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Do gelatin colloids and Hetastarch result in renal tubular injury during shock? | VETgirl Veterinary Continuing Education Podcasts

In today’s VETgirl online veterinary continuing education podcast, we review whether the use of gelatin colloids and hydroxyethyl starch (HES) result in renal tubular injury during shock.

When dealing with hypotension in our dogs and cats, we have a limited array of tools to help us maintain blood pressure. We can use vasopressors to improve the muscular tone of weakened blood vessels, inotropic medications to improve cardiac contractility with the hopes of resultant increased output, and most commonly, we use fluid therapy to increase volume within the blood vessels. For fluids, we can use crystalloids to add water and electrolytes to our blood. Now, although crystalloid administration is a quick way to increase blood pressure, it’s very short-lived and won’t hang out for a long time in the blood vessels as it migrates to the interstitial spaces. Colloids offer a longer lasting effect on blood pressure because they hang out inside the blood vessels longer (by increasing colloid osmotic pressure), but colloids have unique drawbacks. If using blood products to maintain blood pressure in the hemorrhagic model, the patient can experience reactions to the blood donor’s blood. Synthetic colloids offer similar oncotic support to blood products, and last longer than crystalloids in the blood vessels, but do not provide any blood components that may be necessary in hemorrhagic shock. And in recent years, synthetic colloids have been implicated in both humans and in dogs to cause acute kidney injury (AKI) in septic patients. Synthetic colloids have been shown to cause damage to renal tubules with resulting AKI, presumably through osmotic injury. Renal tubular cells are thought to ingest molecules of the synthetic colloid through the process of pinocytosis. The presence of colloid materials within the cells results in an osmotic shift of fluid into the cell, causing cellular swelling and disruption of cellular function. We don’t know why this happens more readily in patients already compromised by illness such as sepsis. But our college has now widely changed our once frequent use of synthetic colloids based on the results of studies in septic canines. Now, most of us old hats have vast experience using synthetic colloids in many diseases other than just sepsis and have been met with great success in managing blood pressure issues with their use without any perceivable negative impact on body systems (unless the patient becomes fluid overloaded from overzealous fluid therapy or poor cardiac function). So what diseases are considered “safe” for synthetic colloid use? There is so much legwork to be done in this field for us to determine in which illnesses it is safe to use synthetic colloids, and thankfully the veterinary community is making strides towards understanding this fluid type’s effects on the body across various illnesses. VETgirl’s take? The use of colloids are still an excellent way of fluid resuscitating a patient, but should be avoided in the azotemic patient and the poisoned nephrotoxicant patient.

So, in today’s podcast, we will be focusing on the use of colloids in hemorrhagic shock and evaluating the effects that synthetic colloids have on the kidneys in this condition as compared to autologous fresh whole blood and to crystalloid therapy separately. In a recent JVECC 2019 article, Boyd et al out of Australia wanted to evaluate the effects of synthetic colloids in a study entitled Evaluation of biomarkers of kidney injury following 4% succinylated gelatin and 6% hydroxyethyl starch 130/0.4 administration in a canine hemorrhagic shock model. This study was performed on ex-racing greyhounds and approved by the animal ethics committee. Prior to inclusion in the study, all dogs had the following diagnostics performed: physical exam, PCV, TP, urinalysis, and ultrasound of the kidneys and bladder. All dogs received pre-medication with an intramuscular injection of methadone, induction with alfaxalone, and isoflurane gas anesthesia for maintenance. All dogs received infusions of sodium lactate (Hartmann’s solution), at 10 ml/kg/hr and fentanyl at 2µg/kg/hr. Blood was removed via passive flow from the femoral artery catheter into blood collection bags and any blood that was not given back to the patient was donated to a blood bank. Once patient mean arterial pressure reached 50 mmHg, blood removal was stopped. In order to maintain a BP of 50 mmHg, blood was removed via manual extraction with 60 mL syringes. Dogs were maintained at a blood pressure of 50 mm Hg for 60 minutes, after which time they were administered one of the four study fluids over 20 minutes: autologous whole blood, 6% hydroxyethyl starch (HES), 4% succinylated gelatin (GELO), or 80 mL/kg of crystalloids. All canines were euthanized at the end of the study and cadavers were used for further study at the University. Diagnostics monitored through the study included heart rate, arterial blood pressure, central venous pressure, pulse pressure variation, cardiac output at baseline, at 60 minutes of hypotension, at end of fluid administration, and at 40, 100, and 160 minutes after fluid administration. Cardiac output was measured by lithium dilution. Urine was collected throughout the procedure via urinary catheter and evaluated for evidence of inflammation, creatinine clearance, and fractional excretion of sodium. A total of 27 greyhounds were included in this study with an overrepresentation of males (23) compared to females (4), but 2 males and 1 female were excluded from the study due to problems with study equipment.

Immediately at the end of fluid administration, the fresh whole blood group had the highest venous-arterial difference in carbon dioxide partial pressure and the lowest diuretic effect. The crystalloid group showed greater hemodilution and exhibited the greatest diuresis. The biomarker urine neutrophil gelatinase-associated lipocalin concentration (uNGAL), was significantly increased in the 4% succinylated gelatin group compared to all other groups, indicating renal tubular damage. Confirmation of marked proximal tubular damage in the 4% succinylated gelatin group as compared to all other groups was made on review of renal histopathology. All colloid groups showed variable increases in indicators of renal inflammation compared to the crystalloid group, but only the 4% succinylated gelatin group showed clinically significant changes in the kidneys.

This study demonstrated significant increases in renal tubular injury biomarkers following 4% succinylated gelatin administration in a shock model as compared to hydroxyethyl starch, fresh whole blood, and crystalloids. Most notable were increase in uNGAL, urine clusterin concentration (uCLUST), urine cystatin c (uCYSC), and urine kidney injury molecule-1 concentration (uKIM). These biomarkers indicate the development of AKI despite the fact that other indicators of AKI such as glomerular filtration rate and creatinine clearance were normal in the 4% succinylated gelatin group. Interestingly, the hydroxyethyl starch group showed only mild increases in some of the AKI biomarkers, and the incidence of microvesiculation in the renal tubular cells was the same in the HES group as compared to the fresh whole blood and crystalloid groups. These findings would suggest that use of hydroxyethyl starch in hemorrhagic shock is not likely to cause AKI (or at least not more likely than fresh whole blood or crystalloid administration).

So, what can we take away from this VETgirl podcast? We can take from this study that gelatin colloids can cause renal tubular injury and should not be used to treat hemorrhagic shock. We can also take from this study that using hydroxyethyl starch in the hemorrhagic shock model is not likely to cause AKI, so hydroxyethyl starch can be used to help maintain blood pressure until blood replacement with canine donor or autologous blood can be accomplished. I know further research is being done on this important area, so in the meantime, VETgirl will continue to use hydroxyethyl starch only as needed!

Abbreviations:
AKI – Acute kidney injury
HES – hydroxyethyl starch
GELO – 4% succinylated gelatin
FWB – fresh whole blood
uNGAL – urine neutrophil gelatinase-associated lipocalin concentration
uCLUST – urine clusterin concentration
uCYSC – urine cystatin c
uKIM – urine kidney injury molecule-1 concentration

References:
1. Boyd CJ, Claus MA, Raisis AL, et al. Evaluation of biomarkers of kidney injury following 4% succinylated gelatin and 6% hydroxyethyl starch 130/0.4 administration in a canine hemorrhagic shock model. J Vet Emerg Crit Care 2019;1–11.

 

 

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