LAUTECH TEACHING HOSPITAL (LTH) is a state owned teaching hospital, a young teaching hospital established in the year 1999 from a state hospital. It is located in OSOGBO the state capital of Osun state in southwest Nigeria. It is a tertiary hospital and receives referrals from primary, secondary and sometimes from neighboring tertiary centers; the catchment areas are Osun, parts of Oyo, Kwara, Ondo and Ekiti states. The emergency room (ED) has fifteen admission bed spaces.
3.2 STUDY POPULATION
The emergency department (ED) of LAUTECH Teaching Hospital (LTH), Osogbo receives an average of 3247 patients yearly. This includes all adult emergencies except obstetric
emergencies. Surgical patients account for about 1468 (45.2%) of the total patient load.
Presentation of acute abdominal abdomen accounts for about 242 (16.5%) of the surgical patients. About 16-37 patients present with features of acute abdomen monthly.
3.3 STUDY DESIGN
This is a prospective randomized double-blind placebo clinical trial using the synthetic opioid analgesic –Tramal brand of Tramadol as the active agent, and water for injection (WFI) as placebo. A blind study is chosen because this reduces the chances of the patient and the
investigators seeing what they hope to see or what they are predetermined to see and clinical randomized controlled trial because this kind of design provides the greatest justification for concluding causality, it is subject to the least bias and considered the epitome of all research designs.22
All patients that fit into the inclusion criteria were randomized after obtaining verbal informed (understood) and written signed consent. Four pre-designed proformas or forms (1-4) were completed as stated below.
Form 1: This is the pre-analgesia entry form- This form contains details of the patient’s entry identification data and bio-data, pre-analgesic clinical findings; pre-analgesic pain score (p1), the area of tenderness on abdominal palpation and other abdominal signs, the provisional diagnosis (dia1) and provisional decision-(deci-1). This form was completed before the administration of the formulated study agent.
Form 2: The immediate post analgesic outcome form 2: This form was completed 15-20 minutes after administration of the study agent, it contains any changes in the clinical findings, new symptoms and signs, the score of the residual pain (p2), the change in the area of tenderness, the diagnosis(dia2) based on the new prevailing clinical features and plan of treatment or decision (deci-2).
CHANGE IN PALPATION (CPAL) (This describes the change in area\region of tenderness or the disposition of the patient to abdominal palpation)
On abdominal examination, the area\location\spread\distribution of tenderness and disposition of the patient to accept palpation of the abdomen or the tender area after injection of study agent.
The change in palpation, CPAL, was recorded as follows:
(1) Change in area or region of tenderness: Narrowing or localization of area of tenderness (2) Change in disposition to tenderness: Patient holding the examining hand before but not after the injection of study agent.
(3) No change in area of tenderness
(4) Patients with both 1 and 2 positive were recorded as 1
(5) Patients with both 2 and 3 were recorded as 2
Form 3: The Postoperative outcome form 3. This contains the operative findings for the patient operated upon, it also contains the post-operative diagnosis (dia3). If the patient is not operated upon, then the diagnosis after adequate investigations or the diagnosis upon discharge is recorded as diagnosis 3 (dia 3). This dia3 is the definitive diagnosis.
Form 4: The end of trial outcome form 4. This was completed upon discharge from in-patient treatment. The form 4 contained the definitive management complications, outcome upon discharge and the duration of admission.
3.4 PAIN ASSESSMENT
The 0-10 numerical rating scale (NRS) was employed for this study; Patients were asked to record their pre- and post analgesic pain levels on a scale, with 0 representing no pain and 10 representing unbearable (worst ever experienced) pain.21,23
The numerical rating scale (NRS) was employed for this study because it can be assessed more objectively and easily with statistical methods compared to the others which are mostly ordinal variables. It also does not require ranking or re-grouping which may lead to loss of some information. Similar pain rating scale have been utilized in south-west Nigeria15 and for this study, the scale was also further validated by carrying out a pilot study using the NRS.
3.5 FORMULATION OF THE STUDY AGENTS
The study agents were prepared by a third party (supervisors) in the absence of the
investigator to ensure blinding. The agents were prepared using vials of tramal brand of tramadol [Grunenthal, Germany, Lot 676M03, NAFDAC No. 04-0483] and water for injection, WFI, (sterile water) in batches of six every 48hrs i.e. each batch was made up of three active agent-tramal and
three placebo samples. The preparation was done under aseptic condition using surgical gloves and needles and syringes.
PREPARATION OF ACTIVE AGENTS
To prepare the active agents, vials of water for injection (WFI) and tramal injection were obtained
The vials of WFI were cleaned with spirit and then 2mls of WFI was withdrawn and replaced with 2mls (100mg) of the injection tramal. The needle puncture sites were located at similar sites in all the vials and then sealed with plaster.
PREPARATION OF THE PLACEBO
All the WFI vials were punctured at sites similar to the puncture sites made on the WFI vials that contained the active agents. None of the content was withdrawn; the vials were then sealed with plaster at the puncture sites to make all the vials look identical.
After the preparation all the vials (those containing the active agents and those containing the placebo) looked identical.
STORAGE
Prepared study agents were stored in a refrigerator in the ED until used, study agents not used after 48hrs of formulation were discarded and new study agents formulated this is to reduce risk of contamination as much as possible.
3.6 DOUBLE BLINDING AND RANDOMIZATION
All the prepared agents in the identical vials of water for injection were labeled randomly.
The third party (supervisors) who prepared the agents kept the coding numbers to the active agents\the placebo until the end of the study when the analysis was commenced. There were equal
numbers of active agents and placebos in all the batches as earlier noted. The agents were administered randomly, and the results were documented as stated above in the forms 1-4.
SAMPLING STRATEGY
ELIGIBILITY: Patients that presented at the ED of LTH OSOGBO with symptom of Acute abdomen for which surgical consultation was required and who fit into the inclusion criteria for the study were included (NB. Not all consecutive patients were recruited for this study, but, only the patients that were reviewed by the investigator and fit the inclusion criteria)
Inclusion Criteria
1) patients aged 18 - 60years, (This age group has been used for study on tramadol25.Patients younger than 18 years may not be able to understand the instruction on the rating scale and may require lower dose of the active agent-tramadol. Patients above 60 years of age are advised to be given lesser dose of tramal (50mg) hence including patients below 18 or above 60 years may increase the confounding variables in the study)
2) Acute abdomen
3) Surgical Consultation required
4) Verbal (understood) and written consent Exclusion Criteria
1) Patients less than 18 years and 60 years and above25 ( see reason above in inclusion criteria) 2) Altered Sensorium or obtunded patients
3) Communication barriers & cognitive impairment 4) Drug and alcohol intoxication
5) Hypotensive 6) epileptics
7) patients on antipsychotic 8) pregnant or lactating patients 9) Allergy to study agent
10) Failure to obtain/give consent / failure to comprehend the instruction on the study instrument irrespective of the age
3.7 SAMPLE SIZE DETERMINATION
A retrospective review of accuracy of the provisional diagnosis of each of the 242 with acute abdomen (refer to section on study population above) managed in the 24 months preceding this study showed a correct provisional (preemptive) diagnosis of 145 i.e. 60 percent accuracy of clinical diagnosis. The diagnostic accuracy was confirmed in comparison with the final post-operative diagnosis, the diagnosis after investigations or retrospectively upon discharge.
The above knowledge was used to find the sample size for this study as follows
This study involves two groups; active agent and placebo groups (first assuming the sample sizes are equal in the two groups), the following questions were considered22,24
1. What is the desired level of significance, v, for this study? (this was taken as 5%), v
= 1.96 (The two-tailed z value).
2. What should be the chance of detecting an actual difference, that is, the power of the study (u)? This was set at 75%, 0.67.
3. How large should the difference be between the proportion in one group and the proportion in the other group (P1-P2) for it to be clinically significant? We take for this study P1 as 0.60 (60%, accuracy of clinical (preemptive) diagnosis in LTH ED in the retrospective study as stated above), and P2 as 0.85 (that is to achieve accuracy of 25% difference from 60% either way i.e. after two tailed analysis). Hence, a
difference in proportion of 0.25 will be considered significant.
The formula for sample size (n) calculation for each group in comparison of two proportions is as follows: in the modified Kirkwood formula.24
n = (u + v)2{P1(1-P1) + P2(1- P2)}/ (P1- P2)2.
n = (1.96+0.67)2{0.60(1-0.60) + 0.85(1-0.85)}/ (0.60-0.85)2 = 40.67 ≈ 41.
Hence, at least 41 patients were needed in each group for this study
3.8 DATA COLLECTION AND ANALYSIS
Collected data was entered into a computer and backed up. The investigator filed the hard copies of the proformas safely.
Comparison of the outcome measures was done after un-blinding using statistical program:
SPSS (statistical package of social sciences).
Data are presented, as proportions, ratios, percentages etc, and the significance analysis was done using chi-square and paired t-test. The significant p-value is taken as 5% (0.05).
The diagnosis, decision and effect on operation rate analysis are based on the intention to treat analysis ( i.e. patients are considered to be members of which ever group to which they were originally assigned regardless of whether or not they take the appropriate or prescribed therapy in part or completely)
CONSENT
Approval/clearance was obtained from the ethical committee of LTH Osogbo.
Surgery department and ER staffs were notified appropriately. Patients’ verbal (understood) and informed written consent was gained in the presence of a witness (the nursing staff on duty at the ER) before randomization.
3.9 DRUG SELECTION
The agent of study tramadol is a synthetic Opiate and one of the cheapest and readily available. It is free of most of the side effects of other opiates. Added, respiratory depression is not clinically significant at the recommended dose.19 It also has very limited popularity as recreational drug.19
DOSE SELECTION: The recommended dose is 50-100mg for adults (1-1.5mg/kg) and 1-2mg/kg for paediatric age group every 4-6hrs.19, 25-28 The selected dose was 100mg for this study as has been recommended for adults19 and also used27 the side effects are minimal at the recommended dose The Number Needed to Treat(NNT) is 4.7 for 100gm and 8.3 for 50mg which makes the 100mg dosage more efficacious while remaining safe.
ROUTE OF ADMINISTRATION OF STUDY AGENT
Available routes of administration are oral, intramuscular, intravenous and suppository.8,19,20
I/V route was employed for this study because:
(a) Most of the patients may have associated gastric stasis, nausea and vomiting or may be placed on nil per oris
(b) The intravenous route has faster onset of action, better bioavailability and the effect is less erratic compared to other routes.
UNBLINDING
This was done upon commencement of analysis other indications which could have
necessitated premature un-blinding such as new severe clinical symptoms and signs appearing after injection of the study agents which could be side effects of the injected agent were not present.
3.10 MEASURE OF OUTCOME PRIMARY OUTCOME
Post analgesic disposition i.e. change or no change in the diagnosis and course of treatment or decision
The parameters for measure of the primary outcome 1) Change in clinical findings
2) Change in diagnosis
3) Delay in the definitive treatment\ decision 4) Change in treatment
5) Change in laparotomy rate 6) Rate of misdiagnosis
SECONDARY OUTCOME
1. Hospital-stay-in time (duration of admission) 2. Complication rate and pattern of complication 3. Change in pain score following analgesia
END OF TRIAL
Entries for each patient ended upon discharge or death of patient.
Patient randomization was stopped after 90 patients.
3.11 SURVEY INSTRUMENTS
Pain assessment scale (NRS: 1-10)
Analgesic: Tramadol AND Water for Injection (Placebo)
Entry and outcome forms (PROFORMA)
3.12 LIMITATIONS
Formulation of study agents every 48hrs was cumbersome, time consuming and not cost effective, it would have been better to get a pharmaceutical company involved in the
formulation of the study agents but the study agents were obtained from retail outlets where our patients purchase their drugs because it will be representative of what we use for our patient rather than to have the pharmaceutical company prepare them specially.
There was wastage of a large amount of prepared study agents due to refrigeration time of more than 48hrs.
The potency of the active agent (tramadol) could not be verified, as they were not analyzed before use.
The use of statum dose of analgesic rather than successive incremental doses until pain is relieved could affect the results but could result in impaired sensorium.