Objective Nociceptive Assessment in Ventilated ICU Patients: A Feasibility Study Using Pupillometry and the Nociceptive Flexion Reflex

Summary

Pain assessment in anesthetized patients who cannot communicate with the outside world in any way remains challenging despite the development of innovative objective pain evaluation tools. In this project, the pupillary dilation reflex and the nociception flexion reflex are assessed in critically ill, mechanically ventilated adult patients.

Abstract

The concept of objective nociceptive assessment and optimal pain management have gained increasing attention. Despite the known negative short- and long-term consequences of unresolved pain or excessive analgosedation, adequate nociceptive monitoring remains challenging in non-communicative, critically ill adults. In the intensive care unit (ICU), routine nociceptive evaluation is carried out by the attending nurse using the Behavior Pain Scale (BPS) in mechanically ventilated patients. This assessment is limited by medication use (e.g., neuromuscular blocking agents) and the inherent subjective character of nociceptive evaluation by third parties.

Here, we describe the use of two nociceptive reflex testing devices as tools for objective pain evaluation: the pupillary dilation reflex (PDR) and nociception flexion reflex (NFR). These measurement tools are non-invasive and well tolerated, providing clinicians and researchers with objective information regarding two different nociceptive processing pathways: (1) the pain-related autonomic reactivity and (2) the ascending component of the somatosensory system. The use of PDR and NFR measurements are currently limited to specialized pain clinics and research institutions because of impressions that these are technically demanding or time-consuming procedures, or even because of a lack of knowledge regarding their existence.

By focusing on the two abovementioned nociceptive reflex assessments, this study evaluated their feasibility as a physiological pain measurement method in daily practice. Pursuing novel technologies for evaluating the analgesia level in unconscious patients may further improve individual pharmacological treatment and patient related outcome measures. Therefore, future research must include large well-designed clinical trials in a real-life environment.

Introduction

Many critically ill patients in the Intensive Care Unit (ICU) are prone to experience pain during daily care or during diagnostic or therapeutic procedures. Substandard nociceptive evaluation and consequent suboptimal pain management may increase stress and anxiety¹. Persistent pain not only increases circulating catecholamines, compromises tissue perfusion and reduces oxygen delivery² but also activates catabolic hypermetabolism, thus contributing to hyperglycemia, lipolysis and muscle loss. All of these elements impair the healing process and increase the risk of infections^3,4,5,6.

As stated by the International Association for the Study of Pain (IASP), clinicians must use pain assessment tools that are valid for all patients, and self-reports remain the golden standard for pain evaluation. However, there are many situations in which patients are unable to communicate, especially because of critical illness or when they are mechanically ventilated (MV). The increased interest in ICU patient-related outcome measures has amplified the need for structured and reliable techniques for nociceptive assessment when a patient is unable to report pain and discomfort. Attempts to address this need have been hampered by the lack of specific, reproducible and feasible monitoring tools. In recent years, considerable effort has been directed toward providing physicians with more objective nociceptive parameters. However, many studies executed in the ICU have focused on the use of vital signs as possible surrogates for pain assessment and underlie not to use blood pressure or heart rate as a specific parameter for pain^7,8.

As reported in previous research, untreated pain significantly compromises patient outcomes and should therefore always be assessed independently of vital signs, and assessments should not be influenced by a patient's inability to communicate^{7,8,9,10,11,12}. This approach of objective nociceptive assessment has gained considerable support due to the known negative consequences of pain. Especially in ICU patients, physiological and psychological effects can be substantial and long-lasting and may significantly decrease health-related quality of life^13,14.

Currently, no objective pain monitoring protocol exists that can readily be applied to a large group of critically ill patients. The implementation of objective assessment tools in ICU patients could optimize pain management and thus prevent the development of central sensitization syndromes. Moreover, opioid-induced hyperalgesia (OIH), chronification of pain, and long-lasting pain-related morbidity may decrease. Finally, the application of nociceptive reflex evaluation tools may provide a unique translational platform on which new pharmacological analgesic compounds can be tested.

The aim of the proposed methodology is to provide an overview of the technical requirements and provide a precise description of the protocols used to assess nociceptive reflexes in non-communicative ICU patients. Overall, we aim to provide a comprehensive guide for the use of objective pain measurement tools in the ICU and in other circumstances in which sedated or unconscious patients need to be assessed.

Critically ill unconscious adults admitted to the ICU were screened for study inclusion from October 2016 until December 2017. All were mechanically ventilated and received a strict analgosedation protocol containing propofol/remifentanil or propofol/sufentanil, which are the two most commonly used schemes in our hospital. A history of ophthalmologic surgery, known pupil reflex disorders, Horner or Adie's syndrome, previous eye trauma, cranial nerve lesions or acute intracranial hypertension caused by traumatic brain injury, tumor compression or bleeding, fulminant stroke, known (poly)neuropathy related to diabetes or other neurological conditions known to influence reflex activity, intra- or extracorporeal treatment (pacemaker, intra-aortic balloon pump, extracorporeal life support), chronic opioid use (>3 months), age <18 years, and the use of topical interfering eye drops (atropine, phenylephrine), α2 adrenergic agonists¹⁵, the use of other analgosedation protocols than described by the inclusion criteria or neuromuscular blocking agents were defined as exclusion criteria.

The demographic variables and medical data of the enrolled subjects, including the Simplified Acute Physiology Score II (SAPS II),¹⁶ were extracted from the digital patient data management system (e.g., Metavision).

Pain Assessment

ICU patients were screened for study inclusion, which required a medical history and admission diagnosis to assess the inclusion and exclusion criteria mentioned above. Physiological reflexes were assessed in the ICU environment under real-life conditions: no specific modifications were made regarding temperature or noise control. Reflex assessment was executed during daytime working hours at the individual patient room of approximately 20 °C. All generated data (reflex characteristics) can be stored by each of the two devices when this function is enabled on the touch screen display.

Measurement of the Pupil Dilation Reflex

A pupillometry device was used for pupil dilation reflex (PDR) assessment using infrared video recording for quantitative pupil size evaluation. For the application of standardized nociceptive stimulation, two low-impedance Ag-AgCl electrodes were placed on the skin area innervated by the median nerve on the left arm after skin preparation (Figure 1). The current was fixed at 60 milliampères (mA) with a maximum acceptable resistance of 5 kOhms, defining a voltage limitation of 300 volts (V).

PDR assessment was performed using an inbuilt pupillary pain index (PPI) measurement protocol that generates an automatic electric stimulation pattern for dynamic pupil reflex evaluation. Standardized noxious stimulation was applied with increasing intensity (from 10 mA to 60 mA with incremental steps of 10 mA, a duration of 1 s, and a pulse width of 200 µs) until pupillary dilation greater than 13% ([maximal diameter – minimal diameter]/maximal diameter * 100) or maximal stimulation at 60 mA was achieved. When the defined criteria were reached, stimulation was automatically interrupted, and a PPI score was displayed (Table 1). Baseline pupil size (before standardized noxious stimulation), pupil reflex amplitude (PRA), stimulation intensity and the PPI score were recorded. The duration of PDR measurement was between 2 and 16 seconds depending on the number of required stimulations.

Several studies have suggested the use of pupillometry in non-communicative ICU adults. Paulus et al. demonstrated that PDR evaluation may predict analgesia requirements during endotracheal aspiration¹⁷. Moreover, this method may be able to reveal different levels of analgesia and could have discriminatory properties regarding different types of noxious procedures^18,19. Recently, scientific interest has been directed toward the use of specific protocols for PDR assessment because of their low stimulation currents. The PPI protocol suggested in our approach has been previously investigated in anesthetized adults, revealing a significant correlation between PDR and opioid administration²⁰. Furthermore, Sabourdin et al.²¹ demonstrated that PDR can be used to guide individual intraoperative remifentanil administration and therefore reduce intraoperative opioid consumption and postoperative rescue analgesia requirements.

Measurement of the Nociceptive Flexion Reflex

To assess the role of primary afferent fibers in the transmission of nociceptive signals from peripheral nociceptors to the sympathetic chain, the nociceptive flexion reflex (NFR) was evaluated. Reflex elicitation is mediated after A-delta fibers are activated by a complex interaction between neurons located in the dorsal horn of the spinal cord²². Rhudy and colleagues described the RIII reflex, a late response of the NFR with high-threshold nociceptive characteristics measured electromyographically (EMG) over the biceps femoris muscle after nociceptor activation.²³

Increasing electrical stimulations are performed via cutaneous Ag-AgCl electrodes at the lateral malleolus, triggering the solely sensory sural nerve. The reflex response is evaluated in time and amplitude through EMG recording (Figure 2; Reprinted with permission of PH Dr med. Jan Baars, Managing Director, Dolosys GmbH.).

Following Willer et al., using the described reflex registration setup, the required stimulation intensity to elicit the NFR (threshold tracking) can be used as an objective nociceptive assessment correlating with subjective pain scores^{24,25,26,27,28}. Subsequently, numerous studies have been conducted to identify reflex characteristics (mainly reflex threshold and amplitude) and their correlation with pain intensity sensation in conscious adults. These studies revealed that the reflex threshold and response amplitude is closely related to pain intensity^27,29,30.Furthermore, standardized NFR scoring criteria, such as the reflex peak and the mean reflex EMG activity, can be used as reliable criteria for defining this NFR^23,31,32. According to recent research, the defined reflex characteristics contributing to the NFR, despite their empirically derived origin, showed good test-retest reliabilities^33,34. The duration of NFR recording, taking into account the (variable) step size range (0.5 mA – 2 mA), interstimulus interval of 8 seconds with an interval randomization of 20% to avoid possible habituation and reflex range between 90 – 180 ms after stimulation³⁵, was between 5 and 15 minutes depending on the necessary stimulation intensity to elicit the NFR and therefore the number of required stimulations (maximum of 100 mA).

Protocol

This single-center cohort study was performed in accordance with the ethical standards of ICH-GCP and the Declaration of Helsinki after it was approved by the institutional review board and ethics committee of the Antwerp University Hospital, Belgium (study identifier: 16/33/334). The study was registered at Clinicaltrials.gov (NCT02916004) before its initiation. All included patients were sedated in accordance with the standard hospital sedation protocol before study enrollment. The patients …

Representative Results

We used both reflex assessments in a total of 40 critically ill ventilated subjects (38% females) at the ICU department using the previously described protocol. Patients with various indications for analgo-sedation were included: 58% for primary respiratory insufficiency, 23% due to multiple organ failure, 10% of the patients had a septic shock, and 9% were defined as being sedated for other reasons (e.g., cardiogenic reasons). All measurements were performed by the same investig…

Discussion

This paper describes the application of two nociceptive reflex devices for objective (patient-independent) pain assessment in adult ICU patients. Moreover, the evaluation of the PDR and the NFR characteristics are described.

Pain and delirium are common in hospitalized patients, often in combination, and may adversely affect outcome parameters. In the ICU, opioids are frequently administered, sometimes in combination with other sedative agents, to protect patients against stressful stimuli suc…

Materials

Neurolight Algiscan	ID Med, Marseille, France	Pupillometre 13235	Infra red camera for pupil dilation reflex measurement
Paintracker	Dolosys GmbH, Belin, Germany	Paintracker V1 2497	Nociception flexion reflex assessment tool
Red DotTrace Prep	3M, Ontario, Canada	CV-0001-7353-0	Skin surface preparation tape
Electrodes – BlueSensor N	Ambu, Ballerup, Denmark	BlueSensor N N-00-S/25	Low-impedance Ag-AgCl skin electrodes