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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Feline Hypertension

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Episode based on:

ISFM Consensus Guidelines on the Diagnosis and Management of Hypertension in Cats. J Fel Med Surg 2017. 19:288–303.

1. Evidence base:

Guidelines based on comprehensive review of currently available literature; where clinical studies and scientific data were not available the Guidelines represent consensus opinion of the Panel.
Many areas where more data is required which may either confirm recommendations in these Guidelines or cause some to be modified.

2. Secondary versus primary hypertension:

Feline hypertension more commonly diagnosed in association with another disorder, i.e. secondary hypertension more common than primary (idiopathic) hypertension.
Most common associated disorder is chronic kidney disease followed by hyperthyroidism; there are others but they are much less common.
Unlike in humans, prevalence of hypertension in cats with diabetes mellitus is typically low, but often confounded by concomitant conditions such as CKD.

In secondary hypertension “the relationship between the hypertension and the underlying disease may not always be understood.”
Concurrent underlying disease must be managed as well as possible – which will help management of hypertension as well.

3. Target organ damage:

Can be severe and potentially irreversible
Main target organs: eyes, heart and vasculature, brain, kidneys
Problem(s) relating to TOD may be reason for presentation; especially vision impairment due to hypertensive ocular changes.

“Hypertensive ocular changes have been reported in approximately 50% of hypertensive cats…However, the high prevalence of reported ocular lesions may reflect the relatively late diagnosis of hypertension in many studies.”

“The retina and choroid have separate blood supplies and both can suffer hypertensive damage…with an array of fundic lesions visible on ophthalmoscopy”.

“Many cats with severe hypertensive ocular damage present with blindness and bilateral mydriasis resulting from complete retinal detachments and/or intraocular haemorrhage; the changes are often irreversible…Lesions that are not associated with an impaired menace response or pupillary light deficits...are much more amenable to anti-hypertensive treatment…highlighting the importance of early diagnosis and management. Detection of early hypertensive ocular lesions requires an ocular examination to be performed on all cats at risk of developing lesions.”

4. Monitoring and Underdiagnosis:

Early diagnosis followed by appropriate therapeutic management should help reduce hypertension-associated morbidity associated; however authors suggest monitoring is generally performed infrequently probably leading to underdiagnosis.
Encouraged to identify and monitor patients at risk of developing hypertension.

5. Which cats should we monitor blood pressure in?

Authors’ recommendations:

  • Any cat that has been diagnosed with a recognised risk factor for hypertension, such as chronic kidney disease or hyperthyroidism, should have their blood pressure measured at the time this diagnosis is made and then every 3-6 months thereafter.
  • Any cat that has an unexplained disease compatible with hypertensive target organ damage should also have their blood pressure measured immediately and then every 3-6 months thereafter.
  • Check blood pressure at least every 6–12 months in healthy cats aged eleven years or older.
  • Check blood pressure every 12 months in healthy cats aged 7-10 years.

Should we consider checking blood pressure every 12 months in healthy adult cats 3–6 years of age? “The main purpose of monitoring in this age group is to obtain baseline measurements for the individual cat. As few cats in this age category have hypertension, great care is needed in the interpretation of elevated BP measurements, especially in the absence of [target organ damage] or a clear underlying disease.”

5. Ensure BP is measured as accurately as possible with a reproducible technique:
   
Major take-home message alert!!!

“Indirect measurement of BP in cats can be readily performed, although care is needed with both the choice and use of the equipment to ensure meaningful and accurate results are obtained.”

Recommend using either Doppler sphygmomanometry or high-definition oscillometry; HDO is more accurate, reliable and consistent and easier to perform than traditional oscillometry.

Only systolic blood pressure measurements should be used for clinical assessment. Diastolic and mean arterial pressure readings are less accurate and should generally be ignored.

Use of standardised protocols imperative to improve accuracy and reproducibility of measurements.

Guidelines include extensive recommendations by the Panel covering:

  • Cat’s environment
  • Acclimatisation
  • Personnel
  • Restraint and positioning
  • Choice and position of cuff
  • Actual use of equipment
  • Taking and interpreting measurements

Consistency is essential.

“Blood pressure is labile and varies considerably within and between cats, depending in part on their level of arousal, activity or stress.”

Clinical assessment of systolic blood pressure is also affected by many external variables including:

  • Operator
  • Conditions
  • Environment
  • Equipment
  • Position of the cat
  • Size of the cuff
  • Site of measurement

6. ‘White coat hypertension’:

Temporary physiological increase in blood pressure due to excitement- or more likely anxiety-related sympathetic activation associated with veterinary visit.

7. Defining normal blood pressure:

“Establishing reference intervals for estimated [systolic blood pressure] in healthy cats using Doppler or oscillometric equipment is fundamental to the clinical diagnosis of hypertension, and also for determining therapeutic targets in affected cats.”

Provide results from three different studies but: “there is a wide discrepancy between different studies; this reflects, at least in part, the different populations examined, and differences in types of equipment and the way equipment was used. Thus, having a standardised technique is of paramount importance.”

Categories proposed by The International Renal Interest Society (IRIS):

  • Systolic blood pressure (SBP) <150mmHg = normotensive with minimal risk of target organ damage
  • SBP 150-159mmHg = borderline hypertensive with low risk of target organ damage
  • SBP 160-179mmHg = hypertensive with moderate risk of target organ damage
  • SBP >=180mmHg = severely hypertensive with high risk of target organ damage

Strict categorisation is problematic as blood pressure is labile and target organ damage is not only related to severity of hypertension but also duration and relative change.

8. Criteria for therapeutic intervention and appropriate therapeutic targets:

Criteria as per the Guidelines:

“While individual circumstances should always be carefully assessed, based on current knowledge the Panel suggests that antihypertensive therapy is generally justified if SBP is measured carefully and when:

a. Indirect SBP is ≥150 mmHg on a single occasion, and there is clear evidence of ocular or neurological TOD [target organ damage].

Note: if clinical signs do not respond appropriately to adequate antihypertensive therapy, the diagnosis should be reassessed and other potential causes of the signs investigated.

b. Indirect SBP is ≥160 mmHg on at least two separate occasions, and there is evidence of TOD including ocular, neurological, cardiac or kidney damage.

c. Indirect SBP is ≥170 mmHg on at least two separate occasions, and the clinician does not consider ‘white coat hypertension’ is likely to be the cause.

d. Indirect SBP is <150 mmHg, but there is clear evidence of active ocular TOD.

Note: cats should be monitored carefully. If there is any doubt about the diagnosis of hypertension, the need for long-term therapy should be reassessed by trial withdrawal of therapy once stable, and monitoring of BP and clinical signs.

Cats with SBP <150 mmHg and evidence of potential TOD should have their clinical signs and BP monitored carefully, and other possible causes of the signs investigated.”

Therapeutic target:

SBP <160mmHg generally associated with decreased risk of target organ damage and hopefully an improvement in patient’s health
Indeed may be more prudent to aim for <150mmg in long-term

9. What treatment should you use?

“Based on current data, amlodipine besylate is the treatment of choice to manage feline hypertension and is effective in the majority of cats, but the dose needed to successfully manage hypertension varies between individuals.”

Guidelines also cover approach to amlodipine dosing and routine BP monitoring.

“It is worth noting that the Guidelines were supported financially by an educational grant from Ceva to the ISFM and Ceva is a manufacturer of amlodipine; however I don’t think this invalidates the statement about amlodipine being the current treatment of choice.” (Shailen)

Amlodipine causes vasodilation (peripheral arterial dilator) via calcium channel blockade; good response seen in many hypertensive cats suggests increased vascular tone may be a common component of feline hypertension.

Adjuvant therapy required in some cats:

E.g. ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers
Less effective; typically used in addition to not instead of amlodipine.

“The choice of adjunctive therapy to help manage hypertension may in part be dictated by any concurrent or underlying disease. For example, ACE inhibitors or ARBs may be indicated in CKD patients to help manage proteinuria”.

NB. Whenever hypertension is diagnosed, it is important to search for, and treat, underlying diseases as most cases of feline hypertension are secondary.

10. Emergency treatment of hypertension:

Hypertension generally chronic; acute presentations may be due to:

Acute onset of clinical signs due to target organ damage
Acute elevations of blood pressure (e.g. possible in acute kidney injury (AKI))

Aggressive intervention with oral +/- parenteral antihypertensive therapy may be tempting/seem rational but lack of definitive evidence to support positive risk-benefit assessment. 
Uncontrolled abrupt reduction in systolic blood pressure or development of hypotension can precipitate myocardial, cerebral or renal ischaemia and should be avoided.

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Hepatic Encephalopathy in Dogs and Cats

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Episode based on:

Lidbury JA, Cook AK, Steiner JM. Hepatic encephalopathy in dogs and cats. J Vet Emerg Crit Care 2016. 26 (4):471-487.

“The aims of this article are to comparatively review the pathogenesis, clinical presentation, diagnosis, and management of HE in dogs and cats. Gaps in the understanding of HE in dogs and cats and areas worthy of future study are also highlighted.”

What is Hepatic Encephalopathy?

“the spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of other known brain disease” from Hepatic encephalopathy – definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna 1998 (Hepatology, 2002).

Hepatic Encephalopathy – Classification

Three types in human medicine:

  • Type A: due to acute liver failure in the absence of pre-existing liver disease.
  • Type B: associated with portal systemic bypass without intrinsic hepatocellular disease; e.g. congenital portosystemic shunting in dogs and cats.
  • Type C: associated with cirrhosis and portal hypertension or acquired portal systemic shunting. Subcategorised according to duration and characteristics. Distinction made in people between ‘overt HE’ (signs of impaired mental status) and ‘covert HE’ (no altered mental status).

“can be applied to dogs and cats if the definition of type C HE is broadened to include cases associated with all intrinsic hepatocellular disease and portal hypertension or acquired portal systemic shunting.”

Covert HE currently not recognised in dogs and cats – likely exists but challenging to diagnose.

Schemes for grading severity exist in human medicine. No universally accepted guidelines to grading in dogs or cats. Some authors have adapted human grading schemes for use in dogs, e.g. Proot et al, 2009.

Hepatic Encephalopathy – Pathogenesis

Ammonia:

Evidence (more and better quality in people) for central role of ammonia dysmetabolism.
Gastrointestinal tract is main source of ammonia. Especially via breakdown of nitrogenous products (e.g. urea) by urease producing gastrointestinal microbial organisms; but also via conversion of glutamine to ammonia within intestinal mucosa.

Ammonia and the liver:

Liver is main site of ammonia detoxification (kidneys and skeletal muscle much less so): failure of hepatic detoxification leads to hyperammonaemia and higher cerebral exposure.

Main causes of inadequate hepatic detoxification:

1) Portosystemic shunting (PSS):

Most common reason in dogs and cats
Ammonia-rich splanchnic blood from the gastrointestinal tract bypasses hepatic uptake and flows directly into systemic circulation.
Two types of portosystemic shunt, extrahepatic and intrahepatic
Congenital vascular anomalies or acquired collateral blood vessels secondary to prehepatic or hepatic portal hypertension

[From http://communityvet.net/2010/04/when-protein-turns-toxic-jesse-story/pss/]

[From http://communityvet.net/2010/04/when-protein-turns-toxic-jesse-story/pss/]

2) Intrinsic liver dysfunction despite receiving ammonia-rich blood:

Due to acute liver failure or potentially chronic cirrhotic changes

Ammonia and the brain:

Brain is involved and active in ammonia handling
Ammonia passes freely across the blood brain barrier (BBB) in healthy individuals
Ammonia and pathogenesis of hepatic encephalopathy:

  • One of the most appealing theories is ammonia causes astrocyte swelling
  • Other potential mechanisms too
  • May also contribute to neurological dysfunction by increasing BBB permeability

“Dogs and cats with HE are often hyperammonemic, and successful treatment of HE is usually associated with a reduction in serum ammonia concentrations. However, patients may have HE despite a blood ammonia concentration within the reference interval suggesting that other mechanisms also play a role in the pathogenesis of HE.” (authors cite Rothuizen, van den Ingh, 1982).

Other pathogenic mechanisms of HE:

Infection and inflammation may play a role:

Clinical evidence in people
Non-infectious or infection systemic inflammatory response syndrome (SIRS) is common in people with both acute liver failure and cirrhosis
Inflammatory mediators may trigger HE by exacerbating cerebral effects of ammonia

Systemic inflammation also a potential phenomenon in dogs and cats with acute liver failure…“However, the relationship between inflammation and canine HE needs to be better defined. To the authors’ knowledge, this relationship has not been studied at all in cats.”

Others:

Neurosteroids found in high concentrations in the brain
Oxidative stress
Manganese
Amino acid balance

Hepatic Encephalopathy – Precipitating factors

People:

At least one trigger identified in 88 to 90% of those affected
Individuals with one or more triggers have a worse prognosis than those without
Most commonly reported include: gastrointestinal bleeding, constipation, diarrhoea, infection, hypokalaemia, hyponatraemia, and excess dietary protein.

Number of same factors can potentially precipitate HE in dogs and cats; some have been described in the veterinary literature. “However, the evidence base to support the role of many of these factors in veterinary species is weak or nonexistent.” Further investigation of the factors that may predispose dogs and cats to HE is needed.

Hepatic Encephalopathy – Clinical presentation

Signalment reflects most common causes of HE in dogs and cats, namely congenital or acquired portosystemic shunts.

Canine breeds most likely to be have congenital PSS (in descending order): Havanese, Yorkshire Terrier, Maltese, Dandy Dinmont Terrier, Pug, Miniature Schnauzer, Standard Schnauzer, and Shi Tzu. (Tobias, Rohrbach, 2003)

No studies evaluating which breeds are most likely to develop acquired shunting. Probably most likely in breeds predisposed to chronic hepatitis. Wide age range but typically older than dogs presenting for congenital PSS.

Congenital PSS reported in several cat breeds; unclear which – if any – are predisposed.
The authors say that although congenital shunts have been reported in a number of cat breeds, it is not clear which if any cat breeds are predisposed to HE and large-scale epidemiological studies will be needed to ascertain this.

Clinical signs:

Initially often subtle and episodic; can progress in intensity and frequency
May be exacerbated by eating
In one study (Lidbury et al, 2012)):

  • Most common historical findings: obtundation, altered behaviour, head pressing, ataxia, apparent seizures, vomiting, lethargy, ptyalism, apparent blindness, and shaking.
  • Most common neurological findings: obtundation, ataxia, weakness, conscious proprioceptive deficits, seizures, circling, cranial nerve deficits, stupor, and tremor.

Signs of HE in cats reportedly broadly similar to those in dogs. 

Hepatic Encephalopathy – Diagnosis

In veterinary medicine, based on:

  • Presence of consistent clinical signs
  • Exclusion of other causes of encephalopathy
  • Laboratory findings
  • Imaging studies, and
  • Response to treatment

Currently no way to evaluate dogs and cats that have HE but without impaired mental status.

Measuring blood ammonia concentration:

May or may not be elevated in dogs with HE

“In individual dogs, fasting ammonia concentrations poorly predict the severity of HE.” (Rothuizen, van den Ingh, 1982)

When accessible, seems to be performed routinely or at least commonly in veterinary patients suspected of having HE; not the case in human medicine.

Appropriate sample handling is critical:

  • Ammonium ions are extremely labile in plasma and ammonia may be released by red blood cells ex vivo.
  • Samples should be collected in a lithium heparin or EDTA tube, placed immediately on ice, and the plasma separated from the red blood cells as soon as possible.
  • Plasma must be kept cooled and should be analysed within 30 minutes of collection.

In-house and point of care analysers available: Reliability? Validation in dogs and cats?

“Measurement of pre- and postprandial serum bile acid concentrations is a useful test for diagnosing hepatobiliary disease, including portosystemic shunting, in dogs and cats. A definitive diagnosis of portosystemic-shunting requires diagnostic imaging or surgical exploration. Several imaging modalities are useful for this purpose, including angiography, abdominal ultrasonography, portal scintigraphy, computed tomography angiography, and MRI angiography. These imaging modalities, apart from portal scintigraphy, frequently allow the anatomic characterization of the shunt vessel(s)….For patients with acquired liver disease, a histological diagnosis is often necessary to define the underlying cause.”

Hepatic Encephalopathy – Treatment

Treating the underlying cause:

Various techniques for attenuation of congenital PSS
“Generally, signs related to HE improve after shunt attenuation…although incomplete closure can lead to persistent compromise. Dogs with a poorly developed portal vasculature may develop portal hypertension after shunt closure. This triggers the development of [acquired collateral circulation] with possible recurrence of HE. Postoperative seizures can also occur, the pathogenesis of which is unknown.”

Post-attenuation seizures “can occur in dogs and cats that do not have HE or other metabolic causes of seizures….Typical histological changes of the cerebrum in animals undergoing necropsy include selective “ischemic” neuronal necrosis and other changes that are consistent with ischemia or hypoxia. Withdrawal of endogenous benzodiazepines [post-congenital shunt] attenuation has also been proposed as a potential mechanism.”

Attenuation of acquired shunts contraindicated; these shunts are a compensatory response to portal hypertension and closure results in an acute exacerbation of portal hypertension.

General supportive care and treatment of precipitating factors:

Standard practice around:

  • Maintenance of fluid and electrolyte balance
  • Routine care of the comatose or stuporous patient
  • Management of suspected intracranial hypertension
  • Antimicrobial therapy for confirmed or highly suspected infection
  • Gastroduodenal ulcer treatment and prophylaxis

Warm water enemas:

Advised in this review to be performed in severely affected dogs and cats with HE until signs improve (reference is a single author book chapter).
Help remove blood and faecal matter from colon; therefore decrease bacterial ammonia production.
Also indicated for constipated patients with HE of all severity grades.

Nutrition:

Typical recommendation is protein-restricted diet containing specific types of protein sources.
Cats reportedly have a higher dietary protein requirement than dogs.
Diets recommended for HE also tend to have other modifications including reduction in some substances and supplementation with others.

“Although several commercially available diets are marketed for dogs and cats with HE, the optimal diet formulation has not been established.”

Lactulose:

A non-absorbable disaccharide
Potential beneficial effects:

  • Trapping of ammonium ions within the colon leading to decreased absorption of ammonia into the portal circulation
  • Inhibition of ammonia production by colonic bacteria
  • Stimulation of incorporation of ammonia within bacterial proteins
  • Reduced intestinal transit times leading to decreased bacterial ammonia release
  • Increased faecal excretion of nitrogenous compounds

Placebo controlled studies in humans support efficacy for treating overt HE. While lactulose is “commonly used to treat HE in dogs and cats [both acutely and chronically]…there are no studies that have critically evaluated the efficacy of this drug.”

Can be given per rectum after a cleansing warm water enema in acutely compromised patients but “it has not been proven that this has any benefits over a plain warm water enema.”

Antimicrobial therapy:

Aim to reduce ammonia production by altering intestinal microbiome
Neomycin:

  • Poor gastrointestinal absorption
  • Use no longer recommended in people as inadequate evidence of efficacy and risk of serious renal injury and ototoxicity
  • No good quality information about its use for HE in dogs and cats.

Metronidazole and vancomycin have also been used to treat HE in people; may be better tolerated in people than neomycin but their efficacy has not been rigorously established. Clinical trials have not been reported describing the efficacy of metronidazole for HE in dogs and cats.

Rifaximin (semisynthetic derivative of rifampicin) is US Food and Drug Administration approved for maintaining remission of HE in people. “The pharmacokinetics of rifaximin has been reported for dogs and this drug has been reported to be well tolerated in this species…The lack of apparent adverse effects is a potential benefit compared to neomycin and metronidazole. However, the safety and efficacy of this drug in dogs and cats with HE have not been established. Current costs are also likely to be prohibitive.”

Intravenous ampicillin (or potentiated amoxicillin) may be used in dogs or cats that cannot receive oral medications
Use of oral ampicillin also been reported

Anticonvulsants:

“Anticonvulsant drugs should be administered to patients with HE if seizures occur and in patients that seizure after attenuation of a congenital portosystemic shunt. Additionally, they are sometimes given to patients prior to shunt attenuation in an attempt to reduce the occurrence of postoperative seizures.”

“The use of diazepam and midazolam to treat seizures due to HE is controversial and there are no clinical trials that have evaluated the efficacy of these drugs in this setting. As diazepam is hepatically metabolized its half-life may be prolonged in dogs and cats with HE. Therefore, the dose and frequency that is used should be reduced in order to avoid causing profound sedation…In people benzodiazepine administration is considered to be a precipitating factor for HE.”

Levetiracetam:

  • Rapidly acting anticonvulsant with few side effects identified so far
  • Can be given intravenously or orally to dogs and cats
  • Principal route of excretion is renal so suitable for patients with hepatic compromise.
  • Use in dogs undergoing congenital PSS attenuation may be well tolerated and may reduce occurrence of postoperative seizures (Fryer et al, 2011).

Phenobarbital and propofol may also be used if required in acute situations
Potassium bromide can be used as an adjunct to other anticonvulsant drugs in dogs; of little use in emergency scenario due to very long half-life and delayed onset of action.

Other potential treatment options in people:

  • Flumazenil (intravenous benzodiazepine receptor antagonist): role of endogenous benzodiazepines in the pathogenesis of HE is controversial; only consensus is that flumazenil is useful when treating human patients with HE who have taken benzodiazepines.
  • L-ornithine-L-aspartate (or LOLA): thought to increase the rate of ammonia detoxification; early positive findings with clinical use in people with overt HE but further work is needed.
  • L-carnitine: several potentially beneficial mechanisms of action have been proposed in ammonia toxicity; some positive early findings in people but more work is needed. 
  • Prebiotics, probiotics and synbiotics: controversy in the evidence base in people and further well-designed large-scale clinical trials are needed.

Application to veterinary emergency and critical care

“HE is a relatively common but potentially life-threatening complication of hepatobiliary disease in dogs and cats. Veterinarians working in emergency or critical care settings must be able to promptly recognize, diagnose, and manage this condition. Although increased blood ammonia concentrations strongly suggest HE, it is important for clinicians to be aware of the limitations of this diagnostic tool. It is also essential that predisposing factors are quickly identified and addressed and that appropriate supportive care is provided.”

“Although there are several well-established treatments for HE in dogs, none of them are supported by robust scientific evidence. Clinical trials of the drugs currently used to treat HE are needed to help optimize treatment protocols.”

Papers mentioned in this episode:

Fryer KJ, Levine JM, Peycke LE, et al. Incidence of postoperative seizures with and without levetiracetam pretreatment in dogs undergoing portosystemic shunt attenuation. J Vet Int Med 2011. 25(6):1379–1384.

Lidbury JA, Cook AK, Steiner JM. Hepatic encephalopathy in dogs and cats. J Vet Emerg Crit Care 2016. 26 (4):471-487.

Lidbury JA, Ivanek R, Suchodolski JS, Steiner JM. Clinical feature of hepatic encephalopathy in dogs: 80 cases (1991–2011). J Vet Int Med 2012. 26(3):781 (Abstract).

Mehl ML, Kyles AE, Hardie EM, et al. Evaluation of ameroid ring constrictors for treatment for single extrahepatic portosystemic shunts in dogs: 168 cases (1995–2001). J Am Vet Med Assoc 2005. 226(12):2020–2030.

Proot S, Biourge V, Teske E, Rothuizen. Soy Protein Isolate versus Meat-Based Low-Protein Diet for Dogs with Congenital Portosystemic Shunts. J Vet Int Med 2009. 23(4):794-800.

Rothuizen J, van den Ingh TS. Arterial and venous ammonia concentrations in the diagnosis of canine hepato-encephalopathy. Res Vet Sci 1982. 33(1):17-21.

Taboada J, Dimski DS. Hepatic encephalopathy: clinical signs, pathogenesis, and treatment. Vet Clin North Am Small Anim Pract 1995. 25(2):337–355.

Tobias KM, Rohrbach BW. Association of breed with the diagnosis of congenital portosystemic shunts in dogs: 2,400 cases (1980–2002). J Am Vet Med Assoc 2003. 223(11):1636–1639.

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