1 To the Editor

The recent SARS-CoV2 pandemic has led to a very significant increase in the number of patients hospitalized in intensive care for COVID-19-related acute respiratory failure (C-ARF) resembling adult respiratory distress syndrome (ARDS). Deep sedation combining one or more hypnotics, an opiate and a neuromuscular blocking agent (NMBA) is necessary to facilitate care and mechanical ventilation [1]. The assessment of adequate sedation or nociceptive events in ICU patients may be performed using clinical scales such as the Richmond Agitation Sedation Scale (RASS) and the Behavior Pain Scale (BPS); however, these scales cannot be used in curarized patients [2].

In our unit, for ARDS patients reveiving NMBAs, we generally monitor the levels of sedation using the bispectral index (BIS) and of curarization using a curameter measuring the train-of-four (TOF) count [3, 4].

During the COVID-19 pandemic, because the device was available in the Anesthesiology Department, we also used the CONOX® monitor (Fresenius Kabi, Brézins, France) for sedation monitoring [5]. This monitor developed for anesthesia uses electroencephalographic data to extract two indices ranging from 0 to 100: the qCON, reflecting the level of narcosis (with good agreement with the BIS) and the qNOX, reflecting level to nociceptive stimulation [6, 7]. There is however a non-resolved discussion as to what the qNOX index reflects. Apparently, qNOX includes electroencephalogram (EEG) frequency bands and predictive data on the probability of movement to the painful stimulus but is not clear how. The qNOX is an empirical index, not developed based on the specific activity of certain brain centers and developed by classifying the EEG into responders/non-responders to painful stimuli with data of theoretical models of drug effects [6, 7].

However, there are currently no data concerning the use of CONOX® in curarized intensive care patients. We retrospectively studied the variations of qCON and qNOX during closed tracheal suction in the supine position in intubated, sedated and curarized intensive care patients for severe SARS-CoV2 pneumonia, to determine if qNOX variations could be observed during a noxious stimulus such as tracheal suction.

This was a non-interventional retrospective study carried out during the COVID-19 pandemic from January to May 2021 after a favorable opinion from the Ethics Committee (Comité d’Éthique de la Recherche en Anesthésie-Réanimation, CERAR). The necessity for written informed consent was waived because to the retrospective nature from this study. During this period, 15 intensive care patients with C-ARF requiring curarization were monitored by CONOX®. The choice of sedation agents was made by the attending physician. The doses of hypnotic agents were adjusted to maintain the qCON between 40 and 60 and NMBA levels were adjusted to maintain a TOF count of 0 during the time of deep sedation. The doses of opioids were adapted according to usual clinical practice at the discretion of the attending physician [2]. The suction technique was performed using closed tracheal suctioning systems by the attending nurse according to usual clinical practice.

All data were retrieved from the patient’s electronic file (demographic data, ventilatory parameters, etc.) and from the CONOX® monitor. For each patient, the qCON and qNOX were collected every 15 s from 1 min before tracheal suction until 5 min after. The variations of these indices were analyzed by Friedman’s test with p < 0.05 considered to be statistically significant (MedCalc® 18.2.1, MedCalc Software bvba, Ostend, Belgium).

Patient characteristics are described in the Table 1. In total, 12 men and 3 women were analyzed. All patients had C-ARF with documented SARS CoV2 infection using polymerase-chain reaction (PCR) testing. All patients were on general anesthesia combining hypnotic agents (midazolam or a combination of propofol and ketamine), opioids (sufentanil or remifentanil) and NMBA (cisatracurium) with TOF count equals to 0 at the time of tracheal suction [8].

Table 1 Patient characteristics (n = 15). Results expressed as median [Q1-Q3] or n (%)
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We observed a statistically significant increase in the median qNOX values within the first minute following tracheal suction, which was not observed for qCON (Fig. 1). However, a wide range of individual values were observed for both indexes, providing wide interquartile ranges and greater dispersion of variability after the first second post-stimulus. Moreover, there is no clear explanation on the signal of change that generates qNOX variations which may correspond to partial activation of the frontal EEG or of the relationship between different frequency bands, or may also be an example of an electromyogram-reflected response. It is also difficult to define the phenomenon as a painful nociceptive or irritative reflex response to tracheal stimulation and therefore not possible in this case to differentiate which type of phenomenon is triggering qNOX and then how best to prevent it. Although non-significant for qCON, the increase in both indexes following tracheal suction is consistent with a perturbance of the EEG, which raises the question of what is detected: lack of hypnosis, analgesia, or both of them?

Fig. 1
figure 1

Variations of qCON and qNOX following tracheal suction (n = 15). Values are presented as median (circles) and Q1-Q3 (error bars)

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Furthermore, because of the retrospective nature of this study, the sedation protocol and the suction technique were not standardized which may have provided bias in our results. Besides, remifentanil was administered at a fixed rate not based on weight or any other covariate which may have led to different concentrations and different effects in each patient.

In summary, we tried to measure a nociceptive response using CONOX® after tracheal suction in mechanically ventilated patients but it is difficult to conclude that the same source of information, which is the raw EEG, in patients sedated with different combinations of drugs that have different mechanisms of action is a reliable way to distinguish between the level of hypnosis and nociception.

Nevertheless, the results from this small retrospective study suggest that an increase in qNOX values in curarized patients with C-ARF on deep sedation may be helpful to detect painful events such as tracheal suction while qCON values may to assess the level of hypnosis. This may be of interest since behavior scales such as the Richmond Agitation Scale Sedation Scale (RASS) or BPS cannot be used in this type of patients. However, further well-designed prospective studies are required to determine the interest of qCON and qNOX monitoring in ICU patients on deep sedation, in particular when NMBAs are used.