# Noradrenaline in resuscitation of septic shock

An extensive elaboration of noradrenaline and its properties can be found elsewhere. This is a brief summary, to help one answer questions like  Question 21 from the first paper of 2009, which was all like "briefly outline what initial agent you will use to treat the circulatory disturbance and how would you initially titrate the dose of the agent". The circulatory disturbance was vasodilated shock, which you had to work out by manually calculating the SVRI.

In short:

• SVR = [MAP-CVP] × 80 / CO
• Normal values: SVR = 700-1600,  SVRI = 1800-2400
• Causes of low SVR in sepsis: nitric oxide synthase activation, smooth muscle relaxation in acidosis and hypoxia, vasodilating inflammatory mediators, relative vasopressin and cortisol insufficiency, and decreased catecholamine sensitivity due to acidosis.
• Improve SVR by arterioconstriction
• Improve cardiac output by feeble β-1 effect at high doses

## Measurement of vasodilation

Vasodilation can be viewed in a number of ways; a practical approach (which does not involve the direct measurement of small vessel caliber) is to evaluate it using the index of systemic vascular reistance, which is the relationship of the systemic arterio-venous pressure gradient to the cardiac output. The basic principle is that flow is equal to the pressure gradient divided by resistance, and thus resistance is the pressure gradient divided by flow.

SVR = ([MAP-RAP] × 79.9) / CO

or,

SVRI = ([MAP-RAP] × 79.9) / CI

A normal SVR is 700-1600 dyn.s/cm5

A normal SVRI is 1970-2390 dyn·sec/cm5·m2

The CICM examiners have actually expected their fellowship candidates to perform this calculation in a previous SAQ paper (specifically, Question 19 from the first paper of 2006).

## Vasodilated shock states

Generally speaking, these states are characterised by decreased SVR and increased cardiac output.

Thelist below is not all-inclusive, but covers the most frequently encountered forms:

Low-SVR, high-cardiac-output states

• Septic shock
• Anaphyactic shock
• Vasodilation due to pharmacological agents (eg. nitrates)
• Vasodilation due to severe liver disease (which is also probably endotoxin mediated)

Low-SVR, low-or-normal-cardiac-output states

• Neurogenic (spinal) shock
• Vasodilation due to SIRS following a global hypoxic/ischaemic injury
• SIRS due to cardiopulmonry bypass

## Pathogenesis of vasodilation in septic shock

In sepsis, there are numerous mechanisms mediating the systemic loss of vascular resistance.

Question 21 from the first paper of 2009 asks the candidate to briefly mention some of these.

A brief answer would consist of a list, resembling this one:

### Causes of vasodilation in septic shock

A more detailed explanation has not been examined thus far. For a more detailed overview, one has no specific source to site. Many articles come up in a search for "pathophysiology of septic shock", but none answer this specific question. Perhaps the single broadest overview is afforded by our very own L.I.G Worthley's "Shock: a review of pathophysiology and management: Part I and Part II.

## The use of noradrenaline in septic shock

Noradrenaline is the prototypic vasopressor, and is discussed at length elsewhere.

### Rationale

Its beneficial effects in sepsis include the following:

• Reversal of decreased SVR by arterial vasoconstriction
• Mildly increased cardiac output by its vestigial β-1 effects (it's hardly the primary goal)

## References

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Russell, James A., et al. "Vasopressin versus norepinephrine infusion in patients with septic shock." New England Journal of Medicine 358.9 (2008): 877-887.

Myburgh, John A., et al. "A comparison of epinephrine and norepinephrine in critically ill patients." Intensive care medicine 34.12 (2008): 2226-2234.

Cohn, Jay N. "Systemic Vascular Resistance." Captopril and Hypertension. Springer US, 1980. 77-86.

Zweifach, B. W. "Direct observation of the mesenteric circulation in experimental animals." The Anatomical Record 120.1 (1954): 277-291.

Ince, Can. "The microcirculation is the motor of sepsis." Critical Care 9.Suppl 4 (2005): S13.

Landry, Donald W., et al. "Vasopressin deficiency contributes to the vasodilation of septic shock." Circulation 95.5 (1997): 1122-1125.

Parrillo, Joseph E. "Pathogenetic mechanisms of septic shock." New England Journal of Medicine 328.20 (1993): 1471-1477.

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Landry, Donald W., et al. "Vasopressin deficiency contributes to the vasodilation of septic shock." Circulation 95.5 (1997): 1122-1125.

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McGillivray-Anderson, Karen M., and J. E. Faber. "Effect of acidosis on contraction of microvascular smooth muscle by alpha 1-and alpha 2-adrenoceptors. Implications for neural and metabolic regulation." Circulation research 66.6 (1990): 1643-1657.

Hermreck, ARLO S., and ALAN P. Thal. "Mechanisms for the high circulatory requirements in sepsis and septic shock." Annals of surgery 170.4 (1969): 677.

Nduka, O. Okorie, and Joseph E. Parrillo. "The pathophysiology of septic shock." Critical care clinics 25.4 (2009): 677-702.

Hotchkiss, Richard S., and Irene E. Karl. "The pathophysiology and treatment of sepsis." New England Journal of Medicine 348.2 (2003): 138-150.

De Backer, Daniel, et al. "Pathophysiology of microcirculatory dysfunction and the pathogenesis of septic shock." Virulence 5.1 (2014): 73-79.

King, Elizabeth G., et al. "Pathophysiologic mechanisms in septic shock."Laboratory Investigation 94.1 (2014): 4-12.

Anantasit, Nattachai, et al. "Serious Adverse Events Associated With Vasopressin and Norepinephrine Infusion in Septic Shock*." Critical care medicine 42.8 (2014): 1812-1820.

Gkisioti, Sotiria, and S. D. Mentzelopoupus. "Vasogenic shock physiology."Open Access Emerg Med 3 (2011): 1-6.

Worthley, L. I. "Shock: a review of pathophysiology and management. Part I." Critical Care and Resuscitation 2000; 2: 55.

Worthley, L. I. "Shock: a review of pathophysiology and management. Part II."Critical Care and Resuscitation 2000; 2: 66.

Martin, C., et al. "Norepinephrine or dopamine for the treatment of hyperdynamic septic shock?." CHEST Journal 103.6 (1993): 1826-1831.

Bai, Xiaowu, et al. "Early versus delayed administration of norepinephrine in patients with septic shock." Crit Care 18 (2014): 532.