Using inotropes and vasopressors in anesthesia (Proceedings)

Arterial hypotension is a common anesthetic complication. Perfusion of vital organs depends largely on arterial blood pressure. Mean arterial blood pressure (MAP) below 60 mmHg and systolic blood pressures below 80 mmHg can result in reduced perfusion of the vital organs. Oxygen debt can ensue in morbidity and mortality. Cardiac arrest can follow a severe episode of hypotension. Assuming that the patient does not have any preexisting problem(s), the hypotension is more likely anesthetic-induced.

Signs and evidence supporting the presence of arterial hypotension in anesthetized dogs and cats should be present before treatment is initiated. Direct blood pressure measurement using a pressure transducer is the golden standard for clinical blood pressure measurement. It provides second-by-second changes in blood pressure which leads to a faster response on the part of the anesthetist. Without the direct blood pressure measurement, Doppler appears to be a helpful tool in making decision during anesthesia. Most oscillometric pressure measurements fail when the patient is moderately to severely hypotensive. Hypotension may be manifested as weak peripheral pulses. It is important to remember that a strong peripheral pulse does not guarantee a normal MAP. The arterial pulse is the difference between the systolic and diastolic pressures. A large difference between the two pressures will result in a very strong pulse and yet the MAP may be low.

During anesthesia, it may be difficult to ascertain the exact cause of arterial hypotension. General causes of arterial hypotension include one or a combination of the following: 1) reduced inflow to the heart (e.g., blood loss), 2) reduced pumping function of the heart (e.g., deep anesthesia), and 3) reduced vascular resistance (e.g., sepsis). In a healthy dog or cat presented for elective procedure, the anesthetics administered are the most cause of arterial hypotension. Some dogs and cats are very sensitive to the cardiovascular depressant effect of inhalant anesthetics. Blood loss during surgery can also result in hypotension. Preexisting conditions that can result in hypotension during anesthesia include hypovolemia, shock, cardiomyopathy, valvular heart disease, arrhythmias, hypothyroidism, hypoxemia and Addisonian crisis. Drugs, blood or blood products administered during anesthesia can cause anaphylactoid reaction. The most common manifestation of anaphylactoid reaction during anesthesia is hypotension.

If the patient does not have any preexisting problem(s) and the hypotension is more likely anesthetic-induced, the vaporizer setting or infusion rate of the IV anesthetic should be reduced. IV bolus administration of crystalloid at 10 ml/kg over 10 minutes should also be done. If hypotension persists, the administration of positive inotrope or vasopressor should be done.

The positive inotropes and vasopressors that are used in anesthesia are sympathomimetics. There are three main adrenergic receptors acted upon by the sympathomimetics: beta-1, beta-2, and alpha receptors. Stimulation of the beta-1 receptors leads to increased cardiac contractility and heart rate On the other hand, beta-2 stimulation results in peripheral vasodilation. Peripheral vasoconstriction is the main effect following alpha receptor stimulation. Vasopressin does not work on adrenergic receptors. It directly produces vasoconstriction of the systemic circulation through the V1 vascular smooth muscle receptors.

The choice of positive inotrope and vasopressor during anesthesia will depend on the case and the availability of these drugs in the clinic. The specific drugs are discussed below.

Dopamine

Dopamine is an endogenous catecholamine that acts as neurotransmitter in the central nervous system and as hormone in the systemic circulation. It is a precursor to norepinephrine. When given as a drug, it does not cross the blood-brain barrier and it does not affect the central nervous system directly. It has a dose dependent action on the different receptors. When given at low doses of 0.5-3.0 ug/kg/min, the receptors mainly affected are the dopaminergic receptors. Dopaminergic receptors, when stimulated, increase renal and mesenteric perfusion. Increasing the dose to 4.0-10.0 ug/kg/min results in beta-1 stimulation. High doses of 10-20 ug/kg/min will cause activation of the alpha-1 receptors leading to peripheral vasoconstriction. It should be given as a CRI and bolus administration should be avoided. It can be diluted with 0.9 saline and 5% dextrose in water.

When a hypotensive patient is not responsive to fluid boluses (including colloid administration) and reduced vaporizer setting of inhalant, dopamine is usually the first adrenergic drug chosen. The infusion rate can start at 5.0 ug/kg/min and it is adjusted based on the response of the patient. If blood pressure does not increase, the rate is increased to 7.5-10.0 ug/kg/min. The author sets the maximum rate to 20.0 ug/kg/min. If the patient is still not responding to this dose, another inotrope or vasopressor will be tried. When the patient responds to the initial rate of administration, the dopamine rate of administration is reduced with goal of maintaining the MAP between 70-90 mmHg. If the MAP continues to rise reaching a MAP above 90 mmHg, the author prefers to stop the infusion and restart it when the MAP reaches the low 60s.

Higher doses of dopamine can lead to tachycardia and arrhythmias. When this happens, the rate of administration should be reduced. If there is no contraindication, the fluid rate can be increased if the patient continues to be hypotensive. Another option is to change to a drug that has more alpha effect. Tachycardia and arrhythmias are related to the beta-1 receptor stimulation. Norepinephrine has weaker beta-1 effects and stronger alpha-1 effects compared with dopamine and can be chosen as an alternative drug at this point. Another choice will be ephedrine which will be discussed later.

High doses of dopamine should be avoided in patients with renal failure, mitral regurgitation, dilated cardiomyopathy, and congestive heart failure. The peripheral vasoconstriction will reduce renal perfusion and for the cardiac conditions mentioned above, increased afterload will result in worse cardiac performance.

Dobutamine

Dobutamine is a synthetic catecholamine that primarily stimulates the beta-1 receptors increasing myocardial contractility. It has weak effects on the alpha-1 and beta-2 receptors. Hypotensive patients that have preexisting conditions like chronic renal failure, mitral regurgitation, dilated cardiomyopathy, and congestive heart failure will benefit from dobutamine administration. Similar to dopamine, it is given as a CRI without the need for initial bolus administration. It can be diluted with 0.9% saline or 5.0% dextrose in water. In dogs, the rate of administration ranges from 5-20 ug/kg/min. It is best to start at the lower range of the dose. In cats, lower doses (2-5 ug/kg/min) are used because higher dose may cause seizure. Compared with dopamine, dobutamine appears to produce less dramatic changes on the blood pressure because of its concomitant effect on the beta-2 receptors. Even though the cardiac output is increased markedly, only modest change may be seen with the blood pressure. At much higher dose, dobutamine can lead to tachycardia and arrhythmias.

Patients in vasodilatory shock can be given dobutamine with the addition of a vasopressor like norepinephrine or vasopressin. Signs indicating that vasodilatory shock is occurring during anesthesia include tachycardia and persistent hypotension despite fluid loading and administration of a positive inotrope.

Ephedrine

Ephedrine is a synthetic noncatecholamine with beta and alpha effects. It has more beta effect than alpha. It is an indirect-acting sympathomimetic causing the release of norepinephrine from the sympathetic nerve endings. As such, it is associated with tachyphylaxis, a phenomenon characterized by reduced response following repeated administration. With ephedrine, the stores of norepinephrine will decrease after repeated administration resulting in less effect.

Ephedrine can be used as the initial inotropic treatment when hypotension persists during anesthesia or as an alternative when dopamine or dobutamine is ineffective. Ephedrine can be given as an IV bolus injection eliminating the need for a syringe pump or other forms of CRI gadgets. The high concentration (50.0 mg/ml) of ephedrine preparation leads to difficult dosing considering its dose of 0.05-0.2 mg/kg. For example, a dog weighing 10 kg will need 0.02 ml of ephedrine if 0.1 mg/kg dose is chosen. For more accurate dosing, especially in smaller patients, the author dilutes ephedrine with saline. Two tenths (0.2) ml of ephedrine is mixed with 0.9% saline (9.8 ml) making a total volume of 10 ml. The concentration will be 1.0 mg/ml. Using the 0.1 mg/kg dose, the dose for a 10 kg dog will be one ml (1 ml/10 kg). This dose can be repeated if there is no response after 5 minutes. The duration of action of ephedrine is about 20 minutes.

The author observes more increase in heart rate following ephedrine administration compared with dopamine and dobutamine. Ephedrine should be avoided in patients in chronic renal failure because it decreases renal blood flow.

Epinephrine

Epinephrine is another endogenous catecholamine with potent alpha and beta effects. It is not routinely given to treat hypotension during anesthesia because of the higher incidence of arrhythmia. However, it is the inotrope of choice for patients in cardiac arrest. It is administered IV as a bolus injection to cause peripheral vasoconstriction. The main objective of CPR is to increase cerebral and coronary perfusion and by causing peripheral vasoconstriction, the blood moves preferentially to the heart and brain during chest or cardiac compression. In this setting, the dose of epinephrine is 0.02-0.05 mg/kg. This is considered the low dose for CPR. High dose of epinephrine has been associated with a hyperdynamic state and higher morbidity and mortality following return to spontaneous circulation.

Epinephrine is also given to patients that develop anaphylaxis. In addition to causing peripheral vasoconstriction and bronchodilation, it also inhibits the release of inflammatory mediators from mast cells and basophils. The dose for anaphylaxis is 0.01 mg/kg IV.

In rare occasions, critically ill patients that have severe hypotension despite fluid loading and use of other inotropes, epinephrine can be tried as a CRI using the dose of 0.025-0.3 ug/kg/min. The author prefers to use norepinephrine first before using epinephrine.

Norepinephrine

Norepinephrine is a natural catecholamine with strong alpha-1, moderate beta-1, and weak beta-2 effects. It is not the first choice for a vasopressor in patients that have no or minimal systemic disturbance. It can be used immediately in patients that are known to have compensated or vasodilatory shock. These patients should have received fluid loading before norepinephrine administration. With appropriate fluid resuscitation, it can increase blood pressure, renal blood flow, and urine output in shocky patients. It is administered as a CRI with a dose range of 0.5-5.0 ug/kg/min. It can be given simultaneously with an inotrope (dobutamine) if myocardial depression is strongly suspected. Its effect on the heart rate is variable.

Norepinephrine should be avoided in patients with chronic renal failure, dilated cardiomyopathy, mitral regurgitation, and congestive heart failure.

Isoproterenol

Isoproterenol is a synthetic catecholamine with potent beta-1 and beta-2 effects. It is more potent than epinephrine and norepinephrine in increasing myocardial contractile force, heart rate, and cardiac output. It is not used for hypotensive patients during anesthesia because it causes peripheral vasodilation counteracting its positive effect on myocardial contractility. It is highly arrhythmogenic and the electrical activity of the heart should be watched very closely.

Isoproterenol is indicated in patients with sick sinus syndrome or third degree heart block and need general anesthesia. These patients are not responsive to atropine. When placement of temporary pacemaker is not possible, isoproterenol will increase the heart rate. By increasing the heart rate, the cardiac output will improve. It is given as a CRI using a dose range of 0.1-2.0 ug/kg/min. It is advisable to start at the lowest rate and adjust the infusion rate based on the increase in heart rate. It should not be given as a bolus injection.

Phenylephrine

Phenylephrine is a synthetic noncatecholamine with a direct effect on the alpha receptors. By producing peripheral vasoconstriction, it decreases cardiac output and heart rate. The reduction in heart rate is a reflex response to the increase in systemic blood pressure. It is not the first choice in treating hypotension during anesthesia. If the primary cause of hypotension is peripheral vasodilation, e.g., acepromazine overdose, phenylephrine can be given immediately. If the patient is volume depleted and the cause of hypotension is anesthesia-related, phenylephrine should be reserved for later use.

It can be given as a bolus or CRI. The dose for bolus injection is 5-20 ug/kg and can be given every 10-15 minutes as needed. For CRI, the rate is 0.1-0.5 ug/kg/min.

Vasopressin

As mentioned above, vasopressin causes peripheral vasoconstriction by stimulating the V1 vascular smooth muscle receptors. It is not used routinely in hypotensive anesthetized patients. It is reserved for patients in vasodilatory shock refractory to fluid resuscitation, dopamine, dobutamine, or norepinephrine infusions. Anesthetized critically ill patients, not necessarily in the state of vasodilatory shock, that develop profound hypotension during a surgical procedure will also benefit from vasopressin infusion.

Higher doses of vasopressin have been associated with ischemia of the heart, gastrointestinal tract, and skin. The lower dose should be used. Extrapolating from human studies, it appears that a dose of 0.01-0.04 U/kg/hour will be a reasonable starting point. It is important to remember that vasopressin should only be used in conditions refractory to fluid resuscitation and positive inotropes. It can be given simultaneously with a positive inotrope. The explanation behind this is that the vasopressin will make the adrenergic receptors sensitive again to the effect of the sympathomimetic. Vasopressin is given in such a low dose that its effect may not be seen immediately.

Table 1. Positive inotropes and vasopressors used in anesthesia

Summary

Management of hypotension during anesthesia is often successful by simply giving fluid boluses and reducing the inhalant agent's vaporizer setting. The ones that will not respond are mainly patients in vasodilatory shock and are critically ill. A positive inotrope should be included in the management of hypotension during anesthesia if the patient does not respond to fluid loading and lighter plane of anesthesia. If the patient does not respond to a positive inotrope, a drug that will cause peripheral vasoconstriction can be used subsequently or simultaneously with a positive inotrope.