Journal papers

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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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.]

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Antimicrobial Stewardship in Companion Animal Practice

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Bacteriology Refresher

Bacteria: single-celled microbes; often function as multicellular aggregates (biofilms)
Five morphological groups: cocci (spherical) and bacilli (rods) most common
Exist as single cells, in pairs, chains or clusters
Gram positive: thick cell wall
Gram negative: comparatively thin cell wall which includes a lipid membrane containing lipopolysaccharides (LPS, endotoxin) and lipoproteins
Also aerobic versus anaerobic growth; obligate or facultative

Antibacterials Refresher

Must remember the distinction between theoretical in vitro assertions and in vivo behaviour/effects in real clinical patients with different diseases and sites of infection

Broad- vs. narrow-spectrum classification according to the range of bacteria they are meant to be effective against. Commonly used but no clear and logical definitions for these terms. 

Bactericidal vs. bacteriostatic:

  • Bactericidal antibiotics kill bacteria directly
  • Bacteriostatic antibiotics stop bacteria from growing
  • May be much more relevant under strict laboratory conditions; more arbitrary and inconsistent in clinical situations

Time- vs. concentration-dependent:

Time-dependent:

  • Key pharmacodynamic parameter = time that plasma concentration remains above the minimum inhibitory concentration (MIC) during the dosing interval
  • MIC = lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation
  • Higher concentration does not result in greater antibacterial activity
  • Key element is how long the concentration remains above the MIC at the site of infection rather than how high the concentration reaches
  • Dosing interval is critical; missing doses can compromise efficacy
  • Examples include penicillins, cephalosporins and carbapenems

Concentration-dependent:

  • Key pharmacodynamic parameter = ratio between peak plasma drug concentration and the MIC of the antibiotic in question
  • I.e. antibacterial activity is related to how high the concentration reaches at the site of infection rather than how long it remains above the MIC during the dosing interval.
  • Examples include the fluoroquinolones and the aminoglycosides.

Beta-lactam Antibacterials

Most widely used antibiotics in dogs and cats?

Amoxicillin-clavulanate:

Amoxicillin ‘potentiated’ by addition of potassium clavulanate
British Small Animal Veterinary Association’s Formulary (8th edn.):

  • Amoxicillin active against certain Gram-positive and Gram-negative aerobic organisms and many obligate anaerobes but not against those that produce beta-lactamases (e.g. E. coli, Staph aureus)
  • Clavulanate increases spectrum of action and restores efficacy against amoxicillin-resistant bacteria that produce beta-lactamases
  • More difficult Gram-negative organisms (e.g. Pseudomonas, Klebsiella) usually resistant 

Cephalosporins:

  • First-generation (e.g. cefalexin (cephalexin)) active predominantly against Gram-positive bacteria
  • Successive generations (e.g. cefuroxime is second generation) have increased activity against Gram-negative bacteria (albeit often with reduced activity against Gram-positive organisms)

Fluoroquinolones:

British Small Animal Veterinary Association’s Formulary (8th edn.):

“Ideally fluoroquinolone use should be reserved for infections where culture and sensitivity testing predicts a clinical response and where first- and second-line antimicrobials would not be effective”.

Active against Mycoplasma and many Gram-positive and Gram-negative organisms, but relatively ineffective against obligate anaerobes

Metronidazole:

Treatment of anaerobic infections, giardiasis and other protozoal infections

Antimicrobial Stewardship

Derived from this review article:

Guardabassi L, Prescott JF. Antimicrobial Stewardship in Small Animal Veterinary Practice: From Theory to Practice. Vet Clin N Am – Sm Anim Prac 2015. 45(2):361–376.

Nature of the problem:

“Antimicrobial resistance [or AMR] is one of the greatest challenges currently facing small animal veterinary medicine. During the past decade, various multidrug-resistant bacteria (MDR) have emerged and spread among dogs and cats on a worldwide basis. The major current MDR organisms of concern are methicillin-resistant Staphylococcus pseudointermedius (MRSP) and Escherichia coli producing extended-spectrum β-lactamase (ESBL). However, these bacteria are just the tip of the iceberg because multidrug resistance has diffused in other common bacterial pathogens encountered in general practice, such as Pseudomonas aeruginosa and enterococci. Additional MDR bacteria that are more likely to be isolated from animals presenting to referral centers include methicillin-resistant Staphylococcus aureus (MRSA), carbapenemase-producing E coli and Klebsiella pneumoniae, and MDR Acinetobacter baumannii.

All these MDR bacteria are frequently resistant to all conventional antimicrobials licensed for animal use and therefore pose a serious threat to animal health by increasing the risk of therapeutic failure and the recourse to euthanasia. MRSP/MRSA and MDR gram-negatives are important hospital-associated pathogens that can be transmitted from patient to patient through contact with personnel, with healthy animal carriers, and with contaminated environmental surfaces. Significant public health concerns exist because of the possible risk of animal-to-human transmission and in part also because of the increasing use in small animals of critically important antimicrobials authorized for human use only, such as carbapenems.

From the owner’s perspective, infections caused by MDR bacteria contribute to increased veterinary expenditures because of additional and more expensive antimicrobial treatments, longer hospitalization, more visits, and more diagnostic tests. Moreover, the negative consequences of MDR infections in household pets include emotional and social effects on the owners and their families. Hospitals and clinics affected by outbreaks of MDR bacterial infections also can be impacted economically by the loss of revenue due to loss of reputation and decreased case load, decontamination procedures, closure, and coverage of patient bills. This situation is worsened by the slow development of new antimicrobial drugs observed over the past decades. The few truly new agents are reserved for human use in hospitals and it is unlikely that these drugs will be authorized for veterinary use in the years to come. Thus, it is of paramount importance to preserve the efficacy of the veterinary antimicrobial products available today.”

Antimicrobial stewardship programs (ASPs) are a cornerstone of the response to the AMR crisis in human medicine; still largely underdeveloped in veterinary medicine.

“the aim of this article is to indicate the necessary steps that should be taken to establish ASPs in small animal veterinary practice, taking into consideration the many and remarkable differences between the human and the veterinary sector, and indeed the remarkable differences within veterinary medicine. Although the article highlights the structural and economic constraints that make implementation of ASPs used in human health care facilities difficult in small animal practice, it provides suggestions and approaches to overcome such constraints and to move toward practical implementation of effective veterinary-specific ASPs in small animal hospitals and clinics. We emphasize the multidimensional and the “mind-set” nature of “good stewardship practice” (GSP), as well the importance of an entire team-based commitment similar to that required for implementation of infection control practices.”

Antimicrobial paradox in small animal practice:

“One of the most effective strategies to manage AMR in human hospitals is to reduce the overall consumption of antimicrobial agents and rationalize the use of the most valuable drugs (eg, carbapenems, fourth-generation cephalosporins, glycopeptides), which are generally reserved for empirical treatment of life-threatening infections or infections that cannot be treated otherwise on the basis of susceptibility data. This strategy is almost completely flipped in small animal practice, where the listed drugs are not authorized and the most powerful veterinary antimicrobials, namely β-lactamase–resistant penicillins, cephalosporins, and fluoroquinolones, are widely used as empiric first-line agents in primary care, including treatment of mild or self-limiting infections….

…High consumption of these drugs provides a strong selective pressure in favor of MDR bacteria resistant to extended-spectrum β-lactams and fluoroquinolones” but the authors acknowledge that “they are indispensable drugs for management of common bacterial infections in small animals, including complicated skin and urinary tract infections and various life-threatening conditions”.

What is antimicrobial stewardship?

“The term “antimicrobial stewardship” is used to describe the multifaceted and dynamic approaches required to sustain the clinical efficacy of antimicrobials by optimizing drug use, choice, dosing, duration, and route of administration, while minimizing the emergence of resistance and other adverse effects. The word stewardship implies the obligation to preserve something of enormous value for future generations, and resonates in a way that “prudent use” or “judicious use” does not. GSP is the active, dynamic process of continuous improvement in antimicrobial use, and is an ethic with many steps of different sizes by everyone involved in antimicrobial use. Stewardship thus links, for example, front-line veterinary practitioners with laboratory diagnosticians, owners, drug regulators, and pharmaceutical companies.”

Examples of elements encompassed by the term antimicrobial stewardship that affect the emergence and spread of resistance include practice guidelines, dosage considerations and clinical microbiology data.
Also “A 5R approach to stewardship: Acceptance of responsibility for resistance as a potential effect of antimicrobial use, and for reduction, replacement, refinement, and review of antimicrobial use on an ongoing basis.”

In human medicine antibiotic stewardship is very much something that is attended to at the individual hospital level. In veterinary medicine it tends to be more about national and international surveillance and guidelines and potentially “legal (regulatory) interventions imposed by national authorities to restrict or ban specific drugs, to limit profit derived from antimicrobial dispensation, and taxes or penalties to prevent antimicrobial overuse”. While the authors support this “broad, multifaceted, approach to sustaining the efficacy of antibiotics for the long term” they also “recognize the need for establishing hospital-based ASPs in small animal practice.”

Establishing an antibiotic stewardship programme:

“No guidelines are available for development of ASPs in small animal clinics”
Article presents information and guidelines from non-veterinary specific resources

Role of microbiology laboratory:

“Liaison with a microbiologist at the diagnostic laboratory, which in contrast to human hospitals is normally placed outside the clinic environment, is an essential aspect for implementation of ASPs in small animal veterinary practice. The microbiology laboratory is not only supposed to provide timely and accurate species identification and antimicrobial susceptibility testing. Its role and responsibilities go beyond correct specimen testing and reporting of results, and include attention to the preanalytical...and postanalytical...components of testing. Selective reporting of susceptibility profiles can be used to discourage unnecessary use of broad-spectrum agents that are not licensed for veterinary use...Indiscriminate reporting of positive culture and susceptibility data on likely contaminants or nonpathogenic commensals should be avoided, because this practice may lead to inappropriate antimicrobial use. Last, but not least, the microbiology laboratory should generate annual reports summarizing the trends of AMR at the clinic level or at least at the regional level.”

Antimicrobial stewardship strategies:

“Various strategies have been shown to improve appropriateness of antimicrobial use and cure rates, decrease failure rates, and reduce health care–related costs in human hospitals”.
Article provides an overview of the most successful strategies used in human hospitals with focus on their implementation in small animal veterinary practice. Including:

Educational approaches:

“outstanding example of a readily and freely accessible Web-based and app-linked resource aimed to support companion animal veterinarians to develop practice policies for antimicrobial stewardship is the PROTECT site of the British Small Animal Veterinary Association”
[http://www.bsava.com/Resources/PROTECT.aspx]

PROTECT = Practice policy, Reduce prophylaxis, Other options, Types of bacteria and drugs, Employ narrow spectrum, Culture and sensitivity, and Treat effectively.

Federation of European Companion Animal Veterinary Associations has released several posters addressing responsible use of antimicrobials, appropriate antimicrobial therapy, and hygiene and infection control in veterinary practice.
[http://www.fecava.org/content/guidelines-policies]

Development and implementation of guidelines:

“General (generic) guidelines providing statements of principles of prudent antimicrobial use have been developed in recent years by most national veterinary organizations…Although important from a conceptual standpoint, their clinical guidance and impact is likely limited. Standard texts have included investigator recommendations on first-choice, second-choice, and last-resort antimicrobial agents… More recently, evidence-based clinical antimicrobial use guidelines have been developed using approaches similar to those for human guidelines. These have typically involved national or international expert panels reviewing and assessing the quality and strength of published literature to produce recommendations for diagnosis and management of specific conditions….The impact of national practice guidelines is likely higher than for international guidelines, because they take into account local factors regarding legislation, drug market availability, and prevalence of resistance.

Many veterinary specialty organizations also have developed guidelines, ranging from generic prudent use guidelines to practice-specific or disease-specific guidelines…Veterinary practice guidelines are negatively affected by numerous knowledge gaps regarding dose-effect relationships between antimicrobial use and resistance, antimicrobial consumption, resistance prevalence, drug-to-drug superiority, and optimal duration of treatment. However, although there are limitations, national guidelines are an essential milestone for development of [local antimicrobial policies] and more complex [antimicrobial stewardship programs] at the clinic level”.

Generic guidelines provided in paper (with references):

  1. Antimicrobials should be used only when there is evidence or at least a well-founded clinical suspicion of bacterial infection
  2. Antimicrobials should not be used for treatment of self-limiting infections
  3. Antimicrobial, pathogen, infection site, and patient factors should be considered when choosing an appropriate treatment
  4. Cytology should be used as a point-of-care test to guide antimicrobial choice for relevant disease conditions (eg, otitis and urinary tract infections)
  5. Antimicrobial susceptibility testing should be performed if:
    • There is suspicion of a complicated or life-threatening infection
    • The patient does not respond to initial treatment
    • The patient has a recurring or refractory infection
    • The patient is immunosuppressed
    • There is a need to monitor the outcome of therapy (eg, long treatment period)
    • The patient is at risk of infection with multidrug-resistant bacteria
  6. As narrow a spectrum therapy as possible should be used
  7. Topical therapy should be preferred over systemic therapy for treatment of superficial skin infections
  8. Antimicrobials should be used for as short a time as possible
  9. Extra-label use should be avoided when on-label options are reasonable
  10. Use of critically important antimicrobials not authorized for veterinary use should at least be restricted to rare and severe patient conditions (eg, diagnosed, life-threatening bacterial infections that cannot be treated by any other available antimicrobials, provided that treatment has a realistic chance of eliminating infection)
  11. Antimicrobial therapy should never be used as a substitute for good infection control, and good medical and surgical practices
  12. Perioperative prophylaxis should be used only when indicated, and follow standard guidelines
  13. Clients should be educated to ensure compliance

“Although there has been a marked increase in available guidelines, there has been little assessment of their impact on practice.”

“The effort spent on introducing guidelines, on educating health care providers, and in monitoring the response to guidelines is often slight compared with the effort of development, but critical to success. Compliance with guidelines may be poor because of inadequate communication, differences in opinion regarding recommended treatments, and resentment of measures to prescribe individual decisions….Thus, it is crucial that national and local veterinary professional and regulatory organizations allocate sufficient time and resources to promote guidelines and facilitate compliance.”

Other antimicrobial stewardship strategies mentioned:

  • Prescription approval
  • Post-prescription review
  • Computer-based decision support

Article also covers:

  • Measuring the outcomes of antimicrobial stewardship programs
  • Potential barriers to their implementation

Key points:

  • “There is increasing recognition of the critical role for antimicrobial stewardship and infection control in preventing the spread of multidrug-resistant bacteria in small animals.
  • Establishment of antimicrobial stewardship programs requires (1) coordination ideally by an infectious disease specialist or at least by a clinician with strong interest in and good knowledge of antimicrobial resistance and therapy, (2) commitment by the clinical staff, and (3) collaboration with the microbiology laboratory.
  • Even in the absence of specialist help, by accessing the increasingly available resources, veterinary clinics should at least develop, implement, and periodically update local antimicrobial policies indicating first-choice, restricted, and reserve drugs.
  • Educational approaches, clinical guidelines, preprescription approval, postprescription review, and computer-based decision support are the most effective strategies to accomplish best practices in antimicrobial stewardship.
  • The main barriers to implementation of antimicrobial stewardship programs comprise (1) economic sustainability; (2) lack of formally trained infectious disease specialists; (3) limited use of culture and antimicrobial susceptibility testing; (4) scientific knowledge gaps for assessment of resistance, development of evidence-based guidelines, and optimization of antimicrobial therapy; and (5) absence of standardized methods for evaluating the outcomes of antimicrobial stewardship programs.”

In 2015 ACVIM published a “Consensus Statement on Therapeutic Antimicrobial Use in Animals and Antimicrobial Resistance” in the Journal of Veterinary Internal Medicine.
[http://onlinelibrary.wiley.com/doi/10.1111/jvim.12562/epdf]

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

I mention my Small Animal Emergency Medicine App for iPhone/iPad in this episode which you can find HERE. An Android version is in development.

 
 
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What's Magnesium Got To Do With It?

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This episode is based on:

Humphrey S, Kirby R, Rudloff E. Magnesium physiology and clinical therapy in veterinary critical care. J Vet Emerg Crit Care 2015. 25(2):210-225.

“Magnesium (Mg) is a cation with an escalating role in critical care medicine.”

Is this true?
If it is, is it a good thing?
Is the evidence base supporting this escalating role theoretical, experimental or clinical? 

Background theory

“magnesium plays a pivotal role in cellular energy production and cell-specific functions in every organ of the body. Excess or deficiency of this important cation can result in life-threatening complications.”

Majority (99%) intracellular, especially bone
Plasma magnesium: protein-bound, complexed (anions e.g. citrate, phosphate), ionised
Ionised Mg physiologically active form

Plasma [Mg] may not reflect cellular environment
Changes in plasma [Mg] may not reflect changes in total body [Mg]

Intracellular [Mg] maintained at 0.5–1 mmol/L despite significant fluctuations in extracellular [Mg].

Cellular functions:

“Magnesium plays a pivotal role in the electrophysiology and ion flux across cell and mitochondrial membranes” ultimately impacting on energy production and release.
Affects cellular functions via relationship with intracellular calcium; in general competes with or otherwise influences calcium movement.

Various other functions mentioned in article.

Total body magnesium content dependent upon intestinal and renal absorption and excretion

Measuring Magnesium

“Accurate measurement of total body magnesium is a challenge due to its intracellular location and activity. The current clinical standard is to quantitate serum total or ionized magnesium concentrations…Monitoring the biologically active serum ionized magnesium concentration is preferred over total serum magnesium concentration.”

Serum quantitation may not accurately reflect total body magnesium content – unresolved
Research methodologies that allow intracellular magnesium to be measured may become available for clinical use

Magnesium disorders

“Total body magnesium concentration is affected by dietary intake, gastrointestinal function, hormonal balance, redistribution of the magnesium cation, and excretion into a third body space or urine. Magnesium disorders can manifest with a multitude of clinical signs, none of which are specific for the magnesium disorder.”

Article includes summary of mechanisms, causes, clinical signs, and treatment recommendations for magnesium excess and deficiency.

*Patient may have clinical signs that are compatible with a magnesium disorder – but they will not be pathognomic for one
*Abnormal plasma [Mg] may support that signs are due to a magnesium disorder – but not necessarily
*Decision to treat: empirical; based on risk-benefit assessment

Magnesium excess

“The two most commonly reported causes of magnesium excess in both human and veterinary patients are renal failure and iatrogenic causes…Hypermagnesemia can occur when magnesium-containing drugs such as antacids, laxatives, or enemas are administered to patients with underlying renal disease….Hypotension is one of the key clinical complications of magnesium excess.”

[Martin LG, Matteson VL, Wingfield WE, et al. Abnormalities of Serum Magnesium in Critically III Dogs: Incidence and Implications. J Vet Emerg Crit Care 1994. 4(1):15-20]

  • Naturally occurring total hypermagnesaemia reported to occur in up to 13% of critically ill dogs admitted to the ICU of one teaching hospital
  • Found that dogs with hypermagnesaemia were 2.6 times more likely to die of their underlying disease than dogs with normal serum magnesium
  • Dogs with renal disease had the highest median values for serum magnesium 

Remember to critique the paper methodology yourself before attributing any significance to these reported results!

“The concept that naturally occurring hypermagnesaemia may have prognostic value warrants further study”
 
Magnesium deficiency

Total body magnesium deficiency can exist despite normal serum magnesium concentration.
“A diagnosis of ionized hypomagnesemia has been associated with a prolonged hospital stay in dogs…ileus in horses following colic surgery…as well as a prolonged hospital stay and a higher incidence of mortality in hospitalized cats…The hospital length of stay for critically ill dogs with hypomagnesemia was reported to be twice as long as those with normal serum magnesium….Hypomagnesemia was also associated with concurrent hyponatremia and hypokalemia in dogs.” Reference canine paper above, one equine paper and one feline paper.

“Hypomagnesemia is common in critically ill human patients”
“Although magnesium-depleted patients may represent a subset of patients with more severe disease, hypomagnesemia appears to be an independent predictor of outcome”. Reference one human study.
If there is good quality evidence that hypomagnesaemia is common in critically ill human patients, does the same apply to critically ill dogs, and what about critically ill cats?

Keep an evidence-based perspective to all this…..

  • Hypokalaemia can become refractory to standard potassium replacement therapy as a consequence of magnesium deficiency. Magnesium replacement may be necessary before potassium supplementation is effective.
  • Magnesium also apparently serves as a cofactor for insulin release and function, as well as in maintenance of appropriate cellular sensitivity to insulin. Insulin resistance may develop secondary to magnesium deficiency.
  • Diabetic ketoacidosis: “hypomagnesemia is a common finding in diabetic ketoacidotic people. Ketoaciduria and glucosuria promote urinary magnesium excretion, which can be exacerbated with fluid diuresis. In addition, significant cellular redistribution of magnesium occurs as it moves from the extracellular space to the intracellular compartment with insulin therapy. Close monitoring for clinical signs of a magnesium deficit is necessary since a total body deficit may not be reflected in the measured serum magnesium concentration.”
  • Calcium and magnesium are affected in a similar manner by hormones. As many as one-third of human patients with low serum magnesium may concurrently have low serum calcium. Correction of magnesium deficiencies may be required with refractory hypocalcaemia.
  • Magnesium deficiency has been shown to affect gastrointestinal function and motility.  Magnesium deficiency should be considered a differential in any patient with decreased stomach or intestinal motility.
  • “Magnesium has been successfully used in the treatment of preeclampsia and eclampsia in women since 1912…The anticonvulsant of choice for treating seizures due to eclampsia is magnesium…Hypomagnesemia may also be a factor in dogs presenting with eclampsia and should be considered when managing dogs with signs of eclampsia.”
  • "Cardiac conduction abnormalities are one of the most common and serious manifestations of magnesium deficiency. Cardiac arrhythmias associated with hypomagnesemia include ventricular tachycardia, ventricular fibrillation, supraventricular tachycardia, atrial fibrillation, digitalis toxicity associated arrhythmias, and torsades de pointes (TdP).” But the authors point out that “Magnesium's role in the pathogenesis of arrhythmias is difficult to ascertain since magnesium deficits often coexist with potassium and calcium deficiencies….Multiple studies in both human and veterinary patients have documented resolution of TdP after magnesium sulfate infusion… Magnesium supplementation decreases the incidence of ventricular arrhythmias and atrial fibrillation following cardiopulmonary bypass and coronary artery bypass in humans with magnesium deficiency.” Some human medics use magnesium in the treatment of ventricular dysrhythmias.

Treatment of magnesium disorders

“The decision to treat a suspected or diagnosed magnesium disorder will depend on the severity of the clinical signs and the magnitude of change from normal range of the serum magnesium level of the patient.”
Provide some more detailed treatment recommendations with mostly human medicine references

Magnesium excess

Hypermagnesaemia treated by replacing magnesium-containing medications or fluids with magnesium-free ones.
Promoting urinary excretion and inhibiting renal tubular reabsorption of magnesium are mainstays of treatment for moderate to severe hypermagnesaemia and when clinical signs are apparent (e.g. cardiac arrhythmia, hypotension). Use IV sodium chloride +/- diuretics.
Acute magnesium toxicity from iatrogenic overdose treated with additional calcium gluconate
“Hemo- or peritoneal dialysis using magnesium-free dialysate may be necessary to treat symptomatic magnesium excess resulting from kidney disease or iatrogenic overdose.” 

Magnesium deficiency

“If the magnesium deficit is mild, dietary changes and oral magnesium salts such as magnesium carbonate or oxide may be sufficient to increase magnesium intake….Oral magnesium supplementation…should be considered in small animal patients at risk for chronic mild magnesium deficit, for example, those with GI malabsorptive diseases or chronic digoxin or loop diuretic therapy.”

“Animals symptomatic for low magnesium should be treated with an IV infusion of magnesium sulfate or magnesium chloride” and they recommend accounting for the magnesium content of any IV fluids being used when calculating magnesium supplementation doses.”

“the optimum dosage and rate of magnesium administration has not been defined for veterinary patients”

Reportedly a single experimental canine study has been the basis of the magnesium sulfate dose recommendation in dogs and cats.

Magnesium Infusion as an Adjunct to Therapy

“The multifaceted role of magnesium in cells has led researchers and clinicians in human medicine to explore the effects of infusing magnesium as an adjunct to therapy for various conditions.”
Cite a reference from 1974 for potential use in shock resuscitation
“Current studies of brain injury, spinal injury, pain, sepsis and systemic inflammatory response syndrome, hypercoagulable states, eclampsia, tetanus, and ischemia have demonstrated potential beneficial effects from magnesium administration. In these situations, magnesium administration is not given to replace a documented magnesium deficiency but instead given for its beneficial effects in specific cells. Though all syndromes reported in people may not be common in veterinary patients, knowledge of the possible mechanisms of action of magnesium infusion on various tissues may allow extrapolation into the veterinary population of patients.”

The authors say that current studies have demonstrated potential beneficial effects in a variety of scenarios. We should explore the evidence for that statement further to ensure that we are happy that it is legitimate.
And, is extrapolating from humans to veterinary patients a legitimate practice?

“Magnesium sulfate has been utilized in the treatment of autonomic dysfunction associated with severe generalized tetanus in both people and dogs.” Reference a single case report from JVECC in 2011. Much greater anecdotal experience exists but to date use of magnesium in tetanus remains inconclusive.

Risk-benefit assessment:

“The administration of magnesium as an adjunctive therapy in the tetanus patient has not been associated with adverse side effects” – may not help but unlikely to do any harm so maybe give it a go?
Potential to actually induce hypermagnesaemia

Conclusions:

  • “Magnesium is an important intracellular cation required for energy production and cell function in every organ.
  • Changes in magnesium homeostasis have consistently been correlated with increases in morbidity and mortality in veterinary and human critical patients.
  • Assessment of serum magnesium concentration should become a routine part of critical patient evaluation since the clinical signs and conditions associated with magnesium disorders can be nonspecific and varied.
  • Equipment to measure serum ionized or total magnesium is readily available in-hospital.
  • However, measurement of serum magnesium may not reflect total body magnesium concentration.
  • The serum magnesium concentration combined with clinical signs and conditions associated with magnesium disorders are used to make the diagnosis and to monitor treatment.
  • Research is exploring the role of magnesium infusions as an adjunct to standard therapy for clinical disorders such as head trauma, reperfusion injury, and vascular disease.
  • Future studies are expected to better define the role of magnesium in critical illness and investigate potential benefits of magnesium infusion in veterinary patients.”

SJ: “I guess my position is that when it comes to the clinical aspects and recommendations that the authors make, I don’t necessarily disagree, however I am also not sure that there is the evidence base in dogs and cats to support the statements at this time. So for me it is most definitely an area of on-going interest to see what more comes to light going forward.”

Please do get in touch if you have any comments or questions using the contact form, via email at shailenjasani@gmail.com, via Twitter @VetEmCC or via Facebook at the Veterinary ECC Small Talk page.

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I mention my Small Animal Emergency Medicine App for iPhone/iPad in this episode which you can find HERE. An Android version is in development.

 
 
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