e7 Abstract Oxygen (O2) delivery, the maintenance of which is fundamental to supporting children with critical illness, is a func tion of blood O2 content and flow This chapter reviews red blood cell[.]
e7 Abstract: Oxygen (O2) delivery, the maintenance of which is fundamental to supporting children with critical illness, is a function of blood O2 content and flow This chapter reviews red blood cell (RBC) physiology and dysfunction relevant to this issue Flow (rather than content) is the focus of O2 delivery regulation: O2 content is relatively fixed, whereas flow fluctuates widely Thus, blood flow volume and distribution vary to maintain coupling between O2 delivery and demand Conventional RBC physiology influencing O2 delivery (O2 affinity and rheology) is reviewed, and a new paradigm for O2 delivery homeostasis is presented based on coordinated gas transport and vascular signaling by RBCs Malfunction of this signaling system is implicated in a wide array of pathophysiologies and may be explanatory for the dysoxia frequently encountered in the critical care setting Key words: red blood cell, erythrocyte, oxygen delivery, blood flow, vasoregulation, hemostasis, nitric oxide, antioxidant systems 88 Hemoglobinopathies M.A BENDER AND ANNE MARSH PEARLS • 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 a- and b-like globin polypeptide chains and iron-containing heme rings Each has a highly evolved structure essential for optimal pairing of a- and b-like chains, as unpaired peptides are unstable and initiate cellular damage The resultant a2b2 Hb plays a critical role in the transport and regulation of carbon dioxide, pH, and nitric oxide (NO) in addition to oxygen (O2) Thus, Hb synthesis is a highstakes 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) This ratio inverts during the first year of life, explaining why phenotypes limited to the b-globin gene, such as sickle cell and most b-thalassemias, usually not manifest until several months of age Expression of the chromosome 16–based a-like genes differs; the embryonic z-gene parallels the expression of e, but the twin a-genes are expressed from the fetal period onward Thus, a abnormalities manifest in utero, potentially with devastating consequences (e.g., hydrops fetalis) The resultant Hb a-chain2, b-chain2 heterotetramers are developmentally expressed (eFig 88.1) Globin Gene Loci The a- and b-like genes reside within multigene loci and are transcribed at unparalleled levels in both tightly tissue-specific and developmentally specific patterns.1–3 This and their involvement in human disease has made these loci paradigms for gene regulation and pathophysiology The five genes of the b-globin locus reside in a cluster on chromosome 11 The genes are expressed in an erythroid and developmentally stage-specific manor, the e, Ag and Gg, and d and b genes being expressed primarily during the embryonic, fetal, and postnatal periods, respectively At birth, the majority of b-like chains are g and the rest are b 1040 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.4 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 1040.e1 Embryonic Hemoglobins Hemoglobin (% at birth) Hemoglobin (% in adults) Gower ζ2ε2 Portland ζ2γ2 Gower α2ε2 Hb F α2γ2 (90) Hb A α2β2 (10) Hb A α2β2 (97) Hb A2 α2δ2 (2.5) Hb F α2γ2 (