Diphenhydramine as an Adjunct to Moderate Sedation

9

Bronchoscopy

Section A

Diphenhydramine as an Adjunct to Moderate Sedation in Outpatient Flexible

Bronchoscopy

Rodeo A. Abrencillo, MD; Lenar T. Yessayan, MD, Tom Smoot, PharmD; Mohammed

Al-Jasmi, MD; Geneva B. Tatem, MD; Michael J. Simoff, MD, FACP, FCCP^*

Division of Pulmonary and Critical Care Medicine

Henry Ford Hospital

Abstract

Background Diphenhydramine is commonly used to decrease sedative usage in outpatient bronchoscopy, however, data to

support this practice is lacking. Methods We conducted a single-center retrospective analysis of all outpatient bronchoscopies

from November 2013 to February 2016. Each subject that was included had two bronchoscopies: no diphenhydramine used

(control) versus diphenhydramine used (intervention). The primary objective was to determine if diphenhydramine

administration decreases total midazolam usage. Additionally, we explored potential medication cost savings. Results Of 1164

patients with greater than 1 outpatient bronchoscopy, 61 unique subjects fulfilled the primary inclusion criteria resulting in

122 procedures. The mean dose of diphenhydramine was 38.3±15.12 mg. Procedure time was 22.9±16 mins in the

intervention group and 23.2±17.8 mins in the control group (p= 0.907). Mean opiate dose administered was 5.6±2.6 mg versus

6.2±2.4 mg in the intervention and control group, respectively (p= 0.113). Mean midazolam dose was 8.4 ± 3.2 mg in

intervention group and 10.2±3.8 mg in control group (difference: -1.795 mg, p= 0.005). In a multivariate analysis, mean

midazolam use remained lower in the diphenhydramine group after adjusting for age, procedure time and opiates used,

(difference -1.29±3.53 mg, p= .004). There was no significant difference for the total cost of medication between the control

and the diphenhydramine group ($6.21±2.70 vs. $6.23±2.53, p= .968). Conclusions Intravenous administration of

diphenhydramine during outpatient bronchoscopy resulted in a small but statistically significant reduction in midazolam usage

with no notable cost advantage.

Keywords: Sedation, bronchoscopy

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10

Diphenhydramine as an Adjunct in Outpatient Flexible Bronchoscopy

were retrospectively reviewed after the approval of

our institutional review board (IRB#10248). During

this period, a combination of physician preference,

expected procedure duration, and patient factors led

to a decision as to whether or not diphenhydramine

was employed as an adjunctive agent during

bronchoscopy. Adult patients were selected for the

study if they had at least 2 outpatient bronchoscopies

during which there was differential use of

diphenhydramine. So, each patient had at least one

bronchoscopy with no diphenhydramine used

(labeled as the control procedure) and one

bronchoscopy in which diphenhydramine was used

(labeled as the intervention procedure). Thus, each

patient served as his/her own control. If there were

more than 3 bronchoscopies for a patient, the most

recent pair (control versus intervention) were

selected. Bronchoscopies done as in-patient were

excluded. Baseline characteristics collected at the

time of each bronchoscopy included age, body mass

index, outpatient use of alcohol, current ongoing use

of benzodiazepines, opiates, antidepressants and anti-

psychotics. The outpatient medications were grouped

based on their class (e.g. opiates included morphine

and other synthetic narcotics).

1. Introduction

Moderate sedation is a common practice in

outpatient bronchoscopy. 1,2 It has been shown to

safely shorten procedure times and improve patient

experience. 3 4 However, sedation practices in

bronchoscopic procedures, including the use of

diphenhydramine, vary between institutions 2,5-7 .

Diphenhydramine exert a sedative and hypnotic

effect by antagonizing central nervous system

histamine H1 receptors8,9 and it may also mitigate

opioid-related respiratory depression.10 Because of

this properties, it’s use has been described in multiple

procedures

including

gastrointestinal

endoscopies11,12, dental procedures13 ,cardiac

catheterization14 and bronchoscopy. 15-19 The

anticholinergic properties of diphenhydramine may

decrease cough and secretions in bronchoscopy9,20

however the more potent anticholinergic agent,

atropine, failed to demonstrate these benefits in a

randomized clinical trial 21. Though used in

bronchoscopy primarily to reduce complications

related to cumulative sedative dosages16,17,22,23, to

our knowledge, no analytical studies have evaluated

patient-related outcomes of diphenhydramine use in

2.2. Bronchoscopy

flexible

bronchoscopy

and

guidelines

in

bronchoscopy have not endorsed its use24,25 With

this in mind, the primary objective of this study was

The procedure time was measured from the time

of the “critical pause” to the bronchoscope’s

withdrawal past the nose or mouth. Mean procedure

time was determined for each group. All

bronchoscopic procedures were aggregated based on

procedure group types (i.e., airway examination only,

transbronchial biopsy, endobronchial ultrasound, etc.)

and their mean times were calculated.

to

determine

whether

diphenhydramine

administration would decrease the need for other

sedative medications during outpatient flexible

bronchoscopy. We specifically wanted to assess

whether diphenhydramine decreases the total dose of

benzodiazepine and opioid administered thereby

providing cost savings. In addition, we sought to

determine if diphenhydramine use has an impact on

procedure-related complications.

2.3 Medications

The total and mean doses (milligrams) of

benzodiazepines and opiates were determined for

each group. Opioid doses were converted to

morphine-equivalent doses for uniform comparison.

The timing of diphenhydramine administration with

reference to the first midazolam dose was also

computed. As the use of diphenhydramine varied

according to the bronchscoscopist performing the

2. Methods

2.1. Patients

All outpatient bronchoscopies at Henry Ford

Hospital from November 2013 to February 2016

Diphenhydramine as an Adjunct to Moderate Sedation

11

procedure, the physician performing the procedure

was also included in all analyses. Doses of other

medications used as adjuncts during the procedure

were also recorded..

determine the difference in midazolam use between

the two groups after adjusting for age, duration of

procedure and total morphine equivalent dose

administered. Categorical variables were presented as

frequencies and percentages, and continuous

variables as mean and standard deviation. Cost

analysis was performed using the average wholesale

price (AWP) of the vials used for the procedures.

Additionally, the cost for ondansetron, meperidine,

naloxone and flumazenil was computed if they were

used. Cost for procedure related admission and

nursing monitoring was not included in this study.

2.4 Complications

Each procedure encounter was reviewed for any

naloxone or flumazenil usage. Charts were evaluated

for any admission in the 24-hour period after the

procedure

and

any

procedural

hypotension.

Hypotension was defined as systolic blood pressure

of less than 90mmHg taken 2 consecutive times (re-

checked immediately) at any point during the

procedure..

3. Results

Of the 1164 patients with greater than 1 outpatient

bronchoscopies in the study period, there were 61

unique subjects that fulfilled the primary inclusion

criteria resulting in 122 procedures (Figure 1). The

patients were predominantly female (56%) and their

characteristics (Body mass index, age, alcohol use

and outpatient medication use) at the time of each

bronchoscopy were similar (Table 1). Four patients

did not have their weight or height recorded;

therefore, no BMI was computed. These subjects

were the same 4 patients in both groups. There was

no difference on outpatient medications use between

the control and the diphenhydramine group (Table 1).

2.5 Cost for medications

The average wholesale price of each vial of

medications used in our bronchoscopy suite was used

to compute the mean costs of medications used in the

control and diphenhydramine groups. As a practical

approach, if another vial was opened, the cost of that

particular vial was added to the total cost even though

part of it was wasted.

2.6 Statistical analysis

To determine study size for this investigation, we

evaluated prior research by Tu et al who found that

diphenhydramine use in colonoscopy decreased

midazolam dose by 0.55 mg. However, in their study,

the average midazolam used was only around 3-4

mg.11 Our bronchoscopic procedures average

midazolam usage was estimated to be 10mg (roughly

between 8-12 mg). Using these data, we calculated

that we would require 60 subjects to have 80% power

to detect a reduction in midazolam dose of more than

2 mg, using an alpha of 0.05. In our analyses,

variables with dichotomous outcomes were compared

using McNemar’s test. Differences on continuous

variables between the groups was determined using

Paired t-test. Conditional logistic regression was used

to compare use of diphenhydramine between

bronchoscopists. A multivariate model was applied to

Figure 1. Flow diagram of patient selection

12

Diphenhydramine as an Adjunct in Outpatient Flexible Bronchoscopy

regards to use of diphenhydramine (Table 3).

Table 1. Patient Characteristics

Age (years), mean ± SD

Control

(n=61)

Diphenhydramine

(n=61)

P value

56.77 ± 13.57

57 ± 13.54

0.034

Body mass index (kg/m2), mean ± SD

Alcohol use, N (%)

31.56 ± 9.16

16(26.2)

22 (36.1)

42 (68.9)

20 (32.8)

2 (3.3)

32.5±8.24

17 (27.9)

23 (37.7)

40 (65.6)

16 (26.2)

2 (3.3)

0.096

1.00

Benzodiazepine use, N (%)

Opioid use, N(%)

1.00

0.727

0.125

1.00

Antidepressant use, N (%)

Antipsychotic use, N (%)

3.2 Medication Dosages and Timing

3.1. Bronchoscopic procedures

All patient received midazolam as the preferred

procedural benzodiazepine. The diphenhydramine

group required 1.795 mg less midazolam which was a

17.6% dose reduction (8.4 ± 3.2mg vs. 10.2 ± 3.8 mg,

p =0.002) (Figure 2). There was no significant

difference in the morphine equivalence dose used

between the 2 groups (5.6 ± 2.5 mg vs. 6.2 ± 2.4 mg,

p = 0.113) (Figure 2). In a multivariate model, after

adjusting for age, procedure time and morphine

equivalence, the mean midazolam dose was lower in

the diphenhydramine group in comparison to the

control group (difference -1.29 ± 3.53 mg, p =

0.004). Most patients received either a 25 mg or 50

mg dose of diphenhydramine. The mean dose used of

diphenhydramine was 38.3 ± 15.1 mg. On average,

diphenhydramine was administered 12.3 ± 23.3

minutes before to the first dose of benzodiazepine. .

Three subjects in the diphenhydramine group

received 50 mg of meperidine while no subject

The distribution of each procedure type between

the diphenhydramine group and the control group is

shown in Table 2. All bronchoscopies had an airway

examination performed. Sole airway examinations

were done in 52 procedures (42.6%). The remainder

were distributed in procedure types that involved

multiple combinations of biopsy with or without the

use of ultrasound, bronchial wash or brush and

balloon dilatation. There was no difference between

the diphenhydramine group and the control group in

the frequency of a procedure type (Table 2). The

mean procedure time was same in both groups (23.2

± 17.8 minutes in control group vs. 22.9 ± 16.3

minutes in diphenhydramine group, p=0.907). The

mean time interval between the two bronchoscopies

was 206.1 ± 189 days. Three bronchoscopists

performed 92% of the procedures. The remainder

were distributed among 6 pulmonologists. There was

no significant difference between the groups with

received

meperidine

in

the

control

group.

Interestingly, the mean midazolam used in this

subgroup who received meperidine was higher

compared to the subgroup who had not received

meperidine (11.33±1.15 mg vs 8.27±3.20 mg). There

were 7 patients who received ondansetron: 5 in the

Figure 2. Difference in mean midazolam and

morphine dose requirement

Diphenhydramine as an Adjunct to Moderate Sedation

13

diphenhydramine group and 2 in the control group

with a mean dose of 3.1 ± 1.1 mg. 1

diphenhydramine is a poor substitute for midazolam

if additional sedation is required.12 As opioids tend

to reduce the total doses of other sedatives18,26 and

as the length of the procedures ultimately influence

the total sedative dose, we adjusted for both factors.

Age was also adjusted because it was statistically

different in both groups. The significant reduction of

total midazolam dose was persistent (difference of

1.29 mg, p= 0.004) after these adjustments. While the

dose reduction was small, this could be important

in the geriatric population. The elderly tend to be

more sensitive to sedatives because of reduced

hepatic metabolism, decreased renal function and

3.3 Complications

There were no hypotensive episodes in either

group and none received naloxone or flumazenil

during their outpatient bronchoscopy. Three patients

were

admitted

within

24

hours

in

the

diphenhydramine group and 5 in the control group (p

= 0.717). Table 4 describes the cause of admission in

those patients. Medication Cost analysis The mean

cost difference of midazolam was $-0.66 ($3.50 ±

1.17 vs $4.16 ± 1.24, p= 0.002) in favor of the

diphenhydramine group. However, after accounting

for the cost of diphenhydramine, the control and

intervention group had similar expenses ($6.20 ±

$2.69 vs. $6.07 ± $2.30, p = 0.74). There were no

additional cost difference when meperidine and

ondansetron were added (control $6.21 ± $2.70 vs.

intervention $6.23 ± $2.53, p = 0.97) (Table 5).

reduced tissue and blood esterases.28 In fact, the

current

guideline

for

flexible

bronchoscopy

recommend modifying initial and subsequent doses

of sedatives for patients who were 70 or older.25

However, it should also be kept in mind that

diphenhydramine has a longer half-life in the elderly

and that they may be more sensitive to its

anticholinergic properties. 29 Our study population

appeared relatively younger (mean 56.89 years) and

the potential impact in the elderly was not explored in

this study. With the decreased total midazolam use in

the diphenhydramine group, we expected a lower

total cost of medication for patients who received

diphenhydramine as demonstrated by Tu et. al.11

However, there were no cost differences between

4. Discussion

Sedative dose reduction in bronchoscopy is

important because complications from procedural

sedation are typically dose and agent dependent.26

Moreover, bronchoscopy uses a higher average doses

of benzodiazepine relative to gastrointestinal

procedures (5- 10 mg IV of midazolam compared to

only 3-5 mg IV in GI endoscopic procedure).

4,11,12,27 Our study demonstrated a significant

decrease of 18% (1.8 mg, P = .005) in total

midazolam dose with diphenhydramine use in

outpatient flexible bronchoscopy. Though there was a

concern for potentially deeper and longer sedation in

the intervention group because of diphenhydramine’s

long half-life, none received flumazenil or naloxone

during any of the encounters. Similar dose reduction

was noted in a randomized double-blind placebo-

controlled trial of 258 colonoscopy patients that

demonstrated a significant decrease of procedural

midazolam (13.7%) and meperidine (10.1%) doses

with diphenhydramine pre-medication with no effects

on procedural/recovery time and complication rates.

groups

after

accounting

for

the

cost

of

diphenhydramine. This was likely a result of the

small incremental cost of the opioids added to the

cost of diphenhydramine ultimately negating the

small difference of $0.66 in midazolam cost saving. It

was difficult to assess the unexpected admission rates

related to bronchoscopy because of low event rates.

Several studies used hypoxia as a complication of

sedation in bronchoscopy with varying definitions

(saturations usage.

11

A

more recent randomized trial of 200

colonoscopy patients, however, demonstrated that

14

Diphenhydramine as an Adjunct in Outpatient Flexible Bronchoscopy

Table 2. Type of Bronchoscopic Procedures and Procedure Duration

Control

Diphenhydramine

(n=61)

P value

0.907

(n= 61)

Procedure time (min), mean ± SD

23.17±17.79

22.93±16.3

Procedure type

Airway examination only

TBBX + bronchoalveolar lavage

Endobronchial biopsy

EBUS TBNA

27 (44.3)

14 (23)

5 (8.2)

1 (1.6)

4 (6.6)

25 (41)

15 (24.6)

3 (4.9) .

7 (11.5)

1 (1.6)

0.727

1.00

0.688

0.125

1.00

EBUS + periph brush+ wash

Peripheral EBUS TBBX+ brush+

Balloon dilatation

5 (8.2) .

4 (6.6)

is independent of sedative and ventilation activity in the guinea

pig. Pharmacology 1998;57:57-64.

10. Babenco HD, Blouin RT, Conard PF, Gross JB.

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Endosc 2006;63:87-94.

12. Sachar H, Pichetshote N, Nandigam K, Vaidya K, Laine L.

Continued midazolam versus

diphenhydramine in difficult-to-sedate patients: a randomized

double-blind trial. Gastrointest Endosc

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Diphenhydramine as an Adjunct in Outpatient Flexible Bronchoscopy

Supplemental Tables

Diphenhydramine as an Adjunct to Moderate Sedation

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Diphenhydramine as an Adjunct in Outpatient Flexible Bronchoscopy