The Effects of Subanesthetic S-ketamine on Postoperative Delirium and Cognitive Function in the Elderly Undergoing Non-cardiac Thoracic Surgery: a Protocol for Randomized, Double-blinded, placebo-and Positive-controlled, Non-inferiority Trial
Phase: EARLY_PHASE1
Conditions: Postoperative Delirium, Elderly Patients
Sponsor: Affiliated Cancer Hospital & Institute of Guangzhou Medical University

The effects of subanaesthetic S-ketamine on postoperative delirium and 
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cognitive function in elderly patients undergoing non-cardiac thoracic 
2 
surgery: a protocol for a randomised, double-blinded, placebo- and 
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positive-controlled, non-inferiority trial  
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(SKED Trial) 
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Identifier: NCT05242692 
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Date of the document: June 1, 2022 
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The effects of subanaesthetic S-ketamine on postoperative delirium and 
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cognitive function in elderly patients undergoing non-cardiac thoracic 
2 
surgery: a protocol for a randomised, double-blinded, placebo- and 
3 
positive-controlled, non-inferiority trial  
4 
(SKED Trial) 
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Introduction 
6 
Postoperative delirium (POD) is a neuropsychiatric disorder in elderly 
7 
patients, manifested as an acute onset of altered and fluctuating 
8 
consciousness, inattention, and disorganised thinking. POD occurs in hospital 
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up to 1 week postoperatively or until discharge (whichever occurs first), and 
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typically the highest incidence is observed during the first 72 hours. [1] The 
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incidence of POD varies between 4% to 60%, depending on the age and 
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surgical type, although its incidence is underestimated since the hypoactive 
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subtype is not well appreciated. [2-7] Postoperative delirium is associated with 
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prolonged hospital stay, long-term cognitive and social dysfunction, and even 
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death. [8-10] The 1-year survival probability is reduced by approximately 10% 
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for each additional day of postoperative delirium. [11] The pathophysiological 
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mechanisms of delirium have not been well-elucidated, and 
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neuroinflammation remains a topic of mainstream research interest. 
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Furthermore, its development results from the complicated interaction of 
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multifactorial risks, such as pain, opioids, sleep deprivation, and inflammation, 
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which poses a challenge for the prevention and treatment of postoperative 
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delirium. [12] Although various techniques, including multi-component non-
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pharmacological interventions, are suggested to reduce the risks, there is 
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limited pharmacological methods to reduce the incidence of delirium. [13] 
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Dexmedetomidine is a highly selective 𝜶-2 adrenergic receptor agonist that 
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is associated with sedative, sympatholytic, and anti-inflammatory effects, and 
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has the highest-ranking possibility of preventing postoperative delirium in a 
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recent network meta-analysis. [10] Furthermore, the plausibility of 
1 
dexmedetomidine’s positive effects on postoperative delirium is enhanced by 
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evidence of less anticholinergic activity and opioid-sparing properties. [14] 
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Postoperative prophylactic low-dose dexmedetomidine could remarkably 
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reduce the incidence of delirium during seven days after non-cardiac surgery; 
5 
[15] moreover, perioperative infusion of dexmedetomidine halved the 
6 
incidence of delirium in the elderly after major cardiac and non-cardiac 
7 
surgery without the increase in adverse effects. [16,17] A randomised 
8 
controlled trial found that intraoperative dexmedetomidine did not decrease 
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postoperative delirium or affect cognitive function in the elderly undergoing 
10 
major non-cardiac surgery. [18] A meta-analysis including 11 RCTs revealed 
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that perioperative dexmedetomidine reduced the incidence of POD in elderly 
12 
patients after non-cardiac surgery, but this came at the cost of an increased 
13 
incidence of hypotension and bradycardia. [19] A meta-analysis of 1301 
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patients undergoing cardiac surgery revealed that dexmedetomidine 
15 
decreased postoperative delirium. [20] Nevertheless, this meta-analysis 
16 
should be interpreted with caution, because several of the included studies 
17 
did not consider delirium as the primary outcome, the methodology of delirium 
18 
assessment varied, and dexmedetomidine administration was also 
19 
inconsistent, with differing doses and durations. Furthermore, the finding that 
20 
dexmedetomidine prevents postoperative delirium is also controversial. In the 
21 
DECADE trial, continuous infusions of dexmedetomidine, started at induction 
22 
and maintained for 24 hours, failed to reduce delirium in patients recovering 
23 
from cardiac surgery. Notably, dexmedetomidine non-significantly aggravated 
24 
delirium, probably mediated by hypotension. [21] However, the plausibility that 
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dexmedetomidine prevents POD should be discussed separately, because 
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physiopathology and incidence of delirium is quite different between non-
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cardiac surgery and cardiac surgery (frequent cerebral embolism). The 
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heterogenous ways that dexmedetomidine is administrated (pre- or post-
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operative or both, bolus, continuous et al) also complicated the analysis even 
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more. As with all pharmacological treatment options, the side effects of 
1 
dexmedetomidine are bradycardia and hypotension in a dose-dependent 
2 
manner, and more strikingly in the elderly; hence, close haemodynamic 
3 
monitoring is warranted.  
4 
Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor 
5 
antagonist, is pharmacologically rationalised as an effective medication for 
6 
reducing postoperative delirium, probably due to its neuroprotective 
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properties. Under surgical conditions, the enhanced AMPA/NMDA signalling 
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caused by the activation of cytokine receptors, and high mobility group box 1 
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facilitate an increased influx of glutamate in hippocampal neurones, which 
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ultimately promotes glutamate toxicity. [22] Ketamine can mitigate neuronal 
11 
apoptosis by inhibiting the activation of NMDA receptors and the transduction 
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of excitatory signals. [23] The assumption of ketamine’s beneficial effects on 
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delirium is also strengthened by evidence of its opioid-sparing and 
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antidepressant effects. Depression and delirium, induced by similar 
15 
pathophysiological mechanisms, are thought to overlap. [24,25] A small 
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sample size of a randomised controlled trial indicated that a low-dose single 
17 
bolus of ketamine at induction significantly attenuated delirium after cardiac 
18 
surgery. However, the PODCAST study showed that low-dose ketamine failed 
19 
to decrease postoperative delirium, pain, and opioid consumption, and 
20 
generated a dose-dependent increase in the occurrence of negative 
21 
experiences. [26] The PRIDe study offered no possibility for ketamine to 
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prevent postoperative cognitive decline, including delirium. [27] Ketamine 
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remains an off-label treatment for treatment-POD with factors that limit 
24 
widespread use including its dissociative effects and abuse potential. 
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S-ketamine is the S (+) enantiomer of ketamine, which has a higher affinity 
26 
with aspartate receptor and 𝞵 opioid receptor. The anaesthetic potency of S-
27 
ketamine is two-fold higher than that of racemic ketamine, and it has higher in 
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vivo clearance rate characterized by lower incidence of adverse reactions. 
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[28] Animal experiments showed that S-ketamine, rather than racemic 
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ketamine, could alleviate the injury of hippocampal neurones exposed to 
1 
glutamate in rodents; a subanaesthetic dose of S-ketamine could remarkably 
2 
mitigate neuroinflammation by inhibiting microglia proliferation and TLR4/NF-
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𝝹B signalling pathway activation, which consequently improved 
4 
neurocognitive function. [29,30] Additionally, S-ketamine could promote the 
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plasticity of hippocampal neurones and improve the function of neurones in 
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the prefrontal and hippocampal neural circuits. [31] A study on healthy 
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volunteers showed that S-ketamine exhibited pro-neuroplastic effects on 
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hippocampal structure, which may improve cognitive function after surgery. 
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[32] Moreover, a recent study on human metabolome revealed that S-
10 
ketamine decreases the levels of circulating branched chain amino acids 
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which inhibit the synthesis and release of serotonin and noradrenaline in the 
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brain. Thus, S-ketamine could, in theory, increase the effects of serotonin and 
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noradrenaline in the brain, and contribute to the improvement of depression 
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and cognitive impairment. [33] Furthermore, we hypothesize that the 
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sympathomimetic and analgesic properties of S-ketamine might partially 
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explain its non-inferior property for delirium prevention compared to 
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dexmedetomidine. Though S-ketamine has stronger potency and lower 
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incidence of adverse reactions, the evidence that it reduces the incidence of 
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postoperative delirium is fairly insufficient. 
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Since the effects of S-ketamine on postoperative delirium are lack of good 
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quality evidences, we designed the current prospective, randomised, double-
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blinded, placebo- and positive-controlled, non-inferiority trial to investigate the 
23 
effect of intraoperative prophylactic S-ketamine on postoperative delirium in 
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elderly patients undergoing thoracic surgery compared to dexmedetomidine.  
25 
Methods 
26 
Study setting and design  
27 
This study will be conducted at the Cancer Hospital and Institute of 
28 
Guangzhou Medical University (Guangzhou, Guangdong, China, with 
29 

principal investigator [PI] Dr Yonghua Yao). The study activities are expected 
1 
to commence in March 2022 and be completed in December 2023. The study 
2 
design is in accordance with the standard protocol items for randomised trials 
3 
guidelines. The overall schedule is illustrated in Table 1, and the Consolidated 
4 
Standards of Reporting Trials flow diagram is shown in Figure 1. The current 
5 
study protocol is the fifth version. 
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Table 1. Schedule of enrolment, interventions, and assessments for the trial 
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Enrolment 
Allocation 
Post-allocation 
Closeout 
 
Preoperative 
assessment 
Allocation 
Before 
induction 
recovery 
4-hour 
after 
surgery 
24-hour 
after 
surgery 
48-hour 
after 
surgery 
72-hour 
after 
surgery 
96-hour 
after 
surgery 
30-day 
after 
surgery 
60-day 
after 
surgery 
TIME POINT 
-T1 
T0 
T1 
T2 
F1 
F2 
F3 
F4 
F5 
F6 
F7 
ENROLMENT: 
 
 
 
 
 
 
 
 
 
 
 
Eligibility screen 
X 
 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
Allocation 
 
X 
 
 
 
 
 
 
 
 
 
INTERVENTIONS: 
 
 
 
 
 
 
 
 
 
 
 
S-ketamine 
 
 
 
 
 
 
 
 
 
 
 
Dexmedetomidine 
 
 
 
 
 
 
 
 
 
 
 
Normal Saline 
 
 
 
 
 
 
 
 
 
 
 
ASSESSMENTS: 
 
 
 
 
 
 
 
 
 
 
 
Postoperative 
delirium 
(3D-CAM) 
 
 
 
 
X 
X 
X 
X 
X 
 
 
Pain severity 
(NRS) 
 
 
 
 
X 
X 
X 
 
 
 
 
Sleep quality 
(NRS) 
 
 
 
 
 
X 
X 
X 
X 
 
 
Cognitive 
function 
(TICS-40) 
 
 
 
 
 
 
 
 
 
X 
X 
Haemodynamic 
variables 
 
 
 
 
 
 
 
 
 
 
 
Emergence 
delirium 
(RASS) 
 
 
 
X 
 
 
 
 
 
 
 
Plasma 
biomarkers 
(ACh，BDNF, 
TNF-𝜶) 
 
 
X 
X 
 
 
 
 
X 
 
 
 
9 
Participant recruitment 
10 
Inclusion criteria 
11 
1. Aged 60 to 90 years old. 
12 
2. Both sexes. 
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3. American Society of Anaesthesiologists (ASA) physical status classification I-III. 
1 
4. Diagnosed with pulmonary, oesophageal or mediastinal disorders. 
2 
5. Undergoing open or video-assisted thoracic surgery, including lobectomy, 
3 
segmentectomy, pneumonectomy, oesophagectomy, or resection of the mediastinal 
4 
tumour. 
5 
6. General anaesthesia with one lung ventilation (OLV) or bronchial blocker. 
6 
7. An expected operation duration of 2 hours or more. 
7 
8. Voluntary participation in the trial and signed informed consent. 
8 
Exclusion criteria 
9 
1. History of severe psychiatric disease. 
10 
2. History of glaucoma or hyperthyroidism. 
11 
3. History of severe hepatic (Child-Pugh grade C) or renal (requirement for renal 
12 
replacement therapy) disorders. 
13 
4. Body mass index (BMI) ˃ 35 kg/m2. 
14 
5. Dementia history or baseline Mini-Mental State Examination (MMSE) score of < 23. 
15 
6. Severe audio-visual impairments, or inability to speak Mandarin or Cantonese 
16 
precluding communication. 
17 
7. Sinus bradycardia (heart rate < 50 beats per minute, bpm), sick sinus or Wolff-
18 
Parkinson-White syndrome, or 2nd degree atrioventricular block and over. 
19 
8. Uncontrolled hypertension (baseline value > 200/110 mm Hg). 
20 
9. Allergic to dexmedetomidine or S-ketamine.  
21 
10. Taking sedatives, antidepressants or glucocorticoids.  
22 
11. Alcohol or Illicit drug misuse disorder. 
23 
12. Life expectancy of less than two months due to extensive tumour metastasis.  
24 
 
25 
Participants consent  
26 
All patients scheduled for thoracic surgery will be screened one day before 
27 
the operation for eligibility at the preoperative evaluation clinic (or on Friday 
28 
for those who will undergo surgery the following Monday). Eligible patients will 
29 

be informed by the study team coordinator. For the sake of voluntary 
1 
participation, all patients will be informed about the aims, procedures, 
2 
benefits, possible risks of study, and how to react if risks occur. If interested in 
3 
enrolment, the patients or their next of kin will sign the written consent form in 
4 
triplicate. 
5 
 
6 
Randomisation and blindness 
7 
A randomisation code will be generated in a block size of six on the website of 
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http://www.Randomization.com and kept in a sealed opaque envelope by an 
9 
anaesthetist nurse. The patients will be randomly allocated by a ratio of 1:1:1 
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to the S-ketamine group (S group), dexmedetomidine group (D group), or 
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control group (C group) by an anaesthetist nurse. Dispensing and labelling of 
12 
the study drugs will be performed by a pharmacist. Both the anaesthetist 
13 
nurse and the pharmacist will not be involved in the following research or 
14 
follow-up. The randomisation protocol will be kept secure by the anaesthetist 
15 
nurse. The primary investigator, and the clinicians collecting the data, are 
16 
allowed to unmask the randomization protocol only when both recruitment and 
17 
the database are closed. 
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The labelled “Study medication” syringes (50 ml), identical in appearance, 
19 
and the infusion regimen formulated by the pharmacist based on the 
20 
randomisation, will be distributed to the attending anaesthesiologists 
21 
responsible for anaesthetic management as soon as the research team 
22 
informs the central pharmacy about the patient heading for surgery. In order 
23 
to avoid anaesthesiologists’ speculation about the randomised assignment, 
24 
the study drugs will be infused at the same rate (see Table 2). The 
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anaesthesiologists, patients, investigators responsible for follow-up, and 
26 
statisticians will be all blinded to the randomised allocations until the final 
27 
statistical analyses are completed. The blindness will be unmasked by the 
28 
primary investigator in a medical emergency, including deterioration of the 
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patient’s condition intraoperatively or adverse events postoperatively. 
30 

 
1 
Standard anaesthetic management  
2 
On the day of the operation, the patients will be admitted to the operating 
3 
room after random assignment. Vital signs will be routinely monitored, 
4 
including heart rate (HR), blood pressure (BP), oxyhaemoglobin saturation by 
5 
pulse oximetry (SpO2), end-tidal carbon dioxide partial pressure (EtCO2), 
6 
nasopharyngeal temperature, and urine output throughout surgery. Pre-
7 
oxygenation with 100% oxygen for 15 min before the induction of anaesthesia 
8 
will be delivered to the patient using a face mask. Atropine will be 
9 
administered intravenously in avoidance of excessive secretions. 
10 
After arterial line and central venous line are cannulated under ultrasound 
11 
guidance, anaesthesia induction will be performed by administration of 
12 
midazolam (0.05 mg/kg), propofol (1-2 mg/kg) or etomidate (0.2 mg/kg), and 
13 
sufentanil (0.2-0.4 𝞵g/kg). After the patient becomes unconscious, rocuronium 
14 
(0.6 mg/kg) will be injected intravenously. Bronchial intubation will be 
15 
performed smoothly with a video laryngoscope after 3-minute positive 
16 
pressure ventilation. The tip of double lumen tubes (DLTs) will be inserted into 
17 
the glottis under direct vision and advanced until a mild resistance is 
18 
perceived. After the fibreoptic bronchoscope is fully lubricated, it will be 
19 
advanced into the tracheal lumen of the DLTs until the carina is identified. 
20 
Afterwards, the ideal position of the bronchial lumen (the blue bronchial cuff 
21 
should be invisible for left DLTs, the opening in the upper lobe of the right lung 
22 
should be visible for right DLTs) will be verified. Dual-controlled ventilator 
23 
modes (i.e. pressure-controlled ventilation with volume guaranteed or 
24 
pressure-regulated volume control) will be applied. One-lung protective 
25 
ventilation regimen will be conducted by a combination of tidal volumes (Vt) of 
26 
6 ml/kg or lower, by predicted body weight, with a positive end-expiratory 
27 
pressure of 6 cmH2O or beyond based upon guidelines and expert opinion for 
28 
optimal practice during OLV. [34] High inspiratory fractions of oxygen (FiO2 > 
29 
70%) will be administered to maintain SpO2 higher than 94%. In addition, 
30 

continuous positive airway pressure (CPAP) regimen will be considered when 
1 
necessary. The respiratory rate will be adjusted to maintain EtCO2 at 35-45 
2 
mmHg. Sedative maintenance will be performed with a TCI (target-controlled 
3 
infusion) of propofol according to the Schnider model at a plasma 
4 
concentration (Cp) of 2-3 𝞵g/ml to maintain the bispectral index value 
5 
between 40 and 60. Analgesic maintenance will be achieved with a TCI of 
6 
remifentanil according to the Minto model at a Cp of 1-6 ng/ml to fluctuate the 
7 
HR and BP within the baseline value ± 20%. An intermittent bolus of 
8 
rocuronium will be administered to maintain TOF < 1 intraoperatively. Forced 
9 
air-warm blankets will be used to ensure an intraoperative body temperature 
10 
of 36-37°C. The surgeon will implement an intercostal nerve block (T3-7) with 
11 
20 ml of 0.5% ropivacaine under direct thoracoscopic view before placing a 
12 
chest tube. The sign of a successful block is the presence of pleural 
13 
displacement. All participants will be given hydromorphone (0.015 mg/kg) 
14 
when a chest tube is placed for the sake of prophylaxis of hyperalgesia. 
15 
 A patient-controlled analgesia (PCA) device, with hydromorphone (0.15 
16 
mg/kg) and ondansetron (12 mg) in a total volume of 100 ml, will be 
17 
connected to the intravenous cannula at the end of surgery. The device is 
18 
programmed to administer a background dose of 2 ml/h, as well as a bolus 
19 
dose of 0.5 ml with a lockout interval of 15 min for 48 hours. Hydromorphone 
20 
(0.008 mg/kg) will be administered if the numeric rating scale (NRS) score is > 
21 
5 despite the PCA regimen. Residual neuromuscular blockade will be 
22 
routinely reversed with neostigmine (40 𝞵g/kg) and atropine (20 𝞵g/kg), and 
23 
the endotracheal tube will be removed when the patients are able to follow 
24 
verbal commands. 
25 
 
26 
Study drugs administration  
27 
S-ketamine (50 mg, 2 ml) is diluted to 50 ml (1 mg/ml) with 48 ml normal 
28 
saline; dexmedetomidine (200 𝞵g, 2 ml) is diluted to 100 ml (2 𝞵g/ml) with 98 
29 
ml normal saline; the control group only receives 50 ml normal saline in light 
30 

of blindness. All drugs are identical in appearance, packaged in identical 50 
1 
ml syringes labelled with “Study medications”. The loading dose of study 
2 
drugs will be infused within 10 minutes before induction, and the maintenance 
3 
dose will be infused at a constant rate continuously until skin closure. In the 
4 
preliminary trial, we found that a loading dose of 0.4 𝞵g/kg 
5 
dexmedetomidine lead to obvious bradycardia and transient hypertension 
6 
events. Therefore, we modified the loading dose of dexmedetomidine to 0.2 
7 
𝞵g/kg; In addition, in order to ensure blindness, the infusion speed of 
8 
dexmedetomidine is consistent with that of S-ketamine, which also reduces 
9 
the side effects of dexmedetomidine. The detailed administrative protocol of 
10 
study drugs is shown in Table 2. 
11 
 
12 
Table 2 Study drugs and administrative protocol (take a 60 kg patient as 
13 
an example) 
14 
Group 
Concentration 
Loading 
dose 
Maintenance 
dose 
S-ketamine 
1 mg/ml 
0.25 mg/kg 
0.1 mg/kg/h 
i.e. The administrative protocol of a 60 kg patient will be a loading dose of 
15 ml and a maintenance dose of 6ml/h 
Dexmedetomidine 
2 𝞵g/ml 
0.2 𝞵g/kg 
0.2 𝞵g/kg/h 
i.e. The administrative protocol of a 60 kg patient will be a loading dose of 
15 ml and a maintenance dose of 6 ml/h 
Control 
Normal saline 
—— 
—— 
i.e. The administrative protocol of a 60 kg patient will be a loading dose of 
15 ml and a maintenance dose of 6 ml/h 
 
15 
Data collection  
16 
The following data will be collected through patient interviews and 
17 
abstractions from the electronic medical record system: 
18 

Preoperative data collection 
1 
1. Patient demographic data including age (years), sex, height (cm), weight (kg), BMI 
2 
(kg/m2), and education level (years). 
3 
2. ASA classification, Charlson comorbidity index, baseline MMSE, and type of surgery. 
4 
3. Plasma biomarker concentrations including acetylcholine (ACh), brain-derived 
5 
neurotrophic factor (BDNF) and tumour necrosis factor-𝜶 (TNF-𝜶) before the 
6 
administration of study drugs (T1). 
7 
Intraoperative data collection 
8 
1. Haemodynamic parameters including HR (bpm), mean arterial pressure (MAP, mmHg), 
9 
SpO2 and BIS value at 15-minute intervals. 
10 
2. Hypotension and bradycardia episodes (see Table 3). 
11 
3. Hypertension and tachycardia episodes (see Table 3). 
12 
4. Duration of desaturation (SpO2 < 94%, minutes). 
13 
5. The cumulative dosage of noradrenaline (𝞵g) and atropine (mg). 
14 
6. The consumption of propofol (mg) and opioids (converted to morphine milligram 
15 
equivalent by Global RPH, MME). 
16 
7. Surgery, anaesthesia and OLV duration (minutes). 
17 
8. Time to extubation (minutes, duration from discontinuation of propofol to removal of 
18 
the tracheal tube). 
19 
9. Emergence agitation (Richmond Agitation-Sedation Scale, RASS score ≥ 1). 
20 
10. Plasma biomarker concentrations at the end of operation (T2). 
21 
Postoperative data collection 
22 
1. Incident postoperative delirium between 4 h after surgery and the 4th postoperative day, and 
23 
twice daily from postoperative day 1 to postoperative day 4 (8:00-10:00 am) with an 
24 
interval of at least 6 hours. 
25 
2. Severity and duration of delirium. 
26 
3. Postoperative pain at 4 h, 1 and 2 days after surgery. 
27 
4. Consumption of hydromorphone (mg). 
28 
5. Quality of sleep within 4 days after surgery. 
29 
6. Cognitive function at 30 and 60 days after surgery. 
30 

7. Plasma biomarker concentrations at the 4th day after surgery (T3). 
1 
  Data Safety and Monitoring Committee (DSMB) is consist of three senior 
2 
anaesthesiologists and one surgeon who are blinded to the study. The DSMB 
3 
will provide independent oversight of the SKED trial and will review the study 
4 
data for the participant safety as well as CRF storage. The data will be 
5 
entered into the Epidata V4.6 database protected by password only 
6 
accessible to DSMB. Then, the data will be exported from Epidata database 
7 
to a statistical package for analysis by biostatisticians independent of the 
8 
study. 
9 
 
10 
Outcomes 
11 
Primary outcomes 
12 
The primary outcome will be the incidence of postoperative delirium as 
13 
defined by any positive assessment between 4 h after surgery and the 4th 
14 
postoperative day. 
15 
Secondary outcomes 
16 
The main secondary outcome will be the subtype, severity and duration of 
17 
postoperative 
18 
delirium.  
19 
Other prespecified secondary outcomes will be the incidence of emergence 
20 
delirium; pain 
21 
severity at 4 h, 1 and 2 days after surgery; quality of sleep within 4 days after 
22 
surgery;  
23 
cognitive function at 30 and 60 days after surgery; plasma biomarker (ACh, 
24 
BDNF, TNF-𝜶)  
25 
concentrations at T1-3; and incidence of adverse events. 
26 
 
27 
Measurement of outcomes 
28 
Measurement of delirium 
29 

Delirium will be assessed using a validated 3-minute diagnostic confusion 
1 
assessment method (3D-CAM Chinese version, with a sensitivity of 84%–99% 
2 
and specificity of 90%–97%) [35,36] or Confusion Assessment Method for the 
3 
Intensive Care Unit (CAM-ICU), for patients who have a tracheal tube or 
4 
underwent tracheostomy. [37] 3D-CAM resolves the four diagnostic features 
5 
of delirium: (1) acute onset and fluctuating course, (2) inattention, (3) 
6 
disorganised thinking, and (4) altered level of consciousness. A patient who 
7 
displays both features 1 and 2, with either feature 3 or 4, will be diagnosed 
8 
with delirium (see Figure 2). [35] Delirium assessments will be performed only 
9 
when patients can be aroused sufficiently with an RASS score of -3 to 4 
10 
(Supplementary Table 1). Patients with postoperative delirium will be 
11 
classified into three subtypes. Hyperactive delirium will be defined when the 
12 
RASS score ranges from 1 to 4; hypoactive delirium will be defined when the 
13 
RASS score ranges from -1 to -3, and mixed delirium will be defined when the 
14 
RASS score ranges from 1 to 4 and -1 to -3 alternatively. The severity of 
15 
postoperative delirium will be rated using the CAM-Severity short-form scale 
16 
(Supplementary Table 2). Mild-to-moderate delirium will be defined as a CAM-
17 
S score of 3 to 5, while severe delirium will be defined as a CAM-S score of 6 
18 
to 7. [38]  
19 
Four investigators who are not involved in perioperative care will be 
20 
responsible for postoperative delirium assessments and will be trained by a 
21 
psychiatrist with regard to symptoms, diagnosis, and treatment of delirium. 
22 
Furthermore, the psychiatrist will explain the protocols of 3D-CAM and CAM-
23 
ICU in detail, and will perform the simulation training of delirium assessment 
24 
until a kappa value over 0.8 is achieved between investigators and 
25 
psychiatrists. The training process will be repeated every 4-6 months 
26 
throughout the study. In addition, the chart-based delirium identification 
27 
instrument with the information primarily derived from electronic medical 
28 
records system and recalling descriptions of caregivers will be employed to 
29 

detect any cases of delirium in patients that may occur outside of in-person 
1 
delirium assessments (Supplementary Table 3). [39] 
2 
Pain and sleep quality measurement 
3 
Postoperative pain at rest and during a cough will be evaluated using an 11-
4 
point NRS (0 = [no pain], 0 < NRS < 4 [mild pain], 4 ≤ NRS < 7 [moderate 
5 
pain], 7 ≤ NRS <10 [severe pain], NRS = 10 [worst pain imaginable]). 
6 
Postoperative sleep quality will also be evaluated using the NRS (0 = best-
7 
quality sleep, 10 = worst-quality sleep).  
8 
Cognitive function measurement 
9 
Postoperative cognitive function will be assessed using the Chinese version of 
10 
the Telephone Interview for Cognitive Status-40 (TICS-40). The TICS-40 
11 
scale used in this study consists of nine items with a maximum score of 40 
12 
points, including the following variables and corresponding points: address (3 
13 
points), current date (5 points), counting backwards (2 points), word-list 
14 
recalling (10 points), subtractions (5 points), object naming (2 points), 
15 
repetition (1 point), the president and prime minister’s names (2 points), and 
16 
delayed recall of the word list (10 points). A score below 21 will be defined as 
17 
mild cognitive impairment (Supplementary Table 4). [40] 
18 
Biomarkers concentration measurement 
19 
Venous blood (approximately 6 ml) will be sampled and stored on ice in 
20 
vacutainer tubes containing EDTA. Within 30 min, the samples will be 
21 
centrifuged at 4°C for 20 min at 2000× g to obtain plasma and then stored at -
22 
80°C. We will measure ACh, BDNF, and TNF-𝜶 levels by enzyme-linked 
23 
immunosorbent assay method (in accordance to manufacturer’s instructions). 
24 
The biomarker assay will be performed by a specialist who is blinded to the 
25 
randomization. (Supplementary text for the rationales of biomarkers selected) 
26 
 
27 
Adverse events  
28 
An adverse event (AE) can be any unfavourable and unintended symptom or 
29 
side effect temporally associated with the use of study medications. The 
30 

potential AEs that may be considered in this trial are bradycardia, 
1 
hypotension, tachycardia, hypertension, arrhythmia, nystagmus, 
2 
hypersalivation, euphoria, emergence agitation, hallucinations, and 
3 
nightmares. It is possible, but very unlikely, that low-dose S-ketamine (50 mg 
4 
in total) administered intraoperatively will cause these psychiatric effects. 
5 
Potential adverse events and medical rescue are shown in Table 3. [41] 
6 
Serious AEs are rare, life-threatening events that may be associated with 
7 
the study drugs or perioperative incidents, such as death or serious cardio-
8 
cerebral vascular events. 
9 
 
10 
Table 3 The definitions of adverse events and corresponding medication 
11 
rescue 
12 
Adverse events  
Severity 
Definition  
Treatment 
Hypotension 
(SBP<90 mm Hg or 
DBP<50 mm Hg or 
MAP<80% baseline) 
Mild 
Moderate 
Severe 
Life-
threatening 
SBP 80-89 mm Hg 
SBP 70-79 mm Hg>2 
min 
SBP 60-69 mm Hg>1 
min 
SBP 60-69 mm Hg 
and 
unresponsive to  
noradrenaline or 
SBP<60 
mm Hg 
Close monitoring 
Noradrenaline 4 
𝝁g $ 
Noradrenaline 8 
𝝁g # 
Intensive 
intervention 
and suspend the 
study 
Hypertension 
(SBP>140 mm Hg or 
DBP>90 mm Hg or 
MAP>120% baseline) 
Mild 
 
Moderate 
 
 
Severe 
 
 
Life-
threatening 
SBP 141-160 mm Hg 
or 
DBP 91-100 mm Hg 
SBP 160-170 mm Hg 
or 
DBP 101-110 mm Hg 
>3 min 
SBP 171-180 mm Hg 
or 
DBP 111-120 mm Hg 
>2 min 
SBP>180 mm Hg or 
DBP>120 mm Hg 
and 
Close monitoring 
 
Urapidil 12.5 mg 
 
Urapidil 25 mg or  
NG 50 𝝁g 
Intensive 
intervention 
and suspend the 
study 

unresponsive to NG 
Bradycardia 
(HR<60 bpm) 
Mild 
Moderate 
Severe 
Life-
threatening 
HR 55-60 bpm 
HR 50-54 bpm>3 min 
HR 40-50 bpm>2 min 
HR<40 bpm and 
unresponsive to 
atropine  
Close monitoring 
Atropine 0.5 mg 
Atropine 1.0mg  
Intensive 
intervention 
and suspend the 
study 
Tachycardia 
(HR<60 bpm) 
Mild 
Moderate 
Severe 
Life-
threatening 
HR 90-100 bpm 
HR 101-110 bpm>3 
min 
HR 111-130 bpm>2 
min 
HR>130 bpm and 
unresponsive to 
Esmolol 
Close monitoring 
Esmolol 20 mg 
Esmolol 40 mg  
Intensive 
intervention 
and suspend the 
study 
Hypoxemia 
(SpO2<94%) 
Mild 
Moderate 
Severe 
Life-
threatening 
SpO2 90%-94%  
SpO2 80%-90%>3 
min 
SpO2 70%-79%>2 
min 
SpO2<70% and 
unresponsive to two-
lung 
ventilation 
Close monitoring 
CPAP 
Two-lung 
ventilation 
Intensive 
intervention 
and suspend the 
study 
Emergence delirium 
Mild  
Severe 
RASS 1-2 
RASS 3-4 
Limb restraint 
Propofol 30 mg 
Hallucination/Nystagmus NA 
3D-CAM 
Haloperidol 10 mg 
3D-CAM, 3 minutes diagnostic confusion assessment method; CPAP, 
1 
constant positive airway pressure; HR, heart rate; NA, not applicable; NG, 
2 
nitro-glycerine; RASS, Richmond Agitation-Sedation Scale. 
3 
$ followed by continuous infusion with 0.01-0.1 𝞵g/kg/min when necessary 
4 
# followed by continuous infusion with 0.1-0.2 𝞵g/kg/min when necessary 
5 
 
6 
Sample size calculation 
7 
The sample size was calculated for the main outcome, the incidence of 
8 
postoperative delirium, using PASS software version 11.0. Based on previous 
9 
studies and our recently completed data, we estimated that the incidence of 
10 

POD in elderly patients undergoing non-cardiac thoracic surgery was 40%. 
1 
[12,42-46] Assuming that dexmedetomidine is associated with a 40% relative 
2 
reduction in the incidence of postoperative delirium, the non-inferiority margin 
3 
rate ratio (RR) of S-ketamine versus dexmedetomidine will be set at 1.5. 
4 
[15,27,47,48] To achieve a two-sided type I error of 5% and 80% power, 729 
5 
participants (243 patients per arm) will be recruited. To accommodate a 5% 
6 
dropout rate, the final sample size will be 780 (260 patients per arm). 
7 
 
8 
Statistical methods 
9 
Kolmogorov-Smirnov test will be used to evaluate the normal distribution of 
10 
continuous variables. Normally distributed data will be presented as means ± 
11 
standard deviation (SD), and non-normally distributed data will be presented 
12 
as medians with interquartile ranges. Categorical data will be summarised as 
13 
counts (proportions). 
14 
The absolute standardised difference (ASD) will be used for the comparison 
15 
of baseline data among the three groups, that is, the absolute difference in 
16 
means, mean ranks, or proportions divided by the combined SD. Baseline 
17 
variables with ASD>0.013 (i.e.,1.96 ×
18 
/(260 + 260 + 260)/(260 × 260 × 260)) are considered to be imbalanced 
19 
and will be adjusted for in all analyses when necessary. 
20 
For the primary outcome, the incidence of postoperative delirium, the 
21 
intention-to-treat approach and per-protocol (PP) approach will be performed. 
22 
Pearson’s chi-square test will be applied to compare proportions with the 
23 
primary outcome among groups. The difference among groups will be 
24 
expressed as RR and 95% confidence interval (CI), while non-inferiority will 
25 
be identified if the upper limit of 95% CI of RR is < 1.5. For the secondary 
26 
outcomes, only the PP approach will be used. Normally distributed data will 
27 
be analysed with one-way analysis of variance (ANOVA); Non-normally 
28 
distributed data will be analysed with Kruskal-Wallis test. The median 
29 

difference will be calculated using the Hodges-Lehmann estimation on the 
1 
basis of the Kruskal-Wallis test. Adverse events that are presented as 
2 
incidences will be compared by calculating the 95% CI of the incidence 
3 
difference: incidence (S group) – incidence (D group), and noninferiority will 
4 
be achieved if the upper limit of 95% CI is < 5%. The superiority for outcomes 
5 
will be assessed when noninferiority is verified.  
6 
To account for correlation among repeated measurements, such as numeric 
7 
rating scores for pain and sleep quality, plasma biomarker concentrations, 
8 
and cognitive function, will be compared using generalised estimating 
9 
equation analysis among groups. The time to delirium will be calculated with 
10 
the Kaplan-Meier estimator, and the differences among groups will be 
11 
assessed by the log-rank test. The number needed to treat will be estimated 
12 
for the primary outcome. 
13 
Missing values will be adjusted using random forest imputation in the 
14 
missForest package. However, missing values, due to fatigue in the 
15 
assessment or the patient's inability to cooperate, will be imputed with positive 
16 
results or means in the corresponding treatment group and time point. If the 
17 
patient did not have a delirium assessment at all (e.g. dropout or death), no 
18 
values will be imputed. The last assessment is used to replace the missing 
19 
value to estimate the incidence of postoperative delirium in patients who are 
20 
discharged or die within 4 days, while the missing value of assessment per 
21 
day does not need to be replaced. 
22 
The P values and CIs reported from one-way ANOVA and Kruskal-Wallis 
23 
test will be considered to illustrate statistical significance if they are less than 
24 
0.017 and 98.3%, respectively, accounting for three pairwise comparisons. 
25 
The family-wise significance and CI levels among the three groups will be set 
26 
at 0.05% and 95%, respectively. For the pain intensity score, a 1.1 decrease 
27 
will be considered the minimal clinically important difference. [49] 
28 
 Analyses will be conducted using IBM SPSS version 25.0 (SPSS Software, 
29 
Chicago, IL, USA), R statistics version 4.1.2 (R Project for Statistical 
30 

Computing), and GraphPad Prism version 8.0 (GraphPad Software, San 
1 
Diego, CA, USA). 
2 
 
3 
Ethics and confidentiality 
4 
Ethical approval was obtained from the Institutional Review Board of the 
5 
Cancer Hospital and the Institute of Guangzhou Medical University 
6 
(ZN202119). The study has also been registered at Chictr.org.cn with the 
7 
identifier ChiCTR2100052750. The personal information of the participants 
8 
will not be disclosed unless authorisation is approved. In addition, each 
9 
participant will be provided with a unique identity code, the information of 
10 
which will be properly secured. The CRF and Epidata database will be 
11 
retained for a minimum of 10 years. 
12 
 
13 
Patient and Public Involvement 
14 
No patients or public representatives were involved in the design of this trial. 
15 
 
16 
Dissemination 
17 
At the end of the trial, we commit to making public disclosure available despite 
18 
the outcome. Public disclosure will include publication in an appropriate 
19 
journal or oral presentation at an academic meeting. The PI will be considered 
20 
the first or corresponding author. The investigators who contribute a minimum 
21 
of four months to the trial will be co-authors; otherwise, they will be 
22 
acknowledged in the publication.  
23 
 
24 
Discussion  
25 
Lung cancer ranks first among all malignancies in China, and anatomic 
26 
pulmonary resection is a major component of multimodal therapy according to 
27 
the lung cancer guidelines. [12] However, more than 40% of patients 
28 
undergoing lung cancer surgery are inflicted by severe depression-related 
29 
psychological suffering postoperatively. [50] Depression is an independent 
30 

predictor of postoperative delirium in patients who undergo orthopaedic and 
1 
cancer surgeries. [24] Based on its pharmacological mechanisms and 
2 
antidepressant effects, we speculate that S-ketamine would be non-inferior to 
3 
dexmedetomidine in reducing postoperative delirium to some extent in the 
4 
elderly, with fewer episodes of hypotension or less opioid consumption. 
5 
Hypotension is pertinent to delirium, and minimisation of intraoperative 
6 
hypotension episodes is recommended to reduce postoperative delirium. [51] 
7 
Additionally, the administration of opioids (long-acting opioids in particular) is 
8 
closely related to postoperative delirium in a dose-dependent manner. Hence, 
9 
it is critical to abate opioid consumption in order to curtail delirium. [8] 
10 
Although previous studies have demonstrated that ketamine failed to reduce 
11 
the incidence of postoperative delirium in patients undergoing major cardiac 
12 
or non-cardiac surgery, we will deploy a different administrative protocol to 
13 
evaluate the effect of an isomer of ketamine on postoperative delirium 
14 
accompanied by dexmedetomidine as a positive comparator and by an 
15 
optimal sample size. Dexmedetomidine is a highly recommended agent in the 
16 
prevention and treatment of postoperative delirium; however, it is commonly 
17 
accompanied by hypotension and bradycardia in the elderly. As the 
18 
prevention of postoperative delirium is more practical and effective than the 
19 
treatment itself, creating a means of prevention for delirium is extraordinarily 
20 
indispensable. We believe that the possible result will be one of the following: 
21 
(1) S-ketamine will be non-inferior to dexmedetomidine in the prevention of 
22 
postoperative delirium; meanwhile, more stable haemodynamics, lower 
23 
postoperative pain severity, or other beneficial secondary outcomes will be 
24 
observed with S-ketamine intervention. Side effects will be compared between 
25 
groups, all of which will be our desirables. This suggests that S-ketamine will 
26 
be an optimal choice for limiting delirium emergence in the elderly, and further 
27 
studies should be performed to evaluate its effect on long-term cognitive 
28 
function. (2) S-ketamine will be non-inferior to dexmedetomidine in 
29 
postoperative delirium prevention with comparable secondary outcomes; 
30 

however, it will be accompanied by frequent side effects. This indicates that 
1 
S-ketamine will be clinically valueless for delirium prevention, which is also 
2 
possible in view of the results from previous studies on ketamine (PODCAST 
3 
and PRIDe study). (3) S-ketamine will be inferior to dexmedetomidine in the 
4 
prevention of postoperative delirium, which is probably because 
5 
dexmedetomidine is recognised as the most effective medication for delirium, 
6 
and fewer studies have compared the two drugs.  
7 
  The SKED protocol has many limitations. First, the current trial is launched 
8 
at special 
9 
time when inclusion may be constrained by local SARS-CoV-2 pandemic. As 
10 
such, the 
11 
research period may take longer than anticipated. Second, this is a single-
12 
centre study  
13 
that exclusively involves thoracic surgery; therefore, the generalisability may 
14 
not be  
15 
extrapolated. Third, an anticipated non-inferiority margin ratio of 1.5 in our trial 
16 
may be  
17 
too large, and consequently, the sample size may be underestimated. Fourth, 
18 
a dropout  
19 
rate of 5% seems a bit low as advert events due to dexmedetomidine may be 
20 
higher than  
21 
that, if so, we would enlarge the sample size upon approval from the IRB. 
22 
 
23 
 
24 
 
 
25 

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24 
 
25 
 
26 
Figure legends 
27 
Figure 1. Consolidated Standards of Reporting Trials (CONSORT) flow 
28 
diagram. 
29 

Figure 2. Overview of 3-minute Diagnostic Confusion Assessment Method 
1 
(3D-CAM) assessment. 
2 
 
3 
 
4 
 
5 
 
6