Sage Journals: Discover world-class research

Abstract

Objectives

The objective was to determine survival and changes in creatinine concentrations after administration of 6% tetrastarch (hydroxyethyl starch [HES] 130/0.4) vs crystalloids in critically ill cats.

Methods

The medical records were reviewed for cats admitted to the intensive care unit with at least two plasma creatinine measurements and initial concentrations not exceeding the upper reference interval. Cats were excluded if they had received HES prior to admission or if they had received fluid therapy for <24 h between initial and subsequent measurements. Changes in creatinine concentrations were evaluated as the percentage change from initial values to the maximum subsequent measurements. Cats receiving only crystalloids were assigned to the crystalloid group; cats receiving only HES or HES and crystalloids were assigned to the HES group.

Results

Ninety-three cats were included in the study (62 in the crystalloid group, 31 in the HES group). The total median cumulative HES dose was 94 ml/kg (range 26–422 ml/kg) and 24 ml/kg/day (range 16–42 ml/kg/day). No difference was detected between the groups for age, sex, body weight or mortality. The HES group had a significantly longer length of hospitalisation (P = 0.012), lower albumin concentrations (P <0.001), higher Acute Patient Physiologic and Laboratory Evaluation scores (P = 0.037) and higher incidence of systemic inflammatory response syndrome (P = 0.009) and sepsis (P = 0.013). There was no significant difference in initial, maximum or maximum change in creatinine concentrations between the groups. Moreover, there was no significant difference in maximum change in creatinine concentrations in the subgroups of cats with systemic inflammatory response syndrome or sepsis.

Conclusions and relevance

In this population of cats, the administration of HES did not result in a significantly greater increase in creatinine from values measured on admission or higher mortality compared with administration of crystalloids. Further prospective studies are needed to assess both safety and efficacy of HES in cats before recommendations can be made.

Introduction

Hydroxyethyl starch (HES) solutions have been widely used as resuscitation fluids in both humans and animals. However, recent randomised clinical trials (RCTs) and meta-analyses have uncovered alarming associations between HES administration and both acute kidney injury (AKI) and mortality in critically ill people,^1–4 leading drug authorities to take drastic measures limiting their use. As of 2013, and after being on the market for over three decades, HES is now considered contraindicated in critically ill patients, as well as in those with burns, coagulopathies, kidney disease or sepsis.^5,6 Indeed, the use of HES is now largely restricted to patients with acute haemorrhage. Despite these decisions, the debate surrounding the safety and efficacy of HES is still ongoing among academics.^7–11

Guidelines for use of HES in veterinary patients, embedded in review articles and book chapters, have largely been adopted from those published in human medicine or are based on authors’ personal preferences.^12–15 Moreover, evidence of the effects of HES on kidney function in small animals yields conflicting results.^16–19 Given the limited availability of blood products for cats and potential adverse effects associated with the administration of human serum albumin,²⁰ HES is often the only alternative for volume expansion and when colloid osmotic pressure support is required. Therefore, studies evaluating the safety and efficacy of HES in cats are necessary to elaborate rational fluid therapy guidelines for this species.

The aim of this retrospective study was to evaluate the effects of administration of a waxy maize-derived 6% tetrastarch (130/0.4) on survival and creatinine concentrations in critically ill cats. To our knowledge, no previous study has investigated the effects of HES on renal function in critically ill cats.

Materials and methods

The medical records database was reviewed for cats admitted to the intensive care unit (ICU) between 2010 and 2015 with at least two measurements of creatinine concentrations during hospitalisation. Cats were included if the measured creatinine at admission did not exceed the laboratory’s upper reference interval (53–141 µmol/l [0.60–1.60 mg/dl]) and they received intravenous fluids for at least 24 h between the initial and subsequent creatinine measurements. Cats were excluded if they had received HES prior to initial creatinine measurements or if substantial data were missing from the records.

Data collected included age, sex, body weight, length of hospitalisation, cumulative dose of HES, clinical diagnosis, survival to discharge, plasma creatinine concentrations, and initial haematocrit and plasma protein and albumin concentrations. In addition, data from urinalyses, cytology and bacterial culture were collected when available. All cats were evaluated for systemic inflammatory response syndrome (SIRS) on admission, based on the presence of at least three of the following criteria: heart rate >220 beats per min (bpm) or <140 bpm, respiratory rate >40 breaths per min, rectal temperature>40°C (104°F) or <37.8°C (100°F), and leukocyte counts>19,000 cells/μl or <5000 cells/μl.²¹ The presence of sepsis was diagnosed if cats met the SIRS criteria and bacterial infection was confirmed on cytology and/or bacterial culture. An Acute Patient Physiologic and Laboratory Evaluation (APPLE_full) score was calculated based on mentation score, rectal temperature, mean arterial pressure (MAP), body cavity fluid score (from focused assessment sonography for trauma scans,²² radiographs, conventional ultrasound and echocardiography), haematocrit, plasma urea, chloride and lactate concentrations. The worst APPLE_full score evaluated during the first 24 h of admission was used for data analysis. Missing variables were replaced with normal values, equal to 0 in the score.²³

Plasma creatinine concentrations evaluated were those measured at admission (T0) and the maximum concentration measured at any time between 24 h after admission and discharge or death (T1_max). The change in creatinine concentrations from T0 to T1_max was evaluated as a percentage change (T1_max% = [T1_max/T0] × 100). All plasma creatinine concentrations were measured using the same automated chemistry analyser (Cobas c501; Roche Diagnostics), following the manufacturer’s instructions.

For the identification of AKI, all cats were evaluated according to the IRIS AKI grading criteria²⁴ and the Veterinary Acute Kidney Injury Staging System (VAKI) (stage 0: creatinine increase <150%, stage 1: increase of 150–199% or 26.5 μmol/l; stage 2: increase of 200–299%; stage 3: increase of ⩾300% or >354 μmol/l).²⁵

Cats that received only crystalloids (mostly buffered polyionic solutions [Plasma-Lyte; Baxter] and, very occasionally, isotonic saline [NaCl 0.9%; Fresenius Kabi]) were assigned to the crystalloid group (CRYS group); cats that received only HES (6% tetrastarch 130/0.4 [Voluven 6%; Fresenius Kabi]) or both HES and crystalloids were assigned to the HES group (HES group). Subgroups of patients meeting SIRS and sepsis criteria were established within each group.

Statistical analyses were performed using commercial software (MedCalc Statistical Software version 16.2). Summary statistics were performed and data were analysed for normality by examining normal plots and using the D’Agostino–Pearson test. Comparison between groups for categorical data were evaluated using Fisher’s exact test. Comparison between groups for continuous data were evaluated using independent-samples t-tests for normally distributed data and Mann–Whitney tests for non-normally distributed data. Significance was set at P <0.05 throughout.

Results

Ninety-three cats met the inclusion criteria (62 in the CRYS group, 31 in the HES group). Frequent diagnoses (those attributed to at least 10% of cases) included hepatobilliary and pancreatic disease, polytrauma and pyothorax (Table 1). The majority of cats were domestic shorthair (69.9%). Cats in the HES group received a total median cumulative HES dose of 94 ml/kg (range 26–422 ml/kg) and 24 ml/kg/day (range 16–42 ml/kg/day), with a median length of administration of 3.7 days (range 1–13 days).

Table 1

Frequent diagnoses (attributed to ⩾10% at least in one group)

Frequent diagnoses	CRYS group (n = 62)	HES group (n = 31)
Hepatobiliary and pancreatic disease	24.2%	19.4%
Polytrauma	21.0%	9.7%
Pyothorax	8.1%	16.1%

CRYS group = cats treated only with crystalloids; HES group = cats receiving only hydroxyethyl starch (HES) or HES and crystalloids

No significant difference was found between the groups for age, body weight or sex. Cats in the HES group had significantly longer hospitalisation, lower haematocrit, and lower albumin and total protein concentrations at admission (Table 2). Overall mortality was 14% (13 cats). No significant difference was found between the groups for mortality (all deaths were due to euthanasia, 12 because of poor prognosis and one for unclear reasons; Table 2), and no difference was found between cats that died and those that survived for haematocrit (P = 0.222), total protein (P = 0.461) or albumin concentrations (P = 0.248). In addition, no difference was found between cats that died and those that survived for cumulative HES dose in the HES group (P = 0.519).

Table 2

Patient characteristics in 93 cats treated with hydroxyethyl starch (HES group) and crystalloids (CRYS group)

Parameter	CRYS group (n = 62)	HES group (n = 31)	P value
Sex
Female, n (%)	26 (42.9)	16 (51.6)	0.388
Male, n (%)	36 (58.1)	15 (48.4)
Median (IQR) age (years)	5.4 (2.7–9.0)	5.0 (2.2–8.9)	0.613
Median (IQR) length of hospitalisation (days)	6 (4–8)	8 (6–12)	0.012
Median (IQR) body weight (kg)	4.4 (3.6–5.6)	4.1 (3.8–4.6)	0.264
Total protein (g/l)	67.1 ± 9.1	57.8 ± 9.7	<0.001
Total protein (g/dl)	6.71 ± 0.91	5.78 ± 0.97	<0.001
Albumin (g/l)	28.8 ± 6.8	19.8 ± 6.7	<0.001
Albumin (g/dl)	2.88 ± 0.68	1.98 ± 0.67	<0.001
Haematocrit (%)	33.2 ± 8.2	29.5 ± 6.8	0.031
Presence of SIRS, n (%)	13 (20.9)	15 (48.4)	0.009
Presence of sepsis, n (%)	5 (8.0)	9 (40.9)	0.013
Median (IQR) APPLE_full score	41.5 (38.0–47.0)	46.0 (42.0–51.0)	0.037
Mortality, n (%)	8 (12.9)	5 (16.1)	0.754

Data are mean ± SD unless otherwise indicated. Significant values are in bold

IQR = interquartile range; SIRS = systemic inflammatory response syndrome; APPLE_full = Acute Patient Physiologic and Laboratory Evaluation

An APPLE_full score was established for all cats. Missing data represented measurements of lactate (96.8%), MAP (5.3%) and imaging assessment of at least one body cavity (7.5%). The HES group had a significantly higher APPLE_full score than the CRYS group (Table 2). Moreover, significantly more cats in the HES group were classified as having SIRS or sepsis (Table 2). However, no difference was found between cats that died and those that survived for APPLE_full scores (P = 0.292), or presence of SIRS (P = 0.748) or sepsis (P = 0.205).

Creatinine concentrations at T0, T1_max and T1_max% did not differ significantly between the groups (Table 3, Figures 1 and 2). Moreover, no significant difference in T1_max% was found between the groups for cats classified as having SIRS or sepsis (Table 3), and no difference in T1_max% was found between cats that died and those that survived (P = 0.358).

Table 3

Plasma creatinine concentrations in 93 cats treated with hydroxyethyl starch (HES group) and crystalloids (CRYS group)

Parameter	CRYS group (n = 62)	HES group (n = 31)	P value
Mean ± SD T0 (µmol/l)	85.5 ± 21.9	86.6 ± 25.5	0.820
Mean ± SD T0 (mg/dl)	0.97 ± 0.25	0.98 ± 0.29	0.820
T1_max (µmol/l)	83.5 (70.0–99.0)	85.0 (71.8–99.0)	0.588
T1_max (mg/dl)	0.95 (0.79–1.12)	0.96 (0.82–1.12)	0.588
T1_max% in all cats	100.0 (81.0–113.0)	99.0 (81.3–129.3)	0.533
T1_max% in cats with SIRS	109.0 (92.8–117.8)	115.0 (92.8–134.3)	0.596
T1_max% in cats with sepsis	100.0 (90.0–114.0)	99.0 (85.0–153.0)	0.740

Data are median (interquartile range [IQR]) unless otherwise indicated

T0 = plasma creatinine concentration at admission; T1_max = maximum creatinine concentration measured at least 24 h after fluid therapy; T_1max% = percentage change in creatinine concentrations between T0 and T1_max; SIRS = systemic inflammatory response syndrome

Figure 1

Box and whisker plots showing the maximum percentage change in creatinine concentrations in cats receiving crystalloids alone (CRYS group) or hydroxyethyl starch (HES) 130/0.4 with or without crystalloids (HES group)

Figure 2

Frequency chart showing the percentage of cases with different percentage changes in creatinine concentrations in cats receiving crystalloids alone (CRYS group) or HES 130/0.4 with or without crystalloids (HES group)

AKI according to the IRIS AKI grading criteria was found in two cats in the CRYS group (one each in grade II and grade III) and in four cats in the HES group (three in grade II and one in grade III) (P = 0.116). Based on the VAKI staging system, AKI was present in four cats in the CRYS group (one in stage 1 and three in stage 2) and four cats in the HES group (three in stage 1, and one in stage 3) (P = 0.061). Two cats meeting the SIRS criteria (7.1%) and one cat diagnosed with sepsis (7.1%) were classified as having AKI with at least one of the staging systems.

Discussion

Several RCTs have shown an association between HES administration and both AKI and mortality in people.^1–3 The proposed mechanism may be related to osmotic nephrosis following HES accumulation in proximal tubular epithelial cells, where it is stored in lysosomes, causing cellular swelling and dysfunction.^1,26 Although HES accumulation has been documented in canine kidneys, this has not thus far been shown to result in functional renal damage.²⁷ To our knowledge, tissue storage of HES has not been documented in cats.

One of the three recent retrospective studies evaluating HES-associated AKI in critically ill dogs found an increased risk for AKI and mortality after pentastarch administration.¹⁸ The second study showed a higher mortality rate but no increased risk of AKI after tetrastarch.¹⁷ The third study also evaluating tetrastarch could not demonstrate either an increased mortality rate or increased risk of AKI.¹⁹ This apparent discrepancy in clinical findings may, in part, be due to the different HES preparations used. Indeed, it is known that the older-generation pentastarch may have a lower safety profile than some of the newer-generation tetrastarch products available.²⁸ In addition, differences within the cohort population and, in particular, different endpoint definitions of AKI make direct comparison between these three studies difficult. One prospective study, evaluating AKI in dogs with septic peritonitis, found increasedlevels of the urinary biomarker neutrophil gelatinase-associated lipocalin in dogs that received HES.¹⁶ Similarly to the aforementioned studies, patients were not randomised in the prospective study, which might have led to the more severely ill patients receiving HES.

In the present study, no differences in absolute or percentage changes in creatinine were found between cats receiving HES and those receiving crystalloids alone. Moreover, no difference was found between the groups for the development of AKI. However, only six and eight cats developed AKI based on IRIS and VAKI staging, respectively. These contradicting findings may be due to interspecies differences in kidney morphology and function,²⁹ in terms of metabolism³⁰ and excretion of HES.³¹ Whether this may be the case for cats is unclear as investigations on HES metabolism in this species are lacking. In addition, the deleterious effects of HES on the kidneys are both time-related and dose-dependent, and most human studies evaluated 90 day mortality and AKI.^1–3,32 In the present study, the median length of administration was relatively short and mortality could be evaluated only to hospital discharge. Additionally, the median dose did not exceed the manufacturer’s recommendations,³³ which was a point criticised in human RCTs.¹⁰

Renal damage associated with HES may be exacerbated by pre-existing kidney injury,²⁶ and such patients were largely enrolled in the aforementioned human RCTs.^1,3 Likewise, the definition of AKI was a two-fold increase in creatinine, regardless of initial creatinine concentrations in the canine retrospective study showing pentastarch-associated AKI.¹⁸ However, similarly to the canine tetrastarch study,¹⁷ in the present study cats with azotaemia were excluded to avoid possible bias of pre-existing kidney disease. Whether or not this disparity in study design was, at least in part, responsible for the discrepant findings of these studies, is not clear.

Human septic patients have a higher incidence of AKI (13%−64%) than other critically ill patients.³⁴ A high incidence of HES-associated AKI observed in human RCTs was found in a cohort of septic patients.¹ Indeed, one human RCT conducted on all ICU patients (regardless of presence of sepsis) failed to demonstrate HES-associated AKI.³ In the present study, no association between HES administration and increased creatinine was found, but the cohort was cats admitted to the ICU with a variety of diseases and only 14/93 cats were diagnosed with sepsis. Larger numbers of septic cats should therefore be evaluated for HES-associated AKI before recommendations can be made.

A further reason for apparent discrepant findings between veterinary and human studies with regard to HES-associated AKI may be a general higher severity of illness and more aggressive and longer treatments in human ICU patients. This may be reasonable to assume given cost restrictions for clients, an option for euthanasia and a lower social value in veterinary patients.

A lack of association between HES administration and mortality in cats in the present study conflicts with findings in both dogs and people. Although, development of AKI was a risk factor for mortality in people receiving HES,¹ studies in cats failed to demonstrate an association between creatinine concentrations and survival, which might account for this inconsistency.^35–37

Creatinine is considered to be a very insensitive and late biomarker for AKI.³⁸ Nonetheless, current AKI staging systems in both people and small animals are based on creatinine levels, urinary output and glomerular filtration rates.^{24,25,39–41} Urinary biomarkers have gained popularity as more sensitive methods of assessing AKI, but the lack of standardisation of the assays makes them less assessable for routine measurement in small animals.³⁸ Whether evidence of HES-associated kidney injury may be found in cats using more sensitive biomarkers remains to be elucidated.

No association was found between the presence of SIRS or sepsis and mortality in this study. However, SIRS criteria for dogs and cats were established in the 1990s and early 2000s using small groups of patients,^42,43 and their validity has been questioned.^44,45 Variability in performance of SIRS criteria and the diagnosis of sepsis based on these criteria may therefore have contributed to the lack of association with mortality in this study. Recently, these criteria were replaced in people by the sequential (sepsis-related) organ failure assessment (SOFA) score,⁴⁶ which showed good capacity to predict outcome in dogs,⁴⁷ but has not been evaluated in cats.

The apparent lack of association between APPLE_full scores and mortality may be due, at least in part, to missing data (particularly lactate) in a large proportion of cats. Nevertheless, as missing data were replaced with normal values, this would have artificially lowered the score. If the actual scores were higher, this would have resulted in an even higher disagreement with the score’s predicted mortality of 30%−50% compared with the actual mortality of 14% in the present study. Given that neither of the two feline APPLE_full and APPLE_fast scores have been evaluated outside of their original setting, their validity in other settings remains unclear. Both differences in cohorts and overall mortality between the original feline APPLE score publication and the present study, and possible differences in performance between the institutions, may have contributed to the inaccurate predictions.

Other limitations of this study are largely related to its retrospective nature and the relatively small number of cats evaluated. Diagnoses differed between the two groups, resulting in heterogeneity, which might have biased results. All treatments were given at the discretion of clinicians and the use of potential nephrotoxic drugs prior to or during hospitalisation was not evaluated. Overall mortality was low, which might be the result of different criteria for ICU admission compared with other institutions. Measurements of creatinine following fluid therapy were performed at different time points, and long-term assessment was not possible. Moreover, cats with azotaemia on admission were excluded, such that the effects of HES on feline kidneys with pre-existing disease were not evaluated. Lastly, multiple univariate analyses were performed to investigate the impact of possible predictor variables on outcome (alive/dead) and group (HES/CRYS) as the number of cats was too low for multivariate analysis with the desired number of predictor variables based on previous recommendations.⁴⁸

Conclusions

This study showed no association between HES administration and AKI or mortality in a population of ICU cats using recommended doses over a short period of time. Further prospective studies are needed to establish the safety of HES in specific subpopulations of cats, such as those with sepsis or pre-existing renal disease, and over longer time periods. Despite several decades of HES use in cats, additional research on both safety and efficacy is warranted.

Footnotes

Accepted: 23 September 2016

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

References

Perner

Haase

Guttormsen

, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med 2012; 367: 124–134.

Brunkhorst

Engel

Bloos

, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358: 125–139.

Myburgh

Finfer

Bellomo

, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012; 367: 1901–1911.

Zarychanski

Abou-Setta

Turgeon

, et al. Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis. JAMA 2013; 309: 678–688.

European Medicines Agency. Hydroxyethyl-starch solutions (HES) should no longer be used in patients with sepsis or burn injuries or in critically ill patients. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Hydroxyethyl_starch-containing_solutions/human_referral_prac_000012.jsp&mid=WC0b01ac05805c516f2013 (2014, accessed October, 14 2016).

US Food and Drug Administration. Hydroxyethyl starch solutions: FDA safety communication – boxed warning of increased mortality and severe renal injury and risk of bleeding. http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm358349.htm (2013, accessed October, 14 2016).

Schindler

Marx

. Evidence-based fluid management in the ICU. Curr Opin Anaesthesiol 2016; 29: 158–165.

Wiedermann

. Low-quality trials as a source of heterogeneity in the association of hydroxyethyl starch 130/0.4 or 0.42 with excess mortality in sepsis. Chin Med J 2016; 129: 116–117.

Doshi

. Data too important to share: do those who control the data control the message? BMJ 2016; 352: i1027.

10.

Chappell

Jacob

. Hydroxyethyl starch – the importance of being earnest. Scand J Trauma Resusc Emerg Med 2013; 21: 61.

11.

Cazzolli

Prittie

. The crystalloid-colloid debate: consequences of resuscitation fluid selection in veterinary critical care. J Vet Emerg Crit Care (San Antonio) 2015; 25: 6–19.

12.

Davis

Jensen

Johnson

, et al. 2013 AAHA/AAFP fluid therapy guidelines for dogs and cats. J Am Anim Hosp Assoc 2013; 49: 149–159.

13.

Mazzaferro

Powell

. Fluid therapy for the emergent small animal patient: crystalloids, colloids, and albumin products. Vet Clin North Am Small Anim Pract 2013; 43: 721–734.

14.

Glover

Rudloff

Kirby

. Hydroxyethyl starch:a review of pharmacokinetics, pharmacodynamics, current products, and potential clinical risks, benefits, and use. J Vet Emerg Crit Care (San Antonio) 2014; 24: 642–661.

15.

Adamik

Yozova

Regenscheit

. Controversies in the use of hydroxyethyl starch solutions in small animal emergency and critical care. J Vet Emerg Crit Care 2015; 25: 20–47.

16.

Cortellini

Pelligand

Syme

, et al. Neutrophil gelatinase-associated lipocalin in dogs with sepsis undergoing emergency laparotomy: a prospective case-control study. J Vet Intern Med 2015; 29: 1595–1602.

17.

Yozova

Howard

Adamik

. Retrospective evaluation of the effects of administration of tetrastarch (hydroxyethyl starch 130/0.4) on plasma creatinine concentration in dogs (2010–2013): 201 dogs. J Vet Emerg Crit Care (San Antonio) 2016; 26: 568–577.

18.

Hayes

Benedicenti

Mathews

. Retrospective cohort study on the incidence of acute kidney injury and death following hydroxyethyl starch (HES 10% 250/0.5/5:1) administration in dogs (2007–2010). J Vet Emerg Crit Care (San Antonio) 2016; 26: 35–40.

19.

Sigrist

Kaelin

Dreyfus

. Historical cohort study evaluating the effect of hydroxyethyl-starch (HES-130/0.4) on serum creatinine and AKI-stage in dogs admitted to the ICU (2013–2015) [abstract]. J Vet Emerg Crit Care (San Antonio) 2016; 26 Suppl 1: S25.

20.

Cohn

Kerl

Lenox

, et al. Response of healthy dogs to infusions of human serum albumin. Am J Vet Res 2007; 68: 657–663.

21.

De Laforcade

. Systemic inflammatory response syndrome. In: Silverstein

Hopper

(eds). Small animal critical care medicine. 2nd ed. St Louis, MO: WB Saunders, 2014, pp 30–34.

22.

Boysen

Lisciandro

. The use of ultrasound for dogs and cats in the emergency room: AFAST and TFAST. Vet Clin North Am Small Anim Pract 2013; 43: 773–797.

23.

Hayes

Mathews

Doig

, et al. The Feline Acute Patient Physiologic and Laboratory Evaluation (Feline APPLE) Score: a severity of illness stratification system for hospitalized cats. J Vet Intern Med 2011; 25: 26–38.

24.

IRIS. Grading of acute kidney injury. http://iris-kidney.com/pdf/iris-grading-of-acute-kidney-injury-(final).pdf (2013, accessed October, 14 2016).

25.

Thoen

Kerl

. Characterization of acute kidney injury in hospitalized dogs and evaluation of a veterinary acute kidney injury staging system. J Vet Emerg Crit Care (San Antonio) 2011; 21: 648–657.

26.

Dickenmann

Oettl

Mihatsch

. Osmotic nephrosis: acute kidney injury with accumulation of proximal tubular lysosomes due to administration of exogenous solutes. Am J Kidney Dis 2008; 51: 491–503.

27.

Schortgen

Brochard

. Colloid-induced kidney injury: experimental evidence may help to understand mechanisms. Crit Care 2009; 13: 130.

28.

Westphal

James

Kozek-Langenecker

, et al. Hydroxyethyl starches: different products – different effects. Anesthesiology 2009; 111: 187–202.

29.

Bankir

de Rouffignac

. Urinary concentrating ability: insights from comparative anatomy. Am J Physiol 1985; 249: R643–R666.

30.

Mocharla

Hodes

. Alpha-amylase gene transcription in tissues of normal dog. Nucleic Acids Res 1990; 18: 1031–1036.

31.

Yacobi

Gibson

McEntegart

, et al. Pharmacokinetics of high molecular weight hydroxyethyl starch in dogs. Res Commun Chem Pathol Pharmacol 1982; 36: 199–204.

32.

Sirtl

Laubenthal

Zumtobel

, et al. Tissue deposits of hydroxyethyl starch (HES): dose-dependent and time-related. Br J Anaesth 1999; 82: 510–515.

33.

Fresenius Kabi Austria GmbH

. Voluven (HES 130/0,4) 6%-Solution. http://www.pharmazie.com/graphic/A/87/1–23687.pdf (2012, accessed October 14, 2016).

34.

Case

Khan

Khalid

, et al. Epidemiology of acute kidney injury in the intensive care unit. Crit Care Res Pract 2013; 2013: 479730.

35.

Segev

Nivy

Kass

, et al. A retrospective study of acute kidney injury in cats and development of a novel clinical scoring system for predicting outcome for cats managed by hemodialysis. J Vet Intern Med 2013; 27: 830–839.

36.

Lee

Chan

Hsu

, et al. Prognostic factors and a prognostic index for cats with acute kidney injury. J Vet Intern Med 2012; 26: 500–505.

37.

Worwag

Langston

. Acute intrinsic renal failure in cats: 32 cases (1997–2004). J Am Vet Med Assoc 2008; 232: 728–732.

38.

De Loor

Daminet

Smets

, et al. Urinary biomarkers for acute kidney injury in dogs. J Vet Intern Med 2013; 27: 998–1010.

39.

Kdigo

. Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012; 2: 1–138.

40.

Lee

Chang

Chan

, et al. Prognosis of acute kidney injury in dogs using RIFLE (Risk, Injury, Failure, Loss and End-stage renal failure)-like criteria. Vet Rec 2011; 168: 264.

41.

Segev

Kass

Francey

, et al. A novel clinical scoring system for outcome prediction in dogs with acute kidney injury managed by hemodialysis. J Vet Intern Med 2008; 22: 301–308.

42.

Hauptman

Walshaw

Olivier

. Evaluation of the sensitivity and specificity of diagnostic criteria for sepsis in dogs. Vet Surg 1997; 26: 393–397.

43.

Brady

Otto

Van Winkle

, et al. Severe sepsis in cats: 29 cases (1986–1998). J Am Vet Med Assoc 2000; 217: 531–535.

44.

Okano

Yoshida

Fukushima

, et al. Usefulness of systemic inflammatory response syndrome criteria as an index for prognosis judgement. Vet Rec 2002; 150: 245–246.

45.

Balk

. Systemic inflammatory response syndrome (SIRS): where did it come from and is it still relevant today? Virulence 2014; 5: 20–26.

46.

Seymour

Liu

Iwashyna

, et al. Assessment of clinical criteria for sepsis: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315: 762–774.

47.

Briganti

Bergaglio

Ceccherini

, et al. The sequential organ failure assessment (SOFA) score in predicting mortality in critical dogs [abstract]. J Vet Emerg Crit Care 2016; 26 Suppl 1: S27.

48.

Peduzzi

Concato

Kemper

, et al. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol 1996; 49: 1373–1379.

Effect of tetrastarch (hydroxyethyl starch 130/0.4) on plasma creatinine concentration in cats: a retrospective analysis (2010–2015)

Abstract

Objectives

Methods

Results

Conclusions and relevance

Introduction

Materials and methods

Results

Discussion

Conclusions

Footnotes

Conflict of interest

Funding

References