Objective: To test the hypothesis that systemically administered neuromuscular blocking drugs acutely alter resting pupil size or the direct reflex response to light in anesthetized humans. Design: Patients were randomized to receive an intravenous injection of saline (0.15 mL/kg), pancuronium bromide (0.1 mg/kg), or vecuroniumbromide (0.15 mg/kg) after induction of general anesthesia and tracheal intubation. Setting: The University of California, San Francisco, Moffitt-Long Hospitals. Patients: Healthy adults (American Society of Anesthesiologists physical status I or II) of either sex scheduled for elective surgery requiring general anesthesia, tracheal intubation, and muscle relaxation of an anticipated duration of 2 or more hours. Main Outcome Measures: Measurements of resting pupil size, direct reflex response to light, and constriction velocity were obtained in double-blinded fashion using infrared pupillometry. Results: Pupillary size, reflex amplitude, and constriction velocity were not altered by the presence of either vecuronium or pancuronium. Tetanic stimuli and concomitant isoflurane administration respectively increased and decreased pupillary light reflex amplitude, indicating that pupillary responses were not fixed. Conclusion: We conclude that systemically administered neuromuscular blocking drugs (vecuronium and pancuronium) do not acutely affect the pupillary light reflex in healthy, anesthetized patients.

Neuromuscular Blocking Drugs Do Not Alter the Pupillary Light Reflex of Anesthetized Humans

Pupil dilation is mediated by a sympathetic output acting in opposition to parasympathetically mediated pupil constriction. While light stimulates the parasympathetic output, giving rise to the light reflex, it can both inhibit and stimulate the sympathetic output. Light-inhibited sympathetic pathways originate in retina-receptive neurones of the pretectum and the suprachiasmatic nucleus (SCN): by attenuating sympathetic activity, they allow unimpeded operation of the light reflex. Light stimulates the noradrenergic and serotonergic pathways. The hub of the noradrenergic pathway is the locus coeruleus (LC) containing both excitatory sympathetic premotor neurones (SympPN) projecting to preganglionic neurones in the spinal cord, and inhibitory parasympathetic premotor neurones (ParaPN) projecting to preganglionic neurones in the Edinger-Westphal nucleus (EWN). SympPN receive inputs from the SCN via the dorsomedial hypothalamus, orexinergic neurones of the latero-posterior hypothalamus, wake- and sleep-promoting neurones of the hypothalamus and brain stem, nociceptive collaterals of the spinothalamic tract, whereas ParaPN receive inputs from the amygdala, sleep/arousal network, nociceptive spinothalamic collaterals. The activity of LC neurones is regulated by inhibitory α2-adrenoceptors. There is a species difference in the function of the preautonomic LC. In diurnal animals, the α2-adrenoceptor agonist clonidine stimulates mainly autoreceptors on SymPN, causing miosis, whereas in nocturnal animals it stimulates postsynaptic α2-arenoceptors in the EWN, causing mydriasis. Noxious stimulation activates SympPN in diurnal animals and ParaPN in nocturnal animals, leading to pupil dilation via sympathoexcitation and parasympathetic inhibition, respectively. These differences may be attributed to increased activity of excitatory LC neurones due to stimulation by light in diurnal animals. This may also underlie the wake-promoting effect of light in diurnal animals, in contrast to its sleep-promoting effect in nocturnal species. The hub of the serotonergic pathway is the dorsal raphe nucleus that is light-sensitive, both directly and indirectly (via an orexinergic input). The light-stimulated pathways mediate a latent mydriatic effect of light on the pupil that can be unmasked by drugs that either inhibit or stimulate SympPN in these pathways. The noradrenergic pathway has widespread connections to neural networks controlling a variety of functions, such as sleep/arousal, pain, and fear/anxiety. Many physiological and psychological variables modulate pupil function via this pathway.

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Functional Organization of the Sympathetic Pathways Controlling the Pupil: Light-Inhibited and Light-Stimulated Pathways.

The overall aim of the research described in this thesis was to investigate the basic mechanisms of the pupil of the eye in relation to human vision and brain function. It also evaluates the potential application of new research techniques to clinical studies that involve assessment of the visual function.

Pupil response components were investigated in normal subjects and in patients with damaged visual pathways. A series of experiments were carried out to investigate the pupil response to periodic modulation of several stimulation parameters such as: luminance contrast, stimulus size, spatial and temporal frequency content, and colour.

Much larger responses were found for square-wave as compared to sinusoidal luminance modulation. A model with two populations of neurones (sustained and transient) was developed to explain the non-linear combination of two response components in the light reflex. In contrast to these findings, responses to isoluminant coloured stimuli or sinusoidal gratings whose spatial average luminance is equal to that of the background do not depend of the temporal wave-form of the stimulation. Studies in patients with lesions to specific areas in the brain suggest that these responses are caused by a transient weakening of the steady central sympathetic inhibition to parasympathetic neurones innervating the sphincter muscle as a result of cortical processing of specific stimulus attributes such as colour and spatial structure.

Pupil measurements in patients suffering from demyelinating neurological disorders such as multiple sclerosis and optic neuritis also confirm the existence of distinct pupil response components and reveal selective loss to chromatic and luminance pathways. The results indicate a preferential damage to thinner axons which are thought to predominantly mediate the chromatic responses. These studies suggest that the use of modern pupillometric techniques in neuro-ophthalmology can yield useful information on the extent of the damage and the progression of disease in lesions of the optic nerve.

A study of pupil response components in human vision

The modifications of the sympathetic pupillodilator activity in the light reflex have been demonstrated by recording the electrical discharge of single preganglionic fibres in the cervical sympathetic nerve.

R. Perinetti Casoni

Papers

Sympathetic preganglionic pupillodilator fibres in the light reflex.