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Methocarbamol use is associated with decreased hospital length of stay in trauma patients with closed rib fractures
The American Journal of Surgery xxx (2017) 1e5
Contents lists available at ScienceDirect
The American Journal of Surgery journal homepage: www.americanjournalofsurgery.com
Methocarbamol use is associated with decreased hospital length of stay in trauma patients with closed rib fractures Asad E. Patanwala a, *, Ohoud Aljuhani a, Brian J. Kopp b, Brian L. Erstad a a b
Department of Pharmacy Practice & Science, College of Pharmacy, The University of Arizona, 1295 N Martin Ave, PO Box 210202, Tucson, AZ, 85721, USA Department of Pharmacy Services, Banner University Medical Center, 1501 N Campbell Ave, Tucson, AZ, 85724, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 May 2016 Received in revised form 4 January 2017 Accepted 5 January 2017
Background: The objective of this study was to evaluate the effect of methocarbamol on hospital length of stay in patients with closed rib fracture injuries. Methods: This was a retrospective cohort study conducted in an academic medical center in the United States. Adult trauma patients, who sustained closed rib fractures, were included. Patients were categorized based on whether they received methocarbamol or not during admission. The primary outcome of interest was time to hospital discharge in days (i.e. length of hospital stay). A Cox Proportional Hazards Model was constructed to determine if methocarbamol use was associated with a greater likelihood of earlier discharge. Results: A total of 592 patients were included in the final study cohort. Of these, 329 received methocarbamol and 263 did not receive methocarbamol. In the Cox Proportional Hazards Model methocarbamol use was associated with a greater likelihood of being discharged from the hospital (HR 1.47, 95% CI 1.21 to 1.78, p < 0.001). . Conclusions: The use of methocarbamol after traumatic rib fractures may result in a reduction in the length of hospital stay. Summary: Methocarbamol may improve patient recovery after rib fractures by decreasing intercostal muscle spasm. This may decrease time to hospital discharge and pulmonary complications in patients with rib fractures. © 2017 Published by Elsevier Inc.
Keywords (MeSH): Methocarbamol Wounds and injuries Muscle relaxants Central Neuromuscular agents
1. Introduction Patients with rib fractures often have prolonged pain and disability after injury.1 The intensity of pain in the acute post-injury period is predictive of the development of chronic pain.1 Although opioids are recommended first line for severe pain, multimodal therapy is suggested after injury, especially during the period when pain intensity is highest.2 Multimodal therapy involves the use combinations of analgesics from different classes, or which have different mechanisms to target multiple pain pathways. This has been shown to optimize pain control in the perioperative setting.2 In patients with rib fractures, it is theorized that spasm of the adjacent intercostal muscles contributes to pain.3 This in turn has
* Corresponding author. E-mail addresses: [email protected] (A.E. Patanwala), aljuhani@ pharmacy.arizona.edu (O. Aljuhani), [email protected] (B.J. Kopp), [email protected] (B.L. Erstad).
the potential to depress breathing, result in pneumonia, complicate post-injury care, and lead to an increased duration of hospital stay.4 Thus skeletal muscle relaxants may have a role as part of a multimodal regimen by decreasing intercostal muscle spasm, leading to improved outcomes such as reducing complications (e.g. pneumonia) and duration of hospitalization. However, there is a gap in the literature regarding the routine use of muscle relaxants in this setting. Methocarbamol is a central nervous system depressant that causes muscle relaxation and has previously been evaluated in the trauma population.5 In this aforementioned study, patients with various types of traumatic injuries were given methocarbamol for acute pain as part of a multimodal regimen. Patients who received methocarbamol did not have better pain control or improved outcomes such as a reduction in hospitalization. However, this was a heterogeneous population and it is possible that only certain subsets of patients may benefit such as those with rib fractures. Patients with rib fractures have intercostal muscle spasm, and thus may be more likely to benefit from a medication that causes muscle
http://dx.doi.org/10.1016/j.amjsurg.2017.01.003 0002-9610/© 2017 Published by Elsevier Inc.
Please cite this article in press as: Patanwala AE, et al., Methocarbamol use is associated with decreased hospital length of stay in trauma patients with closed rib fractures, The American Journal of Surgery (2017), http://dx.doi.org/10.1016/j.amjsurg.2017.01.003
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A.E. Patanwala et al. / The American Journal of Surgery xxx (2017) 1e5
relaxation. Other studies in non-trauma patients have also evaluated the effect of single preoperative doses of methocarbamol on post-operative pain.6,7 In these studies methocarbamol use was associated with diminished post-operative pain and opioid consumption, suggesting that it may have a role for perioperative care when muscle spasm is a concern. At our institution, methocarbamol is commonly used for patients after rib fractures, which enabled us to evaluate its effect in the current investigation. At this time there are no studies of methocarbamol use in trauma patients with rib fractures. The objective of this study was to evaluate the effect of methocarbamol on hospital length of stay in patients with closed rib fracture injuries. We hypothesized that patients who received methocarbamol would have a decreased time to hospital discharge. The secondary objective was to compare the rates of pulmonary complications occurring during hospitalization. We hypothesized that patients who received methocarbamol would be less likely to have pulmonary complications during their recovery. 2. Material and methods 2.1. Study design and setting This was a retrospective cohort study conducted in an urban academic medical center in the United States. The institution is designated as a level 1 trauma center by the American College of Surgeons. The hospital does not have a protocol in place specifically for the management of patients with rib fractures. Thus medication selection is based on provider preference. The Institutional Review Board that maintains oversight of the hospital approved the study prior to data acquisition. 2.2. Patient selection An electronic hospital administrative database (University HealthSystem Consortium Clinical Database Resource Manager) was used to obtain the patient cohort of interest at our institution. This database has been previously validated for accuracy.8 The database was queried for patients admitted between April 1st, 2014 and December 31st, 2015. This represented the full range of dates for which data were available. All adult trauma patients (age 18 years) with closed rib fracture injuries were included. Patients with closed rib fractures were identified based on International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnoses codes. The following codes were used to identify patients with rib fractures: 807.0, 807.00, 807.01, 807.02, 807.03, 807.04, 807.05, 807.06, 807.07, 807.08, and 807.09. 2.3. Study variables and measurements The following variables were considered to be relevant to the study: age, sex, race, ethnicity, need for endotracheal intubation, need for blood component transfusion, need for chest tube, inhospital mortality, discharge status, hospital length of stay, ICD-9CM diagnosis codes, Charlson Comorbidity Index (index of comorbid conditions calculated as a sum of pre-specified conditions),9 Injury Severity Score (range from 0 to 75; higher value indicating greater overall severity of injury), and Abbreviated Injury Severity for the chest region (chest AIS) and head region (Head AIS) (range from 0 to 6; higher value indicating greater injury).10 Severe head injury was defined as a Head AIS of >3, similar to a previous investigation.11 Injury severity scores were derived from ICD-9-CM codes similar to the Agency for Healthcare Research and Quality, which has been validated as an accurate predictor of survival.6,12 The ICDPIC package in STATA 13 was used to derive Injury
Severity Scores (body regions and total). Patients were categorized based on whether they received oral methocarbamol during hospital admission or not. Data regarding methocarbamol obtained were dose per day and number of days of treatment. The secondary outcome was pulmonary complications. This was defined as occurrence of any one of the following: bacterial pneumonia (481, 482 [482.0e482.9], 483 [483.0, 483.1, 483.8]), ventilator associated pneumonia (997.31), atelectasis (518.0), or aspiration pneumonia (measured as a complication in the database thus ICD-9-CM code was not needed). 2.4. Outcomes and data analysis The primary outcome of interest was time to hospital discharge in days (i.e. length of hospital stay). This variable was right censored if patients were transferred to another hospital or died during hospitalization. Kaplan Meier curves were compared between the methocarbamol and no methocarbamol groups using the log-rank test. A Cox Proportional Hazards Model was constructed to determine if methocarbamol use was associated with a greater likelihood of discharge after adjusting for pertinent confounders. The intent was not to develop a parsimonious or a predictive model, but rather to adjust for potential confounding. The following confounders were considered to be pertinent based on our clinical experience and were added to the model: age, sex, race/ethnicity, need for endotracheal intubation, need for blood component transfusion, need for chest tube, Charlson Comorbidity Index, Injury Severity Score, and Abbreviated Injury Severity for the chest region, and severe head injury (injury severity variables were ICD9 derived). We tested for interactions between injury severity and methocarbamol because it is possible that the effect of methocarbamol may be more effective with higher severity of injury. To minimize the potential for selection bias, a propensity score analysis was conducted by calculating propensity scores using all available covariates. The effect of methocarbamol on the primary outcome was then evaluated after adjusting for this propensity score. The proportional hazards assumption was tested using the time-dependent covariate method. The goodness-of-fit of the model was assessed by Cox-Snell residuals. Influential observations were identified visually by likelihood displacement values. A sensitivity analysis was conducted by excluding influential observations to determine if it changed the results. Categorical variables, including our secondary outcomes were compared between the methocarbamol and no methocarbamol group using the Fisher's exact test. Normally distributed continuous variables were compared between the two groups using an unpaired student's t-test. Non-normally distributed continuous variables were compared using the Wilcoxon rank-sum test. If there were missing values in <5% of a variable than is was replaced with the most common value for categorical variables. There were no missing data in continuous variables and the only variable with some missing data was race. This was in <5% of the sample. It was estimated that using a hazard ratio of 1.5 (increased likelihood of discharge home in the methocarbamol group), standard deviation of 0.5, probability of failure of 80%, alpha of 0.05, and power of 80%, a total of 239 patients would be required in the study (approximately 120 in each group). All analyses were conducted using STATA 13 (College Station, Texas) and a two-tailed alpha of 0.05 was considered to be statistically significant. 3. Results 3.1. Study cohort There were 613 patients overall who had closed rib fractures
Please cite this article in press as: Patanwala AE, et al., Methocarbamol use is associated with decreased hospital length of stay in trauma patients with closed rib fractures, The American Journal of Surgery (2017), http://dx.doi.org/10.1016/j.amjsurg.2017.01.003
A.E. Patanwala et al. / The American Journal of Surgery xxx (2017) 1e5
during the study time frame. Of these, 21 were less than 18 years and were excluded. Thus 592 patients were retained in the final study cohort. There were no other exclusions. In the sample, 329 received methocarbamol and 263 did not receive methocarbamol. In the overall sample, the mean age was 55.6 ± 18.5 years, and 67.7% were male. The majority of patients were White Non-Hispanic (62.5%), followed by Non-White Hispanic (30.1%), and Non-White Non-Hispanic (7.4%). The mean injury severity score was 16.6 ± 8.9, and the median Chest Abbreviated Injury Scale was 3 (IQR 2 to 3), severe traumatic brain injury occurred in 52 (8.8%), endotracheal intubation was needed in 71(12.0%), chest tube was needed in 88 (14.9%), and blood component transfusion was needed in 87 (14.7%). The Charlson comorbidity index was as follows: no comorbid conditions (60.6%), one condition (21.6%), or two or more conditions (17.7%). The median time to discharge home was 8 days (95% CI 7e9 days). The median dose of methocarbamol used (rounded to 500 mg tablet) was 1500 mg/day (500 mg every 8 h) for a median duration of 4 days (IQR 3e7 days).
3.2. Main results The methocarbamol and no methocarbamol groups were comparable with respect to demographics and overall Injury Severity Score (Table 1). However, there was imbalance in the injury scores for the chest region, severe head injury, endotracheal intubation, chest tube, blood transfusion, and comorbidities between groups (Table 1). The median time to discharge was 5 days (95% CI 4e5 days) in the methocarbamol group and 8 days (95% CI 6e9 days) in the no methocarbamol group. Fig. 1 shows the Kaplan Meier curves for time to discharge home in the two groups. The methocarbamol group was significantly more likely to be discharged home sooner (p < 0.001). In the Cox Proportional Hazards Model methocarbamol use was associated with a greater likelihood of being discharged
Table 1 Baseline comparisons between groups. Variable Demographics Age in years (mean, SD) Sex, Male (n, %) Race/Ethnicity (n, %) White, Non-Hispanic Non-White, Hispanic Non-White, Non-Hispanic Clinical data Endotracheal intubation (n, %) Chest Tube (n, %) Blood component transfusion (n, %) Charlson comorbidity index (n, %) 0 1 2 or more Injury severity score (median, IQR)a Severe head injury (n, %)a Chest abbreviated injury scale (n, %)a 0 1 2 3 4 5 a
Derived from ICD9 codes.
Methocarbamol (n ¼ 329)
No Methocarbamol (n ¼ 263)
P-value
54.1 (17.9) 226 (68.7)
57.5 (19.1) 175 (66.5)
0.029 0.596 0.774
210 (63.8) 95 (28.9) 24 (7.3)
160 (60.8) 83 (31.6) 20 (7.6)
22 (6.7)
49 (18.6)
<0.001
60 (18.2) 33 (10.0)
28 (10.7) 54 (20.5)
0.011 <0.001 <0.001
224 (68.1) 72 (21.9) 33 (10.0) 16 (11e22)
135 (51.3) 56 (21.3) 72 (27.4) 16 (9e22)
20 (6.1)
32 (12.2)
0 (0) 21 (6.4) 60 (18.2) 196 (59.6) 50 (15.2) 2 (0.6)
0 (0) 57 (21.7) 72 (27.4) 108 (41.1) 24 (9.1) 2 (0.8)
0.221 0.012 <0.001
3
Fig. 1. Kaplan Meier curves of time to hospital discharge.
home (HR 1.47, 95% CI 1.21 to 1.78, p < 0.001). No significant interactions were identified in the model. Other variables in the model significantly associated with the outcome of interest were Injury Severity Score and Charlson Comorbidity Index (Table 2). A plot of Cox-Snell residuals showed that the model fit the data well. The proportional hazards assumption was met using the timedependent covariate method (p ¼ 0.739). We identified two observations that were potentially influential. After excluding these observations in a sensitivity analysis, it did not change the results. A sensitivity analysis was also conducted by conducting a propensity score analysis. In the propensity score analysis, methocarbamol remained significantly associated with time to hospital discharge (HR 1.36, 95% CI 1.12 to 1.64, p ¼ 0.001). We also evaluated the subset of patients who had isolated rib fractures (n ¼ 89). In this subset, the median time to discharge was 4 days (95% CI 3e5 days) in the methocarbamol group and 5 days (95% CI 4e9 days) in the no methocarbamol group (p ¼ 0.012). Pulmonary complications occurred in 98 (16.6%) patients in the cohort. Patients who received methocarbamol were less likely to develop these complications (11.3% (n ¼ 37) versus 23.2% (n ¼ 61); p < 0.001). Pulmonary complications consisted of bacterial pneumonia (7.0% (n ¼ 23) versus 14.5% (n ¼ 38); p ¼ 0.004), aspiration pneumonia (0.6% (n ¼ 2) versus 3.8% (n ¼ 10); p ¼ 0.007), ventilator associated pneumonia (0.3% (n ¼ 1) versus 1.9% (n ¼ 5); p ¼ 0.093), and atelectasis (4.9% (n ¼ 16) versus 9.1% (n ¼ 24); p ¼ 0.048). Thus each complication occurred to a lesser extent in the methocarbamol group. 4. Discussion The key finding in this study was that methocarbamol use was associated with a shorter time to hospital discharge, which supports our hypothesis. The results remained true after adjusting for important covariates. The likelihood of discharge was approximately 1.5 times higher with methocarbamol. We are aware of only one previous investigation in trauma patients that has investigated the use of methocarbamol.5 This was a retrospective study that included trauma patients with a wide variety of injuries. This previous study did not show a benefit in terms of pain control during the first three days of methocarbamol use. However, there were few patients with rib fractures in this previous study. Our current investigation shows that there may be a benefit to using methocarbamol in some subsets of patients who are at higher risk for muscle spasm related pain. Patients in the methocarbamol group were also less likely to
Please cite this article in press as: Patanwala AE, et al., Methocarbamol use is associated with decreased hospital length of stay in trauma patients with closed rib fractures, The American Journal of Surgery (2017), http://dx.doi.org/10.1016/j.amjsurg.2017.01.003
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A.E. Patanwala et al. / The American Journal of Surgery xxx (2017) 1e5
Table 2 Cox proportional hazards model. Variable
Hazard ratio
95% CI
P-value
Methocarbamol Age (years) Sex (male) Race/Ethnicity White, Non-Hispanic Non-White, Hispanic Non-White, Non-Hispanic Endotracheal intubation Chest tube Blood component transfusion Charlson comorbidity index Total injury severity scorea Severe head injurya Chest abbreviated injury scalea
1.47 1.00 1.11
1.21 to 1.78 0.99 to 1.00 0.92 to 1.34
<0.001 0.511 0.265
[Reference] 0.90 0.74 0.49 0.89 0.71 0.78 0.95 1.30 1.14
0.74 0.52 0.34 0.69 0.53 0.68 0.93 0.88 0.99
0.305 0.090 <0.001 0.404 0.022 <0.001 <0.001 0.194 0.071
a
to to to to to to to to to
1.10 1.05 0.69 1.16 0.95 0.88 0.96 1.92 1.32
Derived from ICD9 codes.
develop pulmonary complications during hospitalization. Previous national estimates have shown that complications such as pneumonia can occur in up to 6% of patients with rib fractures.13 Our complication rate related to pneumonia was similar. In addition, a considerable number of complications in our study were due to atelectasis. Rib fracture injuries result in shallow breathing, which can lead to progressive atelectasis. Also, patients may have an impaired cough because of pain during breathing. This resulting decrease in vital capacity and reduced ability to clear secretions increases the risk for pneumonia. It is possible that methocarbamol helped patients have a better pulmonary toilet, which lead to improved recovery, decreased complications and reduced time to hospital discharge. After rib fractures, patients often have long-term morbidity due to pain, which may be because of the transition from acute to chronic pain.14 In one study, patients had a decreased quality of life and only 30% returned to work over 24 months post injury.14 Thus early optimal management is imperative to blunt the development of neuroplasticity and chronic pain syndromes. However, we are not aware of any national guidelines regarding pain management after rib fractures. Given the severity of pain experienced by these patients, pain management in this setting typically involves the use of systemic opioids, regional anesthetic techniques, or non-opioid analgesics (e.g. acetaminophen, non-steroidal anti-inflammatory agents).15 The evidence-base overall is weak and thus pain management is extrapolated from the general management of pain in hospitalized patients. Although not specific to rib fractures, guidelines by the American Pain Society recommend a multimodal approach.2 This involves using analgesics with different mechanisms of action, which may be synergistic and reduce adverse effects and opioids consumption. Muscle relaxants such as methocarbamol are a part of this multimodal analgesic armamentarium. The mechanism of methocarbamol has not been fully elucidated, but it related to a central nervous system depressant effect that results in muscular relaxation.16 The extent to which muscle spasm around the fractured bone contributes to pain is unknown. Anecdotally, we know that this is occurs with rib fractures, which lead to the use of methocarbamol at our institution. There was an imbalance between groups with regard to a few important confounders. Patients who received methocarbamol appeared to have higher severity injuries in the chest region and were more likely to receive a chest tube. Conversely, the comparator group was more likely to have severe head injuries, require endotracheal intubation, and blood transfusions. It is uncertain how this affected the outcomes overall because some of these characteristics favor the methocarbamol group and others favor the control group. Overall injury severity scores were similar between
groups. We adjusted for all of these variables in the regression analysis and the results held true. To confirm that the results were robust, we also performed sensitivity analysis by calculating propensity scores. This did attenuate the results slightly, but the differences remained significant and it did not change our conclusions. Ideally, we would just include patients with isolated rib fractures, which would give us a homogenous group. We did look at this subset in the population, which also showed a decreased time to discharge with methocarbamol. But this subset is underpowered to adjust for potential confounders. Even within a sample of isolated rib fractures, the severity of chest injury would vary and thus it would be very difficult to perform such a study in a real world setting and obtain and absolutely homogenous population. The study has some important limitations. This was a retrospective evaluation of an administrative database; thus we were restricted to the data available in the database, accuracy of ICD-9CM coding, and physician documentation. There are clinical measures, which were not available such as pain scores that would have been beneficial to compare between the groups. It was also not possible to quantify use of opioids and other adjunctive medications due to the manner by which these were coded in the database. Thus we have to make the assumption that these were used to an equivalent extent in both groups to enable comparisons. Conversely, the use of methocarbamol could have reduced opioid consumption, which would have been an important finding. For this study, our focus was on meaningful outcomes such as length of stay and complications. At our institution a reduction in length of stay and complications has been the main impetus that has contributed to the use of methocarbamol. Our hypothesis was based on clinician reports of the effect of this therapy on the outcomes measured in this study. Thus these results are meaningful even without the clinical variables that we were not able to obtain. There is the possibility that we did not include confounders that may have influenced our results. However, we did take into account some of the important variables such as injury severity comorbidity, need for endotracheal intubation, transfusion, severe head injury and chest tube placement. Survival analysis requires an assumption of independent censoring, which we considered to be reasonable for this analysis. 5. Conclusions The use of methocarbamol after traumatic rib fractures may improve recovery and result in a reduction in the length of hospital stay. Patients given methocarbamol may also have fewer pulmonary complications such as atelectasis and pneumonia. These results are hypothesis generating and a prospective randomized controlled trial is needed to confirm these findings. Conflicts of interest and source of funding None. References 1. Fabricant L, Ham B, Mullins R, Mayberry J. Prolonged pain and disability are common after rib fractures. Am J Surg. 2013;205:515e516, 511-515; discusssion. 2. American Pain Society (APS). Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. sixth ed. 2008. Glenview, IL 60025. 3. Haegerstam GA. Pathophysiology of bone pain: a review. Acta Orthop Scand. 2001;72:308e317. 4. Easter A. Management of patients with multiple rib fractures. Am J Crit Care. 2001;10:328e329, 320-327; quiz. 5. Aljuhani O, Kopp BJ, Patanwala AE. Effect of methocarbamol on acute pain after traumatic injury. Am J Ther. 2015. http://dx.doi.org/10.1097/MJT.00000000000
Please cite this article in press as: Patanwala AE, et al., Methocarbamol use is associated with decreased hospital length of stay in trauma patients with closed rib fractures, The American Journal of Surgery (2017), http://dx.doi.org/10.1016/j.amjsurg.2017.01.003
A.E. Patanwala et al. / The American Journal of Surgery xxx (2017) 1e5 00364. 6. Hidalgo DA, Pusic AL. The role of methocarbamol and intercostal nerve blocks for pain management in breast augmentation. Aesthet Surg J. 2005;25: 571e575. 7. Looke TD, Kluth CT. Effect of preoperative intravenous methocarbamol and intravenous acetaminophen on opioid use after primary total hip and knee replacement. Orthopedics. 2013;36:25e32. 8. Sutton JM, Hayes AJ, Wilson GC, et al. Validation of the University HealthSystem Consortium administrative dataset: concordance and discordance with patient-level institutional data. J Surg Res. 2014;190:484e490. 9. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373e383. 10. Baker SP, O'Neill B, Haddon Jr W, Long WB. The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care.
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J Trauma. 1974;14:187e196. 11. Patanwala AE, Erstad BL, Roe DJ, Sakles JC. Succinylcholine is associated with increased mortality when used for rapid sequence intubation of severely brain injured patients in the emergency department. Pharmacotherapy. 2016;36: 57e63. 12. Osler T, Rutledge R, Deis J, Bedrick E. ICISS: An international classification of disease-9 based injury severity score. J Trauma. 1996;41:386e388, 380-386; discussion. 13. Brasel KJ, Guse CE, Layde P, Weigelt JA. Rib fractures: relationship with pneumonia and mortality. Crit Care Med. 2006;34:1642e1646. 14. Marasco S, Lee G, Summerhayes R, Fitzgerald M, Bailey M. Quality of life after major trauma with multiple rib fractures. Injury. 2015;46:61e65. 15. Karmakar MK, Ho AM. Acute pain management of patients with multiple fractured ribs. J Trauma. 2003;54:615e625. 16. Methocarbamol Tablet [package Insert]. Sandoz Inc., Princeton, NJ 08540.
Please cite this article in press as: Patanwala AE, et al., Methocarbamol use is associated with decreased hospital length of stay in trauma patients with closed rib fractures, The American Journal of Surgery (2017), http://dx.doi.org/10.1016/j.amjsurg.2017.01.003
Contents lists available at ScienceDirect
The American Journal of Surgery journal homepage: www.americanjournalofsurgery.com
Methocarbamol use is associated with decreased hospital length of stay in trauma patients with closed rib fractures Asad E. Patanwala a, *, Ohoud Aljuhani a, Brian J. Kopp b, Brian L. Erstad a a b
Department of Pharmacy Practice & Science, College of Pharmacy, The University of Arizona, 1295 N Martin Ave, PO Box 210202, Tucson, AZ, 85721, USA Department of Pharmacy Services, Banner University Medical Center, 1501 N Campbell Ave, Tucson, AZ, 85724, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 May 2016 Received in revised form 4 January 2017 Accepted 5 January 2017
Background: The objective of this study was to evaluate the effect of methocarbamol on hospital length of stay in patients with closed rib fracture injuries. Methods: This was a retrospective cohort study conducted in an academic medical center in the United States. Adult trauma patients, who sustained closed rib fractures, were included. Patients were categorized based on whether they received methocarbamol or not during admission. The primary outcome of interest was time to hospital discharge in days (i.e. length of hospital stay). A Cox Proportional Hazards Model was constructed to determine if methocarbamol use was associated with a greater likelihood of earlier discharge. Results: A total of 592 patients were included in the final study cohort. Of these, 329 received methocarbamol and 263 did not receive methocarbamol. In the Cox Proportional Hazards Model methocarbamol use was associated with a greater likelihood of being discharged from the hospital (HR 1.47, 95% CI 1.21 to 1.78, p < 0.001). . Conclusions: The use of methocarbamol after traumatic rib fractures may result in a reduction in the length of hospital stay. Summary: Methocarbamol may improve patient recovery after rib fractures by decreasing intercostal muscle spasm. This may decrease time to hospital discharge and pulmonary complications in patients with rib fractures. © 2017 Published by Elsevier Inc.
Keywords (MeSH): Methocarbamol Wounds and injuries Muscle relaxants Central Neuromuscular agents
1. Introduction Patients with rib fractures often have prolonged pain and disability after injury.1 The intensity of pain in the acute post-injury period is predictive of the development of chronic pain.1 Although opioids are recommended first line for severe pain, multimodal therapy is suggested after injury, especially during the period when pain intensity is highest.2 Multimodal therapy involves the use combinations of analgesics from different classes, or which have different mechanisms to target multiple pain pathways. This has been shown to optimize pain control in the perioperative setting.2 In patients with rib fractures, it is theorized that spasm of the adjacent intercostal muscles contributes to pain.3 This in turn has
* Corresponding author. E-mail addresses: [email protected] (A.E. Patanwala), aljuhani@ pharmacy.arizona.edu (O. Aljuhani), [email protected] (B.J. Kopp), [email protected] (B.L. Erstad).
the potential to depress breathing, result in pneumonia, complicate post-injury care, and lead to an increased duration of hospital stay.4 Thus skeletal muscle relaxants may have a role as part of a multimodal regimen by decreasing intercostal muscle spasm, leading to improved outcomes such as reducing complications (e.g. pneumonia) and duration of hospitalization. However, there is a gap in the literature regarding the routine use of muscle relaxants in this setting. Methocarbamol is a central nervous system depressant that causes muscle relaxation and has previously been evaluated in the trauma population.5 In this aforementioned study, patients with various types of traumatic injuries were given methocarbamol for acute pain as part of a multimodal regimen. Patients who received methocarbamol did not have better pain control or improved outcomes such as a reduction in hospitalization. However, this was a heterogeneous population and it is possible that only certain subsets of patients may benefit such as those with rib fractures. Patients with rib fractures have intercostal muscle spasm, and thus may be more likely to benefit from a medication that causes muscle
http://dx.doi.org/10.1016/j.amjsurg.2017.01.003 0002-9610/© 2017 Published by Elsevier Inc.
Please cite this article in press as: Patanwala AE, et al., Methocarbamol use is associated with decreased hospital length of stay in trauma patients with closed rib fractures, The American Journal of Surgery (2017), http://dx.doi.org/10.1016/j.amjsurg.2017.01.003
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A.E. Patanwala et al. / The American Journal of Surgery xxx (2017) 1e5
relaxation. Other studies in non-trauma patients have also evaluated the effect of single preoperative doses of methocarbamol on post-operative pain.6,7 In these studies methocarbamol use was associated with diminished post-operative pain and opioid consumption, suggesting that it may have a role for perioperative care when muscle spasm is a concern. At our institution, methocarbamol is commonly used for patients after rib fractures, which enabled us to evaluate its effect in the current investigation. At this time there are no studies of methocarbamol use in trauma patients with rib fractures. The objective of this study was to evaluate the effect of methocarbamol on hospital length of stay in patients with closed rib fracture injuries. We hypothesized that patients who received methocarbamol would have a decreased time to hospital discharge. The secondary objective was to compare the rates of pulmonary complications occurring during hospitalization. We hypothesized that patients who received methocarbamol would be less likely to have pulmonary complications during their recovery. 2. Material and methods 2.1. Study design and setting This was a retrospective cohort study conducted in an urban academic medical center in the United States. The institution is designated as a level 1 trauma center by the American College of Surgeons. The hospital does not have a protocol in place specifically for the management of patients with rib fractures. Thus medication selection is based on provider preference. The Institutional Review Board that maintains oversight of the hospital approved the study prior to data acquisition. 2.2. Patient selection An electronic hospital administrative database (University HealthSystem Consortium Clinical Database Resource Manager) was used to obtain the patient cohort of interest at our institution. This database has been previously validated for accuracy.8 The database was queried for patients admitted between April 1st, 2014 and December 31st, 2015. This represented the full range of dates for which data were available. All adult trauma patients (age 18 years) with closed rib fracture injuries were included. Patients with closed rib fractures were identified based on International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnoses codes. The following codes were used to identify patients with rib fractures: 807.0, 807.00, 807.01, 807.02, 807.03, 807.04, 807.05, 807.06, 807.07, 807.08, and 807.09. 2.3. Study variables and measurements The following variables were considered to be relevant to the study: age, sex, race, ethnicity, need for endotracheal intubation, need for blood component transfusion, need for chest tube, inhospital mortality, discharge status, hospital length of stay, ICD-9CM diagnosis codes, Charlson Comorbidity Index (index of comorbid conditions calculated as a sum of pre-specified conditions),9 Injury Severity Score (range from 0 to 75; higher value indicating greater overall severity of injury), and Abbreviated Injury Severity for the chest region (chest AIS) and head region (Head AIS) (range from 0 to 6; higher value indicating greater injury).10 Severe head injury was defined as a Head AIS of >3, similar to a previous investigation.11 Injury severity scores were derived from ICD-9-CM codes similar to the Agency for Healthcare Research and Quality, which has been validated as an accurate predictor of survival.6,12 The ICDPIC package in STATA 13 was used to derive Injury
Severity Scores (body regions and total). Patients were categorized based on whether they received oral methocarbamol during hospital admission or not. Data regarding methocarbamol obtained were dose per day and number of days of treatment. The secondary outcome was pulmonary complications. This was defined as occurrence of any one of the following: bacterial pneumonia (481, 482 [482.0e482.9], 483 [483.0, 483.1, 483.8]), ventilator associated pneumonia (997.31), atelectasis (518.0), or aspiration pneumonia (measured as a complication in the database thus ICD-9-CM code was not needed). 2.4. Outcomes and data analysis The primary outcome of interest was time to hospital discharge in days (i.e. length of hospital stay). This variable was right censored if patients were transferred to another hospital or died during hospitalization. Kaplan Meier curves were compared between the methocarbamol and no methocarbamol groups using the log-rank test. A Cox Proportional Hazards Model was constructed to determine if methocarbamol use was associated with a greater likelihood of discharge after adjusting for pertinent confounders. The intent was not to develop a parsimonious or a predictive model, but rather to adjust for potential confounding. The following confounders were considered to be pertinent based on our clinical experience and were added to the model: age, sex, race/ethnicity, need for endotracheal intubation, need for blood component transfusion, need for chest tube, Charlson Comorbidity Index, Injury Severity Score, and Abbreviated Injury Severity for the chest region, and severe head injury (injury severity variables were ICD9 derived). We tested for interactions between injury severity and methocarbamol because it is possible that the effect of methocarbamol may be more effective with higher severity of injury. To minimize the potential for selection bias, a propensity score analysis was conducted by calculating propensity scores using all available covariates. The effect of methocarbamol on the primary outcome was then evaluated after adjusting for this propensity score. The proportional hazards assumption was tested using the time-dependent covariate method. The goodness-of-fit of the model was assessed by Cox-Snell residuals. Influential observations were identified visually by likelihood displacement values. A sensitivity analysis was conducted by excluding influential observations to determine if it changed the results. Categorical variables, including our secondary outcomes were compared between the methocarbamol and no methocarbamol group using the Fisher's exact test. Normally distributed continuous variables were compared between the two groups using an unpaired student's t-test. Non-normally distributed continuous variables were compared using the Wilcoxon rank-sum test. If there were missing values in <5% of a variable than is was replaced with the most common value for categorical variables. There were no missing data in continuous variables and the only variable with some missing data was race. This was in <5% of the sample. It was estimated that using a hazard ratio of 1.5 (increased likelihood of discharge home in the methocarbamol group), standard deviation of 0.5, probability of failure of 80%, alpha of 0.05, and power of 80%, a total of 239 patients would be required in the study (approximately 120 in each group). All analyses were conducted using STATA 13 (College Station, Texas) and a two-tailed alpha of 0.05 was considered to be statistically significant. 3. Results 3.1. Study cohort There were 613 patients overall who had closed rib fractures
Please cite this article in press as: Patanwala AE, et al., Methocarbamol use is associated with decreased hospital length of stay in trauma patients with closed rib fractures, The American Journal of Surgery (2017), http://dx.doi.org/10.1016/j.amjsurg.2017.01.003
A.E. Patanwala et al. / The American Journal of Surgery xxx (2017) 1e5
during the study time frame. Of these, 21 were less than 18 years and were excluded. Thus 592 patients were retained in the final study cohort. There were no other exclusions. In the sample, 329 received methocarbamol and 263 did not receive methocarbamol. In the overall sample, the mean age was 55.6 ± 18.5 years, and 67.7% were male. The majority of patients were White Non-Hispanic (62.5%), followed by Non-White Hispanic (30.1%), and Non-White Non-Hispanic (7.4%). The mean injury severity score was 16.6 ± 8.9, and the median Chest Abbreviated Injury Scale was 3 (IQR 2 to 3), severe traumatic brain injury occurred in 52 (8.8%), endotracheal intubation was needed in 71(12.0%), chest tube was needed in 88 (14.9%), and blood component transfusion was needed in 87 (14.7%). The Charlson comorbidity index was as follows: no comorbid conditions (60.6%), one condition (21.6%), or two or more conditions (17.7%). The median time to discharge home was 8 days (95% CI 7e9 days). The median dose of methocarbamol used (rounded to 500 mg tablet) was 1500 mg/day (500 mg every 8 h) for a median duration of 4 days (IQR 3e7 days).
3.2. Main results The methocarbamol and no methocarbamol groups were comparable with respect to demographics and overall Injury Severity Score (Table 1). However, there was imbalance in the injury scores for the chest region, severe head injury, endotracheal intubation, chest tube, blood transfusion, and comorbidities between groups (Table 1). The median time to discharge was 5 days (95% CI 4e5 days) in the methocarbamol group and 8 days (95% CI 6e9 days) in the no methocarbamol group. Fig. 1 shows the Kaplan Meier curves for time to discharge home in the two groups. The methocarbamol group was significantly more likely to be discharged home sooner (p < 0.001). In the Cox Proportional Hazards Model methocarbamol use was associated with a greater likelihood of being discharged
Table 1 Baseline comparisons between groups. Variable Demographics Age in years (mean, SD) Sex, Male (n, %) Race/Ethnicity (n, %) White, Non-Hispanic Non-White, Hispanic Non-White, Non-Hispanic Clinical data Endotracheal intubation (n, %) Chest Tube (n, %) Blood component transfusion (n, %) Charlson comorbidity index (n, %) 0 1 2 or more Injury severity score (median, IQR)a Severe head injury (n, %)a Chest abbreviated injury scale (n, %)a 0 1 2 3 4 5 a
Derived from ICD9 codes.
Methocarbamol (n ¼ 329)
No Methocarbamol (n ¼ 263)
P-value
54.1 (17.9) 226 (68.7)
57.5 (19.1) 175 (66.5)
0.029 0.596 0.774
210 (63.8) 95 (28.9) 24 (7.3)
160 (60.8) 83 (31.6) 20 (7.6)
22 (6.7)
49 (18.6)
<0.001
60 (18.2) 33 (10.0)
28 (10.7) 54 (20.5)
0.011 <0.001 <0.001
224 (68.1) 72 (21.9) 33 (10.0) 16 (11e22)
135 (51.3) 56 (21.3) 72 (27.4) 16 (9e22)
20 (6.1)
32 (12.2)
0 (0) 21 (6.4) 60 (18.2) 196 (59.6) 50 (15.2) 2 (0.6)
0 (0) 57 (21.7) 72 (27.4) 108 (41.1) 24 (9.1) 2 (0.8)
0.221 0.012 <0.001
3
Fig. 1. Kaplan Meier curves of time to hospital discharge.
home (HR 1.47, 95% CI 1.21 to 1.78, p < 0.001). No significant interactions were identified in the model. Other variables in the model significantly associated with the outcome of interest were Injury Severity Score and Charlson Comorbidity Index (Table 2). A plot of Cox-Snell residuals showed that the model fit the data well. The proportional hazards assumption was met using the timedependent covariate method (p ¼ 0.739). We identified two observations that were potentially influential. After excluding these observations in a sensitivity analysis, it did not change the results. A sensitivity analysis was also conducted by conducting a propensity score analysis. In the propensity score analysis, methocarbamol remained significantly associated with time to hospital discharge (HR 1.36, 95% CI 1.12 to 1.64, p ¼ 0.001). We also evaluated the subset of patients who had isolated rib fractures (n ¼ 89). In this subset, the median time to discharge was 4 days (95% CI 3e5 days) in the methocarbamol group and 5 days (95% CI 4e9 days) in the no methocarbamol group (p ¼ 0.012). Pulmonary complications occurred in 98 (16.6%) patients in the cohort. Patients who received methocarbamol were less likely to develop these complications (11.3% (n ¼ 37) versus 23.2% (n ¼ 61); p < 0.001). Pulmonary complications consisted of bacterial pneumonia (7.0% (n ¼ 23) versus 14.5% (n ¼ 38); p ¼ 0.004), aspiration pneumonia (0.6% (n ¼ 2) versus 3.8% (n ¼ 10); p ¼ 0.007), ventilator associated pneumonia (0.3% (n ¼ 1) versus 1.9% (n ¼ 5); p ¼ 0.093), and atelectasis (4.9% (n ¼ 16) versus 9.1% (n ¼ 24); p ¼ 0.048). Thus each complication occurred to a lesser extent in the methocarbamol group. 4. Discussion The key finding in this study was that methocarbamol use was associated with a shorter time to hospital discharge, which supports our hypothesis. The results remained true after adjusting for important covariates. The likelihood of discharge was approximately 1.5 times higher with methocarbamol. We are aware of only one previous investigation in trauma patients that has investigated the use of methocarbamol.5 This was a retrospective study that included trauma patients with a wide variety of injuries. This previous study did not show a benefit in terms of pain control during the first three days of methocarbamol use. However, there were few patients with rib fractures in this previous study. Our current investigation shows that there may be a benefit to using methocarbamol in some subsets of patients who are at higher risk for muscle spasm related pain. Patients in the methocarbamol group were also less likely to
Please cite this article in press as: Patanwala AE, et al., Methocarbamol use is associated with decreased hospital length of stay in trauma patients with closed rib fractures, The American Journal of Surgery (2017), http://dx.doi.org/10.1016/j.amjsurg.2017.01.003
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A.E. Patanwala et al. / The American Journal of Surgery xxx (2017) 1e5
Table 2 Cox proportional hazards model. Variable
Hazard ratio
95% CI
P-value
Methocarbamol Age (years) Sex (male) Race/Ethnicity White, Non-Hispanic Non-White, Hispanic Non-White, Non-Hispanic Endotracheal intubation Chest tube Blood component transfusion Charlson comorbidity index Total injury severity scorea Severe head injurya Chest abbreviated injury scalea
1.47 1.00 1.11
1.21 to 1.78 0.99 to 1.00 0.92 to 1.34
<0.001 0.511 0.265
[Reference] 0.90 0.74 0.49 0.89 0.71 0.78 0.95 1.30 1.14
0.74 0.52 0.34 0.69 0.53 0.68 0.93 0.88 0.99
0.305 0.090 <0.001 0.404 0.022 <0.001 <0.001 0.194 0.071
a
to to to to to to to to to
1.10 1.05 0.69 1.16 0.95 0.88 0.96 1.92 1.32
Derived from ICD9 codes.
develop pulmonary complications during hospitalization. Previous national estimates have shown that complications such as pneumonia can occur in up to 6% of patients with rib fractures.13 Our complication rate related to pneumonia was similar. In addition, a considerable number of complications in our study were due to atelectasis. Rib fracture injuries result in shallow breathing, which can lead to progressive atelectasis. Also, patients may have an impaired cough because of pain during breathing. This resulting decrease in vital capacity and reduced ability to clear secretions increases the risk for pneumonia. It is possible that methocarbamol helped patients have a better pulmonary toilet, which lead to improved recovery, decreased complications and reduced time to hospital discharge. After rib fractures, patients often have long-term morbidity due to pain, which may be because of the transition from acute to chronic pain.14 In one study, patients had a decreased quality of life and only 30% returned to work over 24 months post injury.14 Thus early optimal management is imperative to blunt the development of neuroplasticity and chronic pain syndromes. However, we are not aware of any national guidelines regarding pain management after rib fractures. Given the severity of pain experienced by these patients, pain management in this setting typically involves the use of systemic opioids, regional anesthetic techniques, or non-opioid analgesics (e.g. acetaminophen, non-steroidal anti-inflammatory agents).15 The evidence-base overall is weak and thus pain management is extrapolated from the general management of pain in hospitalized patients. Although not specific to rib fractures, guidelines by the American Pain Society recommend a multimodal approach.2 This involves using analgesics with different mechanisms of action, which may be synergistic and reduce adverse effects and opioids consumption. Muscle relaxants such as methocarbamol are a part of this multimodal analgesic armamentarium. The mechanism of methocarbamol has not been fully elucidated, but it related to a central nervous system depressant effect that results in muscular relaxation.16 The extent to which muscle spasm around the fractured bone contributes to pain is unknown. Anecdotally, we know that this is occurs with rib fractures, which lead to the use of methocarbamol at our institution. There was an imbalance between groups with regard to a few important confounders. Patients who received methocarbamol appeared to have higher severity injuries in the chest region and were more likely to receive a chest tube. Conversely, the comparator group was more likely to have severe head injuries, require endotracheal intubation, and blood transfusions. It is uncertain how this affected the outcomes overall because some of these characteristics favor the methocarbamol group and others favor the control group. Overall injury severity scores were similar between
groups. We adjusted for all of these variables in the regression analysis and the results held true. To confirm that the results were robust, we also performed sensitivity analysis by calculating propensity scores. This did attenuate the results slightly, but the differences remained significant and it did not change our conclusions. Ideally, we would just include patients with isolated rib fractures, which would give us a homogenous group. We did look at this subset in the population, which also showed a decreased time to discharge with methocarbamol. But this subset is underpowered to adjust for potential confounders. Even within a sample of isolated rib fractures, the severity of chest injury would vary and thus it would be very difficult to perform such a study in a real world setting and obtain and absolutely homogenous population. The study has some important limitations. This was a retrospective evaluation of an administrative database; thus we were restricted to the data available in the database, accuracy of ICD-9CM coding, and physician documentation. There are clinical measures, which were not available such as pain scores that would have been beneficial to compare between the groups. It was also not possible to quantify use of opioids and other adjunctive medications due to the manner by which these were coded in the database. Thus we have to make the assumption that these were used to an equivalent extent in both groups to enable comparisons. Conversely, the use of methocarbamol could have reduced opioid consumption, which would have been an important finding. For this study, our focus was on meaningful outcomes such as length of stay and complications. At our institution a reduction in length of stay and complications has been the main impetus that has contributed to the use of methocarbamol. Our hypothesis was based on clinician reports of the effect of this therapy on the outcomes measured in this study. Thus these results are meaningful even without the clinical variables that we were not able to obtain. There is the possibility that we did not include confounders that may have influenced our results. However, we did take into account some of the important variables such as injury severity comorbidity, need for endotracheal intubation, transfusion, severe head injury and chest tube placement. Survival analysis requires an assumption of independent censoring, which we considered to be reasonable for this analysis. 5. Conclusions The use of methocarbamol after traumatic rib fractures may improve recovery and result in a reduction in the length of hospital stay. Patients given methocarbamol may also have fewer pulmonary complications such as atelectasis and pneumonia. These results are hypothesis generating and a prospective randomized controlled trial is needed to confirm these findings. Conflicts of interest and source of funding None. References 1. Fabricant L, Ham B, Mullins R, Mayberry J. Prolonged pain and disability are common after rib fractures. Am J Surg. 2013;205:515e516, 511-515; discusssion. 2. American Pain Society (APS). Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. sixth ed. 2008. Glenview, IL 60025. 3. Haegerstam GA. Pathophysiology of bone pain: a review. Acta Orthop Scand. 2001;72:308e317. 4. Easter A. Management of patients with multiple rib fractures. Am J Crit Care. 2001;10:328e329, 320-327; quiz. 5. Aljuhani O, Kopp BJ, Patanwala AE. Effect of methocarbamol on acute pain after traumatic injury. Am J Ther. 2015. http://dx.doi.org/10.1097/MJT.00000000000
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A.E. Patanwala et al. / The American Journal of Surgery xxx (2017) 1e5 00364. 6. Hidalgo DA, Pusic AL. The role of methocarbamol and intercostal nerve blocks for pain management in breast augmentation. Aesthet Surg J. 2005;25: 571e575. 7. Looke TD, Kluth CT. Effect of preoperative intravenous methocarbamol and intravenous acetaminophen on opioid use after primary total hip and knee replacement. Orthopedics. 2013;36:25e32. 8. Sutton JM, Hayes AJ, Wilson GC, et al. Validation of the University HealthSystem Consortium administrative dataset: concordance and discordance with patient-level institutional data. J Surg Res. 2014;190:484e490. 9. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373e383. 10. Baker SP, O'Neill B, Haddon Jr W, Long WB. The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care.
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Please cite this article in press as: Patanwala AE, et al., Methocarbamol use is associated with decreased hospital length of stay in trauma patients with closed rib fractures, The American Journal of Surgery (2017), http://dx.doi.org/10.1016/j.amjsurg.2017.01.003