These are the physiological effects of infusing one litre of 0.9% sodium chloride solution into a patient.
What am I giving?
Change to the initial conditions
The saline distributes rapidly (within about 15 minutes) from the intravascular to the interstitial compartment. And there, it is stuck.
The cells have active pumps and the membrane is impermeable to sodium; similarly, chloride is trapped.
Because normal saline is isoosmotic with the extracellular fluid, water does not have any osmotic pressure to shift between compartments, and it distributes itself according to the proportional distribution of sodium (i.e. about 25% of it stays intravascular and 75% enters the interstitial fluid).
(This may not be entirely accurate. Because the osmolality of the extracellular fluid increases, some water undegoes a shift into the extracellular compartment. The new equilibrium point is 290.2 mOsm/L. To achieve this, a whole 25ml of water has to move up into the extracellular compartment. So, the intravascular volume increases not by 250ml, but by... 256ml. What a big difference that makes. In order to remain detached from pedantic hair-splitting, I have opted to omit this from all the further calculations.)
Plasma osmolality doesn't change much, because it has received a load of essentially isoosmolar fluid.
You will notice that the osmolality of the compartments increases by 0.2 mmol/L from your maths; but the osmoreceptors dont care.
The intravascular compartment volume increases by 250ml or so – from 5000ml to 5250ml. The increase in intravascular volume is 5% - outside the volume receptor sensitivity threshold.
Did that just happen?
So, if neither baroreceptors nor osmoreceptors fail to react, does that mean that your organism simply neglects to notice this fluid bolus?
Of course not.
The detected change is not the change of osmolality or intravascular volume, but rather the oncotic pressure. Because intravascular protein concentration decreases, plasma oncotic pressure decreases.
Glomerulotubular balance ensures a return to homeostasis by increasing free water excretion (the mechanism is triggered by a decrease in peritubular capillary oncotic pressure; it decreases the rate of water resorption from the proximal tubule).
This autoregulatory mechanism normally ensures that changes in the glomerular filtration rate don't alter the rate of sodium and water excretion. The peritubular capillary carries blood from the glomerulus, where ultrafiltration had concentrated the blood. The degree to which this blood was concentrated now determines the degree of water reabsorption.
Reabsorption leads to dilution of peritubular capillary blood, and thus oncotic homeostasis is maintained. If this blood happens to already be dilute (eg. after your saline bolus) the rate of water resorption will decline, and more water will be excreted in the urine. As more water is excreted the oncotic pressure will gradually return to normal.
How long does this 250ml volume expansion take, and how long does it last?
Short answer: Not long.
Again, I refer this question to Lobo et al (2003), who infused a bunch of healthy males with 2 litres of saline over 1 hour, and observed that the fall in hematocrit and serum albumin produced by this took about 6 hours to resolve. From this we can infer that the 25% of normal saline which remains intravascular takes about 6 hours to excrete in the urine.
After that, you are back to where you started from in terms of intravascular volume.
Will the serum sodium rise appreciably?
No, not really. To the total stores of extracellular sodium (lets say its concentration is 140 mmol/L, over 14 litres of ECF) we have just added another 150. Because we have also added 1000ml of water, the sodium concentration will only rise to 140.6 mmol/L, which is outside the error range of many laboratories. So you may not even notice.
Will the serum chloride rise appreciably?
Well, actually... Yes.
if the chloride was 100 mmol/L, and we have just added 150 mmol, the extracellular chloride level will rise to 103. Whats more, its here to stay. Lobo's healthy volunteers still had elevated chloride at the end of the measurement period (8 hours). In order to maintain electroneutrality, with rising chloride levels more and more bicarbonate is lost (through the kidneys) and a normal anion gap metabolic acidosis develops.
With one bag, its not a big deal, but imagine for a second an emergency department with nothing but saline in stock, and a severely septic patient. After 6 litres of "goal directed" saline, one is left with an ECF volume expanded to 20 litres (little of which is intravascular, given the leaky capillaries). The serum sodium harmlessly rises to 143, but the chloride is now 115. An ICU consult is solicited for shock with metabolic acidosis refractory to fluid challenges. Hilarity ensues.
The reader with some experience of managing sodium disturbances will at this stage raise some valid concerns. A couple of paragraphs above, this author's simplified calculations suggest that the serum sodium will rise by 0.6 mmol/L. However, if we use the well-weathered Adrogue-Madias formula, we will get a different value (140.3 mmol/L). If a higher concentration of sodium is used (eg. you give 1000ml of 3% saline, with 514 mmol/L of sodium) the discrepancy becomes even greater. This could be dangerous: underestimating the rate of replacement could give rise to all sorts of hideous neurological complications. Also, it throws doubt over the whole discussion: do you believe the calculations of a nameless intensivist blogger, or a well established tool for calculating sodium replacement?
Well, as it turns out, you should trust neither.
Let us try to unravel the source of this discrepancy:
As you throw a litre of saline into the system, it immediately increases the extracellular fluid volume by 1000ml, and the extracellular sodium by 150 mmol. At this stage, one might expect the sodium to remain exclusively in the extracellular fluid, intracellular sodium being a tightly controlled concentration. That would change the osmolarity of the extracellular fluid, causing some minor fluid shifts, which I have basically ignored.
The Adrogue formula, however, expects the sodium and water to equilibrate between the compartments.
Surely, that can't be right. The mechanisms maintaining the Gibbs-Donnan equilibrium rely on the intracellular sodium concentration remining low, and though some sodium must sneak through into the cells, the cell membrane must surely act as more of a barrier-it should not be completely porous to the movements of this electrolyte.
Ergo, the Adrogue formula should underestimate the sodium increase following an infusion. But does it?In 2006, Liamis et al published a study looking at the sodium changes in 189 patients receiving saline (hypertonic in only a few cases), comparing the actual change with that which was predicted by the Adroque-Madias formula. Though the formula was good enough for government work, it really did seem to predict a much lower increase in sodium, particularly in the patients who had lower extracellular fluid volume:
" ...in every subgroup, the achieved serum sodium was higher than the anticipated one, but the difference failed to reach statistical significance because of the low number of patients in each subgroup. The discrepancy was particularly marked and actually achieved statistical significance in the hypovolemic group, with the rise in serum sodium being two to three times larger than predicted by the formula. "
In short, it appears that faced with real clinical scenarios, the formula does really underestimate the sodium increase. There's a great article by Nguyen & Kurtz (2004) which goes through the limitations of the Adrogue-Madias formula with greatmatematical rigor, and basically their conclusions were that the equation fails to take into account several important factors such as the change of total body water with ongoing infusion and the normal expected ratio of intracellular to extracellular sodium. Not to mention factors completely external to the formula but still important clinically, like the urinary and GI losses of sodium, or gains of sodium through diet and medications, or the effects of turning off the ADH secretion by increasing volume. The effects of this inaccuracy would be amplified wherever the patient is so volume-depleted that the contributed infusion volume would contribute a significant fraction of the total body water, eg. where you've given 3000ml of saline to a 60kg dehydrated patient.
What's the upshot of all this? An editorial from the 2006 journal where Liamis published wisely counsels that "there is ultimately no substitute for the close monitoring of the serum sodium". In summary, no formula is sufficiently capable of predicting any individual sodium repletion with enough accuracy to allow you to prescribe a replacement regimen and then walk away irresponsibly.