Fluids, Vasopressors, and Inotropes

Fluid Resuscitation in Shock

• Types of Fluids: Crystalloids (e.g., Saline, Ringer’s Lactate)
  • Composition
  • How its distributed
  • Considerations

Crystalloids

Crystalloids, including normal saline and Ringer’s lactate, are the most commonly used fluids for resuscitation in shock. These solutions are favored due to their availability, low cost, and relatively safe profile.

Composition

1. Normal Saline: Composed of sodium chloride in water, normal saline has a higher chloride content than plasma, which can lead to hyperchloremic metabolic acidosis with large volume infusion.
2. Ringer’s Lactate: Contains sodium, potassium, calcium, chloride, and lactate (metabolized to bicarbonate in the liver), making it more physiologically balanced compared to normal saline.
3. Plasma-Lyte: Plasma-Lyte contains sodium, potassium, magnesium, chloride, acetate, and gluconate. This composition closely resembles human plasma, making it a balanced electrolyte solution.

Distribution

Crystalloids are distributed throughout the extracellular fluid compartment. After infusion, only about one-third remains in the intravascular space, with the remainder diffusing into the interstitial space. This necessitates larger volumes to achieve the same intravascular volume expansion as colloids.

Considerations for Fluid Resuscitation

1. Patient-Specific Factors: Underlying comorbidities, the nature of shock (e.g., hemorrhagic, septic), and the presence of metabolic derangements influence the choice of fluid.
2. Risk of Acid-Base Imbalance: High chloride content in normal saline can exacerbate acidosis, while Ringer’s lactate may be more beneficial in buffering metabolic acidosis.
3. Volume Overload: Over-resuscitation with crystalloids can lead to edema, including pulmonary edema, particularly in patients with compromised cardiac or renal function.
4. Monitoring: Continuous assessment of hemodynamics, urine output, and laboratory parameters (like lactate and electrolytes) is crucial to guide fluid therapy and avoid complications.

Colloids (e.g., Albumin, Hydroxyethyl Starch)

Colloids are used in fluid resuscitation to manage shock, with types including albumin and hydroxyethyl starch (HES). These solutions consist of large molecules intended to remain within the intravascular space for extended periods, thereby increasing plasma osmotic pressure and reducing the need for additional fluid.

Composition and Distribution

1. Albumin: Albumin, a natural protein, is distributed in both intravascular and extravascular fluids. In a healthy state, about 5% of intravascular albumin leaks per hour into the extravascular space, with a distribution half-time of approximately 15 hours. However, this rate can increase significantly in conditions like septic shock, impacting its distribution and effectiveness.
2. Hydroxyethyl Starch (HES): HES, a semisynthetic colloid, has been shown to increase the risk of acute kidney injury (AKI) and has no major advantage over crystalloid solutions in shock management. Therefore, its use in shock patients is now generally discouraged.

Clinical Considerations

1. Albumin in Shock: The role of albumin in fluid therapy is complex and still debated. While it has theoretical benefits due to anti-inflammatory and antioxidant properties, clinical data have shown mixed results. Albumin can improve mean arterial pressure (MAP), but its effect on mortality is similar to that of crystalloid infusion. It’s recommended to avoid albumin in patients with traumatic brain injury and use it cautiously in those with chronic liver disease or hepatorenal syndrome.
2. Colloid versus Crystalloid: The choice between colloids and crystalloids in fluid resuscitation is influenced by the patient’s condition and the type of shock. Colloids can increase the risk of global increased permeability syndrome in patients with sepsis due to alterations in glycocalyx and increased endothelial permeability. This can lead to the extravasation of colloids’ large molecules, diminishing their primary advantage.
3. Fluid Resuscitation Strategy: In managing fluid resuscitation, the rate of fluid administration is crucial. A slower infusion rate may limit vascular leakage and avoid abrupt increases in hydrostatic pressure.
4. Outcomes with Different Fluid Types: Recent studies, including large randomized controlled trials (RCTs), have assessed the effectiveness of different fluid types in critically ill patients. These studies have generally found no significant difference in mortality or renal outcomes when comparing balanced crystalloids with saline 0.9% or other fluid types.
5. Acute Kidney Injury (AKI): HES has been associated with an increased risk of AKI. This is particularly significant in critically ill patients, where renal function is already compromised or at risk.
6. Risk of Increased Mortality: Some studies have indicated that the use of HES may be associated with increased mortality, especially in certain patient populations like those with sepsis or in intensive care settings.

Blood Products in Resuscitation

Blood products are critical components in the management of certain types of shock, particularly hemorrhagic shock. They include packed red blood cells (PRBCs), fresh frozen plasma (FFP), platelets, and cryoprecipitate, each with unique compositions and functions.

1. PRBCs (Packed Red Blood Cells)
   • Composition: Concentrated red blood cells, with most of the plasma removed.
   • Function: Primarily used to increase oxygen-carrying capacity in patients with significant anemia or blood loss.
   • Used for symptomatic anemia or significant blood loss. Risks include transfusion reactions and volume overload. Indicated when hemoglobin levels fall below certain thresholds, varying based on patient condition.
2. FFP (Fresh Frozen Plasma)
   • Composition: Liquid portion of blood, rich in clotting factors.
   • How it’s Made: Collected from donor blood and rapidly frozen to preserve clotting factors.
   • Function: Used to treat deficiencies in clotting factors, such as in disseminated intravascular coagulation (DIC) or massive transfusion protocols.
   • Apart from clotting factor deficiencies, FFP is used to reverse anticoagulant effects, especially in liver failure. Risks include TRALI and allergic reactions. Indicated in massive transfusions and in patients with coagulopathy.
3. Platelets
   • Composition: Cell fragments essential for blood clotting.
   • How it’s Made: Separated from whole blood or collected via apheresis.
   • Function: Essential in managing bleeding due to platelet deficiencies or dysfunction, often used in patients undergoing chemotherapy or bone marrow transplant.
   • Administered when platelet counts fall below specific thresholds (e.g., <10,000/μL in chemotherapy patients). Risks involve alloimmunization and transfusion-related sepsis. Used in active bleeding scenarios and prophylactically in certain conditions.
4. Cryoprecipitate
   • Composition: Contains concentrated clotting factors, including fibrinogen, factor VIII, von Willebrand factor, and factor XIII.
   • How it’s Made: Produced by thawing frozen plasma at a specific temperature range.
   • Function: Used primarily to correct hypofibrinogenemia, such as in massive hemorrhage, liver disease, or cardiac surgery.
   • Indicated for hypofibrinogenemia in massive hemorrhage, liver disease, and during cardiac surgery. Risks include TACO and allergic reactions. Used in rare congenital clotting factor deficiencies.

• Evidence-Based Guidelines for Fluid Therapy in Shock
  • Hemorrhagic shock
  • Distributive shock

Fluid	Na+ (mEq/L)	Cl- (mEq/L)	K+ (mEq/L)	Intravascular Volume Expansion
0.9% Sodium Chloride	154	154	0	~250-300 mL
Lactated Ringers	130	109	4	~250-300 mL
Plasma-Lyte	140	98	5	~250-300 mL
5% Albumin	130-160	130-160	0-4	~500-600 mL
25% Albumin	130-160	130-160	0-4	~800-1000 mL
Dextrose 5%	0	0	0	~100-200 mL

• Barlow A, Barlow B, Tang N, Shah BM, King AE. Intravenous Fluid Management in Critically Ill Adults: A Review. Crit Care Nurse. 2020 Dec 1;40(6):e17-e27.
• 25% Albumin, being a concentrated colloid solution, provides significantly higher intravascular volume expansion compared to other fluids listed, especially when 1 liter is administered.
• The values for intravascular volume expansion are approximate and can vary based on patient-specific factors and clinical context.

It’s important to note that 25% Albumin is often used in smaller volumes due to its concentration, and its effects can be more potent than less concentrated solutions. Always consider patient-specific needs and clinical indications when choosing and administering these fluids.

References

Li, Geng., Xiaoxue, Tian., Z, W, Gao., Aiqin, Mao., Lei, Feng., Chao, He. (2023). Different Concentrations of Albumin Versus Crystalloid in Patients with Sepsis and Septic Shock: A Meta-Analysis of Randomized Clinical Trials.. Journal of Intensive Care Medicine,  doi: 10.1177/08850666231170778

Barlow A, Barlow B, Tang N, Shah BM, King AE. Intravenous Fluid Management in Critically Ill Adults: A Review. Crit Care Nurse. 2020 Dec 1;40(6):e17-e27. doi: 10.4037/ccn2020337. PMID: 33257968.

Franziska Schabinski et al. “Effects of a predominantly hydroxyethyl starch (HES)-based and a predominantly non HES-based fluid therapy on renal function in surgical ICU patients.” Intensive Care Medicine, 35 (2009): 1539-1547. https://doi.org/10.1007/s00134-009-1509-1.

M. Lissauer et al. “Association of 6% hetastarch resuscitation with adverse outcomes in critically ill trauma patients..” American journal of surgery, 202 1 (2011): 53-8 . https://doi.org/10.1016/j.amjsurg.2010.05.002.

L. Simon et al. “Rossi’s Principles of Transfusion Medicine.” (2002). https://doi.org/10.1002/9781119013020.

Theusinger OM, Madjdpour C, Spahn DR. Resuscitation and transfusion management in trauma patients: emerging concepts. Curr Opin Crit Care. 2012 Dec;18(6):661-70. doi: 10.1097/MCC.0b013e328357b209. Erratum in: Curr Opin Crit Care. 2013 Fab;19(1):74. PMID: 22914428.

Vasoactive Agents: Vasopressors and Inotropes

Norepinephrine

Norepinephrine, a key agent in managing hypotension that does not respond to fluid therapy, is a first-line vasopressor and a powerful adjunct in managing critically ill patients. It is crucial for the interprofessional team to be well-versed in the pharmacokinetics and pharmacodynamics, indications, and potential adverse effects of norepinephrine.

Classification and Mechanisms of Action

• Norepinephrine is classified as a sympathomimetic drug, primarily acting as an alpha-adrenergic receptor agonist, with some beta-adrenergic effects. It causes vasoconstriction, thereby increasing blood pressure and improving perfusion to vital organs.

Indications for Use in Different Shock Scenarios

• Norepinephrine is primarily indicated for treating hypotension and shock that is unresponsive to fluid resuscitation. It is especially effective in septic shock but is also used in other forms of shock, like cardiogenic and anaphylactic shock, where blood pressure support is necessary.

Pharmacodynamics and Pharmacokinetics

• Norepinephrine’s onset of action is typically rapid, occurring within a minute of intravenous administration. Its half-life is very short, approximately 2 to 3 minutes, due to rapid uptake and metabolism by both neuronal and extraneuronal tissues. The duration of its effects, however, can vary depending on the dose and individual patient response but generally lasts as long as the infusion is maintained.

Safety and Adverse Effects

• While norepinephrine is crucial in managing life-threatening hypotension, it must be used cautiously due to its potential adverse effects. These include arrhythmias, decreased renal perfusion, and tissue necrosis at the site of infusion if extravasation occurs. Continuous monitoring of blood pressure and titration of the drug to the desired response is necessary to minimize these risks.

Dosage and Administration

• The dosage of norepinephrine varies greatly depending on the clinical situation. It is administered as a continuous intravenous infusion, with the initial dose typically ranging from 8 to 12 mcg/minute, which is then titrated to the desired response. The maintenance dose generally lies between 2 to 4 mcg/minute. In cases of extravasation, immediate action, including administration of phentolamine, is recommended to mitigate local ischemic damage.

Norepinephrine Literature:

1. Muhammad Azfar bin Ruslan et al. (2021, Western Journal of Emergency Medicine): This systematic review and meta-analysis evaluated the effectiveness and safety of norepinephrine in septic shock patients. While norepinephrine was found to be superior in reducing the incidence of arrhythmia, the evidence was insufficient to confirm its superiority in reducing mortality and achieving the target mean arterial pressure (MAP).
2. Barry Burstein et al. (2021, Shock): This study examined the outcomes associated with norepinephrine use among Cardiac Intensive Care Unit (CICU) patients with severe shock requiring high-dose vasopressors. The study found that the use of norepinephrine was associated with lower mortality in these patients, suggesting a benefit in preferentially using norepinephrine for patients with more severe shock.
3. Soo Jin Na et al. (2022, PLOS ONE): This study found that using norepinephrine as a first-line vasopressor in cardiogenic shock did not reduce in-hospital mortality or arrhythmia incidence. However, it did reduce the need for additional vasopressors. The study compared the effectiveness of norepinephrine to dopamine in cardiogenic shock.
4. Xin Lu et al. (2022, Esc Heart Failure): This research explored the relationship between norepinephrine use and outcomes in cardiogenic shock patients under real-world conditions. The study found no association between norepinephrine use and improved survival, highlighting the need for further research on its effectiveness in clinical practice.
5. Gustavo A. Ospina-Tascón et al. (2023, Critical Care Medicine): The study investigated the effects of immediate norepinephrine administration versus initial fluid loading in endotoxic shock. Results showed that immediate norepinephrine administration improved regional and intestinal microcirculatory flows, required less resuscitation fluids, and lower vasopressor doses.
6. F. Xu et al. (2022, American Journal of Emergency Medicine): This study focused on the impact of early norepinephrine initiation in septic shock patients. Findings indicated that early initiation was associated with lower 28-day mortality, longer survival, shorter duration of supportive norepinephrine use, invasive mechanical ventilation, and potential delay or reversal of organ failure.

References

• Smith MD, Maani CV. Norepinephrine. 2023 May 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 30725944.
• Soo, Jin, Na.et al. “Dopamine versus norepinephrine as the first-line vasopressor in the treatment of cardiogenic shock.” PLoS One. 2022 Nov 3;17(11):e0277087.
• Xin, Lu., Xue, et al. “Norepinephrine use in cardiogenic shock patients is associated with increased 30 day mortality.” ESC Heart Fail. 2022 Jun;9(3):1875-1883
• Gustavo, A et al. Immediate Norepinephrine in Endotoxic Shock: Effects on Regional and Microcirculatory Flow. Crit Care Med. 2023 Aug 1;51(8):e157-e168.
• Xu F, Zhong R, Shi S, Zeng Y, Tang Z. Early initiation of norepinephrine in patients with septic shock: A propensity score-based analysis. Am J Emerg Med. 2022 Apr;54:287-296. doi: 10.1016/j.ajem.2022.01.063. Epub 2022 Feb 3. PMID: 35227959.
• Vedrenne-Cloquet M, et al. Low Dosing Norepinephrine Effects on Cerebral Oxygenation and Perfusion During Pediatric Shock. Front Pediatr. 2022 Jul 6;10:898444. doi: 10.3389/fped.2022.898444. PMID: 35874564; PMCID: PMC9298794.
• Burstein B, Vallabhajosyula S, Ternus B, Murphree D, Barsness GW, Kashani K, Jentzer JC. Outcomes Associated With Norepinephrine Use Among Cardiac Intensive Care Unit Patients with Severe Shock. Shock. 2021 Oct 1;56(4):522-528.

Detailed Overview of Individual Agents

• Vasopressors (e.g., Norepinephrine, Epinephrine, phenylephrine, dopamine, Vasopressin)
  • Classification and Mechanisms of Action
  • Indications for Use in Different Shock Scenarios
  • Pharmacodynamics and Pharmacokinetics
  • Safety and Adverse Effect
• Inotropes (e.g., Dobutamine, Milrinone)
  • Classification and Mechanisms of Action
  • Indications for Use in Different Shock Scenarios
  • Pharmacodynamics and Pharmacokinetics
  • Safety and Adverse Effect
• Angiotension II, Methylene blue, hydroxycobalamin
  • Classification and Mechanisms of Action
  • Dosing considerations
  • Indications for Use in Different Shock Scenarios
  • Pharmacodynamics and Pharmacokinetics
  • Safety and Adverse Effect

Epinephrine

Classification and Mechanisms of Action

• Epinephrine, also known as adrenaline, is a catecholamine with potent α-, β1-, and β2-adrenergic receptor activity. Its primary mechanisms involve α1-induced vasoconstriction, which increases systemic vascular resistance, and β1 receptor activity, which enhances heart rate and myocardial contractility. The β2 effects promote bronchodilation and contribute to vasodilation in certain vascular beds.

Indications for Use in Different Shock Scenarios

• Epinephrine is indicated in several shock scenarios, including anaphylactic, cardiogenic, and certain forms of septic shock. While it’s a cornerstone in the management of anaphylaxis, its use in cardiogenic shock is more nuanced due to concerns about increased myocardial oxygen demand. In septic shock, it may be employed when norepinephrine is insufficient, particularly if additional inotropic support is required.

Dosage and Administration

• Low-Dose Epinephrine:
  • Dosage Range: Typically starts at 0.01-0.05 μg/kg/min. This dosing predominantly stimulates β-adrenergic receptors, increasing cardiac output and heart rate with less pronounced vasoconstriction.
• Moderate-Dose Epinephrine:
  • Dosage Range: Can range from 0.05 to 0.1 μg/kg/min. This dosing begins to exert more significant α-adrenergic effects, leading to increased systemic vascular resistance and mean arterial pressure.
• High-Dose Epinephrine:
  • Dosage Range: Can range from 0.1 to 0.5 μg/kg/min and may be increased as needed based on clinical response. At these higher dosages, the α-adrenergic effects predominate, causing significant vasoconstriction.

Pharmacodynamics and Pharmacokinetics

• Epinephrine acts quickly upon administration, with effects seen almost immediately <1 min and duration lasting 2-10 minutes. It has a very short half-life, typically ranging from 2 to 3 minutes. It is rapidly inactivated by widespread enzymes, mainly monoamine oxidase (MAO) The pharmacokinetics of epinephrine is complex, as it undergoes rapid inactivation by monoamine oxidases and catechol-O-methyltransferase. This results in a very short half-life, necessitating continuous infusion for sustained effects.

Safety and Adverse Effects

• Epinephrine’s adverse effects are dose-dependent and can include tachyarrhythmias, myocardial ischemia due to increased oxygen demand, and hyperlactatemia. The latter is not necessarily a sign of poor tissue perfusion but rather an epinephrine-induced shift in metabolism. Caution is advised due to potential for exacerbating myocardial ischemia, particularly in cardiogenic shock following a myocardial infarction.

Epinephrine Literature:

1. The CAT study demonstrated that epinephrine may lead to transient metabolic disturbances without significantly impacting mortality or time to achieve MAP goals compared to norepinephrine.

2. In cardiogenic shock post-AMI, epinephrine may cause detrimental effects on myocardial oxygen consumption and lactate levels, raising concerns about its use in these patients.

3. A combination of norepinephrine and dobutamine was found to be more effective and safer than epinephrine alone in non-AMI cardiogenic shock scenarios.

4. In septic shock with low cardiac output, the decision between norepinephrine (with or without dobutamine) and epinephrine should be tailored to the patient’s hemodynamic profile and underlying pathophysiology.

References:

• Myburgh JA, et al. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. The Lancet. 2007;370(9588):676-684. DOI:10.1016/S0140-6736(07)61344-0.
• Annane D, et al. Epinephrine and norepinephrine in cardiogenic shock. Critical Care Medicine. 2021; DOI:10.1097/CCM.0000000000004745.
• Levy B, Clere-Jehl R, Legras A, Morichau-Beauchant T, Leone M, Frederique G, Quenot JP, Kimmoun A, Cariou A, Lassus J, Harjola VP, Meziani F, Louis G, Rossignol P, Duarte K, Girerd N, Mebazaa A, Vignon P; Collaborators. Epinephrine Versus Norepinephrine for Cardiogenic Shock After Acute Myocardial Infarction. J Am Coll Cardiol. 2018 Jul 10;72(2):173-182.
• Levy B, Perez P, Perny J, Thivilier C, Gerard A. Comparison of norepinephrine-dobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock. A prospective, randomized pilot study. Crit Care Med. 2011 Mar;39(3):450-5
• Annane D, Vignon P, Renault A, Bollaert PE, Charpentier C, Martin C, Troché G, Ricard JD, Nitenberg G, Papazian L, Azoulay E, Bellissant E; CATS Study Group. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet. 2007 Aug 25;370(9588):676-84.

Dopamine

Dopamine is a catecholamine that acts on alpha-1, beta-1, and dopaminergic receptors. It has variable effects on blood pressure, cardiac output, and organ perfusion depending on the dose and the underlying pathophysiology. At low doses (0.5-2 mcg/kg/min), dopamine stimulates mainly dopaminergic receptors, causing renal and mesenteric vasodilation and increased urine output. At moderate doses (2-10 mcg/kg/min), dopamine also activates beta-1 receptors, resulting in positive inotropic and chronotropic effects on the heart. At high doses (>10 mcg/kg/min), dopamine stimulates alpha-1 receptors, producing vasoconstriction and increased systemic vascular resistance.

Dopamine is sometimes used as a first-line agent for patients with hypotension and low cardiac output due to cardiogenic shock, especially if they have signs of low systemic vascular resistance or oliguria. However, dopamine has several drawbacks that limit its usefulness and safety. Dopamine can cause tachyarrhythmias, myocardial ischemia, and increased myocardial oxygen demand. Dopamine may also increase mortality in patients with cardiogenic shock compared to norepinephrine, according to a recent meta-analysis. Moreover, dopamine has no proven benefit over norepinephrine for improving renal function or survival in patients with septic shock.

Classification and Mechanisms of Action

Dopamine, a natural precursor to norepinephrine and epinephrine, is an endogenous catecholamine with diverse receptor activity, including dopaminergic receptor types 1 and 2, α-1 and β-1 adrenergic receptors, and in some studies, type 4 dopaminergic receptors. Its dose-dependent hemodynamic effects are attributable to the varied receptor affinities, leading to increased cardiac output (CO) and systemic vascular resistance (SVR) through different mechanisms at varying dosages.

Dosage and Administration

• Low-Dose Dopamine (0.5-2 µg/kg/min): Typically results in vasodilation via dopaminergic receptors and may increase renal blood flow and diuresis, though clinical benefits in renal outcomes are debatable.
• Intermediate-Dose Dopamine (2-10 µg/kg/min): Stimulates β-1 adrenergic receptors, increasing contractility and heart rate, potentially benefiting CO and stroke volume.
• High-Dose Dopamine (10-20 µg/kg/min): Predominantly activates α-1 adrenergic receptors, leading to vasoconstriction and a subsequent increase in SVR and mean arterial pressure (MAP).

Pharmacodynamics and Pharmacokinetics

Dopamine’s onset of action is rapid, typically within 5 minutes of administration, with a short half-life of approximately 2 minutes, necessitating continuous infusion to maintain therapeutic levels. Its effects, including changes in MAP, CO, and SVR, are dose-dependent and can result in either decreases or increases in MAP, largely influenced by the variable systemic vascular resistance.

Safety and Adverse Effects

Adverse effects associated with dopamine are also dose-dependent, with low doses potentially causing hypotension due to vasodilation and high doses leading to tachyarrhythmias due to increased cardiac workload. Concerns regarding the use of dopamine in shock scenarios have arisen due to its association with increased mortality and arrhythmias in certain patient populations, as highlighted by the SOAP II trial.

Dopamine Literature

1. Historical use of dopamine has seen a decline after studies such as the SOAP II trial demonstrated increased arrhythmias and no mortality benefit in septic shock.
2. Dopamine’s role in renal protection is contested, with studies showing no significant improvement in renal support requirements or outcomes.
3. The Surviving Sepsis Campaign and other bodies recommend against dopamine as a first-line vasopressor in shock, favoring norepinephrine or epinephrine based on various studies and guidelines.

Reference

• Hollenberg SM. Vasopressor support in septic shock. Chest. 2007 Nov;132(5):1678-87. doi: 10.1378/chest.07-0291. 
• Sonne J, Goyal A, Lopez-Ojeda W. Dopamine. [Updated 2023 Jul 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK535451/
• De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, Brasseur A, Defrance P, Gottignies P, Vincent JL., SOAP II Investigators. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010 Mar 04;362(9):779-89.
• Bhatt-Mehta V, Nahata MC. Dopamine and dobutamine in pediatric therapy. Pharmacotherapy. 1989;9(5):303-14. [PubMed]
• Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet. 2000 Dec 23-30;356(9248):2139-43.
• Ponikowski P et al.  2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016 Jul 14;37(27):2129-2200. 
• Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637.

Phenylephrine

Classification and Mechanisms of Action

Phenylephrine is a selective α1-adrenergic receptor agonist known for increasing blood pressure primarily through vasoconstriction. It has limited β-adrenergic activity, which makes it a therapeutic option for hypotensive patients who may experience tachyarrhythmias with β-agonists. In certain cases, phenylephrine may also increase cardiac output (CO) and contractility.

Pharmacodynamics and Pharmacokinetics

The action of phenylephrine on α1 receptors results in a dose-related increase in systemic vascular resistance (SVR) and mean arterial pressure (MAP), enhancing venous return to the heart. This can lead to an increase in global tissue oxygen use in septic shock, although it may redistribute blood flow from splanchnic circulation and affect lactate uptake rates. The pharmacokinetics involve a rapid onset and short duration of action due to its metabolism by monoamine oxidase (MAO) enzymes.

Safety and Adverse Effects

Phenylephrine’s safety profile includes concerns about decreased splanchnic perfusion and an increase in arterial lactate concentrations. However, data suggest that these effects may not be as pronounced as once thought, and in certain scenarios, such as high-cardiac output septic shock or aortic stenosis, phenylephrine may be preferred due to its limited effect on heart rate and myocardial oxygen demand.

Dosage and Administration

• Weight-Based Dosing: Phenylephrine dosing may start at 0.5 to 9 µg/kg/min, titrated to patient response. Considerations for individual hemodynamics and end-organ perfusion are crucial for determining the appropriate dosing range.
• Non–Weight-Based Dosing (based on ~80 kg patient):
  • Continuous Infusion: IV: Initial dose: 40 to 160 mcg/minute; titrate to desired MAP; usual dosage range: 20 to 400 mcg/minute. It is important to adjust the dose based on clinical response and blood pressure goals. Doses up to ~730 mcg/minute have been reported in the literature, although such high doses are less common and typically reserved for refractory cases where other vasoactive medications might be insufficient or contraindicated.

When administering phenylephrine, close monitoring of blood pressure, heart rate, and signs of organ perfusion is necessary. Adjustments to the infusion rate should be made cautiously, considering the potential for rapid changes in vascular tone and blood pressure.

Clinical Literature

• Retrospective studies and randomized controlled trials (RCTs) have examined phenylephrine’s role in various shock states, including septic and cardiogenic shock. The literature has produced mixed results regarding phenylephrine’s impact on mortality and renal outcomes.
• The Surviving Sepsis Campaign guidelines have shifted away from recommending phenylephrine as a first-line vasopressor, reflecting evolving evidence and expert opinion.
• In patients with septic shock and concurrent atrial fibrillation, studies have investigated the role of phenylephrine as a potential alternative to norepinephrine, with considerations for its influence on heart rate control and ventricular function.

References

• Lexi-Comp. Phenylephrine: Drug information. In: Lexi-Drugs [database on the Internet]. Hudson (OH): Lexicomp, Inc.; [updated 2023 Jan 1; cited 2024 Jan 19].
• Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637.
• Haiduc M, Radparvar S, Aitken SL, Altshuler J. Does Switching Norepinephrine to Phenylephrine in Septic Shock Complicated by Atrial Fibrillation With Rapid Ventricular Response Improve Time to Rate Control? J Intensive Care Med. 2021 Feb;36(2):191-196
• Law AC, Bosch NA, Peterson D, Walkey AJ. Comparison of Heart Rate After Phenylephrine vs Norepinephrine Initiation in Patients With Septic Shock and Atrial Fibrillation. Chest. 2022 Oct;162(4):796-803
• Richards E, Lopez MJ, Maani CV. Phenylephrine. [Updated 2023 Oct 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK534801/

Dobutamine

Classification and Mechanisms of Action

Dobutamine is a synthetic catecholamine with strong β1-adrenergic receptor agonist activity and mild β2 and α1 effects. It primarily exerts its pharmacologic effects by stimulating β1 receptors in the heart, leading to increased myocardial contractility and stroke volume, which results in enhanced cardiac output without a substantial increase in heart rate.

Pharmacodynamics and Pharmacokinetics

Dobutamine’s inotropic effect is dose-dependent, with a rapid onset of action within 1 to 2 minutes after initiation of the infusion, peaking in 10 to 20 minutes. Its elimination half-life is short, typically less than 2 minutes in healthy individuals, necessitating continuous infusion to maintain therapeutic effects. Metabolism occurs primarily through catechol-O-methyltransferase (COMT) in the liver and other tissues.

Safety and Adverse Effects

Dobutamine is generally well-tolerated when used within the therapeutic dosage range. However, it can increase myocardial oxygen consumption, which may be problematic in patients with ischemic heart disease. Other potential adverse effects include tachyarrhythmias, increased blood pressure, and, rarely, development of tolerance with prolonged use.

Dosage and Administration

Dobutamine is administered as a continuous intravenous infusion. The starting dose is typically 2.5 to 10 mcg/kg/min, which can be titrated based on clinical response and hemodynamic measurements. The maximum recommended dose is usually 20 mcg/kg/min, although higher doses have been used in acute care settings.

• Impact on Systemic Vascular Resistance (SVR) and Heart Rate:
  • Dobutamine has a vasodilatory effect due to its mild β2-adrenergic receptor activity, which can lead to a decrease in SVR.
  • At lower doses, the β2 effect of dobutamine might contribute more significantly to decreased SVR, improving cardiac output through reduced afterload.
  • The impact on HR is dose-dependent, with higher doses more likely to cause an increase in HR.

Clinical Literature

• Hollenberg SM, et al.
  • This study evaluated the vasoactive properties of dobutamine in circulatory shock. The findings indicated that dobutamine effectively increased cardiac output primarily through β1-adrenergic receptor stimulation, with minimal changes in SVR and HR. It emphasized the importance of dobutamine in managing cardiogenic shock, especially when preserving heart rate is clinically important​
• Metra M, et al.
  • The study aimed to assess how chronic beta-blocker therapy with metoprolol or carvedilol affects the hemodynamic response to the inotropic agents dobutamine and enoximone in patients with chronic heart failure (HF). The hemodynamic effects of these agents were measured by pulmonary artery catheterization in 29 patients, both before and after 9 to 12 months of beta-blocker treatment. The results showed that metoprolol slightly decreased the decline in mean pulmonary artery pressure (PAP) and pulmonary wedge pressure (PWP) during dobutamine infusion but enhanced the response to enoximone. Carvedilol, however, significantly inhibited the increase in heart rate, stroke volume index (SVI), and cardiac index (CI) that is typically seen with dobutamine, even causing an increase in PAP, PWP, and vascular resistances. The response to enoximone was either maintained or enhanced with carvedilol. These findings suggest that the hemodynamic benefits of dobutamine are attenuated in patients treated with carvedilol, highlighting the need for careful selection and monitoring of inotropic therapy in HF patients on beta-blockers​
• Lowes BD, et al
  • The objective was to compare the effects of milrinone and dobutamine on patients with decompensated heart failure who were also undergoing chronic treatment with carvedilol, a beta-blocker. Twenty patients were prospectively enrolled, and their inotropic responses to both drugs were evaluated via right-heart catheterization. Milrinone was observed to significantly increase cardiac index without notably changing heart rate, and it also reduced mean pulmonary artery pressure, pulmonary capillary wedge pressure, and mean arterial blood pressure, with an increase in left ventricular stroke volume index. In contrast, dobutamine only increased the cardiac index at higher infusion rates (15-20 µg/kg/min), which are not typically used in heart failure management due to associated increases in heart rate, mean systemic pressure, and mean pulmonary artery pressure, without affecting the left ventricular stroke volume index or pulmonary capillary wedge pressure. The study concluded that milrinone and dobutamine exhibit distinct hemodynamic profiles in patients treated with carvedilol, information that is critical when choosing inotropic therapy for heart failure management.

References

• Hollenberg SM. Vasoactive drugs in circulatory shock. Am J Respir Crit Care Med. 2011 Apr 1;183(7):847-55.
• Ruffolo RR Jr. The pharmacology of dobutamine. Am J Med Sci. 1987 Oct;294(4):244-8.
• Uhlig K, Efremov L, Tongers J, Frantz S, Mikolajczyk R, Sedding D, Schumann J. Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome. Cochrane Database Syst Rev. 2020 Nov 5;11(11):CD009669
• Metra M, Nodari S, D’Aloia A, Muneretto C, Robertson AD, Bristow MR, Dei Cas L. Beta-blocker therapy influences the hemodynamic response to inotropic agents in patients with heart failure: a randomized comparison of dobutamine and enoximone before and after chronic treatment with metoprolol or carvedilol. J Am Coll Cardiol. 2002 Oct 2;40(7):1248-58.
• Lowes BD, Tsvetkova T, Eichhorn EJ, Gilbert EM, Bristow MR. Milrinone versus dobutamine in heart failure subjects treated chronically with carvedilol. Int J Cardiol. 2001 Dec;81(2-3):141-9. doi: 10.1016/s0167-5273(01)00520-4. PMID: 11744130.

Isoproterenol

Classification and Mechanisms of Action

• Isoproterenol is a nonselective beta-adrenergic agonist that exerts its effects on both beta-1 (β1) and beta-2 (β2) receptors. Activation of these receptors initiates a cascade via adenylate cyclase, which converts adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP), a second messenger that enhances heart rate (HR) and myocardial contractility. The β2-adrenergic receptor activation also leads to peripheral vasodilation and relaxation of bronchial, gastrointestinal, and uterine smooth muscle.

Pharmacodynamics and Pharmacokinetics

• The hemodynamic effects of isoproterenol, such as increased HR and myocardial contractility, are immediate due to its rapid onset of action when administered intravenously. The duration of these effects lasts approximately 10-15 minutes. Isoproterenol is metabolized via conjugation in various tissues, including hepatic and pulmonary systems, and has an elimination half-life of 2.5 to 5 minutes. The drug and its metabolites are primarily excreted in the urine as sulfate conjugates.

Safety and Adverse Effects

• The use of isoproterenol can lead to tachyarrhythmias due to its positive chronotropic effect. Other potential adverse effects include palpitations, headache, and tremor. Due to its vasodilatory effects, isoproterenol can decrease SVR, which may require careful monitoring and dose adjustment, particularly in patients with ischemic heart conditions.

Dosage and Administration

• Isoproterenol is typically administered intravenously with an initial infusion rate of 0.5 to 5 µg/min. For heart block, a bolus followed by an infusion is recommended, with the bolus dosing ranging from 0.02 to 0.06 mg, followed by an infusion at 5 µg/min.
  

Clinical Literature

• Mueller et al
  • Key findings from the study include:
    • Isopreterenol led to a 63% increase in cardiac index and a 26% increase in heart rate. However, while coronary blood flow increased by an average of 12 ml/100 g/min, myocardial oxygenation deteriorated, as evidenced by increased lactate production. This suggests that isoproterenol might not be beneficial in coronary shock due to its adverse impact on myocardial oxygenation.
  • Kriwisky et al.
    • Case report of haloperidol induced torsade de pointes that was successfully treated with an intravenous infusion of isoproterenol

References

• 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., American Heart Association Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Quality of Care and Outcomes Research; and Mission: Lifeline. Contemporary Management of Cardiogenic Shock: A Scientific Statement From the American Heart Association. Circulation. 2017 Oct 17;136(16):e232-e268.
• Szymanski MW, Singh DP. Isoproterenol. [Updated 2023 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK526042
• Hollenberg SM. Vasoactive drugs in circulatory shock. Am J Respir Crit Care Med. 2011 Apr 1;183(7):847-55.
• Kislitsina ON, Rich JD, Wilcox JE, Pham DT, Churyla A, Vorovich EB, Ghafourian K, Yancy CW. Shock – Classification and Pathophysiological Principles of Therapeutics. Curr Cardiol Rev. 2019;15(2):102-113
• Puri PS. Modification of experimental myocardial infarct size by cardiac drugs. Am J Cardiol. 1974 Apr;33(4):521-8. doi: 10.1016/0002-9149(74)90612-2. PMID: 4818050.
• H. Mueller, S. Ayres, S. Giannelli, E. F. Conklin, J. Mazzara and W. Grace. “Effect of Isoproterenol, l‐Norepinephrine, and Intraaortic Counterpulsation on Hemodynamics and Myocardial Metabolism in Shock following Acute Myocardial Infarction.” Circulation, 45 (1972): 335–351. https://doi.org/10.1161/01.CIR.45.2.335.
• W. H. Wilson and S. Weiler. “Case report of phenothiazine-induced torsade de pointes..” The American journal of psychiatry, 141 10 (1984): 1265-6 . https://doi.org/10.1176/AJP.141.10.1265.

Vasopressin

Classification and Mechanisms of Action

• Vasopressin, also known as antidiuretic hormone (ADH), is an endogenously produced peptide hormone that acts primarily on V1a, V1b, and V2 receptors. In terms of hemodynamics, vasopressin increases mean arterial pressure (MAP) by enhancing systemic vascular resistance (SVR) through V1a-mediated vasoconstriction, particularly in skin, soft tissue, and the splanchnic vascular bed. V2 receptors in the renal distal tubules and collecting ducts facilitate water reabsorption, contributing to its role in fluid homeostasis.

Pharmacodynamics and Pharmacokinetics

• Vasopressin exhibits a rapid onset of action with intravenous administration infusion starting within 15 minutes. The duration of action being dose-dependent but traditionally last 20 minutes post discontinue of infusion. Metabolism occurs via conjugation in various tissues, and the drug is excreted in the urine primarily as sulfate conjugates.

Safety and Adverse Effects

• The use of vasopressin can be associated with adverse effects such as reflex bradycardia due to increased SVR, and excessive vasoconstriction may lead to compromised organ perfusion, particularly in the coronary and mesenteric circulation. Caution is warranted in patients with impaired cardiac function due to the potential for increased myocardial oxygen demand.

Dosage and Administration

• For management of vasodilatory shock, vasopressin is typically initiated at a continuous infusion fixed rate of 0.03 to 0.04 units/min with some studies allowing titration from 0.01 to 0.06 unit/min for shock. It may be used as a component of combination therapy with catecholamines to reduce the dose of catecholamines required. Dosage adjustments are based on blood pressure response and tissue perfusion.

Clinical Literature

• VASST Trial (Vasopressin vs. Norepinephrine in Septic Shock Study):

• A pivotal trial that evaluated the role of vasopressin in septic shock management.
• Randomized comparison between vasopressin and norepinephrine as primary vasopressors.
• Noted that while there were no significant differences in 28-day mortality rates between the two groups, an interesting finding was that patients with less severe septic shock (norepinephrine dose < 15 mcg/min) had improved survival rates when treated with vasopressin.
  • In post hoc analysis, patient who received combination of vasopressin and steroids had a statistically significant reduction in 28-day mortality.
• Highlighted the importance of considering patient subgroups and therapy combinations.

VANISH Trial (Vasopressin vs. Norepinephrine as Initial Therapy in Septic Shock):

• Followed up on the VASST trial, incorporating the assessment of corticosteroid use alongside vasopressin and norepinephrine administration.
• The trial found no statistically significant differences in 28-day mortality but did note a potential renal advantage for vasopressin use.
• Did not observe the possible synergistic effect between corticosteroids and vasopressin that was suggested by the VASST trial.

References

• Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, Pogson DG, Aya HD, Anjum A, Frazier GJ, Santhakumaran S, Ashby D, Brett SJ; VANISH Investigators. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA. 2016 Aug 2;316(5):509-18.
• Russell JA, Walley KR, Gordon AC, Cooper DJ, Hébert PC, Singer J, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ; Dieter Ayers for the Vasopressin and Septic Shock Trial Investigators. Interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock. Crit Care Med. 2009 Mar;37(3):811-8. doi: 10.1097/CCM.0b013e3181961ace. PMID: 19237882.
• Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877-87. 
• Hollenberg SM. Vasopressor support in septic shock. Chest. 2007 Nov;132(5):1678-87. doi: 10.1378/chest.07-0291. 
• Holmes CL, Patel BM, Russell JA, Walley KR. Physiology of vasopressin relevant to management of septic shock. Chest. 2001 Sep;120(3):989-1002. doi: 10.1378/chest.120.3.989. PMID: 11555538.
• “Vasopressin Injection, USP.” FDA.gov, U.S. Food and Drug Administration, 2023.
• Vail EA, Gershengorn HB, Hua M, Walkey AJ, Wunsch H. Epidemiology of Vasopressin Use for Adults with Septic Shock. Ann Am Thorac Soc. 2016 Oct;13(10):1760-1767.

Milrinone

Classification and Mechanisms of Action

Milrinone is classified as a phosphodiesterase 3 (PDE3) inhibitor with inotropic and vasodilatory properties. Its mechanism of action involves the inhibition of PDE3, an enzyme that breaks down cyclic adenosine monophosphate (cAMP) within cardiac and vascular smooth muscle cells. By preventing the degradation of cAMP, milrinone increases intracellular cAMP, which enhances calcium influx into the myocardial cells, thus increasing contractility (positive inotropy). Additionally, elevated cAMP levels lead to vasodilation in the systemic and pulmonary vascular beds.

Pharmacodynamics and Pharmacokinetics

Milrinone leads to an immediate increase in cardiac output by improving myocardial contractility and reducing afterload due to vasodilation. It has a relatively quick onset of action, with effects noticeable within minutes after administration, and a moderate duration of action, typically lasting for several hours. Milrinone is predominantly eliminated by renal excretion, which necessitates dose adjustments in patients with renal impairment to avoid toxicity.

Safety and Adverse Effects

While milrinone is effective in increasing cardiac output, it may also lead to hypotension due to its vasodilatory effects. Other adverse effects can include arrhythmias, headache, and hypokalemia. Its use in chronic heart failure has been associated with an increased risk of hospitalization and mortality, so its use is generally limited to acute decompensated heart failure or perioperative settings.

Dosage and Administration

Milrinone is typically administered as a continuous intravenous infusion. The recommended starting dose is 0.25 µg/kg/min, which may be titrated based on clinical response and tolerance. A loading dose is not always necessary and should be used with caution to avoid hypotension and other adverse effects.

Clinical Literature

• Lowes BD, et al
  • The objective was to compare the effects of milrinone and dobutamine on patients with decompensated heart failure who were also undergoing chronic treatment with carvedilol, a beta-blocker. Twenty patients were prospectively enrolled, and their inotropic responses to both drugs were evaluated via right-heart catheterization. Milrinone was observed to significantly increase cardiac index without notably changing heart rate, and it also reduced mean pulmonary artery pressure, pulmonary capillary wedge pressure, and mean arterial blood pressure, with an increase in left ventricular stroke volume index. In contrast, dobutamine only increased the cardiac index at higher infusion rates (15-20 µg/kg/min), which are not typically used in heart failure management due to associated increases in heart rate, mean systemic pressure, and mean pulmonary artery pressure, without affecting the left ventricular stroke volume index or pulmonary capillary wedge pressure. The study concluded that milrinone and dobutamine exhibit distinct hemodynamic profiles in patients treated with carvedilol, information that is critical when choosing inotropic therapy for heart failure management.
• PROMISE Trial (Prospective Randomised Milrinone Survival Evaluation):
  • Aimed to determine the long-term impact of milrinone on survival in chronic heart failure patients.
  • Randomized 1088 patients to receive either oral milrinone or placebo for six months.
  • Found that milrinone use was associated with a significant increase in all-cause mortality (28% increase) and cardiovascular mortality (38% increase), especially in patients with Class IV heart failure.
  • There was also an increase in hospitalizations and adverse events like hypotension and syncope.
  • These results have limited the use of oral milrinone in clinical practice due to its association with increased mortality and morbidity.
• OPTIME-CHF Trial (Outcomes of Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure):
  • Assessed the efficacy of milrinone in patients with systolic heart failure exacerbations not in cardiogenic shock.
  • 951 patients were randomized to receive milrinone infusion for 48 hours or placebo.
  • The trial reported more frequent hypotension, arrhythmias, and no significant difference in length of stay, inpatient mortality, 60-day mortality, or readmission rates between milrinone and placebo groups.
  • Post hoc analysis indicated that patients with ischemic heart failure etiology experienced worse outcomes when treated with milrinone compared to non-ischemic counterparts.
  • These findings led to recommendations against the routine use of milrinone in chronic heart failure exacerbations due to increased risks, particularly in patients with underlying ischemic heart disease.
• DREMI Trial
  • The DOREMI trial compared the efficacy of milrinone and dobutamine in patients with cardiogenic shock, finding no significant difference in a composite outcome of in-hospital death, cardiac arrest, advanced cardiac therapy, nonfatal myocardial infarction, stroke, or initiation of renal replacement therapy. Among the 192 randomized patients, the primary composite outcome occurred in 49% of those in the milrinone group and 54% in the dobutamine group, indicating similar risks associated with both inotropes. Secondary outcomes also showed no significant differences, suggesting that either drug may be a viable option for inotropic support in cardiogenic shock management.

References

• Hollenberg SM. Vasoactive drugs in circulatory shock. Am J Respir Crit Care Med. 2011 Apr 1;183(7):847-55.
• Lowes BD, Tsvetkova T, Eichhorn EJ, Gilbert EM, Bristow MR. Milrinone versus dobutamine in heart failure subjects treated chronically with carvedilol. Int J Cardiol. 2001 Dec;81(2-3):141-9. doi: 10.1016/s0167-5273(01)00520-4. PMID: 11744130.
• Motwani, S. K., and Saunders, H. (2021). Inotropes. Anaesth. Intensive Care Med. 22 (4), 243–248. 
• Cuffe MS, Califf RM, Adams KF Jr, Benza R, Bourge R, Colucci WS, Massie BM, O’Connor CM, Pina I, Quigg R, Silver MA, Gheorghiade M; Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) Investigators. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002 Mar 27;287(12):1541-7.
• Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML, et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med. 1991 Nov 21;325(21):1468-75. 

Angiotensin 2

Classification and Mechanisms of Action

Angiotensin II is a synthetic version of a naturally occurring peptide hormone within the renin-angiotensin-aldosterone system (RAAS). It works by binding to angiotensin II type 1 receptors on vascular smooth muscle cells causing vasoconstriction, and stimulates aldosterone release, leading to increased blood pressure.

Pharmacodynamics and Pharmacokinetics

• Metabolism: Angiotensin II is metabolized by aminopeptidase A and angiotensin converting enzyme 2 into angiotensin-(2-8) and angiotensin-(1-7), respectively.
• Half-life elimination: Less than 1 minute IV
• Time to peak: Approximately 5 minutes

Safety and Adverse Effects

• Thromboembolic disease (>10%)
• Peripheral ischemia, tachycardia (1-10%)
• Potential for bronchoconstriction; caution in asthma.

Dosage and Administration

• For vasodilatory shock states, initiate with a continuous infusion of 10 to 20 ng/kg/minute IV, titrating by up to 10 to 15 ng/kg/minute every 5 minutes to achieve the target MAP.
• Maximum initial dose: 80 ng/kg/minute for the first 3 hours.
• Maximum maintenance dose: 40 ng/kg/minute.
• No dosage adjustments necessary for kidney or hepatic impairment.

Clinical Literature

ATHOS-3 Trial (Angiotensin II for the Treatment of High Output Shock):

• This pivotal trial evaluated the efficacy of angiotensin II for septic and other distributive shock states and was instrumental in the FDA’s approval of the drug.
• The study included 344 patients who were randomized to receive angiotensin II or placebo if they required more than 0.2 μg/kg/min of norepinephrine-equivalent dose vasopressors.
• The primary endpoint was the mean arterial pressure (MAP) response at hour 3, targeting an increase of at least 10 mmHg or achieving a MAP of 75 mmHg.
• About 70% of the patients responded to angiotensin II, meeting the primary endpoint, while only 23.4% responded to an increase in baseline vasopressor dosage.
• Secondary outcomes indicated no significant differences in all-cause mortality between the treatment groups but highlighted a notable reduction in vasopressor use when angiotensin II was employed.

Wieruszewski et al.

• This retrospective study across five medical centers in the United States assessed the safety and effectiveness of angiotensin II in vasodilatory shock refractory to catecholamine vasopressors.
• Among 270 patients, 67% demonstrated hemodynamic responsiveness to angiotensin II, showing a significant increase in MAP and reduction in vasopressor dosage compared to nonresponders.
• Responders to angiotensin II were more likely to have higher baseline lactate concentrations and concurrent vasopressin administration.
• This study provided further evidence of angiotensin II’s favorable hemodynamic impact, with a lower likelihood of 30-day mortality noted in responders. However, arrhythmias were observed in 28 patients (10%).

Reference

• GIAPREZA (angiotensin II) Injection for Intravenous Infusion. Initial U.S. Approval: 2017 Manufactured for: La Jolla Pharmaceutical Company. San Diego, CA 92121. Revised: 1/2018
• Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, Busse LW, Altaweel L, Albertson TE, Mackey C, McCurdy MT, Boldt DW, Chock S, Young PJ, Krell K, Wunderink RG, Ostermann M, Murugan R, Gong MN, Panwar R, Hästbacka J, Favory R, Venkatesh B, Thompson BT, Bellomo R, Jensen J, Kroll S, Chawla LS, Tidmarsh GF, Deane AM; ATHOS-3 Investigators. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-430.
• Buchtele N, Schwameis M, Jilma B. Angiotensin II for the treatment of vasodilatory shock: enough data to consider angiotensin II safe? Crit Care. 2018 Apr 16;22(1):96.
• Wieruszewski PM, Wittwer ED, Kashani KB, Brown DR, Butler SO, Clark AM, Cooper CJ, Davison DL, Gajic O, Gunnerson KJ, Tendler R, Mara KC, Barreto EF. Angiotensin II Infusion for Shock: A Multicenter Study of Postmarketing Use. Chest. 2021 Feb;159(2):596-605