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Preoperative Medication: Sedative Hypnotics and Other Agents and Issues

 

Preoperative Medication

Overview

  • 3Patient Assessment-Estimating the extent and basis of patient anxiety

    •  The extent of anxiety appears to be associated with the particular procedure being performed:

      • 85.7% of patients were about to undergo cancer surgery and 79% of patients about to undergo major genitourologic procedures report anxiety

      • 57.2% of patients undergoing other procedures report anxiety

    •  Patient presurgical concerns (ranked in order):

      1. Blindness

      2. Cancer diagnosis

      3. Loss of an organ

      4. Absence of a diagnosis

      5. Postoperative pain {the anesthesia provider, using a variety of techniques and medications, can minimize the unphysiologic condition of pain; The presence of postoperative pain may be a contributing factor for postoperative cardiovascular morbidity}

  • Psychological factors to consider

    • Appropriate levels of fear-the anesthesia provider may help set the patient's expectations:

      • postsurgical dissatisfaction may be related to unrealistic presurgical expectations, possibly due to inadequate or incomplete preoperative discussion with the patient concerning the procedure and possible outcomes

    •  Presurgical explanations should take into account the anxiety-state of the patient, i.e. a very anxious patient may have even further anxiety as a result of such discussions 

    •  Anesthesia providers may aid the patient in coping with preoperative anxiety by suggesting that patients focus their attention to other more pleasing or at least distracting activities

    •  Examples of effect of coping mechanisms which can be promoted by the anesthesia provider

      1.  Helping the patient view themselves as part of rather than separate from the health-care providing team. This type of "empowerment" reduces the likelihood of the patient regarding himself as an "victim" and can help the patient recognize their role in the decision-making process that led to surgery

      2.  The anesthesia provider may help the patient assume a level of control concerning their environment and situation-for example use of breathing control in promoting relaxation.  Providing opportunities for control may be especially important for children and young adolescence -- for example allowing a child to choose on which finger the pulse oximeter is to be placed would be such an example

      3.  Relaxation methods: The anesthesia provider may suggest contraction/relaxation cycles of muscles in a small region, such  toes or ankles

      4.  Mental distraction-such  music, selective attention, etc.  approaches which promote relaxation may be useful.

  • Time of administration: 1-2 hours before anesthesia induction

  • Outpatient setting: IV premedication just before surgery

    • Typically drugs are given closer to the time of surgery, i.e. the patient may arrive at the surgical setting without being premedicated (possibly anxious) with the idea of receiving medication just before the procedure

  • Primary goals for premedication (premedication agents may include antihistamines, antiemetics, alpha2 adrenergic receptor agonists, antacids, histamine receptor (H2) antagonists, opioids, benzodiazepines, gastrointestinal stimulants)

    • Anxiolytic effects -- reduction in patient anxiety with expected  reduction in circulating catecholamines

    • Sedation

    • Reduction in preoperative pain (analgesic effect)

    • Amnesia-the use of an amnestic agent is common with midazolam (Versed) often employed.  Midazolam (Versed) belongs to the benzodiazepine category of drugs

    • Reduction in secretion -- antisialagogue effect

    • Increase in gastric fluid pH with a decrease in gastric fluid volume-these effects are designed to reduce risk which may be associated with aspiration

    • Reduction of autonomic nervous system reflex responses-To accomplish this effect sometimes antimuscarinic agents are used in as a consequence surgical stimulation of muscarinic receptors are less likely to provoke adverse cardiac effects (e.g. bradycardia, arrhythmias)

    • Reduction in required anesthetic amounts -- Premedication with sedative-hypnotic agents and/or opioids to reduce the amount of anesthetic required to achieve a given level of anesthesia.  The advantages may include more rapid emergence upon completion of the case

    • Prophylaxis with respect to allergic reaction (e.g. antihistamines may be helpful)

  • Additional premedication issues:

    •  Reduced cardiac activity (e.g., an anticholinergic drug such as atropine may prevent bradycardia associated for example with surgical-induced stimulation of muscarinic receptors). To manage cardiac vagal activity, antimuscarinic agent should be administered DURING surgery, just prior to the expected need or in response to vagal stimulation

    • Reduction/avoidance of postoperative nausea and vomiting-facilitated with I. V. antiemetic drug administration JUST PRIOR to awakening (this approach is probably better than waiting for symptom developments and then treating the nausea)

    •  Postoperative analgesia may be best approached by use of IV opioids or neuraxial opioids JUST PRIOR to symptom development-here administration may be best provided just before awakening or just before a painful surgical action

  • Circumstances in which sedative-hypnotic (depressant) or some other pharmacological premedication would be warranted:

    1. Cardiac surgery

    2. Cancer surgery

    3. In the presence of pre-existing pain

      • Pain management is extremely important in all perioperative phases.  

        • This point of view is consistent with the consideration that pain is "unphysiologic". 

        • Preoperative pain may cause hypertension and other effects which may cause cardiovascular problems.  

        • Similarly, inadequate post-operative pain management may contribute to postoperative cardiac morbidity/mortality

    4. Regional anesthesia

  •  Some circumstances in which sedative-hypnotic (depressant) pharmacological premedication would NOT be warranted:

    1. In the hypovolemic patient

    2. In the presence of significant, severe pulmonary disease (additional respiratory depression associated with sedative-hypnotics would be ill-advised)

    3. Intracranial pathology

    4. Reduced level of consciousness

    5. Probably not in elderly patients

    6. Newborns (< 1 years of age)

  • Factors that influence the choice those drugs for premedications and associated dosages

    • Whether the surgery is classified as "inpatient" or "outpatient"

    • Whether the surgery is being performed as an elective or emergency procedure

    • Concerns about the ability of the patient to tolerate the drug

    • Patient age & weight & physical status

    • Anxiety level of the patient-Recall that an anxious patient is likely to have elevation of circulating catecholamines which may cause a suboptimal cardiovascular preoperative state

    • Whether the patient has had an adverse response to the particular medication during a previous procedure-This consideration emphasizes how important an adequate history or chart review is in deciding medication choice.

  • 3Routes of Administration:

    • Most common = intramuscular

      • Complications associated with intramuscular administration:

        • Sciatic nerve injury

        • Suboptimal drug absorption

        • Frequently "intramuscular" injection is actually deposited in adipose tissue, not muscle [frequency = 95% for women; 85% for men]

    • Administration for children (children may find needles and rectal administration objectionable)

      • Intranasal administration for children may be best; intranasal route of administration results in more rapid onset (compared to oral) with for example midazolam (Versed) and is also  beneficial because the approach does not require patient cooperation

    • Incremental intravenous sedation -- problem

      • Enough time must be allowed for the drug to take effect before additional dosage delivery

    • Oral premedication -- problem

      • Peak effect may not be realized before induction and significant and prolonged drug presence may complicate emergence following short surgical procedures [residual premedication, taken orally, maybe removed by stomach suctioning after induction]

 

Benzodiazepines

  • Overview:

    • Most commonly used sedative/anxiolytic

    • Anxiolytic effectiveness is observed at dosages which do not result in cardiopulmonary depression or excessive sedation

    • Certain benzodiazepines also exhibit significant anterograde amnesia (amnesia subsequent to drug administration).  

      •  Examples of these benzodiazepines include midazolam (Versed) and lorazepam (Ativan).

      •  These agents may also cause, on predictably, some degree of retrograde amnesia as well.

    • Benzodiazepines may also be used the night before schedule surgery in management of pre-surgical insomnia-- examples include lorazepam (Ativan), temazepam (Restoril), & triazolam (Halcion)

    • Sometimes benzodiazepines used pre-surgically can result in prolonged and excessive sedation.  Patients receiving lorazepam (Ativan) at high dosages (total dose > 4 mg orally at 5 ug/kg) may be most susceptible to this excessive sedation.  

      • A benzodiazepine antagonist, flumazenil (Romazicon) may be used to reverse benzodiazepine effects.

    • Intramuscular injection of diazepam (Valium) may be painful because diazepam (Valium) is dissolved in the irritating solvent propylene glycol; intramuscular injections of midazolam (Versed) does not cause local irritation since the chemical characteristics of midazolam (Versed) do not require the use of propylene glycol as a solvent (an aqueous solvent is used)

  •  Adverse Effects: benzodiazepines

    •  Major adverse effects

      • Respiratory depression

      • Reduction in cognitive & motor function

    •  Inpatient considerations:

      • If cognitive function need not be immediately returned to normal following procedure, lorazepam (Ativan) (oral) may be appropriate the morning of surgery

    •  Outpatient considerations:

      • Diazepam (Valium) (oral)

      • Midazolam (Versed) (IV), particularly appropriate

    • Factors/conditions which increase likelihood of preoperative excessive sedation associated with the use of benzodiazepines and other sedative hypnotics:

      • Infancy, advanced age (elderly patients), chronic debilitating disease or malnutrition, pregnancy, renal dysfunction, hepatic dysfunction, pulmonary dysfunction, adrenal insufficiency, myasthenia gravis, myotonia, sickle cell disease, acute drug/ethanol intoxication5.

  • 3Comparisons: midazolam (Versed), diazepam (Valium), and lorazepam (Ativan)
      Midazolam (Versed) Diazepam (Valium)  Lorazepam (Ativan)
    Dosage (oral) 0.3-0.5 mg/kg 0.15-0.2 mg/kg 0.015-0.03 mg/kg
    Time to peak effect thirty minutes-60 minutes 1-1.5 hours 2-4 hours
    Duration 1-2 hours 2-2.5 hours 4-6 hours
    Elimination halftime (time to reduce drug concentration by 50%) 1-4 hours 20-100 hours (includes active metabolites) 8-24 hours
    Apparent volume of distribution (Vd) 1.1-1.7 L/kg 0.7-1.7 L/kg 0.8-1.3 L/kg
    Presence of active metabolites yes, but relatively weak in effect prominent none
    Metabolic mechanism hydroxylation & conjugation hydroxylation & conjugation conjugation; conjugation reactions are less likely to be affected by age or the presence of hepatic disease
    Clearance

    6-11 ml/kg per minute

    0.2-0.5 ml/kg per minute

    0.7-1 ml/kg per minute

    Lipid solubility

    high

    high intermediate
    Effect of age in the elderly, midazolam (Versed) half-life may be increased by as much as eight hours in the elderly the half-life of diazepam (Valium) may be increased by several days  
    • 3Midazolam (Versed) & diazepam (Valium) comparisons:

      • Pharmacokinetic issues:

        • Midazolam (Versed): short half-life (1-4 hours); diazepam (Valium), including active metabolites: long half-life 20-100 hours

        • In elderly patients, diazepam (Valium) half-life may be extended to several days (midazolam (Versed) half-life may be extended by eight hours)

      •  Diazepam (Valium) metabolites: oxazepam which is Serax and desmethyldiazepam are active

      •  Weak midazolam (Versed) metabolites suggest that in the outpatient setting, midazolam (Versed) would be preferred.  Quicker recovery &  greater amnesia have been found with midazolam (Versed).

      •  Midazolam (Versed) in combination with opioids: cautious use in view of possible respiratory depression leading to inadequate oxygenation.  Nalbuphine (0.2 mg/kg) & midazolam (Versed) (0.09 mg/kg) may be the most appropriate combination in order to minimize respiratory complications at least in patients undergoing minor oral surgery

    •   Pediatric uses of  Midazolam (Versed)3:

      • Oral midazolam (Versed) (0.5 mg/kg) is useful in preventing "facemask phobia"

      • Following oral administration (midazolam (Versed), 0.5 mg/kg) the child is typically easily separated from parents and willing to accept monitoring and facemask

      • At a midazolam (Versed) dosage of 0.75 mg/kg, most pediatric patients {90%} undergo induction without crying or combative behavior

      • At these dosages, midazolam (Versed) effects last <  1 hour and do not appear to prolong recovery

      • Midazolam (Versed) administration (occasionally in combination with atropine, e.g.) can be facilitated by mixing with cherry syrup or with a melted popsicle.

      •  Special circumstances:

        •  In pediatric patients with congenital heart disease, midazolam (Versed) may improve oxyhemoglobin saturation in most cases; however in some children with cyanotic heart disease (3 of 17 tested) desaturation may occur with a reduction of greater than 10%.  

          • Accordingly,  pulse oximetry monitoring is essential.

      • Children with a compromised airway: midazolam (Versed) premedication would not be advised because apnea following midazolam (Versed) administration may be associated with an inability to mask ventilate

        • Crying itself (which may be made less likely by midazolam (Versed) administration) can worsen airway obstruction in the presence of, for example, epiglottitis or laryngeal papillomatosis, a condition of multiple papilloma grows on the larynx caused by a viral infection-this condition occurs with approximately equal frequency and children and adults.  

        Laryngeal papillomatosis, Epiglottitis

    • "The arrows point to multiple papilloma growths on the larynx caused by a viral infection. Permission to reproduce photo courtesy of the University of Pittsburgh Voice Center.

    • (Ed. note: This is a photograph that shows how laryngeal papillomatosis--RRP of the larynx--does not invariably present with a traditional cauliflower-appearance.)"
       

     

    Papillomatosis
     

    • From On-Line Airway Atlas 2000, John Sherry, II, M.D 1999,2000

    Epiglottis (with Abscess)

    • From On-Line Airway Atlas 2000, John Sherry, II, M.D 1999,2000

     

    • Intranasal midazolam (Versed) administration (0.2 mg/kg)

      • Less patient cooperation required (appropriate for combative children)

      • Quicker onset compared to oral Route of Administration

      • Occasionally (rare), midazolam (Versed) made evoked a hyperexcitability reaction-some anesthesia providers may wish to employ midazolam (Versed) only with relatively uncooperative patients

    • 3Lorazepam (Ativan)

      • Overview

        • No active metabolites; short half-life (approximately 15 hours)

        • Half-life not influenced by patient age

      • Pharmacokinetic/metabolism characteristics

        • Reduced, compared to diazepam (Valium), rate of CNS access secondary to relatively less lipophilicity

        • Onset of action for both diazepam (Valium) & lorazepam (Ativan) is similar, about 30-60 minutes

        • CNS effects e.g. psychomotor impairment, may be observed for 12 hours following the single lorazepam (Ativan) dose

        • Metabolism:

          • Glucuronidation (conjugation) followed by renal excretion

          • Glucuronidation reactions tend to be less susceptible to effects of aging or hepatic disease, i.e. typically no significant change in half-life as a function of age or liver dysfunction

      • Comparing lorazepam (Ativan) and diazepam (Valium):

        • Dosage -- 2 mg orally of lorazepam (Ativan) is about equal to 10 mg oral diazepam (Valium)

        • Sedation following a single 2 mg dose less about five hours

        • At higher dosages, such as 5 mg, anterograde amnestic effects may last up to about eight hours

        • Disorientation following the 5 mg dose may last as long as 17 hours; this finding suggests that the upper dosage limit for lorazepam (Ativan) perhaps should be 4 mg

        • Diazepam (Valium) --

          • At the 10 mg level: typically no amnesia

          • At the 20 mg level, about 30% of patients exhibit amnesia {4 mg of lorazepam (Ativan) (oral) results in an amnesia frequency of > 70%}

      • Lorazepam (Ativan) uses:

        • Appropriate for patients undergoing major surgical procedures which will be followed by intensive care unit monitoring

        • Advantage for seriously ill (critically ill) patients include:

          • Absence of myocardial depression or vascular smooth muscle relaxation even at doses above 9 mg 

        • Concerning typical premedication in patients with heart disease, sedative and anxiolytic action of flurazepam (Dalmane) (orally administered; 0.06 mg/kg, administered 90 minutes prior surgery) was comparably effective to a more traditional premedication regimen consisting of intramuscular morphine (0.1 mg/kg) combined with scopolamine

    Benzodiazepine pharmacology

    Diazepam (Valium)

    Midazolam (Versed)

     

    1Opioids

    • Overview

      •  Advantages for use in preoperative medication:

        1. Absence of myocardial depressant effects

        2. Alleviate the preoperative pain

        3. Management of discomfort associated with invasive monitor insertion

        4. Management of pain which may be associated with establishing regional anesthetia

      • Preoperative opioids may limit or eliminate the need for supplemental analgesics during the early postoperative phase

        • Pain experienced by lightly anesthetized patients may cause CNS changes that exacerbate pain postoperatively. 

          •  For example, in support of this hypothesis, a higher opioid concentration is required for suppression of C-fiber activation if pain has caused previous C-fiber activity

      • Generally,  in the absence of preoperative pain there may be no compelling reason to include a narcotic for preoperative anesthetic medication.  

        • On the other hand, opioid administration to patients experiencing preoperative pain not only relieves pain but also may induce a euphoric state.

    • Commonly used opioids for premedication

      • Most commonly used: morphine and meperidine (Demerol)

        •  Morphine:

          • intramuscular injection; good absorption with peak plasma levels obtained in about 45-90 minutes

          • intravenous administration: the effects occur more rapidly, usually within 20 minutes

        •  Meperidine (Demerol):

          • Relative to morphine intramuscular injection yields a less predictable time to onset

      • One advantage of including morphine as part of preoperative medication:

        • Morphine tends to suppress tachycardic responses to surgical stimulation during volatile anesthetic administration

    • Contexts for opioid administration:

      • Intramuscular: appropriate for nitrous oxide-opioid anesthesia

      • Intravenous administration:  appropriately administered immediately before induction (fentanyl (Sublimaze) is a good choice in this application)

      • Pain associated with regional anesthesia or associated with invasive monitoring catherization or even large intravenous lines may justify treatment with preoperative opioids.  

        • As would be expected for many agents, dosage reduction may be required for the elderly patient.  

        • Elderly patients may have reduced pain sensitivity that may exhibit an enhanced analgesic response to the opioid

      • Occasionally preoperative opioids are administered in advance of a nitrous oxide-opioid anesthesia plan -- the rationale is that previous opioid administration allows the anesthesia provider to gauge the  patients ensuing intraoperative opioid response. 

        • For postoperative pain, preoperative opioids may be employed; however, it is probably preferable to either provide administration in to recover room setting or perhaps most appropriately provide IV opioids during the emergence

        • Preoperative opioid administration may lower anesthetic requirements

        • For facemask induction, opioids may be used in combination with other agents-in this case opioid-mediated respiratory depression may decrease ventilation during spontaneous breathing which will reduce the rate of inhalational drug uptake. {the circumstance might arise if for some reason intravenous induction agents may not be used}

          • In this eventuality, the anesthesia provider may have to control ventilation, overcoming opioid-induced respiratory depression

    •  Adverse Effects:

      • Minimal cardiovascular effects are noted, except for high-dose meperidine (Demerol)

      •  Respiratory depression: associated with reduced responsiveness to CO2 (medullary respiratory center depression)

        • Even low-opioid doses reduce carotid body hypoxia responsiveness -- accordingly, anesthesia providers may wish to administer supplemental oxygen for those patients receiving opioids as premedication

          • The problem of using opioid agonist-antagonist agents, which cause reduced respiratory depression, is that they also are less effective analgesic drugs.  Also, these partial agonists may cause dysphoria (instead of the more expected euphoric response), a condition and not desirable in the preoperative time frame -- or probably any other time frame

      • Orthostatic hypotension secondary to peripheral vascular smooth muscle relaxation: 

        • Opioids prevent the expected compensatory peripheral vascular vasoconstriction.  

        • This effect is in addition to opioid- promoted histamine release that tends to cause a hypotensive reaction. 

        • The hypotensive  response will be more profound in patients who are hypovolemic. 

        • Hypotensive reactions can be avoided by ensuring that patients remained supine following opioids (and other) premedication agents.

      •  Nausea & vomiting: These effects are frequently associated with opioid administration, possibly occurring as a result of stimulation of the medullary chemoreceptor trigger zone or vestibular apparatus stimulation leading to motion sickness.

        • The likelihood of nausea and vomiting may be reduced by placing the patient in a recumbent position; however, the use of opioids because of their tendency to cause nausea and vomiting perhaps should be avoided in the same-day outpatient setting or if the surgical procedure's themselves are likely to cause nausea and vomiting {i.e. some gynecological and opthalmological surgeries}

      •  Delayed gastric emptying, which is associated with nausea symptoms, has two important consequences-(1) altered absorption rate for orally-administered agents and (2) and increased risk of pulmonary aspiration

      • Opioids may also cause smooth muscle constriction (biliary spasm {choledochododenal sphincter spasm, i.e. sphincter of Oddi}).  Manifestation consists of an upper right quadrant pain secondary to smooth muscle constriction

        • Patients with biliary tract disease should perhaps not receive opioids.  

        • Also pain associated with biliary spasm, e.g. caused by an opioid, may be difficult to distinguish from angina particularly since pain from either angina or biliary spasm would be relieved by smooth muscle relaxation due to sublingual nitroglycerin. 

        • Opioid-induced pain, however, would be relieved by administration of a pure opioid antagonist such as naloxone (Narcan) or naltrexone (ReVia) or possibly glucagon.  These drugs would not reverse true anginal pain.

        • Meperidine (Demerol) is less likely than morphine to cause biliary tract spasm.

      •  Pruritis-probably secondary to histamine release; 

        • Accordingly opioids may cause flushing and dizziness.  

        • Since opioids are miotic agents, pinpoint pupils may occur.

    • Specific agents:

      • Morphine:- dosage (5-15 mg, IM Route of Administration)

        • Well absorbed following IM administration

        • Time to onset: 15-30 minutes with peak effect at about 45-90 minutes with total duration of action as long as about four hours

          • With intravenous usage, significant, peak effects occur within about 20 minutes

        • Side reactions as noted for the opioid group in general, including ventilation depression; orthostatic hypotension as well as nausea and vomiting secondary to effects on the chemoreceptor trigger zone (CTZ) or on the vestibular apparatus

        • Reduction in GI motility

        • Preoperative use of morphine reduces cardioacceleration associated  with surgical stimulation and volatile anesthetic agents

      • Meperidine (Demerol) dosage:  (50-150 mg, IM Route of Administration)

        • Less potent compared to morphine (about 10% as potent)

        • Route of Administration: oral or parenteral

        • Single dosage effect duration: 2-4 hours with intramuscular injection providing a variable time to peak effect and duration

        • Elimination: mainly through hepatic metabolism

        • Cardiovascular effects: positive chronotropic effect secondary to antimuscarinic drug effects.

      • Fentanyl (Sublimaze):dosage-1-2 ug/kg intravenous for preoperative analgesia

        • Alternative Routes of Administration:

          • Oral (transmucosal) fentanyl (Sublimaze)-- 5-20 ug/kg [used in children & adults to diminish preoperative anxiety & pain)

            • Transmucosal fentanyl (Sublimaze) is associated with a high incidence of preoperative gastrointestinal disturbance (nausea & vomiting) typically at doses > 15 ug/kg:  Therefore, transmucosal fentanyl (Sublimaze) at these dosages is not recommended for patients < 6 years of age

        • Fentanyl (Sublimaze) issues:

          • Significant respiratory (ventilation) depression

          • Significant bradycardia

          • Fentanyl (Sublimaze) plus benzodiazepines may result in unwanted synergistic effects requiring close observation

          • Histamine release is NOT associated with fentanyl (Sublimaze)

          • Fentanyl (Sublimaze) administration does not cause myocardial depression

      • Agonist-antagonist agents

        • These drugs, e.g. pentazocine (Talwain), butorphanol (Stadol), nalbuphine exhibit reduced respiratory depression compared to pure opioid agonists; however, these drugs also have comparatively limited analgesic effects.

        • These partial agonist, given preoperatively, reduce the efficacy of pure opioid agonist given postoperatively to control postoperative pain.  Partial agonist  administration can in fact limit or reverse analgesia caused by the presence of the pure agonist

    • 4Side effect incidence following preoperative opioid administration: [1 hr following dosage]-- original citation: Forest, w.H., Brown, B.W. et al.: "Subjective responses to six common preoperative medications", Anesthesiology 47:241, 1977.

      • Morphine (5-10 mg):

        • Dry mouth 80%

        • Slurred speech 33%

        • Dizziness 15%

        • Nausea 7%

        • Relaxation 20%

      • Meperidine (Demerol) (50-100 mg):

        • Dry mouth 85%

        • Slurred speech 45%

        • Dizziness 20%

        • Nausea 12%

        • Relaxation 25%

    References:

    • 1Preoperative Medication in Basis of Anesthesia, 4th Edition, Stoelting, R.K. and Miller, R., p 119- 130, 2000) 

    • Hobbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives; Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc., 1996, pp. 364-367.

    • 3Sno E. White The Preoperative Visit and Premedication in Clinical Anesthesia Practice pp.  576-583 (Robert Kirby & Nikolaus Gravenstein, eds) W.B.  Saunders Co., Philadelphia, 1994

    • 4John R. Moyers and Carla M. Vincent Preoperative Medication in Clinical Anethesia, 4th edition (Paul G. Barash, Bruce. F. Cullen, Robert K. Stoelting, eds) Lippincott Williams & Wilkins, Philadelphia, PA, 2001

    • 5Kathleen R. Rosen and David A. Rosen, "Preoperative Medication" pp. 61-70 in  Principles and Procedures in Anesthesiology (Philip L. Liu, ed) J. B. Lipincott Company, Philadelphia, 1992 

     

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