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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