Background
Critically ill patients often require intravenous fluid therapy for treatment of shock, dehydration, or maintenance of adequate volume and hydration status. There are many decisions that must be made when prescribing fluid therapy, including fluid type, rate, volume, and what to monitor. In addition to the cardiovascular effects, it is important to consider effects of fluid therapy on other body systems. Many critically ill patients are at risk of acute kidney injury (AKI). Given their role as regulators of fluid and electrolyte status, the kidneys are very sensitive to effects of fluid therapy.
Volume Status
Historically, a large focus of fluid therapy has been avoiding hypoxic kidney injury secondary to hypovolaemia and hypotension. Maintaining renal perfusion is vital. When hypoperfusion is due to absolute hypovolaemia, rapid administration of intravenous fluids is an effective treatment. However, this has broadened to the non-specific belief that intravenous fluids are 'good' for the kidneys, that most hypotension should be treated with aggressive fluid administration, and ongoing infusion of above maintenance fluid rates is beneficial to prevent or treat AKI. In reality, hypotension in critical illness is often multifactorial. Management requires assessment of vascular tone and cardiac contractility, and treatment of derangements in these with sympathomimetics. Furthermore, the kidneys are highly susceptible to dysfunction secondary to fluid overload. As they are enclosed in a rigid capsule, increases in interstitial fluid volume will increase intraparenchymal pressure. This will have a twofold effect on glomerular filtration pressure (and thus glomerular filtration rate) by both reducing renal perfusion pressure and increasing backpressure in the proximal tubule. Thus, it is unsurprising that fluid overload is a significant negative prognostic factor in human AKI.1
The recognition of the importance of fluid balance in AKI prompted the development of a conceptual model of four phases of intravenous fluid therapy in critical illness.2 The four phases are rescue, optimisation, stabilisation, and de-escalation. In the rescue phase, lasting minutes to hours, there is overt life-threatening shock, and intravenous fluid boluses are likely to be necessary and lifesaving. Once immediate life-threatening shock has been resolved, the optimisation phase of a few hours requires much more diagnostic data and a substantial amount of critical thought to justify further fluid boluses. I approach the optimisation phase by gathering data to answer the following sequential questions:
1. Does tissue oxygenation appear to be adequate for cellular respiration?
2. If not, is this due to an alteration in cardiac output, vascular tone, arterial oxygen content or several of these?
3. If reduced cardiac output is most likely, is it preload responsive (i.e., will increasing preload effectively increase stroke volume and thus cardiac output)?
4. If increasing preload will likely improve cardiac output, is using intravenous fluid to do this associated with the best risk/benefit profile?
The stabilisation phase, lasting a few days, is marked by haemodynamic stability and the focus of fluid therapy is avoiding further positive fluid balance. De-escalation shifts the focus to clearing excess accumulated fluid. Whilst this approach has not been thoroughly evaluated in small animals, it conceptually makes sense and can be practically useful.
Synthetic Colloids
In addition to decisions about fluid balance, different types of IV fluids can have further effects on the kidney. The use of synthetic colloids for volume resuscitation has become increasingly controversial, mainly due to concern over AKI. Synthetic colloid fluid products contain large molecules of hydroxyethyl starch (HES), modified gelatin, or dextran. A recent survey3 showed that HES solutions are the most frequently used synthetic colloid in small animals. However, both gelatin and dextran use were also reported in Europe and other regions.
The pathophysiology of AKI secondary to synthetic colloids is not completely understood. The leading hypothesis is osmotic nephrosis, where pinocytosis of colloid molecules leads to intracellular accumulation, cell swelling, and ultimately cell dysfunction.4 Evidence of osmotic nephrosis has been described in a case series of critically ill dogs, where it was associated with the cumulative dose of HES.5
The bulk of the evidence regarding synthetic colloids and AKI focuses on HES, as this has been the most commonly used synthetic colloid in both humans6 and small animals3 over recent decades. Growing concern over AKI led to several landmark clinical trials in humans, where HES was shown to be associated with biochemical evidence of AKI7,8 and increased usage of renal replacement therapy,8-10 a surrogate marker for AKI. These studies were in critically ill humans, primarily those with sepsis, which is thought to increase susceptibility to colloid-induced AKI. These findings have led to recommendations that HES be avoided in populations of critically ill humans at high risk of AKI, including sepsis11 and trauma,12 and usage has subsequently decreased.6 Evidence in small animals is less conclusive. Experimental models of acute haemorrhage found no association between HES and biomarkers of AKI13,14 or histologic renal tubular injury scores.13 These studies were performed in previously healthy dogs, so they may not be directly clinically applicable to many scenarios where HES is used, such as sepsis. Three historical cohort studies have been performed in critically ill dogs, with differing conclusions. One found an association between AKI and the composite outcome of AKI and death,15 one found an association between duration of HES therapy and AKI,16 and the last found no association between HES and AKI.17 It should be noted that this study design is susceptible to confounding by severity of illness, where HES may have been administered to sicker dogs that also had more AKI because of their severity of illness. Whilst attempts can be made to statistically account for this, they can only correct for severity of illness based on other information that was recorded. Randomised clinical trials are required to completely overcome this obstacle. Our group recently performed a randomised, blinded clinical trial comparing HES to a crystalloid control.18 There were no differences in urine biomarkers of AKI or VAKI scores. However, the severity of illness, as assessed by APPLEfast score, was only moderate and there was a low frequency of sepsis. If further smaller studies are performed, they should focus on high risk groups such as septic animals. Alternatively, the ideal studies would be larger multicentre trials with patient-centred outcomes, but these are logistically challenging. Research in cats is limited to two historical cohort studies, which did not detect any evidence of AKI.19,20
There is smaller body of research into the renal effects of fluids containing gelatin in small animals. However, restrictions to HES distribution have prompted the search for viable alternatives. An experimental model of haemorrhagic shock in greyhounds showed that gelatin was associated with greater increases in several biomarkers of AKI and greater histologic evidence of renal tubular cell microvesiculation, compared with HES, crystalloid, and fresh whole blood.13 The biomarker elevations were of a large magnitude, which was consistent with a similar previous haemorrhagic shock model that did not have a control group.21 These findings are also consistent with experimental animal models in other species, where greater evidence histologic22,23 and biomarker24,25 evidence of AKI was found with gelatin administration, compared with HES. Several of those studies22-24 also reported osmotic nephrosis-like lesions. The use of gelatin in humans remains controversial. Meta-analyses have shown less AKI risk compared with HES,26 and no difference in AKI risk compared with crystalloids.27 Despite this, use of gelatin colloids in humans has substantially declined between 2007 and 2014,6 likely due to concern over HES being broadly applied to all synthetic colloids. Notwithstanding, gelatin is still used in some human hospitals, and further research is required. Our research group recently performed a randomised clinical trial in humans admitted to the ICU following cardiac surgery, where gelatin was associated with increases in biomarkers of AKI, compared with crystalloid.28
Whilst dextran solutions are now rarely available, there is evidence of their ongoing use in Europe.3 Dextran solutions are known to cause osmotic nephrosis, however clinical evidence for risk of AKI is mostly limited to case reports in humans.4 Historical cohort studies in humans29-31 have shown differing conclusions, but no clinical trials have been performed. There has not been any published clinical research in veterinary medicine.
In summary, all synthetic colloids should be considered to have the potential to cause or perpetuate AKI. However, the differences between the types of colloid, the patient populations most at risk and the degree of risk are unclear. Synthetic colloids should be used with caution in patients at risk of AKI.
Chloride
Administration of fluids with a supraphysiologic chloride concentration, such as 0.9% NaCl or hypertonic saline, promotes hyperchloraemia. An increased chloride concentration in glomerular filtrate activates tubuloglomerular feedback, leading to afferent arteriolar and mesangial constriction. Subsequently, there is decreased glomerular filtration rate and renal perfusion.32 A landmark before–after study33 and two randomised clinical trials34,35 have provided evidence that high-chloride fluids contribute to AKI in humans. Further clinical trials are ongoing. There is minimal published research in small animals at this time. However, there is evidence that hypochloraemia is associated with non-survival in dogs and cats.36,37
Conclusions and Clinical Relevance
Fluid therapy can both help and harm the kidney. It is prudent to administer intravenous fluid only when there is good evidence that it is necessary. Balanced isotonic crystalloids seem to be the least injurious to the kidney. Use of other fluid types should be reserved for cases where there is a strong rationale for benefit.
References
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