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.
- 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.
- Rationale for noradrenaline:
- Improve preload by venocosntriction
- Improve SVR by arterioconstriction
- Improve cardiac output by feeble β-1 effect at high doses
- Evidence for noradrenaline:
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
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
- Nitric oxide synthase induction by cytokines and endotoxin
- Direct vascular smooth muscle response to acidosis and hypoxia - this is mediated by the activation of ATP-sensitive K+ channels, which which hyperpolarise the smooth muscle cell membranes, preventing contraction and producing vasoplegia.
- Inflammatory mediators produced by activated leucocytes
- Vasodilatory mediators (eg. histamine bradykinin and serotonin) produced by leukocytes and platelets
- Relative vasopressin deficiency
- Relative adrenal insufficiency, resulting in peripheral catecholamine insensitivity
- Acidosis, resulting in peripheral catecholamine insensitivity
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.
Its beneficial effects in sepsis include the following:
- Increased preload by venoconstriction
- Reversal of decreased SVR by arterial vasoconstriction
- Mildly increased cardiac output by its vestigial β-1 effects (it's hardly the primary goal)
- There was a time when its vasoconstricting effects were thought to be deleterious.
- Thankfully, this belief - now appearing absurd to most recent ICU trainees - was challenged with some observational cohort studies, which suggested that it may in fact have a positive survival effect.
- The VASST investigators have confirmed that noradrenaline is non-inferior to vasopressin
- Earlier trials have confirmed that noradrenaline is superior to dopamine
- Myburgh et al have demonstrate that noradrenaline has fewer side-effects than adrenaline, and that both are equivalent in effectively achieving haemodynamic goals.
- It appears that the earlier use of noradrenaline is associated with decreased mortality; or rather, that "every 1-hour delay in norepinephrine initiation during the first 6 hours after septic shock onset was associated with a 5.3% increase in mortality"