referred to their primary care physician and an anesthesiologist to create a pain management plan

prior to the day of surgery. Buprenorphine is mixed opioid agonist/antagonist that tightly binds at

the μ-receptor and has a long and varied half-life (24 to 60 hours). It can inhibit the analgesic

benefits of traditional opioids in the postoperative period, resulting in uncontrolled pain, decreased

patient satisfaction, and the potential for adverse events due to the need for very high doses of

opioids.

14 As positive-pressure ventilation impedes venous return within a closed thorax, decreases in systolic

pressure associated with a respiratory pattern can be detected. In patients with sinus rhythm with

stable cardiac contractility, the degree of systolic pressure variation (SPV) is inversely related to the

intravascular volume status of the patient. The normal range of SPV is 5 to 10 mm Hg. Other

measures such as pulse pressure variation (PPV) use similar physiologic assumptions to assess

volume status.

15 Enhanced recovery programs incorporating preoperative optimization, standardized surgical and

anesthesia protocols, and goal directed therapy may improve patient outcomes and reduce costs.

16 Postoperative acute pain management may require a multimodal approach that incorporates opioids,

peripheral nerve blockade, and nonopioid analgesics. Chronic pain patients can be particularly

difficult to manage and may require preoperative optimization by an anesthesiologist.

The goal of intraoperative anesthesiology interventions is to enable the safe conduct of otherwise

painful interventional procedures with maintenance of patient cardiopulmonary, renal, and neurologic

homeostasis while optimizing procedural conditions. The state of general anesthesia is a combination of

hypnosis, amnesia, analgesia, and muscle relaxation. This state can be achieved by administration of

single or multiple anesthetic agents via inhalational or intravenous routes. Historically, anesthesia was

achieved by inhaling volatile anesthetic vapors that produced each of these conditions in proportion to

the concentration achieved in the central nervous system. Anesthesia can also be achieved by using a

balance of multiple pharmacologic agents, each targeted to produce a specific effect. These are the

hypnotic/sedatives, analgesics, and neuromuscular blocking agents. As the concentration of

hypnotic/sedative and analgesic agents increases, cardiovascular and respiratory functions may be

progressively blunted. For this reason, modern anesthetics usually require titration of these agents to

optimize conditions for the surgery while maintaining cardiovascular stability.

Surgical anesthesia is administered with a high degree of safety 30 to 40 million times a year in the

United States, despite the serious potential complications of technical or judgment errors. The high

degree of success of both surgical and anesthetic outcomes is due to the efforts of thousands of surgeons

and anesthesiologists who have advanced the art and science of their field.1 Although modern surgical

techniques, regional or neuraxial blockade procedures, and systemic analgesics have made it possible to

ameliorate perioperative pain, significant challenges in postoperative pain management remain. Pain

not only is unpleasant, but also can provoke a stress response within the body, leading to significant

adverse physiologic effects.

ANESTHETIC AGENTS AND THEIR PHYSIOLOGIC EFFECTS

Inhalation Agents

1 Anesthetics are generalized depressants of consciousness, pain, cardiopulmonary function, motor

function, and recall. The potent inhalation agents (e.g., isoflurane, sevoflurane, desflurane) produce

these effects in a dose-dependent fashion. The measurement used to compare the potency of inhalation

agents is the minimum alveolar concentration (MAC), an empirically derived number defined as the

expired percent concentration required to prevent movement on painful stimulation (incision) in half of

experimental subjects. There is significant patient-to-patient variability independent of underlying

comorbidities. Compounding this variability are the effects of age, weight, pre-existing heart disease,

liver disease, and medications other than the inhalational anesthetic. Table 13-1 lists the modern

commonly used inhalation agents and their MACs and side effects. In general, all agents depress blood

pressure by myocardial depression and vasodilation, resulting in systemic hypotension. There is a

generalized depression of cerebral function and cerebral metabolic rate of oxygen consumption,

although cerebral blood flow may increase because of cerebrovascular dilatation and a loss of flowmetabolism coupling. Renal blood flow and glomerular filtration rate are reduced by 20% to 50%. The

412

http://surgerybook.net/

body’s normally tight regulation of core body temperature is lost, resulting in a redistribution of heat

from the core to the periphery. The combination of these effects, the cold environment of the operating

room, and open body cavities make the patient extremely vulnerable to hypothermia (core body

temperature <36°C).

Intravenous Sedatives/Hypnotics

Several commonly used intravenous sedative/hypnotic medications can also be used in lieu of an

inhalational anesthetic to achieve the hypnotic component of the state of anesthesia. A constant

intravenous infusion of these medications is used to achieve and maintain a blood concentration that

results in the loss of consciousness and prevents recall. Unlike the inhalational agents, currently, there is

no ability to measure the patient’s expired or blood concentration of these intravenous agents. As a

result, the infusion rate is titrated to effect by observing patient movement (if muscle relaxants are not

used concurrently) and hemodynamic responses to procedural stimuli. Of note, the sedative/hypnotic

intravenous agents do not possess clinically useful muscle relaxant or analgesic properties and must be

combined with other agents to deliver a “balanced” anesthetic. The most commonly used intravenous

agent for maintenance of anesthesia is propofol, a lipid-soluble substituted isopropyl phenol, that

produces hypnosis and sedation through interactions with Γ-aminobutyric acid (GABA), the primary

inhibitory neurotransmitter of the central nervous system. When administered as a continuous infusion,

propofol can achieve minimal levels of sedation, deep sedation, or general anesthesia. Additional details

regarding the use and side effects of propofol are discussed later. Other classic agents such as

benzodiazepines can also be used as maintenance infusions, but do not enable the rapid return to

consciousness that propofol offers. A novel, highly specific α2

-receptor agonist, dexmedetomidine, has

recently demonstrated an exciting role as an intravenous sedative/hypnotic that also has analgesic

effects and a lack of respiratory depression. In the perioperative setting, it is currently limited to use as

an adjunct to propofol and inhalational anesthetics for general anesthesia or as a sole agent during

procedural sedation.

Table 13-1 Common Inhalation Agents: Minimum Alveolar Concentrations and

Effects

Muscle Relaxants

2 To prevent movement and to facilitate the surgical exposure, neuromuscular blocking agents are

generally used. These drugs are competitive or noncompetitive inhibitors of the neurotransmitter

acetylcholine at the neuromuscular junction. The only noncompetitive inhibitor used clinically is

succinylcholine. This drug rapidly binds to the nicotinic receptors and produces depolarization at the

neuromuscular junction, clinically manifesting as fine-muscle fasciculations occurring about 30 to 60

seconds after injection. Succinylcholine cannot be reversed, but has a short duration of action (<10

minutes) because it is quickly hydrolyzed in the plasma by cholinesterase. Because of rapid onset and

short duration of action, succinylcholine is frequently used to facilitate endotracheal intubation when it

must be accomplished quickly, or when quickly regaining neuromuscular function is beneficial.

All other clinically useful muscle relaxants are termed competitive inhibitors and do not cause

depolarization when they attach at the neuromuscular junction (nondepolarizing). Because these agents

413

http://surgerybook.net/

compete with endogenous acetylcholine, the block produced is in direct proportion to the concentration

of the agent relative to the concentration of acetylcholine. If the concentration ratio is low enough,

competitive relaxants can be reversed if the concentration of acetylcholine is artificially elevated.

Acetylcholine concentration can be increased by giving a drug that blocks its metabolism, an

anticholinesterase (e.g., neostigmine). The neuromuscular blocking agent is still present, but motor

function returns if the acetylcholine concentration is high enough to overwhelm the blocking agent.

There is a ceiling to which anticholinesterase drugs can safely elevate circulating acetylcholine; above

this threshold, a novel selective relaxant binding agent, suggamadex, may be used to reverse the effects

of specific nondepolarizing neuromuscular blocking drugs (rocuronium and vecuronium). Using

anticholinesterases to reverse neuromuscular relaxants is not analogous to using naloxone to reverse the

effects of opioids. The reversal agent neostigmine does not compete or combine with the relaxant.

Unfortunately, there are systemic consequences to increasing the plasma concentration of

acetylcholine. Acetylcholine is the predominant neurotransmitter in the preganglionic sympathetic and

parasympathetic nervous systems and in the postganglionic parasympathetic nervous system. For this

reason, an anticholinergic drug (atropine or glycopyrrolate) must be given with the anticholinesterase

to prevent the undesirable effects of a generalized acetylcholine overdose. Given these side effect

profiles of anticholinesterase drugs, the selective relaxant binding agent suggamadex – recently

approved for use in the US – offers new promise for reversing high levels neuromuscular blockade. The

common neuromuscular blocking drugs and their doses, durations, and side effects are listed in Table

13-2; common regimens of reversal agents are shown in Table 13-3.

3 Postoperative residual neuromuscular blockade is now recognized as a common problem after

routine administration of nondepolarizing muscle relaxants. The evaluation of depth of muscle

relaxation is a subjective process based upon empirical pharmacokinetics or visual inspection of a

patient’s peripheral nerve response to an artificial electrical stimulation. During peripheral nerve

stimulator monitoring, two electrode patches are placed on the patient’s skin along the course of a

peripheral nerve which innervates a distinct and observable muscle group. Commonly used monitoring

locations include the ulnar nerve, ophthalmic branch of the facial nerve, or the posterior tibial nerve.

Next, the electrodes are connected to a hand-held device which delivers four short transcutaneous bursts

of electricity, ranging from 10 to 100 mA every 0.5 seconds, hence the term “train-of-four monitoring.”

A clinician visually inspects the response to each electrical stimulation. In a patient without any

pharmacologic neuromuscular blockade, the strength of the fourth muscle response (or “twitch”)

matches that of the first. In the face of complete pharmacologic competitive inhibition of neuromuscular

transmission, no muscular twitches are observed at all. At varying levels of neuromuscular blockade in

between, the fourth, third, or second twitch may be absent. Due to competitive blocking of the

neuromuscular junction nicotinic receptor, each incremental stimulation results in a weaker response

because of increasingly limited receptors available for stimulation. The ratio between the strength of

the fourth twitch and the first twitch is known as the train-of-four ratio. During normal neuromuscular

transmission, the ratio is 1. Historically, a ratio of 0.7 was considered adequate muscular strength for

extubation. However, more recent literature suggests that a ratio between 0.7 and 0.9 still exposes the

patient to significant risks of atelectasis, hypoxemia, aspiration, pneumonia, and possibly reintubation.

In routine practice, a clinician is incapable of assessing a concept as precise or nuanced as train-of-four

ratio. As a result, the number of twitches observed is typically reported, that is, 0/4, 1/4, 2/4, 3/4, 4/4.

A patient with 3/4 or 4/4 twitches is capable of responding to cholinesterase inhibitors and return to

normal function. A patient with 0/4, 1/4, or 2/4 is unlikely to respond to cholinesterase inhibitors with

full return of muscular strength. Data from multiple centers have demonstrated that a significant

proportion of patients demonstrated residual neuromuscular blockade of <0.9 in the recovery room

despite reversal.

Table 13-2 Common Neuromuscular Blocking Drugs and Reversal Agents

414