Summary
Intravenous (IV) anesthetics were first discovered for their clinical utility in 1656 by Sir Christopher Wren, an architect, physicist, and astronomer at the University of Oxford while using a goosequill to inject opium into a dog to produce sleep [1]. In 1909, Ludwig Burkhardt became the first surgeon to deliberately use IV ether in a 5% solution to sedate patients for head and neck surgery, finding that a higher concentration caused thrombophlebitis and hemolysis, whereas a lower concentration proved too weak a sedative. The first barbiturate hexobarbital was used in 1932, soon being used for over 10 million cases by 1944. In 1989, the first propofol lipid emulsion formulation was launched in the United States, marking the beginning of the modern age of IV sedation pharmacology [2].
Introduction
Intravenous (IV) anesthetics were first discovered for their clinical utility in 1656 by Sir Christopher Wren, an architect, physicist, and astronomer at the University of Oxford, while using a goosequill to inject opium into a dog to produce sleep [Reference Roberts and Jagdish1]. In 1909, Ludwig Burkhardt became the first surgeon to deliberately use IV ether in a 5% solution to sedate patients for head and neck surgery, finding that a higher concentration caused thrombophlebitis and hemolysis, whereas a lower concentration proved too weak a sedative. The first barbiturate hexobarbital was used in 1932, soon being used for over 10 million cases by 1944. In 1989, the first propofol lipid emulsion formulation was launched in the United States, marking the beginning of the modern age of IV sedation pharmacology [Reference Baker and Naguib2].
Inhaled anesthetics were commonplace in the operative theatre long before IV use, although IV propofol is used in nearly all operations today, which is estimated to be 300 million annually [Reference Weiser, Regenbogen and Thompson3]. Propofol, along with volatile anesthetic agents, are the main components of present-day general anesthesia, accounting for a multitude of advantageous outcomes in clinical practice and perioperative medicine [Reference Schraag, Pradelli and Alsaleh4]. A current high-powered meta-analysis found that the three biggest benefits of propofol-based total IV anesthesia (TIVA) included decreased risk of postoperative nausea and vomiting (PONV), lower pain scores (i.e., high patient satisfaction), and decreased time in the postanesthesia care unit (PACU) [Reference Schraag, Pradelli and Alsaleh4]. Another meta-analysis of over 4000 subjects investigating the superior safety profile of TIVA found low-quality evidence that propofol-based TIVA decreases the likelihood of postoperative cognitive dysfunction (e.g., postoperative delirium) [Reference Miller, Lewis and Pritchard5]. This finding was of particular interest to geriatric surgery, which boasts a higher risk of postoperative delirium and has an increasing incidence of surgery each year.
IV anesthetic repurposing is emerging for classic disease processes such as sedation for the coronary artery bypass graft (CABG) procedure and sedation with etomidate for endoscopic retrograde cholangiopancreatography (ERCP). For example, volatile anesthetics such as sevoflurane have long been the mainstay anesthetic agent for CABG procedures; yet emerging evidence suggests that propofol-based TIVA is noninferior [Reference Landoni, Lomivorotov and Nigro Neto6]. On another note, ERCP has long been performed under propofol-based TIVA; yet use of etomidate is now validated as a safe alternative [Reference Park, Park and Hyun7].
Additionally, a new frontier of IV anesthetic use is rapidly emerging for clinical entities such as depression and status epilepticus. Ketamine, an N-methyl-D-aspartate (NMDA) antagonist, is becoming a well-accepted alternative pharmacotherapy in treatment-resistant depression and nonsuicidal self-injurious behavior [Reference Tadler and Mickey8, Reference Mathew, Shah and Lapidus9]. This is a novel and impactful discovery in an age of increasing mental disease. And the list of IV agents for treatment of refractory status epilepticus now boasts midazolam, propofol, pentobarbital, thiopental, and ketamine [Reference Reznik, Berger and Claassen10].
As exciting new pharmacotherapies are decreasing perioperative morbidity, we review barbiturates, benzodiazepines, ketamine, etomidate, dexmedetomidine, and propofol in this article as mainstay anesthesia agents. In addition, the adjunctive use of perioperative multimodal therapy, including opioids, local anesthetics, midazolam, and dexmedetomidine, is discussed. Finally, we will review in detail the inclusion of TIVA and adjunctive agents in Enhanced Recovery After Surgery (ERAS) protocols, a niche of anesthesia that is becoming widely popular in the United States.
Intravenous Anesthetic Agents
The hunt continues for the ideal IV agent. There are currently several options that are in clinical practice that all serve their own purpose; however, not one single agent has been able to encompass all ideal effects. The ideal IV anesthetic would provide amnesia with ultrarapid action, causing little to no cardiorespiratory depression, with concurrent ultrarapid metabolism. In addition to the aforementioned characteristics, the IV agent would be highly potent, reversible, stable in formulation, void of irritants, affordable, and easy to administer [Reference Barash, Cullen, Stoelting, Barash, Cullen and Stoelting11].
IV agents also have innumerable techniques of use, including, but not limited to, premedication, induction of general anesthesia, sedation for procedures and monitored anesthesia care (MAC) cases, and treatments of ailments including seizures, pain, and PONV. Further specific indications and uses are described, categorized by medication, below.
As seen below in Table 6.1, the majority of IV anesthetics used today have targets of gamma-aminobutyric acid (GABA) receptor modulation. With a primary objective of increasing GABA’s efficiency, this mechanism occurs via GABA potentiation, as well as via inhibition of counteracting and excitatory neurotransmission of glutamate [Reference Brohan and Goudra12, Reference Butterworth, Mackey, Wasnick, Butterworth, Mackey and Wasnick13]. If large boluses of these types of medications with this action are administered, they can cause burst suppression on electroencephalography (EEG) and act as an anticonvulsant, with the exception of methohexital.
Table 6.1 Mechanisms of action/pharmacokinetics
| MOA | Absorption | Distribution | Biotransformation | Excretion | |
|---|---|---|---|---|---|
| Barbiturates | GABAA | IV, IM, PO PR | Redistribution | Hepatic oxidation to water-soluble, N-dealkylation, desulfuration | Renal, bile (methohexital) |
| Ketamine | NMDA antagonist | IV, IM, IN, PO, SC, E | Redistribution | Hepatic, N-demethylation | Renal |
| Propofol | GABAA | IV | Redistribution | CYP P450, plasma esterases | Renal |
| Etomidate | GABAA | IV | Redistribution | Conjugation, extrahepatic metabolism | Renal |
| Benzodiazepines | GABAA | IV, IM, IN, PO, PR, SL, B | Redistribution | Glucuronidation to water-soluble | Renal |
| Dexmedetomidine | α2-agonism | IV, IN | Redistribution | Rapid hepatic conjugation, N-methylation, hydroxylation | Renal, bile |
IV, intravenous; IM, intramuscular; PO, per os; PR, per rectal; IN, intranasal; SC, subcutaneous; E, epidural; SL, sublingual; B, buccal.
Regarding pharmacokinetics, all IV anesthetics share very similar properties. Their distribution throughout the body is determined by blood flow to vessel-rich organs (brain, heart, kidneys, liver), before transitioning to muscles, with eventual deposition in vessel-poor tissues (fat, bone) [Reference Butterworth, Mackey, Wasnick, Butterworth, Mackey and Wasnick13]. Their metabolism is considerably hepatic, with renal excretion, though there are exceptions (see Table 6.1). The more lipid-soluble the anesthetic, the more readily it crosses the blood–brain barrier (BBB), which implies a faster onset of action. Dosing for IV anesthetics can range based on the desired effect, as shown in Table 6.2; the various organ effects are shown in Table 6.3.
Table 6.2 Dosing of anesthetics
| Premedication | Sedation | Induction | Maintenance | |
|---|---|---|---|---|
| Thiopental | 2.5–5 mg kg−1 | |||
| Methohexital 1% | 0.2–0.4 mg kg−1 IV | 1–2 mg kg−1 IV | 50–150 μg/(kg min) | |
| Ketamine | 2.5–15 μg/(kg min) |
| 0.1–0.5 mg min−1 | |
| Propofol | 25–100 μg/(kg min) | 1–2.5 mg kg−1 IV | 50–200 μg/(kg min) | |
| Etomidate | 0.1–0.2 mg kg−1 load, 0.05 mg kg−1 Q5 min PRN | 0.2–0.5 mg kg−1 IV | ||
| Midazolam |
| 0.01–0.1 mg kg−1 | 0.1–0.4 mg kg−1 | 0.25–1 μg/(kg min)Footnote a |
| Dexmedetomidine | 0.5–1 μg kg−1 IN | 0.5–1 μg kg−1 loadFootnote b, 0.3–0.7 μg/(kg hr) | N/A |
a As an adjunct to volatiles.
b Over 15 minutes.
Table 6.3 Organ effects of anesthetics
| Agents | Neuro (CBF/ICP/CMRO2) | CV (BP/HR/CO) | Respiratory (TV/RR) | Renal (RBF/GFR) | Unique characteristics |
|---|---|---|---|---|---|
| Barbiturates | ↓↓↓/↓↓↓/↓↓↓↓ | ↓/↑/N | ↓↓/↓↓ | ↓/↓ | Rate of administration can vary effects dramatically, can precipitate porphyria |
| Ketamine | ↑↑/↑↑/↑ | N | N | N | Closest to “ideal” IV agent as provides amnesia, analgesia, and unconsciousness |
| Propofol | ↓↓↓/↓↓↓/↓↓↓ | ↓↓/V/↓Footnote a | ↓↓↓/↓↓ | N | No tolerance; however, PRIS |
| Etomidate | ↓↓↓/↓↓↓/↓↓↓ | N | N | N | Transient inhibition of 11-β hydroxylase, myoclonic activity |
| Benzodiazepines | ↓↓/↓↓/↓↓ | ↓/V/↓ | (↓/↓)Footnote a | N/N | Most effective anxiolytic |
| Dexmedetomidine | N/N/V | ↓/V/V | N/N | N/N | No GABA effect |
a Clinically insignificant.
CBF, cerebral blood flow; ICP, intracranial pressure; CMRO2, cerebral metabolic rate of oxygen; BP, blood pressure; HR, heart rate; CO, cardiac output; TV, tidal volume; RR, respiratory rate; RBF, renal blood flow; GFR, glomerular filtration rate; IV, intravenous; N, no change, minimal, or offsetting effects; V, variable effect; PRIS, propofol infusion syndrome; GABA, gamma-aminobutyric acid.
Naturally, IV agents that contain irritants or stabilizing agents, such as propylene glycol or phenols, consequently cause pain on injection [Reference Desousa14], notably thiopental, diazepam, lorazepam, propofol, and etomidate. All of the IV medications can be administered as a single bolus versus an infusion, which will alter immediate organ effects. If considering an infusion, it is important to understand the concept of context-sensitive half-life, which is discussed later in this chapter. Context-sensitive half-life, or context-sensitive half-time, is defined as the time taken for blood plasma concentration of a drug to decline by half after an infusion designed to maintain a steady state has been stopped [Reference Butterworth, Mackey, Wasnick, Butterworth, Mackey and Wasnick13]. As shown in Figure 6.1, the context-sensitive half-times of various IV agents are plotted against time. Context-sensitive half-time can help predict when a drug is cleared and the patient is no longer sedated by that respective agent.
Barbiturates include thiopental, thiamylal, methohexital, and phenobarbital. They work by depressing the reticular activating system (RAS), directly potentiating the gamma-aminobutyric acid-A (GABAA) receptor, prolonging the duration of chloride channel opening. Historically, these agents served well as induction agents for both pediatric and adult anesthetics; however, with the advent of propofol, their routine use has decreased. Barbiturates treat raised intracranial pressure (ICP) and may be beneficial as neuroprotective agents against ischemia during deep hypothermic circulatory arrest, stroke, and aneurysm surgery. It is worth noting that production of porphyrins is increased through stimulation of aminolevulinic acid synthetase and therefore should be avoided in patients with porphyria.
Benzodiazepines include short-acting (midazolam and triazolam), intermediate-acting (alprazolam, clonazepam, lorazepam, oxazepam, temazepam), and long-acting (chlordiazepoxide, diazepam, flurazepam) agents. They work similarly to barbiturates, with potentiation of the GABAA receptor, but differently by increasing the frequency of chloride channel opening. Benzodiazepines assist as an excellent preoperative medication for anxiolysis, sedation, and induction of anesthesia. As previously mentioned, they suppress seizure activity by inhibiting GABA. Midazolam is the most commonly used benzodiazepine in the operating room. Typically, 1–2 mg IV before induction provides substantial anxiolytic effects, and reduced dosage should be considered in the elderly. Benzodiazepines have dose-dependent respiratory depression and caution should be exercised when co-administering opioids, as hypotension can occur in hemodynamically unstable patients.
Ketamine is an analog of phencyclidine, causing dissociation of the thalamus from the limbic cortex. Ketamine works by noncompetitive inhibition of the NMDA receptor. It is also the only analgesic of IV agents discussed in this chapter that has weak opioid agonist activity (μ > κ > δ). Additionally, it has properties of a weak GABA agonist, adrenergic agonist (α1 and β2), and muscarinic antagonist. Ketamine is a direct myocardial depressant, but an indirect sympathomimetic. Ketamine is the only IV anesthetic that has low protein binding [Reference Stoelting, Miller, Stoelting and Miller15].
Ketamine uses include induction of general anesthesia, intramuscular use for uncooperative patients, for adults and children without IV access, deep sedation, and newer ideas, including treatment of treatment-resistant depression and refractory status epilepticus. Ketamine can be helpful in difficult airway cases, as respiratory function appears to be preserved, though an antisialagogue should be considered. Ketamine is a helpful aid in trauma patients, and is commonly used for chest tube placement and bone reduction by orthopedic surgeons. It has also been beneficial as an adjunct to analgesia in the opioid-tolerant patient. Ketamine should be avoided in the critically ill who have exhausted their adrenergic capacity, in patients with severe right heart dysfunction due to increased pulmonary vascular resistance, and in those with severe hypovolemia.
Etomidate is another IV anesthetic, a carboxylated imidazole, that depresses the RAS, with GABAA receptor potentiation. Etomidate is notably dissolved in propylene glycol, which is known to cause pain on injection. Myoclonus is very common after administration, and there is dose-dependent inhibition of the adrenocortical system via 11β-hydroxylase; however, no studies have demonstrated an adverse effect on outcome [Reference Stoelting, Miller, Stoelting and Miller15]. Common applications for etomidate include deep sedation, as well as induction of general anesthesia, especially in those with compromised cardiac function.
Propofol is a lipid emulsion formulation, standardized to 1% propofol, 10% soybean oil, and 1.2% purified egg phospholipid as an emulsifier, with 2.25% glycerol as a tonicity-adjusting agent and sodium hydroxide to adjust the pH [Reference Feng, Kaye, Kaye, Belani and Urman16]. Bacterial retardants are added, as the above-mentioned formulation supports bacterial growth. Propofol should be used immediately or at least within 6 hours of vial opening [Reference Stoelting, Miller, Stoelting and Miller15].
It is the most commonly used IV anesthetic that currently exists in clinical practice [Reference Stoelting, Miller, Stoelting and Miller15]. It is also easily titratable and commonly used for maintenance of intraoperative and postoperative sedation. Children will typically require higher doses. Low-dose propofol can be used for central line placement, as well as as an alternative agent for PONV. If given in high-dose infusions for an extended period of time, propofol can cause propofol infusion syndrome (PRIS), which presents with metabolic acidosis, hypertension, hypertriglyceridemia, and renal failure.
Dexmedetomidine is a highly selective α2-adrenergic agonist, approximately eight times more specific than clonidine, with 1620:1 α2/α1 receptor favorability [Reference Srivastava, Sarkar and Kumar17]. By stimulating α2 receptors in the locus ceruleus, there is a decrease in norepinephrine release. Action on the descending noradrenergic pathways inhibits norepinephrine release and inhibits pain transmission at the dorsal horn of the spinal cord [Reference Tang and Xia18, Reference Grewal19]. Dexmedetomidine has been used extensively as a nonopioid adjuvant for perioperative pain relief. Because of the central and peripheral receptors, dexmedetomidine can have a paradoxical effect on hemodynamics. Upon bolus administration, due to α1 activity, hypertension may result, which is avoided with a loading dose over 15 minutes. At peak effect of an infusion, hypotension and bradycardia are generally present. Dexmedetomidine has minimal to no respiratory depression, and therefore has been useful in sedation. Common applications include sedation for MAC and intensive care unit (ICU) patients, and preventing emergence delirium, as well as awakening from general anesthesia and ICU recovery [Reference Barash, Cullen, Stoelting, Barash, Cullen and Stoelting11].
Significant attenuation of stress response to tracheal intubation/extubation allows for assistance during awake fiberoptic techniques. Dexmedetomidine reduces minimal alveolar concentration, and therefore reduces opioid, muscle relaxant, and inhalational anesthetic requirements.
Novel Intravenous Agents
Attempts are being made for improvement in IV drug profile. More favorable characteristics would include less or no pain on injection, more predictable and consistent termination of action, and drug utility irrespective of, and unbound by, renal or liver failure. Shockingly, drug development approaches almost $3 billion dollars, with only roughly 12% approval rate for entering clinical development [Reference DiMasi, Grabowski and Hansen21]. Although newer formulations are in the pipeline, drug development is not inexpensive.
Most current drugs in the development process share and emulate existing formulations with slight modifications to their structures. However, not all of these agents have been successful, and some have already been removed from the market. These agents include fospropofol, novel propofol formulations (and micro- to macro-emulsions), remimazolam, cyclopropyl-methoxycarbonyl metomidate, methoxycarbonyl etomidate, and AZD 3043.
Fospropofol is a prodrug of propofol appearing to allay microbial concerns, as well as causing decreased pain on injection as it is water-soluble. Fospropofol used in endoscopic procedures is approved for use of MAC sedation, not general anesthesia. However, fospropofol does have a longer onset of action, and therefore has less precision upon administration.
Remimazolam is an amnestic that has a similar onset time to midazolam and remifentanil. Because it is metabolized by tissue esterases, no concerns about accumulation of the products are warranted.
Cyclopropyl-methoxycarbonyl metomidate also appears to be demonstrating some early promise in animal studies [Reference Barash, Cullen, Stoelting, Barash, Cullen and Stoelting11]. The less potent brother of etomidate has a shorter duration of action and less adrenocortical suppression. It is metabolized by blood and tissue esterases, but the drug remains in early clinical trials.
Adjuvant Agents
Adjuvants are medications that can be administered in smaller doses when used in combination to achieve maximum benefits while minimizing side effects [Reference Brown, Pavone and Naranjo22]. Multimodal general anesthesia utilizes the advantage of various drug combinations targeting different sites in the nociceptive pathway and arousal systems [Reference Brown, Pavone and Naranjo22]. As previously discussed, the ideal IV agent would fulfill many characteristics, but adjuvants can supplement those gaps. Adjuvant agents include antiinflammatories, analgesics, and local anesthetics, which will be discussed heavily in their respective chapter, but also gabapentin and magnesium. This chapter will also discuss below adjuvant use in conjunction with regional anesthetics.
Ketorolac is a nonsteroidal antiinflammatory drug (NSAID) that acts by inhibiting cyclooxygenase-1 and 2 (COX-1 and COX-2), which decreases the production of prostaglandins. Prostaglandins are produced in response to tissue damage, leading to inflammation and pain. Ketorolac is a potent analgesic that is recommended for moderate to severe pain and a very useful IV adjuvant in attempts to spare the use of opioids. Ketorolac is typically used for a short period of time to avoid gastrointestinal bleeding and damage to the kidneys. Though the intramuscular route is an option, IV dosing includes 15–30 mg every 6 hours, but not exceeding 60–120 mg a day (dependent on kidney function).
Acetaminophen is produced in many formulations, and the mechanism of action remains unknown. It is suggested that it works similarly to ketorolac in that it decreases the production of prostaglandins, though likely a more central process than with NSAIDs, which work at the site of tissue damage. Acetaminophen is beneficial in treating mild to moderate pain and should be used as an adjuvant to analgesia in the anesthetic. Rectal and oral routes are commonly used successfully in pediatric analgesics. However, IV dosing includes 15 mg kg−1 (not to exceed 75 mg kg−1 per day in children <12 years old), given over 15–30 minutes every 6 hours, but not exceeding 4 g, with caution in those with liver disease.
Opioids act primarily at several receptors (μ, κ, δ) and prevent nociceptive transmission at the level of the spinal cord, brain, and peripheral nociceptors. Their action is mediated via the G protein-coupled receptor mechanism, causing hyperpolarization of afferent sensory neurons [Reference Brown, Pavone and Naranjo22–Reference Busch-Dienstfertig and Stein24]. They are often used as adjuvants with local anesthetics to prolong the duration and quality of postoperative analgesia [Reference Swain, Nag, Sahu and Samaddar23]. Table 6.4 provides dosing through different sites of administration for different opioids.
