Quantification of respiratory depression during pre-operative administration of midazolam using a non-invasive respiratory volume monitor

Abstract

Background: Pre-operative administration of benzodiazepines can cause hypoventilation-a decrease in minute ventilation (MV)-commonly referred to as "respiratory compromise or respiratory depression." Respiratory depression can lead to hypercarbia and / or hypoxemia, and may heighten the risk of other respiratory complications. Current anesthesia practice often places patients at risk for respiratory complications even before surgery, as respiratory monitoring is generally postponed until the patient is in the operating room. In the present study we examined and quantified the onset of respiratory depression following the administration of a single dose of midazolam in pre-operative patients, using a non-invasive respiratory volume monitor that reports MV, tidal volume (TV), and respiratory rate (RR).

Methods: Impedance-based Respiratory Volume Monitor (RVM) data were collected and analyzed from 30 patients prior to undergoing orthopedic or general surgical procedures. All patients received 2.0 mg of midazolam intravenously at least 20 minutes prior to the induction of anesthesia and the effects of midazolam on the patient's respiratory function were analyzed.

Results: Within 15 minutes of midazolam administration, we noted a significant decrease in both MV (average decrease of 14.3% ± 5.9%, p<0.05) and TV (22.3% ± 4.5%, p<0.001). Interestingly, the corresponding RR increased significantly by an average of 10.3% ± 4.7% (p<0.05). Further analysis revealed an age-dependent response, in which elderly patients (age≥65 years, n = 6) demonstrated greater reductions in MV and TV and a lack of compensatory RR increase. In fact, elderly patients experienced an average decrease in MV of 34% ± 6% (p<0.05) compared to an average decrease of 9% ± 6% (p<0.05) in younger patients.

Conclusions: We were able to quantify the effects of pre-operative midazolam administration on clinically significant respiratory parameters (MV, TV and RR) using a non-invasive RVM, uncovering that the respiratory depressive effect of benzodiazepines affect primarily TV rather than RR. Such respiratory monitoring data provide the opportunity for individualizing dosing and adjustment of clinical interventions, especially important in elderly patients. With additional respiratory data, clinicians may be able to better identify and quantify respiratory depression, reduce adverse effects, and improve overall patient safety.

Conflict of interest statement

Competing Interests: We have the following interests. Jaideep Mehta and Gary Mullen own stock in Respiratory Motion Inc. Jordan Brayanov was an employee of Respiratory Motion Inc. at the time this manuscript was written and collaborated with co-authors on data analysis, manuscript preparation, and publication decision. Respiratory Motion Inc. provided the devices used for data collection in this study. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Fig 1. Average RVM measurements across the entire thirty patient cohort pre (left) and post (right) administration of 2mg of midazolam.

(A) MV decreased significantly from 7.41 ± 0.62 L/min (mean ± SEM) to 5.95 ± 0.46 L/min, with an average decrease of 14.3% ± 5.9% (p<0.05). (B) Similarly, TV decreases significantly from 460 ± 30 mL to 340 ± 30 mL, an average decrease of 22.3% ± 4.5% (p<0.001). (C) In contrast, RR increased slightly from 16.6 ± 0.7 breaths per minute to 17.8 ± 0.7 breaths per minute, an average increase of 10.3% ± 4.7% (p<0.05).

Fig 2. Thirty-second snapshots of RVM traces from a 66 y/o male patient (165 cm, 78 kg, BMI: 29 kg/m2) undergoing a left hip replacement surgery.

These traces show a clear and immediate decrease in both MV and TV following midazolam administration, coupled with marginal and delayed decrease in RR. (A) Pre-midazolam values (2 min pre-dose) were taken as baseline. (B) Within 5 min of the dose, breathing was notably depressed with MV and TV effectively decreased by half, while RR marginally increased. (C) Ten minutes post-midazolam, MV and TV had decreased from pre-dose values by 69.3% and 62.9% respectively (MV: 9.9 to 3.0 L/min; TV 600 to 220 ml) while RR only decreased by 17.9% (16.4 to 13.6 b/min). (D) At 15 minutes post-midazolam, MV and TV had further decreased from pre-dose values by 81.9% and 70.4%, respectively (MV: 9.9 to 1.8L/min; TV: 600 to 180ml). RR finally shows a substantial decrease of 39.0% (RR: 16.4 to 10.0 breaths per minute).

Fig 3. Examples of two different patterns of respiratory depression in two representative subjects. Panels A and B: 31 y/o male, 185 cm, 82 kg, BMI: 24 kg/m2. Panels C and D: 61 y/o female, 173 cm, 82 kg, BMI: 27 kg/m2.

Comparison of traces before (A and C) and after (B and D) benzodiazepine administration shows that respiratory depression may manifest as both tachypnea with low TV (B) as well as intermittent apnea (D).

Fig 4. A time-lapse capturing one representative patient’s onset of respiratory depression during the 20 minutes following the administration of midazolam.

Note that this is the same patient as in Fig 3A and 3B (31 y/o male). MV and TV decrease about 3–4 minutes after the dose and remain low as compared to pre-dose values, whereas RR increases and remains above baseline.

Fig 5. Age-specific analysis of respiratory depression following administration of 2mg of midazolam.

Average changes in MV, TV, and RR following midazolam are shown for all patients (yellow), younger patients (green), n = 24, age 43 ±14 years, and older patients (red), defined as 65 years and older, n = 6, age 70 ±6 years. Both the young and elderly demonstrated significant decreases in TV (20% ± 5% and 30% ± 4% respectively, p0.05) and the resulting MV was significantly lower, with an average decrease of 34% ± 6% (p