Table 7.3 BIS levels and levels of sedation/anesthesia

BIS

of surgical stimulation, but during surgery the antinociceptive influence leads to a decrease in BIS. Ketamine causes a dose-dependent activation of the EEG with subsequent increase in BIS values.

The concept of “entropy” has been applied to the EEG, as a way of quantifying its degree of order [17, 18]. One particular entropy concept, Shannon entropy, has been shown to correlate with anesthetic drug effect [19]. In essence, Shannon entropy measures the predictability of future amplitude values of the EEG based on amplitude values previously observed in the signal. Spectral entropy applies this Shannon entropy concept. Presently, the only commercially available entropy module (M-Entropy, Datex-Ohmeda, Finland) looks at two spectral entropy indicators: “state entropy” (SE) covering the dominant EEG frequency (0.8–32 Hz) and “response entropy” (RE) over the complete range of frequencies (0.8–47 Hz). The latter range includes both EEG and EMG components. The SE has a range (0–91) and RE (0–100) with lower numbers denoting a deeper level of anesthesia.

Vanluchene ALG et al. [20] compared BIS and spectral entropy in patients receiving a propofol infusion with or without remifentanil. BIS and spectral entropy accurately detected loss of consciousness to verbal command and decreased proportionately when remifentanil was used.

It is important to understand that BIS displays considerable variability within study populations, so making it difficult to identify sensitive and specific threshold values. Importantly, no BIS value predicts an individual threshold. Level of consciousness monitors is no substitute for vigilance, their true merit lies in their ability to enable the anesthetist to tailor the anesthetic to the individual.

7.5 Agents Used in Sedation

7.5.1 Propofol

A phenolic derivative (2,6 diisopropylphenol) is highly lipid soluble, a weak organic acid (pKa = 11), and almost entirely unionized at pH = 7.4. It is close to being the ideal agent for sedation and possesses a very favorable pharmacokinetic profile, with fast induction and ability to rapidly change sedation level together with a prompt recovery. Propofol exerts its effects via the E subunit of the GABAA receptor as well as releasing the neuroinhibitory transmitter, glycine. Sedation and amnesia are dose related though the amnesic effect is not as powerful as midazolam [9, 21]. Anxiolysis is not dose related. Pain on injection can occur, especially if a small calibre vein is used. Propofol is a poor analgesic [6] but has valuable antiemetic properties [21]. Doses in excess of 200 mg/h can induce hypotension and bradycardia. In the office setting, this can be offset with the use of low dose ketamine [22].

7.5.2 Benzodiazepines

Midazolam is the favored benzodiazepine (BDZ). Midazolam is a clear solution with a pH = 3.5 but is unique in that its structure depends on the surrounding pH. With increasing pH, the diazepine ring closes becoming unionized and lipid soluble [23]. Midazolam has the highest clearance (6–10 ml/kg/min) of all the commonly used BDZ and has a reasonable onset/offset profile but considerably slower than propofol. Like other benzodiazepines, midazolam is an agonist at the BZD receptor site (interface between D,J subunits on the GABAA receptor) and is a good sedative with excellent amnesic properties but no analgesic action [24]. Flumzenil is a specific antagonist, thereby providing a layer of safety, though it clears faster than midazolam and rebound sedation can occur.

7.5.3 Clonidine and Dexmedetomidine

These drugs are D2 adrenoceptor agonists, possessing potent anxiolytic and sedative actions. These agents stimulate D2 adrenoceptors in the lateral reticular

nucleus, so reducing central sympathetic outflow and in the spinal cord promote opioid release thereby modulating the descending noradrenergic pathway involved in spinal nociceptive processing. Clonidine has a relatively slow onset/offset profile with a distribution halflife of 1.2 h and an elimination half-life of 14.6 h. So, if used orally, the dose must be given 30–60 min before surgery. Clonidine at high doses (5 Pg/kg orally or 4 Pg/ kg intravenous) has analgesic properties, does not impair respiration or induce nausea/vomiting [25]. Cardiovascular instability is more common in the elderly.

Dexmedetomidine is up to eight times more potent than clonidine, has a faster onset/offset profile (elimination half-life 2 h), making it more readily titratable. It is much more expensive with concerns being raised regarding hemodynamic instability and associated nausea/vomiting [26].

Both agents impair thermoregulatory mechanisms and can decrease postoperative shivering.

7.5.4 Ketamine

Developed in the 1960s, ketamine, a phencyclidine derivative, is a racemic mixture of S(+) enantiomer, which is two to three times more potent than the R(−) enantiomer. The (S+) enantiomer causes less dysphoria and is the preferred preparation in Europe. S(+) also has a role moderating opioid-induced hyperalgesia. Ketamine is water soluble forming an acidic solution with pH = 3.5–5.5 and is known to act by inhibiting the NMDA receptor in a noncompetitive manner, producing dissociative anesthesia. EEG analysis depicts dissociation between thalamocortical and limbic systems. Outpatient anesthesia has provided the foundation for its resurgence with low dose (0.5–1.0 mg/kg) regimes providing weak sedation but excellent analgesia. Additionally, ketamine’s stimulation of the sympathetic nervous system counters the hypotension and respiratory depression associated with propofol [22]. Dose-related nausea/vomiting can be troublesome. Sedative doses of propofol can allay the disturbing dysphorias/hallucinations.

7.5.5 Opioids

Despite techniques employing propofol, ketamine, and clonidine, the author’s practice is not devoid of opioids.

From an office-based perspective, remifentanil has provided substantial interest. Remifentanil is a very potent, pure P agonist with a time-independent context half time (duration of action determined by metabolism not distribution). The elimination halflife is 3–10 min, being metabolized by nonspecific plasma and tissue esterases. This contrasts with alfentanil, sufentanil, and fentanyl all having longer context sensitive half times. Notwithstanding its intense analgesic action, remifentanil is a poor anxiolytic and amnesic [27]. Hemodynamic instability does not seem to be a problem and probably due to its ultrashort duration of action, nausea/vomiting is less common. Perhaps its major drawback in the office setting is the profound respiratory depression this agent induces [28].

7.5.6 Acetaminophen

A para-aminophenol derivative, acetaminophen has no effect on cyclooxygenase in vitro and is a capable antipyretic and analgesic in mild to moderate pain. In Europe, the use of the intravenous preparation is ubiquitous. In an office-based practice, acetaminophen has secured a role through its opioid-sparing effect. Overdose can be fatal as it leads to exhaustion of hepatic glutathione reserves and possible liver failure.

7.5.7Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

NSAIDs inhibit the enzyme cyclooxygenase (COX). Cyclooxygenase exists as two isoenzymes. COX-1 (the constitutive form) mediates the synthesis of thromboxane, produces prostaglandins controlling renal blood flow, and is instrumental in forming the protective gastric mucosal barrier. Platelets generate thromboxane on exposure to collagen, adenosine, and adrenaline thereby encouraging hemostasis through vasoconstriction and platelet aggregation. COX-2 (the inducible form) is produced where there is tissue damage. It amplifies the inflammatory response yet paradoxically generates prostcyclin (PGI2) in the vascular endothelium. Prostacyclin causes vasodilatation and inhibits platelet aggregation.