The effect of artificial colloid solutions on renal function in severely ill dogs
MeSH keywords:acute kidney injury, dog, plasma substitutes
Colloid solutions are compounds with high molecular weight that remain intravascularly after their intravenous administration, thereby increasing colloid oncotic pressure. Colloids are of two types: natural (whole blood, albumins) and artificial (dextran and gelatine solutions, hydroxyethyl starches). Indications for artificial colloids (AC) administration include hypovolemic shock, hypoalbuminemia, haemorrhage, sepsis, hypotension or fluid accumulation in the interstitial space. Their use can be greatly beneficial; however, it can lead to anaphylactic reactions, coagulopathies, acute kidney injury (AKI) and hepatic impairment, especially when given in patients with sepsis. The aim of this systematic review was to investigate the association between AC administration and AKI development in intensive care unit (ICU) in dogs. The studies were collected from the major medical electronic databases. Only three studies met the inclusion criteria. These studies were evaluated for their methods, the limitations were identified, and the results were presented. As it turns out from the three studies, the administration of 6% hydroxyethyl starch (HES) 130/0.4 and 250/0.5/5:1 is not associated with AKI and it does not increase the mortality rate in ICU patients, when given constantly up to 10 days or in low doses. This review is highly informative, as until today, there are no guidelines for AC administration in companion animals. AC administration seems to be beneficial and safe in some cases, when given in low doses and for specific time period. However, the existing data is limited, and further clinical studies are needed to establish safer results.
Colloid solutions are consisted of large molecules (>10 kDa), that tend to remain intravascularly after intravenous administration, and they increase blood viscosity as well as colloidal pressure (Silverstein & Hooper 2015a). They can be natural or artificial. Artificial colloids (AC) may consist of various molecular weights particles. In the past, these solutions were characterized from their average molecular weight (Mw) per weight. Later, colloids were described by their average molecular weight (Mn) (calculating the total weight of molecules divided by the number of molecules). In clinical practice, understanding these terms is important, because the oncotic pressure generated by these solutions depends on the number of the present particles, whereas their duration is determined by the size of those particles (DiBartola 2012a).
Molecules of colloid solutions are larger than the endothelial pores of the capillaries. Therefore, they cannot pass through the endothelial pores, maintaining the intravascular colloid osmotic pressure. Colloid solutions are negatively charged and tend to attract sodium ions and water, thus increasing even more the intravascular volume (Gibbs-Donnan effect) (Rudloff & Kirby 2001).
The duration effect of AC administration on the circulating blood volume is related to the type of their molecules, as their half-life in blood plasma is proportional to their size. Starchy AC are mainly excreted by kidneys. Small molecules are subjected to renal glomerular filtration and they are quickly expelled through renal excretion, causing transient osmotic diuresis. On the contrary, larger molecules must firstly be dispersed and metabolized into smaller molecules and then be excreted by renal or gastrointestinal system (Silverstein & Hopper 2015a, Seymour & Gleed 1999).
AC commonly used in Veterinary Medicine are of three types: hydroxyethyl starch (HES) derivatives, dextrans and gelatines.
The composition of HES derivatives results from partial amylopectin hydrolysis and the following characteristics are used for the distinction of HES solutions (DiBartola 2012b, Silverstein & Hopper 2015a, Byers 2017):
- Concentration mainly affects the initial volume. A typical concentration of 6% is normovolemic in vivo, so 1 L of the solution can replace 1 L of blood loss. Concentrations range from 6% to 10%.
- Molecular substitution refers to the conversion of the initial substance when adding a hydroxyethyl group. The higher the degree of molecular substitution, the greater the resistance of decomposition of molecules. Therefore, the solution remains intravascular for a long time period. The 0.7 value suggests that the HES solution has an average of 7 hydroxyethyl residues per 10 glucose subunits. Starches with this substitution degree are called hetastarches and similar names can be used to describe other substitution degrees (0.4 tetrastarch, 0.5 pentastarch, 0.6 hexastarch).
- Hetastarch has an average molecular weight of 450 kDa, pentastarch 260 kDa and tetrastarch 130 kDa. The decomposition of larger molecules is slower and therefore solutions with higher average molecular weight are long-acting.
- C2:C6 ratio refers to the position at the initial glucose molecule where the molecular substitution takes place. The higher the C2:C6 ratio, the longer the half-life of the solution and the maintenance in the blood.
Dextrans are linear polysaccharides, produced by specific species of the bacteria Leuconostoc, growing in a sucrose substrate. They can be found in low or high molecular weight solutions (dextrans-40 and dextrans-70, respectively), with a half-life in blood plasma estimated from 1 to 3 and 2 to 6 hours, respectively. Dextrans-40 have an average molecular weight of 40 kDa and are contained in 6% solutions (60 g L-1), whereas dextrans-70 have an average molecular weight of 70 kDa and are contained in 10% solutions (100 g L-1).
Gelatines are formed from bovine collagen hydrolysis, electrified or urea crosslinked. There are three types of gelatine formulations and these are acid-polygelatine, succinylated gelatine and urea crosslinked gelatine. In comparison with the rest of the AC solutions, gelatines have low molecular weight, thus they can be rapidly excreted by renal system (DiBartola 2012a).
The administration of AC solutions is indicated for hypovolemic shock revitalization, hypoalbuminemia, blood loss, sepsis, unresponsive hypotension or fluid accumulation in the interstitial space (Seymour & Gleed 1999). There is no proven consensus regarding the proper use of AC and their possible complications/adverse effects, in both human and veterinary medicine (Wong & Koenig 2017).
In human medicine, AC administration can cause coagulation abnormalities, acute kidney injury (AKI) and increased mortality. Itching, liver disease and anaphylactic reactions are some other reported side effects. Moreover, the administration of HES can lead to impairment of platelet function, reduction in von Willebrand and VIII factors and acquired fibrinogen deficiency or dysfunction. Dextrans and gelatines have also been proven to interfere in primary and secondary haemostasis. Furthermore, all types of AC have been related to renal dysfunction. However, HES solutions are more frequently implicated in such complications (Cazzolli & Prittie 2015).
In veterinary medicine, lack of scientific evidence leads to the use of dose rates, indications and guidelines based on human and laboratory animal research (Adamik et al. 2015). Similar complications have also been reported in animals, following AC administration such as coagulation disorder, anaphylactic reaction, AKI and deaths.
Especially, in animals treated with HES solution, von Willebrand and VIII factors can be reduced up to 40% and the active partial thromboplastin time as well as the platelet aggregation formation can be prolonged. Nevertheless, these abnormalities have no clinical significance and do not cause haemorrhage when the solutions are being used according to manufacturer's instructions, and their administration is avoided in animals with hereditary coagulation disorder (Mazzaferro 2008). HES solutions administration has also been related to AKI, anaphylactic reactions, accumulation in tissues and itching (Adamik et al. 2015).
Dextrans with low molecular weight can cause renal failure from renal tubular obstruction, when used in animals suffering from renal impairment. In addition, they can alter coagulation profile as well as the blood type, because of their ability to cover the surface of erythrocytes and platelets (Mazzaferro 2008). The administration of dextrans and gelatines solutions has been related to high risk of anaphylactic reactions, and as a result they are rarely been chosen for treatment in veterinary medicine (Wong & Koenig 2017).
In veterinary medicine, clinicians tend to avoid AC solutions administration. The aim of this review is to investigate the association between AC solutions administration and AKI development as well as increased mortality rate in ICU dog patients.
The studies were searched in two databases, the United States National Library of Medicine (PubMed) and the Elsevier's Scopus. For this review the following phrases were used as keywords in order to detect the studies: acute kidney injury and colloids in dogs, colloids in critically ill dogs and acute kidney injury, hetastarch in dogs and acute kidney injury and dextran in dogs and acute kidney injury (Table 1). In order to have more accurate results and avoid any personal mistakes, all members of the team took part in the research procedure. The suitability of studies for this systematic review was determined according to the following inclusion and exclusion criteria.
|MeSH Keywords||Results||Related to the topic||Relevant|
|Acute kidney injury and colloids in dogs||PubMed: 20 Scopus: 9||PubMed: 7 Scopus: 4||1|
|Colloids in critically ill dogs and acute kidneyinjury||PubMed: 2 Scopus: 0||PubMed: 1 Scopus: 0||1|
|Hetastarch in dogs and acute kidney injury||PubMed: 13 Scopus: 16||PubMed: 6 Scopus: 8||3|
|Dextrans in dogs and acute kidney injury||PubMed: 17 Scopus: 4||PubMed: 1 Scopus: 1||0|
Studies were suitable for the review if:
- They were written in English
- They were clinical, retrospective and retrospective cohort studies
- They included ICU dog patients
- The patients were suffering from AKI
- AC solutions were administered
Studies were excluded from the review if:
- They were written in a language other than English
- They were available only in an abstract form
- They were irrelevant to the AC effect on renal function in ICU dog patients
- They were experimental
- They included species other than dog
- AC solutions were not administered
- They were narrative reviews
Firstly, studies were selected by screening the titles and abstracts in order to exclude the irrelevant ones and distinguish the most appropriate. Then, the reviewers read the whole texts. Totally, 81 articles were found, from which studies that appeared twice and those that had irrelevant subject were removed. Finally, only three studies were suitable and met the inclusion criteria (Figure 1).
The aim of the first study (Sigrist et al. 2017) was to compare the AKI grades after HES or crystalloid solutions administration, at time point 0, 2-10 days (short-term AKI grade) and 11-90 days after the administration (long-term AKI grade). AKI grades were defined by International Renal Interest Society (IRIS) guidelines in dogs and they were modified according to the aim of the review. This study was conducted on 184 dogs admitted to the ICU. For up to 16 days maximum 94 of 184 dogs received ≥1 mL kg-1 6% HES 130/0.4, whereas 90 of 184 received isotonic crystalloid fluids. There were differences between the two groups, such as age, blood product requirements, serum albumin concentration and diagnosis. However, these differences were statistically non-significant risk factors. Therefore, the study results were not strongly biased by these parameters. The study showed that short- and long-term AKI grades of both groups were significantly non-different. Additionally, there was no significant association among HES exposure or the amount (ml kg-1) of HES daily and an increase in AKI grade. However, HES administration for a time period within or greater than 10 days was significantly associated with an increase in AKI grade.
The goal of the second study (Hayes et al. 2015) was to determine the frequency of AKI development and death in a population of ICU dogs treated with HES, in comparison with the whole ICU population. AKI development was defined as a double increase in admission serum creatinine concentration or development of oliguria/anuria of <0.5 ml kg-1 h-1. This study was conducted on 422 dog patients admitted to the ICU. For a specific time period up to 134 hours, 180 of 422 dogs received 10% HES (250/0.5/5:1) either as incremental boluses and dose 8.2 ml kg-1 daily, or as a continuous rate infusion and dose 5-1.3 ml kg-1 daily. The rest of the dogs (242/422) were not treated with HES. There were differences between the two groups, such as age, gender, diagnosis, serum albumin concentration and the administration of crystalloids, HES or blood products. However, these differences were statistically non-significant risk factors. Data were collected during hospitalization. Hence, long-term effects of HES administration are limited. This study revealed that HES administration was evaluated as an independent predictor of AKI development or increased death rate in animals treated with. However, there was a correlation between the amount of HES administered and an increased rate of mortality or AKI development, when compared with animals treated with lower dose rates of HES.
The third study (Adamik et al. 2015) aimed to evaluate changes in plasma creatinine concentrations 2-13 days (T1) and 2-12 weeks (T2) after initiation of fluid treatment (T0: creatinine concentration at admission to the ICU). This study was conducted on 201 dogs admitted to ICU with initial plasma creatinine concentration not exciding laboratory reference values. One-hundred-fifteen out of 201 dogs were treated with crystalloid solutions alone and the rest (86) received 25 ml kg-1 daily of 6% HES 130/0.4 with or without crystalloid solutions for at least 24 hours. Creatinine was measured at various time points after fluids administration in every patient, reflecting different AKI grade each time. There was non-significant difference observed in creatinine concentrations measured at various time points between the groups.
Three retrospective studies dealing with acute renal failure were evaluated for serum creatinine concentration changes and increased death rate in animals admitted to the ICU, which were treated with 6% HES 130/0.4 and HES 250/0.5/5:1 for a specific time period. It seemed that the administration of this specific colloid did not affect AKI development or mortality rate compared to animals not treated with it. However, the first study showed that there might be a correlation between the time period this AC was used and an adverse outcome. More specifically, 6% HES 130/0.4 administration over 10 days was significantly associated with an increase in AKI grade in ICU patients. In the second study, the amount of HES administered was associated with a high risk of mortality or AKI development if compared with animals treated with lower doses of HES. Lastly, the third study revealed that HES administration did not affect creatinine concentration of the examined canine population.
However, there were some general limitations. The nature of this review as well as the retrospective style of the examined studies resulted in various limitations in interpreting and drawing conclusions. An important limitation is the absence of adequate stratification of the patients, thus introducing serious bias in the interpretation of their severity of illness and possible relation to kidney injury. Another limitation is the lack of randomization of fluid types administered, as HES was administered in life-saving cases of critically ill dogs, which had increased possibility of death or AKI development. Furthermore, the selection of fluid treatment was at the discretion of the veterinarian that undertakes the case. Another factor of concern is the co-existing hypoalbuminemia in patients treated with HES, which can lead to bad prognosis. Lastly, the previous use of nephrotoxic substances was not evaluated at any of these studies.
Until today, only three studies in veterinary medicine have been published and relate AC administration to AKI development or increased mortality rate in dogs admitted to ICU. Results show that 6% HES 130/0.4 and 250/0.5/5:1 administration did not affect AKI development or mortality rate in dogs admitted to ICU, when given constantly up to 10 days or in low doses. However, further clinical studies are needed to establish safer results.
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