A hint about inotropes and vasopressors

dr.amr moustafa kamel 1

A hint about vasoactive drugs in the ICU


Important definitions Inotropes: are a group of drugs that increase the myocardial contractility ,

thus increasing the cardiac output (COP) and the systolic blood pressure.

Vasopressors: are a group of drugs that produce widespread vasoconstriction and increasing the peripheral vascular resistance and the diastolic blood pressure through arteriolar vasoconstriction , and increasing the venous return to the heart and thus the (COP) by venular vasoconstriction.

Cardiac output: the volume of blood pumped by one ventricle in one minute. It equals to the stroke volume (SV) X the heart rate.

Stroke volume: it’s the volume of the blood pumped by a single ventricle in each heart beat. It depends on the blood volume return to the heart (preload), the vascular resistance facing it (afterload), and the contractility of the heart.


Mean arterial blood pressure: the average blood pressure present in the arterial tree through out the cardiac cycle. Its calculated by (diastolic pressure+ 1/3 pulse pressure). It’s considered to be the perfusing pressure of the body organs, and it’s widely accepted that it should be maintained above 60 mmHg for adequate organ perfusion and oxygenation.

Circulatory shock: a medical emergency referring to inadequate tissue perfusion. It’s typical signs are hypotension, tachycardia, cold cyanosed peripheries, disturbed conscious level (DCL), Oliguria, metabolic acidosis due to inadequate tissue supply of oxygen increasing anaerobic metabolism and lactic acid levels.

Oliguria: urine output less than 0.5ml/kg/hr in adults and less than 1ml/kg/hr in infants

Mixed venous oxygen saturation (SvO2): the percentage of oxygen present in the venous blood collected from all the body just as it leaves the RT side of the heart and before it enters the lungs. It is normally between 60 – 80 %.


ReceptorsAlpha 1 receptors: present mainly in the smooth muscles of blood

vessels supplying the skin, gastrointestinal tract, urinary system including the renal arteries, and the brain. Activation elevates the ABP but can cause digital and skin gangrene , renal impairment up to renal failure.

Beta 1 receptors: present in the heart where its stimulation causes excitatory effects (increasing heart rate , contractility & excitability), and in the kidney increasing renin release. Activation increases the COP but can cause tachycardia and tachyarrythmias.

Dopamine D1 receptors: present in the renal, splanchnic (mesenteric), coronary, and cerebral vascular beds; stimulation of these receptors leads to vasodilatation & diuresis.


The rational use of vasoactive drugs is guided by fundamental concepts:

1. One drug, many receptors – A given drug often has multiple effects because of actions upon more than one receptor.

2. Vasoactive drugs are not a definitive treatment. They are merely a method to support the MAP and perfusion of vital organs till identifying and managing the cause of the shock state.

3. Dose-response curve – Many agents have dose-response curves, such that the primary receptor subtype activated by the drug is dose-dependent. eg. dopamine stimulates beta-1 receptors at doses of 2 to 10 mcg/kg per minute, and alpha 1 receptors when doses exceed 10 mcg/kg per minute.

4. Direct versus reflex actions – A given agent can affect MAP both by direct actions on adrenergic receptors and by reflex actions triggered by the pharmacologic response. Nor adrenaline acts on beta-1 in the heart to cause tachycardia. However, the elevated MAP from nor epinephrine's alpha 1 receptor-induced vasoconstriction results in a reflex decrease in heart rate. The net result may be a stable or slightly reduced heart rate when the drug is used.


5. Correct diagnosis of the underlying cause of shock - Choice of an initial agent should be based upon the suspected underlying etiology of shock

6. titration , gradual application and gradual withdrawal— The dose should be titrated gradually up to achieve effective blood pressure or end-organ perfusion. If maximal doses of a first agent are inadequate, then a second drug should be added to the first.

7. Correction of acid-base and electrolyte imbalance is crucial for adequate myocardial response to vasoactive drug therapy- hypocalcaemia, acidosis, hyponatremia, hypothermia all have –ve inotropic effect.

8. Volume resuscitation — Repletion of adequate intravascular volume, when time permits, is crucial prior to the initiation of vasopressors. Vasopressors will be ineffective or only partially effective in the setting of coexistent hypovolemia.

9. Continues monitoring - all patients on hemodynamic support should be continuously monitored by invasive blood pressure if possible or NIBP, ECG, pulse oximetry, UOP hourly, CVP /2 hours, random blood sugar /4 hours, and clinically for the level of consciousness and peripheral cyanosis & gangrene.


10. Route of administration — Vasopressors and inotropic agents should be administered through an appropriately positioned central venous catheter. This facilitates more rapid delivery of the agent to the heart for systemic distribution and eliminates the risk of peripheral extravasations.

11. Subcutaneous delivery of medications — Critically ill patients often receive subcutaneously injected medications, such as LMWH and insulin. The bioavailability of these medications can be reduced during treatment with vasopressors due to cutaneous vasoconstriction.

12. Condition of the adrenal gland functions- adrenal insufficiency should be suspected in any critically ill pt. with “vasopressor-resistant hypotension”. Other clues for adrenal insufficiency include failure of weaning from mechanical ventilation, lethargy, hypoglycemia hyponatremia & hyperkalemia. Prompt treatment with 50-100 mg hydrocortisone IV / 8 hours is sufficient to alleviate the condition.

13. Avoid turning & limit mobilization- use other methods to avoid bed sores and pressure ulcers (elevate heels, air mattress)

14. Give by infusion: they are all given through intravenous slow infusion as they all posses a very short half life (minutes).

15. Correction of concurrent anemia: keep hemoglobin levels>10 gm/dl.

Calculation & preparation of vasoactive agents


Calculating the desired dosage to be administered for these drugs presents a great difficulty for most junior staff in the ICU. however these can be simplified by following 2 rules:o for drugs administered in nanograms per kg per minute (ng/kg/min) as

adrenaline, isoprenaline and nor adrenaline use single concentration technique.its done simply by (multiplying 3 x pt’s body weight in kg, then divide the outcome by 100). The value obtained is the number of mg of the drug added to 50 ml D5%W or NS 0.9%, . By this way each 1 ml/hr infusion by the syringe pump equals to 10 ng/kg/min.

3 X BW in kg = number of mg of the drug added to the 50 ml syringe .

100 . e.g. A 65 year old pt. 80 kg, presented to the ICU with hypotension Bp

70/30 mmHg, bradycardia 50 bpm. You decide to put the patient on adrenaline infusion 100 ng/kg/min to support the circulation. How do proceed ?


Multiply 3 x 80 = 240, then divide 240/100 = 2.4 . So 2.4 mg of adrenaline (2.4 ml as in Egypt the ampoule conc. Is 1mg/ml) is added to 50 ml NS .and the syringe is adjusted to infuse 10ml/hr. that is equal to 100 ng/kg/min.

o For drugs infused in microgram/kg/min (µg/kg/min) like dopamine, dobutamine and nitroglycerine, it’s better to use the fixed dose formula. it starts by knowing the required dose of the drug and using it to deduct the infusion rate of the syringe pump.

infusion rate (ml/hr) = desired dose in (µg) x body weight in kg x 60

concentration in the syringe in (µg)

e.g. a 70 yr old, 75 kg pt. DM, HTN, presented to the ICU with sever hypertensive crisis Abp 210/110 mmHg. You decide to put him on nitroglycerine infusion 0.5 µg/kg/min. how do you proceed, knowing that in Egypt nitroglycerine vials are 50 ml with concentration 1mg/ml ?


the volume of the drug in this case is 50 ml, so no need to add it to another 50 ml of NS, just use as it is and simply draw in the 50 ml syringe.using the previous formula: 0.5 x 75 x 60 = 2250. and the concentration in the syringe is 1mg/ml = 1000 µg/ml . Dividing 2250 by 1000 we get 2.25 ml / hr. that is the no. we insert in the syringe pump.

another e.g. a 60 yr old female, DM, HTN, 50 kg BW presented to the ICU for postoperative care after left lower limb amputation due to wet gangrene complicating a sever case of infected diabetic foot. Pt is toxic, lethargic, feverish temp. 38.8°C, tachycardic P=135 Bpm, hypotensive Abp= 85/40 mmHg. You diagnose the pt. with septic shock, and start nor adrenaline infusion at 100 ng/kg/min. after 48 hrs the nurse informs you that the UOP of the pt. dropped from 50 ml/ hr to less than 5 ml/hr. the consultant of the ICU orders gradual withdrawal of the nor adrenaline infusion and introduction of dopamine infusion at a diuretic dose of 3 µg/kg/min. how to prepare both drugs ??


For nor adrenaline infusion 50 x 3 / 100 = 1.5 mg of the drug should be added to 50 ml D5%W. since nor adrenaline ampoules are 4mg in 4 ml so take 1.5 ml from the ampoule and add to the syringe. By adjusting this syringe to 10 ml/ hr infusion rate we get 100 ng/kg/ min.

For dopamine we require 3 µg/kg/min. so 3 x 50 x 60 = 9000. divided by the concentration of dopamine in a 50 syringe. Dopamine ampoules are 200 mg in 4 ml. adding this 4 to 46 ml NS gives us a solution of 50 ml with a concentration of 200/50 = 4 mg/ml = 4000 µg/ml. so dividing 9000/4000 = 2.5 . That is the rate of infusion you need to input in the syringe pump to get dopamine infusion at a diuretic dose of 3 µg/kg/min.


Classification of vasoactive drugs

Catecholamines Non-Catecholamines

these include adrenaline, noradrenalin, dopamine, dobutamine & isoprenaline.

Both dobutamine and isoprenaline are synthetic Catecholamines, not present normally in nature.

These include Phosphodiestrase enzyme inhibitors (PDE III) as milrinone. Calcium sensitizer (levosemindan) and the antidieuretic hormone vasopressin.


MECHANISM OF ACTION


Mechanism of action


Beta 1 receptors are G-protein coupled receptors, they act by activating a Gs (G-stimulatory) protein. Gs activates adenylyl cyclase, leading to an increase in levels of intracellular cAMP. Increased cAMP activates protein kinase A, which phosphorylates cellular proteins. The most important of which to our concern is the L- type calcium channel (LTCC), which opens causing influx of Ca2 , this causes increase in cytosolic Ca2 , which in turn causes activation of the (RyR) ryanodine receptors on the Sarcoplasmic Reticulum (SR) causing massive release of stored Ca2 in them a phenomenon called Calcium-induced calcium release (CICR). This Ca2 binds to cardiac troponin C (CTnc) removing the inhibitory effects of (CTnI).This causes movement of tropomyocin which normally covers the myosin binding sites on the actin filament. this allows actin-myosin interaction. After the contraction ends Ca2 is pumped back to the Sarcoplasmic reticulum through (SERCA) ATPase.

increased intracellular Ca2 in the cardiac myocytes was associated with increased O2 consumption, increased risk of arrhythmias & increased apoptosis.


Individual agents


ADRENALINEIt’s a natural catecholamine normally produced in the adrenal medulla by

methylation of nor adrenaline. It’s present as dark ampoules containing 1 ml at concentration of 1 mg/ml.

indications:• acute asthmatic attacks • resuscitation of non shockable cardiac arrest (asystole & electromechanical

dissociation)• Anaphylaxis• sever hypotension due to any cause (e.g. POST HIGH SPINAL INJURY

ASSOCIATED WITH BRADYCARDIA)• Post arrest as infusion unless sever tachycardia or hypertension occurs

Epinephrine is the first-line catecholamine in cardiopulmonary resuscitation and anaphylactic shock. As a vasopressor and as an inotrope, epinephrine is usually considered a second-line agent.


Epinephrine is a potent mixed α- and β-adrenergic agonist. Because of its mixed properties, epinephrine increases both mean arterial BP by vasoconstriction (α1-adrenergic effect) and cardiac output (β1-adrenergic effect).

Dosage : from 50 ng/kg/min upto 1500 ng/kg/min. usually the starting dose is 100ng/kg/min. Doses less than 50ng/kg/min is considered purely inotropic and can cause hypotension by activation of β2 receptors in blood vessels.

Caution in known cases of: 1. Known hypersensitivity to sympathomimetic amines. 2. coronary insufficiency (ISHD). 3. Arrhythmias.4. Hypertension 5. Cerebral arteriosclerosis. 6. Hyperthyroidism.7. In obstetric patients with a maternal blood pressure in excess of

130/80mmhg.


NORADRENALINENorepinephrine is an endogenous catecholamine that has potent α1- > β1-adrenergic

effects. The primary vasoactive effect of norepinephrine is arterial and venous vasoconstriction. The inotropic properties of norepinephrine are usually offset by increases in after load due to the α1 potent action which leads to reflex bradycardia.

Indications: First choice vasopressor, mainly used in distributive shock with marked vasodilatation as:

SEPTIC SHOCK, POST HIGH SPINAL INJURY ASSOCIATED WITH TACHYCARDIA, PHEOCHROMOCYTOMA SURGERY AFTER TUMOR EXCISION, TOTAL SPINAL AFTER

SPINAL ANETHESIA, MASSIVE HAEMORRAGE WITH TACHYCARDIA till blood products are available.

Dosage: should be added to D5%W start with 50ng/kg/min up to 4000ng/kg/min. it’s present in

dark ampoules containing 4mg/4ml.

Caution: in pt’s with mesenteric vascular occlusion, intestinal or renal infarctions, peripheral vascular insufficiency.


DOPAMINEIs an endogenous catecholamine, naturally present as a neurotransmitter in the

CNS. It’s used in the ICU as an infusion due to it’s multitude of actions on different receptors according to the dose of the infusion.

At a low dose (0.5 – 3 µg/kg/min) it activates the Dopaminergic receptors in the splanchnic and renal vasculature leading to VD and increased GFR and hence the UOP.

At intermediate dose (3 – 8 µg/kg/min) activation of the cardiac beta 1 receptors occurs with +ve inotropic, chronotropic effects.

At high doses (10 – 20 µg/kg/min) activation of alpha 1 receptors with increased peripheral vascular resistance and afterload. At very high doses > 20 µg/kg/min. this vasoconstrictor action overwhelms the dopaminergic vasodilator action and may compromise the blood flow to the limbs, kidney & mesentery.

Its used mainly as a second line inotrope and vasopressor. And as a diuretic agent to increase renal blood flow and UOP in cases where the OLIGURIA is due to low systemic blood pressure or marked renal vasoconstriction.

It’s available as 200 mg ampoules in 5 ml.


DOBUTAMINEIt’s a synthetic catecholamine with marked β1 and very little α and β2 actions.

it’s considered the first choice inotrope in cardiogenic shock especially in acute cases with maintained Abp. Chronic cases of heart failure show down regulation of beta receptors which may render the dobutamine infusion ineffective. Also, non specific activation of β2 receptors however small can cause marked pressure drop and accentuate the shock state especially in hypovolemic patients.

Dosage: 2 to 20 mcg/kg/minute. Maximum: 40 mcg/kg/min. Titrate to desired response.

Side effects include tachycardia, tachyarrythmias and increased myocardial oxygen consumption. Hypotension is another possible outcome.

Commercially it’s present as 250 mg either in 5 ml or 25 ml ampoules.


PDE3 INHIBITORSA group of drugs that acts mainly through direct inhibition of PDE enzyme

leading to decreased destruction of CAMP. With increased CAMP levels inside the myocytes +ve inotropy is achieved, while in the arterial blood vessels vasodilatation occurs hence their unique action as inodilators.

amrinone (INOCOR) and milrinone (PRIMACOR) are the most commonly used agents of this family. They are considered second line agents in cardiogenic shock that have synergistic effects with dobutamine, especially in cases with maintained ABP as they produce profound vasodilatation. Side effects include tachyarrythmias especially AF, hypotension.

Dosage: for amrinone: loading dose of 0.75-1.5 mg/kg over 5 minutes followed by

infusion of 2 – 10 µg/kg/min.For milrinone: loading dose 50 µg/kg IV over 10min, then 0.5 µg/kg/min.


CALCIUM SENSITIZERS


These are drugs that act to increase the contractility of the heart without increasing the concentration of cytosolic Ca++. Unlike previous inotropes which act through the beta adrenergic receptor cascade to increase cytosolic Ca++ and hence the myocardial oxygen consumption, the risk of arrythmogenesis and apoptosis, this group act by binding to troponin c in the presence of Ca++ and increasing the troponin sensitivity to Ca++ . This stabilizes the tropomyocin changes allowing the actin –myosin interaction to ensue at normal Ca++ levels. it also binds to vascular ATP dependant K+ channels which results in hyper polarization and causes vascular relaxation with reduction in both preload & afterload.

Note that it can be used concurrently with dobutamine as they have synergistic effects, with vasopressors in pts with low systolic blood pressure and even with beta blockers in post myocardial infarction pts with tachyarrythmias.

Side effects: as with other inodilators, hypotension & as with other inotropes tachyarrythmias are still the most common side effects although less than other agents.

Dosage: 0.05 – 1.5 µg/kg/min infusion.


ISOPRENALINEisoprenaline is a synthetic catecholamine which stimulates both β1&2

adrenoceptors producing an increase in cardiac output by increasing myocardial contractility and heart rate. It’s vasodilator action surpasses the increase in the COP caused by it’s +ve inotropic action so the net result is decreased MAP.

Indications: Isoprenaline is used to treat severe bradycardia where use of electronic temporary pacing is not available or appropriate. Isoprenaline can be used for cardiogenic or septic shock and acute Stokes-Adams attacks.

Dosage: 0.5 to 5 µg/min, (0.01-0.03µg/kg/min).Isoprenaline and adrenaline should not be administered simultaneously

because both drugs are direct cardiac stimulants and their combined effects may induce serious arrhythmias. Beta receptor blocking agents and isoprenaline inhibit the effects of each other. If heart rate exceeds 110 beat/min, its wise to stop the infusion and monitor the pt closely.

It’s available in the form of 0.2 mg/ml ampoules, either 1ml or 5ml volume.


VASOPRESSIN Vasopressin or antidieuretic hormone is a potent endogenous hormone,

which is responsible for regulating plasma osmolality and volume. In high concentrations, it also raises blood pressure by inducing moderate vasoconstriction by stimulating V1 receptors and reducing NO activity in the vascular smooth muscles.

Indications: mainly as an adjunct to norepinephrine to treat catecholamine resistant shock in septic shock, post cardiac surgery & other vasodilatory shock (Anaphylactic). It’s main usage in the ICU however remains to control GI bleeding due to esophageal varices.

Vasopressin is available as a 20 unit/ml injection. For continuous intravenous infusion, it should be diluted with normal saline or D5%W to a final concentration of 0.1 to 1 unit/ml.

Dosage: infusion rates of 0.01 to 0.03 units/min can be used with other vasopressor in shock state. In GI bleeding the dose is increased to 0.2 – 0.4 unit/min.


comparison of intravenous inotropic agents currently used in management of heart failure, in relationship to factors that most commonly determine choice of

agents for individual patients.


EFFECTS OF SOME VASOACTIVE AGENTS


So how do we react to a shocked patient?


A,B,C,DSecure the airwayMaintain breathingEstablish IV access

Carful history and examinationABG and labsECG and CVP

Urinary catheter

If polytrauma plz remember to put a neck collar and move the pt

as one block

If there is a surgical cause (stuck valve,

massive hge) do surgical

consultation

Start IV crystalloids 500ml – 1000ml

Over 30 minsAnd monitor the

response

UNLESS overt pulmonary edema is

present with CVP>15


MAP<60 & CVP<15 cmH2O

MAP<60 but CVP>15 cmH2O

Measure the CVP every 10 minutes and the MAP every 5 minutes along

with other clinical indices

REPEAT ONCE

STOP

Still no response

echocardiography

INOTROPES

VASOPRESSOR


WHAT IS THE END POINT OF RESUSCITATION? WHAT ARE YOU AIMING FOR?

1) Clinical indices: normalization of MAP, pulse rate, respiratory rate, UOP, skin warmth, conscious level & the CVP value is helpful, but they should not be used as markers of adequate resuscitation.

2) Mixed venous O2 saturation: should be aimed to be >70%. For samples obtained from Central venous catheter they are 5 – 10% less. Lower than normal values indicate imbalance between oxygen delivery and demand.

3) Base deficit: indicate ongoing acidosis and tissue hypo perfusion. Should be less than -2 mmol/L.

4) Lactate levels: a product of anaerobic metabolism. Should be normalized.

NB: use all parameters together not a single one as each has its limitations. And remember the trend in these parameters is much more important than the mere value.


ONE LAST NOTIFICATIONIn case of peripheral administration in emergency situation, if subcutanuos

extravasation of a vasopressor agent occurs, plz do the following:

1. Discontinue the agent peripherally and start it immediately centrally.2. DO NOT PULL OUT THE PERIPHERAL CANNULA3. Administer subcutaneous phentolamine (Regitine) using the cannula.

Comes in 5 mg per 1 ml vials or 10 mg in 1 ml. dilute 1 ml in 9 ml of NS. A dose of 0.1 to 0.2 mg/kg (up to a maximum of 10 mg) should then be injected through the catheter and subcutaneously around the site. Administered as soon as the extravasation is detected.

4. Consult plastic surgery.


THANK YOU

Health & Medicine

A hint about inotropes and vasopressors