Sepsis

Sepsis and the Glycocalyx

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Sepsis

Evidence base:

Growing interest in evidence-based veterinary medicine (EBVM)
Many challenges with practical implementation; especially quantity and quality of evidence.
Sepsis is a prime example of this.

Veterinary sepsis teaching is largely extrapolated from clinical human studies +/- minimally relevant animal experimental work.
Sepsis management in human medicine remains on an evidence-based journey. Situation is even less clear in veterinary medicine.

What is sepsis?

Disease continuum with progression of severity.

Long-standing definitions:

Sepsis = systemic inflammatory response syndrome (SIRS) due to confirmed or highly suspected infection.
In veterinary patients sepsis is most often due to bacterial infection. Often gram-negative; their endotoxin (lipopolysaccharide) is a very potent trigger of inflammation. Mixed infections and gram-positive infections also described.

(SIRS:

Activation of systemic inflammation caused by excessive production of inflammatory mediators (e.g. TNFα, IL-1, IL-6). Overwhelms anti-inflammatory mechanisms.
Most commonly triggered by infection. But there are non-infectious causes.
Excessive production of pro-inflammatory mediators disrupts homeostasis. Causes:
Loss of vascular tone with generalised vasodilation
Disruption of endothelial permeability barrier leading to vascular leak
Activation of coagulation
May progress to include acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), multiple organ dysfunction and death)

Severe sepsis = sepsis that results in organ or body system dysfunction.
Cardiovascular system often first concern. Patient with systemic hypoperfusion and confirmed/highly suspected infection has severe sepsis.
Other organs and systems may also be affected.

Septic shock = patient with hypoperfusion or hypotension that is refractory to intravenous fluid resuscitation.

SEPSIS-3 definitions:

Recently suggested updates in human medicine.
Work done by Task Force convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine.

New definitions:

  • Sepsis = life-threatening organ dysfunction due to a dysregulated host response to infection
  • Severe sepsis no longer used
  • Septic shock = subset of patients with sepsis and profound circulatory, cellular, and metabolic abnormalities

SOFA score and quickSOFA score used to identify organ dysfunction.

Still early days; not without critics and problems. Need to be prospectively evaluated and potentially adapted.

All much less clear in veterinary medicine!

Sepsis management:

Early goal directed therapy (EGDT):

Introduced by Emmanuel Rivers with publication of a single centre trial in The New England Journal of Medicine in 2001.
Randomly assigned patients who arrived at an urban emergency department with severe sepsis or septic shock to receive either six hours of early goal-directed therapy or standard therapy (as a control) before admission to the intensive care unit.
Ultimately concluded that early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock.
Since then many other studies have been published that apparently also identified outcome benefits.

In sepsis circulatory abnormalities lead to an imbalance between systemic oxygen delivery and oxygen demand.
Abnormalities include intravascular volume depletion, peripheral vasodilatation, myocardial depression, and increased metabolism.
Result is global tissue hypoxia or shock
Physiologically, aim of management is to adjust cardiac preload, afterload, and contractility to optimise tissue oxygen delivery.

Five key parameters monitored intensively and managed aggressively to specified targets:

  • Central venous pressure (CVP)
  • Mean arterial blood pressure (MAP)
  • Urine output
  • Mixed venous oxygen saturation
  • Haematocrit

Interventions include fluid resuscitation, inopressor agents, blood product transfusion, and mechanical ventilation.

EGDT became well known and many people supported its use.
Presumptively extrapolated as gold standard best practice to veterinary medicine too. Though few able to deliver this care due to practical and resource (expertise, equipment, financial, personnel) limitations.

Some critiqued the Rivers study and the EGDT approach. E.g. not widely adopted in Australasia.

Surviving Sepsis Campaign:

First set of "Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock" published in 2004.
SSC administered jointly by the European Society of Intensive Care Medicine, International Sepsis Forum, and the Society of Critical Care Medicine.

Objective:

"to develop management guidelines for severe sepsis and septic shock that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis." 

EGDT largely incorporated into first 6 hours of sepsis management (resuscitation bundle); disseminated internationally as standard of care for early sepsis management.
Again, extrapolated to veterinary medicine too.

Updated guidelines published every 4 years.

ProCESS (USA), ARISE (Australasia), ProMISe (UK):

Three large scale multicentre randomised controlled trials published recently. 
Reported that human sepsis mortality at an all-time low
Concluded that in a general population of human patients with severe sepsis and septic shock, EGDT did not confer a mortality benefit compared with usual resuscitation.
Ability to generalise from these studies – including to veterinary medicine – depends on consistency of treatment provided as part of usual resuscitation across individual hospitals.

Again there have been critiques of these three recent trials.

Bottom line for veterinary practice:

If we are able to deliver a high level of standard care we will be doing right by our patients. The aspects of management that are now being emphasised are ones that we should also be able to do well.

So what does that mean?

  • Early recognition of patients that are septic or at high risk of becoming septic
  • Intravenous fluids for volume resuscitation to improve systemic perfusion
  • Early use of inopressor agents
  • Starting intravenous antibiosis early
  • Looking for sources of infection. And establishing control of the source of infection as well as possible as soon as possible.
  • Close regular monitoringAnd tailored goals that make sense for the individual patient.

Early recognition of patients that are septic or at high risk of becoming septic:

Spectrum of severity; keep your radar on
Some patients are severely compromised with marked hypoperfusion and obvious infection; straightforward diagnosis (e.g. really sick dogs with septic peritonitis)
Some patients have severe infection that is yet to cause systemic consequences
Some patients have systemic abnormalities but elusive focus of infection

Effects on major body systems (cardiovascular, respiratory, central nervous system (especially brain)):

Especially signs of systemic cardiovascular compromise, hypoperfusion, hypotension, possibly full blown shock
Major cause of hyperdynamic distributive shock in dogs; but some dogs with sepsis have a hypodynamic picture.
Cats classically have hypodynamic picture

Not every septic patient is pyrexic. Temperature may be inappropriately ‘normal’, or hypothermic.

Lactate:

Complex relationship between sepsis and blood lactate
Inappropriately high lactate for given cardiovascular/perfusion status possible flag for sepsis.
Not every septic patient has notable hyperlactataemia

Intravenous fluids for volume resuscitation to improve systemic perfusion:

Synthetic colloids were previously used early and commonly in septic patients
Recent evidence in human patients and experimental +/- clinical animal studies suggests negative risk-benefit assessment. Potential harms in critically ill patients including acute kidney injury. No proven benefits.
Side-lined for majority of human patients with sepsis
Conclusions extrapolated to veterinary practice

So intravascular volume resuscitation involves using a replacement isotonic crystalloid with a bolus strategy.
Less aggressive approach advocated in recent times due to increasing recognition of harms of excessive fluid administration/over-resuscitation.
Again, extrapolated to veterinary practice.

Albumin:

Natural colloid
Has been used extensively in human sepsis management
Canine albumin still not widely available and using human albumin in dogs and cats creates additional risks.

Early use of inopressor agents:

Hypoperfusion in sepsis due to hypovolaemia, peripheral vasodilation and myocardial depression
In addition to volume replacement, early inopressor use makes sense to squeeze vessels (especially venous capacitance) and boost cardiac pump
Noradrenaline (norepinephrine) current agent of choice in human medicine where available and affordable. Albeit not total consensus.
Extrapolated by some to veterinary practice.

Dopamine fallen out of favour in human medicine due to negative risk-benefit assessment.

Starting intravenous antibiosis early:

Early aggressive antibiosis justified in patients with confirmed sepsis.
Likewise in patients with suspected sepsis. But must be reasonable and think critically in terms of index of suspicion. Not carte blanche to adopt ‘just in case’ approach in all patients!
Antibiotics massively overused in veterinary and human medicine. Significant bacterial resistance challenges.

Broad-spectrum, including gram-negative coverage where involvement suspected
Do not withhold until samples collected for microbiology; but do collect samples for microbiology!

Looking for sources of infection. And establishing control of the source of infection as well as possible as soon as possible: 

Prioritise resuscitation, stabilisation and maintenance of stability
Identifying focus of infection may involve e.g. good thorough physical examination, point of care ultrasound, diagnostic imaging, and/or collection of fluid and cell samples.
In some patients antibiotics and own immune system will be curative
In other cases other interventions are required (e.g. exploratory laparotomy; abscess drainage).
Some early though non-definitive source control may be possible with modern non-invasive techniques 

Close regular monitoring
And tailored goals that make sense for the individual patient.

Looking for improvement in, and ultimately normalisation of, physical examination perfusion parameters.
Likewise blood pressure. Generally cited blood pressure targets: mean systemic arterial blood pressure > 65-70 mmHg, systolic blood pressure > 90mmHg.
Also normalisation of or significant improvement in hyperlactataemia. Slow lactate clearance may indicate worse prognosis.

Urine output can also help to inform perfusion status and response to treatment.
Urinary catheter placement not recommended in all patients with confirmed/suspected sepsis:
Foreign body
Carries risk of ascending potentially resistant hospital-acquired infection
Causes patient discomfort
Placement may require sedation
Helpful when present though.

Other treatments not discussed include: blood product transfusion; treatment for critical illness related corticosteroid insufficiency (CIRCI).

Glycocalyx

What is the glycocalyx?

Gel-like acellular epithelial layer endothelium of blood vessels (and part of heart, lymphatics)
Important in fluid dynamics and various pathophysiological states
Meshwork of glycoproteins, proteoglycans and various soluble molecules
In a dynamic equilibrium with adjacent flowing blood
Constantly changing in thickness and composition; sheds and regenerates

What are the functions of the glycocalyx?

1) Key determinant of vascular permeability:

Integrity important for normal microvascular fluid exchange
Disrupted by inflammatory cells and cytokines, and ischaemia-reperfusion
Increases vascular permeability leading to oedema
Hallmarks of SIRS and sepsis as well as other disease states
Ubiquitous nature of glycocalyx helps explain why localised infection can have widespread consequences.

2) Mechanical protection for endothelium
3) Creates a microenvironment for receptor binding, local growth and repair. Protects the vascular wall.
 

What is the relevance of all this?

Traditional Starling model of vascular fluid exchange has been revised.

"In the last 5 years or so, we have had a better understanding of capillary fluid dynamics, particularly in conjunction with an appreciation of the glycocalyx. We now know that the glycocalyx normally ‘traps’ about a litre and half of plasma water in it (due to its hydrophilic chemical composition!) and that normally in the capillaries, there is a central moving layer of plasma and a relatively immobile layer closer to the endothelium….the bit that is bound to the glycocalyx. This explains the differences in measured capillary and venous hematocrit values, and also why Crystalloid : Colloid equivalence is 1.3 : 1 rather than 4: 1 as previously thought.
We have also acquired a better understanding of the mechanisms of edema formation in critical illness and more importantly, the magical phenomenon of improved diuresis that we have all marvelled at, during the recovery phase.
In short, we have kinda debunked the original Starling theory of fluid dynamics in the capillary.
We now know that the colloid osmotic pressure in the intravascular space will only oppose the outward movement of water, and increasing the colloid osmotic pressure by synthetic colloids will not reverse the flow and draw fluid from the interstitial to the intravascular space. ( Multiple trials , starting with the SAFE trial have proved the futility of using synthetic colloids !) What they end up doing is, probably drawing water from the glycocalyx in the intravascular space itself and dehydrating and then disintegrating this vital layer. As a result you will find a transient improvement in blood pressures, but afterwards, a lot of this fluid will track into the extravascular space. Any hyperosmolar solution can do this including Soda Bicarb….we have all seen the very transient increase in blood pressure after bicarb which has always been incorrectly attributed to ‘reversal of acidosis’…bah!!
Extravasation of fluid from the capillaries is predominantly dependant on capillary hydrostatic pressure and not on decreased intravascular colloid osmotic pressure— because we have realised that interstitial and intravascular colloid osmotic pressures are very close to each other.
The way to prevent overloading and thus extravasation would be to minimise rapid increases in capillary hydrostatic pressure. How can we do that? – By small volume crystalloid boluses and early use of alpha1 agonists—the latter work by afferent arteriolar constriction and thus minimising huge increases in capillary hydrostaic pressures. This is where Marik’s argument takes a strong foothold.
Albumin is needed for the integrity of glycocalyx, — explaining why albumin is making a comeback into our fluid armamentarium.
The lymphatics have assumed a pivotal role in the normal mechanisms that prevent edema formation. We have realised that they are a very active conduit to return of interstitial fluid to the central circulation, and they they have contractile collecting ducts and passages that are calcium dependant. They are inhibited by the terrible twins ANP and BNP—therefore shutting down in active sepsis, where the twins tend to dominate. (This also partly explains the peripheral edema commonly seen with Ca channel blockers when they are used as antihypertensives). Once the sepsis resolves, ANP and BNP levels drop and the lymphatics recover their contractile elements. All the interstitial fluid can now be returned to the central circulation causing an improved diuresis.
In any case, fluids should only be used as any other drug should be— only if needed. We need to realise that fluid requirement and fluid responsiveness are two completely different things and focus on appropriate fluid balance rather than branding it as either restrictive or liberal." (John, retired human intensivist)

Does this affect how we manage our patients clinically, and if so, how?
Can the glycocalyx serve as a novel therapeutic target?

At present, mostly discussion and theorising
Recognition of the glycocalyx and its complexity helps to:
Better understand the pathophysiology of sepsis
Explain some of what we see in clinical patients
Explain why no single magic bullet has been found for the treatment of sepsis; too complex for this. 

Sepsis damages the glycocalyx. Management should aim to minimise further damage, e.g.

Avoid fluid over-resuscitation while simultaneous improving systemic perfusion (and therefore hopefully microcirculatory blood flow) adequately
Address infection promptly to minimise further stimulation of inflammation

If physiological corticosteroids are beneficial in CIRCI, this may be through an effect on the glycocalyx (unproven).

Much work underway looking for potential therapies to help bolster and repair damaged glycocalyx. Unlikely to be a single magic bullet; rather multiple therapies and small gains.

Even if such a treatment is identified and supported by good evidence in human patients, does not mean same effect will be recognised in veterinary patients.

References/Resources:

SEPSIS-3 definitions:

Singer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315:801-10

PulmCrit - Top ten problems with the new sepsis definition
http://emcrit.org/pulmcrit/problems-sepsis-3-definition/ 

Vincent JL, Martin GS, Levy MM. qSOFA does not replace SIRS in the definition of sepsis. Critical Care 2016; 20:210
http://ccforum.biomedcentral.com/articles/10.1186/s13054-016-1389-z

Reading J. The Third International Consensus Definitions for Sepsis and Septic Shock,
https://bloggingforyournoggin.wordpress.com/2016/11/27/the-third-international-consensus-definitions-for-sepsis-and-septic-shock/ 


EGDT, Surviving Sepsis Campaign, Recent trials:

Rivers E, Nguyen B, Havstad S, et al. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. N Engl J Med 2001; 345:1368-1377
http://www.nejm.org/doi/full/10.1056/NEJMoa010307#t=article

Surviving Sepsis Campaign Guidelines

2016 Surviving Sepsis Guidelines: A Review and Analysis

Nguyen B, Jaehne AK, Jayaprakash N, et al. Early goal-directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe, and ARISE. Critical Care 2016; 20:160
https://ccforum.biomedcentral.com/articles/10.1186/s13054-016-1288-3

The PRISM Investigators. Early, Goal-Directed Therapy for Septic Shock — A Patient-Level Meta-Analysis. N Engl J Med 2017; 376:2223-2234
http://www.nejm.org/doi/full/10.1056/NEJMoa1701380

Veterinary lactate study:

Cortellini S, Seth M, Kellett-Gregory LM. Plasma lactate concentrations in septic peritonitis: A retrospective study of 83 dogs (2007-2012). J Vet Emerg Crit Care (San Antonio). 2015 May-Jun;25(3):388-95.
http://onlinelibrary.wiley.com/doi/10.1111/vec.12234/full

Glycocalyx: 

Scott Weingart. Think You Understand Fluids – Cause I don’t have a grasp yet.
EMCrit Blog. Published on November 29, 2013. Accessed on September 14th 2017.
Available at [https://emcrit.org/emcrit/best-fluids-comment-ever/]. 

Woodcock TE, Woodcock TM. Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy. Brit J Anaesthesia 2012. 108 (3): 384–394.

Chelazzi C, Villa G, Mancinelli P, et al. Glycocalyx and sepsis-induced alterations in vascular permeability. Critical Care 1025; 19(1)

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Steroids and Shock!

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Exogenous therapeutic steroids include hydrocortisone, dexamethasone, betamethasone, methylprednisolone etc. All have glucocorticoid activity but vary with respect to mineralocorticoid activity.

SHOCK:

Essentially, critically low systemic tissue oxygen delivery
Typically due to systemic hypoperfusion:

  • Four types of ‘hypoperfusion’ shock: hypovolaemic, (mal)distributive, cardiogenic, obstructive
  • May be present concurrently
  • Some include septic shock and/or anaphylactic shock as separate types

Some older resources recommended (often high dose) steroid use in shock but things have changed, e.g.

“High dose fast-acting corticosteroids are no longer recommended for use in shock…recent studies have not demonstrated significant benefit and it actually may cause increased deleterious effects.” (Dexamethasone entry, Plumb’s Veterinary Drugs online, 2015).

LITERATURE

Unable to identify any recent reviews of steroid use in shock in general
Vast majority is on use of steroids in septic shock in people, either clinical studies or review articles citing experimental animal studies and clinical human trials.

STEROID USE IN SHOCK

On-going debate for many years, e.g.

  • “Role of corticosteroids in the treatment of circulatory collapse states” from Clinical Pharmacology and Therapeutics in 1970
  • “Should corticosteroids be used in shock?” from Medical Clinics of North America in 1973
  • “Steroids and severe hemorrhagic shock” from Surgery 1977.

“Should corticosteroids be given in shock?” from Drugs and Therapeutics Bulletin in 1976, Volume 14, Issue 4:

“The adrenals respond to shock by increased cortisol secretion…Any beneficial effect of corticosteroids is therefore not due to the correction of adrenal insufficiency.” See more on this later.

“The effects of corticosteroids in shock are difficult to study because of the variety of causes and the lack of animal models which mimic the conditions found in man.”

“There is insufficient evidence to support the use of corticosteroids in traumatic, haemorrhagic, neurogenic or cardiogenic shock. In patients with endotoxin shock it seems reasonable to give a glucocorticoid if there has been no improvement in response to adequate fluid replacement and ventilation together with an appropriate antibiotic regime…Endotoxaemia is the only form of shock in which corticosteroids may be helpful. Very large doses are needed. An adequate prospective trial of this therapy is, however, badly needed.”

Using references from the 1950s, 1960s and early 1970s!

Some animal experimental studies of high dose methylprednisolone use in haemorrhagic shock models.

Steroids in Septic Shock

Sepsis’: systemic inflammatory response syndrome (SIRS) that is due to a confirmed or suspected infectious cause.
Severe sepsis’: sepsis in which there is evidence of organ dysfunction; organ dysfunction may also include hypotension or tissue hypoperfusion which is essentially seen as dysfunction of the cardiovascular system.
Septic shock’: sepsis-induced hypotension or tissue hypoperfusion which persists despite adequate fluid resuscitation.

Sepsis-induced hypotension or tissue hypoperfusion:

  • Distributive shock with generalised vasodilation which increases the capacity of the intravascular space and causes a relative hypovolaemia
  • Also some absolute hypovolaemia with fluid being lost from the circulation through the leaky inflamed blood vessels
  • +/- Some degree of myocardial dysfunction
  • +/- Impaired cellular ability to take up and utilise oxygen

Proposed pathophysiology of sepsis is complex!

HUMAN LITERATURE

Experimental and clinical papers from as far back as the 1940s
E.g. “Effect of cortisone on acute streptococcal infections and post-streptococcal complications” (Journal of Clinical Investigation, 1951)

Lot of further work published since then on steroid use in septic shock:

  • Non-human and human experimental work
  • Clinical studies including prospective RCTs – mostly adults but also some paediatric

BENEFIT-RISK

Potential benefits of steroid in septic shock:

In septic shock pro-inflammatory pathways may have overwhelmed anti-inflammatory pathways and endogenous glucocorticoids so supplementing glucocorticoids may be helpful?
Various suggested molecular and cellular pathophysiological mechanisms by which glucocorticoids may further help to augment compensatory anti-inflammatory response.

Through various (often not definitively proven) mechanisms steroids may help to restore both cardiovascular system dysfunction and indeed organ dysfunction in other sites.

Potential risks:

Steroid-induced immunosuppression may impair ability to resolve primary infection and also predispose to new onset hospital-acquired (potentially multidrug resistant) superinfections.
Gastrointestinal ulceration and bleeding, muscle weakness

If we are saying that steroids can theoretically play a beneficial role in septic patients and in particular septic shock, then should the aim be to give all septic patients steroids on the basis that if some is helpful, more is even better? Or put another way is there a rationale for supraphysiological steroid use?

If using steroids in this supraphysiological way does not make sense or is not supported by the evidence, then is there a role for physiological steroid use to top up glucocorticoid activity in the face of potentially overwhelmed/depleted/inadequate endogenous reserves?

CURRENT HUMAN (and VETERINARY?) RECOMMENDATIONS

Do not use steroids in all patients with septic shock
Use steroids at appropriate doses for (rare) patients known to have a specific infection for which steroids are indicated
On-going debate about use of ‘low dose’ ‘physiological’ steroids in patients with possible ‘relative adrenal insufficiency’ or ‘critical illness-induced corticosteroid insufficiency’…

Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012

Adults:

“We suggest not using intravenous hydrocortisone as a treatment of adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability…If this is not achievable, we suggest intravenous hydrocortisone alone at a dose of 200mg per day.”

Grade 2C = weak recommendation based on low quality evidence.

Paediatrics:

“We suggest timely hydrocortisone therapy in children with fluid-refractory, catecholamine-resistant shock and suspected or proven absolute (classic) adrenal insufficiency.”

Grade 1A = strong recommendation with high quality evidence.

“Timing of Corticosteroids in Refractory Septic Shock: A Key or Wishful Thinking?” (Editorial, Critical Care Medicine 2014): 

“Corticosteroid administration in the refractory critically ill patient with presumed sepsis has shadowed our practices almost since the clinical development of these hormones and the inception of modern critical care. Most, if not all of us, have witnessed a near miraculous stabilization of a patient hovering near death’s door when a bolus of hydrocortisone, methylprednisolone, or dexamethasone has been administered to that patient. Clearly, for the rare individual with primary adrenal failure (Addison’s disease), this would be mandatory therapy, but for the wide spectrum of septic patients with suspected adrenal insufficiency, corticosteroid resistance, or other, there is insufficient compelling data to show benefit to a broader use of corticosteroids in septic patients.”
“Mysteries related to the use of steroids in septic shock remain unsolved. The first and foremost is identifying a test that will help clinicians decide whether to initiate steroids in the first place. Creating such a test is largely complicated by intrinsic changes that occur during septic shock…As the inherent difficulties in developing such a test continue to be investigated, practitioners who use steroids in patients with refractory septic shock may consider using them earlier on after diagnosis.”

American Journal of Respiratory and Critical Care Medicine, 2012:

“This concise evidence-based review highlights the strengths and weaknesses of the current data to inform the practicing clinician as to which patients are likely to derive significant benefit from corticosteroid treatment, while we await more definitive guidance from future multicenter, prospective, randomized, controlled trials designed to better answer these important therapeutic questions.”

Paediatric Critical Care Medicine, 2013:

“The literature on the use of steroids in pediatric shock is limited in amount and methodological quality and demonstrates conflicting results. The limited evidence on which current guidelines are based strongly supports the need for a well-designed, pragmatic randomized controlled trial on the use of steroids in pediatric shock to inform future guidelines.” 

Burkitt Creedon JM. Controversies surrounding critical illness-related corticosteroid insufficiency in animals. J Vet Emerg Crit Care 2015. 25(1):107-112.

**Please feel free to contact me if you would like a copy of this paper**

“…continued controversy over adrenal function testing and the use of glucocorticoids in [human] patients with severe sepsis and septic shock.

Unfortunately, even less is known and understood about normal and abnormal corticosteroid metabolism and the possible benefit of corticosteroid therapy in critically ill veterinary patients. The purposes of this review are to describe the controversies surrounding CIRCI and the use of hydrocortisone in critically ill patients and to present published diagnostic and therapeutic strategies in companion veterinary species.”

Aetiology of CIRCI is unknown and “There is almost certainly interindividual variation in its pathophysiology…and more than one mechanism may be present concurrently in the same patient. It is also unknown whether different mechanisms may be at play in different species, as very limited to no data regarding appropriate corticosteroid metabolism are available in veterinary species”.

Diagnosis of CIRCI:

“The complicated and likely multifactorial nature of CIRCI's pathogenesis…has led to significant controversy regarding the best way to identify patients with the syndrome. Baseline cortisol concentration, delta cortisol concentration using standard vs low-dose ACTH stimulation test protocols, endogenous hormone ratios, measurement of total vs free cortisol, response to treatment, and other methods have been advocated by various authors as appropriate method(s) for detecting cortisol insufficiency or resistance in critical illness in people.

It is probably most accurate to say that due to disparate data from different studies and resultant clinical equipoise, the human critical care community does not advocate any method of diagnosis for CIRCI at present. In a practical sense, the “diagnosis” of CIRCI in people is currently made by evaluating response to treatment with low-dose hydrocortisone, because current guidelines recommend treating pressor-resistant septic shock patients with hydrocortisone without or with no regard to HPA axis assessment.”

Of course less is known about the best way to identify CIRCI in critically ill dogs and even less in critically ill cats. The author also mentions some studies relating to foals.

Treatment:

“The dose is referred to as “low,” “physiologic,” “stress,” or “replacement,” depending on author…Whether this approach is appropriate in horses, dogs, and cats is unknown. The required dose for any individual patient (human or veterinary) is unknown, as the precise glucocorticoid deficiency or responsiveness in any critically ill individual cannot be determined. Meta-analyses confirm that while these lower doses of corticosteroids may confer benefit in people with septic shock, higher doses are not beneficial and may be detrimental.”

Lack of consensus about treatment of CIRCI in human medicine
Decision to treat is murkier and treatment methods more variable in veterinary medicine

Treatment regimens have been published primarily in case reports, reviews, and book chapters, with no reliable clinical trial data available in veterinary species

Review article ends with:

“Considering the substantial controversy and uncertainty that still surround the syndrome of CIRCI, it is fortunate that another large-scale, multicenter trial investigating the use of hydrocortisone in septic shock is currently underway…This trial began enrollment in February 2013, and aims to include 3800 people with septic shock. Results of this investigation may significantly influence CIRCI identification and management in people. However, because of species differences in endogenous cortisol metabolism and in responsiveness to exogenous steroids, studies in individual veterinary species will be required to make specific recommendations in companion animals. Until further data become available, practitioners will continue to make clinical judgments regarding the diagnosis and treatment of corticosteroid insufficiency in critically ill patients.”

EPISODE SUMMARY:

Use of steroids in shock in general is not recommended unless that patient happens to have a steroid-responsive disease as the cause of their shock; this is rare.
‘Low dose’ or ‘physiological’ steroids can be used in patients with septic shock – or other critical illness – that is refractory to fluid resuscitation and exogenous catecholamine use; many veterinary practitioners may not have access to vasopressor/inotropic agents.

  •  A positive response to low dose steroid use suggests the presence of CIRCI
  • Hydrocortisone is typically suggested; dexamethasone may be less preferable but can still be used
  • ***Much remains to be clarified about this in human and especially veterinary medicine in terms of which patients are the best candidates, when to start steroids, what protocol to use and so on.***

Please feel free to contact me if you would like a copy of Dr. Burkitt’s paper for educational purposes.

I would also love to hear any thoughts or comments about this episode and about your practice. 

PAPERS THAT INFORMED OR ARE MENTIONED IN THIS EPISODE:

Annane D. Corticosteroids for severe sepsis: an evidence-based guide for physicians. Ann Int Care 2011.
http://link.springer.com/article/10.1186/2110-5820-1-7/fulltext.html 

Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. BMJ 2004; 329:480–484.

Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for treating severe sepsis and septic shock. Cochrane Database Syst Rev 2004; (1):CD002243.

Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA 2009. 301:2362–2375.

Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002. 288:862–871.

Burkitt JM, Haskins SC, Nelson RW, et al. Relative adrenal insufficiency in dogs with sepsis. J Vet Intern Med 2007. 21:226–231.

Burkitt Creedon JM. Controversies surrounding critical illness-related corticosteroid insufficiency in animals. J Vet Emerg Crit Care 2015. 25(1):107-112.

Couetil LL, Hoffman AM. Adrenal insufficiency in a neonatal foal. J Am Vet Med Assoc 1998. 212:1594–1596. 

Durkan S, de Laforcade A, Rozanski E, et al. Suspected relative adrenal insufficiency in a critically ill cat. J Vet Emerg Crit Care 2007. 17:197–201.

Greenberg SB; Coursin DB. Timing of Corticosteroids in Refractory Septic Shock: A Key or Wishful Thinking? Crit Care Med 2014. 42(7):1733–1735.

Hahn EO, Houser HB, Rammelkamp CH, et al. Effect of cortisone on acute streptococcal infections and post-streptococcal complications. J Clin Invest 1951. 30(3):274–281.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC436257/ 

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