http://surgerybook.net/

Table 13-3 Drugs for Antagonizing Nondepolarizing Neuromuscular Blockadea

The use of subjective train-of-four monitor is inferior to objective acceleromyography, a calibrated

device used to accurately establish the train-of-four ratio. It requires careful calibration and setup, and

access to the patient’s arm and hand. Although clinically effective at eliminating the limitations of

subjective train-of-four monitoring, its use remains limited because of the time spent in set up, and an

underappreciation of the frequency of residual neuromuscular blockade. It has been promoted by

patient safety experts, and is beginning to demonstrate increased penetration in Europe.

In addition to the limitations intrinsic to nerve monitoring devices themselves, nerve monitoring must

be performed with caution, as muscles in the body are not equally sensitive to muscle relaxants. The

diaphragm is most resistant to neuromuscular blockade, whereas the neck and pharyngeal muscles that

support the airway are most sensitive. It is possible for an intubated patient to spontaneously ventilate

and even to produce a large negative inspiratory effort and yet develop complete airway obstruction

when extubated because of the effects of residual muscle relaxant on the upper airway muscles.

As described earlier, a novel class of compounds known as selective relaxant binding agents, – currently

comprised of only one FDA-approved drug, suggamadex – may serve to revolutionize the practice of

neuromuscular blockade and its reversal. Such compounds are able to rapidly reverse the effects of

profound levels of muscle relaxation (0/4 twitches) created by steroidal nondepolarizing muscle

relaxant agents such as rocuronium, vecuronium, or pancuronium. Rather than attempting to increase

the concentration of acetylcholine, these agents physically bind free muscle relaxant molecules within a

cyclodextrin ring structure. This decreases the concentration of free muscle relaxant and allows

acetylcholine to function normally at the neuromuscular junction. The cyclodextrin–muscle relaxant

combination is then eliminated via the kidney. This offers the ability to rapidly (<3 minutes) reverse

profound muscle relaxation as surgical conditions warrant.2 This will enable profound relaxation during

wound closure, and then immediate reversal of blockade just prior to extubation. Its significant expense,

approximately $US 200 for a single dose of reversal of deep blockade, has limited its use.

Opioids (Narcotics) and Other Intravenous Analgesics

4 Narcotics and synthetic analogues belong to the class of drugs called opioids. The most commonly used

drugs in this family are morphine, fentanyl, and hydromorphone. Since the mid-1980s, a series of

synthetic opioids have been developed with fentanyl as the prototype. More recently developed

415

http://surgerybook.net/

synthetics (sufentanil, alfentanil, and remifentanil) are more potent and of varying duration (Table 13-

4). Opioids produce profound analgesia and respiratory depression. They have no amnesic properties,

minimal direct myocardial depressive effects, and no muscle-relaxant properties. Opioids can produce

significant hemodynamic effects indirectly by releasing histamine or blunting the patient’s sympathetic

vascular tone because of analgesic properties. The latter effect depends on the degree of sympathetic

tone that is present at baseline. Acutely injured patients may be hypovolemic and in pain, with high

sympathetic tone and peripheral vascular resistance. Patients in this condition can experience dramatic

drops in systemic blood pressure with minimal doses of opioids. For this reason, it is important to titrate

narcotics in small incremental doses. Because of the lack of direct myocardial depression and the

absence of histamine release with the synthetic opioids, they are frequently used as the primary

anesthetic in combination with an amnesic agent and a muscle relaxant in patients with significant

myocardial dysfunction.

When opioids are titrated intravenously, patients first become apneic because of the respiratory

depressive effect (shifting the CO2

response curve), but they still breathe on command. As the dose

increases, patients become apneic and unresponsive.

Opioids are primarily analgesic and not amnesic. Patients can be totally aware and have substantial

recall of conversations despite appearing completely anesthetized. All opioids can be reversed with

naloxone. The duration of action of naloxone can be shorter than that of the opioid, and patients must

be observed carefully for renarcotization after they have been treated with naloxone. Naloxone reversal

of opioids can be dangerous because the agent acutely reverses not only the analgesic effects of the

opioid but also the analgesic effects of native endorphins. Naloxone treatment has been associated with

acute pulmonary edema and myocardial ischemia and should not be used electively to reverse the

effects of a narcotic. It is appropriately used in an emergency situation when the airway is poorly

controlled and the patient is not ventilating because of an opioid overdose.

Table 13-4 Analgesics

Propofol

5 Propofol is a lipid-soluble substituted isopropyl phenol that produces a rapid induction of anesthesia in

30 seconds followed by awakening in 4 to 8 minutes after a single bolus. Intravenous propofol can

effectively produce total anesthesia (for less stimulating procedures), including amnesia, some

analgesia, and some degree of muscle relaxation. Propofol is unique because it is rapidly cleared

through hepatic metabolism to inactive metabolites in a way that the patient becomes alert soon after

cessation of the infusion. However, as the duration and dose of the maintenance infusion is increased,

the time to return to consciousness is also significantly increased. This context-sensitive half-life of

propofol must be incorporated into expectations of a “quick wake-up.” Propofol has direct antiemetic

properties and is a valid alternative to inhalational anesthetics in patients who have demonstrated a

history of prolonged, refractory postoperative nausea and vomiting. It has an important role in

intensive care units when used as a continuous infusion sedative at dosages of 25 to 50 μg/kg/min.

However, prolonged infusions have been associated with a lethal metabolic derangement known as

propofol infusion syndrome, characterized by a profound metabolic acidosis and cardiovascular

compromise.3 Due to dose-dependent direct myocardial depression and peripheral vasodilation, propofol

can produce significant hypotension when IV induction doses are administered. It also produces

416

http://surgerybook.net/

significant pain on injection in peripheral veins. Pain can be diminished or eliminated by pretreatment

with IV lidocaine via the vein to be used for propofol administration. Propofol is insoluble in aqueous

solution and therefore comes dissolved in a lipid emulsion that has the associated risk of bacterial

contamination. Once a vial of propofol is opened, it is not recommended that it be used after 12 hours.

Ketamine

Ketamine is a phencyclidine derivative that produces anesthesia characterized by dissociation between

the thalamus and limbic systems. Induction of anesthesia is achieved within 60 seconds after IV injection

of 1 to 2 mg/kg or within 2 to 4 minutes of intramuscular (IM) injection of 5 to 10 mg/kg. Patients

appear to be in a cataleptic state in which their eyes remain open with a slow nystagmic gaze. The drug

produces intense amnesia and analgesia but has been associated with unpleasant visual and auditory

hallucinations that can progress to delirium. The incidence of these problems can be significantly

reduced if benzodiazepines are also administered with the drug. At low doses (0.1 to 0.2 mg/kg IV or 2

mg/kg IM), patients continue to spontaneously ventilate, but cannot be expected to protect the airway

should vomiting occur. At higher doses, ketamine acts as a respiratory depressant and produces

complete apnea. Ketamine also has direct and indirect sympathetic nervous system stimulatory effects,

which can be useful in hypovolemic patients. These effects are diminished or absent in patients who are

catecholamine depleted. The sympathetic stimulatory effect increases myocardial oxygen consumption

and intracranial pressure, and ketamine is relatively contraindicated in patients with ischemic heart

disease or space-occupying intracerebral lesions. Owing to its analgesic properties and relatively

preserved respiration, ketamine is frequently used as an IV analgesic during debridement procedures, at

doses listed in Table 13-4. IM ketamine (1 to 2 mg/kg) is also very useful for sedating patients who are

difficult to manage (e.g., combative or cognitively disabled patient), so IV access can be obtained.

Ketamine’s most frequent use is in subanesthetic doses as part of multimodal analgesic regimens hoping

to minimize the use of opioids. For procedures requiring general anesthesia that may have significant

postoperative opioid requirements, a preincision ketamine bolus dose with a low-dose intraoperative

infusion may be associated with improved acute and chronic pain outcomes.4

Amnesics and Anxiolytics

Benzodiazepines are the primary class of agents used as amnesics and anxiolytics. The prototype drug,

diazepam, has been more recently replaced by its water-soluble analog of shorter duration, midazolam.

Lorazepam also belongs in this family of agents, but because it has a very long duration of action, it is

not routinely used intraoperatively. Lorazepam has intensive care unit applications (Table 13-5).

Benzodiazepines produce anxiolysis and some degree of amnesia, but have no analgesic properties.

Intraoperatively, midazolam is always used in conjunction with an opioid or inhalation agent.

Midazolam can be used in combination with the short-acting opioid fentanyl to produce conscious

sedation for minor procedures. Benzodiazepines can produce apnea and have synergistic adverse effects

with narcotics. Very small doses of midazolam and fentanyl can quickly produce an unconscious apneic

patient. As with all anesthetics, benzodiazepines used as IV agents for sedation should be given in small

incremental doses to achieve the desired effect. A reversal agent is also available for benzodiazepines

(flumazenil). The recommended dosages of these drugs and the reversal agents appear in Table 13-5.

Table 13-5 Anxiolytics and Amnesics (Benzodiazepines)

417

http://surgerybook.net/

Local Anesthetics

Local anesthetics constitute a class of drugs that temporarily block nerve conduction by binding to

neuronal sodium channels. As the concentration of the local anesthetic increases around the nerve,

autonomic transmission will be blocked first, followed by sensory transmission, and then motor nerve

transmission. These drugs can be injected locally into tissue to produce a field block, around peripheral

nerves to produce a specific dermatomal block, around nerve plexuses to produce a major conductive

block, or into the subarachnoid or epidural space to produce extensive neuraxial blockade. All the

methods have been used to assist in the provision of an alternative form of balanced anesthesia by

supplementing analgesia and muscle relaxation.

Adverse consequences associated with the use of local anesthetics fall into three categories: acute

central nervous system toxicity due to excessive plasma concentration, hemodynamic and respiratory

consequences due to excessive conduction block of the sympathetic or motor nerves, and allergic

reactions. Whenever a local anesthetic is injected, there can be inadvertent intravascular injection or an

overdose of the drug because of rapid uptake from the tissues. Overdose can produce seizures, as well

as cardiovascular collapse from ensuing arrhythmias. Complications can be minimized by withdrawing

before injection to avoid an intravascular injection and limiting dosages to the safe range (Table 13-6).

Table 13-6 Local Anesthetics

6 When local anesthetics are administered for a spinal or epidural block, they produce a progressive

blockade of the sympathetic nervous system, which produces systemic vasodilation. Sympathetic nerves

travel along the thoracolumbar region with the first four thoracic branches, including the cardiac

sympathetic accelerators. A sympathetic blockade of this entire region produces a characteristic

profound systemic vasodilatation and bradycardia. This condition is referred to as total sympathectomy,

and the hypotension that ensues is usually below the minimal cerebral perfusion pressure required to

maintain consciousness. Affected patients are bradycardic, hypotensive, unconscious, and usually apneic.

This disastrous situation is easily remedied if treated quickly with a vasopressor (phenylephrine or

ephedrine) and atropine or small doses of epinephrine (increments of 10 μg for an adult). If not treated

promptly, the situation proceeds to cardiac arrest. In this emergency situation, the treatment of high

doses of epinephrine is 10 to 40 μg/kg, or 1 to 4 mg for an adult. The doses of epinephrine are higher

than in a usual cardiac arrest because of the total sympathectomy.5 Because the level of sympathetic

block is two to six dermatomal levels higher than the sensory block, it is often difficult to obtain a high

spinal sensory level without approaching a total sympathectomy. For this reason, spinal or epidural

techniques can present a prohibitively high risk in patients with severe flow-dependent cardiovascular

disease.

Local anesthetics are chemically divided into two groups: esters and amides. The esters (2-

chloroprocaine and tetracaine) produce metabolites that are related to p-aminobenzoic acid and have

been associated with allergic reactions. Amides (lidocaine and bupivacaine) are rarely associated with

allergic reactions. If an allergic reaction does occur, it is most likely due to the preservative

(methylparaben) used in multidose vials of lidocaine.

418

http://surgerybook.net/