009 Resuscitation Fluids, and Colloids in Hypoproteinaemia

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Cazzolli D, Prittie J. The crystalloid-colloid debate: Consequences of resuscitation fluid selection in veterinary critical care. J Vet Emerg Crit Care 2015. Early View online 22 January.

ABSTRACT

Objective:

To provide a comprehensive review of the current literature in human and veterinary medicine evaluating the impact of resuscitation fluid choice on patient outcome and adverse effects.

Data Sources:

Prospective and retrospective studies, experimental models, and review articles in both human and veterinary medicine retrieved via PubMed.

Human Data Synthesis:

A series of recent, large, randomized controlled trials in critically ill human patients comparing crystalloid versus colloid driven fluid resuscitation algorithms have demonstrated no outcome benefit with the use of natural or synthetic colloids. Synthetic colloidal solutions are associated with an increased incidence of adverse effects including acute kidney injury, need for renal replacement therapy, and coagulopathies. Further, colloidal solutions demonstrate a larger volume of distribution in the setting of critical illness than hypothesized. These findings have created controversy regarding colloid fluid resuscitation in critically ill patients and challenge current resuscitation strategies. A thorough review of the most influential human data is provided.

Veterinary Data Synthesis:

No veterinary clinical outcome data pertaining to fluid resuscitation choice currently exist. Veterinary data from experimental and small clinical trials evaluating the coagulopathic effects of hydroxyethyl starch solutions are described. Data pertaining to the use of natural colloids and albumin products in clinical veterinary patients are reviewed. In addition, data pertaining to the comparative intravascular volume expansion effectiveness of different fluid types in canine patients are reviewed.

Conclusions:

Clinical data from critically ill human patients have failed to demonstrate an outcome advantage associated with colloidal fluid resuscitation and indicate that hydroxyethyl starch solutions may be associated with significant adverse effects, including acute kidney injury, need for renal replacement therapy, coagulopathies, and pathologic tissue uptake. The ability to apply these findings to veterinary patients is unknown*; however, similar pathophysiology may apply, and critical re-evaluation of resuscitation strategies is justified.

*Addition January 2016: subsequent to this podcast episode, the following paper has been published. As always, beware of taking the abstract at face value and ideally critique the paper yourself. Ultimately it should be considered no more than hypothesis generating for future blinded prospective RCTs.

Hayes G, Benedicenti L, Mathews K. 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 2016. 26(1):35-40. 
http://onlinelibrary.wiley.com/doi/10.1111/vec.12412/abstract

OTHER NOTES:

Resuscitation fluids:

  • Intravenous (or intraosseous)
  • Given initially as boluses to restore effective circulating volume and correct hypoperfusion in absolute or relative hypovolaemia
  • Potential for adverse effects 

Isotonic crystalloids:

  • Redistribute extravascularly; potential to cause not just pulmonary but also non-pulmonary tissue and organ oedema – clinical significance?
    • 0.9% sodium chloride (‘normal’ saline):
    • Chloride concentration much higher than plasma
    • Concerns over hyperchloraemia-induced acute kidney injury; also hyperchloraemic metabolic acidosis
    • Falling out of favour in human medicine
  • More physiological (slightly hypotonic) – buffered lactated Ringer’s solution, Hartmann’s, Normosol-R

Colloids:

  • Remain in the circulation for a variable but extended period of time
  • Meant to increase intravascular oncotic pressure
  • Retaining more fluid in the intravascular space and potentially dragging fluid into the circulation from the extravascular space
  • Synthetic: hydroxyethyl starches, gelatins, dextrans
  • Natural: plasma, albumin solutions; other potential benefits irrespective of oncotic effect
  • Hydroxyethylstarches: increased risk of acute kidney injury and potential need for renal replacement therapy in humans

“The absence of a confirmed survival advantage in conjunction with increased documentation of adverse effects is the core of the controversy of continued use of colloidal solutions in the resuscitation of critically ill human patients. Significant disparity exists between the theorized advantages of colloidal therapy and supportive clinical data, particularly in patient cohorts with higher illness severity scores. In the past decade several well-designed RCTs [randomised controlled trials] have been published in human critical care comparing fluid resuscitation with colloid versus crystalloid…Results of these trials have led to safety concerns regarding synthetic colloids and recommendations against their use in several patient populations.”

With respect to efficacy, the authors say: “The efficacy of a resuscitation fluid can be defined as its ability to restore effective circulating blood volume, organ perfusion, and tissue oxygenation while minimizing unnecessary fluid loading that could contribute to a positive fluid balance. In several recent studies in critically ill human patients, the volume-sparing effect of colloidal solutions as compared to crystalloids has been marginal”.

They tell us that “several influential meta-analyses were published in 2013 evaluating the…clinical data on the safety of colloidal fluid resuscitation” available at that time.

“Currently, there are no published data confirming an association between [hydroxyethylstarch] administration and AKI in the veterinary population.”

“There has been minimal clinical evidence to date that the incorporation of colloidal solutions into fluid resuscitation algorithms affords a survival advantage.” 

Care with evidence extrapolation across species (and across subsets of patients of the same species)

“Despite the recent surge in clinical data in the field of human critical care, minimal safety and efficacy data exist in veterinary medicine regarding the use of HES as a resuscitation fluid. The large-scale veterinary clinical trials required to establish an influence of HES resuscitation on patient outcome and adverse effects are likely not logistically feasible in the near future. Veterinary studies are often not powered to detect mortality differences in a diverse patient population with a myriad of underlying comorbidities. Caution must be used when extrapolating human data and associated conclusions to veterinary patient populations given several patient and population-dependent factors, which confer an inherent risk of error. Human and veterinary ICU patients are two distinctly different patient populations.”

Key concept in evidence interpretation: does this study or trial that I am reading actually involve patients that are comparable to the patient I am trying to make a clinical decision about? You need to ask questions such as:

  • Is it the same species?
  • Do the study patients have the same disease or problem as my patient?
  • Are the study patients more or less sick than my patient and do they have similar comorbidities?
  • Were they managed in a similar environment and in a similar way?
  • What other management apart from whatever it is that’s being studied did they receive?
  • And so on. 

“There is compelling evidence supporting avoidance of use of HES solutions in certain human patient populations, including patients with known renal dysfunction and patients with sepsis, systemic inflammation or suspected severe capillary leak and third spacing. The application of these restrictions to veterinary patients may not be justified at the present time; however, as mentioned previously, safety evaluations have not been performed. In addition, although the potential toxicities associated with synthetic colloids are widely acknowledged in human critical care, the potential benefit in hypovolemic resuscitation remains an unsettled dispute. Veterinary clinical data evaluating the effect of synthetic colloid fluid resuscitation on incidence of adverse effects and patient outcome are lacking and warranted.”

Edited email response to listener question about use of synthetic colloids and albumin in hypoalbuminaemia:

“So as you know albumin is the main protein we are concerned with - but there are others. It has a whole host of important functions in the body one of which is to increase plasma oncotic pressure. [Oncotic pressure being one of the Starling's Forces]. By doing this albumin helps to hold on to fluid in the circulation and so in theory if a patient has sufficiently severe hypoalbuminaemia then he/she is more likely to lose fluid from the circulation and develop tissue interstitial oedema which is probably not good for the patient - again, much still to be truly uncovered about this. So the rationale behind using a synthetic colloid in patients with clinically significant hypoalbuminaemia is to try and increase their plasma oncotic pressure and thereby help to reduce the tendency to develop tissue interstitial oedema. To what degree the synthetic colloid achieves this will depend on a number of factors - one of which is the synthetic colloid in question (e.g. the size of the colloid molecules - the gelatins for example are very small so not likely to do much at all).

Some animals that have hypoproteinaemia have disease states which involve some degree of systemic vasculitis with leaky capillaries. In such cases the synthetic colloid molecules could leak out of the circulation taking water with them and actually making the tissue oedema worse rather than improving or preventing it. You cannot really know this in advance. You have to try and see what happens.

It is however really important to remember that synthetic colloids are not proteins. They do not contain albumin or any other protein molecules. They are synthetic colloid molecules in a crystalloid solution and so as far as hypoproteinaemia goes all they may do is help with oncotic pressure but none of the other functions of albumin.

So what about actually giving the patient albumin instead? So few things to say here. In theory if you are hypoalbuminaemic then giving albumin itself makes the most sense. As I mentioned above synthetic colloids only try to address one aspect of what albumin does and they can cause harm in other respects. In the context of using albumin instead of synthetic colloids to resuscitate patients in shock, with sepsis etc. then there have been a number of studies in human medicine and experimentally in animals. Overall I think the conclusion is that in many scenarios they would choose to start with a crystalloid and then consider adding in albumin in preference to a synthetic colloid due to clinical evidence supporting albumin use.

What about in hypoproteinaemia? Well, the first thing I would say is that to a large extent due to the lack of actual clinical evidence this is very opinion and individual specialist based. I know that I do not use intravenous albumin as much as some other specialists do. I don't think anyone would argue that the best way to address hypoalbuminaemia is to try and supplement it enterally - including by placing a feeding tube if needed - to allow protein in nutrition to be absorbed. Alongside that, focusing on what is the actual cause of the hypoalbuminaemia and what can be done about it. I used to get calls from people wanting us to source human albumin for them and when I digged further it sounded more like 'number treating' to me and that enough had not been done to investigate and address the underlying cause and provide nutrition to the patient.

But there may be some cases where the above is not quick enough, there may be a greater sense of urgency to supplement albumin. But the question that follows here is well, when? A lot of people will have a plasma albumin concentration that they read in a book or were taught and quote that as the threshold when wound healing for example becomes compromised. Well, who said? Is there actual good clinical evidence? Don't get me wrong, I am not saying that severe hypoalbuminaemia may not compromise wound healing, but the question is how low does it need to go? Is there one number for all patients or does it depend on the individual patient? And the same debate is true for all the other functions of albumin, e.g. drug carrier etc. When do these become compromised?

With that said you could take the view that as albumin is very important in the body, in any patient with moderate-to-severe hypoalbuminaemia, why not supplement it intravenously as well as then providing nutrition - perhaps including parenteral intravenous nutrition with contains protein as well. This is probably partly why opinions differ - some people are more invested in this argument, others less so. Of course as with everything it is about a risk/cost-benefit analysis. There are potential benefits with improving moderate-to-severe hypoalbuminaemia quickly, are there risks or costs?

Plasma is one option but it is a very inefficient and expensive way of trying to increase albumin - basically it is not an option. In the UK at this time we do not have canine or feline albumin to administer; in the USA I know they have at least at some points in the past had canine albumin available - not quite sure what the current situation is but no doubt it will be coming to wider use. So we are left with using human serum albumin in veterinary patients. Financially this is not that expensive and is an option in that respect. But there are concerns about the fact that it is a human product and therefore has risks in terms of causing hypersensitivity and other reactions in dogs and cats. How real that risk is is something that is debated.

There are some clinical publications on this and in general they do not suggest that we need to be overly concerned about the risks - but they are retrospective studies that aren't great from an evidence-based medicine point-of-view; but not horrendous either. There may be differences in terms of the risk depending on how sick the patient is. Some people believe that in critically ill patients the immune system is so suppressed and overwhelmed that they are actually less likely to have an immune reaction to human albumin than say a trauma case that was basically a healthy animal except the trauma. The risks of giving human albumin to a patient more than once several days apart is another discussion as they may have had time to form antibodies and could then react to the human albumin - but it has been given more than once and this is published.

So look overall I would say that there is some uncertainty about which patients we should be giving intravenous albumin to but my suspicion is that people in practice think this is indicated more often than it is and we should be focusing on addressing the underlying cause and supplementing protein with nutrition. There are some cases where it makes sense to infuse albumin - some differences in opinion about where this patient selection lies. Plasma is not a sensible option and the fact that all we have is human albumin does mean that we need to think about the potential risks even more than when we get access to canine and feline albumin.

Synthetic colloids are not proteins, do not contain proteins. So the only thing they could help with in a hypoproteinamic patient is increasing plasma oncotic pressure to reduce/prevent tissue interstitial oedema. They probably do this in some cases but we really need some decent clinical evidence for all this. Synthetic colloids can also be harmful in a variety of ways, some of which are recent discoveries, and they really are not used much at the moment in human medicine. Personally I am relatively indifferent to their availability.”