Therapeutics

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.

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Steroids and Shock!

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

SHOCK:

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

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

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

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

LITERATURE

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

STEROID USE IN SHOCK

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

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

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

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

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

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

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

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

Steroids in Septic Shock

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

Sepsis-induced hypotension or tissue hypoperfusion:

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

Proposed pathophysiology of sepsis is complex!

HUMAN LITERATURE

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

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

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

BENEFIT-RISK

Potential benefits of steroid in septic shock:

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

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

Potential risks:

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

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

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

CURRENT HUMAN (and VETERINARY?) RECOMMENDATIONS

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

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

Adults:

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

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

Paediatrics:

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

Grade 1A = strong recommendation with high quality evidence.

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

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

American Journal of Respiratory and Critical Care Medicine, 2012:

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

Paediatric Critical Care Medicine, 2013:

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

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

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

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

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

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

Diagnosis of CIRCI:

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

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

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

Treatment:

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

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

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

Review article ends with:

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

EPISODE SUMMARY:

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

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

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

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

PAPERS THAT INFORMED OR ARE MENTIONED IN THIS EPISODE:

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

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

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

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

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

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

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

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

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

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

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

Hardaway RM, Williams CH. Influence of steroids on hemorrhagic and traumatic shock. J Trauma 1987. 27(6):667-670.

Hart KA, Barton MH. Adrenocortical insufficiency in horses and foals. Vet Clin North Am Equine Pract 2011. 27:19–34.

Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med 2008. 36:1937–1949.

Martin LG, Groman RP, Fletcher DJ, et al. Pituitary-adrenal function in dogs with acute critical illness. J Am Vet Med Assoc 2008. 233:87–95.

Martin LG. Critical illness-related corticosteroid insufficiency in small animals. Vet Clin North Am Small Anim Pract 2011; 41:767–782, vi.

Menon K, McNally D, Choong K, Sampson M. A Systematic Review and Meta-Analysis on the Effect of Steroids in Pediatric Shock. Ped Crit Care Med 2013. 14(5):474-480.

Moran JL, Graham PL, Rockliff S, et al. Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective. Crit Care 2010; 14:R134.

Patel GP, Balk RA. Systemic Steroids in Severe Sepsis and Septic Shock. Am J Resp Crit Care Med 2012. 185(2):133-139.
http://www.atsjournals.org/doi/full/10.1164/rccm.201011-1897CI

Peyton JL, Burkitt JM. Critical illness-related corticosteroid insufficiency in a dog with septic shock. J Vet Emerg Crit Care 2009. 19:262–268.

Prittie JE, Barton LJ, Peterson ME, et al. Hypothalamo-pituitary-adrenal (HPA) axis function in critically ill cats. J Vet Emerg Crit Care 2003; 13:165.

Raflo GT, Jones RC Jr, Wangensteen SL. Inadequacy of steroids in the treatment of severe hemorrhagic shock. Am J Surg 1975. 130(3):321-327.

Schoeman JP, Herrtage ME. Adrenal response to the low dose ACTH stimulation test and the cortisol-to-adrenocorticotrophic hormone ratio in canine babesiosis. Vet Parasitol 2008. 154:205–213.

Should corticosteroids be given in shock? Drug Ther Bull 1976. 14(4):14-16. (no authors listed)

Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008. 358:111–124.

Sullivan L, Burkitt Creedon JM. Critical illness-related corticosteroid insufficiency. In: Bonagura JD, Twedt DC. eds. Kirk's Current Veterinary Therapy XV. St. Louis: Elsevier Saunders; 2014, pp. 78–79.

Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012
http://www.sccm.org/Documents/SSC-Guidelines.pdf 

Venkatesh B, Myburgh J, Finfer S, et al. The ADRENAL study protocol: adjunctive corticosteroid treatment in critically ill patients with septic shock. Crit Care Resusc 2013. 15:83–88.

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014 Ketamine

Special K: Is Ketamine Really All That?

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Clinical use first reported in human medicine in 1965; approved for clinical use in 1970
First identified veterinary report: Glen JB. The use of ketamine (CI-581) in feline anaesthetic practice. Vet Rec 1973.

Unravelling story with respect to evidence-based medicine – in people and especially veterinary species. Less so regarding use in anaesthesia, more so regarding sedation and especially analgesia.

 “Ketamine may be the subject of misuse and, therefore, should be stored in the controlled drugs cabinet and its use recorded in an informal register.” (RCVS website, March 2015)

1. How does ketamine work? What does it do?

N-methyl-D-aspartate (NMDA) receptor antagonist:

  • Most widely reported and acknowledged mechanism; thought to be responsible for most clinical effects
  • But “nightmare of the pharmacologist” as myriad other proven/suggested mechanisms and receptors may be involved

2. Ketamine causes a continuum of central nervous system effects:

Dose-dependent CNS effects…with increasing doses: analgesia – sedation – partial dissociation – complete dissociation
Once complete dissociation reached, additional doses prolong duration of action without additional dissociation

Overlap between dose ranges for clinical effects; also depends on individual patient.

Analgesia:

Low/sub-dissociative dose use for analgesia has gained increasing recognition and popularity in last 10 years or so
Analgesic uses include acute emergency pain but also perioperative pain management
Typically as infusion after initial loading dose for analgesia but intermittent bolus therapy also feasible
Analgesic effects both supra-spinal (brain) and spinal
Likely to have both more classically reported anti-sensitisation (“wind up”) CNS effects and direct analgesia

3. Is ketamine contraindicated with raised intracranial pressure?

Long-standing contraindication in veterinary references – seems to have been extrapolated from human references.
Long-standing contraindication in human references – based on small number of poor quality studies from 1970s.

Active on-going clinical research in humans with raised ICP of different causes (e.g. trauma vs. mass lesion vs. hydrocephalus) to test traditional contraindication
Increasing consensus at this time refuting this contraindication and supporting positive risk-benefit profile for ketamine use in general population of acute emergency human patients with suspected/proven raised ICP

Original contraindication reported in veterinary resources extrapolated from human medicine with no species-specific evidence. At this time it seems reasonable and legitimate to discard this ‘myth’ while keeping future evidence under review.

4. Ketamine is sympathomimetic:

Stimulates sympathetic nervous system (by preventing catecholamine reuptake and/or increasing secretion – seems unclear)
May therefore help to support patients with cardiovascular instability and existing sympathetic nervous system-driven compensation
If sympathetic response is blunted/exhausted, ketamine may depress cardiovascular system

5. What about ketamine in cats with hypertrophic cardiomyopathy (HCM)?

Meant to be relatively contraindicated in cats with HCM; sympathomimetic effect may cause a cat with sub-clinical cardiomyopathy to decompensate – especially if obstructive component to HCM.
Relative not absolute contraindication – risk-benefit profile as always
Undoubtedly many cats with sub-clinical HCM will have received ketamine and true significance/risk remains unclear

6. ‘Ketamine head’:

Ketamine emergence, dysphoria, mania, hyperexcitability, spackiness - “ketamine head” (Aoife O’Sullivan); especially cats
Emergence can range from entirely unremarkable to really quite spectacular neurological/neuromuscular signs
Prevention is key. Ensure other agents (e.g. opioid, α2-agonist) on board and active during emergence
Quiet room, minimal stimulation etc.
May require pharmacological intervention

7. Can ketamine be used as a sole agent?

Is it okay for a patient not to have already received another agent (e.g. opioid) that is on board and working at the time of ketamine administration? Or indeed not to at least have one with a rapid onset co-administered alongside the ketamine?

Sole use of ketamine reported in children and seems more recognised
Evidence in adult humans does not seem to support sole use
Suggest (anecdotally) never using ketamine as sole agent in veterinary species – especially due to increased risk of potentially spectacular “ketamine head”

8. Is ketamine contraindicated with raised intraocular pressure?

Another long-standing listed contraindication in human and veterinary medicine; again substantive evidence woefully lacking
Increasingly rebutted as a ‘myth’ in human medicine based on emerging evidence
No good quality clinically relevant canine/feline evidence identified
Author is comfortable to recommend use of ketamine in patients with raised IOP where potential benefits supersede this theoretical and unproven risk

9. Ketamine in caesarean section:

Can and indeed should you be including ketamine as part of your c-section protocol?
Used in women relatively commonly for this purpose; no evidence identified that poses increased risk to mum or baby
Paucity of veterinary evidence and certainly identified demonstrating increased risk
“Absence of evidence is not evidence of absence” but overall happy to recommend pre-, intra- and post-operative ketamine use for c-section
Provides multimodal analgesia. Dose-sparing for potentially more harmful drugs, especially inhalant anaesthetics

10. Other bits ‘n’ pieces:

Other things to highlight about ketamine:
Protective airway reflexes preserved

  • Cats’ eyes remain open – must keep well lubricated
  • Cats reportedly may salivate excessively – reported more in humans
  • Hepatic metabolism in most species; minimal in cats
  • Parent compound and metabolites renally excreted. Available evidence in people at this time does not suggest the need for dose reduction with hepatic or renal impairment.

Use in treatment of refractory status epilepticus reported in people; one published canine case report but actual unpublished clinical experience likely to be greater than this.

Also sometimes used in children with refractory status asthmaticus due to potential bronchodilatory effect from β2-adrenergic receptor stimulation. Unclear if effective in asthmatic cats refractory to standard therapies – very rare patient anyway?

Some papers that informed this episode:

VETERINARY

Kovalcuka L, Birgele E, Bandere D, Williams DL. The effects of ketamine hydrochloride and diazepam on the intraocular pressure and pupil diameter of the dog’s eye. Vet Ophthal 2013. 16(1):29-34.

Pei-Yu Liao, Shi-Chieh Chang, Kuan-Sheng Chen, Hsien-Chi Wang. Decreased postoperative C-reactive protein production in dogs with pyometra through the use of low-dose ketamine. J Vet Emerg Crit Care 2014. 24(3):286-290.

Serrano S, Hughes D, Chandler K. Use of Ketamine for the Management of Refractory Status Epilepticus in a Dog. J Vet Int Med 2006. 20(1):194-197.

Wagner AE, Walton JA, Hellyer PW, et al. Use of low doses of ketamine administered by constant rate infusion as an adjunct for postoperative analgesia in dogs. J Am Vet Med Assoc 2002. 221(1):72-75.

HUMAN MEDICINE

Ahern TL, Herring AA, Stone MB, Frazee BW. Effective analgesia with low-dose ketamine and reduced dose hydromorphone in ED patients with severe pain. Am J Emerg Med 2013. 31(5):847-851.

Beaudoin FL, Lin C, Guan W, Merchant RC. Low-dose ketamine improves pain relief in patients receiving intravenous opioids for acute pain in the emergency department: results of a randomised, double-blinded, clinical trial. Acad Emerg Med 2014. 21(11):1193-1202.

Cohen L, Athaide V, Wickham ME, et al. The Effect of Ketamine on Intracranial and Cerebral Perfusion Pressure and Health Outcomes: A Systematic Review. Ann Emerg Med 2015. 65(1):43–51.

Drayna PC, Estrada C, Wang W, et al. Ketamine sedation is not associated with clinically meaningful elevation of intraocular pressure. Am J Em Med 2012. 30(7):1215-1218.

Green SM, Andolfatto G, Krauss BS. Ketamine and Intracranial Pressure: No Contraindication Except Hydrocephalus. Ann Emerg Med 2015. 65(1): 52-54.

Halstead SM, Deakyne Sj, Bajaj L, et al. The Effect of Ketamine on Intraocular Pressure in Pediatric Patients During Procedural Sedation. Acad Em Med 2012. 19(10):1145-1150.

Heesen M, Bohmer J, Brinck ECV, et al. Intravenous ketamine during spinal and general anaesthesia for caesarean section: systematic review and meta-analysis. Acta Anaes Scans 2015. 59(4):414-426.

Laskowski K, Stirling A, McKay WP, Lim HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anesth 2011. 58(10):911-923.

Anna Rosati, Manuela L’Erario, Lucrezia Ilvento. Rosati A, L’Erario M, Ilvento L. Efficacy and safety of ketamine in refractory status epilepticus in children. Neurol 2012. 79(24):2355-2358.

Terence L. Ahern, Andrew A. Herring, Erik S. Anderson, et al. The first 500: initial experience with widespread use of low-dose ketamine for acute pain management in the ED. Am J Emerg Med 2015. 33(2):197-201.

Tiwari A, Guglani V, Ram Jat K. Ketamine versus aminophylline for status asthmaticus in children: A randomized, controlled trial. Eur Resp J 2014. 44, Suppl 58 281.

Wadia S, Bhola R, Lorenz D, et al. Ketamine and Intraocular Pressure in Children. Ann Emerg Med 2014. 64(4):385-388.

Wang X, Ding X, Tong Y, et al. Ketamine does not increase intracranial pressure compared with opioids: meta-analysis of randomized controlled trials. J Anesth 2014. 28(6):821-827.

Zeiler FA, Teitelbaum J, West M, Gillman LM. The Ketamine Effect on ICP in Traumatic Brain Injury. Neurocrit Care 2014. 21(1):163-173.

Zeiler FA, Teitelbaum J, West M, Goillman LM. The ketamine effect on intracranial pressure in nontraumatic neurological illness. J Crit Care 2014. 29(6): 1096–1106.

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004 Fluid Choice in Tomcat Urethral Obstruction (Blocked Cats)

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Not all blocked cats are hypoperfused on presentation but those that are should be resuscitated with fluid therapy given as boluses to restore perfusion with the approach being tailored to the individual patient. This should be done BEFORE you consider sedating or indeed anaesthetising to attempt catheterisation.

Will I rupture the bladder?

“If I give blocked cats lots of fluid therapy while their bladder is obstructed, won’t I rupture the bladder?"

NO! The risk is very very very small and has to be weighed up against the undoubted benefit of fluid resuscitation in these cases. 

Why won't I rupture the bladder?

For the kidney to make urine it needs to have an adequate blood supply. The blood supply to the kidneys of a blocked cat in shock will be moderately or even severely compromised and this means that the impetus to make urine will be significantly decreased. At the same time as the bladder is obstructed and under high pressure this pressure is transmitted via the ureters to the kidneys; this back pressure on the kidneys will also act to oppose urine production. So on the one hand there is little forward impetus to make urine and on the other hand there is back pressure not to make urine; hence blocked cats in shock are unlikely to be making much urine at all. Obviously as you perform intravenous fluid resuscitation and the blood supply to the kidneys increases you will promote the formation of urine but you will also be going on to deal with the obstruction very soon and so this is not a concern.

** FOR AN IN-DEPTH PRESENTATION AND COURSE NOTES ON THE MANAGEMENT OF BLOCKED CATS PLEASE SEE HERE. **

Does it matter which fluid we choose for the initial resuscitation phase?

A replacement isotonic crystalloid is used. Typical choice is between Hartmann’s (buffered lactated Ringer’s solution, compound sodium lactate) and  0.9% sodium chloride ('normal' saline).

Blocked cats have:

  • Hyperkalaemia: clinically significant life-threatening hyperkalaemia is not uncommon in the more severe cases
  • Acidaemia due to metabolic acidosis: typically less of a concern but can have significant adverse physiological consequences and can be life-threatening if sufficiently severe

0.9% sodium chloride:

Potassium-free; blocked cats are hyperkalaemic so why would you want to give them more potassium?

But...promotes hyperchloraemic acidosis and can exacerbate existing acidaemia.

Hartmann's solution:

Contains 5 mmol/l potassium - as do Normosol-R and Plasmalyte 148; this is nevertheless lower than clinically significant hyperkalaemia and use will decrease potassium concentration through dilution.

But...solution that promotes alkalosis, alkalinising solution; may help resolve metabolic acidosis.

(Also contains small amount of calcium which is no bad thing given that these cats are often hypocalcaemic.)

Bottom line: choice of fluid between these two types has not thus far been shown to be clinically significant....

Drobatz KJ, Cole SG. The influence of crystalloid type on acid-base and electrolyte status of cats with urethral obstruction. J Vet Emerg Crit Care 2008. 18(4):355-361.

Prospective randomised non-blinded study

Cats that presented to the Matthew J. Ryan Veterinary Hospital of the University of Pennsylvania with urethral obstruction between September 2000 and November 2004 were eligible for inclusion.

Inclusion criteria:

  • Baseline blood pH and potassium measured initially
  • At least one subsequent measurement of these parameters within the following 12 hours

Urethral obstruction diagnosed based on compatible clinical signs + large, firm, non-expressible urinary bladder

Exclusion criteria:

  • Owners elected to not pursue treatment and elected euthanasia
  • Baseline blood pH and potassium as well as one subsequent measurement of those variables within 12 hours of admission not obtained

Coin-flip randomisation to receive either Normosol-R or 0.9% sodium chloride.

Blood samples collected before any therapy for analysis of blood pH, bicarbonate, pCO2, base excess, sodium, chloride, potassium, ionised calcium, ionised magnesium, and glucose.
Biochemical analysis of serum urea nitrogen (SUN), serum creatinine, and serum phosphorus performed on some cats.

Further therapy and monitoring at discretion of attending clinician; non-blinded

Results:

  • 68 cats: 39 Normosol-R, 29 0.9% sodium chloride
  • Very similar comparable groups including with respect to initial pH and potassium concentrations
  • While there were no statistically significant differences between groups at baseline, cats in the Normosol- R group had a significantly higher blood bicarbonate concentration at 12 hours and significantly higher blood pH at 6 hours and 12 hours.
  • There were no statistically significant differences in blood potassium concentration or the amount of fluid administered between groups at any time.
  • In comparison with the absolute values, the increase in blood pH from baseline was significantly greater in the Normosol-R group than the 0.9% sodium chloride group at 6 hours and 12 hours following admission and this difference also approached significance at 2 hours.
  • Blood potassium levels declined steadily in both groups and no statistically significant differences were found in the rate of decline from baseline between groups.
  • Cats in the 0.9% sodium chloride group had a significantly higher blood sodium concentration at 2 hours and 6 hours, as well as a significantly higher blood chloride concentration at 6 hours and 12 hours. The increase in blood chloride from baseline was significantly higher in the 0.9% sodium chloride group than in the Normosol-R group at 2 hours, 6 hours, and 12 hours.

Use of Normosol-R was associated with a greater increase from baseline in blood pH and bicarbonate values than was the use of 0.9% sodium chloride.

Although Normosol-R contains 5mmol/l of potassium, the absolute value and rate of decline in blood potassium levels were nearly identical between the groups in this study.

Authors say: “While statistically significant, the differences identified between groups in the present study may not have been clinically significant in this patient population. From both prior research and widespread clinical experience, it is clear that both balanced isotonic crystalloid solutions and 0.9% sodium chloride are acceptable fluid choices for the treatment of most cases of urethral obstruction in cats. However, possi-ble implications of the current study pertain to severely affected cats with profound metabolic acidosis. In these cases, any acidifying effect of 0.9% sodium chloride could be deleterious, as severe metabolic acidosis impairs cardiovascular function, compounding the untoward effects of hyperkalemia and hypocalcemia. The use of a balanced isotonic crystalloid would achieve similar results in the treatment of per-fusion abnormalities and hyperkalemia, along with more rapid improvement in acid–base status.”

Study limitations:

  • Not blinded
  • Treatment not standardised across groups
  • No mention of power calculation with respect to sample sizes needed to show significant different between the groups
  • As always...larger sample size if possible!

Please leave your comments here or get in touch in one the many other ways possible!

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003 Intravenous Lipid Emulsion as an Antidote

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