Introduction
Generally, sodiumbased osmotherapy (SBO) is tonicity therapy with the aim of reducing cerebral edema during states of hypotonic hyponatremia. Depending on the circumstance, plasma tonicity may be increased or decreased. Because the sodium concentration ([Na]) in the plasma at any time (t), P_{Na}(t), and accompanying anions constitute the bulk of plasma tonicity, SBO is predicated on gradual alteration of P_{Na}, in contrast to the relatively rapid P_{Na} increases imposed by steep dialysatetoplasma [Na] gradients associated with conventional hemodialysis. Generally, osmotherapy is carried out when there is severe hyponatremia, oligoanuria, and inability to excrete sufficient electrolytefree water to maintain isotonicity (^{1–3}). Thus, SBO has played a role in patients with end stage liver disease and advanced heart failure.
Osmotic demyelination syndrome may transpire in patients who are hyponatremic with end stage liver disease after abrupt P_{Na} elevations during orthotopic liver transplantation (^{4},^{5}). Correspondingly, presurgical elevation of P_{Na} among individuals prone to osmotic demyelination may be prophylactic. Less commonly, supranormal P_{Na} elevations have been imposed during traumatic brain injury or intracerebral hemorrhage to reduce brain swelling (^{6},^{7}).
To rectify severe plasma hypotonicity, a relatively hypertonic/hypernatric solution is administered in a controlled fashion during continuous renal replacement therapy (CRRT), and P_{Na} is increased at rates consistent with consensus guidelines (^{8}). Controlled P_{Na} elevations can be achieved by hemodialysis, but special device and protocolspecific modifications are required to avoid dialysis disequilibrium syndrome (^{9}). Sustained lowefficiency dialysis or slow continuous ultrafiltration with simultaneous infusion of a solution relatively hypernatric to P_{Na} is also feasible (^{10}). In terms of CRRT, SBO has been conducted with continuous venovenous hemofiltration (CVVH) (^{11},^{12}), continuous venovenous hemodialysis (^{13}), or continuous venovenous hemodiafiltration (^{14}).
General Principles of SBO
SBO can be implemented as a stepwise approach based on established biophysical principles governing sodium transit via predilution CVVH. The following urea and sodiumbased kinetic methodology involves six steps: (1) establishing a timedependent [Na] gradient [∇Na(t)] between the plasma and a replacement fluid (RF) based on a sodium concentration adjustment ratio (NaAR) (Figure 1), (2) estimation of total body water (TBW), (3) determination of sodium ion dialysance (D_{Na}) that approximates the urea hemofilter transfer rate, (4) ontreatment prediction of P_{Na}(t), (5) determination of sodium balance, and (6) troubleshooting.
Predilution CVVH
RF is infused postblood pump and prehemofilter at a specified rate (Q_{RF}) into the plasma flow (Q_{P}) to raise (or lower) P_{Na} from its pretreatment level, Na_{Pre} or P_{Na}(0), to its posttreatment level, Na_{Post} or P_{Na}(t) (Figure 1). Employing a fixedvolume model where TBW volume is constant and analogizing to established urea kinetic principles, the rate change of P_{Na} can be computed over a specified time interval (^{15},^{16}). Thus, sodium advected from the RF gradually increases Na_{Pre} to Na_{Post}, with their difference equaling ΔNa (Equation 1).
To produce an [Na] gradient, a stock RF (RF1) of nominal [Na] Na_{RF1} is adjusted to Na_{RF2,} thereby establishing ∇Na(0), the maximal [Na] gradient at time (0) (Equation 2). ΔNa is also the product of ∇Na(0) and NaAR, and NaAR is the ratio of ΔNa to ∇Na(0) (Equation 3).
Sodium Kinetic Principles
The NaAR is a function of treatment time (t), TBW (V, Watson volume), and D_{Na}. The NaAR is similar to the urea reduction ratio (URR, Equation 4), with equivalence of D_{Na} to the urea clearance constant, K_{Urea} (Equation 4, A and B).
Step 1: Establishing the Sodium Concentration Gradient
Replacement Fluids
To generate ∇Na(0), the sodiumadjusted RF [Na], Na_{RF2}, is often simply assigned an [Na] that is 6–10 mM greater than Na_{Pre}. However, Na_{RF2} can be more rationally determined from intrinsic parameters of predilution CVVH (Tables 1 and 2). First, by predetermining a target Na_{Post}, ΔNa is defined. Second, estimation of NaAR from URR (Equations 3 and 4) and rearrangement of Equation 3 yields Na_{RF2} as Equation 5.In summary, urea kinetics function to approximate NaAR. These principles are illustrated by the following example.
Table 1. 
Sodiumbased
osmotherapy parameters
Row 
Parameter 
Definition 
Units 
1 
ΔNa 
Posttreatment [Na] minus pretreatment [Na] 
mmol/l, mM 
2 
∇Na(0) 
[Na] gradient at time (t)=0 
mmol/l, mM 
3 
[Na] 
Sodium concentration 
mmol/l, mM 
4 
ΣNa 
Sodium balance 
mmol 
5 
D_{Na}

Dialysance of sodium ion 
ml/min 
6 
EffNa_{RF}

Effective replacement fluid [Na] from combined infusions of Na_{RF1} and Na_{H}

mmol/l, mM 
7 
NaAR 
Sodium concentration adjustment ratio 
Dimensionless 
8 
Na_{H}

[Na] of a defined hypo, iso, hypertonic solution H 
mmol/l, mM 
9 
Na_{Pre}

Pretreatment P_{Na}, i.e., P_{Na}(0) 
mmol/l, mM 
10 
Na_{Post}

End treatment P_{Na}

mmol/l, mM 
11 
Na_{RF1}

RF1 [Na], unadjusted replacement fluid 
mmol/l, mM 
12 
Na_{RF2}

RF2 [Na], sodiumadjusted replacement fluid 
mmol/l, mM 
13 
P_{Na}(t) 
Plasma [Na] at time (t) 
mmol/l, mM 
14 
Q_{H}

Solution H flow rate 
ml/min 
15 
Q_{B}, Q_{P}

Respective blood and plasma fluid flow rates 
ml/min 
16 
Q_{RF}

Replacement fluid flow rate 
ml/min 
17 
Q_{UF}

Net ultrafiltration flow rate 
ml/min 
18. 
Q_{Eff}

Combined flow rate of Q_{RF1} and Q_{H}

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 
V_{4M}

Volume of added hypertonic saline (23.4%, 4 M) 
ml, L 
25 
V_{RF1}

Volume of RF1 
ml, L 
26 
V_{RF2}

Volume of RF2 
ml, L 
27 
V_{W}

Volume of added sterile water 
ml, L 
Variables and abbreviations used in text and equations.
Table 2. 
Sodiumbased
osmotherapy equations
Row 
Description 
Equation 
1 
Dialysance of sodium ion 
D_{Na} = –(V/t) × LN(1 – NaAR) 
D_{Na} = Q_{P} × [(Q_{UF} + Q_{RF})/(Q_{P} + Q_{RF})] 
2 
Method 1 calculation of added water volume 
V_{RF2} = V_{RF1} × (Na_{RF1}/Na_{RF2}) 
V_{W} = V_{RF1} × [(Na_{RF1} – Na_{RF2})/Na_{RF2}] 
3 
Method 2 calculation of water exchange volume 
V_{X} = V_{RF1} × (Na_{RF1} – Na_{RF2})/Na_{RF1}] 
4 
Method 3 volume calculation of added 4 M hypertonic saline volume (23.4%) 
V_{4M} = V_{RF1} × (Na_{RF2} – Na_{RF1})/(Na_{4m} – Na_{RF2}) 
5 
Method 4 calculation of solution H fluid flow rate 
Q_{H} = Q_{Eff} × (Na_{RF1} – EffNa_{RF})/(Na_{RF1} – Na_{H}) 
6 
Method 4 replacement fluid 1 (RF1) flow rate 
Q_{RF1} = Q_{Eff} × (EffNa_{RF} – Na_{H})/(Na_{RF1} – Na_{H}) 
7 
Plasma flow rate calculation 
Q_{P} = Q_{B} × (1 – hematocrit) 
8 
Sodium concentration at treatment time (t) 
P_{Na}(t) = P_{Na}(0) + ∇Na(0) × (1 – e^{–DNa
}
^{·t/V}); P_{Na}(0) = Na_{Pre}

P_{Na}(t) = P_{Na}(0) + (Na_{RF2} − Na_{Pre}) × (1 – e^{–DNa
}
^{·t/V}) 
P_{Na}(t) = Na_{Pre} + ([Na_{RF2} − Na_{Pre}] × NaAR) 
9 
Replacement fluid flow rate 
Q_{RF} = Q_{P} × (D_{Na} − Q_{UF})/(Q_{P} − D_{Na}); Q_{UF} = 0 
10 
Sodium balance at time (t) 
ΣNa(t) = P_{Na}(t) × (V − Q_{UF} × t) − (Na_{Pre} × V) 
ΣNa(t) = P_{Na}(t) × (V − Q_{UF} × t) − (P_{Na}(0) × V) 
11 
Sodium concentration adjustment ratio 
NaAR = 1 – e^{–DNa
}
^{·t/V}

NaAR = ΔNa/∇Na(0) = (Na_{Post} – Na_{Pre})/(Na_{RF2} − Na_{Pre}) 
12 
Sodium concentration change at endtreatment time (t) 
ΔNa = ∇Na(0) × NaAR 
ΔNa = Na_{Post} – Na_{Pre}

13 
Sodium concentration gradient, initial 
∇Na(0) = Na_{RF2} – Na_{Pre}

14 
Sodium concentration of RF2 
Na_{RF2} = Na_{Pre} + (ΔNa/NaAR) 
Na_{RF2} = Na_{Pre} + [ΔNa/(1 – e^{–DNa
}
^{⋅t/V})] 
15 
Time at which specified P_{Na} occurs (t_{X}) 
t_{X} = –(V/D_{Na}) × LN[(Na_{RF2} – P_{Na}(t_{X}))/(Na_{RF2} – Na_{Pre})] 
16 
Ultrafiltration rate to achieve net zero sodium balance at time (t) 
Q_{UF}(t) = ([Na_{Post} × V] – [Na_{Pre} × V])/(Na_{Post} × t) 
Q_{UF}(t) = (ΔNa × V)/(Na_{Post} × t) 
17 
Urea reduction ratio 
URR = 1 – e^{–KUrea
}
^{·t/V}

URR = (BUN(0) – BUN(t))/(BUN(0) – BUN_{Dialysate}) 
18 
Watson volume 
V_{Man} = 2.447 – 0.09156 × (age, yr) 
+0.1074 × (height, cm) + 0.3362 × (weight, kg) 
V_{Woman} = –2.097 + 0.1069 × (height, cm) + 0.2466 × (weight, kg) 
See
Table 1 for definitions of variables.
Case 1.
A 42yearold man, 178 cm and 90 kg, is anuric with stage 3 AKI. He has no peripheral edema. Laboratory data: Na_{Pre}, 116 mM; BUN(0), 80 mg/dl; hematocrit, 0.25. The target BUN and P_{Na} after 24 hours of CVVH are 48 mg/dl and 124 mM, respectively. First, NaAR approximating URR is calculated, with BUN_{Dialysate} as “zero.”Second, after NaAR is determined, ΔNa, ∇Na(0), and Na_{RF2} are calculated.The time dependencies of Na_{Post}, NaAR, and ΔNa during prolonged SBO are tabulated in Table 3. Figure 2 demonstrates the effect of increasing ∇Na(0) on P_{Na} at NaAR of 0.4 over 1440 minutes of treatment. The random assignment of a 6–10 mM ∇Na(0) would have suboptimally elevated P_{Na}, underscoring this approach of using NaAR to determine Na_{RF2}. Note the relatively low NaAR complements the large ∇Na(0). Importantly, a low URR of 0.4 provides a therapeutic advantage by mitigating the risk of inducing cerebral edema by lowering overall urea flux.
Table 3. 
Timedependencies of plasma sodium concentration and
sodium concentration adjustment ratio during sodiumbased
osmotherapy
Time (t, min) 
P_{Na}(0) 
NaAR 
ΔNa(t) (mM) 
P_{Na}(t) (mM) 
0 
116.0 
0.0 (0.0) 
0.0 (0.0) 
116.0 (116.0) 
360 
116.0 
0.12 (0.14) 
2.4 (2.9) 
118.4 (118.9) 
720 
116.0 
0.23 (0.27) 
4.5 (5.4) 
120.5 (121.4) 
1080 
116.0 
0.32 (0.37) 
6.4 (7.5) 
122.4 (123.5) 
1440 
116.0 
0.40 (0.47) 
8.0 (9.3) 
124.0 (125.3) 
2880 
116.0 
0.64 (0.71) 
12.8 (14.3) 
128.8 (130.3) 
4320 
116.0 
0.78 (0.85) 
15.7 (16.9) 
131.7 (132.9) 
Predilution continuous venovenous hemofiltration is carried out on a hypothetical 42yearold, 178cm, 90kg man with P_{Na}(0) 116 mM and Watson volume 48.0 L for times shown. The replacement fluid is adjusted from a nominal [Na] of 140 mM to 136 mM to achieve a 20 mM [Na] gradient. Values in parentheses are those of a 42yearold woman with a Watson volume of 39.1 L, treated with the same parameters. P_{Na}, plasma sodium concentration; NaAR, sodium concentration adjustment ratio; ΔNa(t), P_{Na}(t) minus P_{Na}(0); P_{Na}(t), P_{Na} at time (t); [Na], sodium concentration; P_{Na}(0), P_{Na} at time (t) = 0.
Replacement Fluid Manipulation
In predilution CVVH SBO, the Na_{RF1} is frequently lowered from a nominal level of 130 or 140 mM. For Case 1, Na_{RF1} can be adjusted to an Na_{RF2} of 136 mM by several methods (Figure 3) (^{11},^{12}): method 1, diluting RF1 (Na_{RF1} 140 mM) with 147 ml sterile water; method 2, exchanging 143 ml of RF1 (Na_{RF1} 140 mM) for sterile water; and method 3, addition of 7.8 ml of 4 M saline (23.4%) to 5 L of RF1 solution (Na_{RF1} 130 mM).
Effective Replacement Fluid Sodium Concentrations
If institutional policy prohibits RF manipulations, an effective RF [Na] (EffNa_{RF}) equal to the desired Na_{RF2} must be generated via flowrate adjustments of an unadjusted RF1 and a separate solution (H; Figure 3, method 4) (^{14},^{17–19}). Peripheral infusion of 5% dextrose in water (D_{5}W) or sterile water by central vein may be used as “0” mM [Na] solutions (^{20}).
Step 2: Estimating TBW as Watson Volume
Watson Volume
NaAR is a function of time, D_{Na}, and TBW (V, Watson volume). Hence, accurate determination of V is critical. Consequently, the Watson volume, representing TBW as urea space, is used in subsequent calculations because it is a superior estimate of TBW compared to multiplication of body weight by an arbitrary factor, i.e., 0.5–0.6 (^{2},^{21}). For Case 1, initial estimates of V for a 178cm, 90kg man and woman are 48.0 L and 39.1 L, respectively. For initial estimates of V, considerations of edema and third spacing of extracellular fluid are excluded, but accommodations for these factors can be made (see Additional Considerations).
Step 3: Dialysance of Sodium Ion
Sodium Ion Dialysance
Dialysance of sodium ion (D_{Na}) comprises three flow rates: plasma (Q_{P}), RF (Q_{RF}), and net ultrafiltration (Q_{UF}) (^{22}). Q_{P} has the greatest influence on D_{Na} by virtue of its greater magnitude. D_{Na} is also the product of Q_{P} and the filtration fraction as follows.We recommend a blood flow (Q_{B}) of 250–300 ml/min to promote clearance and prevent filter clotting (^{23}). As shown, at a Q_{B} of 300 ml/min and hematocrit (Hct) of 0.25, Q_{P} is 225 ml/min (Equation 7).
Application
In Case 1, NaAR at 1440 minutes equals 0.4. Thus, D_{Na} is resolved by specifying V and t and rearranging Equation 4B as Equation 8.
With D_{Na} known, Q_{RF} is determined by rearranging Equation 6 as Equation 9.
In summary, steps 1–3 determine an NaAR of 0.4 and a ∇Na(0) of 20 mM that yield a ΔNa of 8 mM. Similar results are obtained by increasing D_{Na} (i.e., greater NaAR) and proportionally decreasing ∇Na(0). For example, if NaAR is 0.6, ∇Na(0) becomes 13.3 mM and Na_{RF2} becomes 129.3 mM. Also, the Na_{RF2} that produces a specified ΔNa at time (t) is calculated from Equations 4B and 5 (Equation 10).
Step 4: Plasma Sodium Concentration during Osmotherapy
Targeting the Plasma Sodium Concentration
Because D_{Na} and TBW are constants within the constraints of a fixedvolume model, P_{Na}(t) can be projected over a specified treatment interval (t) (Equation 11).This concept is depicted in Figure 4 where time and volumedependencies of P_{Na}(t) are displayed for a man and woman of equal height and weight. The greater P_{Na}(t) of the woman throughout treatment is attributable to a lesser Watson volume. The time (t_{X}) when a specified P_{Na}(t_{X}) occurs is ascertained by substituting t_{X} into Equation 11 and solving for it.
Step 5: Sodium Balance during Osmotherapy
In a fixedvolume model of SBO, sodium accrual is inevitable as P_{Na} increases. If patient vulnerability to volume overload is present, net ultrafiltration is advised. Consequently, realtime net sodium balance (ΣNa) monitoring is critical and computed by Equation 13.In Case 1, ΣNa(1440) is +384 mmol if Q_{UF} = 0 but –62.4 mmol if Q_{UF} is 0.15 L/h or 3.6 L per day.The Q_{UF} that “zeroes” the sodium load at time (t) is calculated as 3.1 L per 24 hours by Equation 14.
Modeling Sodium Balance
For patients vulnerable to volume excess/overload, ΣNa should be modeled a priori, and we demonstrate this concept as follows.
Case 2.
A 30yearold man with heart failure and stage 3B CKD develops AKI and dyspnea. The admission weight is 2 kg more than his lastreported hospital discharge weight. His vital signs are as follows: height, 170 cm; weight, 80 kg; temperature, 36.5°C; heart rate, 118 bpm; blood pressure 130/80 mm Hg; respiratory rate, 18 per minute; and Watson volume, 44.85 L. His laboratory data are as follows: Na_{Pre}, 120 mM; BUN, 50 mg/dl; serum creatinine, 4.2 mg/dl; and hematocrit, 0.33. Urine output is <0.05 ml/kg·h. A 24hour Na_{Post} target of 126 mM is planned. Predilution CVVH is begun with parameters of Q_{P} 200 ml/min, Q_{RF} 50 ml/min, Q_{UF} 2.5 ml/min, and NaAR 0.74. An NaRF2 of 128 mM is formulated by adding 79 ml sterile water to an RF1 of 130 mM. To achieve net sodium balance of zero after 24 hours, net ultrafiltration of 2.14 L per 24 hours is required, as shown below. Ultrafiltration beyond 24 hours produces net total body sodium loss. Figure 5 depicts the evolution of P_{Na}(t) and ΣNa(1440) if Q_{UF} is 3.6 L per 24 hours.
Sodium Balance with Edema
If the entire 2kg excess weight is assumed isotonic to plasma, total body sodium balance must be recalculated. The Watson volume of the 78kg man was 44.18 L and increased to 46.18 L from 2 L of edema. Achieving zero sodium balance requires just 0.06 L more net ultrafiltration. However, there is a 160mmol sodium excess if edema is considered isotonic plasma (Equation 15). To shed the sodium surfeit, an additional 1.27 L of net ultrafiltration is required. Overall, net ultrafiltration of 3.47 L attains a P_{Na}(1440) of 126 mM at 76.53 kg.
Influence of Exogenous Fluids and Urine Output on Replacement Fluid Sodium Concentration
During SBO, the influence of exogenous cation (sodium and potassium)containing fluids on P_{Na} and ΣNa must be tallied. Only cationic effects require analysis as anions follow pari passu. The RF [Na] is altered by infusions of exogenous fluids and/or urine output and produces a blended solution with an effective [Na] (EffNa_{RF}). Table 4 illustrates the 4hour effects on EffNa_{RF} in a patient who receives three intravenous fluids, 0.45% saline and hypothetical solutions A and B. By evaluating a short time interval, the singular and collective effects of each fluid on EffNa_{RF} are exposed early on. In aggregate, with consideration of all inputs and outputs, the 4hour effects on EffNa_{RF} and extracellular fluid volume are +0.8 mM and +0.05 L, respectively. Extrapolation of this analysis to a 24hour interval may obligate readjustments of Na_{RF1} and/or Q_{UF}. Lastly, elaboration of hypotonic urine increases EffNa_{RF} minimally, unless urine output is copious, i.e., >4 L per day.
Table 4. 
Effects of intravenous solutions and urine output on the effective
replacement fluid sodium concentration
Solution 
RF 
0.45% 
Solution A 
Solution B 
UO 
4Hour Results
^{a}

Flow rate, L/h 
2.0 
Single dose 
Single dose 
Single dose 
−0.1 
— 
Time, h 
4.0 
4.0 
— 
— 
4.0 
— 
[Na], mM 
130.0 
77.0 
154.0 
40.0 
50.0 
— 
Volume, L 
8.0 
0.10 
0.10 
0.25 
−0.40 
8.05 
Cation, mmol 
1040.0 
7.7 
15.4 
10.0 
−20.0 
1053.1 
EffNa_{RF}, mM
^{b}

130.0 
129.3 
130.3 
127.3 
134.2 
130.8 
The replacement fluid is infused simultaneously with three separate solutions as shown, with ongoing urine output. To simplify calculations, the RFpotassium concentration is assumed equal to plasma potassium concentration and not described. RF, replacement fluid with [Na] 130 mM; UO, urine output; [Na], sodium concentration; EffNa_{RF}, effective [Na] of RF and one of the solutions listed and/or UO.
^{a}Aggregate effect of solutions and urine output on EffNa_{RF}.
^{b}Isolated effect of each solution or urine output on EffNa_{RF}.
Acute Sodium Loading
Sodium loading can benefit individuals who are normonatremic with acute brain swelling. In patients who are hyponatremic and hypovolemic, sodium loading may be carried out abruptly by delivery of several smallvolume, hypertonic saline boluses (e.g., 100ml boluses of 23.4% saline) (^{7},^{23}). Subsequent maintenance of the hypertonic state can be achieved with CRRT modalities. Importantly, the gradual sodium loading of SBO should not supplant urgent volume resuscitation where indicated. In brief, the associated risk of sodium loading must be weighed at the outset of SBO, particularly in patients who are volume overloaded or edematous.
Step 6: Troubleshooting
Slow or No Plasma Sodium Concentration Elevation
If P_{Na} fails to increase during SBO, the osmotherapy prescription must be reexamined. Equipment and extracorporeal circuit integrity must be checked, and the effects of all fluid inputs and outputs must be reevaluated. If V is underestimated, the rise of P_{Na} is mathematically inhibited by an NaAR that is lower than calculated. A Q_{UF} increase will not remedy the situation because D_{Na} and NaAR are essentially unchanged. NaAR must be augmented by increasing Q_{P} and/or Q_{RF}. In parallel, ∇Na(0) can be increased to rectify suboptimal P_{Na} elevations. When P_{Na} increases more rapidly than expected per se >1 mM per hour for 4–6 hours, the aforementioned maneuvers should be attenuated, stopped, or even reversed.
Inaccurate NaAR
When BUN is relatively low, e.g., 30–40 mg/dl, calculation of NaAR may be inaccurate. This may transpire when sodium ion and urea clearance are discordant, i.e., abnormal rate of urea metabolism. Accordingly, a D_{Na} of 25–40 ml/min can be prespecified by empirically establishing ∇Na, Q_{P}, Q_{RF}, and, optionally, Q_{UF}.
Additional Considerations
Hyperglycemia from DextroseContaining Solutions
If RF solutions cannot be altered, delivery of a parallel, posthemofilter D_{5}W infusion in pre/postdilution CVVH may provoke concern for induction of hyperglycemia. However, this concern is unwarranted. A maximal rate of carbohydrate infusion of 4 mg/kg⋅min has been suggested to prevent lipogenesis (^{24}). At this metabolic threshold, the patient of Case 1 can tolerate a posthemofilter D_{5}W infusion of 300 ml/h, without hyperglycemia (Table 5). Absent carbohydrate metabolism, this infusion rate, in an extracellular volume of 16 L, increases plasma glucose (P_{Glu}) from 100 to 2150 mg/dl. However, at a submaximal rate of glucose metabolism of 2.65 mg/kg⋅min, P_{Glu} remains stable at 100 mg/dl. Notably, the effective P_{Na} entering the hemofilter is changed minimally. Prefilter D_{5}W infusions have minimal potential for generating severely elevated P_{Glu} due to rapid glucose sieving through the hemofilter. If D_{5}W or sterile water infusion rates are eschewed, less hypotonic solutions can be used, e.g., 0.225% or 0.45% saline solution.
Table 5. 
Theoretical effects of a posthemofilter 5% dextrose infusion on glucose metabolism during pre/postdilution continuous venovenous hemofiltration
Parameter 
Value 
D_{5}W infusion, ml/h 
30 
80 
160 
240 
300 
CHO load, mg/kg·min 
0.28 
0.74 
1.48 
2.22 
2.78 
P_{Glu}, without carbohydrate metabolism for 24h, mg/dl 
125 
500 
1100 
1700 
2150 
Maintenance metabolic rate, mg/kg·min 
0.15 
0.62 
1.36 
2.10 
2.65 
Prehemofilter P_{Na}, mM 
117.0 
117.0 
116.9 
116.8 
116.8 
The effects of a 5% dextrose infusion on glucose metabolism in a hypothetical, nondiabetic, 42yearold, 178cm, 90kg man with Watson volume 48 L and P_{Na}(0) 116 mM (see text, Case 1) after 24 hours of CVVH are displayed. CVVH parameters are: Na_{RF}, 130 mM; Q_{P}, 225 ml/min; combined prehemofilter RF and posthemofilter D_{5}W flow rate, 1.1 L/h (18.3 ml/min); and net ultrafiltration rate, 0 ml/min. Calculations are based on an extracellular fluid volume of 16 L (48 L × 0.33), without expansion of the extracellular fluid space from glucose accumulation. All CHO metabolism is assumed to originate from the D_{5}W infusion. With no CHO metabolism, increasing the CHO load (row 2) by increasing the D_{5}W infusion rate from 0 to 300 ml/h rapidly increases P_{Glu} (row 3). The respective glucose metabolic rates required to maintain P_{Glu} at 100 mg/dl for increasing D_{5}W infusion rates are shown (row 4). The minimal dilutional effect of the increasing D_{5}W infusion rate on hemofilter inlet P_{Na} is shown (row 5). CVVH, continuous venovenous hemofiltration; D_{5}W, 5% dextrose solution; CHO, carbohydrate; P_{Glu}, plasma glucose concentration; P_{Na}(0), plasma [Na] at time (t) = 0; Na_{RF}, RF [Na]; Q_{P}, plasma flow rate; RF, unadjusted replacement fluid; [Na], sodium concentration.
Regional Citrate Anticoagulation
Regional citrate anticoagulation with trisodium citrate (TSC) solutions of 4% ([Na], 408 mM) or 2.2% ([Na], 224 mM) have been used during SBO (^{25–27}). Nevertheless, hypertonic TSC infusions can greatly increase plasma tonicity, necessitating reduction of RF [Na] and/or dialysate [Na] to prevent untoward elevations of P_{Na}. If TSC is used during SBO, a priori sodium modeling is advised with appropriate laboratory monitoring at 4 to 8hour intervals, including ionized calcium levels that will decline with untoward P_{Na} elevations if hypercitratemia occurs.
SBO by Other CRRT Modalities
Aside from predilution CVVH, other CRRT modalities and protocols are available, and some employ pre and posthemofilter RF delivery (^{19}). When Q_{RF} is partitioned pre and postfilter versus prefilter alone, there is an incremental postfilter P_{Na} elevation. Table 6 represents a quantitative analysis for pre and posthemofilter CVVH and reveals only a 0.5mM increment with a 30/70 division of Q_{RF} between pre and postfilter fractions. TSC has been exploited to increase P_{Na} from normal to supranormal levels in patients with cerebral edema (^{6}). However, in acute cerebral edema, rapid induction of hypertonicity via hypertonic saline boluses (4 M) is favored when prompt elevation of plasma tonicity is critical (^{7}).
Table 6. 
Effect of pre and posthemofilter
replacement fluid infusion on end treatment plasma sodium concentration
Variable 
Units 
Predilution Only 
Pre/Postdilution 
Pre/Postdilution 
Q_{P}

ml/min 
200.0 
200.0 
200.0 
Q_{RF}

ml/min 
50.0 
50.0 
50.0 
Replacement fluid 
— 
1.0/0.0 
0.5/0.5 
0.3/0.7 
Pre/postdilution ratio 
D_{Na}

ml/min 
40.0 
44.4 
46.5 
NaAR 
— 
0.76 
0.80 
0.81 
P_{Na}(1440) 
mM 
127.6 
128.0 
128.1 
A hypothetical patient with Watson volume 40 L and P_{Na}(0) 120 mM undergoes 24 hours of continuous venovenous hemofiltration with the following parameters: Na_{RF}, 130 mM; Q_{P}, 200 ml/min, and Q_{RF}, 3 L/h. Three simulations are shown: predilution only and pre and postdilution with Q_{RF} pre and postdilution ratios of 0.5/0.5 and 0.3/0.7. D_{Na}, NaAR, and P_{Na}(1440) increase with an increasing proportion of postdilution Q_{RF.} The maximal P_{Na}(1440) difference among the three pre/posthemofilter combinations is 0.5 mM. Q_{P}, plasma flow rate; Q_{RF}, replacement fluid flow rate; D_{Na}, dialysance of sodium; NaAR, sodium concentration adjustment ratio; P_{Na}(0), P_{Na} at t (0); P_{Na}(1440), P_{Na} at t = 1440 minutes; Na_{RF}, replacement fluid [Na].
Summary
In conclusion, advective SBO by predilution CVVH may be therapeutically exploited in hypotonic conditions with hyponatremia and oligoanuria. We recommend a sixstep protocol based on calculation of NaAR to achieve a timetargeted P_{Na}. A failure of SBO signifies potential miscalculation(s) and/or the influences of external input and output solutions. Recurrent laboratory monitoring and quantitative analysis of these variables is imperative for safe and successful implementation of SBO. Modeling the plasma sodium concentration, sodium balance, and ultrafiltration with our mise en place approach prevents treatmentbased sodium loading (Box 1).
Box 1. Osmotherapy by Predilution Continuous Venovenous Hemofiltration
 (1) Define ΔNa from time (0) to time (t) by defining Na_{Post}, e.g., 8 mM after 24 hours
 ΔNa = Na_{Post} – Na_{Pre}; Na_{Pre} = P_{Na}(0); t = end treatment time
 (2) Define sodium concentration adjustment ratio (NaAR) from time (0) to t via urea reduction ratio (URR), e.g., 30%–70% over 24 hours
 NaAR ≈ URR = (BUN(0) − BUN(t))/(BUN(0) − BUN_{Dialysate})
 (3) Define ∇Na(0)
 ∇Na(0) = ΔNa/NaAR = (Na_{Post} – Na_{Pre})/NaAR = Na_{RF2} – Na_{Pre}
 (4) Calculate Na_{RF2}
 Na_{RF2} = Na_{Pre} + ∇Na(0)
 (5) Adjust Na_{RF1} to Na_{RF2} by methods 1–4 (Figure 3)
 (6) Calculate dialysance of sodium (D_{Na}) from NaAR, Watson volume (V), and t
 D_{Na} = −(V/t) × LN(1 − NaAR)
 (7) Calculate plasma flow rate (Q_{P}) from blood flow rate (Q_{B}) and hematocrit (Hct)
 Q_{P} = Q_{B} × (1–Hct)
 (8) Calculate Q_{RF} from D_{Na} and Q_{P}
 Q_{RF} = Q_{P} × (D_{Na} − Q_{UF})/(Q_{P} − D_{Na}); Q_{UF} = 0
 (9) Model predilution continuous venovenous hemofiltration at specified Q_{P} and Q_{RF} to determine Q_{UF}(t) (see below)
 Monitor P_{Na} at 4 to 6hour intervals
 (10) Calculate sodium balance ΣNa from time (0) to (t)
 ΣNa(t) = P_{Na}(t) × (V − Q_{UF} × t) − (Na_{Pre} × V)
 Note: Adjust for additional inputs and outputs and edema (see text)
 (11) Calculate Q_{UF}(t) for zero sodium balance at time (t)
 Q_{UF}(t) = [(Na_{Post} × V) – (Na_{Pre} × V)]/(Na_{Post} × t) = (ΔNa × V)/(Na_{Post} × t)
Disclosures
J. Yee discloses honoraria from the American Society of Nephrology. S. Frinak, T. Gradinariu, N. Mohiuddin, and J. Uduman have nothing to disclose.
Funding
None.
Author Contributions
S. Frinak was responsible for methodology; S. Frinak, T. Gradinariu, N. Mohiuddin, and J. Yee were responsible for formal analysis; S. Frinak, J. Uduman, and J. Yee conceptualized the manuscript S. Frinak and J. Yee were responsible for supervision and validation; N. Mohiuddin and J. Yee were responsible for visualization; all authors wrote the original draft of the manuscript, and reviewed and edited the manuscript.
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