Corticosteroids in Septic Shock

The objective of using steroids in septic shock is to address the ghostly specter of "relative adrenal insufficiency". This is discussed in greater detail elsewhere. There are several other theoretical benefits, which merit a more involved discussion. Generally, the college love this question, and ask detailed questions about the evidence.

Steroids in shock generally are asked about in Question 10 from the second paper of 2000. Evidence for steroids in sepsis and ARDS is explored in  Question 22 from the first paper of 2008. Steroids in sepsis specifically are discussed in Question 16 from the first paper of 2013.

The "brief summary" below has become distended by severe bloat. A better, more concise review is available from LITFL (Corticosteroids in Refractory Shock and Steroids and Septic Shock Literature Summaries from the CCC). In point form, the key issues are as follows:

Rationale for steroids in sepsis:

  • Reversal of relative adrenal insufficiency
  • Reversal of inflammatory overactivity
  • "Reprogramming" of the immune response (less destructive)
  • Improved response to catecholamines
  • Deactivation of nitric oxide synthase
  • Improved cardiac tolerance of bacterial endotoxin
  • Improved retention of resuscitation fluid
  • Repair (or at least protection) of the endothelial glycocalyx

Classic studies and guidelines  to quote:

Rationale for the use of steroids in sepsis

Djillale Annane, the great champion of steroids in sepsis, has published a 2011 review of the topic which contains within it an excellent summary of what an optimist might expect from their "stress dose" steroid treatment.

Reversal of relative adrenal insufficiency

The concept of relative adrenal insufficiency, and precisely how one might identify "insufficient" patients, is discussed in detail elsewhere. Suffice to say these septic patients seem to require more vasopressors, and seem to die more frequently. Exogenous corticosteroid administration may be helpful in addressing their increased need for cortisol. There are probably several mechanisms responsible for this effect.

Reversal of inflammatory overactivity

At all times, within the human organism there seems to exist a proinflammatory-antinflammatory homeostasis, which is regulated by endogenous cortisol to a considerable extent. The proinflammatory system, mediated by nuclear factor kappa-B (NF-κB), promotes the secretion of inflammatory mediators. In opposition to is, the glucocorticoid receptor alpha (G-GRα) complex regulates antiinflammatory cytokines and dampens the inflammatory response. It would appear that an inadequate cortisol response to stress results in increased proinflammatory activity in critical illness, and thus to greater organ damage, increasing the mortality.

Reprogramming of the immune response

Data collected by Ehrchen et al (2007) suggests that instead of simply inhibiting the immune response, corticosteroids reorganise an redirect it into a less destructive pattern of behaviour. In their study, corticosteroids treatment "did not cause a global suppression of monocytic effector functions but results in differentiation of a specific anti-inflammatory phenotype which seems to be actively involved in resolution of inflammatory reactions." Thus redirected, monocytes go about their reconstructive tasks without laying waste to the organism with corrosive chemicals. The upshot of this could be an improvement in the vessel tone which reflects on vasopressor dose, and the improvement of microcirculatory failure which is observed in sepsis.

Improved responsiveness of α-1 receptors

When one is using α-1 agonists like noradrenaline, one tends to become concerned when the patient requires ever escalating doses. After the administration of corticosteroids, vascular reactivity to α-1 agonists tends to be restored withon several hours. The mechanism for this is poorly understood.

Correction of vasoplegia by deactivation of nitric oxide synthase

Corticosteroids seem to address the cardinal vascular dysfunction in sepsis - the overwhelming activation of nitric oxide synthase (NOS) by bacterial endotoxin and inflammatory cytokines. Mind you, this data comes from rat studies, but the message is clear - one's cardiovascular system can tolerate a whole lot more lipopolysaccharide with steroids than without them.

Improved cardiac tolerance of bacterial endotoxin

Endotoxin tends to depress cardiac function, and early isolated heart muscle studies have demonstrated abundantly that pre-treatment of the muscle with corticosteroids resulted in a marked preservation of contractility. It is difficult to assess exactly how much steroid treatment contributes to the reversal of sepsis-induced cardiomyopathy, but this laboratory evidence is encouraging for the steroid enthusiast.

Improved retention of resuscitation fluid

This may seem silly, but corticosteroids (by exerting a mild mineralocorticoid effect) produce a retention of sodium and water, thereby ensuring that all those litres of crystalloid remain inside the patient. Of course, the leakyness of the capillaries is probably going to distribute all that fluid into useless compartments, but one can hope that at least some of it will remain in circulation, and contribute to the correction of the relative hypovolemia of sepsis.

Repair (or at least protection) of the endothelial glycocalyx

Corticosteroids are among the few "well accepted" techniques which are expected to somehow defend the endothelial glycocalyx from getting denuded in septic shock. This"acceptance" is actually far from solid. The data comes from guinea pig studies. Not just guinea pig studies, but disembodied guinea pig heart studies;and they weren't even investigating a model of sepsis. The hearts were subjected to ischaemia-reperfusion injury; those which had received some hydrocortisone were found to be oozing a little less syndecan-1, a glycocalyx constituent used as a marker of its shedding. The authors concluded that " Hydrocortisone preserves the endothelial glycocalyx, sustaining the vascular barrier and reducing interstitial edema.". To generalise these findings to the population of septic humans under your care would be difficult.

Evidence for the use of steroids in sepsis

 

Initial studies of this technique were favourable. The French in 2002 reported a significant improvement in mortality among their 300-strong cohort of septic patients - from 70% to 58%. These rates seem high, but these patients were extremely ill, requiring 1.1μg/kg/min (75ml/hr) of noradrenaline.

However, subsequently results of the CORTICUS trial published in 2008 refuted the above findings. The CORTICUS investigators did not find any mortality difference associated with the use of steroids.

However, the CORTICUS patients were less "shocked", requiring on average only 0.5μg/kg/min (35ml/hr) of noradrenaline. In fact the CORTICUS investigators enrolled all-comers, regardless of the severity of sepsis, whereas the earlier French group only enrolled the doomed patients, which is reflected in their higher mortality (70% for the placebo group!).

As trial data piled higher, this area of investigation turned into a battle in which meta-analysis publications were the main ordinance. A meta-analysis by Annane - a steroid enthusiast - had concluded (on the basis of 17 trials) that there is an overall mortality benefit. In contrast, Sligl et al performed the same analysis - excluding all but 6 well-designed trials - and came up with the conclusion that steroids did nothing for survival. Both reviewer groups did agree on one thing - shock reversal was more rapid with steroids.

In general, on the basis of the available evidence one is forced to conclude that steroids will not benefit patients with "mild" septic shock, who are not requiring large doses of vasopressors and who are not experiencing multi-organ system failure. However, if you are a patient whose mortality from sepsis is likely to be over 60%, your survival may improve with 200mg/day of hydrocortisone. This is the spirit in which the Surviving Sepsis Guidelines have recommended (2B) that steroids in sepsis should be reserved for those patients who are refractory to fluids and vasopressors. In short, they suggest that nobody should die of sepsis without having some steroids first.

 

References

LITFL have an excellent page, summarising the current literature on steroids in sepsis.

Scott, W. J. M. "THE INFLUENCE OF THE ADRENAL GLANDS ON RESISTANCE: II. THE TOXIC EFFECT OF KILLED BACTERIA IN ADRENALECTOMIZED RATS." The Journal of experimental medicine 39.3 (1924): 457.

Annane, Djillali, et al. "A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin." Jama 283.8 (2000): 1038-1045.

Cooper, Mark S., and Paul M. Stewart. "Corticosteroid insufficiency in acutely ill patients." New England Journal of Medicine 348.8 (2003): 727-734.

Kass, Edward H., and Maxwell Finland. "Adrenocortical hormones and the management of infection." Annual review of medicine 8.1 (1957): 1-18.

Robson, HUGH G., and L. E. Cluff. "Experimental pneumococcal and staphylococcal sepsis: effects of hydrocortisone and phenoxybenzamine upon mortality rates." Journal of Clinical Investigation 45.9 (1966): 1421.

SIBBALD, WILLIAM J., et al. "Variations in adrenocortical responsiveness during severe bacterial infections: unrecognized adrenocortical insufficiency in severe bacterial infections." Annals of surgery 186.1 (1977): 29-33.

Marik, Paul E., and Gary P. Zaloga. "Adrenal insufficiency during septic shock*." Critical care medicine 31.1 (2003): 141-145.

Cohen, Jeremy, et al. "Variability of cortisol assays can confound the diagnosis of adrenal insufficiency in the critically ill population." Intensive care medicine32.11 (2006): 1901-1905.

Annane, Djillali, et al. "Diagnosis of adrenal insufficiency in severe sepsis and septic shock." American journal of respiratory and critical care medicine 174.12 (2006): 1319-1326.

Kromah, Fatuma, et al. "Relative adrenal insufficiency in the critical care setting: debunking the classic myth." World journal of surgery 35.8 (2011): 1818-1823.

Siraux, Valérie, et al. "Relative adrenal insufficiency in patients with septic shock: comparison of low-dose and conventional corticotropin tests." CRITICAL CARE MEDICINE-BALTIMORE- 33.11 (2005): 2479.

Yaegashi, Makito, and Arthur J. Boujoukos. "The low-dose ACTH test in the ICU: Not ready for prime time." Critical Care 10.4 (2006): 313.

Annane, Djillali. "Corticosteroids for severe sepsis: an evidence-based guide for physicians." Annals of intensive care 1.1 (2011): 1-7.

Sprung, Charles L., et al. "Hydrocortisone therapy for patients with septic shock." New England Journal of Medicine 358.2 (2008): 111.

Vassiliadi, Dimitra A., et al. "Longitudinal assessment of adrenocortical responses to low-dose ACTH in critically ill septic patients." Endocrine Abstracts (2013) 32 P26

Annane, Djillali, et al. "Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock." Jama 288.7 (2002): 862-871.

Barnes, Peter J., and Michael Karin. "Nuclear factor-κB—a pivotal transcription factor in chronic inflammatory diseases." New England Journal of Medicine336.15 (1997): 1066-1071.

Kashiwabara, Moto, et al. "Surgical trauma-induced adrenal insufficiency is associated with postoperative inflammatory responses." Journal of Nippon Medical School 74.4 (2007): 274-283.

Ehrchen, Jan, et al. "Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes." Blood 109.3 (2007): 1265-1274.

Boyer, A., et al. "Glucocorticoid treatment in patients with septic shock: effects on vasopressor use and mortality." International journal of clinical pharmacology and therapeutics 44.7 (2006): 309-318.

Szabo, Csaba, et al. "Attenuation of the induction of nitric oxide synthase by endogenous glucocorticoids accounts for endotoxin tolerance in vivo."Proceedings of the National Academy of Sciences 91.1 (1994): 271-275.

MACNICOL, MALCOLM F., ALAN H. GOLDBERG, and GEORGE HA CLOWES. "Depression of isolated heart muscle by bacterial endotoxin."Journal of Trauma and Acute Care Surgery 13.6 (1973): 554-558.

Romero-Bermejo, Francisco J., et al. "Sepsis-induced cardiomyopathy."Current cardiology reviews 7.3 (2011): 163.

Asfar, Pierre, Jan Tuckermann, and Peter Radermacher. "Steroids and Vasopressin in Septic Shock—Brother and Sister or Just Distant Cousins?*."Critical care medicine 42.6 (2014): 1531-1532.

Annane, Djillali, et al. "Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review." Jama 301.22 (2009): 2362-2375.

Sligl, Wendy I., et al. "Safety and efficacy of corticosteroids for the treatment of septic shock: A systematic review and meta-analysis." Clinical infectious diseases 49.1 (2009): 93-101.