Medication effects

General anesthesia often includes the use of inhalational anesthetics, sedatives, opioids, and neuromuscular blocking agents. Delayed emergence may be due to overdose of medications, use of longer-acting anesthetics, drug–drug interactions causing potentiation of anesthetics, or prolonged neuromuscular blockade.

Significant individual variability to anesthetic medications makes optimal dosing of medications clinically challenging. Relative overdosing of anesthetics will prolong awakening time from anesthesia. Elderly and debilitated patients are more susceptible to medication overdose than are younger and healthier patients. Minimum alveolar concentration (MAC) of an inhaled anesthetic is the alveolar concentration at which 50% of patients will not show a motor response to surgical incision. MAC decreases approximately 6% per decade after age 40. Thus, the MAC of an 80-year-old would be roughly 25% lower than the MAC of a young adult. Patients with renal or hepatic insufficiency will have delayed drug metabolism or drug clearance and require dose reduction of some anesthetic medications. Patients with certain co-morbidities (e.g. myasthenia gravis) are much more sensitive to neuromuscular blocking agents.

Although modern anesthetic agents have short durations of action when administered by intravenous (IV) bolus, some may display markedly different pharmacokinetics when administered by continuous IV infusion. Context-sensitive half-life is the time required for plasma concentration of a medication to decrease by 50% and varies by the context (bolus or infusion) of administration. Saturation of body compartments by certain medications may serve to sustain plasma levels and therefore exert prolonged drug effects. Lipid-soluble agents such as fentanyl will demonstrate an increased half-life after 2 hours of continuous infusion. Similarly, propofol will display an increased half-life after 3 to 4 hours of infusion.

Preoperative sedatives may prolong emergence. Benzodiazepines such as midazolam or lorazepam are frequently administered prior to surgery. Sedation may prolong emergence, particularly for short procedures or individuals very sensitive to their effects.^[2] This effect may be particularly important in the elderly population. The scopolamine patch or diphenhydramine may be administered for nausea and vomiting prophylaxis, but may sometimes contribute to prolonged sedation. The sedating side effects of other medications, such as β-blockers and antihypertensives, may have synergistic effects with anesthetics.

The concurrent use of recreational narcotics or acute alcohol intoxication will also interact synergistically with anesthetics and may profoundly delay emergence. This may be observed frequently in trauma and emergency surgery, as traumatic injury and acute intoxication often co-exist. Patients undergoing elective procedures may also be successful in concealing drug use. Occasionally, patients will self-medicate with controlled substances the morning of surgery, either to control for anxiety or to attempt to mitigate the anticipated discomfort.

Interaction between herbal supplements and anesthetic medications has the potential to delay emergence from anesthesia. The effect of perioperative herbal supplement usage is inadequately studied and complicated by the fact that commercially available herbal supplements lack standardization, so significant dosing differences exist between brands or even between batches of the same brand. Herbal medications can cause prolonged sedation after surgery.^[3] A survey published in 2000 showed that 63% of surgical patients at one institution were taking some form of dietary supplement, and the majority of these patients did not disclose them.^[4] Although the American Society of Anesthesiologists recommends discontinuation of herbals 2 to 3 weeks prior to surgery, this does not always occur. Perioperative herbal medications, such as valerian root and kava kava, may have sedative effects that may prolong the effect of anesthetics.^[5] St. John’s wort contains hypericin and hyperforin, which are believed to inhibit neuronal reuptake of serotonin, norepinephrine, and dopamine.^[6] St. John’s wort could contribute to delayed emergence from anesthesia by several mechanisms, and there are reports of delayed emergence where St John’s wort usage was believed to be a factor.^[7]

Residual effects of neuromuscular blockers (NMB) can delay the emergence of patients from anesthesia.^[8] While delayed emergence more typically refers to the patient who has failed to awaken from anesthesia, residual neuromuscular blockade may give the appearance of delayed awakening in a fully conscious individual. Residual neuromuscular blockade should be considered for every case of delayed emergence. The causes of prolonged paralysis may be drug overdose, incomplete reversal, or pseudocholinesterase deficiency if succinylcholine was administered as part of the anesthetic.^[9] Patients with disorders of the neuromuscular junction such as myasthenia gravis are acutely sensitive to non-depolarizing NMB. Aminoglycosides, such as gentamicin, have a synergistic effect with NMB and can potentiate their effects. Likewise, inhalational agents and local anesthetics have the potential to prolong the duration of action of NMB. If the anticonvulsant phenytoin is given acutely, then there may be augmentation of neuromuscular blocking potency.^[10] Metoclopramide can also inhibit plasma cholinesterase and prolongs the action of succinylcholine.

Respiratory failure

Respiratory failure may cause impaired consciousness in the PACU. Risk factors for postoperative respiratory failure include: underlying respiratory disease (sleep apnea, chronic obstructive pulmonary disease), excessive opiates, residual NMB, and baseline airway obstruction.^[11] Patients who do not ventilate effectively during the immediate postoperative period may become hypercarbic to a level that will produce sedation or unconsciousness. Hypercapnia may initially stimulate spontaneous respiration, but excess CO₂ buildup will depress the central respiratory centers. Routine plethysmography is insufficient in detecting hypercarbia. It is important to note that patients may have a normal SpO₂ despite having an elevated CO₂. Patients should be evaluated for respiratory rate and adequacy of ventilatory effort. If hypercarbia is a clinical concern, arterial blood gas analysis should be performed.

Hypoxia will also impair consciousness. Postoperative hypoxemia is most frequently caused by V/Q mismatch, intrapulmonary shunt, and impaired ventilatory effort, but may also be related to airway obstruction in patients making adequate ventilatory effort. Altered mental status combined with hypoxia is a medical emergency requiring immediate intervention.

Metabolic disturbances

A number of underlying metabolic imbalances may be responsible for delayed emergence.^[12] Hypoglycemia will cause delayed emergence because the brain is dependent on glucose as the source of energy. Patients with chronic alcoholism or poorly controlled diabetics are more susceptible to the detrimental effects of low blood sugar, but hypoglycemia should be considered in all patients with delayed emergence. De novo hypoglycemia may present after certain procedures, particularly of the pancreas. Unintentional insulin administration (drug swap) is a rare, but potentially catastrophic medication error which must be considered. Drug–drug interactions are numerous for patients taking oral hypoglycemic agents (see Chapter 16, Table 16.1). Conversely, severe hyperglycemia may also contribute to delayed emergence and often occurs in decompensated diabetics (diabetic ketoacidosis and hyperosmotic hyperglycemic diabetic coma).

Severe electrolyte imbalances may occur as a consequence of a surgical procedure or secondary to an underlying disease process. Mild hyponatremia (<120 mmol/l) is usually asymptomatic, but severe hyponatremia (<110 mmol/l) will cause confusion, irritability, or even coma. Hyponatremia may occur in transurethral resection of the prostate owing to the use of large amounts of glycine or other hypotonic fluids for irrigation. High ammonia levels secondary to glycine metabolism can lead to confusion, agitation, or obtundation. Patients undergoing intracranial procedures can develop syndrome of inappropriate antidiuretic hormone (SIADH), which will cause fluid retention and possibly severe hyponatremia.

Hypothermia may lead to delayed emergence by several mechanisms. A core temperature below 33 °C has an anesthetic effect, but will also potentiate the effects of IV sedatives used in the case. Hypothermia also decreases the MAC of inhalational agents and slows drug metabolism.