Norepinephrine


Article Author:
Matthew Smith


Article Editor:
Christopher Maani


Editors In Chief:
Linda Lindsay


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
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Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
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Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
7/23/2019 7:02:05 PM

Indications

Norepinephrine's predominant use is as a peripheral vasoconstrictor.  Specifically, the FDA has approved its use for blood pressure control in certain acute hypotensive states, as well as a potential adjunct in the treatment of cardiac arrest with profound hypotension.  Also, norepinephrine is generally considered to have more predictive pharmacologic properties than other alpha agonists. This predictive quality, combined with some of its beta-agonism (which improves cardiac function relative to pure alpha agonists), makes norepinephrine a widely used vasoactive agent. It is commonly used in intensive care units to treat hypotension secondary to distributive shock. Specifically, it is the first-line agent for treating hypotension in the setting of sepsis that does not respond to fluid resuscitation.[1]

Mechanism of Action

Norepinephrine is a sympathomimetic amine derived from tyrosine.  It is structurally identical to epinephrine but differs in that it lacks a methyl group on its nitrogen atom.  This difference makes it primarily agonistic at alpha1 and beta1 receptors, with little-to-no beta2 or alpha2 activity.  At low doses (less than 2 mcg/min), the beta1 effects may be more pronounced and potentially increases cardiac output.  However, in doses higher than 3 mcg/min, the alpha1 effects may predominate.  The increased activation of the alpha1 receptors will result in vasoconstriction and dose-dependent increases in systemic vascular resistance.  The ratio of venous to arterial activity is relatively equal.[2][3]

Administration

Because of its relatively short half-life of 2.5 minutes, typically administration of norepinephrine is by continuous infusion. The FDA recommends diluting of the concentrated norepinephrine in dextrose-containing solutions prior to infusion, providing protection against potential oxidation and subsequent loss of drug potency.  The FDA recommends explicitly against using saline as the sole diluent.[4]  A common technique is to start the infusion at 8 mcg to 12 mcg per minute and titrate to the desired pressure.  The average maintenance dose is around 2 to 4 mcg per minute.[5]  If possible, infusions of norepinephrine should use tubing separate from blood products.

It is highly recommended to infuse norepinephrine through large-bore peripheral intravenous catheters or central venous catheters.  Ideally, the peripheral infusion should be in the upper extremity, preferably through an antecubital vein as this provides the least risk of ischemia secondary to extravasation. Lower extremity veins should be avoided if at all possible as occlusive vascular diseases are more likely to occur in the lower extremities. Extravasation into local tissue can cause significant ischemia and subsequent necrosis.  Should extravasation be suspected, the infusion should stop immediately. An attempt should be made to remove (draw back) any of the injected medication. If continuing the infusion is necessary, it should be restarted in a different site, ideally in a different extremity.  The local area should then be infiltrated with phentolamine (see below).[6][7]

It is worth noting that hypotension secondary to hypovolemia should have treatment with fluid resuscitation as a priority.  Using vasopressors such as norepinephrine in a patient who has not had appropriate resuscitation may result in worsening ischemia and an overall decline in clinical status. 

Adverse Effects

The most common adverse effects of norepinephrine relate directly to the activation of alpha1 receptors.  That is, excessive vasoconstriction can result in decreased end-organ perfusion, which is primarily caused by infusions of norepinephrine without appropriately treating hypovolemia; this can be detrimental as most patients who require infusions of norepinephrine already have poor oxygen delivery or utilization. 

Vasoconstriction secondary to alpha1 stimulation can result in reflex bradycardia via the baroreceptor reflex, which is generally not compensated for by the beta1 activity. The overall result is that cardiac output may decrease, or at most stay the same, despite beta1 agonism.  At the same time, the increase in systemic vascular resistance increases the work of the heart by increasing afterload, thereby increasing myocardial oxygen demand. Because of these phenomena, the benefits of norepinephrine for cardiogenic shock are still unclear but merit consideration under certain conditions.[8] 

Pulmonary vascular resistance may increase secondary to norepinephrine administration, which could have negative sequelae in patients with pulmonary hypertension. Decreased hepatic blood flow (secondary to alpha-mediated vasoconstriction) can lead to a transient increase in drugs that undergo hepatic metabolism.

Contraindications

There are no absolute contraindications to administration of norepinephrine.

As mentioned above, it may be contraindicated to use norepinephrine to treat hypotension that is likely secondary to cardiogenic mechanisms.  Additionally, if the hypotension is primarily related to hypovolemia, norepinephrine is probably not the best agent. The FDA does state that its use could be a consideration in low volume states, but only as an emergency measure for maintaining coronary or cerebral perfusion pressure while waiting for appropriate volume resuscitation.

Generally, the use of norepinephrine should be avoided in patients with mesenteric or peripheral vascular thrombosis as the subsequent vasoconstriction will increase the area of ischemia and infarction. 

Profound hypoxia or hypercarbia can sensitize the myocardium to unstable arrhythmias, which could be exacerbated or even be initiated by the use of norepinephrine - this is also the case with specific anesthetic agents, such as halothane and cyclopropane. 

Levophed, the preparation of norepinephrine, typically utilized in a clinical setting, contains sodium metabisulfite, which may cause allergic reactions in susceptible individuals. This effect may be more common in asthmatics. 

Care is necessary when using norepinephrine concomitantly with monoamine oxidase inhibitors or amitriptyline and imipramine-type antidepressants.  The combination of any of these drugs can lead to severe, prolonged hypertension.

Monitoring

Blood pressure requires close monitoring whenever vasopressors such as norepinephrine are in use; this is possible via invasive or non-invasive measurement techniques.  If following non-invasive measurements, then it is recommended to obtain values every 2 to 3 minutes during initial titration and then at least every 5 minutes following the determination of the appropriate maintenance dose.

When being used in low doses for its inotropic effect, it is preferred to titrate the dosage via cardiac output as opposed to blood pressure changes.  Therefore, a method of measuring cardiac output (e.g., echocardiography, pulmonary artery catheter) would be required.

Toxicity

The toxicity of norepinephrine is generally directly related to its mechanism of action. Systemic toxicity manifests as uncontrolled hypertension with signs and symptoms of end-organ ischemia.  Treatment should take into consideration that the hypertension is a result of alpha1 stimulation and agents that antagonize the beta-adrenergic receptor may not be appropriate. Extravasation into surrounding tissue can cause local ischemia and necrosis.  In such cases, treatment is with a 10 to 15 mL saline solution containing 5 to 10 mg of phentolamine.  Phentolamine is an alpha1 antagonist, and this method has been shown to significantly reduce adverse events of extravasation if given within 12 hours.[6][7]

Enhancing Healthcare Team Outcomes

Norepinephrine is a vasopressor that is most appropriate for maintaining mean arterial pressure via an increase in systemic vascular resistance after or during appropriate fluid resuscitation. It has some beta activity, making it more suitable than pure alpha 1 agonists in many situations. (Level I)  However, it should still be used cautiously (or avoided altogether) if a patient has poor cardiac function (acute or chronic) or pulmonary hypertension. (Level IV)

Although the use of this drug can be life-saving, improper monitoring can lead to malignant hypertension, arrhythmias, or tissue necrosis.  Therefore, all members of the interprofessional care team should highly alert and avoid compliance when utilizing this powerful medication. Physicians (including MDs, DOs, PAs, and NPs) will be prescribing this agent, but pharmacy should verify dosing and check for drug interactions, reporting any concerns to the team. Nursing will be performing administration, and be on the lookout of both systemic adverse effects of issues with the administration itself, such as extravasation, and let the physician on duty know immediately if they see anything noteworthy. The best and safest outcome will occur when the critical care and emergency nurses work in concert with the clinicians in monitoring patients on this medication for untoward events; the interprofessional team approach being best to guide optimal therapeutic results. [Level V]


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Norepinephrine - Questions

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A cardiac patient is started on a low-dose norepinephrine infusion while weening off of cardiopulmonary bypass. Which of the following is most likely to be seen as a result?



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A patient comes into the emergency room with sepsis secondary to rupture of an intraabdominal abscess. Her only past medical history is for depression and chronic pain syndrome. She cannot remember the names of her medications. She is induced with general anesthesia and started prophylactically on a norepinephrine infusion. Shortly after beginning the infusion, she has a much greater-than-expected elevation in blood pressure that remains much longer than expected after turning off the infusion. What is most likely the mechanism of this event?



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A rapidly deteriorating patient has been significantly somnolent, likely from opioid-induced hypoventilation. Her PaO2 is 52 mmHg and PaCO2 is 85 mmHg by arterial blood gas. She is hypotensive and she is started on a high-dose norepinephrine infusion. Shortly after, she losses her pulse and CPR is initiated. What was the most likely cause of her cardiac arrest?



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A patient is admitted to the intensive care unit for septic shock. She has a past medical history significant for severe pulmonary hypertension, poorly-controlled type 2 diabetes, and peripheral vascular disease. She remains hypotensive despite adequate volume resuscitation and is started on a norepinephrine infusion. Shortly after, the patient’s respiratory status begins to decline progressively, and she requires intubation for respiratory failure. What was the most likely etiology for her respiratory failure?



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A patient is admitted to the medical intensive care unit for septic shock. He was intubated in the emergency room for somnolence and inability to protect his airway. The physician orders a norepinephrine infusion to be started and the nurse attaches the infusion line to his 20 gauge peripheral IV placed in the emergency room. He continues to have significant hypotension despite a high infusion rate. The nurse then notices that his right upper extremity is pale, mottled and edematous around the IV site. What is the next best step?



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A new drug is being tested. Researchers have determined that this drug causes a rapid influx of calcium in post-ganglionic sympathetic neurons, causing a release of pre-formed vesicles into the synaptic space. What else the most likely physiologic result of this new drug?



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Which of the following neurotransmitters of the sympathetic nervous system is synthesized within the synaptic vesicle of post-ganglionic, presynaptic neurons?



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What should be given to quickly elevate a patient's blood pressure?



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A 68-year-old male with history significant for hypertension and type 2 diabetes mellitus is being treated for pyelonephritis on the general medical floor. Overnight, he rapidly declines. He is transferred to the intensive care unit and thought to be in septic shock. Initial resuscitation is begun with 30 ml/kg of IV crystalloid; however, the patient’s mean arterial pressure (MAP) remains below 60 mmHg. Which of the following would be the most appropriate next step in management?



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A patient in the operating room is given ephedrine for hypotension. This causes a release of preformed vesicles containing norepinephrine, which will act on post-synaptic receptors to increase blood pressure. What will be the primary mechanism of action for the termination of this effect?



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Norepinephrine - References

References

Reynolds PM,MacLaren R,Mueller SW,Fish DN,Kiser TH, Management of extravasation injuries: a focused evaluation of noncytotoxic medications. Pharmacotherapy. 2014 Jun     [PubMed]
Hurst S,McMillan M, Innovative solutions in critical care units: extravasation guidelines. Dimensions of critical care nursing : DCCN. 2004 May-Jun     [PubMed]
Tremblay M,Lessard MR,Trépanier CA,Nicole PC,Nadeau L,Turcotte G, Stability of norepinephrine infusions prepared in dextrose and normal saline solutions. Canadian journal of anaesthesia = Journal canadien d'anesthesie. 2008 Mar     [PubMed]
van Diepen S,Katz JN,Albert NM,Henry TD,Jacobs AK,Kapur NK,Kilic A,Menon V,Ohman EM,Sweitzer NK,Thiele H,Washam JB,Cohen MG, Contemporary Management of Cardiogenic Shock: A Scientific Statement From the American Heart Association. Circulation. 2017 Oct 17     [PubMed]
Rhodes A,Evans LE,Alhazzani W,Levy MM,Antonelli M,Ferrer R,Kumar A,Sevransky JE,Sprung CL,Nunnally ME,Rochwerg B,Rubenfeld GD,Angus DC,Annane D,Beale RJ,Bellinghan GJ,Bernard GR,Chiche JD,Coopersmith C,De Backer DP,French CJ,Fujishima S,Gerlach H,Hidalgo JL,Hollenberg SM,Jones AE,Karnad DR,Kleinpell RM,Koh Y,Lisboa TC,Machado FR,Marini JJ,Marshall JC,Mazuski JE,McIntyre LA,McLean AS,Mehta S,Moreno RP,Myburgh J,Navalesi P,Nishida O,Osborn TM,Perner A,Plunkett CM,Ranieri M,Schorr CA,Seckel MA,Seymour CW,Shieh L,Shukri KA,Simpson SQ,Singer M,Thompson BT,Townsend SR,Van der Poll T,Vincent JL,Wiersinga WJ,Zimmerman JL,Dellinger RP, Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive care medicine. 2017 Mar     [PubMed]
Overgaard CB,Dzavík V, Inotropes and vasopressors: review of physiology and clinical use in cardiovascular disease. Circulation. 2008 Sep 2     [PubMed]
Cryer PE, Physiology and pathophysiology of the human sympathoadrenal neuroendocrine system. The New England journal of medicine. 1980 Aug 21     [PubMed]
Phillips MS, Standardizing i.v. infusion concentrations: National survey results. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2011 Nov 15     [PubMed]

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