Review Article Sodium-Based Osmotherapy in Continuous Renal Replacement Therapy: a Mathematical Approach Jerry Yee ,1 Naushaba Mohiuddin,2 Tudor Gradinariu,1 Junior Uduman,1 and Stanley Frinak1 Abstract Cerebral edema, in a variety of circumstances, may be accompanied by states of hyponatremia. The threat of brain injury from hypotonic stress-induced astrocyte demyelination is more common when vulnerable patients with hyponatremia who have end stage liver disease, traumatic brain injury, heart failure, or other conditions undergo overly rapid correction of hyponatremia. These scenarios, in the context of declining urinary output from CKD and/or AKI, may require controlled elevations of plasma tonicity vis-a`-vis increases of the plasma sodium concentration. We offer a strategic solution to this problem via sodium-based osmotherapy applied through a conventional continuous RRT modality: predilution continuous venovenous hemofiltration. KIDNEY360 1: 281–291, 2020. doi: https://doi.org/10.34067/KID.0000382019 Introduction continuous venovenous hemofiltration (CVVH) (11,12), Generally, sodium-based osmotherapy (SBO) is tonicity continuous venovenous hemodialysis (13), or con- therapy with the aim of reducing cerebral edema during tinuous venovenous hemodiafiltration (14). states of hypotonic hyponatremia. Depending on the circumstance, plasma tonicity may be increased or decreased. Because the sodium concentration ([Na]) General Principles of SBO in the plasma at any time (t), PNa(t), and accompa- SBO can be implemented as a stepwise approach nying anions constitute the bulk of plasma tonicity, based on established biophysical principles govern- SBOispredicatedongradualalterationofPNa,in ing sodium transit via predilution CVVH. The follow- contrast to the relatively rapid PNa increases imposed ing urea- and sodium-based kinetic methodology by steep dialysate-to-plasma [Na] gradients associ- involves six steps: (1) establishing a time-dependent ∇ ated with conventional hemodialysis. Generally, [Na] gradient [ Na(t)] between the plasma and a fl osmotherapy is carried out when there is severe hypo- replacement uid (RF) based on a sodium concentra- natremia, oligo-anuria, and inability to excrete sufficient tion adjustment ratio (NaAR) (Figure 1), (2)estima- electrolyte-free water to maintain isotonicity (1–3). Thus, tion of total body water (TBW), (3) determination of SBO has played a role in patients with end stage liver sodium ion dialysance (DNa)thatapproximatesthe fi disease and advanced heart failure. urea hemo lter transfer rate, (4) on-treatment predic- Osmotic demyelination syndrome may transpire in tion of PNa(t), (5) determination of sodium balance, and patients who are hyponatremic with end stage liver (6)troubleshooting. disease after abrupt PNa elevations during orthotopic liver transplantation (4,5). Correspondingly, presurgical Predilution CVVH fi elevation of PNa among individuals prone to osmotic RF is infused postblood pump and prehemo lter at a fi fl demyelination may be prophylactic. Less commonly, speci ed rate (QRF)intotheplasma ow (QP)toraise supranormal PNa elevations have been imposed during (or lower) PNa from its pretreatment level, NaPre or traumatic brain injury or intracerebral hemorrhage to PNa(0), to its post-treatment level, NaPost or PNa(t) reduce brain swelling (6,7). (Figure 1). Employing a fixed-volume model where To rectify severe plasma hypotonicity, a relatively TBW volume is constant and analogizing to estab- hypertonic/hypernatric solution is administered in a lished urea kinetic principles, the rate change of PNa controlled fashion during continuous renal replacement can be computed over a specified time interval therapy (CRRT), and PNa is increased at rates consis- (15,16). Thus, sodium advected from the RF gradually tent with consensus guidelines (8). Controlled PNa increases NaPre to NaPost, with their difference equal- elevations can be achieved by hemodialysis, but spe- ing DNa (Equation 1). cial device- and protocol-specificmodifications are To produce an [Na] gradient, a stock RF (RF1) of required to avoid dialysis disequilibrium syndrome nominal [Na] NaRF1 is adjusted to NaRF2, thereby (9). Sustained low-efficiency dialysis or slow contin- establishing ∇Na(0), the maximal [Na] gradient at time uous ultrafiltration with simultaneous infusion of a (0) (Equation 2). DNa is also the product of ∇Na(0) and D ∇ solution relatively hypernatric to PNa is also feasible NaAR, and NaAR is the ratio of Na to Na(0) (Equa- (10). In terms of CRRT, SBO has been conducted with tion 3). 1Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, Michigan; and 2St. Clair Specialty Physicians, Roseville, Michigan Correspondence: Dr. Jerry Yee, Division of Nephrology and Hypertension, Henry Ford Hospital, 2799 West Grand Boulevard, CFP-514, Detroit, MI 48202. Email: [email protected] www.kidney360.org Vol 1 April, 2020 Copyright © 2020 by the American Society of Nephrology 281 282 KIDNEY360 Replacement RF2 Fluid ∇Na(t) NaRF2 Q QP RF2 PNa(t) Hemofilter Blood Pump DNa·t DNa – NaAR=1–e V QP – QUF QRF2 + QUF Figure 1. | Plasma sodium concentration is exponentially changed by the replacement fluid sodium concentration and flow rates of plasma, replacement fluid, and ultrafiltration. The extracorporeal circuit is comprised of a hemofilter and replacement fluid. The plasma inflow rate (QP) ∇ is advected by a sodium concentration [Na]-adjusted replacement fluid (NaRF2). The sodium concentration [Na] gradient, Na(t), equals the [Na] difference between NaRF2 and plasma sodium concentration at any time (t), PNa(t). The sodium concentration adjustment ratio (NaAR) is defined by sodium ion dialysance (DNa), time, and total body water volume (Watson volume, V). Hemofilter effluent equals the sum of RF2 flow rate ∇ (QRF2) and net ultrafiltration flow rate (QUF). Na(t), [Na] gradient at time (t) or PNa(t)-to-NaRF2 difference; RF2, [Na]-adjusted replacement fluid 2. DNa 5 NaPost 2 NaPre (Equation 1) Step 1: Establishing the Sodium Concentration Gradient ∇ ð0Þ 5 2 Na NaRF2 NaPre (Equation 2) Replacement Fluids ∇ To generate Na(0), the sodium-adjusted RF [Na], NaRF2, NaAR5 DNa=∇Nað0Þ 5 ðNaPost 2 NaPreÞ=ðNaRF2 2 NaPreÞ is often simply assigned an [Na] that is 6–10 mM greater than (Equation 3) NaPre.However,NaRF2 can be more rationally determined from intrinsic parameters of predilution CVVH (Tables 1 and D fi 2). First, by predetermining a target NaPost, Na is de ned. Sodium Kinetic Principles Second, estimation of NaAR from URR (Equations 3 and 4) The NaAR is a function of treatment time (t), TBW (V, and rearrangement of Equation 3 yields NaRF2 as Equation 5. Watson volume), and D . The NaAR is similar to the urea Na 5 1 ðD = Þ reduction ratio (URR, Equation 4), with equivalence of NaRF2 NaPre Na NaAR (Equation 5) DNa to the urea clearance constant, KUrea (Equation 4, A and B). In summary, urea kinetics function to approximate NaAR. These principles are illustrated by the following example. Case 1. A 42-year-old man, 178 cm and 90 kg, is anuric URR 5 ðBUNð0Þ 2 BUNðtÞÞ=ðBUNð0Þ 2 BUN Þ Dialysate with stage 3 AKI. He has no peripheral edema. Laboratory 2 z = 5 5 2 KUrea t V ð Þ URR 1 e Equation 4A data: NaPre, 116 mM; BUN(0), 80 mg/dl; hematocrit, 0.25. The target BUN and PNa after 24 hours of CVVH are 48 mg/dl and 124 mM, respectively. First, NaAR approximating URR 2 z = 5 2 DNa t V “ ” NaAR 1 e (Equation 4B) is calculated, with BUNDialysate as zero. KIDNEY360 1: 281–291, April, 2020 Sodium-Based Osmotherapy, Yee et al. 283 Table 1. Sodium-based osmotherapy parameters Row Parameter Definition Units 1 DNa Post-treatment [Na] minus mmol/l, mM pretreatment [Na] 2 ∇Na(0) [Na] gradient at time (t)50 mmol/l, mM 3 [Na] Sodium concentration mmol/l, mM 4 SNa Sodium balance mmol 5DNa Dialysance of sodium ion ml/min fl 6 Eff-NaRF Effective replacement uid [Na] from mmol/l, mM combined infusions of NaRF1 and NaH 7 NaAR Sodium concentration adjustment Dimensionless ratio fi 8NaH [Na] of a de ned hypo-, iso-, mmol/l, mM hypertonic solution H 9NaPre Pretreatment PNa, i.e., PNa(0) mmol/l, mM 10 NaPost End treatment PNa mmol/l, mM 11 NaRF1 RF1 [Na], unadjusted replacement mmol/l, mM fluid 12 NaRF2 RF2 [Na], sodium-adjusted mmol/l, mM replacement fluid 13 PNa(t) Plasma [Na] at time (t) mmol/l, mM fl 14 QH Solution H ow rate ml/min fl 15 QB,QP Respective blood and plasma uid ml/min flow rates fl fl 16 QRF Replacement uid ow rate ml/min fi fl 17 QUF Net ultra ltration ow rate ml/min fl 18. QEff Combined ow rate of QRF1 and QH ml/min 19 RF1 Replacement fluid 1 — 20 RF2 Replacement fluid 2 — 21 t Time min 22 URR Urea reduction ratio Dimensionless 23 V Total body water, i.e., Watson volume ml, L 24 V4M Volume of added hypertonic saline ml, L (23.4%, 4 M) 25 VRF1 Volume of RF1 ml, L 26 VRF2 Volume of RF2 ml, L 27 VW Volume of added sterile water ml, L Variables and abbreviations used in text and equations. NaAR URR 5 ðBUNð0Þ 2 BUNð1440ÞÞ=BUNð0Þ Replacement Fluid Manipulation 5 ð80 2 48Þmg=dl=80mg=dl 5 0:4 In predilution CVVH SBO, the NaRF1 is frequently low- ered from a nominal level of 130 or 140 mM. For Case 1, D ∇ Na can be adjusted to an Na of 136 mM by several Second, after NaAR is determined, Na, Na(0), and NaRF2 RF1 RF2 are calculated. methods (Figure 3) (11,12): method 1, diluting RF1 (NaRF1 140 mM) with 147 ml sterile water; method 2, exchanging 143 ml of RF1 (Na 140 mM) for sterile water; and method D 5 2 5 2 5 RF1 Na NaPost NaPre 124 mM 116 mM 8 mM 3, addition of 7.8 ml of 4 M saline (23.4%) to 5 L of RF1 ∇Nað0Þ 5 DNa=NaAR 5 8 mM=0:4 5 20 mM solution (NaRF1 130 mM).