When treating canine diabetic ketoacidosis, do balanced crystalloids provide superior outcomes compared to 0.9% saline?

PICO question 
When treating canine diabetic ketoacidosis, do balanced crystalloids provide superior outcomes compared to 0.9% saline? 
  
Clinical bottom line 
Category of research question 
Treatment and prognosis 
The number and type of study designs reviewed 
Zero 
Strength of evidence 
Zero 
Outcomes reported 
There is currently a lack of studies looking at comparing 0.9% saline to a buffered crystalloid solution (such as Hartmann's) in dogs with diabetic ketoacidosis 
Conclusion 
In view of the strength of evidence and the outcomes from the analysed studies, there is currently no evidence that the use of 0.9% saline or the use of a buffered crystalloid affects the outcome in dogs with diabetic ketoacidosis 
  
How to apply this evidence in practice 
The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources. 
Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care. 
  


A variety of crystalloid fluids are currently available but they differ in buffer composition and ion concentration. In selecting the most appropriate fluid therapy for DKA patients, there are two key elements to consider; sodium content in the fluid, and the alkalising / acidifying property of the fluid. Of course, these two characteristics need to be related to the patient's serum osmolarity, serum sodium concentration and acidbase status.
In contrast to human medicine, where cerebral oedema is described as a complication of DKA, particularly in paediatric medicine, cerebral oedema is rarely a reported complication of DKA in veterinary medicine. Multiple mechanisms are responsible for its development, with the patients initial natraemia and osmolarity playing a key role, alongside the correction of these abnormalities associated with the pathogenesis of the condition (Boysen, 2008;and Long & Koyfman, 2017). One mechanism that results in alterations in sodium levels relates to the patients hyperglycaemic state; accumulation of glucose in the extracellular space leads to intra-cellular dehydration and dilutional hyponatraemia (pseudohyponatraemia). Secondary to the hyperglycaemic osmotic effect, it is sodium concentration (total body sodium content relative to extracellular water content) rather than total body sodium content that changes. Mathematical formulae have been extrapolated in order to estimate the natraemia (corrected sodium) in a normoglycaemic state, excluding the fluid shift caused by hyperglycaemia (Katz, 1973;and Hillier at al., 1999). However, other mechanisms, such as osmotic diuresis, excretion of ketoacids and gastro-intestinal losses, may result in total sodium depletion, all contributing to patient dysnatraemia (Connally, 2002;Wolfsheimer, 1989;Tabor, 2019;and Panciera, 2006).
Neurons are the most sensitive cells to alteration in osmolarity and in order to counter the extra osmolality of plasma during these episodes of hypertonicity, they accumulate intra-cytoplasmatic osmoles (Connally, 2002;Wolfsheimer, 1989; and Tabor, 2019).
The aim of initial fluid therapy in DKA is to improve hyperglycaemia along with patient natraemia without significant changes in osmolarity, or cerebral oedema and further neurologic dysfunction may occur (Connally, 2002;Wolfsheimer, 1989 This requires normal kidney function and a fluid therapy that aims to correct both the patient's sodium and water deficits. Replacement fluid therapy reduces blood glucose and ketone concentrations through different mechanisms, such as dilution, increased glomerular filtration rate, decreased circulating catecholamines and reduction in antidiuretic hormone (ADH) and renin-angiotensin-aldosterone system (RAAS) activation.
In addition to dysnatraemia, DKA patients often have profound metabolic acidosis secondary to multiple mechanisms: overproduction of ketoacids, hypovolaemia (lactic acidosis, volume-responsive azotaemia) and hyperchloraemic metabolic acidosis. The latter occurs mainly as a result of chloride retention when ketoanions are excreted in the urine with sodium and potassium and / or secondary to administration of chloriderich fluids (0.9% saline) ( reduction in serum strong ion difference; this acidosis is generally considered transient and of low impact (Wolfsheimer, 1989). Nevertheless, a causal link between hyperchloraemia and renal vasoconstriction has been hypothesised, which clinically may translate into a higher risk of acute kidney injury (Boysen, 2008;Williams et al., 2020;. In comparison to chloride-rich saline, buffered crystalloids (such as Hartmann's solution, Plasmalyte 148, Ringer's acetate) have a more physiologic chloride concentration and contain anion buffers that avoids hyperchloraemic metabolic acidosis. These balanced crystalloids are on average more expensive than 0.9% saline and some studies also argue that infusion of Ringer's lactate solution may cause an elevation in serum lactate levels that may accumulate in cases of liver insufficiency, or may be converted into glucose, exacerbating hyperglycaemia (Boysen & Dorval, 2014). Finally, from experimental studies and theoretical conceptions it seems that the acetate present in Plasmalyte 148 and Ringer's acetate may be associated with alterations in myocardial activity and patient hemodynamics (Boysen, 2008;Connally, 2002;and Ellekjaer et al., 2019).
From a pathophysiological point of view, it is evident that in DKA, the choice between 0.9% saline and buffered crystalloids is not straightforward; given their different compositions each fluid has advantages and disadvantages.
In veterinary medicine no clinical trials evaluate outcome for dogs with DKA that received 0.9% saline compared to a buffered crystalloid (such as Hartmann's). From the search strategy applied, no papers met the inclusion criteria for this Knowledge Summary.
Some veterinary opinion articles, not directly addressing the PICO question but reviewing the topic of fluid therapy in DKA, suggest 0.9% saline as the fluid of choice because this is the fluid recommended by most of the human DKA guidelines, the acidosis due to chloride-rich fluids is minimal and self-limiting, and its higher sodium content avoids rapid variation in osmolarity, reducing the risk of cerebral oedema. Moreover, the use of buffered crystalloids may lead to overshoot alkalosis when keto-anions and lactate are metabolised, negatively charged lactate can promote further sodium and potassium loss in the urine, and finally in the presence of severe dehydration or shock, a lactic acid may contribute to the already existing acidaemia (Boysen, 2008 Human medicine studies about development of cerebral oedema in DKA found that the type of fluid rarely plays a role; it seems that DKA cerebral oedema is mainly due to reperfusion of ischaemic brain tissue and increased vascular permeability, rather than shifting of water into brain cells, making fluid therapy rarely, if ever, a contributing factor (Chastain, 1981 (Yung et al., 2017). A secondary analysis of two cluster randomised clinical trials found that treatment with balanced crystalloids resulted in more rapid resolution of DKA, compared with 0.9% saline (Self et al., 2020). As already mentioned, there is currently no evidence in veterinary medicine if any particular type of crystalloid fluid is superior to another in hyperglycaemic emergencies. However, veterinary opinion articles and human studies represent a starting point in the analysis of which type of fluid therapy is better in a patient with DKA, highlighting the importance in evaluating certain elements of a fluid's composition (sodium content and alkalising / acidifying property) that may change the outcome in patients with DKA and also may shorten hospitalisation time, potentially reducing the cost of treatment and mortality associated with euthanasia.
In conclusion, there is zero evidence if one particular isotonic crystalloid fluid confers a clinical outcome benefit over others in the treatment of DKA in veterinary medicine. A personalised fluid therapy plan that considers the patient's specific acid-base balance and electrolytes and re-evaluates these values during the treatment may be the best solution in this complex pathology.