Vasodilators for Severe Sepsis

A listener, Dave Glaser, points out that one portion of the EGDT protocol doesn’t get spoken about very often: the use of vasodilators for MAP optimization.

In the original trial, patients in the EGDT arm of the study got a vasodilator if their MAPs were >90. The original trial publication makes no mention of which vasodilator and how many patients received it. If you want that information, you need to go to the Otero et. al publication (Chest 2006;130;1579-1595), which expanded on the original trial with additional information. Here is the relevant excerpt:

Vasodilator Therapy

After adequate volume and hemoglobin targets were met, we surprisingly found that 9% of EGDT patients met the protocol criteria for afterload reduction for a mean arterial pressure (MAP) of > 90 mm Hg by utilizing nitroglycerin therapy. Nitroglycerin was chosen because of its effects on preload, afterload, and coronary vasodilation. All of these patients had a history of hypertension and congestive heart failure. The median baseline Scvo2 was 46% in this subset of patients. Although the use of nitroglycerin was unexpected on study initiation, therapy with afterload reduction is not without precedent in treating sepsis patients.

Cerra et al (J Surg Res 1978;25:180–183) provided vasodilator therapy to sepsis patients with low cardiac output and observed physiologic improvement.

Spronk et al (Lancet. 2002 Nov 2;360(9343):1395-6) found that nitroglycerin may improve microcirculatory flow in normotensive or even hypotensive patients with septic shock.

It is becoming increasingly evident that disordered microcirculatory flow is associated with systemic inflammation, acute organ dysfunction, and increased mortality. Using new technologies to directly image microcirculatory blood flow may help to define the role of microcirculatory dysfunction in oxygen transport and circulatory support.

I can’t remember the last time I saw a patient who would be eligible for this therapy b/c of high MAP. We have given nitroglycerin occasionally for a patient that is not clearing their lactate with a high ScvO2.

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Comments

  1. DocXology says:

    This opens up more questions than answers:

    1) Doesn’t it depend where on the Starling curve the patient is following volume resuscitation or pressor support?
    2) Does an elevated MAP represent pathology, over-treatment (iatrogenesis) or the normal physiological state of the patient?
    3) Which part of the microcirculation are we actually targeting and to what end? (sepsis represents an overall vasoplegic, dilated state with a combination of inappropriate perfusion of some vascular beds and underperfusion of other vascular beds)
    4) Is really possible to target with any precision, the venous or arterial side of the circulation with vasodilators (let alone specific vascular beds of interest).
    5) Finally, is the inappropriate use of the combination of fluids, inotropes and vasoactive drugs according to an unvarying ‘recipe’ doing more harm to some patients than good. Shouldn’t we evaluate all haemodynamic parameters according to the underlying pathophysiology and the baseline co-morbidities and physiological state individual to that patient?

    • All good questions! All treatments must be evaluated in the individual patient. Guidelines and protocols give a starting recipe. The art is being a chef and altering based on the humidity, the quality of you ingredients, and the individual ineffable factors of the day.

  2. With respect to Docxology’s post, the Starling Relationship is probably of limited usefulness as a conceptual tool for the evaluation of the hemodynamic relationships in the patient with sepsis syndrome. The principle and earliest macro-hemodynamic derangement of sepsis may be the inappropriate level of after-load reduction resulting from shunting of flow across the microcirculation and bypass or stasis within the capillary perfusion beds.

    In the referenced article above by Spronk et al, use of orthogonal polarization spectral imaging of the lingual mucosa reveals in ways that words fail to convey the profound dysfunction of the microcirculatory beds and their impressive return to normal appearance with the institution of nitroglycerin infusion (for images see the following slideShare presentation at (http://www.slideshare.net/fmeissner/shock-2011-10954209) slide #100 & #101).

    Sepsis is quintessentially a disease of the microcirculation, which when detected in its earliest stages is highly responsive to therapy, but left to deteriorate and percolate, becomes the highly lethal entity we encounter too often in ER & ICU patients. I have little doubt that NTG infusion is efficacious in its treatment, and that efficacy is probably less dependent on the macro-hemodynamics, i.e., MAP & SBP but more dependent on institution of therapy in the early hyper-dynamic/increased C.O. phase of the illness. Furthermore, the increase in C.O. accompanying early sepsis is related not only to decreased afterload, but additionally increased pulse rate/increased chronotropic behavior of the ventricles as well as increased inotropic performance of the ventricular myocardium across all pulse rate ranges.

    One of the things observed at the bedside, and not adequately adressed in clinical research, is the central role of tachycardia and tachykpnea as early bedside markers of sepsis.

    In my own practice, unexplained tachycardia is always sepsis until proven not to be.

    In patient’s with a early to mid-course sepsis, who have made a good B/P response to vasopressors but have a persistant tachycardia, I have in addition to use of vasodilators, in patient’s selected by bedside echocardiography to demonstrate hyper-dynamic LV systolic function, frequently utilized low-dose and precisely titrated IV beta-blocker therapy in an attempt to mitigate the acute effects of tachycardia on LV performance.

    As we all know, beta blockers have revolutionized the chronic therapy of heart failure patients, but there is increasing data to suggest that acute beta-blocker therapy has many potential benefits in treatment of sepsis syndrome (Shock. 2009 Feb;31(2):113-9. Beta-Blockers in sepsis: reexamining the evidence. Novotny NM, et al). Specifically, the known beta-blocker effects on metabolism, glucose homeostasis, cytokine expression, and myocardial function may be beneficial in the setting of sepsis.

    ((Crit Care. 2009;13(5):230. Epub 2009 Oct 23. Bench-to-bedside review: Beta-adrenergic modulation in sepsis. de Montmollin E)). (free pdf download (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784350/pdf/cc8026.pdf)).

    I believe that serial evaluation of inotropic state of the shock patient via point of care ultrasound is one of the most useful implementations of this technology. It additionally, makes a great contribution to rational shock management when you are trying to resolve physiological derangements using novel strategies such as vasodilator and or beta blocker therapy for sepsis syndrome.

  3. Derek Louey says:

    In response to Dr. Meissner,

    “With respect to Docxology’s post, the Starling Relationship is probably of limited usefulness as a conceptual tool for the evaluation of the hemodynamic relationships in the patient with sepsis syndrome.”

    I never claimed as such.

    “Sepsis is quintessentially a disease of the microcirculation, which when detected in its earliest stages is highly responsive to therapy, but left to deteriorate and percolate, becomes the highly lethal entity we encounter too often in ER & ICU patients.”

    Macrocirculatory function can be addressed i.e. MAP, CO, SVRI with vasopressors and inotropes. The question is whether or not any therapy instituted early can reverse this microcirculatory dysfunction. I am not sure we are there yet with any clear evidence.

    “I have little doubt that NTG infusion is efficacious in its treatment”

    Could you propose the likely mechanism for its benefit considering that the patient is already vasodilated?

    “not adequately adressed in clinical research, is the central role of tachycardia and tachykpnea as early bedside markers of sepsis.”

    These are accepted criteria for SIRS.

    “In my own practice, unexplained tachycardia is always sepsis until proven not to be.”

    Not unreasonable since sepsis is the commonest cause of SIRS. However, once should of course consider pain, anxiety, hypovolaemia, PE etc.

    “there is increasing data to suggest that acute beta-blocker therapy has many potential benefits in treatment of sepsis syndrome (Shock. 2009 Feb;31(2):113-9. Beta-Blockers in sepsis: reexamining the evidence. Novotny NM, et al).”

    In which Montmollin’s article comments “The use of hypotensive drugs such as ?-blockers in severe sepsis and septic shock, however, raises justified safety issues. Manipulation of the ?-adrenergic system in septic shock should be carefully tested in various animal models of sepsis prior to considering its evaluation in
    patients.”

    • Frank Meissner says:

      The macro-circulatory defect in septic shock is low SVR via vasodilation of the small muscular arteries. The micro-circulatory defect is afferent pre-capillary arteriolar vasoconstriction and vasodilitation of the efferent post-capillary venules resulting in capillary leak &/or microcirculatory shunting.

      The putative effect of nitroglycerin in septic shock is to help re-establish normal pressure-flow relationships in the microcirculation. These effects of course must be counter-balanced with any macrocirculatory effects of the NTG infusion via titration of pressors.

      My comment about tachycardia and tachykpnea was in-exact, what I meant to say, but did not say, was that while the recognition of tachycardia and tachykpnea is part of the definition of SIRS, tachycardia and tachykpnea have not to date been a target of pharmacological intervention as has the later changes of hemodynamic compromise, i.e., shock, low blood pressure.

      An experimental hypothesis seems to me to be that early institution of therapy for sepsis that targets the microcirculatory changes of sepsis syndrome (the source of the patient’s tachykpnea – i.e., metabolic acidosis) or the tachycardia attendant to early sepsis prior to development of the frank macrocirculatory changes might mitigate the development of full blown septic shock.

      In particular the high output state of early septic shock is not simply related to decreased SVR, but there is a (+) inotropic stimulus resultant from the early septic state (hyperdynamic LV systolic function) (+) a chronotropic stimulus (tachycardia) – a beta-blocker intervention at this stage of generalized hyperdynamic LV function, i.e., increased CO, incr inotropy, incr tachycardia – may be at a time in the sepsis spectrum where beta-blocker use may blunt the development of full blown sepsis syndrome and be protective.

      A useful analogy would be acute beta-blocker therapy in AMI. Acutely and early in an anterior wall MI with hyperdynamic LV systolic function, tachycardia, and secondary hypertension, use of beta-blockers are protective and mitigate the impact of ongoing ischemia and infarction.

      Use the same beta-blocker regimen for mitigation of tachycardia, but wait 24 hours until the infarction has progressed and hyperdynamic function has given way to hypodynamic function, marginal blood pressure, and severe myocardial stunning, the use of beta blocker at this time in the MI spectrum results in adverse hemodynamic consequences.

      The experimental hypothesis could be that echocardiographic documentation of hyperdynamic LV systolic function in combination with tachycardia and tachykpnea is a marker for that phase in the septic continum when utilization of beta blockers to mitigate and blunt the full sepsis cascade would be useful and advantageous.

      Furthermore, as you recall use of the classical beta blockers (non-selective) results in a vasoconstrictive input to the small muscular arteries since stimulation of the Beta-2 receptors at this site results in a vasodilatory input to the arteries. Thus, again, early on beta-blocker therapy may have the potential to mitigate hypotension.

  4. A nice little review. We have blunt tools for the microcirculation.

    http://anaesthetics.ukzn.ac.za/Libraries/Documents2011/Dr_Alphonsuss_FMM_Booklet.sflb.ashx

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