Tuesday, March 23, 2021

Delayed Emergence Case File

Posted By: Medical Group - 3/23/2021 Post Author : Medical Group Post Date : Tuesday, March 23, 2021 Post Time : 3/23/2021
Delayed Emergence Case File
Lydia Conlay, MD, PhD, MBA, Julia Pollock, MD, Mary Ann Vann, MD, Sheela Pai, MD, Eugene C. Toy, MD

Case 48
A 36-year-old G3P3 woman, 1 day after vaginal delivery, presents for postpartum tubal ligation. She has no significant past medical or surgical history and states she does not wish to be awake during the procedure. The patient is anesthetized with general anesthesia via a rapid-sequence induction, using propofol and succinylcholine, and is intubated with a 7.0 cuffed endotracheal tube. Anesthesia is maintained with sevoflurane, vecuronium, and fentanyl. The operation proceeds uneventfully, and as the obstetricians close, the sevoflurane is turned off. The patient has two twitches, she is given neostigmine and glycopyrrolate to reverse the effects of her neuromuscular blockade. Twenty minutes later, she is still intubated, has made no ventilatory efforts, and appears unarousable.

➤ What is the differential diagnosis for delayed emergence from anesthesia?

➤ Which monitors may be helpful in discerning the diagnosis?

➤ Which medical condition can mimic delayed emergence, and how is it diagnosed?

Delayed Emergence
Summary: A healthy 36-year-old patient, 1 day after vaginal delivery, makes no respiratory effort following general anesthesia for postpartum tubal ligation.

Differential diagnosis: Medication overdose (most commonly opiates), hypoventilation leading to hypercapnia, metabolic abnormalities such as hypoglycemia, and neurologic events.

Monitors: The diagnosis is discerned through physical examination including vital signs, pupillary dilatation, the patient’s response to stimulation such as sternal rub, and an observation of respiratory effort. Monitors which may be helpful in this setting include the Train of Four, capnography, and monitors of anesthetic depth. Additional testing such as blood gas analysis, the glucose concentration, and potentially neurologic imaging may also be indicated.

Medical condition: Persistent neuromuscular blockade, reflecting an overdose or inadequate reversal of nondepolarizing muscle relaxants, or atypical pseudocholinesterase, can mimic delayed emergence. In this setting, mechanical ventilation and sedation may be warranted.


1. Understand the techniques available to evaluate the patient with delayed emergence.
2. Become familiar with the most common causes of delayed emergence.
3. Understand the implications of an atypical pseudocholinesterase enzyme.

Before anesthetizing this patient, it is important to realize that a parturient undergoes a number of physiologic changes throughout her pregnancy, and few will have completely returned to normal on the first day post delivery. In addition to the hemodynamic changes associated with pregnancy, the requirements for volatile anesthetics are diminished. Plasma cholinesterase activity decreases throughout pregnancy, and may be impaired up to 6 weeks postpartum. This is usually of little significance.

Delayed Emergence

Intraoperative Course
This patient received a balanced anesthetic, which means that she received sedation, narcotics, inhaled anesthetic agents, and neuromuscular blocking agents. She has physiologic changes due to pregnancy. There are many reasons why she may have had a delayed emergence.

Overdose. It is possible that a medication has been given in an amount that vastly exceeds a patient’s requirements. Therefore, it is important to evaluate what drugs have been given, in what dosage, and ensure there have been no inadvertent drug mix-ups.

Certain groups of patients are prone to drug overdose, so understanding the patient’s medical history is of paramount importance. For example, patients suffering from impairments of the kidneys and liver may experience prolonged effects of opiates and some muscle relaxants, since these organs are often the primary sites involved in drug metabolism.

Certain medical conditions and physiologic states also render patients more susceptible to specific drugs. For example, patients with myasthenia gravis have increased sensitivity to nondepolarizing muscle relaxants. Similarly, drug requirements vary with age, with the geriatric patient requirements being much lower doses than an adolescent, and the pregnant or postpartum patient often having a lower drug requirement than the nonpregnant woman.

One of the most common scenarios resulting in a delayed emergence is an overly narcotized patient. While opiates are helpful in managing pain, their side effects include sedation, ventilatory depression, and a blunted ventilatory response to hypercapnia. An opiate overdose is typically associated with pinpoint pupils. However, the presence of pinpoint pupils in and of itself does not necessarily indicate an opiate overdose.

An opiate overdose is treated with naloxone, an antagonist at the opiate receptor. In the absence of an arrest or pending arrest, naloxone should be diluted and administered incrementally in small doses as the sudden reversal of nociceptive inhibition may cause an increased sympathetic response resulting in tachycardia, hypertension, and cardiac dysrhythmias. The duration of action of naloxone is approximately half an hour, so re-dosing of naloxone is often required until the patient recovers from the opiate.

Delayed emergence may also be attributed to the effects of benzodiazepines. Midazolam is commonly given preoperatively for anxiolysis and anterograde amnesia. Although the ventilatory depression of benzodiazepines is less than that of opiates or barbiturates, these drugs are long acting, and can be highly sedating in addition to potentiating the effects of other medications leading to airway obstruction and apnea. Benzodiazepines bind to γ-aminobutyric acid type A receptors (GABA), and are antagonized by flumazenil at a dose of 0.2 mg intravenously over 15 seconds in adults. One side effect of flumazenil is seizures.

In addition to the two scenarios mentioned above, a drug overdos is sometimes due to medical errors such as misreading of drug labels, mislabeling of drug syringes, or new or different formulations or strengths of usual medications.

Hypoventilation. Patients with poor ventilation due to airway obstruction, residual muscle paralysis, or excess narcotics can develop hypercarbia leading to sedation and even unconsciousness. This is evaluated by assessing the patient’s respiratory rate and tidal volume, and by analyzing the PaCO2 from an arterial blood gas. Hypoventilation also hinders a patient’s ability to eliminate (exhale) volatile anesthetics, thus slowing their emergence. Treatment consists of improving the patient’s ventilation while administering 100% O2.

Metabolic abnormality. It is possible the patient is unarousable secondary to some type of metabolic derangement. Hypothermia may reduce the metabolism of, and thereby cause prolongation of, anesthetic agents. This can be assessed with a temperature probe. Blood work can be sent to assess for hypoglycemia, severe hyperglycemia, or electrolyte imbalance. Naturally, the best treatment is to identify and correct the abnormality.

Neurological event. Rare causes of delayed emergence include neurological events such as seizure or an ischemic event from intracerebral hemorrhage, embolism, or thrombosis. Understanding the clinical context, the physical examination, and imaging guide the diagnosis and treatment of these rare but devastating disorders.

Residual neuromuscular blockade. In order to provide optimal surgical conditions, neuromuscular blocking agents are administered to provide muscle relaxation and paralysis. In the case of the patient with delayed emergence, it is possible that the patient has indeed emerged from the anesthetic, but still remains paralyzed.

Nondepolarizing neuromuscular blocking agents require reversal of their action by flooding the synaptic cleft with acetylcholine. If insufficient quantities of neuromuscular reversal had been administered or if the level of blockade had been too great for the agents to overcome, patients may remain paralyzed at the end of surgery. Since the advent of Train-of-Four monitoring, the likelihood of an overdose of neuromuscular relaxant drugs sufficient to cause total paralysis (and thus mimic delayed emergence) is low. More likely, patients will be able to move and communicate that they are awake, albeit weakly. Total paralysis following nondepolarizing muscle relaxants is suggestive of underlying pathology at the neuromuscular junction, such as with myasthenia gravis, multiple sclerosis, etc.

Total paralysis following the administration of succinylcholine, is, on the other hand, a well known complication of following the drug’s administration. The effects of succinylcholine are typically short-lived due to hydrolysis by pseudocholinesterase enzymes in plasma. If these enzymes either function abnormally or are present in reduced quantities, then the action of succinylcholine is prolonged and total paralysis may result. The most common form of pseudocholinerase deficiency occurs at a frequency of greater than 1/3,000 cases. Fortunately this type of cholinesterase deficiency only results in a total paralysis of only an hour or so, and since most surgical procedures are longer than 1 hour, it may remain undiagnosed.

First studied by Kalow and Staron in the 1950s, it is now believed that the gene that codes for the pseudocholinesterase enzyme exists on the E1 locus of chromosome 3. It is estimated that 4% of the population carries atypical pseudocholinesterase genes as either heterozygotes or homozygotes. In this population, a much greater dose of succinylcholine arrives at the neuromuscular junction, causing a greatly exaggerated length of time of paralysis. Currently, the only treatment option is continued mechanical ventilation until the paralysis resolves secondary to passive diffusion of succinycholine away from the neuromuscular junction. Administration of fresh frozen plasma or neostigmine is controversial and not recommended.

While preoperative screening for atypical pseudocholinesterase is extremely uncommon, a patient who previously suffered an episode of prolonged paralysis following succinylcholine may be evaluated by a method first described by Kalow and Genest. Dibucaine is a local anesthetic that inhibits normal pseudocholinesterase activity by 70% to 80%, but affects the atypical enzyme by only 20% to 30%. Heterozygotes have about a 50% to 60% inhibition. The amount of enzyme inhibition is termed the “dibucaine number.” In contrast, some patients may have lower amounts of pseudocholinesterase due to a decreased synthetic activity such as seen in liver disease, or lower circulating concentrations resulting from the increase in plasma volume such as seen in normal pregnancy.

In addition to their effects at the neuromuscular junction, deficiencies in pseudocholinesterase may also affect the metabolism of ester-based local anesthetics, such as 2-chloroprocaine. There have been case reports of high epidural blockade in parturient with even mildly abnormal dibucaine numbers.

Total muscular paralysis is differentiated from a delayed emergence from anesthesia in several ways. First, patients may show signs of “light” anesthesia from sympathetic stimulation. Tearing, sweating, tachycardia, hypertension, and pupillary dilatation suggest that the patient either has or is beginning to emerge. Second, muscular paralysis can be detected by an absence of the twitch using a Train-of-Four monitor. The level of awareness can also be assessed by a monitor of anesthetic depth, such as the bispectral index (BIS) monitor.

Postoperative Care
The etiology of delayed emergence is ideally discerned in the operating room if at all possible. Otherwise, the patient is left intubated, and transported to an intensive care unit, or if hemodynamically stable, to the PACU. The treatment for delayed emergence is dependent upon the patient’s pathology, and is by and large supportive.

Comprehension Questions
48.1. You are called to assess a 58-year-old man, status post left colectomy, who became unresponsive on the floor. As you arrive you are told the patient had accidentally received 10 mg of dilaudid instead of the 1 mg he was prescribed. Which of the following medications can you give to reverse this condition?
    A. Naloxone
    B. Flumazenil
    C. Neostigmine
    D. Glycopyrrolate

48.2. A 22-year-old woman undergoes a rapid-sequence induction for her tonsillectomy. Five minutes later she has all four twitches back. Which of the following statements is accurate?
    A. Her pseudocholinesterase enzymes are probably low in quantity.
    B. Her pseudocholinesterase enzymes may not be functioning properly.
    C. Her dibucaine number is probably 30.
    D. She is no longer completely paralyzed.

48.3. A 35-year-old type 1 diabetic male undergoes an open carpal tunnel release with an axillary nerve block. The patient received 2 mg of midazolam for sedation prior to the block, but no additional medications in the operating room. He was alert after the midazolam and early in the case, but near the end of the case, he is somnolent and difficult to arouse. Which of the following is the most appropriate treatment?
    A. Physostigmine
    B. Naloxone
    C. Dextrose
    D. Midazolam

48.4. Which of the following is the most likely cause for the delayed emergence described at the beginning of the case?
    A. Hypoglycemia
    B. Pseudocholinesterase deficiency
    C. Excessive administration of opiates
    D. Residual effects of inhalation anesthetics

48.1. A. This patient has received an overdose of his opiate pain medication. Naloxone will reverse these effects. Most likely, this patient will require a naloxone infusion until dilaudid is metabolized. Flumazenil is a benzodiazepine antagonist. Neostigmine is an acetyl cholinesterase inhibitor. Glycopyrrolate is an anticholinergic.

48.2. D. This patient has no signs of prolonged paralysis following succinylcholine administration. For this reason, she should have normal pseudocholinesterase enzymes in both quantity and activity. Since all her twitches have returned to normal, she is no longer completely paralyzed. Since the dibucaine number represents the percent of the enzyme’s activity, a normal number would be >70.

48.3. C. This patient is likely hypoglycemic and requires dextrose. Use a glucometer to check the blood glucose level. This patient had a peripheral nerve block and had intraoperative medications. Since no muscle relaxant was given, physostigmine would be an inappropriate choice. For much the same reason, opiate was not administered thus eliminating the need for naloxone. Midazolam is a benzodiazepine and would be of no benefit in this situation.

48.4. C. While each of the choices is theoretically a possible etiology for the delayed emergence described at the beginning of the case, the most likely cause is an excessive administration of opiates. Opiates reduce the ventilatory response to CO2, an effect that is synergistic with the residual effects of any inhalation anesthetics which may not have been eliminated. Hypoglycemia is less likely insofar as the patient is not a diabetic, although it has been observed in young, fasting women undergoing surgery late in the afternoon. Pseudocholinesterase deficiency is also a possibility, especially if this patient never had surgery before. However, the incidence of cholinesterase deficiency is much less frequent than somnolence caused by opiates and retained anesthetic agents.

Clinical Pearls
➤ Patients may have comorbidities or physical conditions such as normal pregnancy that make them susceptible to prolonged effects from common anesthetic medications.
➤ Be methodical when evaluating the patient with delayed emergence. Consider their age, medical history, and the intraoperative record including medications given when developing a differential.
➤ Monitors such as vital signs, the physical examination, a Train-of-Four stimulus, capnograph, monitor of anesthetic depth, imaging, and laboratory tests should be available to you to help guide your diagnosis.
➤ If an opiate is reversed with naloxone, remember that the opiate’s half-life may exceed naloxone’s, and that redosing the naloxone may be necessary.


Miller RD, ed. Anesthesia for obstetrics. Miller’s Anesthesia. 6th ed. Philadelphia, PA: Churchill Livingston;2005: 2307-2345. 

Mondero P, Hess P. High epidural block with chloroprocaine in a parturient with low psuedocholinesterase activity. Can J Anaesth. 2001;48(3):318-319. 

Nixon JC, Thiel CJ. Apnea due to inheritance of atypical pseudocholinesterase. Can Med Assoc J. 1964 9;90:1125-1127. 

Savarese JJ, Caldwell JE, Lien CA, Miller RD. Pharmacology of muscle relaxants and their antagonists. In: Miller RD, eds. Miller’s Anesthesia. 6th ed. Philadelphia, PA: Churchill Livingston;2005: 481-573.


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