EVALUATE THE EFFECTS OF KETAMINE (PAIN RELIEF DRUG) IN PREHOSPITAL TRAUMA CARE A CONTROLLED CLINICAL TRIAL IN QUANG TRI, VIETNAM SUMMARY

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1 JOURNAL OF SCIENCE, Hue University, N 0 61, 2010 EVALUATE THE EFFECTS OF KETAMINE (PAIN RELIEF DRUG) IN PREHOSPITAL TRAUMA CARE A CONTROLLED CLINICAL TRIAL IN QUANG TRI, VIETNAM Tran Kim Phung Quang Tri Health Services SUMMARY To compare the analgesic effect and adverse events (nausea/vomiting) of Ketamine versus Morphine analgesia to injury patients during pre-hospital evacuations. Methods: Patients injured in one sector get Ketamine relief (treatment group). Patients from the other sector get Morphine (controlled group). Patient s actual pain was assessed and rated on VAS. The difference VAS1-VAS2 is the indicator of analgesic effect. Adverse effect (nausea/vomiting) based on clinical assessment at the end point and interview. Results: 257 patients included of which: 140 in Ketamine and 117 in Morphine was analysed. Significant difference between VAS1-VAS2, p< No significant difference of analgesic effect between Ketamine and Morphine group, p>0.05. Analgesic effect of Ketamine is very clear in every ISS level, regardless of male, female and age groups. Conclusions: Analgesic effect of Ketamine in trauma care at community is clear, the same analgesic effect of Morphine. Adverse effect (nausea/vomiting) is much lower in Ketamine than Morphine. Key words: Analgesic effect, adverse events, pre - hospital. 1. Introduction Efficient pain relief is crucial in primary life support for trauma victims. Acute pain makes breathing efforts inefficient and thereby adversely affects oxygenation. Persistent pain and anxiety also trigger post injury release of catecholamines and cortisol and thus accelerate a post-injury stress response and aggravate immunosuppression. Uncontrolled post-injury stress response is a heavy risk factor for trauma death. In most pre - hospital trauma systems, opioid analgesics have been the analgesics of choice for the last few decades. These are potent analgesics, however they are not without potentially fatal side - effects. Evacuations are often rough and difficult in rural trauma scenarios; there may be mass casualties; patients may be carried off-road without ambulances; and the first helpers may not be able to provide continuous close 357

2 care and monitoring of vital signs in - field. Opioid analgesics may under such circumstances cause vomiting with risk of airway obstruction, especially so in patients weak from blood loss and hypotension. Airway block due to aspiration of vomit in un/low-conscious patients is considered the most common reason for avoidable trauma death. Also the range of therapeutic doses is narrow in opioids. There is thus a risk that accidental over-dosage causes respiratory depression, hypotension and loss of protective airway reflexes. Ketamine hydrochloride is a non-opioid potent analgesic that has been used for anaesthesia for decades. Ketamine stimulates the sympathetic nervous system and causes moderate increases in the heart rate and systolic blood pressure, a side-effect considered positive in bleeding trauma victims. Ketamine does not affect the respiration and laryngeal reflexes; under ketamine analgesia and anaesthesia the patient breathes spontaneously and maintains full airway control. Thus the drug does not have the dangerous side-effects seen with opioids, even if administered accidentally in doses that are too high. In Vietnam, morphine is routinely used for pre - hospital trauma pain relief. So far, Ketamine has not been used for trauma pain relief outside hospitals. Setting up a systematic pre - hospital trauma system in the province of Quang Tri, we want to study the effect of ketamine analgesia in protracted evacuations. Objectives: This study compared the analgesic effect and adverse effects of ketamine and morphine in pre - hospital trauma care where medical resources were scarce. 2. Methodology Study population Inclusion criteria Any patient in Quang Tri Province that was injured during the study period, regardless of type of trauma, whose pre - hospital life support was provided by trained health workers. The patients were given medical assistance during evacuation to Quang Tri Provincial Hospital (QT-PH), the end-point for this study. Exclusion criteria Refusal of analgesia by patient or patient s family. Deeply unconscious patients (no response to pain stimuli). Patients who had already died on first medical contact in-field. Patients given general or local anaesthesia in-field for invasive life-support measures (airway cut-down, chest tube placement etc.). 358

3 Patients with pre - hospital evacuation time < 10 minutes. Sampling and recruitment A systematic cluster sampling technique was used in this study We divided the province into two geographical sectors ( Sector 1 and Sector 2 ), each sector having approximately the same number of patients and approximately the same transport times. Patients injured in one sector received ketamine pain relief (Treatment Group); patients from the other sector (the rest of Quang Tri province) received morphine pain relief (Control Group). To reduce the impact of systematic failures, the sectors were then crossed over every month: Sector 1 shifts to Control, Sector 2 shifts to Treatment. Both groups were stratified according to injury severity using the Injury Severity Score (ISS, 10): Moderate injuries = ISS <9. Serious injuries = ISS Major injuries = ISS >15. Main variables Analgesic effect: Patient s actual pain assessed and rated on the Visual Analogue Scale (VAS) by the trauma care provider at two points: First (VAS1): at the first contact in-field immediately before life support starts. Second (VAS2): immediately on admission at the provincial hospital. The difference (VAS1) (VAS2) is the indicator of analgesic effect. VAS1 and VAS2 were rated each time by the same health worker. Therefore, all patients were accompanied to the provincial hospital by the local health worker who started the in-field treatment. Adverse events: Nausea and/or vomiting during the pre - hospital phase. Categorical variable, Yes/No, based on clinical assessment at the end-point, plus information from the patient, patient s family and pre - hospital care provider. The intervention Ketamine treatment: Intermittent intravenous dose(s) 0.2mg 0.3mg/kg body weight. The doses were repeated until satisfactory pain relief was achieved as assessed by the trauma paramedic. Each dose was given slowly over more than 60 seconds. Control treatment: 359

4 One intramuscular dose of morphine 10 mg (adults). Sample size n = Z 2 1 / 2. p (1 p ).( Z / 2 Z ) d 2 p 1 = 0.20: nausea/vomit rate by morphine p 2 =0.01: nausea/vomit rate by ketamine The study concluded when at least 125 consecutively injured patients were included in each group (treatment group and control group), the study ended 30 March Time schedule The inclusion of patients started from 1 August 2007 to 1 July Creating data for statistical analyses The statistical analysis was performed using JMP and PEST software. The main outcome variables (analgesic effect and adverse effect on airways) were analysed by sequential statistics using double triangular tests. 3. Results During the study process, a total of 320 samples was collected. Study included 257 samples. Of which : Ketamine n=140, Morphine n= Matched pairs analysis by analgesia Table 3.1. Matched pairs analysis by analgesia Total n = 257 Ketamine n=140 Morphine n=117 VAS VAS Mean Difference Std Error % CI N Correlation t-ratio DF

5 Total n = 257 Ketamine n=140 Morphine n=117 Prob > t <.0001 <.0001 <.0001 Test across group P= Matched pairs analysis by severity level for each analgesia group Table 3.2. Matched pairs analysis by severity level for each analgesia group Moderate Major Severe Ketamine Morphine Ketamine Morphine Ketamine Morphine VAS VAS Mean Difference Std Error Upper95% Lower95% N Correlation t-ratio DF Prob > t <.0001 <.0001 < < <.0001 <.0001 Test Across Groups Mean Difference Prob>F Prob>F Prob>F Matched pairs analysis by Gender Table 3.3. Matched pairs analysis by Gender GENDER MALE FEMALE VAS VAS Mean Difference

6 GENDER MALE FEMALE Std Error Upper95% Lower95% N Correlation t-ratio DF Prob > t <.0001 <.0001 <.0001 Test Across Groups Prob>F Mean Difference Nausea/vomitting Table 3.4. Nausea/vomitting frequency of Ketamine and Morphine Nausea Frequence Vomit Frequence KETAMINE n= MORPHINE n= P< Matched pairs analysis by age (<15) Table 3.5. Matched pairs analysis by age (<15) AGE <15 Ketamine Morphine Male Female VAS VAS Mean Difference Std Error Upper95% Lower95% N Correlation t-ratio

7 AGE <15 Ketamine Morphine Male Female DF Prob > t < Test Across Groups Mean Difference Prob>F F Ratio Prob>F Matched pairs analysis by age (15-54) Table 3.6. Matched pairs analysis by age (15-54) Age (15-54) KETAMIN MORPHIN MALE FEMALE VAS VAS Average difference Standard error % CI Sample size Correlation t-test Degrees of Freedom (df) P value <.0001 <.0001 <.0001 <.0001 <.0001 Test among groups Matched pairs analysis by age (>=55) Table 3.7. Matched pairs analysis by age (>=55) AGE>=55 KETAMIN MORPHIN MALE FEMALE VAS VAS Average difference

8 AGE>=55 KETAMIN MORPHIN MALE FEMALE Standard error % CI Sample size Correlation t-test Degrees of Freedom (df) P value <.0001 <.0001 <.0001 <.0001 <.0001 Test among groups Discussion 4.1.Matched pairs analysis by analgesia In our results there was a statistically significant difference between VAS1 and VAS2 for the total sample, as well as the individual groups: ketamine and morphine p< The mmean difference for the ketamine group was found to be 3.44, which that was slightly higher than the morphine group (3.11), however, no signifcant difference was found between the mean difference of the two groups. P = It also means that: the analgesic effect of ketamine is the same as the analgesic effect of morphine Matched pairs analysis by ISS level for each analgesia group In the ketamine group, the diference between VAS 1 and VAS 2 were 3.35, 3.12 and 3.66, slightly higher in comparison to 3.11, 2.65, 3.27 in the morphine group, respectively. But there was no significant difference in analgesia across each ISS group. p> Matched pairs analysis by gender There was a significant difference between VAS1 and VAS2 in male and female groups, p<0.001 but no significant difference between male and female. p>0.005 It also means that: the analgesic effect of ketamine and morphine is the same with male and female patients Nausea/vomitting In the ketamine group (n= 140) there were 7 cases of nausea, a rate of 5%; 3 cases of vomitng, a rate of 2,14%. In the morphine group (n= 177) there were 36 cases 364

9 of nausea, a rate of 30,77%; 32 cases of vomitng, a rate of 27, 35%. It showed that a higher rate of nausea/vomiting was found in morphine group compared to the ketamine group Matched pairs analysis by age of 6-14 In the ketamine group, there were 14 children, who were injured patients with an age range of 6-14 years. In the morphine group, there were 14 children- injured patients with an age range of 6-14 years (4 females). There was a significant difference between VAS1 and VAS2 in the ketamine and morphine groups, p<0.001 and respectively, but no signifcant difference was found between the mean difference of the two groups. p = Matched pairs analysis by age of In the ketamine group, there were 102 children- injured patients with an age range of years. In the morphine group, there were 85 children- injured patients with an age range of years. There was a significant difference between VAS1 and VAS2 in the ketamine and morphine groups, p<0.001 and respectively, but no signifcant difference was found between the mean difference of the two groups. p = Matched pairs analysis by age of >=55 In the ketamine group, there were 24 children- injured patients with an age range of >=55 years. In the morphine group, there were 25 children- injured patients with an age range of >=55 years. There was a significant difference between VAS1 and VAS2 in the ketamine and morphine groups, p< and respectively, but no signifcant difference was found between the mean difference of the two groups. p = Conclusions A total of 257 samples during pre - hospital evacuation were collected for the study analysis The analgesic effect of both ketamine and morphine were clear. There was a statistically significant difference between VAS1 and VAS2 for the total samples as well as the individual groups assigned to ketamine and morphine The analgesic effect of ketamine was the same as the analgesic effect of morphine. No signifcant difference was found between the mean difference of the two groups. 365

10 5.2. The analgesic effects of ketamine and morphine were clear by ISS, age and gender 5.3. The adverse effects of nausea and vomiting were much lower in the ketamine group than the morphine group (5% vs 30.77%) and (2.14% vs 27.25%), respectively. REFERENCES 1. Husum H, Gilbert M, Wisborg T, Heng YV, Murad M. Respiratory rate as pre - hospital triage tool in rural trauma. J Trauma (2003); 55: Demling RH, Youn Y-K. The stress response to injury and critical illness. In: Weigelt JA and Lewis FR. Surgical Critical Care. Philadelphia, WB Saunders Company; (1996): Hoyt DB, Winchell RJ, Ferris N. Analgesia and sedation. In: Weigelt JA and Lewis FR. Surgical Critical Care. Philadelphia, WB Saunders Company; (1996): Shapiro A, Zohar E, Zaslansky R et al. The frequency and timing of respiratory depression in 1,524 postoperative patients treated with systemic or neuraxial morphine. J Clin Anesth (2005); 17: Moore E, Mattox KL, Feliciano DV. Trauma Manual. New York, McGraw-Hill; (2003): Husum H, Gilbert M, Wisborg T, Heng YV, Murad M. Rural pre - hospital trauma systems improve trauma outcome in low-income countries: a prospective study from North Iraq and Cambodia. J Trauma (2003); 54: Whitehead J. The Design and Analysis of Sequential Clinical Trials. Wiley & Sons, Chichester; (1997). 8. Association for the Advancement of Automotve Medicine. The Abbreviated Injury Scale, 1990 Revision, Update 98. Des Plaines, IL; (1998). 9. JMP 6. Computer software for medica l statistics. SAS Institute, NC, USA; (2006). 10. PEST3. Computer software for sequential statistics. MPS Research Unit, Reading, UK; (1993). 366