IV Induction Agents

Majority of patients (excluding the pediatric population) will come into the operating room with an intravenous catheter (IV). As anesthesiologists, we use this IV to get the patient off to sleep (induction) prior to securing their airway for a general anesthetic. We can also use an IV to administer boluses or continuous infusions of IV anesthetics to obtain various planes of sedation such as light, moderate, and deep sedation.

The introduction of IV catheters and IV fluid therapy emerged in the late 19th-century. Up to the early 1900s, induction of anesthesia was achieved with inhaled anesthetics - a rather slow, unpredictable, and potentially dangerous process. The first short-acting barbiturate, Hexobarbital, was created in Germany in 1932. Thiopental was then introduced into America shortly after.

The goal of induction agents is to have a patient fall asleep (hypnosis) quickly with as few side effects as possible. The primary site of action is in the central nervous system (CNS), but commonly there are cardiac, respiratory, and other side effects associated with induction drugs.  Within the CNS, drugs work on GABA(A) receptors or N-methyl-D-aspartate (NDMA) receptors. Activation of the GABA(A) receptor allows for the inflow of chloride that hyperpolarizes the membrane of neural axons. NMDA receptors are involved with sodium and calcium influx leading to depolarization. Blockade of this receptor leads to the dissociative state seen with ketamine.

Similarly to inhaled anesthetics, after the induction agents have their desired effect in the CNS, this effect fades as the medicine is redistributed to other parts of the body such as muscle and fat. Due to their high lipid solubility, fat creates a large reservoir for IV anesthetics to deposit if continuous infusion are used for a prolonged period of time. This concept is referred to as “context-sensitive half time”, defined as the time to achieve 50% reduction in concentration after stopping a continuous infusion.

Barbiturates

Barbiturates are infrequently used in modern day anesthesia. Methohexital is primarily used for electroconvulsion therapy (ECT) since it does not effect the seizure threshold. After administration, its anesthetic effects last around 4-8 minutes. Methohexital is associated with pain on injection. Cardiovascularly, there is a transient reduction in arterial pressure, decreased cardiac output, and increased heart rate. For the respiratory system, barbiturates depress central respiratory drive and result in a dose-dependent decrease in minute volume and tidal volumes (at high doses respiratory rate decreases too). The ventilatory responses to hypercarbia and hypoxia are depressed as well. Barbiturates can be a trigger for acute intermittent porphyria.

Propofol

Propofol is the most commonly used IV induction agent used in modern day anesthesia. The induction dose to produce unconsciousness is 1.5 to 2.5 mg/kg. Its duration of action is around 4 to 5 minutes. Propofol is a GABA agonist and its mechanism of action is to increase the transport of chloride molecules across the membrane of axons to inhibit further action potentials.

In the CNS, propofol produces a decrease in cerebral metabolic rate of oxygen consumption (CMRO2), it decreases cerebral blood flood (CBF) due to its vasodilation properties, and it reduces intracranial pressure (ICP) which can be useful for patients with space-occupying lesions in their brain. Propofol also have major cardiac effects such as causing a significant decrease in arterial resistance and mild myocardial depression. These effects are magnified in older and/or hypovolemic patients. It is common to see hypotension after propofol administration. It does not lead to any arrhythmias. In the respiratory system, propofol will have a dose-dependent decrease in the central respiratory drive. It also decreases the ventilatory response to hypercarbia and hypoxia.

Because of its poor water solubility, it is formulated in an oil:water emulsion containing soybean oil, egg lecithin, and glycerol. This combination creates a medium well-suited for bacterial growth - special care should be given to avoid contamination. Anesthetic effects of Propofol after administration are short-lived due to redistribution away from the brain and hepatic metabolism. Propofol infusions can be used for sedation (monitor anesthesia care - MAC) and for general anesthesia with total intravenous anesthetics (TIVA) when combined with other agents, such as remifentanil. Pain on injection is common (10-63%) and can be reduced by injecting into a larger vein or by giving IV lidocaine prior to propofol administration. In additional to its hypnotic effects, propofol has antiemetic properties, with doses as low as 10-20 mg boluses. Propofol Infusion Syndrome is a rare but serious side effect that can happen after patients receive large doses infusion (>150-200 mcg/kg/min) for a prolonged period of time. This syndrome will create a scenario that presents as a metabolic acidosis with rhabdomyolysis, progressive bradyarrhythmias, and potentially cardiac arrest. An odd but specific finding is also green urine which is due to the presence of a byproduct of propofol - phenolic or quinol metabolite.

Ketamine

Ketamine first gained its popularity as a versatile anesthetic during the Vietnam War where it was determined to be an “exceptional battlefield anesthetic”. Since then, it has been integrated as an additional tool in the class of IV anesthetics. The induction dose for ketamine is 1 to 2 mg/kg. Instead of the unconscious state produced with propofol, ketamine will create a state of dissociation, meaning the patient will appear awake but they will be unaware of their surroundings. The duration of action is around 5 to 10 minutes.

Ketamine is an NMDA antagonist - which produces the dissociation and also inhibits sensory perception and can have some analgesic effects. Many of the CNS effects of propofol are the exact opposite for ketamine. The CMRO2, CBF, and ICP all increase with ketamine. The intraocular pressure will also increase. Careful and intentional use of ketamine should be practiced whenever you have a patient with CNS or ophthalmic pathology. It also has the potential to produce delirium and hallucinations. This can be partially subdued (or at least not remembered) by administration of a benzodiazepine prior to giving ketamine.

It’s cardiovascular effects usually seen as an increase in blood pressure, increase in cardiac output, and an increase in myocardial O2 consumption. These are the result of increased sympathetic response from reduced norepinephrine and epinephrine reuptake. However, ketamine can also have a negative inotropic effect and can cause cardiac collapse in patients who are depleted of their adrenergic agents (ie. Trauma patients, critical ill patients). For the respiratory system, one of the biggest benefits of ketamine is that it maintains airway patentcy and patients will continue to breath spontaneously while being anesthetized.

Other special considerations when using ketamine are its anticholinergic properties. One of these that we can take advantage of is its bronchodilatory property. This can be particular useful for a patient with underlying COPD or who experiences bronchospasm during induction, emergence, or even during a surgical case. However, an other anticholinergic property that can be slightly cumbersome is its hypersalivation. There are also multiple routes of administration, adding to ketamine’s versatility (ie. PO, IV, IM, intranasal, rectal, transdermal, subcutaneous). Ketamine also works on multiple receptors throughout the body including NMDA, calcium channels, sodium channels, monoaminergic, nicotine, muscarinic, opioid, and GABA receptors. There is also emerging data on its usefulness for neuropathic pain, PTSD, and depression. We are living in a time when more is being discovered about the utility of ketamine and its benefits.

Etomidate

Etomidate was discovered in 1964 and was approved for clinical practice 10 years later. Its initial benefits for an IV induction agent were a quick onset of action, rapid offset, minimal cardiovascular depression, and cerebral protection. However, overtime ICUs began seeing an alarming rise in mortality with patients on etomdiate effusion. It was later discovered the this was related to corticoadrenal suppression. After the discovery of propofol, etomidate become much of a backup drug. Its induction dose is 0.15 to 0.3 mg/kg, producing unconsciousness in less than 2 minutes. Its duration of action is around 3 to 8 minutes.  Like propofol, etomidate works on GABA-A receptors, inhibiting further action potentials down neural axons. In the brain, you see decreased CMRO2, decreased CBF, and ICP is unchanged. Etomidate does carry the potential of causing seizures. In the cardiovascular system, although you see a decrease in peripheral vascular resistance, cardiac output and contractility are maintained leading to stable hemodynamics. For respirations, you see a decreased tidal volume and increased respiratory rate (similar to inhaled anesthetics). You can achieve apnea with high doses.

One of the most regarded special considerations with etomidate is the corticoadrenal suppression. This is because the drug inhibits 11-beta-hydroxylase, leading to a decrease in cortisol and aldosterone synthesis. You also see a fair rate of myoclonus after injection (30-60%). It is also common to have pain on injection and PONV.