These are the physiological effects of infusing one litre of 4% solution of succinylated bovine gelatine.

What am I giving?

This 1 litre of Gelofusine contains 154 mmol of sodium, 120mmol chloride and about 40g of succinylated bovine gelatin.

effect of infusing 1 litre of gelofusine

Change to the initial conditions: distribution of volume

Let us first consider the behaviour of the crystalloid, which is old and familiar.

Again, if we ignore the gelatin, the water is distributed according to the distribution of sodium and chloride, and you would end up with about 246ml in the intravascular compartment and 739ml in the interstitial space.

However, that is boring.

We all already know what would happen if some isotonic sodium-rich fluid was infused into a person, the water would slosh around and generally they would end up with about one quarter of the volume in the vessels, and the rest in the interstitial space.

The exciting part is what happens to those 40 grams of gelatin.

The physico-chemical properties of succinylated bovine gelatin.

This is the irreversibly hydrolysed end-product of collagen. Collagen, an organised helical protein, tends to break down into shorter stands which arrange themselves more chaotically. Hydrolysis of collagen would be known well to anybody who has ever slow-cooked a leg of lamb; the application of heat in the presence of water is relied upon to dissolve the collagen strands in the meat, and make it tender (or, turn it into mush, depending on one's level of skill).

It has a viscosity of around 1.9poise (yes, the unit of viscosity is poise, named after Jean Leonard Marie Poiseuille); that means it is about twice as viscous as water.

The elongated shape of the gelatin molecule lends to it the ability to slip through a healthy glomerular basement membrane in spite of the charge barrier. In comparison, a similarly weighted albumin molecule, being more globular, cannot fit though that sieve, and conventionally its renal excretion rate approaches zero. This is probably the chief difference responsible for the difference in the pharmacokinetics of gelofusine and albumin.

The metabolic fate of bovine gelatin

To answer the question "what happens to all that bovine material", we again turn to the early pioneers of medical research, who (in 1945) held forth extensively on the metabolic fate of intravenously administered bovine gelatin.

clearance of infused gelofusine

As the gelatin is infused, the serum concentration of gelatin increases to a maximum (in the study, serum gelatin concentration rose to about 8g/L. Over the next 4-6 hours there is a rapid fall in serum gelatin concentration, presumably reflecting a redistribution of gelatin into the interstitial compartment. This is consistent with Lobo's human experiments - Lobo found that 50% of the infused volume disappeared into the interstitium at 4-6 hours.

After this initial redistribution, about 80% of the infused gelatin slowly escapes the body via the glomerulus. Certainly, 5 or so days later there is still a little gelatin in the urine.

metabolic fate of infused gelofusine.jpg

What happens to the other 20%, which does not get renally cleared? The general thinking is that it is destroyed by peptidases. Some intelligent army officers in 1955 considered this, and assumed that in patients with renal failure, gelatin clearance would rely on this sort of metabolism. Indeed, on direct observation of oliguric casualty victims, they found that the serum gelatin concentration still followed the normal curve; i.e. instead of being cleared renally, the gelatin was still disappearing somewhere at roughly the same rate.

I am unable to track down the precise details of its metabolism, but it is clear that the peptides which make up gelatin do end up broken up into amino acids, and contribute to nutrition. Certainly, the nitrogen balance of starved protein-depleted dogs seem to be well sustained by IV gelatin alone.

So, at least for a time, you can survive on pure intravenous bovine gelatin.

What if I drank it?

Then you would be in strange company. A crazed British intern had tried some, and likened it to the taste of semen. Certainly, the composition of gelofusine is completely digestable, and if one were to drink the entire 500ml bag, one would be able to metabolise it with a net gain of 12.4 calories.

An even more interesting proposition would be to chill it to 3° , and form some sort of obscene jelly mold.

Complications of bovine gelatin infusion

Vegans may protest the act of being infused with the diluted remains of a murdered animal. Additionally, practicing Hindus may object to it, as it would construe the consumption of beef products, which in their culture is prohibited. So, one may say that the loss of moral high ground is one of the complications.

But, there are also physiological complications.

40 grams of foreign farmyard-derived material has been introduced into your blood stream. It does not belong there. Of course there are consequences.

Early dog experiments with various gelatinous products had yielded results which filled the observers with a certain sort of optimism. it was not antigenic; the puppies did not develop anaphylactic reactions, nor did their kidneys clog with gelatin, nor did their hearts stop from microemboli. However, many issues did arise, though the trend back then was to minimise them.

Procoagulability

There is thromboelastogram evidence that gelofusine increases the rate of clot formation. The early dog studies also reported a markedly (directly observed) increase in the rate of erythrocyte clumping and sedimentation. Does this influence outcomes? Probably not. Colloids dilute the plasma and the concentration of clotting factors decreases. On top of that, gelatin molecules are incorporated into the clot, which may (negatively) influence its strength.

Anaphylaxis

Severe anaphylactic reactions with gelofusine are disturbingly common. About 1 in every 13,000 patients develops one, according to a government guidelines document. It seems that people who are allergic to the MMR vaccine are at greater risk.

Intravascular volume expansion in response to the infusion of gelofusine

As mentioned elsewhere, the embarrassing tendency of the gelatin to coagulate and solidify was ultimately defeated by using increasingly shorter and shorter strands. This was combined with succinylation, which has resulted in a product with a massive anionic charge per molecule, on par with that of albumin.

The 4% gelofusine solution is roughly equivalent (in terms of oncotic pressure) to a jug of 4% albumin, or to normal human plasma (which has 40g/L of albumin in it).

From these comparisons, one might surmise that like albumin, gelatin could be expected to attract about 10-11ml of water per gram into the intravascular space.

But anyway- this is all irrelevant. The pragmatic intensivists would become enraged at this sort of fluff. The real question, they would say, is "how well does this work as a volume expander"?

Experiments with human victims have yielded a satisfying answer to this question. Again, D.N. Lobo is to thank for this. According to his well designed study, after receiving 1 litre of Gelofusine over 1 hour, 79% of the volume managed to stay in the intravascular compartment.

After 6 hours, about half of this volume expansion effect had been lost. The transcapillary escape of gelofusine is much faster than that of human albumin (which stays intravascular for much longer, with 50% still circulating after 48 hours), but much slower than that of any crystalloid (which equilibrates its volume between compartments within a few minutes).

Changes in initial conditions: distribution of the major electrolytes

So, let us observe the patient at the end of an infusion of gelofusine. We will use Lobo's empirical data, and assume that the intravascular volume has expanded by 790ml.

distribution of fluid and electrolytes in reponse to the infusion of gelofusine

Osmoreceptor response

The osmoreceptors remain unperturbed, as the serum osmolality has not budged. Gelofusine is essentially an isoosmolar fluid, and the change in tonicity is minimal.

Baroreceptor response

Here, however, there has been a significant change. As the volume has increased by over 15%, there is a compensatory decrease in heart rate and contractility. The baroreceptor firing rate decreases. This ushers forth the satisfying resolution of tachycardia in a shocked patient you are resuscitating.

References

HOGAN, JAMES J. "The intravenous use of colloidal (gelatin) solutions in shock." Journal of the American Medical Association 64.9 (1915): 721-726.

Braun have a product information pamphlet, detailing the contents and properties of their brand of Gelofusine.

Patel, Kinesh. "End the silence on animal products in drugs." BMJ: British Medical Journal 346 (2013).

Lobo, Dileep N., et al. "Effect of volume loading with 1 liter intravenous infusions of 0.9% saline, 4% succinylated gelatine (Gelofusine) and 6% hydroxyethyl starch (Voluven) on blood volume and endocrine responses: a randomized, three-way crossover study in healthy volunteers." Critical care medicine 38.2 (2010): 464-470.

Parkins, W. M., et al. "Gelatin as a plasma substitute with particular reference to experimental hemorrhage and burn shock." Annals of Surgery 118.2 (1943): 193.

Karoutsos, S., et al. "Thrombelastogram reveals hypercoagulability after administration of gelatin solution." British journal of anaesthesia 82.2 (1999): 175-177.

Hoffman, William S., and Donald D. Kozoll. "The fate of intravenously injected gelatin in human subjects." Journal of Clinical Investigation 25.4 (1946): 575.

Wan, L., R. Bellomo, and C. N. May. "A comparison of 4% succinylated gelatin solution versus normal saline in stable normovolaemic sheep: global haemodynamic, regional blood flow and oxygen delivery effects." Anaesthesia and intensive care 35.6 (2007): 924.

Zekorn, D. "Intravascular retention, dispersal, excretion and break-down of gelatin plasma substitutes." Bibliotheca haematologica 33 (1969): 131. - this sounds like a very useful reference, but I have no access to it.

Howard, J. M., et al. "The fate of dextran and modified gelatine in casualties with renal insufficiency." Surgery, gynecology & obstetrics 100.2 (1955): 207.

Brunschwig, Alexander, et al. "Observations on the Intravenous Injection of Gelatin for Nutritional Purposes." Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, NY). Vol. 52. No. 1. Royal Society of Medicine, 1943.

Apostolou, Effie, et al. "Anaphylaxis to Gelofusine® confirmed by in vitro basophil activation test: a case series*." Anaesthesia 61.3 (2006): 264-268.