Received: 8 March 2020 Accepted: 16 April 2020

DOI: 10.1002/jha2.9

SHORT REPORT

Novel hydration and nutritional strategies for sickle cell disease

Marcy C. Purnell Michong Rayborn

School of Leadership and Advanced Nursing

Practice, The University of Southern Mississippi, Abstract
Hattiesburg, Mississippi Introduction: Sickle cell disease and sickle cell trait affect over 300 million people
Correspondence worldwide. Vaso-occlusive crises (VOCs) are the most common reason that these
Marcy C. Purnell, School of Leadership and patients seek medical care.
Advanced Nursing Practice, The University of
Southern Mississippi, 118 College Drive, Office Objectives: Recently, a newly identified “trigger” (involving glucose and electrolytes) for
317J, Asbury Hall, Hattiesburg, MS 39406-0001. a mechanism of abnormal actin polymerization may offer further understanding with
Email: [email protected]
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.

KEYWORDS

electrolytes, glucose, perioperative management, sickle cell disease, sickle cell trait, vaso-occlusive
crises

1 INTRODUCTION associated with significant morbidity and mortality.3 In 2016, inpa-

tient stays for SCD alone in the United States totaled $811.4 mil-
Sickle cell disease (SCD) is an autosomal recessive disorder and affects lion with a 5-day average length of stay.4 Sickle cell disease patients
approximately 30 million people worldwide with the highest occur- undergo both emergent and elective surgical procedures involving
rences being among individuals of African, Middle Eastern, and Central SCD complications as well as surgeries for indications that are com-
Indian ancestry.1 In many endemic areas where resources are insuf- mon to the general population. The data suggest that these patients
ficient, most individuals with SCD die before reaching adulthood.2 experience higher perioperative complication rates than other pop-
Also, sickle cell trait, which is even more common than SCD, occurs ulations related to vaso-occlusive crises (VOCs) such as acute chest
in approximately 300 million people worldwide and can also be syndrome (ACS), postoperative infection, congestive heart failure, and

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○c 2020 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.

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2 PURNELL AND RAYBORN

cerebrovascular accidents.5 Fluid/hydration therapies used in the man- centration may lead to an abnormal elongation (polymerization) of
agement of these SCD and sickle cell trait patients both in the clinical stiff actin filaments (actin filaments must maintain a uniform length of
and perioperative arenas have been poorly defined possibly due to a ∼37 𝜂m to ensure cytoskeletal membrane integrity/function) that ulti-
lack of understanding of the cascade of events that lead to the “trigger” mately disrupts the spectrin-actin cytoskeletal network, band 3/AE1
for VOCs. Presently, the initial management decisions for hydration anion channels, and aquaporin channels, thereby beginning a cas-
and nutritional management of these patients are made on consensus.6 cade of events that lead to dehydration/loss of neutrality/loss of func-
Recently, a newly identified “trigger” of increased levels of glucose and tion/catastrophic failure of the red blood cell = Sickled RBCs.7
cation (electrolyte) levels and the subsequent abnormal actin polymer- Sickle cell patients are known to develop VOCs under periods of
ization (in the spectrin-actin complex in cytoskeleton of the red blood stress (which often lead to hyperglycemic states) such as anxiety,
cell membrane) may offer further understanding with regard to the emotional stress, dehydration, acidosis, hypoxia, vascular stasis, and
sequence of events that can lead to crisis in those with SCD and sickle increased blood viscosity, and during perioperative period.9,10 These
cell trait and may help define novel strategies for the development of crises often lead to pain, ACS, infections, organ failure, and death.
treatment protocols/standard of care with regard to IV and oral hydra- In sickle cell trait, as stated earlier, the individual has one abnor-
tion/nutritional guidelines in these patients during both clinical and mal allele of the hemoglobin 𝛽 gene and therefore does not have the
perioperative management.7 This review is directed toward the global whole burden of the disease (which may be possibly due to fewer avail-
audience of general physicians, anesthetists, advanced practice practi- able valines and therefore a smaller increase in glycation and ATP-
tioners, nurses and intensivists involved in the collaborative clinical and ATPase availability, etc.). Even without the whole burden of SCD, the
perioperative management of SCD, and sickle cell trait patients. evidence shows that sickle cell trait is associated with morbidities such
as hematuria, renal papillary necrosis, hyposthenuria, splenic infarc-
tion, exertional rhabdomyolosis, and exercise-related sudden death.3
2 NEW TRIGGER MECHANISM IN SICKLE It appears that there may also be an independent association of
CELL DISEASE sickle cell trait with hyphemia, venous thromboembolic events, fetal
loss, neonatal deaths, preeclampsia, and possibly ACS and anemia in
In 1949, there was a discovery of the abnormal sickle protein (HbS) pregnancy.3
mutation in SCD where the 𝛽-globin chains were found to have a Since fluid therapy guidelines (ie, what type of fluid, rate, mainte-
valine in the place of glutamic acid (𝛽6Glu→Val).8 In SCD patients, nance vs bolus, etc.) in SCD and possibly in those patients with sickle
valine replaces glutamic acid on both 𝛽-globin chain subunits on the cell trait have been poorly defined to date, we may begin to look at how
hemoglobin protein, while in sickle cell trait patients this substitution this newly defined polymerization “trigger” may help to advance the
occurs on only one of the 𝛽-globin chain subunits. This was an important knowledge needed to begin to reveal possible novel treatment proto-
discovery, but it has not led to an explanation for the cascade of events cols/standards of care and possible improvement in clinical outcomes
that occur in VOCs and other complications in SCD and sickle cell trait for these patients.6,11
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, 3 CURRENT HYDRATION AND
sickling of the red blood cells and vasocclusive crises, may also offer NUTRITIONAL STRATEGIES IN SICKLE CELL
some new insights into hydration/nutritional strategies as well as fur- DISEASE
ther research studies for both the clinical and perioperative manage-
ment in these patients7 : Intravenous fluid (IVF) and oral hydration/nutrition are an important
part of the current standard of care therapy during both clinical and
(↑ Glucose →↑ HbS (Val) glycation) + (↑ Electrolytes) = VOCs (1) perioperative periods in patients experiencing VOCs with SCD and
sickle cell trait.12,13 However, the specific type of IVF/hydration/diet to
This new finding suggests that the substitution of 𝛽6Glu→Val on the administer during VOCs continues to remain controversial and unclear.
HbS molecule (each red blood cell contains ∼270 million hemoglobin Regarding IVF administration, some clinicians use normal saline (NS),
molecules) along with the increased and irreversible glycation (asso- an isotonic IVF, during treatment for VOCs, others disagree with the
ciated with increased levels of serum glucose) of these extra mutant use of NS due to possible issues related to potential inability to secrete
hydrophobic valines in SCD and in sickle cell trait may ultimately sodium with the hyperosmolar load that patients with SCD-related
increase the subsequently generated ATP-ATPase availability and renal dysfunction may develop.11,14 Therefore, other clinicians rec-
activity via Amadori-mediated pyruvate kinase activity.7 When ele- ommend administering hypotonic IVFs during VOCs.15,16 Rosa et al
vated levels of serum cations/electrolytes (Mg+ , Ca+ , Na+ , K+ ) are reported in a limited study with three SCD patients that maintain-
added to this increased ATP availability, this combination may increase ing hyponatremia (ie, Na = 120–125 mEq/L) reduced the frequency
the ATP G-actin concentration that leads to a critical concentration of VOCs compared with patients treated in the current standard of
threshold that allows for polymerizations of the both the positive and care model.17 Another study of seven patients reported improvement
negative ends of the F-actin filaments.7 Surpassing this critical con- in pain and number of circulating sickle cells after rapid administration
PURNELL AND RAYBORN 3

TA B L E 1 Common IV fluids

Normal osmolarity
Name pH Ingredients in1 L (240-340 mOsm/L) Type of solution
D5W 5.0 5 g dextrose 252 mOsm/L Isotonic
5% Dextrose (170 calories/L) (hypotonic in body)
In water
NS 5.7 154 mEq Sodium 308 mOsm/L Isotonic
0.9% Sodium chloride 154 mEq Chloride
LR 6.6 130 mEq Sodium 273 mOsm/L Isotonic
Lactated Ringer’s solution 4 mEq Potassium
3 mEq Calcium
109 mEq Chloride
28 mEq Sodium lactate
½ NS 5.6 77 mEq Sodium 154 mOsm/L Hypotonic
0.45% Sodium chloride 77 mEq Chloride
3% Sodium chloride 5.0 513 mEq Sodium 1026 mOsm/L Hypertonic
513 mEq Sodium
5% Sodium chloride 5.8 855 mEq Sodium 1710 mOsm/L Hypertonic
855 mEq Sodium
D10W 4.3 10 g Dextrose 505 mOsm/L Hypertonic
10% Dextrose in water (340 calories/L)
D5 ¼NS 4.4 5 g Dextrose 406 mOm/L Hypertonic
Dextrose ¼ 77 mEq Sodium
(0.25%) Saline 77mEq Chloride
D5 ½ NS 4.4 5 grams Dextrose 406 mOsm/L Hypertonic
5% Dextrose in 0.45 sodium chloride 77 mEq Sodium
77 mEq Chloride
D5NS 4.4 5 g Dextrose 560 mOsm/L Hypertonic
5% Dextrose in normal saline 154 mEq Sodium
154 mEq Chloride
D5LR 4.9 5 g Dextrose 525 mOsm/L Hypertonic
5% Dextrose in normal saline (170 calories/L)
130 mEq Sodium
4 mEq Potassium
3 mEq Calcium
109 mEq Chloride
28 mEq Sodium Lactate

of the hypotonic IVF ½ NS (ie, Na = 77 mEq/L, Table 1). Consequently, ods). Also, the AANA’s (2017) Enhanced Recovery after Surgery (ERAS)
the investigators also expressed concerns for this strategy due to the guidelines recommend a carbohydrate beverage (up to 2 h preop-
lack of ability to sustain these low sodium levels due to risk of seizures eratively) for all surgical patients in the preoperative phase (no dif-
and therefore has prohibited the widespread use of this protocol to ferentiation/customization for populations such as sickle cell etc.).19
date.18 Recently, Dr Marcus Carden and colleagues conducted a mul- Despite the lack of clear evidenced-based guidelines, clinicians con-
tiinstitution retrospective cohort study of the use of supplemental flu- tinue to use large IV volumes of NS and crystalloids and concen-
ids for acute VOCs in 20 pediatric emergency departments evaluating trated glucose solutions given over a short period of time.19,20 Car-
outcomes of 400 children (median age, 13.8 ± 4.9 years) with SCD. The den and colleagues reported that 83.2% of clinicians frequently/always
majority (66%) of patients were administered a hyperosmolar NS fluid use isotonic crystalloid bolus (NS or lactated Ringer’s solution), while
bolus (in those with no signs of dehydration) with an average volume of 36.9% frequently/always use isotonic/crystalloid at a maintenance rate
18.2 ± 9.5 mL/kg. These patients who received this hyperosmolar NS (Table 2).20 They also reported a low rate of 10.2% use of hypotonic
fluid bolus reported/experienced smaller improvements in pain scores, fluid (½ NS) for maintenance (Table 2).20
spent more time in the emergency department, and had higher rates of Sickle cell patients are also thought to be continually hypovolemic
readmissions.11 due to hyposthenuria or a renal condition that decreases their ability to
With regard to oral hydration, current NHLBI guidelines suggest concentrate their urine.21 But aggressive hydration of these patients to
encouraging oral hydration, along with analgesics, during VOCs and hypervolemic states (with bolus administrations) may be harmful due
to give IVF only when/if the patient is unable to drink or take liq- to the increased risk of the development of pulmonary edema, hypoxia,
uids by mouth (as in the perioperative period or critical care peri- dyspnea, and atelectasis. Atelectasis is thought to be a major risk factor
4 PURNELL AND RAYBORN

TA B L E 2 Use of IV fluids during adult VOE as administered by TA B L E 3 New considerations for clinical and perioperative
attending, advanced practice providers, residents, and medical management of SCD and sickle cell trait
students in ED20
Guidelines
Variable Result 1. Maintain euvolemia
Number of respondents N = 244 1. Monitor sodium (Na+), Calcium (Ca+), Potassium (K+), and
Type of provider Attending 74.1% Magnesium (Mg+) levels closely.

Advanced practice 3.3% 1. Avoid hypernatremia, hypercalcemia, hyperkalemia, and

practitioner hypermagnesemia.
Resident 19.7% 1. Monitor serum blood glucose closely.
Medical student 1.0%
1. Maintain strict blood glucose control.
Other number 1.6%
Type of fluids and rate of Isotonic crystalloid bolus
administration given
and hypertonic solutions) may offer additional options when a clinician
Frequently/always 83.2%
is ordering IVF hydration in both SCD and sickle cell trait.
Never/rarely 16.4%
These novel hydration and nutritional considerations appear to be
Isotonic crystalloid in contrast to the current hydration/nutritional approaches that were
maintenance
recently reported by majority of clinicians and consist of using a bolus
Frequently/always 36.9%
isotonic crystalloid solutions or hypertonic NS as a first-line choice for
Never/rarely 57.8%
VOCs (Table 2).11,20 It should be restated that careful monitoring of
Hypotonic maintenance sodium levels may be paramount in order to watch for severe hypona-
Frequently/always 10.2% tremia with this approach. Also, the rate of IV fluid hydration needs to
Never/rarely 88.9% be carefully considered with regard to organ function/failure status in
both the young and the aged as certain clinical presentations such as
hypovolemic shock may dictate bolus isotonic crystalloid fluid admin-
istration, etc., while other patients may need other customized care
in the development of ACS, which is responsible for ∼25% of sickle cell choices.
deaths during hospitalizations.22 Ultimately, careful studies need to be conducted to determine if and
at what rate the infusion of hypotonic ½ NS may be indicated in order to
reduce the polymerization trigger, hypervolemic states, and prolonged
4 NOVEL HYDRATION AND NUTRITIONAL hyponatremic states as well as the development of associated compli-
CONSIDERATIONS IN SICKLE CELL DISEASE cations of pulmonary edema and ACS. Also, studies on the tight control
of blood glucose during the clinical and perioperative periods are also
As reported above, earlier studies have highlighted fluid replacement warranted.
strategies to maintain red blood cell integrity by inhibition of the efflux Finally, but just as importantly, studies on controlling sugar and salt
of intracellular K+ , Cl− , and free water.17 Some have also focused on intake via oral hydration/nutritional intake may also be a critical com-
the blocking of Ca2+ activated K+ channel and the K+ /Cl− channels in ponent in the management of these patients. Fluid balance may need
the RBC membrane with limited success.23 Due to the recently iden- careful monitoring in both the clinical and perioperative management
tified potential polymerization trigger involving the influence of glu- due to both the disease process and inability to eat/drink prior to oper-
cose and cation/electrolyte levels on the actin cytoskeletal protein in ative/fasting procedures. Low glycemic index foods may be considered
patients with SCD and sickle cell trait, it appears that attending to along with free water (limiting sugar, sugar substitutes, salt, and salt
the foundational basics of fluid and electrolyte balance and serum glu- substitutes) in order to avoid increasing serum electrolytes and serum
cose management may be critical components in the perioperative and blood glucose (causing abnormal actin polymerization).
clinical management of these patients. There are increased challenges
with managing SCD and possibly sickle cell trait due to the high inci-
dence of elevated sugar and salt intake that occurs in modern society 5 DISCUSSION
today.24 Stressful events/illness are also known to both elevate serum
blood glucose as well as challenge fluid and electrolyte balance. While To date, the approach to treat VOCs has been more experience based
the aforementioned studies were limited due to small sample sizes, rather than evidence based. Studies have suggested that hypotonic
they suggest that low normal or hyponatremic states may reduce pain solutions (maintenance vs bolus) may offer improved outcomes for
and/or VOCs in some SCD patients.17,18 This evidence suggests that patients but there is concern for possible adverse effects with pro-
cautious maintenance with hypotonic IV solution (½ NS) while keep- longed hyponatremic states.17,18 Also, investigations have suggested
ing a close eye on serum glucose and sodium (as well as other elec- that there may be poor outcomes with the use of isotonic and hyper-
trolytes) levels (instead mostly relying on isotonic, isotonic crystalloids, tonic NS and crystalloid boluses in VOCs (except in the cases of severe
PURNELL AND RAYBORN 5

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