Confirmatory Study of HFVI Guided Analgesic Administration in Surgical Subjects

A Prospective, Randomized, PACU Blinded, Clinical Utility Study to Confirm the Safety and Efficacy of HFVI-Guided Analgesic Administration in Surgical Subjects Receiving Balanced Sevoflurane-Fentanyl Anesthesia

The current study is intended to be a prospective clinical performance validation study designed to confirm the clinical utility of HFVI-guided fentanyl administration during sevoflurane anesthesia.

The overall objective of this study is to confirm the safety and efficacy of HFVI-guided analgesic administration in comparison to standard clinical practice. The primary efficacy endpoint will be the amount of postoperative pain reported in the PACU, as measured using a nurse administered Numerical Rating Scale (NRS) pain score.

HFVi was designed to provide a standardized measure of the parasympathetic component (p∑) of the Autonomous Nervous System (ANS). It tracts changes of the p∑ tonus induced by each respiratory cycle (spontaneous or artificial) to measure the relative balance of parasympathetic and sympathetic tone as reflected in the EKG signal.

These rapid changes of the p∑ tonus express themselves at the sinus node level by changes of the time interval separating two R waves of the electrocardiogram. The following normal RR intervals constitute the tachogram (displayed as respiratory pattern on the monitor). The p ∑ component is evaluated after filtering, standardization and re-sampling of the R-R series, by measuring the surface generated by respiratory cycles on the tachogram. Higher p∑ tonus is reflected as a larger measured surface area. In contrast, the measured surface decreases when the p∑ decreases.

HFVi, a measure of the surface area, is expressed in the form of a dimensionless index ranging from 0 to 100. This index reflects the relative activity of the parasympathetic nervous system. It expresses the relative quantity of the present p∑ tonus compared to the Para and sympathetic tonus. The measure of HFVi displayed represents the average of a sequence of measurements: each elementary measure is realized on 64 seconds of data, updated each second using a sliding window.

During development, a probabilistic interpretation of the HFVi was used to relate index values to a clinical state in an anesthetized subject. A significant hemodynamic response (increase of the heart rare or blood pressure of 20% compared to the baseline) within 10 minutes was used as an indicator of nociception/inadequate analgesia.

As a measure of parasympathetic tone, HFVi may be influenced by many factors and thus be difficult to interpret in many of the following situations:

• arrhythmia
• no breathing (ex : apnea due to intubation)
• Respiratory rate lower than 9 cycles/min
• Tidal volume variable on the measuring time, thus 64 seconds
• Irregular breathing (when the patient speaks, laugh or cough)
• pace maker (some types)
• heart transplantation
• Drug use having a significant effect on the sinus cardiac activity

Inclusion Criteria:

• Able to provide informed consent
• American Society of Anesthesiologist Physical Status 1 or 2
• Body Mass Index range of 19-35 kg.m-2.
• Planned spinal or open abdominal surgery expected to last 1-3 hours utilizing a balanced sevoflurane-fentanyl general anesthetic

Exclusion Criteria:

• Subjects are unable or unwilling to give informed consent.
• Emergency surgery
• Women who are currently pregnant or not using a medically acceptable means of birth control
• Cardiac morbidity, including non-regular sinus cardiac rhythm or implanted cardiac pacemaker
• Concurrent medications with a major effect upon the sinus node including prescribed antimuscarinic agents, α2-adrenergic agonists, β1-adrenergic antagonists, and antiarrhythmic agents
• Expected duration of surgery less than 1 hour (60 minutes) or greater than 3 hours (180 minutes)
• Pre-operative chronic opioid use or chronic pain, equivalent to requiring oxycodone 20mg per oral, per day for more than 6 weeks
• Allergy or intolerance to any of the anticipated study medications, such as history of malignant hyperthermia during anesthesia
• Planned use of neuraxial anesthesia
• Clinically significant abnormality or clinically significant unstable medical condition, as indicated by medical history, physical examination, ECG results, or clinical laboratory testing, that in the Investigator's judgment might pose a potential safety risk to the subject or limit interpretation of the trial results, e.g., any uncontrolled thyroid disorders, hepatic, cardiac, pulmonary and renal malfunctioning.