.

(From Center for Children with Special Needs. Sickle Cell Disease—Critical Elements of Care . 5th ed. Seattle: Seattle Children’s Hospital; 2012.)


Management


See eFig. 88.6 for a detailed care plan and eFigs. 88.7 and 88.8 for overviews of acute pain management. An effective management strategy considers whether the pain is acute or chronic. Factors include the underlying tissue damage and nociception and the history of pain episodes, doses of medications required to achieve acceptable analgesia, baseline pain medications, history of tolerance, mental state, how the patient processes pain, coexisting depression, and the presence of anxiety or fear. A multimodal approach is outlined in eFigs. 88.7 and 88.8 , but essential components include (1) environmental manipulation; (2) complementary methods; (3) addressing pathophysiology and triggers (fluids to maintain euvolemia, warmth, and NSAIDs to decrease CTT); and (4) adjunctive interventions, such as physical therapy, ambulation, and incentive spirometry to maintain blood flow and prevent atelectasis and ACS. After these issues have been addressed, providers may focus on opiates and additional medications.


Initial pharmacologic management of severe acute pain episodes includes the initiation of around-the-clock scheduled NSAIDs (many children will have resolution of pain with intravenous [IV] ketorolac ) followed by rapid and repeated doses of opiates (dosed every 20 minutes), transitioning to continuous infusion or patient-controlled analgesia (if developmentally appropriate). , , Although the absence of pain is not a goal, the aim is to relieve pain and suffering and allow rest and health-promoting activities (incentive spirometry and ambulation to reduce the risk of ACS) while avoiding oversedation, which can contribute to the development of pulmonary complications. As cannabinoids have multiple effects on inflammation and neuropathic components of pain and can attenuate hyperalgesia, there is strong rationale for its use in SCD, although this remains controversial socially. Use of l -arginine (a precursor of NO) has resulted in a 50% reduction in overall opiate use in SCD, , and there is increasing evidence for the use of glutamine.


Sepsis.


Detailed sepsis care plans are presented in eFigs. 88.10 and 88.11 . Sepsis has historically been a major cause of morbidity and mortality in SCD. In the 1970s, 20% of patients with SCD in the United States died before age 6 years, primarily from sepsis with encapsulated organisms, particularly Streptococcus pneumoniae . Since that time, the initiation of universal newborn screening in the United States has facilitated identification of affected infants, allowing for early initiation of prophylactic penicillin and the delivery of anticipatory guidance to families regarding fever management and immunizations. Because of these interventions, deaths from sepsis in children with SCD have plummeted. , Currently, the presence of a central line and a history of surgical splenectomy are two of the biggest risk factors for bacteremia. ,




• eFig. 88.10


Clinical guidelines for fever management in sickle cell disease. CBC, Complete blood cell count; Hb S/S, homozygous sickle cell (sickle cell anemia); IM, intramuscular; IV, intravenous; PCN, penicillin; PO, oral; T, temperature; WBC, white blood cell.

(From Center for Children with Special Needs. Sickle Cell Disease—Critical Elements of Care . 5th ed. Seattle: Seattle Children’s Hospital; 2012.)



• eFig. 88.11


Approach to sepsis prevention and treatment in sickle cell disease.


Pathophysiology and etiology


Localized and recurrent infarctions in the spleen lead to the development of functional splenia at an early age in children with SCD. Functional asplenia, a finding observed as early as 3 months of age, places the child at markedly increased risk of overwhelming sepsis, particularly from encapsulated organisms. Reduced clearance of encapsulated organisms results from defects in cellular immunity, the alternate complement pathway, a decrease in memory cells, and opsonizing antibodies. Children with SCD have a 100 to 400 times increased risk of bacteremia from encapsulated pathogens.


Management


The pathophysiology, diagnosis, and management of sepsis are presented in Chapter 110 . Several aspects of sepsis that are unique to SCD are noted in eFig. 88.11 .


Acute chest syndrome


Table 88.2 and eFig. 88.12 summarize detailed care plans. Although definitions of acute chest syndrome vary, the most general one is a new nonatelectatic infiltrate on chest radiograph in a patient with SCD, though more stringent definitions include the requirements of fever, full lung segment involvement, and respiratory symptoms. ACS can progress in hours, is the second leading cause of hospitalization in SCD, and is the most common reason that children 12 years and older are admitted to the ICU. Mortality attributable to ACS is high, accounting for 25% of all deaths in SCD. In children, the mortality rate from ACS is 1%, compared with 4% in adults, with most deaths in children occurring in those younger than 3 years (see Fig. 88.5 ).



TABLE 88.2

Management of Acute Chest Syndrome




































Antibiotics A cephalosporin to cover encapsulated organisms, particularly S. pneumoniae , and a macrolide, as Mycoplasma and Chlamydia are the most common infectious pathogens.
Oxygen Maintain saturations >94%.
Judicious fluid resuscitation Maintain euvolemia. Avoid aggressive fluid resuscitation, as fluid overload may worsen cardiac and respiratory status.
Prevention of atelectasis


  • IS has been shown to prevent development of ACS. Use IS or developmentally appropriate alternatives.



  • Chest physiotherapy and ambulation may be of benefit once atelectasis and consolidation is present.



  • BiPAP or CPAP as a preventive measure is untested but appropriate, as early intervention may prevent atelectasis and minute areas of collapse, preventing progression and the need for intubation.

Pain management Opiates should be carefully titrated to minimize splinting and allow IS while minimizing respiratory depression (small opiate boluses before IS may be helpful). Unfortunately, opiates are often withheld due to concerns of respiratory depression. In fact, pain relief can improve respiratory mechanics, significantly improving clinical status.
Bronchodilators Are indicated, as asthma is common in sickle cell disease, and its presence increases the risk of ACS, and a subset of patients respond independent of documented wheezing.
Corticosteroids Use remains controversial, as they tend to improve ACS but lead to rebound pain. Tapering of even pulsed steroids may reduce the rebound.
Transfusion For multilobar disease, worsening pulmonary status despite conservative methods of treatment, or those who are critically ill.
BiPAP or CPAP For worsening pulmonary status, clinical decline, or those who are critically ill.
Intubation and mechanical ventilation For those who fail noninvasive ventilation. Consider inhaled nitric oxide if hypoxia.
Extracorporeal membrane oxygenation To be considered in those in whom mechanical ventilation and pharmacologic support are not sufficient.

ACS, Acute chest syndrome; BiPAP, biphasic positive airway pressure; CPAP, continuous positive airway pressure; IS, incentive spirometry.



• eFig. 88.12


Clinical guidelines for acute chest syndrome in sickle cell disease. BiPAP, biphasic positive airway pressure; CBC, complete blood count; CPAP, continuous positive airway pressure; CXR, chest x-ray; diff, differential; Hb, hemoglobin; HCT, hematocrit; IV, intravenous; PCA, patient-controlled analgesia; PICU, pediatric intensive care unit; PO, oral; RBC, red blood cell; T, temperature;

(From Center for Children with Special Needs. Sickle Cell Disease—Critical Elements of Care . 5th ed. Seattle: Seattle Children’s Hospital; 2012.)


Risk factors include a history of asthma, high baseline hemoglobin concentration (Hgb), and low HbF. Factors associated with mortality include a prior episode of ACS, development of respiratory failure within 48 hours of presentation, sepsis, and simultaneous presentation with pain. Etiologies vary by age with multiple etiologic factors often present and include bacterial infections with typical and atypical organisms, viral infections, and fat emboli, as well as pulmonary infarction and hemorrhage. In addition, a functionally based etiology is suboptimally controlled chest pain resulting in poor lung expansion and increased atelectasis that then leads to vasoocclusion and inflammation. Plastic bronchitis is a frequent occurrence in ACS ( eFig. 88.13 ).




• eFig. 88.13


Bronchial cast obtained via rigid bronchoscopy from a patient with acute chest syndrome complicated by plastic bronchitis.

(Courtesy Dr. Wendy Su.)


Presentation


ACS frequently occurs 2 to 3 days into a VOE. ACS should be suspected when there is fever, chest pain, cough, or other pulmonary symptoms. However, notably, there is no single pattern of signs and symptoms that predicts ACS, and up to 35% of patients will have a normal pulmonary examination. , As a result, there should always be a low threshold to obtain a chest radiograph to rule out ACS. Leukocytosis and significant drops in Hb and platelets are common. Significant morbidity is associated with ACS, including pneumothorax and empyema, and 14% of patients developed respiratory failure in one study. Risk factors for respiratory failure include (1) extensive lobar involvement, (2) platelet count less than 199,000/µL, and (3) a history of cardiac disease.


Management


Detailed care plans are presented in Table 88.2 and eFig. 88.12 , and management guidelines published by Howard et al. provide a comprehensive approach to treatment. , Management of ACS can be addressed in stages. Although there are not many randomized controlled trials to guide care of ACS, , suggestions for an approach to care are presented in Table 88.2 . All patients should receive conservative care. The use of steroids deserves special attention. Although their use in ACS is controversial (see Table 88.2 ), due to the risk of rebound pain with steroid withdrawal a taper is indicated, even if only pulsed therapies are used (as in asthma or prior to extubation). Transfusion has been shown to significantly improve oxygenation and clinical status in ACS. , , Although transfusion is usually effective at reversing ACS, because of the risks, including alloimmunization, transfusion is not part of initial management unless the patient is severely ill. Although 20% to 70% of patients with ACS are transfused, views differ on performing a simple transfusion targeting a posttransfusion Hgb of 10 g/dL or an exchange transfusion targeting the same Hgb while lowering the HbS to under 30%. , , , Both approaches improve oxygenation and are safe and effective. However, exchange transfusion requires exposure to more donors, is more time-consuming, requires specialized equipment and trained staff, and may require central access in this population with increased thrombotic risk. Thus, a simple direct transfusion is recommended for most situations. , , , The benefit of direct transfusion in patients with a high Hgb (>9 g/dL) is less clear, as a minimal number of red cells can be transfused and exchange may be more advantageous in this circumstance.


Noninvasive ventilation (NIV) lacks robust data to support its routine use but can be helpful for some patients. , One small study determined that bilevel positive airway pressure (BiPAP) use was successful in staving off invasive mechanical ventilation, whereas another found improvement in gas exchange and respiratory rate but not in hypoxemia or patient comfort. Invasive ventilation will be necessary for a subset of patients who have worsening respiratory failure despite attempts at NIV and optimal medical management. There is no consensus as to when to intubate or regarding the optimal ventilation strategy in ACS. Thus, these patients are often treated as children with acute respiratory distress syndrome (see also Chapter 48 ). For patients with refractory hypoxemia, both high-frequency oscillatory ventilation and venovenous extracorporeal membrane oxygenation (ECMO) have been successful. A promising approach to ACS in hypoxic patients is to improve NO metabolism with inhaled NO or oral arginine, a precursor of NO. ,


Stroke.


Clinical guidelines for stroke ( eFig. 88.14 ) provide elements of a detailed care plan. This section focuses on acute, clinically apparent cerebrovascular accident (CVA) related to SCD; a detailed discussion of stroke can be found in Chapter 66 . Before screening and prevention programs, 11% of children with HbS/S or HbS/β-thalassemia developed overt strokes (peak, 2–9 years), with another 20% to 35% having silent cerebral infarctions. Risk factors include anemia, moyamoya disease, history of previous CVA, and abnormal transcranial Doppler (TCD; discussed later). , Patients with HbS/C disease and other compound heterozygotic states do not have this significantly increased risk, although it may be higher than that in the general population. Strokes may be due to ischemia, hemorrhage, or thromboembolic events involving large, medium, and small vessels.




• eFig. 88.14


Clinical guidelines for acute stroke in sickle cell. CBC, Complete blood count; CR, cardiorespiratory; CSF, cerebrospinal fluid; CT, computed tomography; diff, differential; ICU, intensive care unit; HCT, hematocrit; I + O, intake and output; IV, intravenous; RBC, red blood cell; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging.

(From Center for Children with Special Needs. Sickle Cell Disease—Critical Elements of Care . 5th ed. Seattle: Seattle Children’s Hospital; 2012.)


Natural history


Prior to screening and preventive transfusion therapy, approximately 11% of patients with SCD had an overt stroke. Untreated, 50% have a recurrent stroke in the first 2 years, and 66% have recurrence within 9 years. Maintaining the HbS under 30% reduces the recurrence rate to 10%, with many of these “resistant” patients having moyamoya. Screening TCDs using a standardized approach identify patients with high cerebral vessel flow, a finding associated with an excessively high stroke risk within 3 years. Screening TCDs coupled with chronic prophylactic transfusion therapy have decreased the prevalence of first stroke from 11% to 1%. ,


Diagnosis


Although diagnosis is suggested by a history of acute neurologic changes and abnormalities on neurologic physical exam, neuroimaging is needed to confirm the diagnosis. An emergent noncontrast head computed tomograph (CT) scan should be obtained immediately to rule out any surgically amenable hemorrhagic lesions. Magnetic resonance imaging (MRI) and magnetic resonance angiogram (MRA) are needed to confirm the presence of an ischemic stroke. Although MRI and MRA are needed to confirm the diagnosis of an ischemic stroke, if the clinical presentation is highly suggestive of stroke, definitive therapy (transfusion) should never be delayed while waiting for imaging to be obtained. Other etiologies of childhood stroke must be considered and ruled out, including infection, thrombosis, cardiac embolic disease, masses, and trauma with vascular damage.


Management


A detailed stroke management plan is provided in eFig. 88.14 . Acute care and monitoring are similar to that for other children with CVAs (see Chapter 66 ) except that emergent exchange transfusion is accepted as the standard of care in SCD. , The goal is an HbS under 30% (or an HbA >70%) and a final Hgb of 10 g/dL, which is most efficiently accomplished with exchange transfusion. Care must be taken to avoid hypotension with blood withdrawal during the exchange. Due to the importance of transfusing emergently, an initial direct transfusion followed by exchange transfusion to avoid delays in treatment may be appropriate, especially if the Hgb is under 8. Seizures should be treated, but there is no role for seizure prophylaxis. Although tissue plasminogen activator (t-PA) has a role in non-SCD stroke, t-PA or anticoagulant therapy is not recommended in children, in part due to the different pathophysiology. Addition of low-dose aspirin is controversial but is started for some with concerns of an active cerebral vasculopathy. Once stabilized, comprehensive evaluation by physical, occupational, and speech therapists as well as a neurocognitive evaluation are essential to define new postevent baselines and guide future needs. Any child with SCD who has had a stroke should be placed on chronic transfusion therapy to mitigate the risk of developing subsequent strokes; if not possible, hydroxyurea should be considered. , ,


Aplastic crisis


An approach to evaluation and care is provided in eFig. 88.15 . An acute worsening of baseline anemia (by 1–2 g/dL of Hgb) associated with reticulocytopenia (typically <1%) suggests aplastic crisis and is caused by acute infection, such as parvovirus B19. Sickle RBCs survive 10 to 14 days (vs. 60–100 days for normal cells); thus, patients are dependent on a significantly increased reticulocyte production and any decrease can lead to a transient red cell aplasia with rapid development of a profound anemia. Monitoring of Hgb (both absolute and compared with the individual’s baseline), reticulocyte count, and cardiovascular status is essential. Most parvovirus B19 infections will spontaneously resolve. However, IV gamma globulin should be considered to hasten viral clearance if reticulocytopenia persists. Transfusion may be required if the patient demonstrates hemodynamic instability and may be considered if the Hb acutely falls more than 2 g/dL. Profound anemia or cardiac compromise may require a slow transfusion (2 mL/kg per hour), possibly with diuretics, or even exchange transfusion to avoid congestive heart failure.




• eFig. 88.15


Clinical guidelines for acute anemia in sickle cell disease. Bili, bilirubin; CBC, complete blood count; CXR, chest x-ray; Fe, iron; Hb, hemoglobin; Hct, hematocrit; HU, hydroxyurea; LDH, lactate dehydrogenase; MCU, mean corpuscular volume; NL, normal; PE, physical exam; retic, reticulocytes; RUQ, right upper quadrant; TIBC, total iron-binding capacity; T&S, type and screen; UA, urinalysis;

(From Center for Children with Special Needs. Sickle Cell Disease—Critical Elements of Care . 5th ed. Seattle: Seattle Children’s Hospital; 2012.)


Splenic sequestration


An approach to evaluation and care is presented in eFig. 88.15 . Splenic sequestration is characterized by an acutely enlarging spleen with a drop in Hgb of more than 2 g/dL below an individual’s baseline. Mild to moderate thrombocytopenia may also be present. Splenic sequestration occurs in 10% to 30% of children with SCD, most commonly between the ages of 6 months and 3 years, and is often concurrent with a febrile illness. Abdominal pain, nausea, and vomiting are common, and severe episodes of sequestration may progress rapidly to cardiovascular collapse and death. Transfusion is indicated when signs of cardiovascular instability are present and, as with aplastic crises, caution should be taken to avoid contributing to congestive heart failure. If the patient is transfused, it is important to be aware that with transfusion some patients release RBCs from their spleen, resulting in an unexpectedly high Hgb. Care must be taken not to overshoot the desired target, avoiding an Hgb of over 11 g/dL. Though rare, emergent splenectomy may be required. Elective splenectomy is indicated for recurrent episodes of sequestration with cardiovascular compromise.


Pulmonary hypertension


Pulmonary artery hypertension (PAH) confirmed by right heart catheterization affects approximately 6% to 11% of adults and children with SCD. Elevated tricuspid regurgitation velocity indicating PAH occurs in approximately 30% of adults with SCD and is associated with increased mortality. , With approximately 100,000 people with SCD in the United States, this translates into about 30,000 cases of PAH, making SCD the leading cause of PAH nationally. Although there has been concern for overdiagnosing PAH in SCD by an elevated tricuspid regurgitant jet velocity (TRV) on transthoracic echocardiography (TTE), it is increasingly understood that adults with estimated PAPs greater than 25 mm Hg or a tricuspid regurgitation velocity jet velocity (TR jet) of greater than 2.5 m/s have a strikingly higher mortality rate. Thus, it is essential to have a significantly lower threshold for aggressive intervention for PAH in the hemoglobinopathy patient than in others.


Pathophysiology and etiology


Multiple pathways contribute to PAH in the sickle cell patient. Hemolysis leads to NO dysregulation, vascular dysfunction, injury, and inflammation, which can ultimately lead to PAH. Progressive increases in pulmonary vascular resistance related to decreases in NO availability and dysregulation ultimately lead to right ventricular failure and decreased cardiac output. The 2014 American Thoracic Society Guidelines for PAH in SCD define PAH as a resting mean pulmonary arterial pressure equal to or exceeding 25 mm Hg. Frequent confounding factors in the PAH of SCD include (1) hypoxic PAH due to the high incidence of enlarged tonsils, obstructive sleep apnea, asthma, and chronic lung disease; (2) arterial obstructive PAH secondary to increased coagulation and embolic disease; and (3) pulmonary venous hypertension due to cardiomyopathy. Contributing to the high morbidity in SCD are the protean manifestations of mild pulmonary hypertension (>25 mm Hg). The majority of patients with SCD and PAH will be asymptomatic or have mild decreases in exercise tolerance (e.g., 6-minute walk) yet have a 10-fold increased risk of death. Increased mortality for adults with SCD has been associated with a TRV of 2.5 m/second or higher (10 times greater mortality risk), N-terminal pro b-type natriuretic peptide levels of greater than 160 pg/mL (at least 5 times greater mortality risk), and pulmonary artery pressure higher than 25 mm Hg on right ventricular heart catheterization. Sufficient data in children are lacking; thus, some suggest using the American Thoracic Society adult criteria. However, the use of adult diagnostic criteria is controversial, as children do not appear to confer the same increased risk of death within 3 years of diagnosis as their adult counterparts.


Diagnosis


Current diagnostic recommendations have focused on adult patients, leaving guidelines for younger patients contentious. Many use a TRV over 2.5 m/s as measured by echocardiogram as a criterion for diagnosis. Though cardiac catheterization is the gold standard for determination of PAH, it is invasive and expensive. Catheterization is reserved for those with a TRV greater than 2.8 or greater than 2.5 in adults who have additional risks, such as symptoms and elevated brain natriuretic peptide or decreased 6-minute walk. ,


Management


Although there is minimal evidence for specific therapies in the treatment of PAH in SCD, a multitiered approach is accepted by many , : (1) identifying and reversing factors potentially contributing to PAH (e.g., tonsillectomy and adenoidectomy, BiPAP or continuous positive airway pressure [CPAP], and nighttime O 2 if contributing to obstructive sleep apnea [OSA]); (2) optimizing sickle cell–specific care (e.g., hydroxyurea or chronic transfusions); and (3) applying PAH-specific therapies. Hydroxyurea (HU) is the first-line treatment for SCD-specific care, as it decreases hemolysis and sickle cell formation and lowers the incidence of ACS and VOE (both of which are associated with acute increases in pulmonary pressures). Chronic transfusion therapy is the second-line therapy for PAH in SCD, reserved for those who do not respond to HU. Although controversial and lacking data, the mortality risk of PAH is felt to outweigh the potential side effects of transfusion therapy. For those with PAH defined by right heart catheterization, additional therapies are recommended. For those with venous thromboembolism and no additional risk factors for bleeding, indefinite anticoagulant therapy is recommended. Targeted PAH therapies—such as prostacyclin agonists (e.g., iloprost), endothelin receptor antagonists (e.g., bosentan), soluble guanylate cyclase stimulators (e.g., riociguat), or phosphodiesterase-5 inhibitors (e.g., tadalafil)—and other PAH therapies should be considered, but limited data exist for their use (see also Chapter 53 ). Despite considerable enthusiasm for the use of sildenafil, a randomized controlled trial was halted early due to an increase in VOE in the treatment group, emphasizing caution in applying accepted PAH therapies to SCD.


A mainstay of treatment of PAH in the ICU is inhaled NO (iNO), which provides both direct vasodilation of the pulmonary vasculature and simultaneous reversal of the underlying disruption in NO metabolism. The major challenge with iNO is the development of rebound PAH on discontinuation of therapy and difficulty in administration, thus driving a focus on alternative therapies. Blood arginine is diminished in SCD and correlates with TRJ. Oral arginine, a precursor of NO, has been investigated and shown to reduce PAP within 5 days of therapy initiation in a small number of patients with SCD. ,


Multiorgan failure


Multiorgan failure syndrome is defined as severe pain associated with failure of at least two of the following organs: liver, lung, and kidney. It is often associated with severe pain in patients with previously mild disease and a relatively high Hgb. Bone marrow necrosis with fat emboli and widespread vasoocclusion are thought to be responsible, though data are lacking. Patients present with an atypically severe VOE and a fever followed by a sudden and rapid deterioration, including a drop in Hgb and platelets, diffuse encephalopathy, and rhabdomyolysis. Death has been reported in up to 25% of patients. Exchange transfusion should be considered early and can result in rapid recovery of organ function as well as improved survival. Similarly, ECMO has been used successfully. , Antibiotics are often used, though many patients are culture negative. There are isolated reports of success with NO or plasma exchange in those with transfusion-resistant disease, consistent with the idea that this may represent a thrombotic thrombocytopenia–like state.


Renal conditions


The hypoxic, acidotic, hypertonic milieu of the renal medulla is an environment that promotes sickling of RBCs within the renal microvasculature, leading to renal injury. , In SCD, and sometimes even in SCT, sickling in the kidney leads to increased viscosity and ischemia, causing damage to the renal medulla, such as segmental scarring and interstitial fibrosis, which can progress to infarction and papillary necrosis. SCD kidney injury generally presents with hematuria, which can range from microscopic to gross. Conservative management with bed rest, IV fluids, and maintenance of high urine output to avoid the development of thrombosis usually suffices. Transfusions may be needed if blood loss is significant. Vasopressin has been used with some success, as has ε-amino caproic acid, though the latter should be used with caution, as it can lead to thrombosis. If recurrent transfusions are required or bleeding becomes life-threatening, resection of the involved region may be indicated.


Hyposthenuria, or the inability to concentrate urine, occurs almost universally in people with SCD and has an onset in early childhood. It is critical to remain aware of this condition in the ICU, as the production of dilute urine cannot be used as a marker for being euvolemic, and patients are prone to dehydration, leading to vasoocclusive complications. Tubule dysfunction can also occur in SCD, including an incomplete renal tubular acidosis that is worsened by the hyposthenuria. Hyperkalemia may develop secondary to impaired urinary potassium excretion, the use of potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, or β-blockers.


Patients with SCD experience recurrent, often insidious renal insults throughout their lives, leading to the development of chronic kidney disease (CKD) in at least 25% of older adults. Risk factors include hypertension, hematuria, proteinuria, and worsening anemia. Angiotensin-II-receptor-1 blockers and angiotensin-converting enzyme inhibitors can reduce the proteinuria. NSAIDs should be used with caution or avoided in those with CKD. Worsening anemia can be treated with erythropoietin, though patients may have erythropoietin resistance and often need higher doses than others to achieve the desired effect.


Iron overload


Unlike in thalassemia, the iron overload of SCD is primarily related to transfusion. SCD and thalassemic patients show different temporal patterns of iron deposition, with the heart accumulating iron far less readily in SCD than in thalassemia. The acute management in the ICU is similar and is discussed in the Thalassemia section that follows.


Sleep conditions and depression and suicide in sickle cell disease


For a detailed discussion of these topics, see eBox 88.1 .


Jun 26, 2021 | Posted by in CRITICAL CARE | Comments Off on Hemoglobinopathies
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