Evaluate the Effects of Ketamine (Pain Relief Drug) in prehospital trauma

care:A controlled clinical trial in Quang Tri,

Vietnam

Dr. PhD. Tran Kim Phung

Co-operation between TMC, Co-operation between TMC, Oslo UniversityOslo University

and Quang Tri Health Serviceand Quang Tri Health Service

Reason for researchReason for research

• Trauma is the big problem. Death by trauma is Trauma is the big problem. Death by trauma is the first ranking.the first ranking.

• Life support activities such as stop bleeding, Life support activities such as stop bleeding, airway especially pain relef at community are airway especially pain relef at community are very limited.very limited.

• Morphin is consider the main drug for pain relief Morphin is consider the main drug for pain relief in trauma at community but infact it’s very little in trauma at community but infact it’s very little use. It has use. It has adverse event nausea and vomiting adverse event nausea and vomiting and cause opiumand cause opium

• Objective of research: To find out a new pain Objective of research: To find out a new pain relief drug to change Morphinrelief drug to change Morphin

Objective:Objective: To compare the analgesic effect and adverse To compare the analgesic effect and adverse

events of ketamine analgesia versus events of ketamine analgesia versus morphine analgesia to injury patients during morphine analgesia to injury patients during prehospital evacuationsprehospital evacuations

Study populationStudy population

Inclusion criteria Inclusion criteria • Any patient in Quang Tri Province, Any patient in Quang Tri Province,

injured during the study period, injured during the study period, regardless type of trauma, where regardless type of trauma, where prehospital life support is provided by prehospital life support is provided by trained health staff, and the patient trained health staff, and the patient needs medical assistance during needs medical assistance during evacuation to Quang Tri Provincial evacuation to Quang Tri Provincial Hospital (QT-PH) in Dong Ha (end-Hospital (QT-PH) in Dong Ha (end-point for this study). point for this study).

Exclusion criteriaExclusion criteria

• Deep unconscious patients (no response Deep unconscious patients (no response to pain stimuli).to pain stimuli).

• Patients already dead on first medical Patients already dead on first medical contact in-field.contact in-field.

• Patients with head or eye injury.Patients with head or eye injury.• Infants less than 5 years of age.Infants less than 5 years of age.• Patients with pre-hospital evacuation time Patients with pre-hospital evacuation time

< 10 minutes.< 10 minutes.

Sampling and recruitmentSampling and recruitment

• We use systematic cluster sampling: We use systematic cluster sampling: • WeWe divided the study area of Quang Tri divided the study area of Quang Tri

province into two sectors (“Sector 1” and province into two sectors (“Sector 1” and “Sector 2”), each sector having “Sector 2”), each sector having approximately the same number of approximately the same number of patients and approximately same patients and approximately same transport times. transport times.

• Patients injured in one sector get Patients injured in one sector get ketamine pain relief (Treatment Group); ketamine pain relief (Treatment Group);

• Patients from the other sector get Patients from the other sector get morphine pain relief (Control Group).morphine pain relief (Control Group).

Sampling and recruitmentSampling and recruitment

• To reduce the impact of systematic To reduce the impact of systematic failures, the sectors would be crossed failures, the sectors would be crossed over every month: Sector 1 shifts to over every month: Sector 1 shifts to Control, Sector 2 shifts to Treatment. Control, Sector 2 shifts to Treatment.

• Both groups stratified according to injury Both groups stratified according to injury severity using the Injury Severity Score severity using the Injury Severity Score (ISS, ref. 13): Moderate injuries = ISS <9. (ISS, ref. 13): Moderate injuries = ISS <9. Serious injuries = ISS 9 – 15. Major Serious injuries = ISS 9 – 15. Major injuries = ISS >15.injuries = ISS >15.

Main variablesMain variables

1.1.Analgesic effect:Analgesic effect: • Patient’s actual pain assessed and rated on Patient’s actual pain assessed and rated on

Visual Analogue Scale (VAS) by the trauma care Visual Analogue Scale (VAS) by the trauma care provider at two points:provider at two points:

• First (VAS1): at the first contact in-field First (VAS1): at the first contact in-field immediately before life support starts.immediately before life support starts.

• Second (VAS2): immediately on admission at QT Second (VAS2): immediately on admission at QT hospital.hospital.

• The difference (VAS1) – (VAS2) is the indicator of The difference (VAS1) – (VAS2) is the indicator of analgesic effect.analgesic effect.

• VAS1 and VAS2 is rated by the same health VAS1 and VAS2 is rated by the same health worker. worker. VAS3: Pain on admission at QT-hospital VAS3: Pain on admission at QT-hospital rated by the QT hospital-doctors (to validate the rated by the QT hospital-doctors (to validate the accuracy of VAS2 ratings by agreement analysis).accuracy of VAS2 ratings by agreement analysis).

Main variablesMain variables

2.Adverse event:2.Adverse event:

Nausea and/or vomiting during the Nausea and/or vomiting during the prehospital phase. Based on clinical prehospital phase. Based on clinical assessment at end-point plus information assessment at end-point plus information from patient, patient’s family and from patient, patient’s family and prehospital care provider.prehospital care provider.

The interventionThe intervention

Ketamine treatment:Ketamine treatment:• Prehospital pain relief was given by trained Prehospital pain relief was given by trained

health staff (doctors/nurses) in the Quang health staff (doctors/nurses) in the Quang Tri trauma system. Tri trauma system.

• VAS1 rating was done immediately before VAS1 rating was done immediately before in-field life support starts, as part of the in-field life support starts, as part of the clinical examination. clinical examination.

• The first dose of analgesic was given as soon The first dose of analgesic was given as soon as the patient’s airway is controlled. as the patient’s airway is controlled.

• Repeated doses were given during the Repeated doses were given during the transport to QT-hospital according to needs transport to QT-hospital according to needs assessment by the trauma health stassessment by the trauma health staffaff..

The intervention The intervention (continue)(continue)

Ketamine treatment: Ketamine treatment: • intermittent intravenous dose(s) 0.2 – intermittent intravenous dose(s) 0.2 –

0.3mg/kg body weight. The doses are 0.3mg/kg body weight. The doses are repeated until satisfactory pain relief as repeated until satisfactory pain relief as assessed by the trauma health staff. Each assessed by the trauma health staff. Each dose is given slowly.dose is given slowly.

• If more than one dose of ketamine is If more than one dose of ketamine is provided, also atropine was given to provided, also atropine was given to reduce salivation:reduce salivation:

• Atropine, vials of 1 mg/ml: One single Atropine, vials of 1 mg/ml: One single dose of intravenous atropine 0.1 mg/10 kg dose of intravenous atropine 0.1 mg/10 kg body weight.body weight.

The intervention The intervention (continue)(continue)

Control treatment:Control treatment:• One intramuscular dose of morphine 10 One intramuscular dose of morphine 10

mg (adults).mg (adults).• The treatment data (drugs, dosage, time The treatment data (drugs, dosage, time

of doses) was registered in-field by the of doses) was registered in-field by the trauma health sttrauma health staffaff and gathered at the and gathered at the end-point by investigator (doctor) end-point by investigator (doctor)

Time scheduleTime schedule

The inclusion of patients started 1 August The inclusion of patients started 1 August 2007.2007.

The study was concluded when a The study was concluded when a minimum 250 consecutively injured minimum 250 consecutively injured patients were included in treatment group patients were included in treatment group and control group.and control group.

Main Statistic ModelMain Statistic Model

• Matched pairs analysis for Diference Matched pairs analysis for Diference between VAS1 and VAS2between VAS1 and VAS2

• Agreement analysis for evaluation Agreement analysis for evaluation between VAS2 and VAS3between VAS2 and VAS3

• T test for continuous variables; Chi-square T test for continuous variables; Chi-square for categorical variables.for categorical variables.

• p value< 0.05 considered as significant p value< 0.05 considered as significant differencedifference

Inclusion and ExclusionInclusion and Exclusion

320 samples collected during research periods320 samples collected during research periods Exclusion: Exclusion:

Children <5 years oldChildren <5 years oldPatients with deep unconsciousPatients with deep unconsciousPatients used alcohol/beer before injuriesPatients used alcohol/beer before injuriesPatients given other plus analgesia than ketamine Patients given other plus analgesia than ketamine

and morphine (diazepam, atropine, declofenac, and morphine (diazepam, atropine, declofenac, dolargan)dolargan)

Inclusion: 257 patients included (140 in Inclusion: 257 patients included (140 in Ketamin and 117 in Morphine) was analysed Ketamin and 117 in Morphine) was analysed in this studyin this study

Ketamine Morphine

VAS1 7.07 7.26 6.84

VAS2 3.78 3.82 3.72

Mean Difference 3.29 3.44 3.11

Std Error 0.12 0.16 0.18

95% CI 3.06 - 3.53 3.14 - 3.75 2.75 - 3.48

N 257 140 117

Prob > |t| <.0001 <.0001 <.0001

Test across group P= 0.1679

Significant difference between VAS1 and VAS2, Significant difference between VAS1 and VAS2, P<0.0001P<0.0001

No significance between the mean difference No significance between the mean difference across ketamine and morphine group, P>0.05across ketamine and morphine group, P>0.05

Matched Pairs (Difference VAS1-Matched Pairs (Difference VAS1-VAS2)VAS2)

Moderate Major SevereVAS1 6.95 7.01 7.25

VAS2 3.70 4.15 3.78

Mean Difference 3.25 2,86 3.47

Std Error 0.16 0.37 0.20

95% CI 2.93 - 3.56 2.10 - 3.62 3.07 - 3.87

N 131 27 99

Prob > |t| <.0001 <.0001 <.0001

Significant difference between VAS1 and VAS2 in each Significant difference between VAS1 and VAS2 in each ISS group, p<0.001ISS group, p<0.001

ISS groupISS group Major Moderate Severe

Ketamine Morphine Ketamine Morphine Ketamine Morphine

VAS1 7.35 6.73 7.05 6.80 7.55 6.92

VAS2 4.22 4.09 3.70 3.69 3.89 3.65

Mean Difference 3.12 2.65 3.35 3.11 3.66 3.27

Std Error 0.41 0.59 0.21 0.26 0.27 0.30

Upper95% 4.03 3.90 3.76 3.62 4.21 3.87

Lower95% 2.22 1.39 2.93 2.59 3.11 2.67

N 12 15 76 55 52 47

Prob > |t| <.0001 0.0005 <.0001 <.0001 <.0001 <.0001

Test Across Groups

Prob>F Prob>F Prob>F

Mean Difference 0.53 0.47 0.33

Significant difference between VAS1 and VAS2 in each Significant difference between VAS1 and VAS2 in each group ,group ,

No significance difference between the mean difference No significance difference between the mean difference across Ketamine and morphine group in across Ketamine and morphine group in ISSISS

GENDER MALE FEMALE

VAS1 7.07 7.15 6.85

VAS2 3.78 3.81 3.70

Mean Difference 3.29 3.34 3.15

Std Error 0.12 0.13 0.26

Upper95% 3.53 3.61 3.67

Lower95% 3.06 3.08 2.62

N 257 191 66

Prob > |t| <.0001 <.0001 <.0001

Test Across Groups

Prob>F

Mean Difference 0.16

Significant difference between VAS1 and VAS2 in each Significant difference between VAS1 and VAS2 in each group ,group ,

No significance between the mean difference across No significance between the mean difference across male and female group, p>0.05male and female group, p>0.05

AGE < 15 Ketamine Morphine Male Female  

VAS1 7.19 7.31 6.94 7.07 7.47  

VAS2 4.15 4.02 4.4 4.28 3.82  

Mean Difference 3.04 3.29 2.54 2.79 3.65  

Std Error 0.45 0.61 0.58 0.53 0.82  

Upper95% 3.97 4.60 3.95 3.94 5.77  

Lower95% 2.11 1.98 1.13 1.65 1.54  

n 21 14 7 15 6Prob > |t| <.00

010.0001 0.0045 0.0001 0.0068

 

Test Across Groups

 

Mean Difference P=0.45 P=0.40  

• Significant difference between VAS1 Significant difference between VAS1 and VAS2 in each group , and VAS2 in each group ,

• No significance between the mean No significance between the mean difference across male and female difference across male and female group; and ketmaine and morphine group; and ketmaine and morphine group in AGE less than 15. group in AGE less than 15.

Age (15-54) KETAMINE MORPHINE MALE FEMALE

VAS1 7.08 7.25 6.87 7.17 6.70

VAS2 3.81 3.80 3.82 3.83 3.73

Mean Difference

3.27 3.45 3.05 3.34 2.97

Std Error 0.14 0.18 0.23 0.15 0.38

Upper95% 3.55 3.82 3.49 3.65 3.74

Lower95% 2.99 3.09 2.60 3.04 2.20

N 187 102 85 152 35

Prob > |t| <.0001

<.0001 <.0001 <.0001 <.0001

Test Across Groups

Prob>F F Ratio

Mean Difference

0.173 1.021

Age (15-54)Age (15-54)• Significant difference between Significant difference between

VAS1 and VAS2 in each group , VAS1 and VAS2 in each group , P<0.0001P<0.0001

• No significance between the No significance between the mean difference across male and mean difference across male and female group; ketamine and female group; ketamine and morphine group in AGE of 15-54. morphine group in AGE of 15-54. P>F P>F

AGE>=55 KETAMINE MORPHINE MALE FEMALE

VAS1 6.98 7.25 6.71 7.04 6.91

VAS2 3.49 3.78 3.21 3.35 3.63

Mean Difference

3.48 3.47 3.5 3.69 3.29

Std Error 0.24 0.32 0.37 0.25 0.41

Upper95% 3.97 4.12 4.26 4.20 4.13

Lower95% 3.00 2.82 2.74 3.18 2.45

N 49 24 25 24 25

Prob > |t| <.0001 <.0001 <.0001 <.0001 <.0001

Test Across Groups

Prob>F Prob>F

Mean Difference

0.95 0.41

Age >= 55Age >= 55

• Significant difference between VAS1 and Significant difference between VAS1 and VAS2 in each group , P<0.0001VAS2 in each group , P<0.0001

• No significance between the mean difference No significance between the mean difference across male and female group; ketamine and across male and female group; ketamine and morphine group in AGE of 55-90. p>Fmorphine group in AGE of 55-90. p>F

Nausea Percent Vomit Percent Nausea & vomit

Percent

KETAMINE n=140 7 5.00 3 2.14 0 0

MORPHINE n=117 36 30.77 32 27.35 20

Significantly difference between nausea and/ or vomit Significantly difference between nausea and/ or vomit with much higher rate in morphine group, P<0.0001with much higher rate in morphine group, P<0.0001

B. Agreement analysis VAS2 & VAS3

Statistics ParametersKetamine Morphine

Mean level 3.92 3.78 4.13

Mean difference -0.32 0.08 -0.82

Agreement limit (2SDdiff ) 4.36 4.08 4.48

Percentage (%) outliers 11/257 = 4.3%

7/140= 5.7%

8/117= 6.8%

Agreement index (AI)=1- 2SD(Dif) /

mean level

-0.11 - 0.08 -0.08

ConclusionsConclusions

1.Pain relief effect of Ketamine is the 1.Pain relief effect of Ketamine is the same pain relef effect of morphine.same pain relef effect of morphine.

2.Pain relief effect of Ketamine is clear 2.Pain relief effect of Ketamine is clear in each ISS groupin each ISS group

3.Pain relief effect of Ketamine is clear 3.Pain relief effect of Ketamine is clear in each age, and gender group.in each age, and gender group.

4.Adverse effect (vomiting/nausea) 4.Adverse effect (vomiting/nausea) much lower in Ketamine group than much lower in Ketamine group than morphinemorphine

DiscussionsDiscussions

1.1. Ketamine should be used as pain relief Ketamine should be used as pain relief in trauma care outside the hospitalin trauma care outside the hospital

2.2. How to change the doctors/nurses’ habit How to change the doctors/nurses’ habit to use ketamine rather than morphine in to use ketamine rather than morphine in community?community?

Thank you Thank you