UNIVERSITY of CALIFORNIA, IRVINE Intravenous

UNIVERSITY OF CALIFORNIA, IRVINE

Intravenous Acetaminophen: A Non-Narcotic Adjunct for Burn Wound Care

THESIS

submitted in partial satisfaction of the requirements for the degree of

MASTER OF SCIENCE

In Biomedical and Translational Science

Sarah Dobson

Thesis Committee: Professor Sherrie H. Kaplan, Chair Assistant Clinical Professor Nicole P. Bernal Associate Clinical Professor Steven Mills

2014

Page

LIST OF FIGURES………………………………………………………...………………….v

LIST OF TABLES…………………………………………………………..…….……………vi

ACKNOWLEDGEMENTS…………………………………………………………………….vii

ABSTRACT OF THE THESIS…………………………………………...…………...... viii

CHAPTER 1: INTRODUCTION………………………………………………..…………….1

CHAPTER 2: BACKGROUND………………………………………………………...……..3

Burn Wound Care……………………………………………………………...... 3

Background versus Breakthrough Pain……………………………………...... 3

Narcotic Pain Medications…...…………………………………………..…………..4

Intravenous Acetaminophen…………………………………………...…………….5

First-pass Metabolism………………………………………………..……………....8

CHAPTER 3: METHODS……………………………………………………………….……9

Setting…………………………………………………………………..………...……9

Sample…………………………………………………………………………………9

Exclusion Criteria…………………………………………………………………….11

Study Design……………………………………………………………………....…13

Pain Measures…………………………………………………………………….…14

Outcome Measures………………………………………………………………….15

Organizing the Data……………………………………………...………………….16

Analyzing the Data………………………………………………...…………..…….17

Power Analysis…………………………………………………………………….…18

iii CHAPTER 4: RESULTS……………………………………………………….……………19

Demographics…………….……………………………………………..……...……19

Primary Outcome…………………………………………………………..………...21

Secondary Outcome………………………………………..……………………….22

Subgroup Analyses………………………………………………………………....23

CHAPTER 5: DISCUSSION………………………………………………….…………….26

Limitations……………………………………………………..……………….…….29

Proposal……………………………………...…………………………..…….…….30

REFERENCES………………………………………………………………………....……33

APPENDIX……………………………………………………………………………..…….35

iv LIST OF FIGURES

Page

Figure 1: Acetaminophen plasma concentration over time 7

Figure 2: Exclusion criteria flow chart 12

v LIST OF TABLES

Page

Table 1: Characteristics of intravenous versus oral acetaminophen 7

Table 2: Patient Demographics 19

Table 3A: Types of Injuries 20

Table 3B: Location of Injuries 20

Table 4: Amount of narcotics on total days with administration of IV 21 acetaminophen versus days without administration of IV acetaminophen

Table 5: Liver Function Test scores of Alkaline Phosphatase, Aspartate 22

Aminotransferase and Alanine Aminotransferase

Table 6: Amount of narcotics for days with IV acetaminophen versus 23 without IV acetaminophen for patients with <15% Total Body Surface

Area and >15% Total Body Surface Area

Table 7: Amount of narcotics for days with IV acetaminophen versus 24 days without IV acetaminophen for patients with a hospital Length of stay of <7 days and >7 days

Table 8: Amount of narcotics for days with IV acetaminophen versus 25 days without IV acetaminophen for patients with flame/flash burns and with non-flame/flash burns

vi ACKNOWLEDGEMENTS

I would like to express my appreciation to my committee chair, Dr. Sherrie H. Kaplan, for not only her knowledge in various subjects, but for her guidance throughout this program and project. I want to also thank her for all of her hard work and dedication in making this Master’s program as prestigious and well-rounded as it is now. I was honored to have her serve as the chair of my committee and for her endless advice and encouragement. She has helped me in learning how to endure constructive criticism as well as which steps to take to be successful in this program and in my future endeavors.

I also want to thank my committee member and mentor, Dr. Nicole Bernal, for her support throughout my research career and throughout this program. I would like to thank her for her continuous mentorship and guidance. I am a better student and researcher because of what she taught and showed me.

I would like to thank Dr. Steven Mills for his advice and informative recommendations. His support was crucial in helping to develop the guidelines for this project to critiquing the final draft. His advice on the specifics of analysis helped to better the project and provide more comprehensive and reliable data.

I’d like to thank my professor, Dr. John Billimek for his endless statistics advice. He was a wonderfully inspiring teacher who went above and beyond in the effort to make sure I had a firm grasp of the methodologies for capturing, organizing and evaluating the data sets used in this study.

vii ABSTRACT OF THE THESIS

Intravenous Acetaminophen: A Non-Narcotic Adjunct for Burn Wound Care

Sarah Dobson

Master of Science in Biomedical and Translational Science

University of California, Irvine, 2014

Professor Sherri H. Kaplan, Chair

Burn injury is the cause of one of the most severe types of pain. Many studies have shown that burn pain management is inadequate in most burn centers. Multiple studies have shown that intravenous acetaminophen decreases the overall amount of narcotics administered as well as longer time until drug rescue. Intravenous acetaminophen can be incorporated into the multi-modal approach in order to reduce the amount of narcotic pain medications administered so that pain can be controlled more safely and effectively.

This retrospective study analyzed demographic characteristics, amount of narcotics administered on days with and without administration of intravenous acetaminophen prior to burn wound care and effects of multiple doses of intravenous acetaminophen in hepatic function. Forty one patients admitted to the University of

California, Irvine Burn Center between August 2011 and August 2013 were included in the sample.

Comparing the average amount of narcotics administered on days with administration of IV acetaminophen showed no statistically significant difference when

viii compared with amount of narcotics on days with no administration of IV acetaminophen.

After performing subgroup analyses, there were reductions found in amount of narcotics on days when IV acetaminophen was administered. However, these reductions were not statistically significant. There was no deterioration in hepatic function after one or more doses of 1,000mg of intravenous acetaminophen throughout all of the 41 patient’s hospital stays.

The results demonstrated the effectiveness of intravenous acetaminophen in certain groups. On the other hand, there were also groups in which intravenous acetaminophen was clearly ineffective. Furthermore, it has been shown that IV acetaminophen does not cause any potential health risks to the liver. The results of this study, in particular the subgroup analyses, may warrant further evaluation in a prospective, controlled setting. A prospective study would be used to determine whether the use of IV acetaminophen as an adjunct to use of increased dosages of narcotics during burn wound care will provide more effective and consistent pain relief to a larger segment of patients in a burn unit.

ix CHAPTER 1: INTRODUCTION

Burn injury is the cause of one of the most severe types of pain as well as physical and psychological distress (Abdi, Zhou, 2002). Many recent studies have shown that burn pain management is inadequate in most burn centers. (Latarget, 2002).

The two main reasons for poor burn pain control are: 1) the intensity of pain associated with burn wound care varies greatly throughout the hospital stay, which makes pain medication requirements difficult to approximate for the same patient, and 2) there is a lack of knowledge and education by the staff, patients and families concerning the distinctive characteristics of pain experienced by burn patients (Gregoretti, et al., 2008).

If the pain caused from a burn injury is not adequately controlled, there is a greater chance of psychological problems. (Gregoretti, et al., 2008). These problems can occur because of the subsequent anxiety due to their pain, which may lead to the lengthening of the stress response after a burn injury, prolonging the healing of wounds and extending the recovery time. (Byers, et al., 2001, Guyton, 1997, Monafo, 1995). It has been shown that anxiety is not only a factor of pain, but anticipatory anxiety increases pain during dressing changes. (Ashburn, 1995). In order to prevent the development of any psychological problems, a multi-modal approach is necessary in the treatment of burn pain. A multi-modal approach is defined as administering a combination of drugs, each having various pharmacological properties, which may allow for a reduction in the total dosage of single drugs, potentially avoiding adverse events.

(Gregoretti et al., 2008). The multi-modal approach focuses on treating the different aspects of pain, which includes direct pain, neurogenic pain and anxiety. Unfortunately, all of these medications can affect cognition and respiratory status. Treating pain

1 through the use of medications that may have a negative effect on respiration or alter mental status led to the exploration of use of intravenous acetaminophen.

The aim of this study was to identify if: 1) intravenous acetaminophen administered as a pre-medication for wound care reduced the overall amount of intravenous narcotic pain medications administered during wound care, and 2) after one or more doses of 1,000 mg per day of intravenous acetaminophen, it would not result in an adverse effect on liver function.

Along with utilizing the multi-modal approach, pain needs to be evaluated frequently in order to control pain effectively during burn wound care. To assess pain effectively, a variety pain scales have been used (Gregoretti, et al., 2008). The core objective of this study is to identify if intravenous acetaminophen is safe and effective in managing pain in burn patients.

2 CHAPTER 2: BACKGROUND

Burn Wound Care

In the burn survivor patient, the most common non-surgical procedures that occur outside of the operating room are dressing changes; these take place either at bedside or in the hydrotherapy room. The hydrotherapy room contains large whirlpool bathtubs where the patient’s dressings are replaced so they can soak and mechanically debride their burn injuries. (Gregoretti, et al., 2008, MacLennan, et al., 1998). Burn dressings are changed daily during the entire hospital stay, except on days when the patient is in surgery and in the immediate post-surgical period. The initial component of burn wound care is to remove the bandages covering the burn injuries. Then the wounds are cleaned thoroughly. The goal of burn wound care is to remove dead tissue to promote wound healing and prevent any infection. (Kowalske, 2011). Successfully treating and managing pain associated with wound care is a major component of proper and effective burn wound care.

Background Pain versus Breakthrough Pain

Pain experienced by burn patients can be classified as having two general categories: background pain and breakthrough pain. Background pain is defined as the underlying pain that is continuous and present even in the absence of procedures

(Faucher, Furukawa, 2006). This type of pain can be treated with intravenous opioids through continuous infusion or with less powerful but longer acting oral opioids

(Gregoretti et al., 2008).

3 Breakthrough pain is an exacerbation of pain that occurs frequently in burn patients particularly during burn wound care. (Portenoy, Hagen, 1990). Breakthrough pain tends to be acute and short lasting but of great intensity (Abdi, Zhou, 2002). When breakthrough pain occurs, if untreated or uncontrolled, it can result in significant functional and psychological issues that can slow down the healing process and ultimately lengthen the patient’s hospital stay. (Gregoretti, et al., 2008, Byers, et al.,

2001).

Narcotic Pain Medications

Opioids or narcotic pain medications are still the most common agents used to manage burn pain. Opioids are defined as medications that relieve pain by reducing the intensity of pain signals reaching the brain, which eventually reduces the effects of a painful stimulus. (National Institute on Drug Abuse, 2011). They act by attaching to specific proteins known as µ-opioid receptors; these µ-binding sites are discretely distributed in the human brain, with high densities in the posterior amygdala, hypothalamus and thalamus, as well as the terminal axons of primary afferent neurons of the spinal cord (MS-Contin Drug Information: Clinical Pharmacology). When the opioids attach to their receptors, they reduce the perception of pain. (National Institute on Drug Abuse, 2011). Opioids are highly effective in breakthrough pain management because of the rapid onset, high potency and short duration of these agents. These fast-acting medications can provide adequate pain relief during dressing changes, but administration is often limited due to side effects. Despite opioids ability to manage pain, they also cause a variety of adverse reactions such as drowsiness, nausea,

4 constipation, ileus and even respiratory distress. (National Institute on Drug Abuse,

2011). Ileus is defined as the disruption of the normal mobility and activity of the gastrointestinal tract. Respiratory depression is caused when large doses of opioids or narcotics are given and the drug acts directly on the brainstem respiratory center, causing hypoventilation. (Cone, et al., 2013). However, the exact dose which results in respiratory depression can vary greatly from person to person depending on age, weight, liver and renal function; this makes safe and effective usage difficult to standardize. Due to the side effects caused by these narcotic pain analgesics, non- narcotic analgesics such as intravenous acetaminophen are being studied in order to determine whether there is a reduction in side effects that can occur during pain management.

Intravenous Acetaminophen

Intravenous acetaminophen is a non-narcotic pain medication, which was approved for use by the FDA in November 2010. (OFIRMEV injection prescribing information, 2010). Many studies have demonstrated that one gram of intravenous acetaminophen is a safe and effective non-narcotic analgesic for treatment of postoperative pain. (Sinatra, et al., 2005). A prospective, randomized control trial was conducted and was found that IV acetaminophen provided a statistically significant amount of pain relief when compared with placebo. Additionally, the total dosage of morphine decreased by 33% when IV acetaminophen was administered, as compared with placebo (Sinatra, et al., 2005). Furthermore, in a literature review conducted by

Macario in 2010, ten out of the fourteen placebo-controlled studies found either a

5 significant reduction in average opioid consumption or a lower percentage of patients needing additional opioids after receiving IV acetaminophen. Intravenous acetaminophen can be incorporated into the multi-modal approach to improve pain management. More specifically, it can be used in burn patients as a pre-medication given prior to wound care to manage moderate to severe pain with adjunctive opioid analgesics. An advantage of IV acetaminophen is it does not produce sedation nor does it cause other negative side-effects like altered sensorium, nausea, constipation or respiratory depression (Viscusi, et al., 2012). Since the true benefit of IV acetaminophen is not yet known, there is currently no specific protocol for its use in burn centers.

Although the exact site and mechanism of analgesic action of IV acetaminophen is not clearly defined, it appears to produce analgesia by elevation of the pain threshold.

The potential mechanism may involve inhibition of the nitric oxide pathway mediated by a variety of neurotransmitter receptors including N-methyl-D-aspartate and substance P site. Acetaminophen produces a central analgesic effect due to the activation of descending serotonergic pathways. (Graham, Scott, 2005). The peak concentration, half-life and maximum plasma concentration for both intravenous and oral acetaminophen has been described in Table 1 (Viscusi, et al., 2012). The infusion of intravenous acetaminophen results in a rapid increase in plasma concentrations and significantly greater peak levels than oral acetaminophen.

Table 1. Characteristics of intravenous versus oral acetaminophen (Viscusi, et al., 2012) Parameter OFIRMEV Oral acetaminophen (1g) (1g) Cmax 28.4 mcg/mL 15.1 mcg/mL Tmax 0.28 h 0.72 h T1/2 2.39 h 2.66 h Hepatic first-pass exposure NO YES

As demonstrated in Figure 1, intravenous acetaminophen has an analgesic effect, which occurs within five to fifteen minutes of administration, causing a reduction in pain. The effect peaks within one hour and remains effective in the bloodstream for roughly four to six hours. (Viscusi, et al., 2012).

Figure 1. Plasma concentration over time for acetaminophen (Viscusi, et al., 2012)

7 First-Pass Metabolism

Acetaminophen is metabolized by the liver via three primary pathways; oxidation is the one pathway in which acetaminophen is metabolized into the hepatotoxic compound. (Manyike, et al., 2000). Hepatotoxicity is known as chemical-driven liver damage and is relevant when considering that the absorption of oral drugs may result in locally high drug levels in the circulation of the liver; this is known as the “first-pass” effect. (Jahr, Lee, 2010). Because hepatotoxicity associated with the use of oral acetaminophen has been well documented, use of acetaminophen, particularly in high doses, is always of concern. However, intravenous infusion of acetaminophen results in rapid elevations of plasma levels while completely avoiding the “first-pass” effect. A previous study showed that administering acetaminophen intravenously has reduced initial hepatic exposure by approximately 2-fold when compared with the oral route.

(Viscusi, et al., 2012). Furthermore, intravenous acetaminophen has a median time to reach maximum plasma concentration (Tmax) of fifteen minutes, whereas the Tmax for oral acetaminophen administration is 45 to 75 minutes. Lastly, the long-term administration of oral acetaminophen has been proven to cause hepatotoxicity (Viscusi, et al, 2012).

8 CHAPTER 3: METHODS

Setting

The study takes place in the Regional Burn Center at the University of California,

Irvine Medical Center (UCIMC). As of August 2011, the Pharmacy and Therapeutics committee at UCIMC approved intravenous acetaminophen to be used for burn wound care for patients cared for in the burn unit. Intravenous acetaminophen use has not been studied in this setting, specifically for patients admitted with severe burn and skin wounds.

Sample

The Regional Burn Center at UCI treats more than 350 inpatients each year. A convenience sample was used and we included patients admitted to the burn unit between August 2011 and August 2013 who received at least one dose of intravenous acetaminophen during their hospital stay. A heterogeneous group of patients, ranging in age from newborn to the elderly, are treated in the burn unit. Their degree of injury is variable, including partial thickness burns of greater than 5% (TBSA). These burns are generally observed as third degree burns or burns that affected smaller, more focused areas of the body, such as the face, hands, genitalia and/or major joints. Burn injuries can be from various causes such as scald, flame, electrical and chemical burns.

Furthermore, patients who are admitted to the emergency room due to a trauma and acquire injuries such as “road rash” or friction burns are also commonly admitted to the burn unit. Due to skin injury, patients suffering from some non-burn skin diseases are also treated in the burn unit; the most prevalent being: 1) Steven’s Johnson syndrome,

9 which is a rare, life-threatening disorder of the skin and mucous membranes, and 2) necrotizing fasciitis, (sometimes referred to as flesh-eating bacteria), which is a rare but serious infection caused by bacteria that can destroy skin, fat and the tissue covering muscles.

The sample evaluated in this study included a variety of patients with an assortment of burn injuries. The patients in the sample ranged from age 19 to 69 and the majority were male. The Length of Stay (LOS) in the unit varied anywhere from four days to seventy-five days. There were patients with scald, contact, flame/flash and traumatic burns. Additionally, there were patients with three different types of skin diseases: Stevens-Johnson syndrome, necrotizing fasciitis and bullous pemphigoid (an autoimmune disorder that primarily attacks cells in the skin and mouth, causing large blisters). The burns involved the head and neck, posterior and anterior trunk, arms, legs, hands and feet. Lastly, the percent Total Body Surface Area (TBSA) ranged from

0.5% to 51%.

10 Exclusion Criteria

Some of the patients treated in the burn unit between August 2011 and August

2013 were excluded from our evaluation. Our exclusion criteria included patients less than fourteen years of age, those never receiving IV acetaminophen, those with pre- existing hepatic dysfunction, and those requiring sedation during wound care. Patients younger than fourteen years of age were excluded because the standard practice in the burn unit is for children to undergo deep sedation for burn wound care. There is no need for intravenous acetaminophen since the medications used put the patient in a trance-like state. We decided to exclude those admitted with pre-existing hepatic dysfunction because our secondary outcome was to determine whether there was any deterioration of liver function after multiple days of administration of intravenous acetaminophen.

Sixty-two patient records were reviewed (Figure 2). Sixteen patients were found to have had orders for IV acetaminophen but never received it during wound care. After exclusion of these sixteen patients, 46 remained in the sample. Of the 46 patients remaining, five more were excluded for various reasons. These reasons included:

• Younger than 14 years of age

• Admitted with abnormal hepatic function

• Patient required sedation during wound care

62 Patients

Received IV Acetamin.*

No Yes

16 46 Patients Patients

Exclusion Criteria: < 18 y/o; abnormal hepatic function; misc.

Yes No

5 Patients 41 Patients

*Acetamin. = Acetaminophen Figure 2. Exclusion criteria flow chart

12 Study Design

Because there have not been any previous studies performed in this type of setting, we chose to conduct a retrospective chart review. This retrospective study is considered a Phase 1 trial, meaning it was a hypothesis-generating study. The study consisted of gathering preliminary data, which can be used to guide a prospective study or alter patient care practice. We did not conduct a non-equivalent study design because there were no comparisons between two or more groups. It would have been difficult to create a control group for this study since pain varies between patients. More specifically, we were not comparing the effectiveness of more than one medication, only whether intravenous acetaminophen was given and whether it affected the amount of narcotic pain medications administered during burn wound care.

Comparison of the administration of intravenous versus oral acetaminophen was not included because prior studies have shown the adverse impacts of oral acetaminophen (Viscusi, et al, 2012). In addition, many patients cannot take oral acetaminophen because: 1) they are intubated or ventilated and therefore cannot be given any oral medications, and 2) they cannot take oral acetaminophen if they have already received pain medications that contain acetaminophen such as Norco and

Percocet. However, patients are still able to receive intravenous acetaminophen.

13 Pain Measures

During burn wound care, a variety of pain scales are used in order to determine a patient’s severity of pain. Pain severity is generally scored on a scale from zero to ten.

The Numeric Pain Scale is the most commonly used scale: this is for those who are alert and awake enough to communicate with the wound care team. The patients rate their pain on the scale with zero equaling no pain and ten equaling the worst pain of their life. On the other hand, there is a scale for patients who are ventilated, intubated or otherwise unable to communicate; it is known as the Face, Legs, Activity, Cry,

Consolability (FLACC) scale. Based on the patient’s reaction to the dressing changes, the wound care team records a pain score that ranges from zero to ten. In order to assess and treat pain associated with wound care in the burn unit, pain scores are taken immediately before, during and immediately after wound care. Pain scores are categorized into three groups:

• Mild-pain score of 1-3

• Moderate-pain score of 4-6

• Severe-pain score of 7-10

These scores are very subjective, either given by the patient or calculated by a nurse, making them difficult to use for a study primary outcome as the effectiveness of a medication. Because of its subjective nature, one cannot compare the pain scores between patients.

14 Outcome Measures

Primary Outcome

The main objective of this study was to determine whether patients that received intravenous acetaminophen had a reduction in the amount of intravenous narcotic medications administered during wound care. Ultimately, the goal was to determine if intravenous acetaminophen is an effective non-narcotic adjunct for daily burn wound care.

The dichotomous, independent variable was whether intravenous acetaminophen was administered (0=no, 1=yes). The continuous, dependent variable used was the amount of narcotics (in milligrams) administered during burn wound care.

Secondary Outcome

Further determination of whether liver function deteriorates after receiving one or more doses of intravenous acetaminophen during a patient’s hospital stay was evaluated. Patients admitted to the burn unit who are to be prescribed intravenous acetaminophen must present with normal hepatic function.

Subgroup Analysis

Wound care days for all patients were divided up into groups based on characteristics such as burn type, hospital Length of Stay (LOS) and percent Total Body

Surface Area (TBSA). For these groups, the amount of narcotics were compared on days when intravenous acetaminophen was administered versus days when it was not.

15 Organizing the Data

In order to analyze the data correctly, there were multiple steps taken to organize and condense the dataset in excel before transferring the data to the SPSS analysis program. An excel file was created containing each patient’s:

• Study number

• Each day they were in the burn unit

• Whether IV acetaminophen was administered each day

• The amount of narcotics given during wound care each day

There were three main types of intravenous narcotic pain medications administered during wound care: hydromorphone (dilaudid), sublimaze (fentanyl) and morphine.

Dilaudid was the most common intravenous opioid administered during wound care. In order to compare the dosing of the various IV narcotics correctly, it was necessary to equalize them as equivalent amounts of dilaudid. According to McAuley’s medication equivalence chart (2013),

10mg morphine = 1.5mg dilaudid = 100mcg fentanyl.

While dilaudid was the most commonly administered IV pain medication during wound care, some patients received morphine and/or fentanyl. As a result, it was necessary to convert those medications to an equivalent amount of dilaudid.

Another step taken to organize the data was to skip days in which the patient had surgical procedures that precluded wound care. In addition, days were skipped when patients were given propofol or intravenous ketamine, rendering them sedated and unable to communicate pain levels.

16 Analyzing the Data

We used Sigma Plot® 11 to analyze our data. For purposes of this study, the independent variable was whether or not intravenous acetaminophen was administered.

The dependent variable was defined as the amount of narcotics administered; this data was divided into two groups. The first group was classified as the amount of narcotics given during wound care on days when intravenous acetaminophen was administered as a pre-medication to wound care, and the second group was the amount of narcotics given on days when intravenous acetaminophen was not administered prior to wound care.

We determined that both our independent and dependent variables were related so we performed the Paired Samples T-test to analyze the primary outcome as well as the subgroup analyses. In the case of this study, the Paired Samples T-test was used to analyze data for primary outcome and subset analyses. Each patient who had more than one data point for days with IV acetaminophen and days without were analyzed individually in order to determine whether there was a significant increase or decrease in the amount of narcotics administered during wound care. For the primary outcome, we compared the amount of narcotic medications for days when patients received intravenous acetaminophen with days they did not. In order to perform the subgroup analyses, we analyzed the number of days with IV acetaminophen versus days without for each of the following subgroups: Total Body Surface Area less than 15%, TBSA greater than 15%, hospital Length of Stay less than 7 days, hospital LOS greater than 7 days, flame burn and all other types of injuries included in the sample.

17 Initially, pre-wound care pain scores were going to be analyzed in order to identify if there was a decrease in pain scores on days when IV acetaminophen was administered versus days when it was not. However, many of the pre-wound care pain scores were missing for the medical charts. Additionally, we were not able to analyze the data without skewing the results due to the fact that pain cannot be compared between patients.

Power Analysis

A sample size calculation was performed to determine how many wound care days for each group needed to be included to give the study 80% power:

2 x (1.710)2 N = x 7.9 = 185 days

(0.5)2

Standard deviation was found to be 1.710. The mean difference of the amount of narcotics between the two groups was 0.5mg; it was decided by an expert in the burn unit that a difference of 0.5mg between the two groups would constitute a significant reduction. The constant k that is used to get 80% power is 7.9. We determined the sample size to be 185 days per group. Because our sample size was 283 days for the

IV acetaminophen group and 296 days for the no IV acetaminophen group, the study was able to achieve 80% power.

18 CHAPTER 4: RESULTS

Demographics

Demographic characteristics are displayed in Table 2. The ages of the sample ranged from 19 to 69 years old (standard deviation=15.4). Thirty-two out of 41 patients were male, which is an accurate representation of the patients admitted to the burn unit.

The Length of Stay ranged from four to seventy-five days (standard deviation=16.5 days). Lastly, the percent Total Body Surface Area ranged from 0.5% to 50.65%.

Table 2. Patient demographics (n=41)

Characteristic

Mean Age (SD) (Years) 42.268 (15.372)

Gender (%)

Male 32/41 (78.0)

Average Hospital Length of Stay (SD) (Days) 18.317 (16.514)

Average % Total Body Surface Area (SD) 10.166 (10.781)

There were five different types of injuries found in the sample. According to table

3A, the most prevalent type of injury was the flame/flash burn (42.9%). There were no patients in the sample with electrical burns. Three patients (7.1%) endured traumatic wounds; these patients were admitted to the burn unit through the emergency room and included those who were in motor vehicle accidents, some of whom suffered from severe road rash.

19 Table 3A. Types of injuries (n=41) Injury Type Proportion (%)

Scald 9/42 (21.4)

Contact 7/42 (16.7)

Flame/Flash 18/42 (42.9)

Electrical 0/42 (0)

Traumatic Wound 3/42 (7.1)

Skin Disease 5/42 (11.9)

Many patients sustained injuries on multiple locations on their bodies

(Table 3B). The most common injury locations were the arms (25.7%) and the legs

(20.0%).

Table 3B. The location of injury (n=41) Injury Location Proportion (%)

Head/Neck 14/105 (13.4)

Trunk 16/105 (15.2)

Arms 27/105 (25.7)

Hands 16/105 (15.2)

Genitalia 1/105 (1.0)

Legs 21/105 (20.0)

Feet 10/105 (9.5)

20 Primary Outcome

For the primary outcome (Table 4), amount of narcotics administered during wound care on days when intravenous acetaminophen was administered was significantly higher than days when IV acetaminophen was not administered (p=0.002).

Table 4. Amount of narcotics on total days with administration of IV acetaminophen (n=286) versus days without administration of IV acetaminophen (n=296) Mean* (mg) Standard Deviation P-Value

Days with IV 2.114 1.804 Acetaminophen 0.002

Days with no IV 1.635 1.615 Acetaminophen

*Paired Samples T-test was performed to find means, standard deviations, and p-values

Of the 41 individual patients in the sample, nine patients were excluded from individual analysis because they did not have adequate data points for either group. Of the 32 remaining in the sample, six patients showed no change in the amount of narcotics administered during wound care. Ten patients showed an increase in narcotics on days with intravenous acetaminophen when compared with days without IV acetaminophen (See Appendix B). However, there were no patients who showed a statistically significant increase in narcotics.

According to the table shown in Appendix A, 16 patients showed a decrease in narcotics on days when IV acetaminophen was administered. Means and p-values were calculated using the Paired Samples T-test and differences between the two groups were calculated. Although 16 patients showed a reduction in amount of narcotics during wound care on days with IV acetaminophen versus days with no IV

21 acetaminophen, only one patient showed results that were statistically significant. For purposes of clarification and understanding the results reflected in the table as shown in

Appendix A, patient one is being used as an example of how to interpret the results for this particular analysis. For patient one, the mean amount of IV narcotics administered on days with IV acetaminophen was 0.9mg, while the average amount on days with no

IV acetaminophen was found to be 1.588mg. This showed a reduction of 0.688mg of narcotics during wound care on days when intravenous acetaminophen was administered versus days when it was not and the p-value was found to be 0.060.

Secondary Outcome

For the secondary outcome, Liver Function Test (LFT) Scores are shown in

Table 5. The normal values for each of the three tests, Alkaline Phosphatase, Alanine

Aminotransferase (ALT) and Aspartate Aminotransferase (AST). Although the hospital lab may have considered the Liver Function Test scores to be abnormal outside of their given ranges (column 3 of Table 5), what was considered clinically significant requiring action was greater than 300mg/dl.

Table 5. Alkaline Phosphatase, Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) (n=41) Liver Function Tests Normal Clinically Insignificant Abnormal (mg/dl) Mild Increase (mg/dl) (mg/dl) Alkaline 26-110 110-300 >300 Phosphatase 34/41 7/41 0/41 Aspartate 8-40 40-300 >300 Aminotransferase 26/41 15/41 0/41 Alanine 0-60 60-300 >300 Aminotransferase 26/41 15/41 0/41

22 Subgroup Analysis

The number of burn wound care days for patients with TBSA less than and greater than 15% were separated into amount of narcotics (mg) for days with IV acetaminophen versus amount of narcotics for days with no IV acetaminophen (Table

6). For patients who Total Body Surface Area burned was less than 15%, the mean amount of narcotics was 1.921mg versus 1.813mg in the second group (p=0.550). For patients with TBSA greater than 15%, the average amount of narcotics was 2.406mg on days with IV acetaminophen versus 1.477mg on days with no IV acetaminophen

(p=<0.001).

Table 6. Amount of narcotics (mg) for days with IV acetaminophen versus without IV acetaminophen for patients with <15% Total Body Surface Area (n=340) and >15% Total Body Surface Area (n=230) Subgroup Mean* (mg) Standard P-Value Deviation IV Acetaminophen 1.921 1.475 <15% TBSA No IV 0.550 Acetaminophen 1.813 1.741

With IV Acetaminophen 2.406 2.141 >15% TBSA <0.001 Without IV 1.477 1.477 Acetaminophen *Paired Samples T-test was performed to find means, standard deviations, and p-values

When considering short versus long Length of Stay, seven days was used as a number of days to separate the two groups. As shown in Table 7, patients with hospital

Length of Stay less than seven days were administered an average of 1.373mg of IV narcotics on days when IV acetaminophen was administered. Conversely, an average of 1.695mg of narcotics was administered on days when IV acetaminophen was not.

The calculated p-value for this group was 0.550, which is not a statistically significant

23 finding. Patients whose hospital LOS was greater than seven days showed that an average of 2.273mg of narcotics were administered during wound care days with IV acetaminophen as opposed to 1.599mg administered on days without IV acetaminophen (p=<0.001).

Table 7. Amount of narcotics(mg) for days with IV acetaminophen versus days without IV acetaminophen for patients with a hospital Length of Stay of <7 days (n=42) and >7 days (n=499) Subgroup Mean* (mg) Standard P-Value Deviation IV Acetaminophen Length of Stay 1.373 1.106 <7 days No IV 0.550 Acetaminophen 1.695 1.601

IV Acetaminophen Length of Stay 2.273 1.864 >7 days No IV <0.001 Acetaminophen 1.599 1.619

*Paired Samples T-test was performed to find means, standard deviations, and p-values

We then compared patients who sustained a flame/flash burn, the most common type of injury in this study, versus all other injury types found in the study. The average amount of narcotics given to patients with flame/flash burns on wound care days was

2.151mg on days with administration of IV acetaminophen. On the other hand, an average of 2.487mg of narcotics were administered on days without administration of IV acetaminophen (p=0.550). For all injuries other than flame/flash burns, there was a difference of approximately 1.0mg more of narcotics administered on days with administration of IV acetaminophen versus days without (p=<0.001).

24 Table 8. Amount of narcotics(mg) for days with IV acetaminophen versus days without acetaminophen for patients with flame/flash burns (n=155) and with non-flame burns (n=408) Subgroup Mean* (mg) Standard Deviation P-Value IV Acetaminophen Flame/Flash 2.151 1.499 Burn No IV 0.550 Acetaminophen 2.487 1.878

IV Acetaminophen Non-flame/flash 2.210 1.865 Burn No IV <0.001 Acetaminophen 1.238 1.287

*Paired Samples T-test was performed to find means, standard deviations, and p-values

25 CHAPTER 5: DISCUSSION

After analysis of the primary outcome, we found that significantly more intravenous narcotic medications were administered during wound care on days when

IV acetaminophen was given versus days with no administration of IV acetaminophen.

However, this cannot be considered a true daily average dosing for narcotics because it did not take into account the fact that the amount of narcotics ordered per patient and per day could vary dramatically. The range in this study in the doses given was from one to ten milligrams. Since IV acetaminophen did not make a clinically significant difference in the overall average amount of narcotics given per day, we examined the different patient charts and found that indeed there were some patients who had a decrease in the amount of narcotics administered during wound care. This led us to consider that IV acetaminophen may be more effective for certain types of burn injuries.

When comparing patients who demonstrated a decrease in narcotic use with IV acetaminophen versus those who demonstrated an increase, we found there was a trend in the type of burn injury, the Length of Stay and the Total Body Surface Area burned. We then decided to divide patients into subgroups based on the demographic and wound care characteristics and reexamine the average daily doses of narcotics given within each of the subgroups. Placing patients into different subgroups would also help to control the amount of narcotics ordered since patients with similar injuries are more likely to have the same amount of medication ordered.

After dividing patients into two separate groups of less than 15% TBSA and greater than 15% TBSA, the amount of narcotics on days with IV acetaminophen was about 0.1mg higher than on days with no IV acetaminophen; this difference was not

26 statistically or clinically significant. However, when looking at the results for patients who had burns greater than 15% TBSA, there was a significant increase in the amount of narcotics administered when IV acetaminophen was also administered. This would suggest that IV acetaminophen is less likely to relieve pain in patients with larger burn injuries.

When considering Length of Stay, there was a trend for decreased narcotic use with the addition of IV acetaminophen in patients with a shorter Length of Stay. While this was not significant, it does go along with the previous finding that IV acetaminophen is more effective in small burns. A reduction of 0.3mg of narcotics during wound care on days with administration of IV acetaminophen is small but gives us a group to focus on clinically when considering IV acetaminophen and the results may be greater in a prospective type of study. For patients with a hospital LOS greater than seven days, IV acetaminophen was unsuccessful in decreasing the amount of narcotics administered.

When considering the type of injury, we compared flame/flash burns versus all other types of injuries in the sample. This was because flame/flash burns were the most common injury in our sample. We observed a 0.3mg reduction of narcotics in the flame/flash burn group for days when IV acetaminophen was administered. While again this was not statistically or clinically significant, it suggests that different injuries may results in different pain patterns. On the other hand, significantly more narcotics administered during wound care on days when IV acetaminophen was administered for patients who sustained any other type of injury aside from the flame/flash burn would suggest that the effectiveness of different pain medications may be connected to the etiology of the injury, which may stimulate pain receptors differently.

27 The findings for the subgroup analyses are consistent because there were reductions in narcotics for patients with a hospital LOS of less than seven days and patients with flame/flash burns. Patients with a TBSA of less than 15% had no significant difference between days with IV acetaminophen and days without. The sample of patients who received IV acetaminophen and may have benefited had a short

Length of Stay and had smaller burns. Further studies will be necessary to determine the significance of the type of injury on pain patterns. These findings will help guide which parameters to focus on in future studies.

The secondary outcome of the study displays that administration of IV acetaminophen did not negatively affect liver function. Even with one or more days of administration of 1,000 milligrams of IV acetaminophen, patients who did have clinically significant elevations in liver function tests on occasion, there were small increases, but this could be due to many factors that affect hospitalized patients with burns. In this sample of patients, IV acetaminophen seems to have been safely administered in addition to the standard burn patient medications without any cases of transaminitis, which would have stopped the dosing of acetaminophen. Beyond the scope of this study is the possibility of beneficial impact from the use of IV acetaminophen on reduction in narcotic administration.

The constraints of a retrospective study and the variety of ways this study evaluated the available data raised more questions that provided answers. Importantly, it will assist with the development of a prospective study. It demonstrates the importance of determining the direct effects of IV acetaminophen on pain, whether it be through pain scores or the amount of narcotics administered. It also shows the

28 importance of trying to control the amount of pain medication ordered for the patient. In addition, we will subdivide patients exhibiting the kinds of pain characteristics discussed in this study, i.e., Length of Stay less than or greater than 7 days, severity of burns,

Total Body Surface Area less than or greater than 15%, and comparing types of burn to each other. In addition, this study will help in deciding when to include IV acetaminophen as an adjunct to use of narcotics in a multi-modal approach to more effectively management and control pain. The retrospective study shows evidence that patients with less severe burns derived beneficial results from the use of IV acetaminophen. A prospective study would establish protocols for a more consistent and accurate collection of data. A prospective study may lead to development of protocols that would provide similar beneficial outcomes for patients with more severe burn injuries.

Limitations

There are several limitations of this study. Because this was a retrospective study, there was no ability to set up controls for treatment with or without IV acetaminophen. In addition, there was no protocol for identifying which patient should get IV acetaminophen and when IV acetaminophen should be initiated. An additional problem with retrospective chart reviews was the information reported on burn wound care sheets and nurse’s notes may not have been as detailed as if a protocol had been provided and data collected prospectively. Any pain study is challenged with the subjective nature of pain and how pain is perceived by the patient who is asking for

29 medication, and the nurse who is administering it. In addition, the amount of medication given will always be limited by the need for a physician order.

Another limitation was the use of a convenience sample, which was used because there were only a limited number of patients who were admitted to the burn unit who received intravenous acetaminophen. Also, the sample size was small.

However, power was achieved by using days of administration of IV acetaminophen as opposed to comparing patients with each other.

Proposal

In order to develop a protocol for use of intravenous acetaminophen as an adjunct to use of intravenous narcotic pain medications, in particular during burn wound care, and to determine under what circumstances it may provide more effective pain management and control, we will compare intravenous acetaminophen with normal saline solution in a blinded placebo control study. We will determine whether IV acetaminophen is an effective adjunct when incorporated into the multi-modal approach to pain management. We propose to conduct a prospective, double-blinded randomized control trial. Within 30 minutes prior to wound care, the patient will be administered either intravenous acetaminophen or normal saline solution. In order to prevent any bias or distress, both the patient and nurse will be unaware of which will be administered, hence the double-blinded trial. The normal saline solution will be used as the placebo and control for the study. We will compare amounts of narcotic pain medications administered between the two groups. We will be able to determine medication administration patterns, which cannot be determined through a chart review.

30 We will also be able to conduct pain questionnaire before and after treatment to determine the effectiveness of pain control during wound care treatments.

In a prospective study, we may be able to better determine if there is a significant reduction in the use of narcotics during wound care. This study identified subgroups, which may be used to determine cohorts for the prospective study or alternatives for analysis. Secondarily, in a prospective study, we will observe whether there will be a reduction in side effects from a reduction in the amount of opioids administered.

Another important aspect of the prospective study is to integrate learning tools for management of pain in burn patients. If these tools become common practice, and nurses can effectively and accurately assess pain, we may be able to observe a reduction in the amount of narcotics administered during and after wound care. It is the hope that pain management can be tailored to meet the needs of each individual patient by adjusting the dosage and/or combination of medications being administered. It is also of interest to look more closely at the effects of opioids on the overall health and healing of burn patients.

A standard formula for amount of narcotic pain medication has recently been implemented in the burn unit in order to minimize breakthrough pain during wound care.

In addition to the pre-medications dispensed within an hour prior to dressing changes, the formula calls for the administration of one milligram of dilaudid for mild pain (Visual

Analog Scale 1-3), two milligrams for moderate pain (Visual Analog Scale 4-6) and three to four milligrams for severe pain (Visual Analog Scale 7-10).

A prospective study may affirm the potential reduction in narcotic pain medications as well as pain levels after incorporation of intravenous acetaminophen into

31 the multi-modal approach; it may also define the parameters for making adjustments to the mixture and dosage of pain medications being administered to individual patients.

After observing the results of this retrospective study, there is a good indication that IV acetaminophen is effective in reducing amount of narcotics in patients with smaller burns and who have a shorter hospital Length of Stay.

After careful review of this retrospective study and the limitations revealed along the way, limitations identified become an opportunity to see what is possible for a prospective study. If we can achieve the results we initially hypothesized, it could potentially decrease the overall amount of intravenous narcotics being administered during and after wound care, reduce the severity of side effects, while speeding up the healing process in order to get patients home as safely and quickly as possible.

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34 APPENDIX

Appendix A. Individual analysis of patients showing a reduction in amount of narcotics (mg) on days of administration of IV acetaminophen compared to days without (n=16) Patient IV Acetaminophen Mean Difference P-Value (mg) (mg) 1 Yes 0.900 -0.688 0.060 No 1.588 2 Yes 3.333 -1.334 0.345 No 4.667 3 Yes 1.175 -0.075 0.920 No 1.250 4 Yes 2.000 -0.500 0.381 No 2.500 5 Yes 1.536 -0.839 0.488 No 2.375 6 Yes 1.800 -0.414 0.608 No 2.214 7 Yes 2.500 -0.333 0.680 No 2.833 8 Yes 2.900 -1.555 0.204 No 4.455 9 Yes 0.500 -1.333 0.053 No 1.833 10 Yes 3.143 -0.214 0.535 No 3.357 11 Yes 1.000 -0.500 0.711 No 1.500 12 Yes 0.667 -0.833 0.374 No 1.500 13 Yes 0.000 -0.375 0.175 No 0.375 14 Yes 0.375 -0.304 0.370 No 0.679 15 Yes 1.714 -0.064 0.923 No 1.778 16 Yes 0.083 -0.417 0.394 No 0.500 *Paired Samples T-test was performed to find means, standard deviations, and p-value **Differences between the two groups were calculated in excel

35 Appendix B. Individual analysis of patients showing an increase in amount of narcotics (mg) on days of administration of IV acetaminophen compared to days without (n=10) Patient IV Acetaminophen Mean* Difference** P-Value* (mg) (mg) 1 Yes 1.273 +0.508 0.119 No 0.765 2 Yes 2.117 +0.367 0.892 No 1.750 3 Yes 4.667 +1.267 0.377 No 3.400 4 Yes 3.000 +1.357 0.194 No 1.643 5 Yes 2.083 +0.520 0.388 No 1.563 6 Yes 1.796 +0.421 0.335 No 1.375 7 Yes 2.214 +1.464 0.194 No 0.750 8 Yes 3.400 +1.400 0.063 No 2.000 9 Yes 4.000 +1.278 0.272 No 2.722 10 Yes 1.700 +0.300 0.504 No 1.400 *Paired Samples T-test was performed to find means and p-values **Differences between the two groups were calculated in excel