Induction and maintenance of a surgical plane of anesthesia are a necessary but far from sufficient paradigm for the success of general anesthesia – a rapid and comfortable recovery is a critical component.(1) The immediate post-operative period is a sensitive one and the awakening of the child's consciousness, protective airway reflexes and adequate spontaneous ventilation are the main criteria of a safe emergence.(2) Although the majority of patients wake up from anesthesia in a predictable time, there is a distinct group that wakes up from anesthesia a long time later. This is known as delayed recovery or emergence which is a failure to achieve a conscious state within a clinically anticipated time  usually when anesthetic agents have stopped  more than 120 minutes.(3) This delay is not just an inconvenience but also

a serious clinical event, requiring close monitoring and in the worst case scenario, hospitalization in the Intensive Care Unit (ICU).(4)

Delayed recovery can be a complicated process with a variety of causes, and may be a combination of factors related to the patient, the anesthetic and the surgery.(5, 6) Other factors that may affect the pharmacokinetics and pharmacodynamics of anesthetic drugs include advanced age, preexisting neurologic problems, major cardiovascular, hepatic, or renal disease, or the patient's overall metabolic condition.(7) Equally important anesthetic factors include choice of drugs, total dose administered, drug interactions, and possible for long anaesthetic effects due to increased individual variation.(8) Additionally, surgery-related factors including the length of operation, the degree of surgical stress, and complications during surgery (such as significant bleeding or hypothermia) can have a significant effect on the course of recovery.(9)

In Khyber Pakhtunkhwa (KPK) region specially in Hazara division, which has high prevalence of chronic diseases (diabetes, hypertension, ischemic heart disease etc) and heterogeneous population, the factors affecting delayed recovery may pose special challenges. Although the health care system in Hazara is rapidly developing, there are some constraints in terms of availability of resources, advanced monitoring equipment, and costly reversal agents or newer, shorter, and safer anesthetic drugs.(10) Thus, longer recovery times in this environment can negatively affect patient outcomes, with longer stays in the intensive care unit, higher incidence of ventilator-associated pneumonia, higher incidence of pressure ulcers, and an excessive burden of limited healthcare resources. Studies with regards to the outcome of anesthesia are increasing in Pakistan but there is a lack of literature which specifically tries to identify the predictors of delayed recovery that may necessitate the need of admission in a critical care unit (CCU) in the Hazara population.(11, 12) It is important to have a good understanding of these specific risk factors, as this is the key to developing a pre-operative risk factor stratification program and intra-operative management program for each patient, ensuring optimal use of critical care resources and ensuring patient safety. This study was therefore designed to study the clinical and peri-operative factors associated with delayed recovery from general anesthesia which requires post-operative admission in the intensive care unit in Tertiary Care Hospital Abbottabad.

Study Design and Setting: It was a case control study which was done at the Department of Anesthesiology and Intensive Care, Tertiary Care Hospital Abbottabad, in a retrospective manner. The study was conducted after obtaining approval from the Institutional Administration. Study Population: All adult patients (age >18 years) who had elective or emergency surgery under general anesthesia with endotracheal intubation, between January 2023 and August 2025 were included in the study population. Inclusion Criteria: Cased: Post-operative patients who were admitted to the ICU as a result of a prolonged recovery from general anaesthic. Delayed recovery was defined as failure to regain consciousness (eye opening and verbal command) and/or failure to achieve a safe extubation (tidal volume < 5 mL/kg or inability to protect airway) within 120 minutes (2 hours) after the end of surgical procedure. Controls: Subjects that had similar surgery (stratified by major surgery vs. minor surgery) during the same time frame and had an uneventful recovery in the Post-Anesthesia Care Unit (PACU) without needing admission to the Intensive Care Unit (ICU). Exclusion Criteria: Presence of any neurological disease that could potentially affect the assessment of consciousness (such as stroke and severe dementia), Do-Not-Resuscitate (DNR) order, non-delayed recovery ICU admission/other complications (such as sepsis). Sample Size and Sampling: Total number of cases = total number of controls = 90. Patients were identified through checking the admission log from the ICU and medical records. To reduce the likelihood of confounding by surgical factors, controls were chosen using simple random sampling from the PACU discharge log from the same time period as the cases and matched by type of surgery (general, orthopedic, urological etc.). Data Collection: Data was gathered utilizing a standard proforma from electronic and paper based medical records with four key domains. Data collected pre-operatively were demographic, BMI, ASA physical status, co-morbidities (diabetes, hypertension, chronic kidney disease, liver disease, ischemic heart disease) and smoking history. Anesthetic information included the drugs used for induction, muscle relaxants, maintenance (inhalational or total intravenous) and reversal agents used, and the total amount of these drugs used. Surgical and intra-operative parameters recorded were the type of surgery and surgery duration, estimated blood loss, transfusion requirements, use of vasopressors, hypotension (defined as blood pressure of less than 90 mmHg) or hypoxia (defined as oxygen saturation of less than 94%), and end-surgery body temperature. Lastly, after the surgery, the time taken to open the eyes and extubate, causes for delayed recovery, and the length of stay in the ICU were noted. Data Analysis: SPSS version 26.0 was used to enter and analyze data. All variables were provided descriptive statistics. Frequencies and percentages were used to show and compare categorical variables between cases and controls, which were compared using the Chi-square test. The independent samples T test or Mann-Whitney U test was used for continuous variables to calculate means and standard deviations that were compared. A logistic regression analysis (univariate and multivariate) was performed to identify independent predictors of delayed recovery. Univariate analysis p values <0.20 were included in the multivariate model. p-values < 0.05 were taken as significant.

Nineteen cases with delayed recovery and 19 matched controls were excluded from the final analysis due to the fact that they were excluded by the investigator. There were 180 cases (90 delayed and 90 matched controls) in the final analysis because they were excluded by the investigator. Baseline characteristics, intra-operative data and outcomes of cases and controls are provided in the following tables. The age of the cases was significantly greater than in the controls. There was also a higher prevalence of co-morbidities such as diabetes and chronic kidney disease (CKD) among cases and a higher ASA classification. Intra-operatively, the cases had significantly longer operating times and blood loss. These key findings are summarized in three tables.

Table 1: Demographic and Pre-operative Characteristics of Patients

Table 1 shows that cases were significantly older, had a higher burden of co-morbidities, and were more likely to be in a poor pre-operative physical state (ASA III/IV).

Table 2: Intra-operative and Anesthetic Factors

Table 2 demonstrates that the cases had significantly longer and more complex surgeries, characterized by longer durations and greater blood loss. A higher proportion of cases also received a high dose of inhalational anaesthetic agents.

Table 3: Multivariate Logistic Regression Analysis for Predictors of Delayed Recovery

Table 3 identifies the independent predictors of delayed recovery. After adjusting for confounders, ASA III/IV status, the requirement for a blood transfusion, pre-existing chronic kidney disease (CKD), older age, and prolonged surgery duration were the most significant independent factors.

This case-control study managed to find some important factors which lead to delayed recovery from general anesthesia and require an ICU stay in a tertiary care hospital Abbottabad. The findings reveal the complexity and multi-factorial nature of this complication, due to the susceptibility of patients, the complexity of the surgical procedure, and the difficulties faced during the operation. The results of our study are broadly similar to those of the international literature, but offer region-specific data which is essential for a healthcare setting in the Hazara region. ASA physical status and the need for transfusion of blood were the most important predictors in our multivariate analysis. The ASA classification of a patient is a global measure of a patient's health and physiological reserve prior to surgery, and the highest score (ASA III/IV) is the strongest predictor that is intuitively obvious.(13) Such patients tend to have a compromised renal, hepatic or cardiovascular function which greatly influences the pharmacokinetics of anesthetic drug, thus causing accumulation and long duration of action.(14) The link to blood transfusion means that there is probably a significant amount of intra-operative blood loss, leading to hypovolemia, anemia and possible hypotension which may cause cerebral hypo perfusion or metabolic derangements, which will impair the elimination of anaesthetic agents, and slow the return to consciousness. In addition, presence of existing CKD was a strong independent predictor. It is important to note that in KPK the prevalence of CKD is believed to be increasing, and is frequently associated with hypertension and diabetes.(15) The function of the kidneys directly affects the excretion of many drugs employed during anesthesia, such as muscle relaxants and their metabolites, and thus slows their onset of action and prolongs postoperative neuromuscular blockade, which may be confused with delayed recovery of consciousness.(16) The correlation with extended surgery time (more than 4 hours) is consistent with a well-established principle that a longer duration of anesthetic is associated with a higher total dose of anesthetic agents which could result in a higher likelihood of accumulation, particularly of lipid soluble agents, and a higher surgical stress. The link with high-dose inhalational an aesthetics is a factor which may be modifiable, but is probably one of longer and more complicated surgery. It does highlight, however, that anesthesiologists should ensure they use agents with a low organ toxicity and short onset and offset time, such as desflurane, where possible, given high-risk patient population.(17, 18) This study has some limitations, such as its retrospective nature, which depends on the quality of medical record documentation. Delayed recovery (120 minutes) is somewhat arbitrary, but is a widely accepted clinical parameter. Furthermore, this study took place in one Centre and so the results may not be applicable to other centers. Although limited by these factors, the study's strengths include the use of a well-designed case-control design, the identification of specific, actionable risk factors, and its relevance to clinical practice in a resource-limited environment.

Finally, delayed recovery from general anesthesia in the post-operative period is an important issue, the factors behind which are complex such as old age of the patient, poor ASA physical status (ASA III/IV), surgical procedures longer in duration, need for transfusion of blood, and pre-existing chronic kidney disease. These results underline that the risk is not only related to the type of anaesthetic used but mainly to the patient's baseline physiology and intra-operative events. It is essential to identify high-risk patients early in the pre-operative assessment stage and determine a tailored anaesthetic strategy and optimize patients' medical status prior to surgery. This is an important step to take in order to reduce delayed recovery and enhance surgical outcomes in a proactive manner in our environment.

 Recommendations

Establish a uniform approach at all major surgical centers in Hazara for pre-operative risk stratification, which considers the risk factors found in this study (age >60, CKD, high ASA status) in a systematic manner. It should be a part of routine check-up before anesthesia. For high-risk patients, use of total intravenous anesthesia (TIVA) with propofol and remifentanil or rapid-offset inhalational agents (such as desflurane) should be strongly encouraged, as this will reduce the risk of drug accumulation and the emergence process will be shorter. Integrate close intra-operative monitoring and management to reduce other risk factors such as hypotension, significant blood loss, and hypothermia which are important causes of delayed recovery. This is the prompt and aggressive treatment of blood loss, and appropriate replacement of fluids and blood products. Improve early warning systems and detection of patients at risk for delayed emergence in PACU. Have reversal agents (e.g. sugammadex for steroidal muscle relaxants) readily available and make sure that there is an easy and rapid plan for transferring patients to the ICU if the main recovery is not achieved.

 Limitations

The retrospective design of the study might have caused information bias because the information was obtained from pre-existing medical records, which may not contain information on exact drug dosage, exact time of drug administration or the exact depth of the anesthesia. The study was carried out in a single tertiary care hospital of Abbottabad. Therefore, the results of this study might not be applicable to other centers in the Province or country with varying patient characteristics, surgical volume or anesthetic resources. A delayed recovery was defined using a 2-hour time out. This is a typical standard, but somewhat arbitrary, and the patient's underlying cause for waking at 150 minutes versus 210 minutes may be similar. Some patients with more substantial but slightly longer delays may not have been included in this definition. Even after in-depth evaluation, there is a possibility of residual confounding due to unrecorded factors like pre-operative malnutrition, intra-operative electrolyte imbalance or genetic influences on drug metabolism.

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