In Response (2017)

We appreciate the kind words and interest in our recent study from Drs Coursin, Rice, and Kla. We agree that autonomic dysfunction associated with diabetes mellitus (DM) could confound the interpretation of measurements of pupillary unrest under ambient light (PUAL). However, we assert that even if PUAL is diminished by DM (or other patient factors), that does not per se make PUAL measurements unhelpful. By analogy, end-tidal CO2 is frequently deranged in patients with lung disease, but measurements of end-tidal CO2 are still useful in the titration of opioid. The utility of PUAL depends on the relative effect sizes of drug factors compared to patient factors. If the drug effect on a given index is swamped by variability due to patient factors, it is unlikely to be useful. In DM, that may not be the case. Although Hreidarsson and Gundersen1 found evidence that PUAL is reduced in patients with DM, they used a technique for measurement of PUAL that is now considered obsolete due in part to its inability to reject artifact. Their approach has been superseded by the methods described by Lüdtke et al.2 Nevertheless, it is still reasonable to hypothesize that DM reduces PUAL. Bokoch et al3 investigated changes in PUAL by administration of 1 μg/kg fentanyl. Although these data cannot be directly compared to the study by Hreidarsson and Gundersen1 because of differences in measurement technique, we can perhaps gain some insight by comparing the relative changes. Bokoch et al3 observed a decrease of 1.2 to 1.9 SDs (a 40% change) in PUAL after administration of fentanyl, while Hreidarsson and Gundersen1 observed a decrease of 0.6 to 1.0 SDs (a 21%–37% change, depending on lighting conditions) in PUAL in patients with DM. Thus, while the presence or absence of DM would need to be taken into account when interpreting PUAL, the drug effect is likely to be larger for doses of opioids encountered in clinical practice. Furthermore, the diabetic population studied by Hreidarsson and Gundersen1 had poorly controlled disease. Forty-four percent of them suffered from retinopathy, while 30% had peripheral neuropathy. Both of these conditions correlated with PUAL reduction. Patients with relatively well-controlled DM in their study had relatively mild deviations in PUAL, comparable to the normal variation in the population, and these patients would likely require minimal adjustment of expected PUAL values. Aside from simply adjusting expected values, another approach would be to take baseline measurements of PUAL and follow changes in PUAL instead of absolute values. The measurement of PUAL is comparable in invasiveness and patient discomfort to measurements of vital signs such as blood pressure and oxygen saturation and could easily be done in a preoperative clinic. Of course, clinical deployment would require more robust data on the magnitude and variability of changes in PUAL with a variety of patient factors. Our hope is that the preliminary data we presented generate some interest in pupillary unrest measurement as a clinical tool and further studies are designed to perfect the technique. Andrew E. Neice, MDDepartment of AnesthesiaOregon Health and Science UniversityPortland, Oregon[email protected] Merlin D. Larson, MDMatthias Behrends, MDMichael P. Bokoch, MD, PhDDepartment of Anesthesia and Perioperative CareUniversity of California, San FranciscoSan Francisco, California