Measurements of pupillary unrest using infrared pupillometry fail to detect changes in pain intensity in patients after surgery: a prospective observational study.

PURPOSE: The pupil displays chaotic oscillations, also referred to as pupillary unrest in ambient light (PUAL). As pain has previously been shown to increase pupillary unrest, the quantitative assessment of PUAL has been considered a possible tool to identify and quantify pain. Nevertheless, PUAL is affected by various states, such as vigilance, cognitive load, or emotional arousal, independent of pain. Furthermore, systematically applied opioids are known to reduce PUAL, thus potentially limiting its usefulness to detect pain or changes in pain intensity. To test the hypothesis that PUAL can reliably identify changes in pain intensity in a clinical setting, we measured PUAL in patients experiencing substantial pain relief when regional anesthesia interventions were applied after surgery. METHODS: We conducted an observational study at an academic surgery centre following institutional review board approval. Eighteen patients with unsatisfactory pain control following surgery underwent regional anesthesia procedures to improve pain control. We used infrared pupillometry to assess pupillary unrest before and after the regional block. We then compared the changes in pupillary unrest with the changes in pain scores (numeric rating scale [NRS], range 0-10). RESULTS: Eighteen patients received epidural anesthesia (n = 14) or peripheral nerve blocks (n = 4), resulting in improvement of mean (standard deviation [SD]) NRS pain scores from 7.2 (1.7) to 1.9 (1.8) (difference in means, -2.2; 95% confidence interval [CI], -6.3 to -4.1; P < 0.001). Nevertheless, pupillary unrest did not change as pain decreased; the mean (SD) PUAL was 0.113 (0.062) before analgesia and 0.112 (0.068) after analgesia (difference in means, -0.001; 95% CI, -0.018 to 0.015; P = 0.88). CONCLUSION: In this prospective observational study, pupillometric measurements of pupillary unrest did not identify changes in pain intensity in a postoperative, predominantly opioid-exposed patient population. While the sample size was small, the use of measurements of pupillary unrest to detect and quantify pain has to be questioned.

RéSUMé: OBJECTIF: La pupille affiche des oscillations chaotiques, également appelées fluctuations du diamètre pupillaire (FDP). Comme il a déjà été démontré que la douleur augmente les troubles pupillaires, l'évaluation quantitative des FDP a été envisagée comme outil potentiel pour identifier et quantifier la douleur. Néanmoins, les FDP sont affectées par divers états, tels que la vigilance, la charge cognitive ou l'excitation émotionnelle, indépendamment de la douleur. De plus, nous savons que l'application systématique d'opioïdes réduit les FDP, ce qui limite potentiellement leur utilité pour détecter la douleur ou les changements d'intensité de la douleur. Pour tester l'hypothèse selon laquelle les FDP permettent d'identifier de manière fiable les changements dans l'intensité de la douleur dans un cadre clinique, nous avons mesuré les FDP chez les patient·es manifestant un soulagement substantiel de la douleur lorsque des interventions d'anesthésie régionale ont été appliquées après la chirurgie. MéTHODE: Nous avons mené une étude observationnelle dans un centre de chirurgie universitaire après avoir obtenu l'approbation du comité d'éthique indépendant. Dix-huit patient·es dont le contrôle de la douleur n'était pas satisfaisant à la suite d'une intervention chirurgicale ont bénéficié d'interventions d'anesthésie régionale pour améliorer le contrôle de la douleur. Nous avons utilisé la pupillométrie infrarouge pour évaluer les fluctuations du diamètre pupillaire avant et après le bloc régional. Nous avons ensuite comparé les changements dans les fluctuations pupillaires avec les changements dans les scores de douleur (échelle d'évaluation numérique [EVA], plage de 0 à 10). RéSULTATS: Dix-huit patient·es ont reçu une anesthésie péridurale (n = 14) ou des blocs nerveux périphériques (n = 4), ce qui a entraîné une amélioration des scores de douleur moyens (écart type [ET]) sur l'EVA de 7,2 (1,7) à 1,9 (1,8) (différence de moyennes, −2,2 ; intervalle de confiance [IC] à 95 %, −6,3 à −4,1; P < 0,001). Néanmoins, les fluctuations du diamètre pupillaire n'ont pas changé à mesure que la douleur diminuait; la moyenne (ET) des FDP était de 0,113 (0,062) avant l'analgésie et de 0,112 (0,068) après l'analgésie (différence de moyennes, −0,001; IC 95 %, −0,018 à 0,015; P = 0,88). CONCLUSION: Dans cette étude observationnelle prospective, les mesures pupillométriques des fluctuations du diamètre pupillaire n'ont pas permis d'identifier de changements dans l'intensité de la douleur dans une population de patient·es postopératoires, principalement exposé·es aux opioïdes. Bien que la taille de l'échantillon soit petite, l'utilisation de mesures des fluctuations du diamètre pupillaire pour détecter et quantifier la douleur doit être remise en question.

Semimechanistic models to relate noxious stimulation, movement, and pupillary dilation responses in the presence of opioids.

Intraoperative targeting of the analgesic effect still lacks an optimal solution. Opioids are currently the main drug used to achieve antinociception, and although underdosing can lead to an increased stress response, overdose can also lead to undesirable adverse effects. To better understand how to achieve the optimal analgesic effect of opioids, we studied the influence of remifentanil on the pupillary reflex dilation (PRD) and its relationship with the reflex movement response to a standardized noxious stimulus. The main objective was to generate population pharmacodynamic models relating remifentanil predicted concentrations to movement and to pupillary dilation during general anesthesia. A total of 78 patients undergoing gynecological surgery under general anesthesia were recruited for the study. PRD and movement response to a tetanic stimulus were measured multiple times before and after surgery. We used nonlinear mixed effects modeling to generate a population pharmacodynamic model to describe both the time profiles of PRD and movement responses to noxious stimulation. Our model demonstrated that movement and PRD are equally depressed by remifentanil. Using the developed model, we changed the intensity of stimulation and simulated remifentanil predicted concentrations maximizing the probability of absence of movement response. An estimated effect site concentration of 2 ng/ml of remifentanil was found to inhibit movement to a tetanic stimulation with a probability of 81%.

Suppression of pupillary unrest by general anesthesia and propofol sedation.

The pupil undergoes irregular oscillations when exposed to light. These oscillations, known as pupillary unrest in ambient light, originate from oscillatory activity within the Edinger-Westphal nucleus in the midbrain. The midbrain and upper pons also contain nuclei known to be very sensitive to the effects of anesthetics that play a central role in maintaining wakefulness. We hypothesized that anesthetics may display similar effects on wakefulness and pupillary unrest. Repeat measurements of pupillary unrest using infrared pupillometry were performed in 16 patients undergoing general anesthesia and 8 patients undergoing propofol sedation. Pupil scans were analyzed using fast Fourier transformation to quantify the effects of the anesthetics on pupillary unrest. During general anesthesia and deep sedation, observed pupillary unrest values below 0.1 (AU) indicate complete suppression of pupillary oscillations. Pupillary unrest decreased more during general anesthesia [to 24% of baseline (95% CI 17-30%)] than pupil size [51% of baseline (95% CI 45-57%)]. Sedation with propofol was associated with a reduction in pupillary unrest that was correlated to the depth of sedation as assessed by the Richmond Agitation-Sedation Scale and the processed electroencephalogram. Pupillary unrest is caused by oscillatory activity within the midbrain that is affected by the state of wakefulness or by hypnotics directly. Increased sedation and general anesthesia reduce and then abolish pupillary unrest as wakefulness decreases. We speculate that midbrain nuclei responsible for wakefulness and pupillary unrest are either communicating or share a similar sensitivity to the effects of commonly used anesthetics.

Prediction of Opioid Analgesic Efficacy by Measurement of Pupillary Unrest.

BACKGROUND: Pupillary unrest under ambient light (PUAL) is the fluctuation in pupil diameter in time around a mean value. PUAL is augmented by light and diminished by administration of opioids. We hypothesized that, because pupillary unrest is a marker of opioid effect, low levels of PUAL may be associated with reduced opioid efficacy, as measured by changes in the numerical rating scale (NRS) pain scores of patients in the postanesthesia care unit (PACU). METHODS: We used an infrared pupillometer to measure PUAL in patients recovering from ambulatory surgery at 2 different institutions. At both sites, PUAL was quantified using spectral analysis of the Fourier transform of pupil diameter versus time. We measured PUAL and pain scores before and after opioid administration. Protocols for total capture time and lighting conditions varied between the 2 sites. Correlations between PUAL and change in NRS scores were examined using significance testing of Pearson correlation coefficients. Correlations between change in PUAL and change in NRS scores were also examined. Patients were divided into high and low PUAL groups, and high and low response to opioid. A Fisher exact test was used to determine whether there was a significant association between PUAL and opioid response. RESULTS: For patients with pain in the PACU, low levels of pupillary unrest before opioid therapy were associated with minimal or no reduction in pain scores after opioid administration. We noted a significant correlation at both sites between PUAL and pain score reduction with opioids (r = 0.59, P = .0053, and r = 0.57, P = .022.) The Fisher exact test confirmed that patients with PUAL levels above the mean had a more beneficial analgesic effect from opioids than those with low PUAL levels (P = .018). We also noted that change in PUAL was significantly correlated with change in pain score at both sites (r = 0.56, P = .03 and r = 0.55, P = .01). CONCLUSIONS: We observe that the pretreatment magnitude of PUAL is correlated with the analgesic response to opioid therapy, and that patients who exhibit higher levels of PUAL change after opioid administration have a more beneficial analgesic effect from opioids. Larger studies with uniform measurement protocols are required to confirm these preliminary results.

Fentanyl, an agonist at the mu opioid receptor, depresses pupillary unrest.

Pupillary unrest is a chaotic fluctuation in pupil size that is observed in darkness with the onset of drowsiness, and in ambient light. The mechanism of pupillary unrest in darkness as well as in ambient light is unknown but studies suggest that it is caused by fluctuating activity in the Edinger-Westphal (E.W.) nucleus. Neurons in the periaqueductal gray with oscillating firing patterns that are inhibitory to the E.W. nucleus have been described in the cat. We theorized that such oscillating neurons produce pupillary unrest in light and would be depressed by agents, such as opioids, known to depress inhibitory pathways in the midbrain. An infrared pupillometer was used to measure the effect of light on pupillary unrest in eight volunteer subjects, and on 20 patients scheduled for knee arthroscopy who received fentanyl as premedication. Pupillary unrest was quantified through spectral analysis of fast Fourier transforms. Sixteen-second measurements of pupil size at 33 Hz were filtered to eliminate blink artifacts and baseline drift. Pupillary unrest was augmented by excitation of the E.W. nucleus by light and was depressed by 40 ± 20% after the administration of the moderate dose of 1 mcg/kg of fentanyl. Recovery from the drug effect was observed. Based upon the data from this study we propose that pupillary unrest in light originates within oscillating inhibitory neurons that intermittently depress the E. W. nucleus.

The effect of antiemetics on pupillary reflex dilation during epidural/general anesthesia.

UNLABELLED: The effect of dopamine D2 receptor antagonists, such as chlorpromazine and haloperidol, on pupil size in awake subjects suggests that these drugs might also alter pupillary reflex dilation and pupil size during general anesthesia. Forty-seven patients undergoing lower abdominal surgery under combined epidural/general anesthesia were randomized to receive one of the 5 following open labeled drugs: 10 mL saline, 0.13 mg/kg ondansetron, 0.25 mg/kg metoclopramide, 0.5 mg/kg metoclopramide, or 0.02 mg/kg droperidol. Three measurements of reflex dilation were taken at 5-min intervals and after the last measurement (time 0) the drug was administered. Measurements were then taken 5, 10, 20, and 40 min after I.V. drug administration. Reflex dilation was induced by intermittent noxious stimulation of the C5 dermatome with a tetanic electric current (60-70 mamp, 100 Hz, 3-s duration) after a stable level of epidural analgesia had been established with 3/8% bupivacaine and maintained with a continuous infusion. Metoclopramide produced a small decrease in pupil diameter and transiently depressed reflex dilation, whereas droperidol decreased pupil size at 10 min and depressed reflex dilation throughout the 40-min study period. Maximal change in reflex dilation was -6.6 +/- 3.3 mm-sec after droperidol. Ondansetron had no effect on pupil diameter or reflex dilation. When pupillary diameter measurements are used to gauge opioid levels during experimental conditions or during surgical anesthesia, antiemetic medication acting on the dopamine D2 receptor should be avoided. IMPLICATIONS: Miosis is often considered an effect of opioid administration during general anesthesia, but other drugs, such as antiemetics, might produce a similar effect on the pupil. This study demonstrates that 2 antiemetics, droperidol and metoclopramide, constrict the pupil and block the pupillary dilation brought about by nociceptive stimuli.

Infrared pupillometry during uncal herniation.

Infrared pupillary scans have been used extensively as an objective measure of pupillary reflexes during pharmacological studies of human subjects, but no previous scans have documented the pupillary changes during transtentorial uncal herniation. We present infrared pupillary scans from three patients with brain stem compression secondary to expanding intracranial mass lesions. The scans were made with a portable device permitting infrared pupillometry at the patient's bedside. Portable infrared pupillometry records objective measurements of pupillary light reflexes, which provides information useful for diagnosing transtentorial herniation and affords objective measurements of an important endpoint in the management of patients with head trauma or supratentorial mass lesions.