3

cardiovascular and respiratory function and decreasing the potential for adverse drug-related events. An ideal PSA would have a quick onset, be safe in all age groups, equally efficacious through different routes of administration, inexpensive and would accomplish all the goals listed in this paragraph. Unfortunately, at present no single drug exists that has all of the above mentioned features. In ED, PSA for painful procedures is commonly performed using different drug regimens, each having an advantage and a disadvantage at appropriate doses, achieving as many of the desired goals and is currently the standard of care in emergency medicine.

Propofol is a sedative-hypnotic 5agent , neither an opioid nor a

barbiturate, with rapid onset time and short duration of action. It produces

6,7sedation and has anti-nausea effects . 8Bradycardia and depression of

cardiovascular and respiratory 9,10functions are dose dependent

adverse effects. Propofol causes amnesia but does not cause analgesia, which is a potential concern while administering the drug for painful p rocedu re s fo r Emergency Physicians. Ketamine which is a phencyclidine derivative and is

11classified as a dissociative sedative, 12,13provides amnesia and analgesia

when administered. It has little or no effect on respiratory or cardiovascular

5,14function. Ketamine use a single agent for PSA in adults, leads to adverse effects like emergence phenomena and also induces

15-17vomiting or laryngospasm .

Administration of Ketamine & Propofol together, from different syringes, has been successfully used in various

18 19settings, including sedation for gynecologic, opthamologic, 15 12spinal anesthesia, and cardiovascular procedures in children

14and adults. Due to the opposing effects on hemodynamic and respiratory functions of each drug, their combination is favored over others. Friedberg et al confirmed the safety and effectiveness of the combination of Ketamine and Propofol as a PSA for surgical producers in a prospective study of 1,264

20patients. It also has shown to decrease the dose of Propofol 14required to achieve sedative, when Propofol is used in

conjunction with Ketamine. This combination of Ketamine and Propofol also decreases the toxicity of either drug as compared to when they are used alone, because of their complementary effects, which enable the use of decreased

12doses of each drug.

Recent studies have shown “KETOFOL”i.e. administering Ketamine and Propofol mixed together in the same syringe, to be efficacious in the ED as an induction regimen for rapid

21sequence intubation and also as a PSA in the ED, the operating 22-26room, and in ambulatory settings. K/M drug regimen and

P/F drug regimen are capable of providing efficient and safe PSA in the ED for painful procedures, at the same time decreasing the adverse effects of each drug when used alone.

27Godambe SA et al recently conducted a prospective study comparing Ketamine/Midazolam and Propofol/Fentanyl in pediatric population for PSA in the ED setting. There was no study done in the adult population.

The purpose of our study is to validate the potent synergistic analgesic effect of these drugs in emergency settings and to compare the 2 groups of drugs.

2

Abstract

The aim of this study is to compare effectiveness of 2 drug regimens, Propofol & Fentanyl (P/F) and Ketamine & Midazolam (K/M), for brief Emergency Department (ED) procedural sedation and analgesia (PSA) by comparing recovery times (RT) and procedural distress as measured by Visual analogue scale (VAS) and also to assess patient satisfaction and physician satisfaction as measured by Likert scale.

A prospective, controlled comparative trial was conducted on patients with age >18 yrs, who came to ED with isolated limb injury and having pain score of 7 or more on VAS and fasting for at least 4 hours. Patients with respiratory compromise, hemodynamic instability, head injury or raised ICP, psychiatric history, pregnancy, allergy to drugs used in study and inability to understand VAS pain score were excluded.

A total of 40 patients had PSA with 20 receiving K/M and the other 20 receiving P/F in ED. It was observed that: l Mean VAS scores on arrival was 7.3 in P/F to 7.5 in K/M.l Mean VAS score during procedure was 2.9 in P/F and 1.6

in K/M.

l K/M group was 2.4.

l Mean sedation score in P/F was 2.1 & in K/M was 3.2.l Mean RT in P/F was 22.5 & in K/M it was 54.3 minutes. l Total sedation time in P/F was 27.5 and in K/M was 59.5

minutes.

From these observations, it can be concluded that Propofol/Fentanyl offers unique advantages for brief procedural sedation in ED. It is short acting and has rapid offset resulting in shorter post sedation monitoring and smoother recovery profile.

Keywords

Procedural Sedation, Analgesia, Ketamine & Midazolam, Propofol & Fentanyl

Introduction

Physicians underestimate the severity and the degree of pain 1and treat them inappropriately. Results from the National

Hospital Ambulatory Medical Survey, USA, among patients 2evaluated for isolated extremity fractures , confirmed that

42% were treated with an opioid and 64% were treated with an analgesia Many studies have confirmed that the vulnerable population received inadequate analgesia for pain by both physicians and nurses in comparison with other age group patients in a variety of medical and surgical settings. The same insensitivity and lack of success in acute pain management

3was demonstrated in the ED in recent studies.

Even if analgesia is administered, the time required to administer is delayed and opioids are administered in sub therapeutic doses, frequently in the ED. Silka et al showed

st that the average time for administration of 1 dose analgesia after arrival to the ED was 1hr 49 minutes in 38% of the trauma

4patients who were treated with analgesia . Fear of masking the clinical diagnosis was one of the commonest excuses for withholding analgesia and this had no validity nor has been proved by any recent studies. It is the duty of emergency physician to make the patient comfortable without interfering with the clinical diagnosis.

Emergency Physicians should be confident in providing PSA, both safely and effectively and must be comfortable in administering them. Goals of PSA are to provide an adequate level of sedation while decreasing pain, maximizing amnesia, controlling patient's behavior without any delusions, decreasing anxiety, maintaining stable vitals, maintaining good

Mean VAS score post procedure in P/F group was 3 and in

Comparison of Propofol with Fentanyl and Ketamine with Midazolam for Procedural Sedation & Analgesia in the Emergency Department

Procedural Sedation and Analgesia 4 Point Discharge

Criteria Score

ACTIVITY0 – Not able to lift his head or move his extremities on command or voluntarily1 – Spontaneously Lifts his head and moves his extremities on command or voluntarily2 – Able to move around without assistance

BREATHING0 – Apnoeic1 – Dyspnoeic or shallow, irregular breathing2 – Able to breathe deeply and cough on command

CIRCULATION0 Systolic blood pressure < 80 mm Hg1 – Systolic blood pressure > 80 mm Hg and < 100 mm Hg2 – Systolic blood pressure within normal range for patient

–

CONSCIOUSNESS0 Not responding or responding only to painful stimuli1 – Responds to verbal stimuli but falls asleep readily2 – Awake, alert, and oriented to time, place and person (child oriented to parent)

–

Table 1. Procedural Sedation and Analgesia 4 Point 22Discharge Criteria Score.

Characteristics

Demographics

Past Medical History

Mechanism of Injuries

Type of Injuries

Procedures Done

Treatment

Results

Propofol and Fentanyl

Ketamine and Midazolam

TotalStudy

Percentage(%)

Mean Age (years)Patients

Diabetes MellitusHypertensionCoronary Artery DiseaseSeizure DisorderNil

Motor Vehicle AccidentFall from HeightIndustrial AccidentAssault

Dislocation of Joints

Long Bone Fracture

Soft Tissue Injury

Dislocation of JointsLong Bone FractureSoft Tissue Injury

Dislocation of Joints

Long Bone Fracture

Patient's Likert Scale

Physician Likert Scale

Male/FemaleMean Weight, (Kg) Mean Fasting Time, (Mins)

37.65 20

18/259.80 286.6

34.50 20

18/263.50 306.9

36.075 40

36/4 90/461.65 296.75

110117

10730

7

13

1

1073

0911

0155

02416

060.0040.00

2.5057.5040.00

12316

1145

0911

20

4

20

4

40

8

100.00

20.00

2

18

3

1325

2398

57.5022.5020.00

9

31

4

22.50

77.50

10.00

16301

261031

65.0025.00 7.50 2.50

011018

011018

2.50 5.00 2.50 2.5087.50

Not SatisfiedSatisfied

Very Satisfied

Not SatisfiedSatisfied

Very Satisfied

Table 2. Patient Characteristics Observed in the Study

5 4

The main objective is to compare the effectiveness of 2 medication regimens, P/F and K/M, for brief orthopedic emergency department procedural sedation with attention to compare recovery times (RT) and procedural distress as measured by VAS. The secondary objective is to assess the

administering staff and patient satisfaction, Orthopedic surgeon satisfaction as measured by the Likert scale and also to compare the incidence of adverse effects between the 2 groups.

Materials and Methods

This is a prospective, controlled, comparative trial of adult trauma patients registered in the ED of Sri Ramachandra Medical College & Research Institute, a 1500 bedded tertiary care university hospital and a level I trauma center in the South Indian metropolitan city of Chennai.

Sri Ramachandra Medical College & Research Institute receives 4000 trauma patients annualy on an average in the ED, making it ideal for a study of this nature.

Consecutive adult trauma patients who received Ketamine with Midazolam or Propofol with Fentanyl for procedural sedation and analgesia and registered in the ED over a period

st stof 1 year, from 1 January 2010 to 31 December 2010, were recruited in the study. All patients provided informed written consent.

Inclusion Criteria

Patients with age >18 yrs, adult patients coming to ED with isolated limb injury, having a pain score of 7 or more on VAS and who were fasting for at least 4 hours were included in the study.

Exclusion Criteria

Hemodynamically unstable patients, patients with respiratory compromise, suspicion of head injury or raised ICP, presence

of psychiatric history, pregnant women, documented allergy to any of the drugs used in the study and inability to understand VAS pain score were excluded from the study.

Methodology

In the Propofol & Fentanyl group, first Fentanyl at the dose of 1–2 mcg/kg was administered slowly over 1 to 2 minutes intravenously and then titrated appropriately to provide adequate analgesia to the patient. After 5 minutes of Fentanyl administration, an initial slow bolus of Propofol at the dose of 1 mg/kg was administered intravenously and followed by subsequent smaller aliquots of Propofol depending upon the patient response.

In the Ketamine and Midazolam group, first Midazolam at the dose of 0.05 mg/kg to a maximum of 2 mg was administered slowly over 1 to 2 minutes intravenously. After 3 minutes of Midazolam administration, an initial slow bolus of Ketamine at the dose of 1 to 2 mg/kg was administered slowly over 1 to 2 minutes intravenously and followed by subsequent aliquots of Ketamine depending upon the patient response.

Propofol was administered slower than Ketamine due to increased potential of respiratory depression occurring with rapid administration of Propofol. Propofol dosage was titrated adequately to achieve a relative motionless state and adequate muscle relaxation during the reduction of dislocations and fractures. Ketamine dosage was titrated adequately to achieve perfect conditions for manipulation of fracture by the orthopedic surgeon in the ED. Our intent during PSA in the study subjects as defined by American Society of Anesthesia (ASA) was to anticipate “deep” sedation. In order to monitor the respiratory effort of the patient, a portion of the patient's chest was exposed. No patient was pre-oxygenated before drug administration.

Methods of Measurement

PSA data was recorded in a preformatted proforma designed specially for this study. The presedation fasting time, cardio respiratory examination, body weight and all vital signs were documented.

Supplemental oxygen through the nasal prongs at rate of 2 to 5L per minute was recommended but not administered to all patients; when used, it was recorded. The proforma was also used to document the medication doses and frequency of administration. The vital signs during and after the procedure were documented, and the discharge criteria was assessed for every patient and discharged appropriately. The treating Emergency Physician also documented comorbid illness, adjunctive medications administered (like opioid analgesics or any other additional sedation), any adverse events observed and patient and physician satisfaction on a 5-point Likert's scale.

Protocol

Patients were enrolled in the study after obtaining consent from the patient's attendant and the patient. The enrolled patients were assigned to Propofol and Fentanyl drug regimen on odd days and Ketamine and Midazolam drug regimen on

even enrollment days. If multiple reductions were attempted, only the initial attempt was documented.

The start time, recovery time and time to discharge was observed and recorded using a stopwatch. Adverse effects occurring any time after drug administration to the time of discharge were documented.

If the patient's oxygen saturation is 90% or less for any amount of time, it is defined as Transient Desaturation. With oxygen saturation of 90%, if the patient does not respond to airway repositioning or suction, then supplemental oxygen is administered. The time elapsed from the last dose of administration of medication to when the patient returns back to his baseline is called as Recovery Time (RT). The time

stelapsed from 1 dose of administration of medication to when the patient returns back to their baseline is called as total sedation time (TST).

Definitions

Visual analogue scale (VAS): A pain scale using both faces and numbers marked from 0-10 wherein patients had to choose a number between 0-10 with 0 being no pain and 10 being worst pain imaginable.

Adequate analgesia: VAS pain score of 3 or less

Ramsay sedation score: l Alert; Oriented -1 l Awake; Confused -2l Drowsy and Arousable-3l Drowsy and Not arousable- 4

Sedation: defined as a Ramsay score of greater than 2.

Adverse events: The presence of necessity for airway intervention, apnoea, agitation, hypoxia, breathing difficulty, s e i z u r e , r a s h , m y o c l o n u s , hallucinations, vomiting, breathing difficulty and hypotension.

Data Collection and Processing

The data from each patient was collected on a prepared data sheet under the following headings: Patients' demographic data, Co-morbid conditions, Mode of injury and Injuries sustained as a result of the trauma and were documented. The preprocedural medications, adjunctive medication administered or interventions done, orthopedic procedure performed and the presedation fast ing t ime was documented.

VAS pain score was performed using the 10 point visual analogue scale at time of presentation, before procedure, during procedure, after procedure and

at discharge or disposition and were recorded. An individual dose of Ketamine with Midazolam and Propofol with Fentanyl was documented in mg/kgs.

The Emergency Physician, administering the medication for PSA, recorded the vital signs like blood pressure, heart rate, respiratory rate and oxygen saturation before, during, and after each procedure till specific discharge criteria were observed.

22 PSA 4 Point Discharge Criteria Score, is a discharge tool (Table 1) consisting of a 4 item scale. The total discharge criteria score must be equal to or more than 7 before completing the study and discharging the patient from the ED as per his disposition. The Likert's Scale was used to assess the patient and physician’s satisfaction on pain relief with Ketamine with Midazolam and Propofol with Fentanyl and recorded in the proforma. The treating Emergency Physician documented the presence or absence of an adverse event on the proforma during each procedure, including need for an airway intervention, apnoea, hypotension, hypoxia, myoclonus, seizure, rash, dysphoria emergence phenomena (agitation, hallucinations) or vomiting. Time taken for recovery from time of drug administration and final disposition of patient were documented in the proforma.

Outcome Measures

The dose of Ketamine with Midazolam and the dose of Propofol with Fentanyl administered were reported in milligrams per kilogram of body weight. PSA with Ketamine with Midazolam and Propofol with Fentanyl drug regimens were considered efficacious if the procedure was completed without any requirements for adjunctive medications.

Satisfaction ratings were recorded by using a Likert scale as follows undecided:0, satisfied:1, very satisfied:2, dissatisfied:-1 and very dissatisfied:-2. The time from the last dose of medication given until discharge criteria was recorded as RT.

Figure 1. Mean Visual Analogue Scale (VAS) Pain Score that were assessed immediately on arrival to the ED, during the procedure and post procedure. In both the drug regimens

the mean VAS scores were high on arrival and decreased dramatically after PSA during the procedure and after

procedure.

Mean SD Mean SD Mean SD Mean SD Mean SD

Drug Regimens

Heart Rate (beats/ min)

Systolic BP (mmHg)

Diastolic BP (mmHg)

Respiratory Rate

(breaths/ min)

Saturation (%)

On Arrival

KM

KM

KM

During Proce-dure

Post Proce-dure

PF

PF 21.374 126.00 0.44 15.35 2.084 99.45 1.19188.65 11.389 75.505

121.55 9.333 77.75 14.25 1.743 99.65 0.87105.75 17.285 5.250

PF 126.50 19.270 76.50 14.65 1.755 99.9 0.30876.75 12.777 9.333

122.30 7.981 78.25 13.2 1.105 100.0 0.00084 .00 9.353 4.940

21.398125.00 75.50 15.10 1.651 99.9 0.38 81.35 13.838 10.501

82.25 9.973 122.30 7.981 78.00 4.974 12.75 0.967 99.9 0.447

Table 3. The Mean and Standard Deviation of the Heart Rate, Systolic and DiastolicBlood Pressure, Respiratory Rate and Saturation of Study Patients Observed Immediately

on Arrival, during Procedure and after Procedure for both the Drug Regimens.

7 6

Vital sign changes were recorded as the maximum variation documented during procedure or recovery period in comparison with the preprocedural level.

Cessation of breathing for at least 20 seconds with or without decrease in oxygen saturation is defined as apnoea. A decrease from preprocedural levels of the mean arterial blood pressure of 20% is defined as hypotension, which is consistent with the previous literatures assessing the use of Ketamine and Midazolam drug regimen and Propofol and Fentanyl drug

28,29regimen. Oxygen saturation below 90% at any given time during the PSA protocol is defined as hypoxia. An event not causing a change in the vital signs and requiring very minimal intervention, like airway positioning such as chin lift, jaw thrust or even little physical stimulation is considered as a minor adverse event. An event requiring interventions like administration of intravenous medications or fluids, an oral airway placement or ventilatory assistance is considered as a significant adverse event.

Primary Data Analysis

Data collected in the proforma was entered into Microsoft Excel. Frequency and percentage of frequency of occurrence was presented for the category data and mean, medians, with ranges and interquartile ranges (IQR) were presented for the continuous data. Where appropriate 95% confidence intervals (CIs) was reported, the value of p <0.05 was considered statistically significant. Statistical analysis of the data was done using SPSS software Version 17.

Results

This prospective study was conducted over a period of 12 months, during which time a total of 40 patients had undergone PSA wherein 20 patients received Propofol & Fentanyl (P/F) drug regimen and another 20 patients received Ketamine and Midazolam (K/M) drug regimen for painful orthopedic procedures in the ED. There were 36 males (90%) and 4 females (10%) among the 40 patients who enrolled in the study. Men and women were equally distributed between the 2 groups (Table 2).

The mean age among the Propofol & Fentanyl group was 37.65 yrs, with a standard deviation of 15.786 ranging from 20 to 60 years, but the mean age for the Ketamine & Midazolam group was 34.50 years, with a standard deviation of 10.928 ranging from 20 to 60 years. Most of the patients participating in the

study in both the drug regimen groups were free from co- morbid medical illness. One patient (2.5%) had a past medical history of diabetes mellitus, 2 patents (5%) had a past history of hypertension, one patient (2.5%) had a past history of coronary artery disease and 1 patient (2.5%) had a past history of seizure disorder. Thirty-five patients (87.5%) had no significant past medical history.

The causes of trauma, presenting the patient to the emergency department was motor vehicle accidents in 26 patients (65%), falls from height in 10 (25%), Industrial accidents in 3 (7.5%) and assault in 1 patient (2.5%).

The most common presenting injuries the study patients had due to trauma were dislocation of joints in 9 patients (22.5%), long bone fractures in 31 patients (77.5%) and soft tissue injuries in 4 patients (10.0%). All 40 patients (100%) were put on supplemental oxygen. Hypoxia was not recorded in any patient before procedural sedation and analgesia and all of them underwent orthopedic procedures requiring PSA.

The most common indication for PSA was debridement in 23 patients (57.5%), followed by reduction of dislocated joints in 9 patients (22.5%) and pin traction for long bone fractures in 8 patients (20%). Pre-medication was considered in 4 patients (20.0%) of the Propofol and Fentanyl drug regimen and in 4 patients (10.0%) of the Ketamine and Midazolam drug regimen each. So, a total of 8 patients (20%) required premedication during the study.

The pain score was recorded using the 10-point VAS scoring system. Mean VAS Pain Score was assessed immediately on arrival to the ED, during the procedure and post procedure. In both the drug regimens the mean VAS scores was high on arrival and decreased dramatically after PSA during the procedure and after procedure (Figure 1).

The P value was statistically significant for both the study groups during the procedure and at the time of discharge. The mean heart rate on arrival in the Propofol and Fentanyl drug regimen was 88.65 with a SD of 11.389 and that in Ketamine and Midazolam drug regimen was 105.75 with a SD of 17.284, the results being statistically significant (p = 0.039) (Table 3).

T h e m e a n , s t a n d a r d deviation and t h e m e a n d i f f e r e n c e between both t h e d r u g regimens for the sedation s c o r e , t h e recovery time and the total sedation time are illustrated in Table 4. The Ketamine and M i d a z o l a m drug regimen

had better sedation score in comparison to Propofol and F e n t a n y l D r u g Regimen (Figure 2). P r o p o f o l a n d Fentanyl had shorter recovery time and total sedation time over Ketamine and Midazolam drug regimen (Figure 3).

The results of the Patient's Likert scale s h o w e d t h a t 9

patients (45.0%) in the Propofol and Fentanyl drug regimen were satisfied in comparison to 15 patients (75.0%) in Ketamine and Midazolam drug regimen. The results of the Patient’s Likert Scale also showed that 11 patients (55.0%) in Propofol and Fentanyl drug regimen were very satisfied in comparison to the 5 patients (25.0%) in the Ketamine and Midazolam drug regimen.

Using the Patient's Likert scale we found that a total of 24 patients (60%) were satisfied and 16 patients (40%) were very satisfied in both the groups during Procedural Sedation and Analgesia for Orthopedic procedures in the ED. The Physician's Likert scale found that the physicians were satisfied using the Propofol and Fentanyl drug regimen in 9 patients (45%) in comparison to 14 patients (70.0%) in Ketamine and Midazolam drug regimen. The Physician's Likert scale also found that the physicians were very satisfied using the Propofol and Fentanyl drug regimen in 11 patients (55%) in comparison to 5 patients (25%) in K/M group. It was also found using Physician's Likert scale, that the physician was not satisfied using Ketamine and Midazolam drug regimen in one patient (5%).

So, the Physician's Likert Scale found that the physicians were very satisfied with PSA in a total of 23 patients (57.5%), satisfied with PSA in 17 patients (42.5%) and not satisfied with PSA in 1 patient (2.5%). Only 1 patient (2.5%) in Propofol and Fentanyl drug regimen had hypoxia-requiring head tilt and chin lift, followed by bag and Mask Ventilation (Table 5).

Discussion

This research study has shown that the mean recovery time with the Propofol and Fentanyl drug regimen was very much shorter than with Ketamine and Midazolam drug regimen. This study also showed that Propofol and Fentanyl drug regimen are c o m p a r a b l e t o K e t a m i n e a n d M i d a z o l a m d r u g regimen in reducing the distress associated w i t h p a i n f u l o r t h o p e d i c p r o c e d u r e s a n d interventions in the ED.

The mean VAS scores in both the drug regimens were greater on arrival and both the drug regimens were successful in keeping the mean VAS scores low during the procedures. Although the difference in VAS scores between the Ketamine and Midazolam drug regimen and Propofol and Fentanyl drug regimen were statistically significant, they were clinically insignificant. The slightly lower VAS scores in patients who received Ketamine and Midazolam drug regimen may be attributed to the greater mean dose of Ketamine received. Inspite of this, the Ketamine and Midazolam drug regimen produced consistently effective conditions for orthopedic procedures while Propofol and Fentanyl drug regimen had at least some borderline sedation conditions (Refer Fig 1 on page no 6).

No published studies are currently available comparing these 2 drug regimens for procedural sedation and analgesia in adult patients. Godambe et al 27 prospectively compared propofol/fentanyl versus ketamine/midazolam during orthopedic procedural sedation in a pediatric emergency department “Comparison of Propofol/Fentanyl versus Ketamine/Midazolam for brief orthopedic procedural sedation in a pediatric emergency department”. Their results showed that Propofol / Fentanyl had comparable efficacy to Ketamine / Midazolam and also had a shorter recovery time. The results of our studies were similar and reflect Propofol and Fentanyl's unique pharmacokinetics and synergistic effects in combination. Even more, the time from initial drug administration to orthopedic manipulation was greater in the Propofol and Fentanyl drug regimen in comparison to the Ketamine and Midazolam drug regimen.

The treating physicians preferred the Propofol and Fentanyl drug regimen during difficult reductions requiring greater muscle relaxation. As the recovery time with Propofol and Fentanyl drug regimen was shorter, it was also preferred in situations like mass casualty incidents, where multiple patients in the emergency department require Procedural Sedation and Analgesia for orthopedic procedures and interventions.

The treating physicians who preferred Ketamine and Midazolam drug regimen, asserted its ease of use in relation to the decreased time to onset of optimum conditions for orthopedic procedures and interventions. There was only one adverse event (Table 5 below), an incidence of airway obstruction and hypoxemia in a patient who received the Propofol and Fentanyl drug regimen and was resolved by head tilt and Bag and Mask ventilation. This was consistent with

30-33other studies using Propofol. Propofol may cause respiratory depression along with loss of airway tone, necessitating the need for airway interventions. In our study, none of the patients had apnoea or required intubation. The

Mean Standard Deviation

Mean difference betwe en KM

and PF PF KM PF KM Sedation Score

2.10 3.20 0.718 0.696 1.1

Recovery Time

22.50 54.3 6.074 10.912 31.8 minutes

Total Sedation Time

27.50 59.55 6.074 10.620 32.05 minutes

Figure 2. Mean Sedation Scores observed after drug regimen administration.

The Ketamine and Midazolam drug regimen had better sedation score in comparison with

the Propofol and Fentanyl drug regimen

Figure 3. Mean Recovery & TotalSedation time for both the drug

regimens

Apnea Hypoxia Hypotension Vomiting Seizure Agitation Hallucination

Nil 1 Patient Nil Nil Nil Nil Nil

KM Nil Nil Nil Nil Nil Nil Nil

Intervention Nil Bag & Mask Ventilation

Nil Nil Nil Nil Nil

PF

Table 5. Adverse Events - There was only one Adverse Event in the Propofol and Fentanly Group due to Hypoxia which Required Head Tilt and Chin Lift with Bag and Mask Ventilation. No Adverse Effects

were observed in the Ketamine and Midazolam Drug Regimen

Table 4. The Mean, Standard Deviation and the Mean Differences between both the Drug Regimens.

9 8

incidence of this adverse event could have been reduced if an anti-sialagogue had been used as a routine in all patients administered the Propofol and Fentanyl drug regimen.

There was no incidence of dysphoric reactions and vomiting with the use of Ketamine/Midazolam and are consistent with

34-36the incidence reported in other studies. It could be argued that the addition of Midazolam may have prolonged the recovery time with Ketamine. However, in the Ketamine and Midazolam drug regimen, Midazolam mitigated the Ketamine - induced dysphoria as noted in our study as there was no incidence of dysphoria at all in the study patients. Vomiting is an important adverse event that can occur during or after procedural sedation and analgesia. But there was no incidence of vomiting in conjunction with Procedural Sedation and Analgesia as observed in our study. Sherwin et al study found that the incidence of emesis was 2% in the Ketamine/Midazolam group

35in comparison to 12% in the Ketamine/placebo group. Wathen et al, study showed lesser incidence of emesis was observed when Ketamine and Midazolam were given in conjunction,

3619.4% versus 9.6% respectively.

Increased incidence of nightmares seen with Ketamine and Midazolam drug regimen could not be validated as no follow up after discharge from ED was carried out.

An argument can be made that the injured patients usually have delayed gastric emptying time and the regular pre-operative fasting guidelines are inadequate to reduce risk of aspiration. But based on recent journal reviews on ED sedations, there is negligible risk of clinically significant aspiration syndrome occurring. The risk is not increased by failing to adhere to the

37, 38pre-operative fasting guidelines. Because of it's intrinsic anti-emetic properties Propofol use during Procedural sedation and analgesia in the ED setting actually decreases risk of

39vomiting and aspiration. The fasting time observed in the study was in accordance with our hospital policy, with the mean fasting time of 4 hours for both the groups and is consistent with the above-mentioned ASA fasting guidelines for sedation. In the study, none of the patients experienced a clinically significant aspiration event.

Limitations

In our study, we observed several limitations. High acuity of patients in the ED did not permit proper subject recruitment and we recognize this as a limitation of the study. It closely reflects the nature of our clinical practice in the busy tertiary care urban academic emergency departments. The odd and even day randomization of patients to the drug regimen was not the ideal method of randomization but it was a convenient and hassle free method. The study reveled that the patient demographics were closely matched in both the drug regimens for the multitude of characteristics examined.

The dose of medication, each patient received in both the drug regimens was intentionally not standardized. The medications used were carefully titrated by the treating physician to attain desired effective conditions and patient comfort as well to facilitate orthopedic procedure or intervention. The exact dose of medication administered depended on several features like the type of injury, degree of pain or VAS score, dose of

premedication and timing and individual patient conditions. It was difficult to control the dose of analgesic premedication, since most of the patients coming to our ED are referred from outside clinics or hospitals.

The principle investigator and the treating physicians were not blinded to the administered drug regimen. There is a potential for bias on part of the principle investigator as he recorded the various time points during the PSA. This study was conducted only in our ED with a single principle investigator and treating physician. A strict adherence to the study protocol and uniformity of clinical practice by the ED staff were the result of a single primary investigator and treating physician during procedural sedation and analgesia. However a multi-center trial has to be conducted to validate this study specially pertaining to the Recovery Time and Total Sedation Time.

Conclusion

Propofol with Fentanyl offers unique advantages for procedural sedation and analgesia in the ED. It has rapid offset and a short-acting, leading to smoother recovery and shorter post sedation monitoring profile. However it is more risk prone for respiratory depression as compared with Ketamine with Midazolam. Therefore, strict monitoring and greater experience in airway management is recommended with its use.

References

1. Marquie L: Pain rating by patients and physicians: Evidence of systemic miscalibration. Pain2003;102:289

2. Brown JC: Emergency department analgesia for fracture pain. Ann Emerg Med2003;42:197.

3. Ducharme J, Barbar C: A prospective blinded study on emergency pain assessment of therapy. J Emerg Med1995;15:571.

4. Silka PA, Roth MM, Geiderman JM: Patterns of analgesic use in trauma patients in the ED. Am J Emerg Med2002;20:298.

5. Bartfield JM, Flint RD, McErlean M, Broderick J: Nebulized fentanyl for relief of abdominal pain. Acad Emerg Med2003;10:215.

6. Jaffe JH, Martin WR: Opioid analgesics and antagonists. In: Gilman AG, ed.The Pharmacological Basis of Therapeutics, 10th ed. New York: McGraw-Hill; 2001: 569-619.

7. Porter J, Jick H: Addiction rare in patients treated with narcotics. N Engl J Med1980;302:123.

8. Jones JS, Johnson K, McNinch M: Age as a risk factor for inadequate emergency department analgesia. Am J Emerg Med 14:157, 1996. [PMID: 8924137]

9. Oligoanalgesia in the emergency department: short-term beneficial effects of an education program on acute pain, Isabelle et al, Annals of Emergency Medicine, 2007

10. Todd KH, Deaton C, D'Adamo AP, Goe L: Ethnicity and analgesic practice. Ann Emerg Med 35:11, 2000. [PMID: 10613935]

11. Raftery KA, Smith-Coggins R, Chen AH: Gender-associated differences in emergency department pain management. Ann Emerg Med 26:414, 1995. [PMID: 7574121]

12. Acute Pain Management Guideline Panel: Acute Pain Management: Operative or Medical Procedures and Trauma. Guideline Report. Agency for Health Care Policy and Research Publication No. 92-002. Rockville, MD, Agency for Health Care Policy and Research, Public Health Service, US Department of Health and Human Services, 1993.

13. Joint Commission on Accreditation of Healthcare: Pain Management Standards. Available at: http://www.jcaho.org

14. Grubb BD: Peripheral and central mechanisms of pain. Br J Anaesth 81:8, 1998. [PMID: 9771267]

15. Todd KH: Clinical versus statistical significance in the assessment of pain relief. Ann Emerg Med 27:439, 1996. [PMID: 8604855]

16. Paoloni P, Talbot-Stern J: Low incidence of nausea and vomiting with intravenous opiate analgesia in the ED. Am J Emerg Med 20:604, 2002. [PMID: 12442238]

17. Ketamine spares morphine consumption after transthoracic lung and heart surgery without adverse hemodynamic effects, Nesher et al, Pharmacol Res. 2008 Jul;58(1):38-44

18. Perioperative ketamine and morphine for postoperative pain control after lumbar disk surgery, Aveline et al, Eur J Pain. 2006 Oct;10(7):653-8

19. Supplementing desflurane-remifentanil anesthesia with small-dose ketamine reduces perioperative opioid analgesic requirements, Guignard et al, Anesth Analg. 2002 Jul; 95(1):103-8

20. Morphine versus morphine-ketamine association in the management of post operative pain in thoracic surgery, Atangana.R et al, Acta anaesthesiologica Belgica, 2007, vol. 58, no2, pp. 125-127 [3 page(s) (article)] (12 ref.)

21. Walls R, Murphy MF, et al. Manual of Emergency Airway Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2004

22. Willman EV, Andolfatto G: A Prospective Evaluation of “Ketofol” (Ketamine/Propofol Combination) for Procedural Sedation and Analgesia in the Emergency Department. Annals of Emerg Med. 2007 January: Volume 49, Issue 1 , Pages 23-30

23. Arora S: Combining Ketamine and Propofol (“Ketofol”) for Emergency Department Procedural Sedation and Analgesia: A Review. West J Emerg Med. 2008 January; 9(1): 20–23

24. Camu F, Vanlersberghe C. Pharmacology of systemic analgesics. Best Pract Res Clin Anaesthesiol. 2002;16:475–488

25. Frey K, Sukhani R, Pawlowski J, et al. Propofol versus propofol-ketamine for retrobulbar nerve block: comparison of sedation quality, intraocular pressure changes, and recovery profiles. Anesth Analg. 1999;89:317–321

26. Mortero RF, Clark LD, Tolan MM, et al. The effects of small-dose ketamine on propofol sedation: respiration, postoperative mood, pe rcep t ion , cogn i t ion , and pa in . Anes th Ana lg . 2001;92:1465–1469

27. Godambe SA, Elliot V, Matheny D, Pershad J: Comparison of Propofol/Fentanyl Versus Ketamine/Midazolam for Brief Orthopedic Procedural Sedation in a Pediatric Emergency Department. Pediatrics 2003;112;116-123

28. Patterson KW, Casey PB, Murray JP, O'Boyle CA, Cunningham AJ. Propofol sedation for outpatient upper gastrointestinal endoscopy: comparison with midazolam [see comments]. Br J Anaesth. 1991;67: 108–111

29. Vardi A, Salem Y, Padeh S, Paret G, Barzilay Z. Is propofol safe for procedural sedation in children? A prospective evaluation of propofol versus ketamine in pediatric critical care. Crit Care Med. 2002;30: 1231–1236

30. Havel CJ, Strait RT, Hennes H. A clinical trial of propofol vs. midazolam for procedural sedation in a pediatric emergency department. Acad Emerg Med. 1999;6:989–997

31. Clarkson K, Power CK, O'Connell F, Pathmakanthan S, Burke CM. A comparative evaluation of propofol and midazolam as sedative agents in fiberoptic bronchoscopy. Chest. 1993;104:1029–1031

32. Hertzog J, Dalton HJ, Anderson BD, Shad AT, Gootenberg JE, Hauser GJ. Prospective evaluation of propofol anesthesia in the

pediatric intensive care unit for elective oncology procedures in ambulatory and hospital ized children. Pediatr ics . 2000;106:742–747

33. Marcus B, Steward DJ, Khan NR, et al. Outpatient transesophageal echocardiography with intravenous propofol anesthesia in children and adolescents. J Am Soc Echocardiogr. 1993;6:205–209

34. Green S, Rothrock SG, Harris T, Hopkins GA, Garrett W, Sherwin T. Intravenous ketamine for pediatric sedation in the emergency department: safety profile with 156 cases. Acad Emerg Med. 1998;5: 971–976

35. Sherwin T, Green SM, Khan A, Chapman DS, Dannenberg B. Does adjunctive midazolam reduce recovery agitation after ketamine sedation for pediatric procedures? A randomized, double-blind, placebocontrolled trial. Ann Emerg Med. 2000;35:229–238

36. Wathen J, Roback MG, Mackenzie T, Bothner JP. Does midazolam alter the clinical effects of intravenous ketamine sedation in children? A double randomized, controlled emergency department trial. Ann Emerg Med. 2000;36:579–588

37. Hoffman G, Nowakowski R, Troshynski TJ, Berens RJ, Weisman SJ. Risk reduction in pediatric procedural sedation by application of an American Academy of Pediatrics/American Society of Anesthesiologists process model. Pediatrics. 2002;109:236–243

38. American Academy of Pediatrics, Committee on Drugs. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics. 1992;89: 1110–1115

39. Green SM, Krauss B. Pulmonary aspiration risk during emergency department procedural sedation—an examination of the role of fasting and sedation depth. Acad Emerg Med. 2002;9:35–4

Dr Srihari Cattamanchi The Author is Disaster Medicine Fellow,

Harvard Affiliated Disaster Medicine Fellowship, Harvard Medical School,

USA.

Co-authored byDr Maruteshwar Reddy

Emergency Physician, Middle Grade Registrar, Dept. of Accident & Emergency Medicine,

Queen's BHR University Hospital,U.K.

Prof Dr T V RamakrishnanProfessor & Head of Clinical Services,

Dept of Accident & Emergency Medicine, Sri Ramachandra Medical College & Research Institute,

Chennai

This article has been peer reviewed.