Anesthesiology, Article

Respiratory depression in the intoxicated trauma patient: are opioids to blame?

a b s t r a c t

Providing effective pain management to acutely intoxicated trauma patients represents a challenge of balancing appropriate pain management with the risk of potential respiratory depression from opioid administration. The objective of this study was to quantify the incidence of respiratory depression in trauma patients acutely intox- icated with ethanol who received opioids as compared with those who did not and identify potential risk factors for respiratory depression in this population. retrospective medical record review was conducted for subjects identified via the trauma registry who were admitted as a Trauma activation and had a detectable serum ethanol level upon admission. Risk factors and characteristics compared included demographics, Injury Severity Score, Glasgow Coma Score, serum ethanol level upon arrival, urine drug screen results, incidence of respiratory depres- sion, and opioid and other sedative medication use. A total of 233 patients were included (78.5% male). Patients who received opioids were more likely to have a higher Injury Severity Score and initial pain score on admission as compared with those who did not receive opioids. Blood ethanol content was higher in patients who did not receive opioids (0.205 vs 0.237 mg/dL, P = .015). Patients who did not receive opioids were more likely to be intubated within 4 hours of admission (1.7% vs 12.1%, P = .02). Opioid administration was not associated with increased risk of respiratory depression (19.7% vs 22.4%, P = .606). Increased cumulative fentanyl dose was as- sociated with increased risk of respiratory depression. Increased cumulative fentanyl dose, but not opioid admin- istration alone, was found to be a risk factor for respiratory depression.

(C) 2015

Introduction

Recognition of inadequate pain management has prompted efforts across many disciplines to increase appropriate treatment of acute pain in the hospital setting. Effective pain management has been shown to be important for multiple reasons, including patient satisfac- tion, earlier mobilization, shortened hospital stay, and reduced costs [1-4]. Although it may not be possible to eliminate all pain, a substantial effort should be made to minimize the incidence and severity of acute pain.

? Conflicts of interest and source of funding: No authors have declared conflicts of inter- est. No funding was provided for this study.

?? Meetings at which this article will be presented: The Society of Critical Care Medicine,

Critical Care Congress, Orlando, FL, February 2016.

* Corresponding author at: 3181 SW Sam Jackson Park Rd, Mail Code: CR 9-4, Portland, OR, 97239-3098. Tel.: +1 503 494 8007; fax: +1 503 494 5094.

E-mail addresses: [email protected] (E. Shenk), [email protected] (C.A. Barton), [email protected] (N.D. Mah), [email protected] (R. Ran), [email protected]

(R.G. Hendrickson), [email protected] (J. Watters).

Adequate assessment of pain is complex in nonIntoxicated patients, and ethanol intoxication only further complicates pain assessment and determining appropriate treatments. With 31% to 70% of trauma pa- tients presenting with detectable serum alcohol concentrations, this scenario occurs often [5-8]. Trauma patients have a need for effective pain control, but known or suspected intoxication may lead some pro- viders to withhold the use of opioid therapy. Reasons for withholding pain medication include being unable to appropriately assess the pa- tient’s pain, the potential for variable perceptions of pain, unawareness of the patient’s pain tolerance, and the risk of serious adverse effects such as respiratory depression. Intoxicated trauma patients are at par- ticular risk for undertreated pain and for the Negative outcomes that providers are attempting to prevent [4,9].

There are limited data evaluating the interaction between ethanol and opioid medications. The combination is known to cause respiratory depression due to additive central nervous system depressive effects, but data evaluating the risk of respiratory depression in intoxicated trauma patients receiving opioid therapy are lacking [4,10]. The purpose of this study is to determine the rate of respiratory depression seen in intoxicated trauma patients who receive opioids for pain management as compared with those who do not receive opioids.

http://dx.doi.org/10.1016/j.ajem.2015.10.053

0735-6757/(C) 2015

Methods

E. Shenk et al. / American Journal of Emergency Medicine 34 (2016) 250253

Table 1

Baseline demographics

251

From November 2013 to June 2014, all patients 18 years or older who had a detectable blood ethanol level and were admitted as a trau-

Characteristic Treatment group (n = 117)

Comparator group (n = 116)

P value

ma activation to the emergency department (ED) of a single university- affiliated level 1 trauma center were included in this retrospective co- hort study. A detectable blood ethanol level was defined as greater than or equal to 10 mg/dL. Patients were excluded if endotracheal intubation was performed before admission or if the patients had a severe allergic reaction to opioids, were pregnant, met the definition for respiratory depression at admission, were transferred from an outside hospital, or were intubated for reasons other than respiratory depression. This study was approved by the institutional review board.

The primary outcome variable was to evaluate the incidence of re- spiratory depression in intoxicated trauma patients who were adminis- tered opioids as compared with those who were not administered opioid therapy. The secondary outcome was to evaluate risk factors for respiratory depression, specifically looking at fentanyl equivalent dose, blood ethanol content, and midazolam equivalent dose.

Eligible patients were identified via an institutional trauma database, and subject inclusion and exclusion criteria were applied through ex- tensive medical record review. Demographic information, treatment characteristics, and opioid use were gathered from the trauma database and electronic health records. Included patients were separated into 2 groups; the treatment group included those who were administered opioids within 4 hours of ED admission or before endotracheal intuba- tion, and the comparator group consisted of those who were not admin- istered opioids within this time frame.

Respiratory depression was defined as the presence of at least 1 of the following criteria: respiratory rate b 10 breaths per minute, oxygen sat- uration b 90% requiring supplemental oxygen, need for endotracheal in- tubation, and use of naloxone within 4 hours of ED admission.

All opioid doses were converted to fentanyl equivalent doses. The conversion was done using the Hopkins Opioid Program [11]. All doses of benzodiazepines were converted to midazolam equivalent doses. The conversion factor used for converting between midazolam and lorazepam was 3:1 [12].

Data were analyzed using IBM SPSS Statistics 22 Software with a de- fined significance a priori as P b .05 by 2-tailed asymptotic or exact tests. A cross-tabulation and ?2 test with continuity correction was used to assess the association between trauma patients who received opioids and trauma patients with respiratory depression. ?2 with continuity correction was also used to test the significance of ordinal data. All con- tinuous variables were first tested for normality. Normally distributed continuous variables were analyzed by independent-samples t test. Nonparametric variables were analyzed with Mann-Whitney U test. Bi- nary logistic regression was used to measure the effects of fentanyl equivalent opiate dosing, blood ethanol content, and midazolam equiv- alent benzodiazepine dosing on the incidence of respiratory depression in trauma patients who received opiates, either within 4 hours of pre- sentation to the ED or before intubation.

Results

The trauma database identified 268 adult trauma patients admitted with a detectable serum ethanol concentration in the study period. Nineteen patients were excluded for intubation before admission. Of the patients in the treatment group, 2 were excluded for documentation of severe opioid allergies, 3 for intubation due to aggression rather than respiratory depression, and 2 who were treated with hydromorphone infusions, but the electronic health records did not specify the exact dos- age received during the measured time frame. Of the patients in the comparator group, 7 were excluded for documentation of severe opioid allergies and 2 for intubation due to aggression. A total of 117 patients were included in the treatment group and 116 patients in the comparator group.

Age, y 44 (15) 42 (18) .204

Male, n (%)a 88 (75.2) 95 (81.9) .216

GCS a 15 (14-15) 15 (14-15) .014

ISS scorea 9 (4-14) 5 (1-10) .001

Initial pain scorea 8 (6-9) 3 (0-5) b.001

Blood alcohol content, mg/dL 0.205 (0.09) 0.237 (0.104) .015

a Median (interquartile range).

Baseline demographics of included patients are listed in Table 1. The treatment group was more likely to have a higher Injury Severity Scale score (ISS), have a higher initial pain score on admission, and be admit- ted to the ward from the ED as compared with the comparator group (Table 2). Thirty-five patients (29.9%) required supplemental oxygen in the treatment group and 17 patients (14.7%) in the comparator group. Patients in the comparator group were more likely to require en- dotracheal intubation (P = .02) (Table 2). The most common mecha- nism of injury for both groups was motor vehicle accident. Twenty- three patients (9.9%, n = 10 in treatment group, n = 13 in comparator group) had a positive urine drug screen, with the most common expo- sures being opiates, amphetamines, cannabinoids, and benzodiaze- pines. There was not a statistically significant difference in either the rate of positive urine drug screen or any substance between the 2 groups.

Forty-nine patients (21.0%) experienced respiratory depression. Of these patients, 23 (46.9%) were administered opioids. There was no sta- tistically significant difference between the 2 groups in regard to respi- ratory depression and administration of opioids (Table 3). Cumulative fentanyl dose was associated with statistically significant increase in re- spiratory depression (Figure) (Table 4).

Discussion

Given the high prevalence of ethanol intoxication in trauma patients, surprisingly little data are available regarding the risk of respiratory de- pression in intoxicated trauma patients requiring opioid therapy. Trau- matic injuries are known to cause severe pain, and opioids should be administered in adequate doses to relieve patient suffering and reduce trauma-related stress responses [13]. The fear of respiratory depression from opioid administration can be compounded by the presence of

Table 2

Treatment characteristics

Characteristic [mean (+-SD)]a

Treatment group

Comparator group

P value

(n = 117)

(n = 116)

Respiratory rate

14 (4)

13 (3)

.144

Use of supplemental O2

20%

24%

.591

Use of naloxone

0%

2.5%

.081

Endotracheal intubation, n (%)

2 (1.7)

14 (12.1)

.02

Use of benzodiazepines

20%

24%

.410

Midazolam equivalent dose, mg

0.7 (1.7)

1.1 (2.7)

.154

Use of antipsychotics

0%

7.8%

.002

ED LOS, h

4.4 (3.1)

4.8 (3.3)

.319

ICU admission from ED

38%

28%

.106

Ward admission from ED

26%

10%

.002

ICU LOS, d

1 (3.6)

1 (3.1)

.935

Ward LOS, d

1.9 (2.8)

0.8 (3.1)

.007

Mortality, n (%)

1 (0.8)

2 (1.7)

.558

Fentanyl equivalent dose (ug)b

117 (50-200)

0

.000

ICU, intensive care unit; LOS, length of stay.

a Unless otherwise noted.

b Median (interquartile range).

252 E. Shenk et al. / American Journal of Emergency Medicine 34 (2016) 250253

Table 3

Analysis of association of respiratory depression with opioid use

Respiratory depression

Total (n)

Yes [n (%)]

No [n (%)]

Received opioids before intubation or b 4 h of ED presentation

Yes

23 (19.7%)

94 (80.3%)

117

No

26 (22.4%)

90 (77.6%)

116

Total

49 (21%)

184 (79%)

233

P value

.606

acute ethanol intoxication, potentially leading to suboptimal pain man- agement. The available literature regarding respiratory depression and opioid therapy is primarily in nonintoxicated trauma and burn patients, and offers mixed results regarding the risk of respiratory depression with these therapies.

Mildh and colleagues [13] found that there was no clinically signifi- cant hypoventilation in 13 trauma patients who received intravenous oxycodone every 5 to 10 minutes until the patients reported no pain at rest (mean Cumulative dose of 9.5 +-2 mg; range, 0.02-0.14 mg/kg). Conversely, Linneman and colleagues [14] found that in burn patients who received bolus Intravenous fentanyl doses (average dose of 8.0 +- 7.0 ug/kg) for burn wound procedures, 31% (17 of 47) of Nonintubated patients experienced Respiratory complications. None of the patients re- quired intubation, and all returned to baseline respiratory status within 1 hour postprocedure. The authors found no correlation between fenta- nyl dose and respiratory complications [14].

In our study, no association was seen between the incidence of respi- ratory depression and opioid administration. As patients with higher pain scores were more likely to receive opioid therapy, it appears as though we provided pain management in the form of opioid medica- tions when appropriate.

What is harder to discern is why patients who were not treated with opioids required endotracheal intubation more frequently. It is probable that our providers used clinical judgment weighing the safety of opioid administration as compared with the clinical appearance of the patient. Should a patient appear to the provider to be somnolent or unarousable but still maintain their airway and not meet our definition of respiratory depression, it is less likely that opioids would be administered in this pa- tient likely at higher risk of needing endotracheal intubation for airway protection. We were not able to capture these evaluations because of the retrospective nature of the study.

Our study did find an association with fentanyl equivalent dose and increased risk of respiratory depression. Caution should be taken when intoxicated trauma patients require increased doses of opioids.

Limitations

There are several limitations to this study. This study was retrospec- tive in nature and cannot account for the probable selection bias that oc- curred when the providers determined who did or did not receive

25%

Incidence of Respiratory Depression

20%

15%

opioids. In the absence of a method to retrospectively identify all intox- icated patients, we used the surrogate of a detectable blood ethanol level. This likely led to the inclusion of patients who were not clinically intoxicated. It is also possible that not all incidences of respiratory de- pression were captured due to the lack of continuous vital monitoring data available from ED records. Baseline opioid tolerance and use were unavailable for most patients and may have had an effect on the dose- dependent risk of respiratory depression.

Conclusions

Our study is the first of its kind to describe the use of opioid medica- tions in the intoxicated trauma patient. We found that there was no as- sociation between respiratory depression and opioid therapy in trauma patients with a detectable blood ethanol level, yet higher cumulative fentanyl dose is associated with respiratory depression. Clinicians ap- pear to adequately assess pain in our trauma patients, provide opioids to those with elevated pain scores, and withhold therapy more fre- quently in those undergoing endotracheal intubation within 4 hours of admission. As a randomized, prospective, placebo-controlled trial ad- dressing this topic could likely not be feasibly conducted, retrospective reports such as this one likely represent the most robust data presented on the topic.

Author contributions

ES: literature search, study design, data collection, data analysis, Data interpretation, writing, critical revision

CB: literature search, study design, data interpretation, writing, crit- ical revision

NM: literature search, study design, data interpretation, writing, crit- ical revision

RR: study design, data analysis, critical revision RH: study design, data interpretation, critical revision JW: study design, data interpretation, critical revision

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    10%

    5%

    0%

    <50 <100 <150 <200 <250 <300 <350 <400 <450

    Fentanyl equivalent dose (mcg)

    Table 4

    Subgroup analysis of risk factors for respiratory depression

    Figure. Cumulative rates of respiratory depression by fentanyl dose.

    Risk Factor

    P value

    Fentanyl equivalent dose

    .011

    Blood alcohol content

    .519

    Midazolam equivalent dose

    .674

    E. Shenk et al. / American Journal of Emergency Medicine 34 (2016) 250253 253

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