Present study was secondary analysis of a prospective observational study which was approved by the Clinical Research Ethics Committee of Peking University First Hospital on August 4, 2017 (2017, Beijing, China) and registered with Chinese Clinical Trial Registry on September 19, 2017 (chictr. org.cn, ChiCTR-OOC-17012734).(9)Written informed consent was obtained from all participants or their legal representatives.
Elderly patients (aged 65-90 years) were included if they were scheduled to undergo noncardiac surgery with an expected duration ≥ 2 h under general anesthesia. Patients who met any of the following criteria were excluded: (1) refused to participate in the study; (2) previous history of schizophrenia, epilepsy, Parkinson’s Disease, or myasthenia gravis; (3) unable to communicate due to severe dementia, comatose or language barrier; (4) traumatic brain injury or neurosurgery; (5) an American Society of Anesthesiologists (ASA) classification of IV or above; or (6) Emergency surgery.
Preoperative malnutrition was defined as nutritional risk screening 2002 (NRS2002) ≥3. NRS 2002 contains two components: nutritional status and disease severity, giving a total score of 0–6 (Supplementary Table S1).(17) If patient’s age is 70 years or above, an additional 1 score should be added to the above total score. Nutritional status was estimated by using BMI, percent of recent weight loss and change in food intake. Each item of undernutrition is classified into absent, mild, moderate, and severe with relevant score of 0-3 respectively. Disease severity is reflection of stress metabolism which is divided into normal to severe status with score 0-3.
Emergence delirium was defined as any episode of delirium during PACU stay and was assessed by the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) at 10 and 30 min after PACU admission, and before PACU discharge.(9, 18)
Before assessing delirium assessment, the level of sedation/agitation was evaluated with the Richmond Agitation Sedation Scale (RASS).(19) If the patient was over-sedated or unarousable (-4 or -5 on the RASS), delirium assessment was stopped and the patient was marked as comatose. If the RASS was between -3 and +5, delirium assessment was performed. Emergence delirium was classified into 3 subtypes, i.e., hyperactive (with a consistently positive RASS, from +1 to +4), hypoactive (with consistently neutral or negative RASS, from 0 to−3) and mixed. During the study period, investigators who performed delirium assessment did not participate in perioperative care of the enrolled patients.
All investigators who were in charge of delirium assessment were trained to use the CAM-ICU by a psychiatrist.(20) Confusion Assessment Method (CAM) were also trained for postoperative delirium assessment at the meantime.(21) The training program included lectures introducing delirium and the CAM/CAM-ICU, as well as simulation courses with patient-actors.(9) The initial training continued until the diagnosis of delirium reached 100% agreement with the psychiatrist. The training process was repeated at least two times a year. Investigators who performed delirium assessment did not participate in perioperative care of the enrolled patients.
Anesthesia and perioperative management
All patients received standard monitoring on arrival in the operating room including electrocardiogram, non-invasive blood pressure, pulse oxygen saturation, and urine output. During general anesthesia, end-tidal carbon dioxide and bispectral index (BIS) were monitored. Invasive arterial pressure and central venous pressure were used if considered as necessary.
Anesthesia induction was completed by propofol and/or etomidate, opioids (sufentanil and/or remifentanil) and muscle relaxants (rocuronium or cisatracurium). Anesthesia maintenance was conducted by infusion of propofol and/or sevoflurane inhalation. Nitrous oxide could be used as supplementary in necessary. Opioids and muscle relaxants were administered when considered necessary. The target was to maintain bispectral index between 40 and 60.
Muscle relaxants were stopped for at least 30 min before the end of surgery; propofol infusion and/or sevoflurane inhalation were decreased or stopped according to BIS monitoring; sufentanil was administered in necessary. At the end of surgery, Neostigmine (0.05 mg/kg) and atropine (0.02 mg/kg) were used to reverse residual effect of neuromuscular blockade. Patients were extubated when they met the following criteria: (1) easy to wake up; (2) sufficient reflexes that protect the airway; (3) adequate gas exchange (respiration rate 10–30 breaths per minute and tidal volume > 6 ml/kg); and (4) acceptable hemodynamic status (systolic blood pressure ≥ 90 mmHg and heart rate ≤ 100 beats per minute).
As a routine practice, patients were transferred to the PACU after extubation. Patients were monitored in PACU for at least 30 min and then transferred to the general ward when the Aldrete score was higher than 9. Pain severity was assessed with the numeric rating scale (NRS, an 11-point scale where 0 = no pain and 10 = the worst pain). Moderate to severe pain (NRS pain score > 3) was managed with intravenous opioids and/or non-steroid anti-inflammatory drugs (NSAIDs). Tympanic temperature was measured with an infrared ear thermometer. Patients with hypothermia (< 36 °C) were managed with warm air blanket.
Primary outcome was to investigate the relationship between malnutrition and occurrence of emergence delirium.
Data collection and postoperative follow-up
Baseline data included demographics, education, diagnosis, comorbidities, smoking, alcoholism, Charlson Comorbidity Index(22), and ASA classification. Baseline cognitive function was evaluated with the Mini-Mental State Examination (MMSE, scores range from 0 to 30, with higher scores indicating better function) at one day before surgery. Mild cognitive impairment (MCI) was defined as MMSE <27. Intraoperative data included types of anesthetic drugs, site of surgery, as well as duration of surgery.
Postoperative data during PACU stay included NRS pain score, tympanic temperature, and length of PACU stay. In the general wards, patients were followed up twice daily until the 5th day after surgery for the occurrence of delirium and non-delirium complications. From the 6th day after surgery, patients were followed up weekly until discharge. For those who were discharged from the hospital, follow-ups were performed by telephone interview.
As a secondary analysis, we calculated the statistical power based on available data. The incidence of ED was 41.8% (205/490) in malnutrition group and 31.5% (134/425) in control group. Assuming significance at 0.05, this would yield a power of 0.90.
Normality of continuous data was tested by Kolmogorov-Smirnov method in prior. Data with normal distribution were presented as mean± standard deviations (SD) and differences between groups were compared by independent t sample. Data without normal distribution were presented as median (IQR) and differences between groups were compared by Mann-Whitney U test. Categorical data was presented by number (percentage) and differences between groups were compared by Chi-square test.
The relationship between malnutrition and ED was firstly analyzed by univariate analysis, followed by multivariable logistic regression analysis adjusted for confounding factors including the baseline characteristics and perioperative variables that showed an imbalance between patients with and without ED (i.e., P value <0.05).
Two-sided P <0.05 was considered as statistical significance. Statistical analysis was performed using SPSS 24 Inc. Chicago, IL, USA.