A new multicenter study challenges dogma of normal saline boluses (NSBs) to treat acute vaso-occlusive pain in sickle cell disease (SCD).
“When I come home from the hospital my legs are very swollen…and they hurt… I gain 10+ pounds and it takes over two weeks for my legs to get back to their normal size…” This scenario has been retold to me repeatedly by my patients with sickle cell disease. So much so that I have adjusted my usual practice of liberal hydration during acute pain to one of limited hydration with hypotonic fluids for 24 to 48 hours at no more than maintenance fluids. In my review of the literature to support my practice, I noted that the use of intravenous hydration had become the community standard for supportive management of acute vaso-occlusive episodes (VOEs) in SCD in addition to parenteral analgesics, with little supportive evidence. Supplemental hydration is routinely used regardless of the hydration state of the individual patient, with little consistency in the amount, type, and rate of administration.1 The proposed rationale for supplemental hydration (typically with saline) during sickle VOEs is based somewhat on the known molecular mechanisms that trigger erythrocyte sickling and precipitate vaso-occlusion.2 This surmises that a logical approach to treating acute VOEs should include avoiding or inhibiting the predisposing conditions that result in the intermolecular interactions that favor sickling, specifically fever (infections), acidosis, and hypoxia. Individuals with SCD are believed to be predisposed to dehydration due to increased insensible water loss and reduced fluid intake during acute illness, and polyuria from hyposthenuria.1,3-5 It has thus been proposed that dehydration provokes sickling via circulatory stagnation that leads to increased blood viscosity, hypoxia, and eventually acidosis, and that this acidosis can be exacerbated during episodes of febrile illness and infections.
A much less well-touted mechanism responsible for initiating and perpetuating the sickling of erythrocytes is “intracellular” dehydration. Perhaps the clinical focus of VOE management should shift toward interventions that result in rehydrating the red cell rather than increasing intravascular plasma volume with NSB.6 Furthermore, rehydration using hypertonic fluids (normal saline) may be expected to only have an impact on increasing intravascular volume and vasodilation and do very little to rehydrate the sickle erythrocyte.7
The Saline Against Lactated Ringers or Plasma-Lyte in the Emergency Department (SALT-ED) trial and the Isotonic Solutions and Major Adverse Renal Events Trial (SMART) both suggest that giving balanced crystalloids during acute resuscitation resulted in a lower incidence of major adverse kidney events within 30 days compared to saline (4.7% vs. 5.6%; adjusted odds ratio, 0.82; 95% CI, 0.70-0.95; p=0.01).8,9
Recently, investigators challenged the dogma of giving NSBs as part of acute VOE management, which is a common practice in most emergency departments (ED). Using microfluidic in vitro models of the post capillary microcirculation, Dr. Marcus A. Carden and colleagues demonstrated that exposing sickle red blood cells (RBCs) to hypertonic fluids reduced erythrocyte deformability and attenuated vascular occlusion compared with normotonic fluids.10 This provided clinical rationale to investigate the clinical impact of NSB on pain outcomes in patients with SCD. They then conducted a rigorously designed multi-institution retrospective cohort study of the use of supplemental fluids for acute VOEs in 20 pediatric EDs, evaluating outcomes of 400 children (median age, 13.8 +/– 4.9 years) with SCD. Not surprisingly the majority (66%) of patients received a fluid bolus (despite no signs and symptoms of dehydration), with hyperosmolar normal saline almost exclusively (99.2%) representing the fluid of choice. The average volume of fluid infused during the ED stay was 18.2 +/-9.5 ml/kg. Patients who received an NSB had similar pre-triage pain scores and similar overall opioid consumption compared with those who did receive an NSB. However, they experienced smaller improvements in pain scores (p=0.03), spent more time in the ED (p=0.01), and had higher rates of admission (p=0.1). Due to the significant negative association of NSB with poorer pain outcomes in this study that supported a prior single-institution report11 and is supported by findings in non-SCD cohorts, investigators concluded that the routine use of NSBs in patients without clear indication of dehydration is not indicted.
So, why is it so easy to stick to the “tradition” of hydrating patients with SCD using NSB despite no evidence to support this practice, even in the absence of dehydration? There has hitherto been no evidence to support the use of NSBs in euvolemic patients with VOEs, and yet it remains common practice in most pediatric EDs.
In Brief
While the study by Dr. Carden and colleagues was limited by its retrospective cohort design, it does provide strong rationale for more research to determine the appropriate type of intravenous fluids and the amount, if any, that should be administered in the ED to manage VOEs. More physiologic, balanced salt solutions may be better for our patients with SCD given their unique red cell physiology as these are more likely to promote red cell rehydration by driving K, Cl, and water into the RBC. Perhaps my anecdotal practice of limited hyperosmolar fluids is indeed supported by the evidence after all.
References
Competing Interests
Dr. Osunkwo indicated no relevant conflicts of interest.
