Pain Control During Brief Intervention in Deep Sedation: no Pain or no Memory
Conditions: Pain, Acute, Surgical Procedure, Unspecified
Sponsor: ASL Novara

A.S.L. NO 
Azienda Sanitaria Locale 
di Novara 
P.IVA 01522670031 
Sede Legale: viale Roma, 7 – 28100 Novara 
Tel. 0321 374111 – fax 0321 374519 
www.asl.novara.it 
Azienda Sanitaria Locale ASL NO S. C.Anestesia e Rianimazione 
Direttore Dr. Davide Colombo 
Viale Zoppis, 10 – 28021 Borgomanero (NO) 
www.regione.piemonte.it 
 
 
STUDY PROTOCOL 
 
“NOL Index and Sedation: no pain or no memory?” 
Acronym: SedNOL 
v. 1.0 dated 23/10/2023 
 
 
 
Sponsor: 
Azienda Sanitaria Locale of Novara- “Ss. Trinità of Borgomanero” Hospital 
 
Principal Investigator: 
Davide Colombo, MD, PhD 
 
Study Type: 
Prospective, single-center, observational cohort study, non-pharmacological, non-profit 
 
Participating Centers: 
Department of Anesthesia and Intensive Care Unit in “Ss. Trinità of Borgomanero” Hospital 
 
Sponsor: 
None 
 
Version Date 1.0: 
23/10/2023 
 
 
Confidential 
The information contained in this document is provided to you as the principal investigator, potential 
researcher, or a consultant for your review by you, your collaborators, and the institutional review 
committee. The information contained in this document is confidential and, except to the extent 
necessary to obtain informed consent, cannot be disclosed unless such disclosure is required by 
federal regulations and state law. People to whom the information is disclosed must be aware that it 
is confidential and may not be further disclosed. 

A.S.L. NO 
Azienda Sanitaria Locale 
di Novara 
P.IVA 01522670031 
Sede Legale: viale Roma, 7 – 28100 Novara 
Tel. 0321 374111 – fax 0321 374519 
www.asl.novara.it 
Azienda Sanitaria Locale ASL NO S. C.Anestesia e Rianimazione 
Direttore Dr. Davide Colombo 
Viale Zoppis, 10 – 28021 Borgomanero (NO) 
www.regione.piemonte.it 
 
 
Introduction and Background 
The term "nociception" refers to the neural process of encoding noxious stimuli (Loeser, 2008), 
processed by the peripheral and central nervous system (PNS/CNS) (Institute of Medicine, 1987) upon 
activation of nociceptors. Thus, noxious stimuli, including tissue damage, activate nociceptors in 
peripheral structures and transmit information to the dorsal horn of the spinal cord, then through 
ascending spinal pathways to the thalamus and cortical and subcortical structures that process this 
information, generating various types of responses: motor, emotional, memory, etc. The term pain is 
reserved for the conscious perception of actual or potential tissue damage and therefore cannot be 
used in an unconscious state. 
 
General anesthesia is a state of pharmacologically induced, temporary, and reversible coma consisting 
of three elements: hypnosis, analgesia, and muscle relaxation. These are achieved by administering 
two or more drugs to the patient, inducing an artificial sleep so deep that it allows any surgical procedure 
to be performed without feeling any pain, moving, or remembering anything. This means that any 
noxious stimulus is neither processed nor recognized by the brain while anesthesia is in progress. This 
technique is typically used for long-duration or very painful procedures (ISSalute, 2022). 
 
Deep sedation is defined as a drug-induced depression of consciousness during which patients cannot 
be easily awakened but respond to repeated or painful stimulation. In this state, the ability to maintain 
independent ventilatory function may be compromised, often requiring assistance to maintain airway 
patency. Spontaneous ventilation may be inadequate, whereas cardiovascular function is usually 
maintained (2019). Sedation is a continuum and can progress or regress from one level to another, 
inevitably varying the risks and appropriate management to preserve patient safety. Monitoring vital 
parameters, always combined with careful clinical assessment, is therefore indispensable and 
adjustable as needed (SIAARTI-SIED, 2022). 
 
Deep sedation may be the anesthetic technique of choice for short-duration, particularly painful day- 
surgery procedures where complete patient curarization is not strictly necessary. Various drugs in 
current clinical practice can ensure an adequate sedation plan for the procedure, which can be used 
alone or in combination and administered as a single dose or continuous infusion. 
 
In addition to standard perioperative monitoring, monitoring the depth of anesthesia is highly 
recommended by international scientific literature, especially in cases where a protocol involving 
Propofol infusion in TIVA-TCI (Total IntraVenous Anesthesia - Target Controlled Infusion) is used (Klein 
AA, 2021). Conversely, there is currently no recommendation or guideline for nociception monitoring. 
Nociception is typically assessed using indirect methods such as heart rate and blood pressure 
variations. However, these indicators have been shown to be poor surrogates for nociception 
monitoring, as vital signs are influenced by a range of other health conditions (Coluzzi, 2019). 
 
Various other methods have been used to establish the efficacy of analgesics during the intraoperative 
period, such as evaluating patient movement and sweating. However, these indirect parameters are 
largely imprecise because different anesthetic drugs reduce and/or abolish the autonomic nervous 
system's ability to respond to nociceptive stimuli to varying degrees (Kang, 2015). Nevertheless, 
maintaining the balance between nociception and analgesia (the "nociception-antinociception 
balance") is critical to avoid serious postoperative complications (Ghanty, 2019). 
 
It should also be noted that the lack of accurate nociception monitoring during surgery can lead to 
inadequate analgesic doses. Opioid analgesics are widely used in common clinical anesthetic practice, 
and administering an insufficient dose could lead to abnormal recovery, delayed hospital discharge, 
and, in some cases, chronic postoperative pain. On the other hand, administering an excessive dose 
of opioids can cause nausea, vomiting, respiratory depression, increased hospital stay, and treatment 
costs (Won, 2016). 

A.S.L. NO 
Azienda Sanitaria Locale 
di Novara 
P.IVA 01522670031 
Sede Legale: viale Roma, 7 – 28100 Novara 
Tel. 0321 374111 – fax 0321 374519 
www.asl.novara.it 
Azienda Sanitaria Locale ASL NO S. C.Anestesia e Rianimazione 
Direttore Dr. Davide Colombo 
Viale Zoppis, 10 – 28021 Borgomanero (NO) 
www.regione.piemonte.it 
 
 
Recognizing the complexity of this process, a medical monitoring device has been developed: the 
PMD-200™ provides the nociception level index (NOL), an innovative technology developed by 
Medasense Biometrics Ltd. that allows objective measurement of patient nociception by analyzing 
multiple patient parameters. This device uses a non-invasive finger probe with four sensors 
(photoplethysmography 
amplitude, 
galvanic 
skin 
response, 
peripheral 
temperature, 
and 
accelerometry) that extract multiple pain-related physiological signals. Real-time data are analyzed by 
specific algorithms that identify the patient's pain pattern, displayed on a numerical scale from 0 to 100. 
Notably, a value of 25 indicates the threshold beyond which the nociceptive reaction is clinically 
significant. 
The use of this tool has been extensively studied during general anesthesia, demonstrating that 
monitoring nociception response levels with the NOL Index can help reduce postoperative pain, patient 
stress hormone levels (ACTH and cortisol) (Meijer, 2020), and intraoperative opioid use, resulting in 
fewer hypotensive events and associated myocardial and renal damage (Meijer, 2019). Additionally, it 
has been shown that the combined use of the NOL Index and Bispectral Index during general 
anesthesia can provide accurate and complementary information to guide optimal administration of 
analgesic and hypnotic drugs (Meijer, 2020). 
 
The rationale for this study lies in the context of relatively short surgical procedures (lasting between 
30 and 90 minutes) requiring deep sedation anesthesia. The hypnotic efficacy of commonly used 
sedation protocols is widely studied and validated by international scientific literature. It is also 
important to consider that, in some cases, excessive administration of sedatives with insufficient 
analgesic coverage may occur, leading to seemingly acceptable postoperative results, while in reality, 
patients experience painful situations without remembering them. This can be particularly dangerous 
in fragile patients, where heightened adrenergic system activation leads to serious complications. 
Therefore, we ask: “Are our sedation protocols, aside from their hypnotic effectiveness, equally 
effective at the analgesic level?” 
 
Finally, an ethical question must also be highlighted, as proper pain management, in all its forms, is a 
duty the clinician must address. 
 
 
 
Study Purpose 
Evaluate the efficacy of the sedation protocol from a nociceptive perspective through continuous 
intraoperative nociception monitoring (NOL Index). 
 
Primary Objective 
 
The sedation protocol will be considered nociceptively ineffective if the percentage of time the NOL 
index exceeds the threshold of 25, relative to the observation time, is greater than 25%. 
The NOL Index observation time is defined as the interval between reaching an adequate sedation 
level (Bispectral Index - BIS between 40 and 60) and the end of surgical stimulation. 
 
Secondary Objectives 
 
1. Time the NOL index exceeds the threshold of 25, expressed in minutes 
2. Number of peaks with NOL index above 40 
3. Evaluate any correlation between the primary objective and the NRS scale 15 minutes post- 
operation 
4. Evaluate any correlation between the primary objective and the NRS scale 2 hours post-operation 
 5. Evaluate any correlation between the primary objective and the need for rescue analgesic doses 

A.S.L. NO 
Azienda Sanitaria Locale 
di Novara 
P.IVA 01522670031 
Sede Legale: viale Roma, 7 – 28100 Novara 
Tel. 0321 374111 – fax 0321 374519 
www.asl.novara.it 
Azienda Sanitaria Locale ASL NO S. C.Anestesia e Rianimazione 
Direttore Dr. Davide Colombo 
Viale Zoppis, 10 – 28021 Borgomanero (NO) 
www.regione.piemonte.it 
 
 
 
 
requested by the patient. 
 
 
Study Design 
Prospective observational clinical study, non-profit, non-pharmacological, utilizing the medical device 
PMD-200™ (Medasense Biometrics Ltd), in patients undergoing short-duration (less than 90 minutes) 
and particularly painful surgical procedures, with an indication for deep sedation anesthesia. 
 
 
Materials and Methods 
Eligibility Criteria 
Inclusion Criteria 
 Adult patients (>18 years old) 
 ASA Physical Status I – II - III 
Exclusion Criteria 
 ASA Physical Status IV 
 Pregnant or lactating patients 
 Pre-existing cardiac arrhythmias 
 Patients with neuromuscular diseases 
 Patients with psychiatric syndromes under pharmacological treatment 
 Patients with chronic continuous use of analgesics 
 Patients with a history of drug abuse 
 Allergy to one or more active ingredients used in the protocol 
 Refusal of consent 
 
 
Study Population 
 
The study population consists of patients admitted to the "Ss. Trinità of Borgomanero" hospital between 
March 1, 2024, and August 31, 2024, who need to undergo surgical procedures lasting less than 90 
minutes and particularly painful, with an indication for deep sedation anesthesia. 
 
Study Flow-chart 
 
Before enrollment, upon arrival in the operating room and after being properly positioned on the 
operating table, patients will undergo standard intraoperative monitoring with pulse oximetry (SpO2), 
3-channel electrocardiography (ECG), non-invasive blood pressure (NIBP), Bispectral Index (BIS) 
sensor, and a nociception sensor (NOL) will also be placed. Patients will be preoxygenated with a facial 
mask with FiO2 at 100% for 3 minutes. The induction phase of deep sedation anesthesia will be 
conducted with a single bolus of Fentanyl 1mcg/kg and TIVA-TCI of Propofol with a target-controlled 
infusion (Cε) concentration of 4.0 mcg/mL. As soon as the sedation plan shows a Bispectral Index 
between 40 and 60, the observation of the NOL Index will begin. Subsequently, the laryngeal mask will 
be positioned, mechanical ventilation initiated, and the surgical procedure commenced. During this 
phase, maintenance of the anesthesia plan will be ensured by the infusion of Propofol in TIVA-TCI with 
a Cε to maintain the BIS between 40 and 60, and the administration of Paracetamol 1 g, Ketorolac 30 
mg, Dexamethasone 4 mg. At the end of the surgical procedure, the observation of the NOL Index will 
be concluded. Upon awakening, patients will be transferred to the Post-Anesthesia Care Unit (PACU), 
where they will remain until stabilization of vital signs. At this point, 15 minutes post-operation, the pain 
intensity will be recorded using the NRS scale. Subsequently, patients will be discharged to the ward, 

A.S.L. NO 
Azienda Sanitaria Locale 
di Novara 
P.IVA 01522670031 
Sede Legale: viale Roma, 7 – 28100 Novara 
Tel. 0321 374111 – fax 0321 374519 
www.asl.novara.it 
Azienda Sanitaria Locale ASL NO S. C.Anestesia e Rianimazione 
Direttore Dr. Davide Colombo 
Viale Zoppis, 10 – 28021 Borgomanero (NO) 
www.regione.piemonte.it 
 
 
 
 
where, at 2 hours post-operation, they will be interviewed regarding the intensity of post-operative pain 
and if they require any rescue analgesic doses. 
 
Any procedures not explicitly expressed in the protocol will be performed according to normal clinical 
practice. 
 
 
Collection and Management of Clinical Data 
Data collection and management are entrusted to the investigator and/or study staff. Data collection 
will be directly performed on a digital file (spreadsheets - Ms. Excel - Microsoft, Redmond, CA) without 
the use of paper forms. Data will be collected anonymously without identifying codes that allow tracing 
back to the patient's folder and therefore to the patient's identity. The correspondence list between 
demographic data and patient identification codes will be kept at the enrolling center, and only the study 
staff will have access to it. The collected data will include the following: 
 
Anthropometric Data 
 
 Gender
 Age
 Weight
 Height
 Body Mass Index - BMI
 ASA Physical Status
Clinical Data 
 Surgical Procedure performed
 Heart Rate (HR)
 Non-invasive Blood Pressure (NIBP)
 Pulse Oximetry (SpO2)
 Bispectral Index (BIS)
 NOL Index
 NRS Pain Scale
 
 
 
Statistical Analysis 
Continuous variables will be presented as mean and standard deviation or as median and interquartile 
range depending on the distribution. Normal distribution will be assessed using the Kolmogorov- 
Smirnov test. Any sub-analyses and comparisons between subgroups will be performed using 
Student's t-test for parametric data, while the Mann-Whitney test will be used for non-parametric data. 
Categorical variables will be presented as absolute number and percentage relative to the total sample 
size. Any sub-analyses and comparisons between subgroups will be performed using the chi-square 
test or Fisher's exact test depending on the subgroup sizes. In all cases, the null hypothesis will be 
rejected for values of α <0.05. The software used for data analysis and sample sizing is Medcalc v. 
22.013 (MedCalc Software, Ostend, Belgium). 
 
Sample Size Determination 
 
Following the manufacturer's indications, a nociceptive response measured at NOL >25 is considered 

A.S.L. NO 
Azienda Sanitaria Locale 
di Novara 
P.IVA 01522670031 
Sede Legale: viale Roma, 7 – 28100 Novara 
Tel. 0321 374111 – fax 0321 374519 
www.asl.novara.it 
Azienda Sanitaria Locale ASL NO S. C.Anestesia e Rianimazione 
Direttore Dr. Davide Colombo 
Viale Zoppis, 10 – 28021 Borgomanero (NO) 
www.regione.piemonte.it 
 
 
 
 
positive. In the absence of similar studies and reference parameters, we have set, based on clinical 
experience, a mean ≤ 10% of the observation interval, with NOL ≥ 25, as not significant for the presence 
of a nociceptive stimulus (Null Hypothesis). We have also considered a mean ≥ 25% of the observation 
interval, with NOL ≥ 25, as significant for the presence of a nociceptive stimulus. By calculating the 
sample size for a single mean, setting the type I error α to 0.05, power β to 0.8, estimating a standard 
deviation of 30%, the sample size in the study is determined to be 34 subjects. 
 
 
Approval from the Competent Authority 
 
In accordance with current regulations, the principal investigator must obtain approval from the 
appropriate Competent Authority before commencing the clinical study. This study will be conducted in 
accordance with the rules of ICH/GCP (International Conference of Harmonization/Good Clinical 
Practice) and all applicable laws, including the Helsinki Declaration of June 1964, modified by the latest 
World Medical Association General Assembly, Seoul 2008. As this is a non-interventional study, there 
are no specific risks associated with participating in the study protocol. Participation does not entail 
direct benefits to the enrolled patient but will contribute to improving knowledge regarding nociceptive 
stimulation during deep sedation anesthesia for patients undergoing short-duration and particularly 
painful surgical procedures. 
 
 
 
 
Ethics Committee Approval 
The investigator must ensure that the protocol has been reviewed and approved by the local 
independent Ethics Committee before commencing the study. The Ethics Committee must also review 
and approve the informed consent (IC) form and all written information provided to the patient before 
enrollment in the study. If it is necessary to modify the protocol and/or the IC during the study, the 
investigator will be responsible for ensuring the review and approval of such documents as requested 
by the Ethics Committee. The content of such modifications will be implemented only after approval by 
the Ethics Committee. Until then, reference should be made to the previous version of the already 
approved document. 
 
 
 
 
Informed Consent 
The investigator or other designated personnel is responsible for informing individuals about all aspects 
and procedures of the study. The IC must comply with current regulatory procedures: Helsinki 
Declaration (WMA, 2013 latest version, §§ 25-32), Reg. (EU) 536/2014, Charter of Fundamental Rights 
of the European Union (Nice, 2000, art. 3). The investigator (and/or designated collaborator) and the 
subject being offered the study must sign the IC form before the patient initiates any procedures 
indicated in the study. The subject will receive a dated and signed copy of the IC from both parties, and 
the original copy will be kept in the designated archives for the study. The subject's decision to 
participate or not in the study must be entirely voluntary. The participating subject has the right to 
withdraw their consent at any time. 

A.S.L. NO 
Azienda Sanitaria Locale 
di Novara 
P.IVA 01522670031 
Sede Legale: viale Roma, 7 – 28100 Novara 
Tel. 0321 374111 – fax 0321 374519 
www.asl.novara.it 
Azienda Sanitaria Locale ASL NO S. C.Anestesia e Rianimazione 
Direttore Dr. Davide Colombo 
Viale Zoppis, 10 – 28021 Borgomanero (NO) 
www.regione.piemonte.it 
 
 
 
Confidentiality 
The study's Responsible Party ensures that the data of the patients enrolled during the study will be 
safeguarded, stored, and processed in full compliance with privacy regulations, particularly Legislative 
Decree no. 196/2003 and subsequent amendments ("Privacy Code"), the Deontological Code 
regarding data processing for statistical-scientific purposes, and the "Guidelines for the processing of 
personal data within the scope of clinical trials of medicinal products" published in the Official Gazette 
no. 190 of August 14, 2008, and EU Regulation 2016/679. The Investigator and the personnel involved 
in the study must keep all received information (including the protocol), data obtained, and 
documentation generated during the study confidential and will not use the information, data, and 
reports for purposes other than the protocol. These restrictions do not apply to: 1) information that 
becomes publicly available but not due to negligence of the Investigator or their staff; 2) information 
that must be disclosed confidentially to the Ethics Committee or the Institution's Review Board for the 
sole purpose of allowing the evaluation of the study; 3) information that must be disclosed to obtain 
appropriate medical care for a subject in the study. 
 
 
 
 

A.S.L. NO 
Azienda Sanitaria Locale 
di Novara 
P.IVA 01522670031 
Sede Legale: viale Roma, 7 – 28100 Novara 
Tel. 0321 374111 – fax 0321 374519 
www.asl.novara.it 
Azienda Sanitaria Locale ASL NO S. C.Anestesia e Rianimazione 
Direttore Dr. Davide Colombo 
Viale Zoppis, 10 – 28021 Borgomanero (NO) 
www.regione.piemonte.it 
 
 
Bibliography and sitography 
(2019,  
October 
23). 
(American 
Society 
of 
Anesthesiologists) 
from 
https://www.asahq.org/standards-and-practice-parameters/statement-on-continuum-of- 
depth-of-sedation-definition-of-general-anesthesia-and-levels-of-sedation-analgesia 
(2022, Gennaio 04). Tratto da ISSalute: https://www.issalute.it/index.php/la-salute-dalla-a-alla-z- 
menu/a/anestesia-generale 
Coluzzi, F. (2019). Intraoperative nociception : “if you can’t measure it, you can’t manage it”. Minerva 
Anestesiol, 85, 462–464. 
Ghanty, I. &. (2019). The quantification and monitoring of intraoperative nociception levels in thoracic 
surgery : a review. J. Thorac. Dis., 11, 4059–4071. 
Institute of Medicine. (1987). Pain and Disability: Clinical, Behavioral, and Public Policy Perspectives. 
Washington: Marian Osterweis, Arthur Kleinman, and David Mechanic. 
Kang, H. (2015). Intraoperative nociception monitoring. Anesth Pain Med, 10, 227–234. 
Klein AA, e. a. (2021). Recommendations for standards of monitoring during anaesthesia and 
recovery 2021: Guideline from the Association of Anaesthetists. Anaesthesia, 76(9):1212- 
1223. 
Loeser, J. D. (2008). The Kyoto protocol of IASP Basic Pain Terminology. 
Meijer, F. e. (2019). Nociception-guided versus Standard Care during Remifentanil–Propofol 
Anesthesia: A Randomized Controlled Trial. Anesthesiology, 130(5), 745-755. 
Meijer, F. e. (2020). Reduced postoperative pain using Nociception Level-guided fentanyl dosing 
during sevoflurane anaesthesia : a randomised controlled trial. Br. J. Anaesth., 1–9. 
SIAARTI-SIED. (2022). Analgo-sedazione in endoscopia digestiva:. 
Won, Y. J. (2016). Comparison of relative oxycodone consumption in surgical pleth index-guided 
analgesia versus conventional analgesia during sevoflurane anesthesia. Medicine 
(Baltimore), 95, 1–6.