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.

*** If you find these podcasts useful and interesting, PLEASE click on the iTunes icon below, then the "View in iTunes" blue link, and then rate and/or review the podcast. That will be really great and much appreciated. Thank you! ***