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Introduction
Emergence is defined as the transition from the sleep state to full consciousness [1]. Emergence from general anesthesia is usually smooth and uneventful. Inadequate emergence is characterized by a disturbance of activity level in the immediate postoperative period and is classified into two subtypes—emergence agitation and hypoactive emergence. Emergence agitation may consist of hallucinations, delusions, and confusion that manifests as restlessness, moaning, involuntary physical activity, and thrashing [2], while a delayed recovery characterizes hypoactive emergence after anesthesia. However, there are no clear diagnostic criteria defining emergence agitation or hypoactive emergence [3]. The term ‘emergence delirium’ is often misused in the literature as a reference to emergence agitation, whereas agitation and delirium have distinctive descriptions in the Diagnostic and Statistical Manual of Mental Disorders (DSM) Fifth Edition [4]. Problems of post-anesthesia emergence have been shown to occur in 5–10% of general surgery patients of all ages. Its incidence is even higher after the preoperative use of benzodiazepines, breast surgery, abdominal surgery, musculoskeletal surgery, long operation durations, induction of anesthesia with etomidate, a pain numeric rating scale (NRS) of 6 to 10 in the post-anesthesia care unit (PACU), as well as at both extremes of patient age [5–7]. The clinical importance of inadequate emergence in either form has not been thoroughly investigated. It is shown that patients with emergence agitation are at an increased risk of injury, hemorrhage, extended PACU stay, morbidity, mortality, and resource utilization [5,8,9]. However, hypoactive emergence has rarely been studied. Radtke et al. [6] found 60 of 1,868 patients presented hypoactive emergence in their study (3.2%), which was more common for younger age, longer duration of surgery, and intra-abdominal surgery.
This prospective observational study aimed to define the incidence and risk factors of inadequate emergence (both emergence agitation and hypoactive emergence) that was resolved by the time of PACU discharge in adult patients after general anesthesia for elective surgery. It was shown earlier that psychological problems such as depression and anxiety, as well as alterations in organ functions, were significantly higher in substance-dependent patients [10,11]. Furthermore, clinical findings indicate that baseline psychological disorders such as anxiety and depression can be associated with postoperative delirium emergence [12]. Moreover, due to the progressively high frequency of substance dependence in the general population [13,14], we focused our study on substance dependence and its relationship with inadequate emergence.
Materials and Methods
This research was done per the Principles for Medical Research Involving Human Subjects, outlined in the Helsinki Declaration of 1975 (revised 2018). After institutional ethics committee approval with IRB number 86100059 , patients classified with an American Society of Anesthesiologists I–III physical status and undergoing elective general anesthesia during the six months period from March to September 2018 were enrolled in this prospective observational study with their informed consent. The study excluded patients under 18 years old, with a history of dementia, cerebral insult, intracranial surgery, or those under neuraxial and regional anesthesia. Anesthesia was induced according to standard protocols in our department—(1) preoxygenation and intravenous induction using a short-acting narcotic, ketamine, sodium thiopental, or propofol and neuromuscular blockade using succinylcholine or atracurium, (2) maintenance of anesthesia using volatile anesthetics or total intravenous anesthesia, short-acting or long-acting narcotics, and ketamine, (3) reversal of neuromuscular blockade using neostigmine and atropine, and (4) awake extubation and transportation to the PACU. In the PACU, all patients received oxygen if their oxygen saturation was below 95% in room air. Postoperative pain management included optional non-opioid analgesics for mild postoperative pain (NRS 3–4) or opioid analgesics for moderate to severe pain (NRS ≥ 5). Patients were assessed at 10 minutes after admission to the PACU by experienced anesthesia nurses who were blinded to the patient care. The NRS pain score was recorded, and the presence of inadequate emergence and its severity was determined according to the Richmond Agitation-Sedation Scale (RASS, Table 1). Emergence agitation was defined as RASS ≥ +1, normal emergence was defined as RASS between 0 and –1, and hypoactive emergence was defined as RASS ≤ –2 [6].
The following variables for each patient were recorded—age, gender, body mass index; pre-existing medical conditions, psychological disorders, history of substance dependency (alcohol, opium, stimulants, psychedelics; according to DSM IV criteria), type of surgery, smoking, intraoperative estimated blood loss, intravenous fluid administration, transfusion, type and dosage of intraoperative analgesics, having a urinary catheter in the PACU, type and dosage of postoperative analgesics, and postoperative pain score (NRS).
Statistical analysis
This study was conducted as a prospective observational study. Three emergence groups were defined as agitated, normal, and hypoactive. Demographic and descriptive data analyses were done for the study population and the three groups above. Frequencies were expressed as counts (percentage) and continuous variables as mean with standard deviation (SD). After testing the normality with the Kolmogorov-Smirnov test, we used the Student’s t-test and the chi-squared test for univariate analysis. We performed multivariate analyses using a backward binary stepwise logistic regression to examine and determine the odds ratios (OR) of the risk factors for inadequate emergence, with 95% confidence for the CI. Furthermore, the statistical analyses (both univariate and multivariate) were also conducted in the subgroup of patients with a history of substance dependence. We made no adjustments for multiple testing in all these exploratory data analyses. SPSS ver. 22.0 software (IBM Corp., USA) was used for analyses, and the study considered P < 0.05 (two-sided) as significant.
Results
In this study, 1,136 patients were enrolled, including 770 female patients (68%). The mean age was 39 years (range 18–99 yr). Inadequate emergence in the PACU occurred in 231 patients (20.3%), out of which, 158 patients (13.9%) had emergence agitation, and 73 patients (6.4%) had hypoactive emergence. Substance dependence was reported in 95 patients (8%) of whom, 62.1% abused opium, and 37.9% abused stimulants. All patients regained a normal cognitive status before discharge from the PACU. The mean ± SD of stay time in PACU was 47 ± 13 minutes, which was not significantly different in subgroups comparison: substance-dependent vs. normal patients (P = 0.654) as well as patients with vs. without inadequate emergence (P = 0.321).
Univariate analysis
The incidence of inadequate emergence differed significantly between genders (P = 0.002; Table 2), it was more frequent in men (94 of all the male patients included in the study, 25.7%). Inadequate emergence was also seen more in patients over 50 years old compared to younger patients (29.1% vs. 17.9%, respectively, P = 0.001).
In married patients, the incidence of emergence agitation was less than the total of single and divorced patients (12.8% vs. 17.5%, P = 0.009). Hypoactive emergence is more frequent in married patients (7.4% vs. 3.1%). In patients with emergence agitation, 36.36% had a history of neurologic diseases versus 14.23% with other pre-existing illnesses (P = 0.012) (Table 2).
A history of substance dependence was significantly associated with a higher incidence of inadequate emergence (P = 0.001). Emergence agitation was more common in patients with substance dependence than in patients without substance dependence (21.1% vs. 13.3%, P = 0.019). Hypoactive emergence was also more common in patients with substance dependence than in patients without substance dependence (10.5% vs. 6.1%, P = 0.044).
Emergence agitation was significantly less common in patients undergoing gynecological (7.1%) and thoracic surgeries (4.9%) than in patients with other surgeries (19.8%, P < 0.001 and P = 0.034, respectively). Hypoactive emergence was also more frequent in thoracic surgery (25% of all patients with hypoactive emergence, P < 0.001). Conversely, intra-abdominal and laparoscopic surgeries were associated with higher incidences of emergence agitation (28.2% of patients under intra-abdominal surgery vs. 13.1% of other patients, P < 0.001 and 28.6% of patients under laparoscopic surgery vs. 13.0% of other patients, P < 0.001).
The intraoperative consumption of morphine in patients with emergence agitation and hypoactive emergence (mean ± SD dose, 5.52 ± 1.78 mg, and 7.41 ± 2.90 mg, respectively) was significantly higher than in patients with normal emergence (4.70 ± 1.12 mg, P < 0.001). Our results also showed that the intraoperative bleeding administered fluids in patients with emergence agitation and hypoactive emergence was significantly higher than in patients with normal emergence (P < 0.001) (Table 2).
Foley catheter fixation in the PACU correlates with a higher incidence of hypoactive emergence. Of all patients with Foley catheter fixation, 12.8% suffered hypoactive emergence vs. 2.4% in patients without Foley catheter fixation (P < 0.001).
Analgesic drug administration in the PACU seems to be correlated with a higher incidence of emergence agitation (28% vs. 12.9% in patients without analgesic drugs consumption, P = 0.009).
Multivariate analysis
The univariate analysis between both groups (normal emergence vs. emergence agitation) showed that the incidence of emergence agitation was significantly related to 10 variables (age ≥ 50 yr, marital status [divorced patients], pre-existing neurologic disorders, substance dependence, site of surgery, intraoperative bleeding volume, intravenous [IV] fluid administration, intraoperative opioids, and analgesic drug administration in the PACU).
Hypoactive emergence was significantly related to 14 variables (age ≥ 50 yr, male gender, marital status [married patients], education level [less than a bachelor degree], pre-existing hypertension, diabetes mellitus, pre-existing psychological disorders, substance dependence, site of surgery, intraoperative bleeding volume, IV fluid administration, packed cell transfusion, intraoperative opioids, and Foley catheter fixation).
Multivariate analysis by backward binary stepwise logistic regression has shown that out the 10 variables used in our model, seven were significant to the onset of emergence agitation in the PACU (Table 3).
The risk of emergence agitation among single and married patients is reduced by an order about 0.15 times comparing with divorced patients (OR = 0.158, 95% CI [0.039–0.637], P = 0.009; OR = 0.161, 95% CI [0.042–0.615], P = 0.008, respectively). Pre-existing neurologic disease increased the frequency of agitation about 7 times (OR = 6.779, 95% CI [1.359–33.804], P = 0.020) and patients with gynecological and thoracic surgeries had lower risk of emergence agitation compared to other patients (OR = 0.292, 95% CI [0.120–0.712], P = 0.007; OR = 0.230, 95% CI [0.066–0.800], P = 0.021, respectively). Intraoperative bleeding volume and intraoperative morphine administration slightly increased the risk of emergence agitation (OR = 1.001, 95% CI [1.000–1.002], P = 0.047; OR = 1.145, 95% CI [1.027–1.278], P = 0.015, respectively). An interesting observation was that analgesic drug administration in the PACU also increased the risk of agitation about 3 times (OR = 2.989, 95% CI [1.559–5.730], P = 0.001).
For hypoactive emergence, we found six factors which increased the risk of hypoactive emergence (Table 4). Pre-existing hypertension increased the risk about 5 times (OR = 5.382, 95% CI [1.528–18.960], P = 0.009) and history of psychological disorders increased the risk about 4 times (OR = 3.897, 95% CI [1.152–13.180], P = 0.029). Intraoperative alfentanil administration significantly increased the risk of hypoactive emergence (OR = 2.338, 95% CI [1.521–3.593], P < 0.001). Sufentanil and higher doses of morphine administration during operation also increased the risk of hypoactive emergence slightly (OR = 1.024, 95% CI [1.013–1.035], P < 0.001; OR = 1.364, 95% CI [1.208–1.539], P < 0.001, respectively). Surprisingly, Foley catheter fixation significantly correlated to the incidence of hypoactive emergence in the PACU (OR = 9.680, 95% CI [4.531–20.679], P < 0.001).
Univariate analysis in patients with substance dependence
The current study showed that the incidence of hypoactive emergence in patients older than 50 years was significantly more than younger patients (23.1% and 5.9%, respectively, P = 0.033). It is also more common in opium dependence rather than stimulants (15.3% vs. 2.8%, P = 0.045) (Table 5).
Higher amounts of IV fluid administered during surgery were related to more frequency of hypoactive emergence in the PACU. Morphine administration, as an analgesic drug, also had the same effect on the development of hypoactive emergence. Our results showed that analgesic drug administration in the PACU was positively correlated to the occurrence of emergence agitation (58.3% of patients with substance dependence who received analgesic drugs in the PACU vs. 15% of patients without receiving analgesics in the PACU, P < 0.001) (Table 5).
Foley catheter fixation in the PACU also correlated with a higher incidence of hypoactive emergence (80% of all substance-dependent patients with Foley catheter vs. 20% in patients without Foley catheter, P < 0.001) (Table 5).
Multivariate analysis in patients with substance dependence
In patients with substance dependence, analgesic drug administration in the PACU increased the risk of emergence agitation (OR = 86.059, CI [2.175–3405.894], P = 0.018) and history of smoking decreased the risk of emergence agitation (OR = 0.075, CI [0.008–0.708], P = 0.024).
Discussion
Inadequate emergence in adult patients has rarely been examined. Thus, there are only a few recommendations regarding treatment, except for pediatric anesthesia. Caution is warranted for patients at increased risk. Based on pediatric anesthesia, it may be helpful to keep patients away from stressful stimuli by providing a quiet, darkened recovery room. If necessary, it is appropriate to administer additional analgesics and a sedative [15]. IV propofol (0.5 mg/kg) or IV midazolam (0.02 mg/kg) have both been used successfully in treating emergence agitation in children [16,17]. One in every five patients in our study experienced inadequate emergence. It is a significant issue that deserves more attention [5,6,18]. Despite the scarcity of studies with reports on hypoactive emergence [6], emergence agitation has been evaluated more extensively. In children, emergence agitation is frequently a complication, with described incidences up to 60% [19,20]. However, the incidence of emergence agitation in adults has been about 5% in most studies [5,6], which is lower than our observation. There are different scales of agitation assessment, such as the Richmond Agitation-Sedation Scale (RASS), Riker Sedation-Agitation Scale (SAS), Motor Activity Assessment Scale, and the New Sheffield Sedation Scale. They are more precise in the evaluation of agitation than the Ramsay sedation scale, which rates sedation. Studies have demonstrated that both RASS and SAS have excellent inter-rater reliability [21–23]. These scales have been used for adults in intensive care units and are not well-established in the PACU. However, these scales are useful, especially in emergencies.
Emergence agitation
It is crucial to identify patients at risk of emergence agitation to be prepared to prevent emergence delirium. Lepousé et al found that breast and abdominal surgeries extended duration of surgical procedures, intraoperative bleeding, and premedication by benzodiazepines are risk factors for postoperative delirium. Pre-existing neurologic disorders were also correlated with emergence agitation. On the other hand, a known history of illness, long-term treatment by antidepressants, gynecological surgeries, and thoracic surgeries are associated with a lower risk of emergence agitation [5].
We found that age does not influence the occurrence of emergence agitation. Nevertheless, other studies have reported a higher incidence of agitation in younger patients [5]. Radtke and colleagues found that both younger (less than 40 years old) and older patients (greater than 64 years old) showed a higher incidence of emergence agitation than middle-aged patients [6].
In our study, a history of substance dependence was significantly associated with a higher incidence of inadequate emergence (P = 0.001). Patients with opium or stimulant dependence had a higher risk of agitated emergence (20.3% and 22.2%) compared to other patients (13.3%). We could not find any similar study in literature with which to compare our results, so this may be the first study reporting the incidence of inadequate emergence in the PACU in patients with a history of substance dependence.
Although postoperative pain has been identified as a potential risk factor for emergence agitation in other studies [5,6,24], we did not find a significant association between postoperative pain in the PACU (NRS ≥ 5 vs. NRS < 5) with emergence agitation (P = 0.274), notwithstanding the hurdle of assessing the pain accurately during emergence agitation. Nevertheless, we observed an increased rate of emergence agitation with higher doses of intraoperative opioid administration.
Managing emergence agitation demands more staff and financial resources. Restraining an agitated patient may require six or more healthcare people with a risk of injury to the staff. It may cause anxiety for other concurrent patients, especially if they feel neglected. Emergence agitation may increase anesthesia morbidities such as self-extubation, removal of catheters, aspiration pneumonia, or emergency surgery. Emergence agitation also adds to the cost of medical and surgical treatments and may prolong the length of a PACU stay. Therefore, routine monitoring for emergence agitation in the PACU is essential.
Hypoactive emergence
Hypoactive emergence is more common in patients with dependence on opium rather than stimulants (15.3% vs. 2.8%, P = 0.045). Hypoactive emergence has been associated with a history of hypertension, pre-existing psychological disorders, and intraoperative opioid administration (morphine, sufentanil, and alfentanil). Lower doses of alfentanil (1.0 ± 0 mg) were associated with agitation while higher doses (4.4 ± 2.5 mg) was associated with hypoactive emergence. Low-dose sufentanil (15.9 ± 28.7 μg), however, was associated with hypoactive emergence.
Card and colleagues found that total opioid administration (fentanyl equivalents) are associated with postoperative delirium. In their cohort study, patients receiving opioids equivalent to 383 μg fentanyl were six times more likely to develop delirium in the PACU than those receiving 50 μg fentanyl (odds ratio [OR] 6.2, 95% CI [1.7, 22.1]). Higher doses of opioids bore a similar risk of developing postoperative delirium, which could either reflect a ceiling effect of the role of opioids in contributing to postoperative delirium or be merely due to the fewer number of patients receiving such large doses [18].
Foley catheter fixation in the PACU significantly correlates with a higher incidence of hypoactive emergence, which is contrary to an earlier study in which urinary catheterization related to higher rates of emergence agitation [25].
Specific factors in substance-dependent patients
In patients with substance dependence, analgesic drug administration in the PACU related to an increased risk of emergence agitation. Interestingly, smoking history in patients with substance dependence decreased the risk of emergence agitation, potentially because of the nicotinic acetylcholine receptors that modulate aggression [26].
Limitation of the study
The present study did not assess the patients for delirium after discharge from the PACU, especially during their postoperative course in the hospital or long-term outcomes. Moreover, we did not differentiate between chronic substance-dependent patients and acute dependency, or those who abuse substances causally. Another limitation of our study was that we did not consider the effects of different drugs, used as anesthetics during induction and maintenance of general anesthesia, on producing inadequate emergence during the postoperative period. In patients with a history of substance dependence, the incidence of inadequate emergence following general anesthesia appears to be higher than in the general population. While analgesic drug administration in the PACU is a risk factor for emergence agitation, smoking history can decrease its risk in these patients.
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