Canine

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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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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Activated Charcoal

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What is activated charcoal and how is it meant to work?

Form of carbon processed and treated chemically to create a large number of small pores which increase available surface area for binding to other substances, i.e. microporosity increases adsorptive capacity.
Adsorbent, i.e. poison molecules adhere to its surface
Not absorption whereby the poison molecules would dissolve into and permeate the activated charcoal

Activated charcoal fed to animals that have ingested poisons; not absorbed or metabolised itself, instead binds to some/most of the poison still in the gastrointestinal tract
Charcoal-poison mixture then excreted in faeces
Gastrointestinal decontamination minimises systemic toxin absorption
Considered core part of management of small animal poisoning

Which poisons does activated charcoal adsorb well?

What sorts of substances does activated charcoal bind most avidly to?
From a clinical point of view, are there poisons for which we should be using it versus ones for which we shouldn’t?
Is there any evidence about the relative adsorbent capacity of activated charcoal for different small animal poisons?

Adsorptive capacity likely dependent on/influenced by poison-specific factors, e.g. size and polarity of molecules, degree of ionisation etc.

Bates N, Rawson-Harris P, Edwards N. Common questions in veterinary toxicology. J Sm Anim Pract 2015. 56:298-306:

“The binding of activated charcoal has not been tested against all (or even many) drugs and chemicals, but is known not to significantly adsorb a number of substances such as acids and alkalis, alcohols and glycols (ethylene glycol), metals (e.g. iron, lead), oils and petroleum distillates (e.g. white spirit) and detergents.”

However no references cited.

Use of activated charcoal generally not recommended for caustic or corrosive substances due to apparent lack of efficacy; however unable to find good quality evidence.

Should we be using activated charcoal at all?

Some debate!
  
[Human medicine] The American Academy of Clinical Toxicology (AACT) and the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) position paper:

"Single-dose activated charcoal should not be administered routinely in the management of poisoned patients...[as]... there is no evidence that administration of activated charcoal improves clinical outcome."

But…a lack of evidence of a beneficial effect on clinical outcome is not the same thing as evidence of a lack of beneficial effect on clinical outcome.

Veterinary patients?

“What you can know for sure – unless I failed to find them – is that there are no good quality prospective randomised controlled trials in clinical canine and feline patients evaluating the impact of activated charcoal on clinical outcome.” (Shailen Jasani)

Multiple variables to be studied, e.g.

  • Individual poisons
  • Different doses of the same poison
  • Whether or not emesis was induced
  • Time from exposure to administration of activated charcoal
  • Etc.

Risk/Cost-benefit assessment: general perception is low risk and cheap with potential for some/considerable/life-saving benefit.

Relative lack of antidotes and other treatment modalities (e.g. haemodialysis, plasma exchange) in veterinary versus human medicine

Contraindications and potential adverse effects

Not risk free albeit clinically significant adverse effects considered very uncommon/rare
Use common sense – e.g. do not administer orally to patients at increased risk of aspiration due to neurological compromise

Clinically significant acute hypernatraemia:

Most commonly cited mechanism is that activated charcoal draws water osmotically into the GI tract; this is then voided causing volume depletion.
Patients may have other co-existing causes of water loss plus reduced water intake
More likely with concurrent cathartic administration – but anecdotally reported with use of activated charcoal alone

Minimising the risk:

  • Ensure patient is adequately (re)hydrated beforehand
  • Tailor approach with respect to blood testing of hydration parameters and use of fluid therapy to individual patient based on risk assessment (e.g. very young or very old patients, existing vomiting, etc.)
  • Patients discharged on multidose activated charcoal following successful induction of emesis: advise clients to ensure free access to water and to contact clinic if any ongoing vomiting or clinical concern; liberal approach to administering antiemetic/antinausea agent before discharge.  
  • Avoid activated charcoal if ingested poison is known/suspected to be one that (potentially) causes hypernatraemia (e.g. homemade play dough); use cautiously for poisons which may induce diuresis (e.g. theobromine (chocolate)).

Pay attention to dose being dispensed:

  • Recommended dose range 0.5-8 g/kg depending on resource consulted
  • Less precise/more liberal empirical dosing may be acceptable for bigger and asymptomatic patients
  • Calculate and measure out doses in patients where there is clinical/hydration status concern; use low end doses and well-spaced dosing intervals for multidose therapy.

Avoid activated charcoal if possibility of gastrointestinal perforation, obstruction or ileus
Some debate about need to avoid if oral medications or antidotes needed
Avoid if gastrointestinal endoscopy or surgery is likely in the near future
Constipation may occur with multiple dose therapy

Timing of administration

Ideally administer as soon as possible after toxin ingestion; efficacy decreases the more time passes.
Many resources suggest not to administer activated charcoal if more than 2 hours have elapsed; this author typically suggests a longer more liberal time frame.
In reality likely to depend on multiple factors, e.g.

  • Rate of toxin absorption from gastrointestinal tract
  • Presence of food
  • Type of preparation e.g. delayed or sustained release?
  • Whether enterohepatic circulation occurs
  • Other factors influencing gastrointestinal motility and function

Paper mentioned in this episode:

Bates N, Rawson-Harris P, Edwards N. Common questions in veterinary toxicology. J Sm Anim Pract 2015. 56:298-306.

[This podcast is closely aligned with the MedEdLIFE Research Collaborative's Quality Checklist for Podcasts.]

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Dog and Cat Amputees: 'Tripods'

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On this episode of the podcast I am joined by Rene Agredano and Jim Nelson of TRIPAWDS, “the world's largest support community for animal amputees”, to discuss how we as veterinary staff can be better prepared to help clients with dogs and cats that are either facing or have had a limb amputation.

After some background discussion of the Tripawds resource, we discuss:

  • Ethical and moral considerations carers may have around amputation
  • Steps carers can take to prepare for their amputee dog or cat returning home for the first time
  • Client concerns about when their pet will be normal again, pain management, and the surgical incision

The following links were mentioned in the episode:

Tripawds - Help For Three Legged Dogs And Cats

The Tripawds charitable foundation

Tripawds on YouTube

Tripawds Downloads

The PBS Show that Rene mentions, “Why we love dogs and cats”

The Tripawds blog by an ECC vet: Hank the Tank
(backstory for Hank the Tank)

[This podcast is closely aligned with the MedEdLIFE Research Collaborative's Quality Checklist for Podcasts.]

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A Journal of Veterinary Emergency and Critical Care Papers Episode

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Episode based on May/June 2016 issue of the Journal of Veterinary Emergency and Critical Care

Please get in touch to request a copy of any of the papers discussed in this episode so you can read and critique the paper yourself!

Balakrishnan A, Drobatz KJ, Reineke EL. Development of anemia, phlebotomy practices, and blood transfusion requirements in 45 critically ill cats (2009–2011). J Vet Emerg Crit Care 2016. 26(3):406-411.

Anaemia is a relatively common clinical finding in critically ill patients
Likely multifactorial
Repeated phlebotomy to collect blood samples for diagnostic testing may be one of the causes or at least one of the contributing factors. Has been demonstrated in people, especially children, and suggested anecdotally in small animal patients.

“Critically ill cats that develop significant anaemia are often treated with blood transfusions. Red blood cell transfusions can help improve oxygen carrying capacity and may improve survival. However, at least in people, blood transfusions are associated with an increased expense, longer hospital stays, and carry the risk of several potentially life-threatening medical complications such as immunological transfusion reactions, infectious diseases, transfusion associated circulatory overload, and transfusion related acute lung injury.”

Information on this topic is limited in the veterinary literature and the primary objectives of this study were to:

  • Describe the incidence and development of anaemia in critically ill cats
  • Document phlebotomy practices and transfusion requirements in these cats
  • Evaluate the association between these factors on both duration of hospitalisation and outcome

Retrospective study
University of Pennsylvania ICU from 2009 to 2011
Exclusion criteria:

  • Did not stay in ICU for more than 48 hours (to exclude stable post-operative cases recovering in ICU)
  • Documented to have anaemia secondary to underlying chronic kidney disease
  • Incomplete medical records

Final sample size of 45 cats
Variety of primary diagnoses; respiratory disease, congestive heart failure and neoplasia most common
All of the cats were admitted via the emergency room in which they mostly stayed for less than 12 hours but some up to 24 hours
Approximately 20% were anaemic on admission to the hospital
40% developed anaemia before admission to the ICU (contribution of haemodilution from fluid therapy?)
Approximately 75% of the cats who were not anaemic on ICU admission went on to develop anaemia while in the ICU

Cats that developed anaemia after admission to the ICU had a significantly longer duration of hospitalisation than cats that did not develop anaemia while in the ICU.
Median duration: anaemic group 5 days, non-anaemic group 4 days
Range: anaemic group 3-24 days, non-anaemic group 3-13 days
Development of anaemia in the ICU was not statistically associated with outcome, just duration of hospitalisation.

Cats that required a blood transfusion for anaemia were found to have a significantly longer duration of hospitalisation but transfusion was not statistically associated with outcome. 

Phlebotomy:

  • Median number of phlebotomies per day for all cats in the ICU was 3 (range 1–6).
  • The 20 cats that developed anaemia during their ICU stay had a significantly greater number of phlebotomies per day (median 3, range 1–5) than the 7 cats that did not develop anaemia (median 1, range 1–2).
  • Cats that required a pRBC transfusion had a significantly greater number of daily phlebotomies (median 3, range 1–6) than cats that did not require a transfusion (median 2, range 1–4).
  • Cats that had a sampling or central venous catheter had a significantly greater number of phlebotomies (median 3, range 1–6) than cats without either of these catheters (median 1, range 1–2).

Results suggest that cats that developed anaemia after admission to their ICU had a longer duration of hospitalisation, likewise cats that received a blood transfusion. And probably this is because these cats were sicker.
These cats also had more blood samples taken, again probably because they were sicker.
Vicious circle: sicker cats have more blood samples taken = more blood loss = tendency towards or worsening of anaemia
Sicker cats also more likely to have anaemia as a result of other factors, potentially including a poorer regenerative response

Authors did not attempt to calculate any sort of illness severity scores because of the limitations in getting all the necessary data.

“In light of our study findings, adoption of blood conservation strategies should be considered. Blood conservation strategies are widely advocated in human intensive care medicine, particularly in critically ill children and include minimizing daily routine diagnostic phlebotomies, use of small volume or pediatric phlebotomy tubes, point of care and bedside microanalysis, minimization of blood sample wastage, lowering transfusion thresholds and transfusing only in response to physiologic need, and removing central venous and arterial catheters when no longer needed for patient monitoring purposes.”

For cats that do not have an in-dwelling sampling catheter in place, venepuncture is not entirely benign or risk free; unnecessary sampling can also contribute to patient stress, distress and reduced welfare.

Beer KS, Drobatz KJ. Severe anemia in cats with urethral obstruction: 17 cases (2002–2011). J Vet Emerg Crit Care 2016. 26(3):393-397.

“We hypothesized that cats with urethral obstruction and severe anemia requiring transfusion would have higher morbidity and mortality than cats with urethral obstruction without severe anemia.”

From an evidence-based perspective, this study was not able to prove or disprove this hypothesis.

Retrospective study from University of Pennsylvania over nine year period
Several limitations with respect to materials and methods, including small sample size:

  • 46 tomcats with urethral obstruction and anaemia
  • 17 tomcats met inclusion criteria, one of which was a PCV during hospitalisation of less than or equal to 20%
  • 2132 tomcats were treated for urethral obstruction during study period; 17 study cats = incidence of 0.8%

Authors suggest severe anaemia may largely be due to haemorrhage into urinary bladder – but this study does not provide evidence for this suggestion.

Full AM, Barnes Heller HL, Mercier M. Prevalence, clinical presentation, prognosis, and outcome of 17 dogs with spinal shock and acute thoracolumbar spinal cord disease. J Vet Emerg Crit Care 2016. 26(3): 412–418.

“Spinal shock is uncommonly reported in veterinary medicine and occurs when the spinal reflex arcs are anatomically normal but the patient exhibits transient hyporeflexia or areflexia caudal to a lesion….This is followed by a period of gradual return of the segmental spinal reflexes, and eventually hyperreflexia days to months later…In dogs with spinal shock the neurologic examination may yield a multifocal disease process or a lesion within the reflex arc, which could lead a clinician to an inaccurate neuroanatomic localization and differential diagnoses, and inappropriate diagnostic and treatment plan. An increased awareness of the prevalence, clinical presentation, common etiologies, and progress of spinal shock will aid the clinician in recognizing this syndrome.”

Upper motor neuron (UMN) lesion: expect hyperreflexia
Lower motor neuron (LMN) lesion: expect hyporeflexia
Authors key point is: If you examined a patient and found hyporeflexia you may suspect a LMN spinal reflex arc lesion when in fact the actual lesion is an UMN spinal cord lesion cranial to the localisation and the hyporeflexia is the result of spinal shock.

“The purpose of this study was to describe the prevalence and clinical presentation for dogs with thoracic vertebrae 3 (T3) to lumbar vertebrae 3 (L3) spinal lesions and suspected spinal shock.”

Retrospective study; November 2005 to 2010; private referral hospital in North America
986 dogs had spinal MRI performed
263 dogs remained after exclusion criteria applied
17/263 (6%) were diagnosed with spinal shock
94% of these 17 dogs presented within 24 hours of the onset of clinical signs 

Spinal shock following spinal cord injury has previously been described in association with severe spinal cord injury or transection causing loss of motor and sensory function in humans.
Also been observed and reported in a limited number of dogs with severe paraparesis or paraplegia.

“Our study is the first report specifically evaluating the prevalence and clinical presentation of spinal shock in dogs with acute thoracolumbar spinal injury.”

Spinal shock pathophysiology:

  • Studied in both human medicine and limited experimental veterinary studies
  • Complex syndrome
  • Underlying disease processes associated with spinal shock not been clearly defined

In people, a 4 phase model has described the alterations in spinal reflexes and time frame expected for return to function:

  • Phase 1: occurs within 0-24 hours; characterised by areflexia or hyporeflexia caudal to the spinal cord injury 
  • Phase 2: begins 1-3 days after injury; correlated with denervation hypersensitivity
  • Phase 3: 4-30 days post-injury; characterized by reappearance of deep tendon reflexes and the flexor withdrawal reflex
  • Phase 4: 1–12 months post-injury with return of all reflexes; reflexes often exaggerated during phase 4
“Mechanisms for recovery of spinal shock have been described including unveiling of latent synapses, alterations to the density or distribution of neurotransmitters and collateral sprouting of intact axons….The timing of segmental spinal reflex return has been suggested to be dependent on the individual’s amount and type of physical fitness prior to the injury. For example, highly trained athletes may have a shorter recovery of reflexes due to decreased tendon excitability, when compared to an untrained person.”

In this study, fibrocartilaginous embolism FCE) was most commons cause of spinal injury (7/17 dogs)
Acute non-compressive nucleus pulposus extrusion and intervertebral disk herniation were other causes

Results here indicate that dogs with clinical evidence of spinal shock have a high probability of at least partial neurological improvement:

  • 88% of dogs with documented neurological examinations at the time of discharge (1–12 days following diagnosis) had improved or normal reflexes, 75% of which specifically had improved withdrawal reflexes.
  • Remaining dogs lacking recorded neurological examinations at discharge, had improved or normal reflexes on subsequent recheck examinations with the exception of 1 dog.
  • Findings consistent with the previous literature suggesting reflexes often recover faster in non-primates compared to people
  • However, recovery of the withdrawal reflex was longer than 48 hours in many of the dogs in this study
“The lack of standardized follow-up time, especially in the immediate post-injury period, limits interpretation of the recovery process. A concise timeline of recovery is difficult in a retrospective study; therefore, caution should be taken when providing expected recovery times to clients.”
“In conclusion, although uncommon, spinal shock should be considered in any dog presenting with an acute history of thoracolumbar spinal injury and reduced reflexes in the pelvic limbs. Imaging should be pursued between the T3-S3 spinal segments in these patients to account for lesions in the T3-L3 spinal cord segment, which may result in spinal shock. The presence of spinal shock should not dissuade a veterinarian from pursuing appropriate diagnostic testing and therapy for the underlying etiology.”

Swann JW, Maunder CL, Roberts E, et al. Prevalence and risk factors for development of hemorrhagic gastro-intestinal disease in veterinary intensive care units in the United Kingdom. J Vet Emerg Crit Care 2016. 26(3): 419–427.

In human medicine, stress-related mucosal disease (SRMD) refers to the development of erosive lesions of the stomach and intestines in patients admitted to intensive care units (ICUs) for management of severe illness.
SRMD covers a spectrum of disease, from superficial mucosal injury detectable only by gastroduodenoscopy to severe ulceration that results in clinically important haemorrhage.
Overt clinical bleeding due to SRMD was reported to occur in approximately 4% of human patients admitted to a group of ICUs in Canada…
…and development of this disease significantly increased the risk of death during the period of hospitalisation.

“Impaired perfusion of the gastric mucosal barrier (GMB) is the proximate cause of SRMD, but development of the disease is reflective of systemic changes in hemodynamic status and inflammatory cascade”
“several factors have been identified in human patients that increase the risk of development of SRMD…particularly respiratory failure necessitating mechanical ventilation and coagulopathy. Administration of prophylactic gastro-protectant medications reduces the risk of SRMD…but this may be associated with development of other complications, such as aspiration pneumonia, because increased gastric pH permits bacterial colonization of the stomach.”

Haemorrhagic gastro-intestinal (GI) disease has not been described specifically in veterinary ICUs

“The primary aim of this study was to determine the proportion of animals that developed overt hemorrhagic GI disease in veterinary ICU patients. It was hypothesized that this would occur at similar rates to those reported in human ICUs, and that dogs would develop the disease more frequently than cats based on previous evidence suggesting that the GI tract is not the shock organ of cats. Secondary aims were to investigate risk factors for the development of hemorrhagic GI disease, and to determine whether development of these signs was associated with mortality during the period of hospitalization.”

Retrospective multicentre study in three UK teaching hospital ICUs; a lot of the data was collected prospectively
All cases presenting consecutively to the ICUs were considered eligible for enrolment during the period of the study if they were hospitalised for at least 24 hours
Exclusion criteria:

  • History of haemorrhagic GI disease in 48 hours prior to hospitalisation
  • Developed signs of haemorrhagic GI disease within the first 24 hours after admission
  • Surgical procedures involving the GI or upper respiratory tracts
  • Presented with or developed epistaxis or haemoptysis
  • Presented for management of GI disease
  • Sustained 1 or more skull fractures

Cases were not excluded if they:

  • Received gastro-protectant drugs, NSAIDs, glucocorticoids, or anticoagulants prior to admission or during hospitalisation
  • Were diagnosed with diseases that may cause secondary GI signs, such as hypoadrenocorticism

SRMD was defined as haemorrhagic GI disease manifesting as hematemesis, melena, or haematochezia or as mucosal erosions and haemorrhage observed during GI endoscopy.

Final sample size: 272 dogs and 94 cats
Some results:

  • 7.0% (CI: 4.5–10.7) (= 19 dogs) of dogs and no cats across the three centres developed SRMD
  • Among the dogs that received prophylactic gastro-protectant medications, the proportion that developed SRMD was 16.4% (CI: 8.9–28.3), compared to only 4.2% (CI: 2.2–7.8) in dogs that did not receive prophylaxis
  • Decreased serum albumin concentration, the ICU in question, and administration of prophylactic gastro-protectant medications were risk factors for the development of SRMD.
  • The proportion of dogs with SRMD that did not survive to discharge was significantly greater than for dogs that did not develop SRMD
  • Placement of a feeding tube and development of SRMD were associated with mortality

SJ comment:

“Now look as always, please don’t just take these points at face value and start repeating them. That would be entirely inappropriate. For starters we would need more studies, ideally prospective and blinded where possible, to evaluate all of this and demonstrate repeatability. And even then we would need to still be careful to distinguish association from causation.”

 Authors:

“Limitations of this study include the relatively small number of cases included, especially for investigation of risk factors for development of SRMD and mortality…it is possible that unmeasured differences between centers could have acted as confounding or modifying factors. Although much of the data included in this study were collected prospectively, some information regarding development of GI disease was collected retrospectively from clinical records, reducing the reliability and consistency of these findings. Data were also collected by a number of different investigators who may not have been involved in the primary care of the case.

Conclusions:

SRMD was observed in dogs from 3 different veterinary ICUs but was not observed in cats. Decreased serum albumin concentration was associated with development of SRMD, but, using a clinically relevant cut off value, this variable had a poor sensitivity and specificity for prediction of the disease. Development of SRMD and placement of a feeding tube were independently associated with increased mortality while hospitalized, but further studies will be required to determine the effects and potential benefits of prophylactic gastro-protectant therapy in veterinary ICU patients.”

If you would look a copy of any of the papers mentioned in this episode, let me know.

[This podcast is closely aligned with the MedEdLIFE Research Collaborative's Quality Checklist for Podcasts.]

Tweet: Check out FREE audio podcasts from @VetEmCC http://ctt.ec/UqL8b+ Also available in iTunes/Stitcher. #veterinary #podcast