An Astes i Ology

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MEDICAL PROGRESS

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Review Article

Medical Progress

A

NESTHESIOLOGY

Second of Two Parts

R

ICHARD

A. W

IKLUND

, M.D.,

AND

S

TANLEY

H. R

OSENBAUM

, M.D.

From the Department of Anesthesiology, Yale University School of Med-icine, 333 Cedar St., New Haven, CT 06520-8051, where reprint requestsshould be addressed to Dr. Wiklund.

1997, Massachusetts Medical Society.

Local Anesthetics

Local anesthetics can be administered by local or

regional injection to provide anesthesia during sur-gery. Regional injection of local anesthetics is usedfor major nerve block and for spinal (subarachnoid)or epidural block. Although local anesthetics areamong the most widely used anesthetic agents andhave a good record of clinical safety, questions abouttheir toxicity have recently been raised.

The amide local anesthetics (lidocaine, mepiv-acaine, and bupivacaine) have replaced the esters(e.g., procaine) because of their stability and the factthat they do not cause allergic reactions. Because of its high lipid solubility and high affinity for nonspe-cific protein-binding sites, bupivacaine has a muchlonger duration of action than the other amides.However, the avid binding of bupivacaine to non-specific cardiac protein-binding sites after an unin-tentional intravenous injection may lead to pro-found myocardial depression and intractable cardiacarrest. With other amides, such as lidocaine, centralnervous system effects after an excessive dose or anunintended intravenous injection occur at a muchlower blood level (8 to 10 m

g per milliliter) thanthat associated with cardiovascular toxic effects (20

m

g per milliliter). Central nervous system toxic ef-fects caused by local anesthetics can be controlled

with the intravenous administration of benzodiaz-epines (midazolam or diazepam) or thiobarbiturates(thiopental) and protection of the patients airway and management of ventilation. Toxic effects in thecentral nervous system and cardiovascular system oc-cur at the same blood level of bupivacaine (3 to 5 m

g

per milliliter). Prolonged resuscitation and repeatedadministration of epinephrine may not restore cardi-ac function. Reports of profound cardiovascular de-pression have been associated, for the most part,

with the use of a higher concentration of bupiva-caine (0.75 percent). Consequently, this concentra-tion is not recommended for routine use.

Ropivacaine is a new amide local anesthetic witha duration of action similar to that of bupivacaine.

101

Its pharmacokinetic properties are also similar tothose of bupivacaine,

102

although ropivacaine is lesslipid-soluble and therefore less potent. Stereoisom-erism is not present with ropivacaine but is present

with bupivacaine. The R

(rectus) isomer of bupiva-caine stays in the sodium channel for a prolongedperiod, which may result in cardiotoxic effects.

103

The S

(sinister) isomer of bupivacaine stays in thecardiac sodium channel for a shorter period. Thus,it is hypothesized that ropivacaine has clinical phar-macologic characteristics similar to those of bupiva-caine but without cardiotoxic effects. This hypothe-sis is supported by studies of isolated perfused rabbithearts, which have shown that bupivacaine has strong-er cardiodepressant and arrhythmogenic effects thaneither lidocaine or ropivacaine.

104

Lidocaine has been used for spinal and epiduralanesthesia for decades because of the rapid onset andpredictable duration of its action. Recent modifica-tions of the technique of administering spinal anes-thesia are believed to result in high local concentra-tions of spinal preparations of lidocaine (5 percentlidocaine in a hyperbaric or denser-than-cerebrospi-nal-fluid solution of dextrose). A high concentrationof the spinal anesthetic solution may result in a tran-sient radicular irritation, characterized by burningradicular pain starting 24 hours after spinal anesthe-sia and lasting no more than two days.

105

Hampl etal. reported transient radicular irritation in up to onethird of patients receiving lidocaine for spinal anes-thesia; transient radicular irritation did not occur

when bupivacaine was used as the spinal anesthet-ic.

106

In a double-blind study comparing isobaric orhyperbaric lidocaine with bupivacaine for spinal an-esthesia, Pollock et al. reported transient radicular ir-ritation in 13 percent of the patients receiving lido-caine for hernia repair and in 16 percent of thepatients receiving lidocaine for arthroscopy but innone of those receiving bupivacaine.

107

The authorspostulated that surgical positioning and manipula-tion may contribute to the local anesthetic effect.Similar reports of radiculopathy led to the withdraw-al of FDA approval of the use of microcatheters toadminister 5 percent lidocaine for continuous spinal

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The New England Journal of Medicine

anesthesia.

108

It is not clear why these reports are ap-pearing now, after decades of experience with theuse of lidocaine for spinal anesthesia. In early clinicalstudies, transient radicular irritation has not been as-sociated with the use of ropivacaine for spinal anes-thesia.

109

PAIN

The control of pain in the perioperative periodmay improve the outcome, shorten the hospital stay,and allay patients anxiety about surgery.

110,111

Mul-timodal pain relief is based on the additive, or evensynergistic, effect achieved when a variety of medi-cations and techniques are combined to relieve painand minimize complications.

112

Sensory blockadebefore surgical incision, termed preemptive analge-sia, prevents the sensitization of pain receptors andenhanced transmission in spinal neuronal pain path-

ways.

113

Multimodal Analgesia

The chief advance in pain control in the past 20 years has been the concurrent use of multimodal an-algesia and computerized techniques of continuousinfusion. With the multimodal approach to pain re-lief, a variety of agents, including local anesthetics,nonsteroidal antiinflammatory drugs, opioids, a

2

-adrenergic agonists, and N

-methyl-

D

-aspartic acidreceptor inhibitors are combined to maximize theinhibition of pain pathways. These agents are activeat pain receptors, peripheral nerves, the spinal cordlevel, and the cerebral cortex. Additive and synergis-tic effects have been shown when intrathecal (spinal)morphine is combined with intrathecal clonidine,norepinephrine, carbachol, or midazolam in labora-tory animals.

114

Nonsteroidal antiinflammatory drugs are effectiveanalgesics but may be contraindicated in some cir-cumstances. Ketorolac and piroxicam provide excel-lent pain relief after procedures such as laparoscopy,arthroscopy, and even hip arthroplasty. For surgicalprocedures with outcomes that might be endan-gered by hematoma formation, however, nonsteroi-dal antiinflammatory drugs are not prescribed. Sim-ilarly, there is concern about the risk of renal failure

with the use of nonsteroidal antiinflammatory drugsin patients with abnormal preoperative renal func-tion. In patients receiving long-term therapy withnonsteroidal antiinflammatory drugs, the drugs haveto be discontinued before surgery because of theirantiplatelet activity. When their use is appropriate,however, they have the advantage over opioids of notcausing nausea and vomiting.

Peripheral-nerve blocks produce complete anes-thesia within the area of innervation. Analgesia may be prolonged by the addition of opioids or a

2

-adreno-ceptor agonists. Unfortunately, a selective block of peripheral-nerve pain pathways without sensory or

motor blockade has not been achieved with local an-esthetics.

The discovery of morphine receptors in the dorsalhorn of the spinal column led to the neuraxial (sub-arachnoid or epidural) administration of opioids toinduce analgesia.

115

Multimodal therapy with com-binations of opioids or local anesthetics or both hasbeen used for both epidural and spinal anesthesia

with prolonged postoperative analgesia. Neuraxialadministration of opioids allows early ambulation af-ter major surgery without pain or hemodynamic in-stability. Orthostatic hypotension limits ambulation

when local anesthetics continue to be administeredafter surgery for neuraxial pain relief. When opioidsare administered neuraxially, their distribution andefficacy are determined according to lipid solubility.The fentanyl series of opioids is highly lipid-soluble,and neuraxial administration results in rapid systemicabsorption, high blood levels, and a limited der-matomal distribution of analgesia. Morphine, how-ever, is less lipid-soluble and spreads slowly withinthe subarachnoid and epidural spaces, providing moreextensive dermatomal analgesia. Unfortunately, theadministration of neuraxial morphine results in ahigher incidence of complications, including delayedrespiratory depression, pruritus, and urinary reten-tion. Hydromorphone is similar to morphine in pro-ducing neuraxial analgesia but has fewer side effects.

Patient-controlled administration of intravenousor epidural analgesics involves the use of small, com-puterized pumps for the administration of analgesicsolutions. The solutions may contain mixtures of lo-cal anesthetics and opioids or opioids alone. A base-line infusion may be supplemented by bolus dosestriggered by the patient. The frequency of the bo-luses is controlled to prevent inadvertent overdoses.The efficacy of patient-controlled administration isoften monitored with the use of a visual-analoguescale to record the patients perception of the inten-sity of pain, with the goals of rapid pain relief, con-tinuous analgesia, and minimal nursing intervention.Patient-controlled epidural administration is more ef-fective than patient-controlled intravenous adminis-tration in maintaining postoperative analgesia, butpatients find the two methods equally satisfactory.

116

Patient-controlled analgesic techniques, however,have not been shown to reduce the hospital stay af-ter surgery.

a

2

-Adrenoceptor agonists (e.g., clonidine and dex-medetomidine) bind to prejunctional and postjunc-tional receptors and work synergistically with opioidagonists to inhibit afferent neurons and brain-stemnuclei involved in pathways of pain.

117,118 Clonidinehas been shown to induce analgesia, potentiateinhalational anesthetics, augment opioids, produceanxiolysis and sedation, and control hypertension.

119

Epidural administration of clonidine potentiates theeffect of fentanyl, reduces total opioid requirements,



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and reduces the incidence of respiratory depres-sion.

120

However, other than for transdermal use tocontrol hypertension, clonidine is not approved foruse in the United States. Dexmedetomidine, a highly selective a

2

-adrenoceptor agonist, decreases the totalamount of isoflurane required for anesthesia duringabdominal hysterectomy.

121

The addition of theseagents to local anesthetic solutions for epidural orspinal anesthesia significantly prolongs postoperativeanalgesia.

122

Preemptive Analgesia

Surgical stimuli cause central sensitization of ex-citable spinal neurons in addition to lowering thethreshold for peripheral afferent pain terminals. Thiscentral sensitization, termed neuroplasticity, orwindup,

123

appears to be mediated by excitatory amino acid neurotransmitters and neuropeptides.Slow synaptic nerve potentials are generated by A

d

and C fibers in the dorsal-horn neurons. The sum-mation of potentials produces long-lasting depolar-ization of dorsal-horn neurons and facilitates theperception of pain. Activation is tied to increasedcalcium permeability and activation of guanosine tri-phosphatebinding proteins and protein kinase.

106

The clinical relevance of these neurophysiologicchanges is that N

-methyl-

D

-aspartic acidreceptorantagonists prevent neuroplasticity and may play apart in the long-term management of chronic pain.Preemptive analgesia is an important therapeutic ap-proach that uses combinations of local anesthetics,neuraxial blockade, and inhibition of mediators of central neuroplasticity to prevent mechanisms of self-perpetuating pain.

Advances in the management of acute pain, par-ticularly those related to the use of epidural analge-sia, have led to improved outcomes, such as greaterpain relief and satisfaction on the part of patients,

116

decreased postoperative sedation, earlier ambula-tion, a lower incidence of respiratory complications,and an earlier return of bowel function.

124

Increasedblood flow to the lower extremities improves the pa-tency of arterial grafts and reduces the incidence of deep-vein thrombosis.

125,126

Stress-induced sympa-thetic nervous system activity and possibly cardiacmorbidity are reduced when epidural anesthesia andanalgesia are used in high-risk surgical patients.

111

Qualified anesthesiologists have also expanded thetechniques of analgesia to manage chronic pain.

127

NEW TECHNIQUES

Pulse Oximetry and Capnography

Prompted by the Harvard Medical School reporton standards of monitoring during anesthesia,

128

the American Society of Anesthesiologists has become aleader in the adoption of standards of care andguidelines for practice.

129

As a result, pulse oximetry and capnography (the analysis of carbon dioxide in

exhaled air) are now used routinely to monitor gen-eral anesthesia in virtually all surgical patients in theUnited States.

130

Despite optimistic predictions thatthe use of pulse oximetry would reduce the inci-dence of hypoxic injuries during anesthesia, in a pro-spective, randomized study of 20,000 patients at fiveDanish hospitals, there were no significant differenc-es in cardiovascular, respiratory, neurologic, or infec-tious complications between patients who weremonitored with pulse oximetry and those who werenot.

131,132

However, even a sample of 20,000 patientsmay be too small to identify a benefit of pulse oxim-etry, since major complications are fortunately rare.Clearly, noninvasive pulse oximetry provides thephysician with an early warning of impending hy-poxia.

133,134

Infrared capnography is useful for diag-nosis and the management of esophageal intubation,endobronchial intubation, airway obstruction, bron-chospasm, hypermetabolic states, pulmonary embo-lism, venous air embolism, and cardiogenic shock.

135

In addition, it is useful for identifying mechanicalproblems in anesthetic circuits. The benefit of rou-tine use of pulse oximetry and capnography, as wellas the favorable results of costbenefit analyses, hasled malpractice insurers to offer practitioners incen-tives for their use.

136

Airway Management

The laryngeal-mask airway represents a major advance in airway management.

137

The device rests inthe hypopharynx, and an inflatable cuff surroundsthe glottic opening. The proximal end of the laryn-geal-mask airway is similar to a standard endotrache-al tube and can be used to provide anesthetic gasesfor either spontaneous or controlled ventilation. InGreat Britain, the device has replaced the endotra-cheal tube for airway management in approximately 50 percent of patients undergoing surgery, especially those in ambulatory units.

138,139

Use of the laryngeal-mask airway eliminates the need for laryngoscopy and intubation of the trachea. The device can beused for neonatal resuscitation without intubationand can also be used to maintain a patent airway

without the need for mask ventilation.In the United States, the laryngeal-mask airway is

used as an adjunct in airway management and hasnot replaced the endotracheal tube. The main short-coming of the device is that it does not protect therespiratory tree from aspiration of gastric contents inpatients with gastric reflux

140

and is therefore notsuitable for use in patients undergoing emergency surgery, those with symptomatic hiatal hernias orpeptic ulcer disease, or those who are obese or preg-nant. In patients with reduced pulmonary compli-ance, controlled ventilation is difficult to maintain

with the laryngeal-mask airway because the in-creased airway pressure can cause air to leak aroundthe cuff and lead to gastric distention.



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The New England Journal of Medicine

POSTOPERATIVE COMPLICATIONS

Postoperative complications directly related to theadministration of anesthesia range from importantbut self-limited problems, such as protracted nauseaand vomiting, to more serious complications, suchas aspiration pneumonitis, renal failure, and liverdysfunction.

Nausea and Vomiting

Nausea and vomiting account for the majority of unanticipated admissions to the hospital after ambu-latory surgery, particularly in children.

141

In a multi-center study of a variety of anesthetic techniques,Forrest et al. reported that the incidence of postop-erative nausea and vomiting was 18 to 25 percent.

142

Only 0.15 percent of the patients, however, had severe emesis. The incidence of nausea and vomiting was highest with fentanyl-based anesthesia. Otherstudies have shown that the incidence is lower withpropofol than with thiopental for the induction of anesthesia. The emetic effects of anesthetics aremodulated in the chemoreceptor trigger zone andthe emetic center of the central nervous system by serotonergic, histamine, muscarinic, and dopaminer-gic receptors.

143

Traditional antiemetic agents in-clude promethazine (a histamine-receptor antago-nist), atropine (a muscarinic-receptor antagonist),and droperidol (a dopaminergic-receptor antago-nist). Ondansetron, tropisetron, and granisetron (ser-otonergic-receptor antagonists) have been reportedto be highly effective in controlling postoperativenausea and vomiting.

144

The cost of these new agents is offset by the reduction in unanticipatedhospital admissions.

145

Aspiration Pneumonitis

Warner et al. retrospectively reviewed the inci-dence and consequences of pulmonary aspiration of gastric contents during 215,488 anesthetic proce-dures performed between 1985 and 1991.

146

Aspira-tion of gastric contents occurred in 1 of every 3216procedures, but the overall mortality was only 1 in71,829. Sixty-four percent of the patients with aspi-ration of gastric contents had no sequelae. Six pa-tients required mechanical ventilation for more than24 hours; three of the six did not survive. All threepatients who died had severe predisposing condi-tions, such as gastrointestinal obstruction. Thus, therecognition and management of factors that placepatients at risk for aspiration seem to have reducedthe seriousness of this complication as originally de-scribed by Mendelson.

147

Renal Failure and Hepatic Dysfunction

Hepatotoxic effects after exposure to inhaled an-esthetics are thought to be caused by cytochromeP-450mediated oxidative or reductive metabolism

with the production of reactive metabolites.

71

These

metabolites may initiate an immune response thatresults in hepatic necrosis. Nephrotoxic effects arerelated to the extent of metabolism and the durationof very high free fluoride levels in the bloodstream.Clinically relevant toxic effects are limited to the kid-ney and liver. Agents that have been implicated inorgan failure include halothane and the now obso-lete gases chloroform, trichloroethylene, and meth-oxyflurane. Severe but extremely rare hepatotoxiceffects have been reported with enflurane and isoflu-rane.

148,149

The metabolism of sevoflurane also hasthe potential to produce nephrotoxic levels of fluo-ride. Sevoflurane and desflurane have not been re-ported to cause hepatic dysfunction.

In addition to the toxic effects of metabolites, in-halational anesthetics may cause organ dysfunctiondue to decreases in perfusion. Halothane markedly reduces both portal venous and hepatic arterialblood flow in proportion to the degree of anesthe-sia.

150

Decreases in total hepatic blood flow lead toreduced oxygen delivery, which results in organ in-

jury. This mechanism is particularly important in pa-tients with chronic liver disease and portal hyper-tension. Marginal hepatocellular function may becompromised, with reduced total hepatic blood flow,and acute hepatic failure may be precipitated in thepostoperative period. However, decreases in total he-patic blood flow may be due to the use of noninha-lational anesthetics, surgical manipulation, or the useof vasopressors. Similarly, postoperative renal dys-function may result from the hemodynamic effectsof inhalational anesthetics on renal blood flow andantidiuretic hormone secretion.

151

We are indebted to Drs. Paul Barash and Joel Rappeport for their encouragement and assistance with the manuscript.

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102. Emanuelsson BM, Zaric D, Nydahl PA, Axelsson KH. Pharmacoki-netics of ropivacaine and bupivacaine during 21 hours of continuous epi-dural infusion in healthy male volunteers. Anesth Analg 1995;81:1163-8.

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105. Tarkkila P, Huhtala J, Tuominen M. Transient radicular irri tation afterspinal anaesthesia with hyperbaric 5% lignocaine. Br J Anaesth 1995;74:328-9.

106. Hampl KF, Schneider MC, Ummenhofer W, Drewe J. Transient neu-rologic symptoms after spinal anesthesia. Anesth Analg 1995;81:1148-53.

107. Pollock JE, Neal JM, Stephenson CA, Wiley CE. Prospective study ofthe incidence of transient radicular irritation in patients undergoing spinalanesthesia. Anesthesiology 1996;84:1361-7.

108. Rigler ML, Drasner K, Krejcie TC, et al. Cauda equina syndrome af-ter continuous spinal anesthesia. Anesth Analg 1991;72:275-81.

109. van Kleef JW, Veering BT, Burm AG. Spinal anesthesia with ropiv-acaine: a double-blind study on the efficacy and safety of 0.5% and 0.75%solutions in patients undergoing minor lower limb surgery. Anesth Analg1994;78:1125-30.



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