Why does hypoxia happen?

It is hard to avoid anything covid related in medicine at the moment. This pesky virus does raise an important point about pathophysiology however. There has been a collective surprise at the degree of hypoxia these patients can have despite a chest X-ray that doesn’t look that bad and at how comfortable these patients can appear despite their severe hypoxia.
Except there is nothing particularly new about this and it has long been a pitfall for the intern seeing hypoxic patients on the ward. Often one comes across a patient with post operative atelectasis (or viral pneumonia!) who has some opacities on chest X-ray (such as the one pictured above) but a degree of hypoxia seemingly unexplained by the chest X-ray. These patients are often sent for unnecessary CTPAs looking for PE.
Firstly, the sensitivity of chest X-ray for pneumonia and atelectasis is not as great as we think it is. Changes to the lung parenchyma are often more extensive than what is visualized on X-ray. Secondly the hypoxia is occurring on a microscopic level. Hypoxia occurs when there is mismatch between ventilation and perfusion i.e. blood flow to an alveolus is in excess of the lowered oxygen tension in that diseased alveolus. The larger volume of hypoxic blood that mixes with ‘good blood’, the worse it is. This is called shunting. Hypoxic pulmonary vasoconstriction is the reflex that protects against this mismatch but this reflex becomes less efficient with age, the presence of vasodilator drugs (pretty much antihypertensive or antianginal drug you care to mention), and a whole host of other physiological factors some of which may be specific to the disease itself.
Unwell septic patients with their high cardiac outputs will have a large volume of blood rushing through their pulmonary circulation which further decreases ventilation perfusion matching. The end result is that the degree of hypoxia is related much more to things occurring at microscopic level that we can’t see on an X-ray (on top of the fact that X-ray doesn’t tell us the true extent of parenchymal changes anyway). It is not uncommon to have post operative patients with a chest X-ray that looks like the one above but that are on 50-60% inspired oxygen.
These patients are tachypneic (because hypoxia contributes to the ventilatory drive) but they may not appear overly distressed because the work of breathing is more mediated by lung mechanics and the stiffness of the lung rather than the degree of hypoxia. If you’ve ever seen congenital cardiac babies with right to left cardiac shunts and resting saturations of 75% you’ll know what I mean. They can look blue but pretty happy.
So if you have a good reason for shunting (a high pre-test probability) such as being immediately postoperative or having a diagnosis of a viral pneumonia, that probability remains high despite what the chest X-ray might show you, and there is not necessarily a reason to go chasing a PE or invoking the presence of an unknown hemoglobinopathy (as many people are speculating with Covid). Of course, this doesn’t mean that looking for a PE is never indicated and clinical judgement in the individual situation is paramount. But you have to evaluate the patient in front of you, and not a computer screen, and if you understand the pathophysiology you’ll have a much better chance of doing this.
Till next time…

Hyponatremia Part 2: Managing it

The first step when confronted with a low sodium is to ask yourself if it is real. There are two interpretations of the word “real”. Firstly the machine at the lab may have spat out an incorrect result. This occurs if there is excess protein or lipid in the sample, because it affect the calculations made when the sample is diluted. This is not true of blood gas analysers- the blood gas sodium is accurate on a blood gas.

The other is to ask does this actually reflect a low serum osmolarity. We don’t care about hyponatremia so much because of the low sodium itself, but because we assume it reflects low serum osmolarity overall. It is this that actually causes all the troubles of cerebral oedema etc. Most of the time this is a correct assumption because serum osmolarity is


Most of the time the other components don’t play a huge role. But if the glucose is sky high, or you have another osmotically active particle such as mannitol, water will be sucked out of the cells, diluting the sodium. The sodium in this case is “real” however is doesn’t really matter because the overall plasma osmolarity is raised due to the presence of mannitol or craploads of sugar.

An easy way to eliminate this possibility is to check a serum osmolarity.

At the end of the first section we discussed people who had excessive sodium losses. Now, even though these patients might be losing a lot of sodium from the GI tract or the respiratory tract the sodium concentration of these losses is still always LESS than plasma sodium concentration. The total amount of sodium being lost is high but the sodium concentration of lost fluid is still low. So how do these patients become hyponatremic?

Well firstly one of the responses of the kidney to hypovolemia is to activate vasopressin and hold onto free water. However patients with hypovolemia also tend to hold onto sodium – a urine sodium < 20mmol/L fits with hypovolemic hyponatremia. So this doesn’t fully explain it. Even when urinary sodium reabsorption is inhibited, as you might see if the cause of hypovolemia is diuretics, the urine sodium rarely gets above 100mmol/L. So the renal response to hypovolemia of holding onto free water does not fully explain why the sodium drops.

It’s because people continue to drink water, usually from the tap, and the thirstier they feel the more they drink.  In short water and sodium are both lost, the water is replaced, the sodium is not, and the renal response prevents the free water from being excreted. Voila, low sodium levels. However without an ongoing exogenous source of water, hyponatremia will not develop.

So hypovolemic hyponatremia presents with low urine sodium levels, unless the cause is diuretics, or some other form of renal loss, such as acute tubular necrosis where the tubules are damaged, cannot retain sodium and put out vast quantities of urine. One could of course examine the patient and determine that they are hypovolemic as the textbooks advise, but anyone who has worked in clinical medicine for more than 2 minutes will realise that when it comes to differentiating between hypovolemia and euvolemia, one might as well do a rain dance, summon the gods, and ask them what they think. People who are confident in their ability to clinically differentiate between the two are probably deluded.

So the treatment is to expand the plasma volume with a resuscitation fluid and remove the stimulus for vasopressin secretion. Free water will be able to be excreted and the sodium will rise. You should probably do this cautiously- dumping a lot of fluid into someone often removes the vasopressin stimulus quite rapidly and an alarming diuresis can result, one that raises the sodium by more than the 8mmol/24 hours that safety recommends.

It would actually make complete sense to volume expand someone intravenously while at the same time restricting their oral fluid intake. Given that salt water tastes disgusting we tend to drink mostly free water, so expanding someone with salty water while limiting their free water intake is perfectly logical. Maybe best avoided however as people will give you weird looks and if you’ve already induced a diuresis adding on a free water restriction might overcorrect the sodium.

The classic cause of euvolemic hyponatremia is SIADH. The same pathophysiology that we already discussed applies, except this time vasopressin release is stimulated in the absence of hypovolemia, so the kidneys will not be holding onto sodium, and the urine sodium will be > 40mmol/L. However as mentioned, renal losses of sodium from diuretics or ATN will give the same urine chemistry, and this is a common pitfall. SIADH is actually not that common in patients presenting from home. It is more common is postsurgical patients where vasopressin is released due to the surgical stimulus and in little kids who become sick.

Hypervolemia should be more obvious clinically. The pathophysiology here is once again the same except the stimulus for vasopressin release is the sympathetic response to a failing heart. Diuresis is the treatment of choice here. It probably works because frusemide induces a loss of “salty water” and “free water”, but more “free water” and the patient is prevented from taking excessive free water because we usually fluid restrict people who are overloaded. Reducing atrial stretch and the neuroendocrine response to this also probably plays a part.

In all of these conditions the urine osmolarity will be higher than serum because the kidney is reabsorbing water. If the urine osmolarity is low the patient is likely to have psychogenic polydipsia.

If your patient has acute neurological symptoms a bolus of hypertonic saline is in order, and you should ask for help on how to do this.

Lastly you may wonder why the chloride is low- given that chloride is the main anion that balances the cations in the plasma, it is inevitable that a low Na+ leads to a low Cl-.

Hopefully this gives some better understanding of why hyponatremia develops and how to manage it. The key is really understanding the difference between salty water and free water.

Hyponatremia Part 1: Salt versus free water

Hyponatremia is difficult to understand. So I’ve decided to devote two whole posts to unravelling this enigma. The first part deals with normal salt physiology and the often forgotten difference between salty fluids and free water, while part 2 will deal more with the management.

It is important to distinguish between salty water and free water. Salty water refers to your resuscitation fluids like normal saline, Hartmann’s and plasmalyte, which contain 140-150mmol/L of Na. Because they are isotonic with body fluids, these fluids will be confined to the EXTRACELLULAR space, which you might recall is about 15L in a 70kg male. Turns out having fluid that stays in the extracellular space is a good thing if your goal is to expand the blood volume.

In contrast free water is solute free fluid which is hypotonic. Therefore it will distribute itself among TOTAL BODY WATER, which again you might recall is about 40L in a 70kg male. Now, we don’t often give pure water intravenously, but we do give fluids like 5% or 10% dextrose. This essentially functions as free water because the glucose will be taken up by cells leaving the free water component. From the point of view of the blood compartment, this free water is a muddy pig- it slips its way out of your grasp and disappears into the vast expanse of total body water, which is why it is wholly useless for resuscitating someone. The commonly used fluid dex-saline (which is 4% dextrose plus 0.17% saline) contains some salt but one can kind of think of it as free water also.

Herein the questions arises of what kind of fluid do we lose everyday? Most people will remember that the daily requirement for fluid is about 2-3L per day. But what is the composition of this fluid? Does it matter?


Of course it does. A human’s daily requirement for Na is about 70mmol. Read that again. That’s not 70mmol/L. That’s 70mmol TOTAL. So you are losing far more water than you are sodium (relative to normal body concentrations). This is from sweat, respiratory losses, the GI tract and the kidneys. Even though the kidneys can produce highly concentrated urine, they still lose more water than they do sodium. Another factoid you might recall is that the normal urine sodium concentration is 20mmol/L. Even if you are being hammered with a diuretic and losing lots of sodium in the urine, the urine sodium might get up to 80-90mmol/L, but this still falls far short of normal plasma sodium concentrations.

Given the above information it reasons that the function of the 2L of maintenance fluid we chart patients who are nil by mouth should be to maintain plasma osmolarity (given that salt is the main determinant of this). Therefore one should prescribe a maintenance fluid that achieves this, which is the reason that dextrose saline is favoured. Going without maintenance fluid will steadily raise your plasma osmolarity/sodium.

The purpose of 2L of maintenance fluid is not really to maintain blood volume (assuming your patient is euvolemic to begin with). Of course it fulfils this purpose to a degree but the more important determinant of blood volume is the solute load. A sodium load activates vasopressin which allows us to reabsorb water in the kidneys. Water follows sodium in the kidneys and this “sodium attached water” stays in the extracellular space, allowing maintenance of blood volume. As mentioned however the daily sodium load required to achieve this is only 70mmol/day (pretty much what you get with two bags of dex-saline).

The last two paragraphs may be confusing, so let me recapitulate. To maintain blood volume your kidneys must reclaim a certain amount of “water attached to sodium” or “salty water”, and this reclamation is dependent on an adequate sodium load and adequate water intake. However most of the fluid lost by your kidneys is actually “sodium free water” which must be replaced orally or intravenously to maintain serum osmolarity. Of the 2-3L a day of “fluid” one loses (not just from the kidneys), most of it is in the form of “sodium free water”, while “salty water” is a smaller component.

So what happens if I give a euvolemic patient normal saline as maintenance? In order to cope with the solute load (one bag already has twice the daily sodium requirement) and maintain a normal serum sodium concentration the kidneys will activate vasopressin and hold onto more water. The amount of “salty water” will increase, while the amount of “sodium free water” the kidneys can excrete is reduced. The serum osmolarity will be maintained, but at the expense of an expanded extracellular fluid volume. This may not be so much of an issue in healthy patients but you can bet it will significantly increase tissue oedema in those with heart failure, or with inflamed leaky capillaries. People with good kidney function will be able to increase the sodium loss in their kidneys, but remember even when they are losing heaps of sodium in the urine they are still losing more water than they are sodium. The effect will be worse in those with impaired kidney function who are less able to increase urinary sodium losses.

Of course such a maintenance regime may be appropriate in those with ongoing sodium losses. Those with ongoing sodium losses will have trouble maintaining their extracellular fluid volume (and therefore their blood volume) so ongoing sodium replacement will be appropriate. These patients may have vomiting, diarrheoa, losses from stomas or fistulae or renal losses from diuretics or acute tubular necrosis. Which brings us to managing hyponatremia in Part 2…

Plasmalyte is safe (and actually better) in hyperkalemia

In some indistinct corner of a ward somewhere where I spent the majority of my first house officer year, a laminated sign is blu-tacked to the wall which reads as follows:

“Normal Saline is the only fluid that should be used for patients with end stage renal failure”.

While on the face of it this serves to prevent some poor house officer charting fluid with 20mmol KCL in it to a patient on dialysis, normal saline is actually a poor choice for someone with renal failure or hyperkalemia.

While surgeons are known to sometimes insist on some bizarre things, their insistence on using plasmalyte as a resus fluid is well founded. This elegantly balanced crystalloid contains not only physiological amounts of Na and Cl (unlike NaCl which delivers an unphysiologic 150mmol/L of Cl) but also magnesium, acetate and gluconate. The latter two are converted into bicarbonate, and their metabolism provides 66kJ of energy per litre of fluid (1).

Plasmalyte also contains 5mmol per litre of potassium, hence the twitchiness of people to use it in hyperkalemia or renal failure. This worry, however, appears to be a misapplication of physiology.

If you take a second to think about it, there is no reason why addition of normokalemic fluid to plasma should make someone hyperkalemic (for a potassium of 5 is still a normal potassium). In fact, if you replaced all of someone’s plasma with plasmalyte, you could not get a potassium above 5. This is explained much more elegantly in this post on the veritable emcrit blog (2).

The second important point also explained in this post is that most potassium is intracellular and potassium levels are really largely dependent on cellular shifts more than anything else. Normal saline tends to cause a hyperchloremic metabolic acidosis because of the unphysiological quantities of chloride, which impair H+ excretion. Potassium will shift out of cells in response to buffer this. The end result is that potassium levels rise more with the administration of normal saline, even though  it contains no potassium in the bag, than with plasmalyte, which has a significant alkalinising effect (2).

Of course theory is no good without the studies to back it up, and the studies all strongly point in one direction. Three studies (3-5) looked at the perioperative administration of Ringers Lactate (LR) (a fluid similar to plasmalyte which contains 4 mmol/L of potassium) compared to Normal Saline in patients with end stage renal disease undergoing transplantation. Average potassium levels rose in the Normal Saline group in all three studies and fell or stayed the same in the LR groups. In fact, the first study had to be terminated early because 19% of the NS group developed hyperkalemia while none in the LR group did.

To satisfy you fully, let us turn to the evidence for plasmalyte directly. Adwaney and colleagues (6) demonstrated that, in the same setting of renal transplantation, recipients of plasmalyte had a significantly lower need for renal replacement therapy in days 1-3 post-op (OR of 0.15) and had a 2% incidence of hyperkalemia versus 17% in the NS group (despite pre-op potassium being the same).

Also recently Weinberg et al. (7) confirmed that NS caused significantly more hyperkalemia and acidosis in renal transplant recipients than plasmalyte.


The evidence is quite uniform and strong in a way that is uncommon for this type of topic. Not only does plasmalyte appear to be safe in renal failure/hyperkalemia, it is actually safer than normal saline. Understanding why this is the case delivers an important lesson in fluid physiology.



  1. http://www.medsafe.govt.nz/profs/Datasheet/p/plasmalytesol.pdf
  2. https://emcrit.org/pulmcrit/myth-busting-lactated-ringers-is-safe-in-hyperkalemia-and-is-superior-to-ns/
  3. Anesth Analg. 2005 May;100(5):1518-24, table of contents. A randomized, double-blind comparison of lactated Ringer’s solution and 0.9% NaCl during renal transplantation. O’Malley CM1, Frumento RJ, Hardy MA, Benvenisty AI, Brentjens TE, Mercer JS, Bennett-Guerrero E.
  4. Ren Fail. 2008;30(5):535-9. doi: 10.1080/08860220802064770. Effects of normal saline vs. lactated ringer’s during renal transplantation. Khajavi MR1, Etezadi F, Moharari RS, Imani F, Meysamie AP, Khashayar P, Najafi A.
  5. Saudi J Kidney Dis Transpl. 2012 Jan;23(1):135-7. A comparative study of impact of infusion of Ringer’s Lactate solution versus normal saline on acid-base balance and serum electrolytes during live related renal transplantation. Modi MP, Vora KS, Parikh GP, Shah VR.
  6. Perioperative Plasma-Lyte use reduces the incidence of renal replacement therapy and hyperkalaemia following renal transplantation when compared with 0.9% saline: a retrospective cohort study . Anamika Adwaney David W Randall  Mark J Blunden  John R Prowle Christopher J Kirwan. Clinical Kidney Journal, Volume 10, Issue 6, 1 December 2017, Pages 838–844, https://doi.org/10.1093/ckj/sfx040
  7. Effects of intraoperative and early postoperative normal saline or Plasma-Lyte 148® on hyperkalaemia in deceased donor renal transplantation: a double-blind randomized trial. BJA October 2017Volume 119, Issue 4, Pages 606–615. L. Weinberg, L. Harris, R. Bellomo, F.L. Ierino, D. Story, G. Eastwood, M. Collins, L. Churilov, P.F. Mount