Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Anesthetics, general
General information
The inhalational and injectable agents that are covered in separate monographs are listed in Table 1 .
Table 1
Inhalational and injectable anesthetics
| Inhalational | Injectable |
|---|---|
| Halogenated Chloroform Desflurane Enflurane Halothane Isoflurane Methoxyflurane Sevoflurane Trichloroethylene Others Anesthetic ether Cyclopropane Nitrous oxide Xenon |
Barbiturates Methohexital Thiamylal Thiopental Others Alfadolone/alfaxolone Etomidate Ketamine Propanidid Propofol |
The inhalational agents in common use share similar adverse effects, albeit with differing incidences. Initial hopes that new agents will be less problematic generally fade as their use increases and familiarity with their adverse effects grows. Although some untoward reactions related to inhalational anesthetics are unpredictable, it is important for the anesthetist/anesthesiologist to determine which patients are primarily at risk, so that safer use of anesthetic agents and better supervision of surgical patients can be achieved.
Anesthetic combinations
The importance of multiple anesthetics should not be overlooked. For example, patients in whom halothane anesthesia is given twice, at an interval of less than 6 weeks, are at major risk of developing jaundice. Some anesthetists avoid any second exposure to this agent. However, there are several reasons why single agents are often insufficient in anesthesia: different problems require separate treatments; the severity of the adverse effects of individual drugs can sometimes be reduced by the use of combinations; and repeated administration of a single agent can lead to cumulative effects. Drug interactions in anesthesia are therefore potentially common (see below).
Dental anesthesia
Adverse effects of dental anesthesia represent a special problem, about which reliable data are hard to obtain. Several studies of the safety of dental anesthesia have been performed in the USA [ ]; unfortunately, all have weaknesses. More informative is an American survey in which 47 oral and maxillofacial surgeons were approached directly, and all responded [ ]. Among the 74 871 patients to whom they had given general anesthesia, there were 250 cases of laryngospasm, 51 of phlebitis, 30 of dysrhythmias sufficiently severe to require therapy, 17 of hypotension requiring drug therapy, and 13 of bronchospasm. A few patients had allergic reactions requiring drug therapy (n = 4), convulsions (n = 4), hypertension (n = 2), myocardial infarction (n = 2), or vomiting with aspiration (n = 2); in one case an injection was inadvertently given into an artery.
Sedation for endoscopy
Gastrointestinal endoscopy is one of the most commonly performed invasive procedures in clinical practice (for example about 500 000 procedures per annum in Australasia). Propofol is a short-acting intravenous anesthetic with a rapid onset of action and a short half-life, making it eminently suitable for day procedures. However, the use of propofol by non-anesthetists has been controversial because of the perceived risks of its low therapeutic ratio. In many jurisdictions, package inserts insist that it is only for use by anesthetists.
In a review of nurse-administered endoscopy sedation regimens that primarily used propofol the incidence of adverse events was examined [ ]. Respiratory depression, presenting as apnea and hypoxemia, is the most serious adverse event. The authors of this review have suggested that individuals administering propofol must be able to support ventilation. Respiratory depression appears to be more common after upper gastrointestinal endoscopy. Hypotension is also common, particularly in elderly people or in those with impaired left ventricular function. Most of the studies reviewed only examined American Society of Anesthesiology (ASA) Class 1 and 2 patients (i.e. they did not include patients with significant co-morbidity). The reviewers suggested that registered nurse-administered endoscopy sedation with propofol is safe, provided that the nurse is appropriately trained, that there is appropriate monitoring (probably including capnography), and that the nurse must attend solely to the patient and have no other functions to perform simultaneously in the endoscopy suite (for example assisting the endoscopist).
A contrary view has been taken in a prospective study of propofol sedation in 500 ASA 1 and ASA 2 patients undergoing upper gastrointestinal endoscopic ultrasound in a Canadian center [ ]. Propofol sedation (bolus plus infusion) was administered by the endoscopist and not a dedicated nurse. Patients were monitored by clinical observation, pulse oximetry, and automated sphygmomanometry. All received supplementary oxygen 2 l/minute during the procedures. There was oxygen desaturation (defined as an oxygen saturation below 95%) in 16 patients (3%). There was hypoxemia (saturation below 90%) in four patients (0.8%). Increasing the supplementary oxygen to 4 l/minute was all that was required in nine patients. Increasing the supplementary oxygen and jaw lift was needed in one patient. Increasing the supplementary oxygen, jaw lift, and stopping the propofol infusion was necessary in the other six patients. Assisted ventilation was not required. There were no cases of hypotension, bradycardia, or tachycardia. The authors concluded that propofol may be safely administered by endoscopists who are familiar with its pharmacological properties and uses, and that there was a high level of satisfaction for both patient and anesthetist. However, they went on to say that in fact they found using propofol without a dedicated administrator and observer rather stressful, and that most of the endoscopists had returned to using intermittent bolus midazolam + pethidine (meperidine).
The authors of a third prospective randomized study took a different approach, by comparing patient-controlled propofol with patient-controlled remifentanil (an ultra-short acting opioid) in 77 patients undergoing gastrointestinal endoscopy [ ]. Patient satisfaction was high in both groups. There were significantly more awake and oriented patients among those who received remifentanil (46% versus 24%). Unfortunately, nausea was also more common (29% versus 0%). There were two cases of oxygen desaturation (< 92%) in the remifentanil group and none in the propofol group. Monitoring did not include capnography.
The incidence of adverse events related to an endoscopy sedation regimen that included propofol (in addition to midazolam and fentanyl), delivered by specially trained general practitioners, has been examined in a prospective audit [ ]; 28 472 procedures were performed over 5 years. There were 185 sedation-related adverse events, 107 with airway or ventilation problems; 123 interventions were necessary to maintain ventilation. No patients required tracheal intubation and there were no deaths. The authors concluded that appropriately trained general practitioners encountered a low incidence of adverse events and could safely use propofol for sedation during endoscopy. It should be noted that all the general practitioners had some experience in anesthesia or intensive care and were individually trained by the Director of Anesthesia.
Sedation for surgery under regional anesthesia
Sedation during prolonged surgical procedures under regional anesthesia can be quite challenging. The β 2 adrenoceptor agonist dexmedetomidine has potent sedative and analgesic-sparing properties. In therapeutic doses it does not cause respiratory depression, making it attractive for infusion sedation. However, it causes reduced sympathetic outflow, which might cause untoward hemodynamic upset during intraoperative sedation. Dexmedetomidine has been compared with propofol in a prospective randomized trial in 40 patients [ ]. Dexmedetomidine provided slightly slower onset and offset of sedation, higher intraoperative blood pressure, and better postoperative analgesia.
Remifentanil is a highly selective MOR (μ, OP3) opioid receptor agonist with an extremely short onset and offset of action, allowing rapid and accurate titration of infusion rate to drug effect with rapid down-titration in case of respiratory adverse effects. This makes it attractive for sedation. The efficacy and adverse effects profiles of remifentanil and propofol have been compared in a randomized, single-blind trial in 125 patients undergoing surgery with regional anesthesia [ ]. In those given remifentanil, nausea and vomiting were more frequent (27% versus 2%) and there was significantly more respiratory depression (46% versus 19%).
Sedation in intensive care
It has been proposed that a combination of propofol and midazolam may have advantages over either drug alone, reducing adverse effects while preserving the potential benefits (“co-sedation”). Propofol combined with a constant low dose of midazolam (1.0 mg/hour) has been compared with propofol alone for postoperative sedation in a randomized, placebo-controlled, double-blind trial in 60 patients undergoing coronary artery surgery under high-dose fentanyl anesthesia [ ]. Target sedation was achieved more readily with co-sedation (91% versus 79%) but at the expense of prolonged weaning from mechanical ventilation (432 versus 319 minutes). However, it is not clear whether this slightly prolonged time on the ventilator affected length of stay in the ICU.
It remains a source of much concern that those working in operating theaters spend their time in such a polluted environment, in spite of attempts to introduce scavenging of waste anesthetic gases [ ]. This is not without its effects. There is, for example, a relation between asthma and occupational exposure to various respiratory hazards, including anesthetic gases [ ].
The α 2 -adrenoceptor agonist dexmedetomidine has potent sedative and analgesia-sparing properties. In therapeutic doses it does not cause respiratory depression, making it attractive for infusion sedation. However, it causes reduced sympathetic outflow, which might cause untoward hemodynamic upset but might also have beneficial β-adrenoceptor antagonist-like value in patients undergoing cardiovascular surgery. Its use in pediatrics has been anecdotal. Dexmedetomidine has been compared with midazolam in a prospective randomized trial in 30 infants and children undergoing mechanical ventilation [ ]. Dexmedetomidine 0.5 micrograms/kg/hour provided more effective sedation, reduced supplementary morphine requirements, and reduced the number of patients with inadequate sedation. There was no difference in blood pressure, but heart rates were significantly lower in the children who received dexmedetomidine. One infant who received dexmedetomidine and concurrent digoxin developed bradycardia, but this resolved within an hour of withdrawing the dexmedetomidine.
Drug studies
Comparative studies
Halothane versus propofol
A randomized prospective trial in 60 children undergoing outpatient anesthesia showed a 30% shorter time from discontinuation of anesthesia to eye opening and return to full wakefulness in patients receiving propofol alone compared with halothane + nitrous oxide anesthesia [ ]. Propofol was associated with a 17% incidence of emesis compared with 58 and 53% for halothane + nitrous oxide and propofol + nitrous oxide anesthesia respectively.
Isoflurane + nitrous oxide versus propofol
The risk of postoperative nausea and vomiting has been studied in a randomized, controlled trial of total intravenous anesthesia with propofol versus inhalational anesthesia with isoflurane and nitrous oxide in 2010 patients [ ]. It was accompanied by an economic analysis. Propofol total intravenous anesthesia reduced the absolute risk of postoperative nausea and vomiting up to 72 hours postoperatively from 61% to 46%, in inpatients (NNT = 6) and from 46% to 28% in outpatients (NNT = 5). Both anesthetic techniques were otherwise similar. Anesthesia drug costs were more than three times higher for propofol total intravenous anesthesia (as propofol is substantially more expensive than isoflurane + nitrous oxide). However, the patients preferred propofol.
Isoflurane versus sevoflurane
A study of single vital-capacity breath inhalational induction using either isoflurane or sevoflurane combined with 67% nitrous oxide in 67 adults showed that isoflurane was unsuitable for this technique [ ]. There was an 87% incidence of induction complications with isoflurane, including involuntary movements, cough, laryngospasm, and failure of induction.
In 75 patients of ASA grades 1 or 2, recovery from anesthesia after maintenance with isoflurane + nitrous oxide was significantly slower than with sevoflurane + nitrous oxide [ ].
Isoflurane and sevoflurane have been compared in a randomized study in 180 patients undergoing knee arthroscopy [ ]. In those given sevoflurane there were significantly more respiratory and cardiovascular complications and increased nausea and vomiting.
In a comparison of sevoflurane and isoflurane anesthesia in 2008 patients there was a 3–4 minute reduction in time to recovery end-points with sevoflurane [ ]. These differences became larger in anesthetics lasting over 3 hours and were trivial in cases less than 1 hour. Patients aged over 65 years had a 5-minute increase in recovery times after receiving isoflurane. There was no significant difference in the incidence of nausea or vomiting between isoflurane, sevoflurane, and propofol.
Propofol versus sevoflurane
Sevoflurane is pleasant to breathe and has a rapid onset and offset of action. It is challenging the tradition of intravenous anesthetic induction in adult patients. In a meta-analysis of 12 studies in 1102 adult patients, intravenous bolus doses of sevoflurane 7–8% and propofol for anesthetic induction were compared [ ]. Anesthesia maintenance included nitrous oxide 50–70% and either propofol infusion or sevoflurane inhalation, and spontaneous ventilation via a laryngeal mask. Patients in the sevoflurane group were significantly more likely to have postoperative nausea and vomiting (odds ratios 4.2 and 3.2). There were non-significant trends toward greater patient dissatisfaction and a longer induction time in the sevoflurane group, and more frequent apnea in the propofol group. There were no significant complications in either group. Both agents are suitable for anesthetic induction, but propofol retains a small advantage in having better recovery characteristics.
Single-agent induction and maintenance of anesthesia has been compared in a randomized study of 44 patients undergoing elective spinal surgery [ ]. Patients received either propofol 4–6 μg/ml via a target-controlled infusion or sevoflurane 8% for induction, and sevoflurane 3.5% + 67% nitrous oxide for maintenance plus alfentanil as required. Patients in the propofol group required a significantly larger dose of opiate during the procedure (2.2 mg versus 0.3 mg). Two patients who received propofol complained of pain on injection. There was no significant breath-holding or laryngospasm in either group. Heart rate was significantly lower in the sevoflurane group compared with propofol both before and after incision. The numbers of adjustments to the patient’s depth of anesthesia were similar in both groups. The authors concluded that either technique was suitable for spinal surgery. The inclusion of nitrous oxide in the sevoflurane group accounted for the differences in opioid requirements.
The effects of hypercapnia on cerebral autoregulation during sevoflurane or propofol anesthesia have been studied in a randomized, crossover study in eight healthy patients [ ]. Hypercapnia began to inhibit cerebral autoregulation, as measured by transcranial Doppler at a mean value of 56 mmHg P a CO 2 with sevoflurane 1.0–1.1% and at 61 mmHg P a CO 2 with propofol 140 μg/kg/minute. Patients also received remifentanil for analgesia, a drug with no known effects on cerebral autoregulation. The study is important, because one advantage of both propofol anesthesia and sevoflurane anesthesia is the lack of inhibition of cerebral autoregulation at standard doses. Clearly, careful control of ventilation is required for this to be true.
The effects of isoflurane, sevoflurane, and propofol on jugular venous oxygen saturation (S j O 2 ) in patients undergoing coronary artery bypass surgery have been studied [ ]. S j O 2 values were significantly lower in the propofol group 1 hour after bypass, suggesting an imbalance of oxygen supply and demand with propofol. Because anesthetic agents also reduce the cerebral metabolic rate, the implications of this finding are uncertain. However, low S j O 2 values have previously been associated with postoperative neuropsychiatric dysfunction after cardiopulmonary bypass.
Vital capacity inhalational induction of anesthesia with sevoflurane has been compared with intravenous induction using propofol in 56 adults undergoing ambulatory anesthesia [ ]. The patients were randomized to either sevoflurane 8% + nitrous oxide 75% mixture at 8 l/minute (n = 32), or propofol 2 mg/kg bolus (n = 24), without any premedication. Induction time was significantly shorter with sevoflurane (average 51 seconds) than propofol (average 81 seconds). Adverse effects were different in the two groups: sevoflurane caused cough and hiccups, while propofol caused a fall in blood pressure and reduced movements. The overall incidence of adverse effects was similar. Postoperatively, there was mild nausea in 78% of the patients who received sevoflurane compared with 50% for propofol. However, no antiemetics were needed and discharge times were not delayed.
The characteristics of sevoflurane anesthesia have been compared with those of target-controlled infusion of propofol in 61 day-case adults undergoing surgery [ ]. All received nitrous oxide 50% and fentanyl 1 microgram/kg. After insertion of a laryngeal mask airway the propofol target concentration was reduced from 8 to 4 μg/ml and the inspired concentration of sevoflurane was reduced from 8% to 3% and subsequently titrated to clinical effects. Mean times to loss of consciousness and laryngeal mask airway insertion were significantly longer after sevoflurane (73 and 146 seconds respectively) than with propofol (50 and 116 seconds respectively). Sevoflurane was associated with a lower incidence of intraoperative movements (10% versus 55%), necessitating less adjustment to the dose. The incidence of movement in the propofol group was comparable to other studies. Emergence was faster after sevoflurane (5.3 versus 7.1 minutes) but sevoflurane was associated with more postoperative nausea (30% versus 17%) and vomiting (3% versus 0%), resulting in delayed discharge times (258 versus 193 minutes) and a higher total cost. The finding of significantly earlier discharge times after propofol anesthesia was unusual.
Propofol + alfentanil + nitrous oxide anesthesia has been compared with sevoflurane + nitrous oxide anesthesia in 44 patients undergoing dilatation and evacuation of the uterus [ ]. There was significantly less intraoperative uterine bleeding, as estimated by the gynecologist, with propofol. Above-average bleeding occurred in 5% of the patients with propofol anesthesia and 27% of patients with sevoflurane. This result was not surprising, given that sevoflurane reduces uterine tone, while propofol has no effect.
In a prospective randomized study of 120 day-surgery patients, desflurane and sevoflurane were associated with shorter times to awakening, extubation, and orientation than propofol infusion [ ]. Average times to awakening at the end of anesthesia were 5, 5, and 8 minutes respectively. There were no significant differences in time-to-home readiness or actual discharge times. A review of 436 patients undergoing either sevoflurane or propofol-based anesthesia showed no difference in similar recovery end-points [ ].
There has been a prospective randomized comparison of 185 patients who received propofol 6–8 mg/kg/hour and sevoflurane 1.5% for maintenance of anesthesia [ ]. The patients were ventilated via a laryngeal mask and no muscle relaxants were given. Both agents were suitable for this technique. Emergence was significantly faster after sevoflurane but associated with more excitatory phenomena and tachycardia.
Sevoflurane versus thiopental
Sevoflurane 8% plus nitrous oxide 66% has been compared with thiopental 4 mg/kg for induction of anesthesia in brief outpatient procedures [ ]. Sevoflurane was safer, more efficacious, and better accepted by 78 unpremedicated adults with laryngeal cancer undergoing direct laryngoscopy for staging and biopsy. All received suxamethonium 50 mg on loss of the eyelash reflex and the surgeon then performed the laryngoscopy. Hemodynamic stability was greater and immediate recovery was faster after sevoflurane (9.7 versus 11.4 minutes). The incidence of dysrhythmias was also higher with thiopental (19 versus 12 patients). The dysrhythmias were predominantly ventricular extra beats with sevoflurane and ventricular bigemini with thiopental. The high incidence of dysrhythmias was partly due to the lack of opioid medication as part of the anesthetic.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here