12: Intravenous Anesthetics and Benzodiazepines

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CHAPTER 12 Intravenous Anesthetics and Benzodiazepines

Theresa C. Michel, MD

1 What qualities would the ideal intravenous induction agent possess?

The ideal agent would have a rapid onset, producing amnesia, analgesia, and hypnosis with hemodynamic stability. It would have few enduring side effects, few interactions with other medications, and allow for rapid recovery after surgery.

2 List the commonly used induction agents and their properties. Compare their cardiovascular effects

image Sodium thiopental (STP) is a direct myocardial depressant, produces peripheral vasodilation resulting in decreased mean arterial pressure (MAP), and produces a reflex tachycardia.
image Etomidate is an imidazole derivative the induction properties of which result from Gamma-amino butyric acid (GABA) receptor modulation. It is noted for its hemodynamic stability. Cardiac output (CO) and contractility are preserved, and only a mildly decreased MAP is noted. Side effects include pain on injection, nausea and vomiting, hiccups, myoclonus, seizures, thrombophlebitis, and most important, adrenal suppression.
image Propofol: Myocardial depression and peripheral vasodilation are more profound than with thiopental and may result in a more significant decrease in MAP. There are minimal effects on heart rate (HR).
image Ketamine: The sympathomimetic effects result in increased CO, MAP, and HR. It is a myocardial depressant, but usually its sympathomimetic properties dominate.
image Midazolam is the principal benzodiazepine used perioperatively. Benzodiazepines provide anxiolysis, sedation, amnesia, and in high doses unconsciousness. Midazolam has minimal myocardial depression. There is no effect on MAP or CO; HR may increase slightly.
image Opioids: High doses of most opioids have a vagolytic effect, producing bradycardia. The exception is meperidine, which has sympathomimetic effects that produce tachycardia. A decreased MAP may be noted secondary to bradycardia, vasodilatation, blockade of sympathetic response, and histamine release (especially evident with morphine and meperidine).

These effects are noted when these medications are individually administered. When given in concert (e.g., midazolam followed by an opioid followed by pentothal), the effects are synergistic, and hemodynamic instability is not guaranteed (Tables 12-1 and 12-2).

TABLE 12-1 Dosing Guidelines for Anesthetic Induction and Sedation*

image

TABLE 12-2 Cardiovascular Effects of Induction Agents

image

3 Instead of injecting pentothal intravenously, you have inadvertently administered it into the patient’s intra-arterial line. What is the impact on the patient and how should potential problems be addressed?

Intra-arterial STP is likely to cause significant discomfort, vasospasm, and possibly thrombus formation. Leave the catheter in place and inject dilute papaverine, procaine, or lidocaine through the catheter to inhibit smooth muscle vasospasm. If this does not re-establish perfusion, consider brachial plexus block or α-blockade. Also administer heparin to prevent thrombus formation.

4 What are contraindications to STP use?

image Thiopental allergy: STP contains a sulfur molecule that results in an increased risk of histamine release. Patients allergic to sulfates should not receive STP.
image Porphyria: Barbiturates increase porphyrin synthesis and may precipitate an acute porphyria attack with symptoms such as abdominal pain, weakness, autonomic dysfunction, and gastrointestinal and sleep disturbances.
image Use with caution in patients with hypovolemia and poor systolic function because of its cardiovascular depressant effects. STP may be a poor choice in this scenario.
image Advanced age, hepatic dysfunction, and obesity may result in slower redistribution and prolonged effects.

5 How do induction agents affect respiratory drive?

All intravenous induction agents with the exception of ketamine produce dose-dependent respiratory depression manifested by decreased tidal volume, decreased minute ventilation, decreased response to hypoxia, and a rightward shift in the carbon dioxide response curve, culminating in hypoventilation or apnea.

6 How does ketamine differ from other induction agents?

Ketamine is an N-methyl-d-aspartate receptor antagonist with profound analgesic properties. Chemically related to phencyclidine, it causes a dose-dependent dissociative state and unconsciousness and may cause hallucinations or disturbing dreams in the emotionally susceptible. Its amnestic ability is weak. Concurrent administration of a benzodiazepine may decrease the incidence of adverse sensory effects.

The sympathomimetic effects of ketamine result in tachycardia, increased CO, and MAP. It is an ideal induction agent in patients with such conditions as shock, significant hypovolemia, and cardiac tamponade.

As previously mentioned, ketamine has direct myocardial depressant effects that tend not to be manifested because of overriding sympathetic stimulation. However, in catecholamine-depleted states the myocardial depressant effects may become manifest.

Other desirable side effects include bronchodilation and preserved respiratory drive. Undesirable side effects include increased cerebral blood flow, which would be problematic when there is increased intracranial pressure. It increases oral secretions remarkably, is emetogenic, and can cause nystagmus.

7 Discuss the concerns for the use of etomidate in the critically ill patient

Etomidate decreases serum cortisol levels by blocking two enzymes in the cortisol pathway: 11-β-hydroxylase and 17-α-hydroxylase. Clinically significant adrenal suppression and increased morbidity and mortality have been documented in critically ill patients and those with septic shock after receiving even a single dose of etomidate. Annane and associates reported that 68 of the 72 patients (94%) who received etomidate for the induction of anesthesia did not respond to a high-dose cosyntropin stimulation test. This is consistent with other reports of adrenal insufficiency 12 to 24 hours after the administration of etomidate. The results seem to indicate a significant mortality for etomidate anesthetic induction in septic patients. However, the stable hemodynamic properties of etomidate make it a desirable induction agent for patients with shock. As the debate continues and further data are collected, some authors are advocating the use of etomidate in conjunction with exogenous corticosteroid replacement therapy (e.g., 100 mg of hydrocortisone every 8 hours) while measuring stress cortisol levels.

KEY POINTS: Intravenous Anesthetics and Benzodiazepines image

1. Appropriate dosing of intravenous anesthetics requires considering intravascular volume status, comorbidities, age, and chronic medications.
2. Benzodiazepines and opioids have synergistic effects with intravenous induction agents, requiring adjustment in dosing.
3. Ketamine is the best induction agent for hypovolemic trauma patients as long as there is no risk for increased intracranial pressure. It is also a good agent for patients with active bronchospastic disease.
4. Propofol is the least likely of all induction agents to result in nausea and vomiting.
5. Termination of the effects of intravenous anesthetics is by redistribution, not biotransformation and breakdown.

8 Describe propofol infusion syndrome

First reported in the pediatric population in 1992, this syndrome has now been noted in adults as well. Actual incidence is unknown but is estimated to be approximately 1 in 270 patients. The population at risk is critically ill patients receiving high-dose propofol infusions over long periods of time (higher than 4 mg/kg/hr for longer than 48 hours). Critically ill children are at the highest risk. Risk is increased with the administration of exogenous steroids and catecholamines and inadequate carbohydrate intake. Manifestations include cardiac failure, rhabdomyolysis, severe metabolic acidosis, hyperlipidemia, renal failure, and sometimes death. Currently propofol is not approved for use for pediatric intensive care unit sedation. Although the morbidity and mortality are currently very high for those with recognized propofol infusion syndrome and treatment options are limited, best outcomes have been achieved with supportive care such as hemodialysis and cardiorespiratory support.

9 What are some contraindications to the use of propofol?

Propofol contains soy oil and egg lecithin; thus patients with allergies to eggs and soy products should not receive this medication. Propofol crosses the placenta and may be associated with neonatal depression. It has cardiodepressant effects; thus patients with cardiomyopathies and hypovolemia may not be ideal candidates. Finally consider the advisability of its use in patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis.

10 What would be an appropriate induction agent for a 47-year-old healthy male with a parietal lobe tumor scheduled for craniotomy and tumor excision?

Sodium thiopental has the most cerebral protective profile since it decreases cerebral oxygen consumption (CRMO2) and preserves cerebral perfusion pressure. Ketamine should be avoided because it increases cerebral blood flow and intracranial pressure.

11 Describe the mechanism of action of benzodiazepines

Benzodiazepine receptors, which are found on postsynaptic nerve endings in the central nervous system (CNS), are part of the GABA receptor complex. GABA is the primary inhibitory neurotransmitter of the CNS. The GABA receptor complex is composed of two α-subunits and two β-subunits. The α-subunits are the binding sites for benzodiazepines. The β-subunits are the binding sites for GABA. A chloride ion channel is located in the center of the GABA receptor complex.

Benzodiazepines produce their effects by enhancing the binding of GABA to its receptor. GABA activates the chloride ion channel, allowing chloride ions to enter the neuron. The flow of chloride ions into the neuron hyperpolarizes and inhibits the neuron.

Benzodiazepines are metabolized in the liver by microsomal oxidation and glucuronidation. They should be used with caution in those with liver disease and the elderly. The potency, onset, and duration of action of benzodiazepines depend on their lipid solubility. Onset of action is achieved by rapid distribution to the vessel-rich brain. Termination of effect occurs as the drug is redistributed to other parts of the body.

12 What benzodiazepines are commonly administered intravenously?

image Midazolam is lipid soluble and therefore has the most rapid onset and shortest duration of action. Unlike other benzodiazepines, midazolam is both lipid soluble and water soluble and therefore can be manufactured without the pain-inducing solvent propylene glycol. It has a single metabolite with minimal activity. It is by far the most common benzodiazepine used perioperatively.
image Diazepam is slightly slower in onset. It has a long elimination half-life and two active metabolites that may prolong sedation.
image Lorazepam is the least lipid soluble and therefore slowest in onset and longest in duration of action. It also has a long elimination half-life.

13 How should oversedation induced by benzodiazepines be managed?

As a first principle, always provide supportive care. Open the airway and mask-ventilate if needed. Assess the adequacy of the circulation. Second, administer the benzodiazepine antagonist flumazenil. Flumazenil works by competitive inhibition, reversing sedation and respiratory depression in a dose-dependent fashion. Onset is rapid and peaks within 1 to 3 minutes. It should be titrated to effect by administering doses of 0.2 mg intravenously for a maximum dose of 3 mg. It should be used with caution if at all in patients with a history of seizure disorder.

14 What do you tell the nurses who will monitor this patient about possible side effects of flumazenil?

The elimination half-life of midazolam is 2 to 3 hours, whereas the elimination half-life of flumazenil is 1 hour. Resedation is a risk. Flumazenil may be repeated. It may be administered as an infusion at 0.5 to 1 mcg/kg/min.

SUGGESTED READINGS

1 Annane, et al. Etomidate and fatal outcome—even a single bolus dose may be detrimental for some patients. Br J Anaes. 2006;97:116-117.

2 Djillali A. ICU physicians should abandon the use of etomidate!. Intensive Care Med. 2005;31:325-326.

3 Wysowski D.K. Reports of death with use of propofol for nonprocedural (long-term) sedation and literature review. Anesthesiology. 2006;105:1047-1051.

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