Month: January 2018

Amiodarone: Push It, Push It Real Good

by empharmd, posted in EM PharmD Blog

Amiodarone is one of the most pimpable drugs for pharmacy residents/students. From its pharmacology to excipients, there are so many nuances, important points, and pharmacy trivia. In terms of administration, we’re all taught to dilute and filter while administering amiodarone intravenously. In almost all circumstances, this is referring to administration of amiodarone to patients with a pulse. But when we’re at the bedside of a patient with pulseless ventricular tachycardia or fibrillation (pVT/VF) the question becomes should amiodarone be pushed undiluted, or further diluted with D5W?

Naturally, there are conflicting answers and practices. According to the prescribing information, amiodarone MUST be diluted with D5W to concentrations between 1 and 6 mg/mL (for a 300mg load, that would be between 50mL to 300 mL).1 Furthermore, anything more concentrated than 2 mg/mL (that would be 300mg in 150mL) should be administered via a central venous catheter. There are obvious problems to doing this in a cardiac arrest scenario.

What’s the risk of undiluted amiodarone?

Rapid administration of amiodarone is associated with hypotension, based on animal and some human data.2-4 There are three leading theories as to the cause of the hypotension:

1) Excipients in intravenous forms of amiodarone, which are polysorbate 80 and benzyl alcohol (for every 50 mg of amiodarone there is 100mg of polysorbate 80, and 20.2 mg benzyl alcohol).
2) Amiodarone’s beta-blocking/calcium channel blocking properties.
3) Local allergic reaction to one or many of amiodarone’s components.

While the overall quality of the data describing this problem is poor, there are some interesting findings that may support a more rapid, undiluted administration.

A commonly cited paper that supports the undiluted administration of amiodarone, is unfortunately, often misquoted. This study examined the hemodynamic effects of rapid, undiluted amiodarone bolus in pulseless patients was this paper from Finland.5 This was a retrospective study investigating the occurrence of side-effects and outcomes of the patients who received undiluted amiodarone during resuscitative efforts in Helsinki during a 2-year period. The local protocol had been updated to no longer stipulate further dilution of amiodarone (300mg) prior to administration in patients who after three ineffective shocks, one sequence of CPR, and epinephrine 1mg. The protocol included a rapid bolus of approximately 200 mL of Lactated Ringer’s immediately following the amiodarone bolus.

This study showed no difference in blood pressure between patients who received amiodarone versus those who did not. However, that’s not really an appropriate comparison since the populations were too heterogeneous (pVT/VF vs PEA vs asystole) and fails to answer the clinical question at hand. It would have been better to compare a diluted amiodarone versus an undiluted amiodarone bolus in patients with pVT/VF.

Since there is no data that directly answers this question, extrapolating other data sheds some light on the magnitude of the risk.

Munoz et al looked at 20 patients undergoing coronary arteriography who received 5 mg/kg IV of either amiodarone or a polysorbate 80 (aka Tween 80) free amiodarone product.6 Looking at the left ventricular systolic pressure three minutes before and three minutes after administration, the authors found that the polysorbate 80-free version was associated with a significantly smaller decrease in this outcome (amiodarone: 110 + 11 to 86 +/- 11 mmHg; polysorbate 80 free amiodarone: 114 +/- 22 to 106 +/- 19, P = 0.01).  A drop in SBP to the 80s is certainly concerning, however, the dose in this study is much larger than used in routine clinical practice for pVT/VF. For the average 80kg adult this dose would be 450mg. For the average Texan I see, the dose would be 500mg. While this evidence supports the animal models suggesting a hemodynamic effect of rapid undiluted amiodarone, it still does not describe the risk to the patient population I’ve been referring to.2-4

While the evidence is unclear regarding potentially clinically significant vasodilation/hypotension in patients in pVF/VT, it seems as though further dilution and slower infusions do nothing to reduce the incidence of hypotension. In a retrospective cohort analysis, patients that received IV loading doses of conventional amiodarone (polysorbate 80/benzyl alcohol) were compared with patients who received amiodarone with cyclodextrin.7  These patients did not receive “code dose” boluses, but rather, received the initial infusion load (1 mg/min for 6 hours, followed by 0.5 mg/min for 18 hours). Despite the lower rate of infusion, and dilution, there was still a statistically significant difference in incidence of hypotension across all measurements: 0-6 hours, 12-18 hours, 24 hours and requirement of fluid boluses.

The more recent PROCAMIO study, best described elsewhere, also used 5 mg/kg dosing for amiodarone administered over 20 minutes (unclear if the dose was diluted or not).8 Compared to procainamide, amiodarone was associated with more severe hypotension requiring immediate electrocardioversion (amiodarone, 6 patients versus 2 receiving procainamide).  Although, there were more patients in the procainamide arm experiencing hypotension not requiring cessation of infusion (procainamide, 5 patients versus 2 in the amiodarone group).

So where do I land on this? Since we have the backing of AHA, in a pVT/VF scenario, it is reasonable to continue to administer the 300mg bolus of amiodarone undiluted.9 However, in any other case, consider dilution/filter/slow(er) rate of administration. Alternatively, consider stocking non polysorbate 80 containing formulations since they appear to have a smaller hemodynamic impact.

(Side note, cyclodextrin containing amiodarone may not contain polysorbate 80, but must still be filtered during infusion).

  1. “Amiodarone injection [prescribing information].”, Irvine, CA: Teva Parenteral Medicines, Inc., 2008
  2. Platou ES, Refsum H. Acute electrophysiologic and blood pressure effects of amiodarone and its solvent in the dog. Acta Pharmacol Toxicol (Copenh) 1986;58:163-168
  3. Gough WB, Zeiler RH, Barreca P, El-Sherif N. Hypotensive action of commercial intravenous amiodarone and polysorbate 80 in dogs. J Cardiovasc Pharmacol 1982;4:375-380
  4. Somberg JC, Cvetanovic I, Ranade V, Molnar J. Comparative effects of rapid bolus administration of aqueous amiodarone versus 10-minute cordarone I.v. infusion on mean arterial blood pressure in conscious dogs. Cardiovasc Drugs Ther. 2004 Sep; 18(5):345-51
  5. Skrifvars MB, Kuisma M, Boyd J, Määttä T, Repo J, Rosenberg PH, Castren M. The use of undiluted amiodarone in the management of out-of-hospital cardiac arrest. Acta Anaesthesiol Scand. 2004 May;48(5):582-7
  6. Munoz A, Karila P, Gallay P, et al. A randomized hemodynamic comparison of intravenous amiodarone with and without Tween 80. Eur Heart J 1988;9:142-8
  7. Lindquist DE, Rowe AS, Heidel E, Fleming T, Yates JR. Evaluation of the Hemodynamic Effects of Intravenous Amiodarone Formulations During the Maintenance Phase Infusion. Ann Pharmacother. 2015 Dec;49(12):1317-21
  8. Ortiz M et al. Randomized Comparison of Intravenous Procainamide vs. Intravenous Amiodarone for the Acute Treatment of Tolerated Wide QRS Tachycardia: the PROCAMIO Study. Eur Heart J 2016
  9. Kleinman ME, Brennan EE, Goldberger ZD, Swor RA, Terry M, Bobrow BJ, Gazmuri RJ, Travers AH, Rea T. Part 5: adult basic life support and cardiopulmonary resuscitation quality: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015;132(suppl 2):S414–S435

    Quick and Dirty Review: Linezolid

    by empharmd, posted in EM PharmD Blog
    ID in the ED
    Quick and dirty review: Linezolid
    Drug shortages and intravenous fluid shortages are reaching critical mass. Pharmacotherapeutic decisions are being forced, and unusual therapeutic strategies are being implemented. One of these scenarios is the substitution of vancomycin for linezolid for empiric treatment of various infectious disease indications. While a detailed therapeutic review would be more fitting for general practice, the bizzaro world of drug shortages is anything but general. So let’s review linezolid for vancomycin substitution in these strange times.
    What is linezolid
    Linezolid belongs to the oxazolidinone therapeutic class, of which the only other currently available member is tedizolid.  Unlike other antibiotic classes, like penicillins, the oxazolidinones are fully synthetic compounds. Their mechanism of action is as a protein synthesis inhibitor, targeting the 23S rRNA of the 50S subunit and preventing the formation of a functional 70S initiation  complex.1 This mechanism of protein synthesis inhibition may also decrease toxin production in necrotizing skin and soft tissue infections (SSTI) due to toxin producing strains.
    Spectrum of Activity1
    The spectrum of activity of linezolid is limited primarily to gram positive bacteria, including: Streptococci (Group A, B, C, G), coagulase-positive Staphylococci (MRSA, MSSA), coagulase-negative Staphylococci, Enterococci (including VRE), Corynebacterium spp, Listeria monocytogenes, Peptostreptococci and Clostridium spp.
    Linezolid is FDA approved for vancomycin-resistant Enterococcus faecium (VRE) infections, nosocomial pneumonia, community-acquired pneumonia, and skin and skin structure infections.
    PK/PD
    It’s rapid and extensive absorption (oral bioavailability ~ 100 %) allows for 1:1 IV to PO conversion. Distributes widely to well-perfused tissues (Vd = 0.6–0.7 L/kg). Linezolid is metabolized via hepatic oxidation of the morpholine ring to inactive metabolites, and excreted in the urine 30% as parent drug, 50% as metabolites. It’s normal half-life is ~ 4-5 hours, but these metabolites may accumulate in significant renal insufficiency (although it is eliminated by hemodialysis).
    Adverse events of significance
    Serotonin syndrome1-2
    Linezolid is a weak, nonspecific monoamine oxidase inhibitor. As such, any concomitant serotonergic drug can increase the risk of serotonin syndrome. It’s recommended that any offending agent be held for at least 2 weeks prior to initiation of linezolid, but this may not be practical for most patients in the ED. In reality, discontinuation of the serotonergic agent and monitoring for 24 hours after discontinuation of linezolid is a reasonable strategy. It is worth noting that serotonin syndrome has been reported despite stopping the serotonergic agent days prior to initiation of linezolid due to a prolonged serotonergic agent half-life.
    Serotonin modulators that have been implicated in case reports include: SSRIs, SNRIs, TCAs and a series of others agents such as bupropion, fentanyl, lithium, methadone, metoclopramide, mirtazapine, risperidone, tramadol, and trazodone.
    Mitochondrial toxicities3-5
    Some data indicates linezolid directly inhibits intramitochondrial protein synthesis. Linezolid seems to disrupt cellular energy production in tissues that are highly dependent on oxidative phosphorylation. It appears that linezolid may bind to the 16S ribosomal subunit in mitochondrial DNA, which is a region homologus to the linezolid binding site of the bacterial 23S rRNA. This interference with mitochondiral function has led to several clinically relevant adverse events: peripheral and optic neuropathy, lactic acidosis, and myelosuppression.
    Peripheral and optic neuropathy1,5
    A concerning consequence of mitochondrial toxicity is irreversible peripheral and optic neuropathies. Prolonged treatment durations greater than 28 days is the most pertinent risk factor for developing neuropathy. While this adverse effect is unlikely to sway decision making in the ED setting it is worth being aware of if patients present with these symptoms in the setting of prolonged linezolid courses.
    Lactic Acidosis
    Although rare, lactic acidosis has been reported with linezolid; mostly with prolonged durations of use. Patients with recurrent nausea and vomiting, acidosis, or low unexplained bicarbonate levels should be evaluated for linezolid-induced lactic acidosis. While this may not lead to any changes in the course of care in the ED, linezolid when combined with other medications that can impair lactate clearance (ie, epinephrine), it may impair the ability to trend lactate levels as a clinical measure. It may be relevant also in patients who are already on longer courses of linezolid as an outpatient and then present to the ED with signs/symptoms of lactic acidosis.
    Myelosuppression6-8
    Hematologic toxicity, primarily thrombocytopenia, but also including leukopenia, anemia, and pancytopenia have been associated with linezolid use. In phase-III clinical trials the incidence of thrombocytopenia was 2.4% in the linezolid treatment group, however multiple case studies have since found a higher incidence of up to 32%. These effects are thought to be time dependent, with thrombocytopenia occurring more frequently after 2 weeks of therapy, though they may occur earlier. Patients that appear to be at the highest risk for myelosuppression are those with lower baseline hematologic values, concomitant myelosuppressive agents, and those receiving extended durations of therapy. If consideration is given to initiating linezolid in the ED a CBC should be obtained. The good news is that myelosuppressive effects have been found to be reversible after discontinuation therapy.
    Areas linezolid shines (when vancomycin is unable to be used)
    • Coverage of MRSA in pulmonary infections 
      • Linezolid remains active in pulmonary infections while daptomycin is inactivated by surfactant rendering it useless for this indication
    • VRE 
      • When used correctly, linezolid is a cornerstone of VRE therapy 
    • Necrotizing fasciitis
      • Since linezolid is a protein synthesis inhibitor it may decrease exotoxin production.Therefore, if you are treating necrotizing fasciitis with linezolid, you can omit clindamycin from your empiric regimen
    Areas to use caution when using linezolid
    • Bacteremia, endocarditis, endovascular infection.
      • Given the bacteriostatic nature of linezolid it has typically been reserved for salvage therapy in these situations. (Though a systematic review was recently completed suggesting static vs cidal activity may not be as important as we originally thought.
      • In these situations daptomycin is a reasonable alternative to vancomycin
    • Urinary tract infection 
      • Only 30% active component is excreted into the urine limiting its efficacy (vs 78% for daptomycin)9
    Other areas where linezolid may be used (when vancomycin is unable to be used)
    • SSTI
    • Meningitis
    • Bone/Joint infections
    • Intra-abdominal infections (Enterococcal coverage)

    Take home points
    • When vancomycin is unable to be used, linezolid is an option to provide excellent gram-positive coverage in its place (including MRSA with the added benefit of VRE) 
    • Linezolid should be avoided for the empiric treatment of bacteremias, endocarditis, endovascular infections, and UTIs when possible
    • Linezolid has a unique adverse effect profile including serotonin syndrome, myelosuppression, and mitochondrial toxicities which may cause peripheral and optic neuropathies, as well as lactic acidosis
    • Stay tuned for future posts regarding daptomycin, another alternative to vancomycin, and how it compares to linezolid when vancomcyin cannot be used
    • Be sure to check your current supply of linezolid, as there was a recent recall due to white particulate matter that has been identified as mold. Specifically NDC 55150-242-51, batch CLZ160007, expiration August 2018, distributed May 15 through August 14, 2017.
    Scott Dietrich, PharmD
    @PCC_PharmD
    Emergency Medicine Clinical Pharmacist
    University of Colorado Health, North Region

    Tony Mixon, PharmD, BCPS

    @MixonMarkA
    Emergency Medicine/Infectious Disease Clinical Pharmacist
    University of Colorado Health, North Region
    Craig Cocchio, PharmD, BCPS
    @iEMPharmD
    Emergency Medicine Clinical Pharmacist

    Reference:

    1. Zyvox (linezolid) [prescribing information]. New York, NY: Pharmacia and Upjohn; July 2017
    2. Wigen CL1, Goetz MB. Serotonin syndrome and linezolid.Clin Infect Dis. 2002 Jun 15;34(12):1651-2. Epub 2002 May 23
    3. Palenzuela L, Hahn NM, Nelson RP Jr, et al. Does linezolid cause lactic acidosis by inhibiting mitochondrial protein synthesis? [online exclusive article]. Clin Infect Dis 2005;40:e113–16. Available from http://www.journals.uchicago.edu/CID/journal/issues/v40n12/35321/35321.html
    4. De Vriese AS, Coster RV, Smet J, et al. Linezolid-induced inhibition of mitochondrial protein synthesis. Clin Infect Dis 2006;42:1111–17
    5. Narita, M., Tsuji, B. T. and Yu, V. L. (2007), Linezolid-Associated Peripheral and Optic Neuropathy, Lactic Acidosis, and Serotonin Syndrome. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 27: 1189–1197.
    6. Gerson SL, Kaplan SL, Bruss JB et al. Hematologic effects of linezolid: summary of clinical experience. Antimicrob Agents Chemother. 2002 Aug;46(8):2723-6
    7. Minson Q, Gentry CA. Analysis of linezolid-associated hematologic toxicities in a large veterans affairs medical center. Pharmacotherapy. 2010 Sep;30(9):895-903.
    8. Attassi K, Hershberger E, Alam R, Zervos MJ. Thrombocytopenia associated with linezolid therapy. Clin Infect Dis 2002; 34(5):695-698
    9. Product Information: Cubicin(R) intravenous injection, daptomycin intravenous injection. Cubist Pharmaceuticals, Inc., Lexington, MA, 2010.

      Giapreza – A Closer Look at the Pharmacology of Ang2

      by empharmd, posted in EM PharmD Blog

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      Angiotensin-II (Ang2) is now an FDA approved vasopressor. With this new addition to the available options, experts are combing over the available literature to determine whether or not to incorporate it into their daily practice. The ATHOS-3 trial has demonstrated that Ang2 is, at minimum, safe and effective when added to norepinephrine (or other similarly dosed vasopressor).1 While this trial should be critically appraised, and has been done so by EMCrit, REBEL EM and others, I want to take a step back and examine the pharmacology of Ang2. By doing so, hopefully I can add some perspective in how it is exerting its effects and maybe even predict some therapeutic misadventures that are likely to occur once exposed to thousands of patients in real world settings.


      Ang2 is a critical element in the renin-angiotensin-aldosterone system (RAAS). RAAS is analogous to the coagulation cascade, in that, the one we all learned in school tremendously over simplified. Similarly, by stating Ang2 is a vasopressor via agonist actions on the AT1 receptor is an oversimplification. Acknowledging this is a complex pathway, to understand the effects of Ang2 let’s look at some elements of the RAAS in more depth from our core pharmacology textbooks.2,3

      Related image
      Image credit: https://commons.wikimedia.org/wiki/File:Renin-anigotensin_system_and_potential_steps_of_blockage..png

      Ang2 basics

      Angiotensinogen is converted to angiotensin-I (Ang1) by renin. From our understanding of the pharmacotherapy for hypertension, we’re familiar with the conversion of Ang1 by angiotensin converting enzyme (ACE) to Ang2. Ang2, then goes on to exert its effects on angiotensin 1 (AT1), and AT2 receptors.

      • The AT1 agonist effects lead to increased peripheral resistance via the coupling of Gq to activate the PLCβ–IP3–Ca2+ pathway
      • The AT2 agonist effects lead to decreased resistance through numerous mechanisms including NO synthesis, bradykinin production, and inhibition of Ca2+ channel antagonism

      The net effect is AT1 agonist effects, under normal physiological scenarios.

      Lesser known RAAS elements [Ang3, Ang4, Ang(1-7), & ACE2]

      Ang1 is a decapeptide consisting of the following peptide sequence: Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu. Thus Ang1 can be referred to as Ang(1-10) and depending on the location of enzymatic cleavage, downstream Ang metabolites follow a logical nomenclature (ie, Ang(1-7), Ang(2-8), Ang(3-8), etc.). This is relevant since there are other metabolites from Ang1 other than Ang2 that have physiologic effects and follow this nomenclature.

      Ang2 can be converted by aminopeptidase (AP) to Ang3 and again by AP to Ang4 which have effects on AT2 and AT4 receptors, respectively.

      • Ang3 has approximately the same effects of aldosterone equal to Ang2, but is 25% as potent (vs Ang2) on BP elevation, and 10% as potent (vs Ang2) adrenal medulla stimulation.
      • Ang4 has minimal hemodynamic effects but has some fascinating effects on memory and cognition

      ACE2, different from ACE, and expressed in the endothelium of kidneys, heart and testes, produces Ang(1-7) either directly from Ang1 to Ang(1-7), or by metabolizing Ang2 to Ang(1-7). The actions of Ang(1-7) on Mas receptors oppose those of Ang2 similar to AT2 activation. However, in most physiological scenarios the ratio of ACE-Ang2/ACE2-Ang(1–7) favors the effects of Ang2.

      Ang(1-7) is gaining attention in terms of therapeutic benefit itself. There is growing research in humans based on animal models supporting its numerous potential benefits including (but not limited to): anti arrhythmic effects, anti thrombosis, protection of endothelial function, improvement in NO release and increased cardiac output.

      There are several other newly identified components of RAAS including: alamandine, AngA, Ang(1-9), Ang(1-5), MrgD receptors.

      The complex effects of these peptides are outlines in the following table:


       

      Net effects of Ang2

      Once formed, the effects of Ang2 can be described in three main phases: fast pressor response, slow pressor response, and vascular/cardiac remodeling and hypertrophy.

      Fast pressor response

      Naturally, the fast pressor response is the desirable effect of the newly approved Giapreza®, the brand name for Ang2. Breaking down the fast pressor response further, there are three mechanism by which Ang2 exerts the fast pressor response:

      • As previously stated, stimulation of the Gq–PLC–IP3–Ca2+ pathway –> rapid increase in peripheral resistance
        • Ang2 can also increase the blood pressure set point for baroreceptor reflex through actions in the CNS thus cause either no change in HR or a slight decrease
      • Inhibition of norepinephrine reuptake (increased release from nerve terminals) and by enhancing the vascular response to norepinephrine
      • Depolarization of adrenal chromaffin cells leading to release of catecholamines

      Slow pressor response/Vascular and cardiac remodeling
      The slow pressor response, with an onset after days of continuous therapy with Ang2, is a result of sodium reabsorption in the proximal tubule, and further sodium retention through the actions of aldosterone. Ultimately this sodium retention leads to increased plasma volumes. However, Ang2 can have complex effects on renal function. Depending on renal hemodynamics Ang2 can either cause GFR to be increased or decreased.

      • Decreases in GFR can occur as a result of Ang2 through increased resistance renal vascular smooth muscle, by enhancing renal sympathetic tone, and by facilitating intrarenal adrenergic transmission.
      • Increased GFR can occur during renal artery hypotension (i.e. shock), the effects of Ang2 are on the efferent arteriole, thus an increase in GFR. On the flip side, giving this patient an ACEi/ARB would potentiate acute renal failure.

      To a lesser extent, Ang2 stimulates the synthesis of endothelin-1 and superoxide anion. By these mechanisms over time, and from our understanding of the neurohormonal theory of heart failure, Ang2 stimulates remodeling of the cardiovascular system. This inflammatory chemokine and cytokine response to Ang2 involved in vascular and cardiac remodeling also results in increased release of plasminogen activator inhibitor 1 and augmenting the expression of adhesion proteins in vascular cells, which may be of concern in the critically ill.

      Ang2 is certainly not a straightforward drug that we are adding to the already complex pharmacotherapy in shock. While the pharmacology of Ang2 is supportive of the theory of addressing multiple pathways of improving vascular resistance and perfusion, there are numerous unanswered questions.

      Some risks of complications or blunting of benefits of Ang2 could be observed with concomitant neutral endopeptidase inhibitors (aka NEP, neprilysin) such as sacubitril, or DPP4 inhibitors by limiting the production of Ang(1-7).

      Some other critiques of Ang2 I have heard anecdotally include the incidence of thrombosis in ATHOS-3. As outlined above, while this is certainly possibly explained through some of the unwanted effects of Ang2, the available evidence is certainly not sufficiently powered to appropriately describe this risk. A lack of mortality/morbidity benefit is another common critique from pharmacy circles. I think this is another scenario where would we expect a vasopressor to improve mortality in a large, diverse population? Probably not. However, in specific patient cases, there may be a morbidity benefit that may be small but clinically important.

      While it is easy to critique Ang2, and its evidence, we musn’t forget that no available vasopressor has gone through any regulatory approval for use – yet we use them daily. Furthermore, sympathomimetics and vasopressin have similar, complex effects on numerous other physiologic pathways that led to their associated deleterious effects. I believe Ang2 will have a role in management of shock. However, I do not expect it to replace any available regimen, and won’t be surprised if there are serious adverse events that arise in clinical practice.

      1. Khanna A, et al. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-430. PMID: 28528561
      2. Reid IA. Vasoactive Peptides. In: Katzung BG. eds. Basic & Clinical Pharmacology, 14e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=2249&sectionid=175218037. Accessed December 29, 2017.
      3. Hilal-Dandan R. Renin and Angiotensin. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13eNew York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=2189&sectionid=170106980. Accessed December 29, 2017.
      4. Chawla LS, et al. The use of angiotensin II in distributive shock. Crit Care. 2016; 20: 137. PMCID: PMC4882778
      5. https://ccforum.biomedcentral.com/articles/10.1186/s13054-017-1896-6