Novel hydration and nutritional strategies for sickle cell disease

Abstract Introduction Sickle cell disease and sickle cell trait affect over 300 million people worldwide. Vaso‐occlusive crises (VOCs) are the most common reason that these patients seek medical care. Objectives Recently, a newly identified “trigger” (involving glucose and electrolytes) for a mechanism of abnormal actin polymerization may offer further understanding with regard to the sequence of events that cascade to complications such as VOCs in those with sickle cell disease (SCD) and as well as those with sickle cell trait. Methods A literature review to identify the current standard of care guidelines for hydration and nutritional strategies during VOCs in patients with SCD and sickle cell trait was conducted in PubMed, OVID, and Google Scholar. Results This review suggested that current rationales for hydration and nutritional strategies for these patients during periods of crisis are generally based on consensus and have remained largely undefined to date. Conclusion This new trigger, along with this literature review, suggests investigations related to serum glucose and cation (electrolyte) levels may help define novel strategies for the development of protocols/standard of care with regard to intravenous and oral hydration/nutritional guidelines in these patients during both clinical and perioperative management periods.

cerebrovascular accidents. 5 Fluid/hydration therapies used in the management of these SCD and sickle cell trait patients both in the clinical and perioperative arenas have been poorly defined possibly due to a lack of understanding of the cascade of events that lead to the "trigger" for VOCs. Presently, the initial management decisions for hydration and nutritional management of these patients are made on consensus. 6 Recently, a newly identified "trigger" of increased levels of glucose and cation (electrolyte) levels and the subsequent abnormal actin polymerization (in the spectrin-actin complex in cytoskeleton of the red blood cell membrane) may offer further understanding with regard to the sequence of events that can lead to crisis in those with SCD and sickle cell trait and may help define novel strategies for the development of treatment protocols/standard of care with regard to IV and oral hydration/nutritional guidelines in these patients during both clinical and perioperative management. 7 This review is directed toward the global audience of general physicians, anesthetists, advanced practice practitioners, nurses and intensivists involved in the collaborative clinical and perioperative management of SCD, and sickle cell trait patients.

NEW TRIGGER MECHANISM IN SICKLE CELL DISEASE
In 1949, there was a discovery of the abnormal sickle protein (HbS) mutation in SCD where the -globin chains were found to have a valine in the place of glutamic acid ( 6Glu→Val). 8 In SCD patients, valine replaces glutamic acid on both -globin chain subunits on the hemoglobin protein, while in sickle cell trait patients this substitution occurs on only one of the -globin chain subunits. This was an important discovery, but it has not led to an explanation for the cascade of events that occur in VOCs and other complications in SCD and sickle cell trait patients. The recently identified and published "triggers" of glucose and cations/electrolytes that may spark the cascade of events that lead to an abnormal polymerization of the actin protein in the cytoskeleton, sickling of the red blood cells and vasocclusive crises, may also offer some new insights into hydration/nutritional strategies as well as further research studies for both the clinical and perioperative management in these patients 7 : (1) This new finding suggests that the substitution of 6Glu→Val on the HbS molecule (each red blood cell contains ∼270 million hemoglobin molecules) along with the increased and irreversible glycation (associated with increased levels of serum glucose) of these extra mutant hydrophobic valines in SCD and in sickle cell trait may ultimately increase the subsequently generated ATP-ATPase availability and activity via Amadori-mediated pyruvate kinase activity. 7 When elevated levels of serum cations/electrolytes (Mg + , Ca + , Na + , K + ) are added to this increased ATP availability, this combination may increase the ATP G-actin concentration that leads to a critical concentration threshold that allows for polymerizations of the both the positive and negative ends of the F-actin filaments. 7 Surpassing this critical con-centration may lead to an abnormal elongation (polymerization) of stiff actin filaments (actin filaments must maintain a uniform length of ∼37 m to ensure cytoskeletal membrane integrity/function) that ultimately disrupts the spectrin-actin cytoskeletal network, band 3/AE1 anion channels, and aquaporin channels, thereby beginning a cascade of events that lead to dehydration/loss of neutrality/loss of function/catastrophic failure of the red blood cell = Sickled RBCs. 7 Sickle cell patients are known to develop VOCs under periods of stress (which often lead to hyperglycemic states) such as anxiety, emotional stress, dehydration, acidosis, hypoxia, vascular stasis, and increased blood viscosity, and during perioperative period. 9,10 These crises often lead to pain, ACS, infections, organ failure, and death.
In sickle cell trait, as stated earlier, the individual has one abnormal allele of the hemoglobin gene and therefore does not have the whole burden of the disease (which may be possibly due to fewer available valines and therefore a smaller increase in glycation and ATP-ATPase availability, etc.). Even without the whole burden of SCD, the evidence shows that sickle cell trait is associated with morbidities such as hematuria, renal papillary necrosis, hyposthenuria, splenic infarction, exertional rhabdomyolosis, and exercise-related sudden death. 3 It appears that there may also be an independent association of sickle cell trait with hyphemia, venous thromboembolic events, fetal loss, neonatal deaths, preeclampsia, and possibly ACS and anemia in pregnancy. 3 Since fluid therapy guidelines (ie, what type of fluid, rate, maintenance vs bolus, etc.) in SCD and possibly in those patients with sickle cell trait have been poorly defined to date, we may begin to look at how this newly defined polymerization "trigger" may help to advance the knowledge needed to begin to reveal possible novel treatment protocols/standards of care and possible improvement in clinical outcomes for these patients. 6,11

CURRENT HYDRATION AND NUTRITIONAL STRATEGIES IN SICKLE CELL DISEASE
Intravenous fluid (IVF) and oral hydration/nutrition are an important part of the current standard of care therapy during both clinical and perioperative periods in patients experiencing VOCs with SCD and sickle cell trait. 12,13 However, the specific type of IVF/hydration/diet to administer during VOCs continues to remain controversial and unclear.
Regarding IVF administration, some clinicians use normal saline (NS), an isotonic IVF, during treatment for VOCs, others disagree with the use of NS due to possible issues related to potential inability to secrete sodium with the hyperosmolar load that patients with SCD-related renal dysfunction may develop. 11,14 Therefore, other clinicians recommend administering hypotonic IVFs during VOCs. 15 Table 2). 20 They also reported a low rate of 10.2% use of hypotonic fluid (½ NS) for maintenance (Table 2). 20 Sickle cell patients are also thought to be continually hypovolemic due to hyposthenuria or a renal condition that decreases their ability to concentrate their urine. 21

NOVEL HYDRATION AND NUTRITIONAL CONSIDERATIONS IN SICKLE CELL DISEASE
As reported above, earlier studies have highlighted fluid replacement strategies to maintain red blood cell integrity by inhibition of the efflux of intracellular K + , Cl − , and free water. 17 Some have also focused on the blocking of Ca 2+ activated K + channel and the K + /Cl − channels in the RBC membrane with limited success. 23 Due to the recently identified potential polymerization trigger involving the influence of glucose and cation/electrolyte levels on the actin cytoskeletal protein in patients with SCD and sickle cell trait, it appears that attending to the foundational basics of fluid and electrolyte balance and serum glucose management may be critical components in the perioperative and clinical management of these patients. There are increased challenges with managing SCD and possibly sickle cell trait due to the high incidence of elevated sugar and salt intake that occurs in modern society today. 24 Stressful events/illness are also known to both elevate serum blood glucose as well as challenge fluid and electrolyte balance. While the aforementioned studies were limited due to small sample sizes, they suggest that low normal or hyponatremic states may reduce pain and/or VOCs in some SCD patients. 17,18 This evidence suggests that cautious maintenance with hypotonic IV solution (½ NS) while keeping a close eye on serum glucose and sodium (as well as other electrolytes) levels (instead mostly relying on isotonic, isotonic crystalloids, TA B L E 3 New considerations for clinical and perioperative management of SCD and sickle cell trait  Finally, but just as importantly, studies on controlling sugar and salt intake via oral hydration/nutritional intake may also be a critical component in the management of these patients. Fluid balance may need careful monitoring in both the clinical and perioperative management due to both the disease process and inability to eat/drink prior to operative/fasting procedures. Low glycemic index foods may be considered along with free water (limiting sugar, sugar substitutes, salt, and salt substitutes) in order to avoid increasing serum electrolytes and serum blood glucose (causing abnormal actin polymerization).

DISCUSSION
To date, the approach to treat VOCs has been more experience based rather than evidence based. Studies have suggested that hypotonic solutions (maintenance vs bolus) may offer improved outcomes for patients but there is concern for possible adverse effects with prolonged hyponatremic states. 17,18 Also, investigations have suggested that there may be poor outcomes with the use of isotonic and hypertonic NS and crystalloid boluses in VOCs (except in the cases of severe hypovolemic/shock/emergent states). 11,20 It appears that the newly identified molecular modeling trigger of actin polymerization (due to increased glycation in the presence of increased cations/electrolytes over the critical concentration for F-actin elongation) may warrant future clinical investigations to develop consistent and efficacious hydration and nutritional guidelines along with ERAS guidelines during clinical and perioperative management for this challenging disease (Table 3). 7,20 ORCID Marcy C. Purnell https://orcid.org/0000-0002-9599-4874