Extracellular fluid tonicity impacts sickle red blood cell deformability and adhesion

Abstract

Abnormal sickle red blood cell (sRBC) biomechanics, including pathological deformability and adhesion, correlate with clinical severity in sickle cell disease (SCD). Clinical intravenous fluids (IVFs) of various tonicities are often used during treatment of vaso-occlusive pain episodes (VOE), the major cause of morbidity in SCD. However, evidence-based guidelines are lacking, and there is no consensus regarding which IVFs to use during VOE. Further, it is unknown how altering extracellular fluid tonicity with IVFs affects sRBC biomechanics in the microcirculation, where vaso-occlusion takes place. Here, we report how altering extracellular fluid tonicity with admixtures of clinical IVFs affects sRBC biomechanical properties by leveraging novel in vitro microfluidic models of the microcirculation, including 1 capable of deoxygenating the sRBC environment to monitor changes in microchannel occlusion risk and an "endothelialized" microvascular model that measures alterations in sRBC/endothelium adhesion under postcapillary venular conditions. Admixtures with higher tonicities (sodium = 141 mEq/L) affected sRBC biomechanics by decreasing sRBC deformability, increasing sRBC occlusion under normoxic and hypoxic conditions, and increasing sRBC adhesion in our microfluidic human microvasculature models. Admixtures with excessive hypotonicity (sodium = 103 mEq/L), in contrast, decreased sRBC adhesion, but overswelling prolonged sRBC transit times in capillary-sized microchannels. Admixtures with intermediate tonicities (sodium = 111-122 mEq/L) resulted in optimal changes in sRBC biomechanics, thereby reducing the risk for vaso-occlusion in our models. These results have significant translational implications for patients with SCD and warrant a large-scale prospective clinical study addressing optimal IVF management during VOE in SCD.

Normal saline bolus use in pediatric emergency departments is associated with poorer pain control in children with sickle cell anemia and vaso‐occlusive pain

“…25 Further, we have shown that increased extracellular fluid tonicity found in higher sodium IVF such as that found in normal saline can negatively impact the flow of sickle red cells under hypoxic conditions in capillary-sized microchannels and also increases adhesion to human endothelium and laminin under postcapillary venular flow conditions, where vaso-occlusion is thought to take place. 21 Fluid overload in sickle cell disease, which can result from NSB, also puts patients at risk for developing acute chest syndrome. 26 This information, along with evidence that large volumes of saline are associated with hyperchloremic metabolic acidosis, 27,28 suggests that more physiologic, balanced salt solutions may be better resuscitation fluids for patients with SCA and VOE in the ED.…”

“…NSB is given to >50% of children with SCA/VOE, but is associated with poorer pain control; a controlled prospective trial is needed to determine causality. 21 Given the growing controversy surrounding ED use of IVF boluses, we recently investigated the use of IVF to treat VOE in pediatric patients with sickle cell anemia (SCA) presenting to the three EDs at Children's Healthcare of Atlanta, where guidelines discourage the use of NSB in euvolemic patients with uncomplicated, moderate-severe VOE. 2 Treatment of VOE commonly includes analgesics and intravenous fluids (IVFs).…”

“…[18][19][20] We recently showed that increased extracellular fluid tonicity and sodium levels can negatively impact sRBC deformability and adhesion in in vitro models. 21 Given the growing controversy surrounding ED use of IVF boluses, we recently investigated the use of IVF to treat VOE in pediatric patients with sickle cell anemia (SCA) presenting to the three EDs at Children's Healthcare of Atlanta, where guidelines discourage the use of NSB in euvolemic patients with uncomplicated, moderate-severe VOE. In that single-site study, we found significant variation in physician use of IVFs for SCA-related VOE.…”

Vascularized Microfluidics and the Blood–Endothelium Interface

“…In an effort to investigate the role of altered vascular geometries in adhesion and vaso-occlusion in SCD, Mannino et al [44] demonstrated that spatial variation in vascular cell adhesion molecule (VCAM-1) expression correlated directly with disturbed wall shear stress, and in addition that RBC in SCD patients exhibited increased adhesion behavior at the high wall shear stress of bifurcations. In a separate experiment, tonicity of perfused intravascular fluid was altered to mimic the intravenous fluids given to SCD patients in crisis and was found to alter not only adhesivity, but also deformability and their propensity to sickle [118]. Specifically, fluids with higher tonicity (sodium = 141 mEq/L) decreased sickle red blood cell deformability, increasing occlusion and adhesion.…”

Perioperative Management of Sickle Cell Disease: A Narrative Review

“…36 Hypotonic fluids, in theory, decrease RBC sickling and are preferred. 37 – 39 Excessive fluid loading is associated with pulmonary edema and can precipitate acute chest syndrome and thus needs to be avoided. 40 , 41 Exactly how much fluid should be given is unknown.…”