Tag Archives: noradrenaline

Why I don't give vasopressors in sepsis

It’s become popular to use the term ‘vasopressors’ or just ‘pressors’ when noradrenaline/norepinephrine or even (in some places still) dopamine are given. I have resisted this trend and continue to use the term ‘vasoactive’ drugs, on the basis that the effects they produce (and that we may desire) are not limited to a pure alpha adrenergic effect on vascular tone, but they have effects on heart rate and contractility too (as well as preload through venous effects). If you don’t believe me about noradrenaline/norepinephrine, then check out one of my favourite critical care papers of all time: the CAT study.
There are of course real pressors out there – phenylephrine acts on alpha receptors, as does methoxamine. Metaraminol predominantly acts on alpha receptors but does also cause some release of noradrenaline/norepinephrine.
Why is this important? All these drugs will fix hypotension, right? Yes, they should. However should blood pressure be our main treatment goal? What we’re really interested in is organ perfusion, which depends on regional blood flow to vital organs. It’s possible that a drug could fix the measured blood pressure and give a nice ‘macroscopic’ number, while at the same time reducing cardiac output and adversely affecting regional blood flow to organs through local vasoconstrictive effects. My view is that this is more likely with pure ‘pressors’ (like phenylephrine), which is why I avoid them in septic shock and opt for catecholamine infusions (noradrenaline/norepinephrine).
This is important in my practice setting of retrieval medicine, where, prior to interfacility transport, physicians might sometimes be tempted to ‘push pressors’ peripherally rather than insert a central venous catheter and commence a catecholamine infusion. While the former approach might be more expeditious and make the vital signs chart look pretty, one wonders about what effect this is having on tissue oxygen delivery.
A fascinating review of papers on pressor physiology1 suggests these agents have the following effects:

  • conflicting data on changes in myocardial perfusion
  • increase both left and right heart afterload
  • decrease venous compliance with the potential to increase venous return although the impact of this on cardiac output is controversial
  • controversial effect on cerebral bloodflow
  • decrease bloodflow to the kidneys
  • adverse affects on gastrointestinal tract bloodflow

Phenylephrine and methoxamine are direct-acting, predominantly α(1) adrenergic receptor (AR) agonists. To better understand their physiologic effects, we screened 463 articles on the basis of PubMed searches of “methoxamine” and “phenylephrine” (limited to human, randomized studies published in English), as well as citations found therein. Relevant articles, as well as those discovered in the peer-review process, were incorporated into this review. Both methoxamine and phenylephrine increase cardiac afterload via several mechanisms, including increased vascular resistance, decreased vascular compliance, and disadvantageous alterations in the pressure waveforms produced by the pulsatile heart. Although pure α(1) agonists increase arterial blood pressure, neither animal nor human studies have ever shown pure α(1)-agonism to produce a favorable change in myocardial energetics because of the resultant increase in myocardial workload. Furthermore, the cost of increased blood pressure after pure α(1)-agonism is almost invariably decreased cardiac output, likely due to increases in venous resistance. The venous system contains α(1) ARs, and though stimulation of α(1) ARs decreases capacitance and may transiently increase venous return, this gain may be offset by changes in afterload, venous compliance, and venous resistance. Data on the effects of α(1) stimulation in the central nervous system show conflicting changes, while experimental animal data suggest that renal blood flow is reduced by α(1)-agonists, and both animal and human data suggest that gastrointestinal perfusion may be reduced by α(1) tone.

A review of clinical articles2 reveals few evidence-based indications for true pressors. Possible situations where they may be of benefit include intraoperative hypotension, aortic stenosis, during cyanotic episodes in Tetralogy of Fallot, and some obstetric situations. In the setting of sepis, phenylephrine has been compared with noradrenaline in which an initial pilot study found a statistically significant reduction in creatinine clearance and increase in arterial lactate after initiating the phenylephrine infusion. However a subsequent randomised controlled comparison of phenylephrine with noradrenaline/norepinephrine did not show differences in cardiopulmonary performance, global oxygen transport, or regional hemodynamics, although there were only 16 patients in each group3.

Phenylephrine is a direct-acting, predominantly α(1) adrenergic receptor agonist used by anesthesiologists and intensivists to treat hypotension. A variety of physiologic studies suggest that α-agonists increase cardiac afterload, reduce venous compliance, and reduce renal bloodflow. The effects on gastrointestinal and cerebral perfusion are controversial. To better understand the effects of phenylephrine in a variety of clinical settings, we screened 463 articles on the basis of PubMed searches of “methoxamine,” a long-acting α agonist, and “phenylephrine” (limited to human, randomized studies published in English), as well as citations found therein. Relevant articles, as well as those discovered in the peer-review process, were incorporated into this review. Phenylephrine has been studied as an antihypotensive drug in patients with severe aortic stenosis, as a treatment for decompensated tetralogy of Fallot and hypoxemia during 1-lung ventilation, as well as for the treatment of septic shock, traumatic brain injury, vasospasm status-postsubarachnoid hemorrhage, and hypotension during cesarean delivery. In specific instances (critical aortic stenosis, tetralogy of Fallot, hypotension during cesarean delivery) in which the regional effects of phenylephrine (e.g., decreased heart rate, favorable alterations in Q(p):Q(s) ratio, improved fetal oxygen supply:demand ratio) outweigh its global effects (e.g., decreased cardiac output), phenylephrine may be a rational pharmacologic choice. In pathophysiologic states in which no regional advantages are gained by using an α(1) agonist, alternative vasopressors should be sought.

These review articles reinforce my own bias against the use of pure pressors in septic shock, although clearly more clinical research is needed. I am inclined to agree with the reviewers’ concluding statement:
…in all clinical settings, phenylephrine reduces cardiac output, and in most clinical settings has been shown to significantly increase LV afterload. Thus, only in instances in which its regional effects are thought to outweigh its global effects should phenylephrine be used for the treatment of hypotension.
1. The physiologic implications of isolated alpha(1) adrenergic stimulation
Anesth Analg. 2011 Aug;113(2):284-96
2. The clinical implications of isolated alpha(1) adrenergic stimulation
Anesth Analg. 2011 Aug;113(2):297-304
3. Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial
Crit Care. 2008;12(6):R143
Full Text available here

Effect on noradrenaline on tissue oxygen delivery

Some persist in thinking and teaching that the ‘vasopressor’ noradrenaline (norepinephrine) increases mean arterial pressure (MAP) simply by increasing systemic vascular resistance, leading to concerns that it may increase blood pressure at the expense of tissue perfusion. This assertion is contested by many, who now have further support from this study.
In 16 patients with septic shock, various measures of peripheral perfusion were recorded while the dose of noradrenaline was increased to achieve target MAPs. The use of noradrenaline to achieve incremental targets for MAP was associated with increases in global oxygen delivery, cutaneous microvascular flow, and tissue oxygenation in patients with established septic shock; there were no associated changes in the preexisting abnormalities of sublingual microvascular flow. The authors state that these findings suggest that in patients with septic shock, improvements in global hemodynamics and tissue oxygen delivery can be achieved with noradrenaline, without exacerbating microcirculatory flow abnormalities.
The effect of increasing doses of norepinephrine on tissue oxygenation and microvascular flow in patients with septic shock
Crit Care Med. 2009 Jun;37(6):1961-6