الفهرس 
• HistoryOnly 14 pages are availabe for public view
 |  | from | 351 |  |  |
| | | from | 351 | | |
Abstract
Tramadol is an opioid with unique structure used in pain syndromes and abused by addicts. It acts as an agonist on μ-opioid receptors as well as on the noradrenergic and serotonergic systems. Its overdose has been one of the most frequent causes of drug poisoning in the country in the recent years, especially in male young adults due to its alleged enhancement of sexual performance.
The present study comprised a clinical part and an experimental part.
The clinical part was designed to construct a predictive model for tramadol intoxicated cases. Over a period of one year (between October 2010 and September 2011), the Poison Control Center (PCC) of Ain Shams University Hospitals received 1020 cases of tramadol intoxication. Out of these 1020 cases, two hundred and two (202) patients of both sexes were selected for this study. The selected patients were above 15 years in age, previously healthy and free from renal, hepatic, cardiovascular or respiratory diseases to avoid any effects of these diseases on the obtained results. Pregnant females, patients with history of epilepsy or co-administered benzodiazepines, barbiturates, alcohol, cannabis or opiates with tramadol were also excluded from the study.
These patients were classified according to their pattern of management in the Poison Control Center (PCC) of Ain Shams University Hospitals into three groups: Emergency department cases (group I), Inpatient cases (group II) and Intensive Care Unit (ICU) cases (group III). The patients in the later group were further subdivided according to their outcome into two subgroups: Patients admitted to Intensive Care Unit (ICU) and survived (group IIIa) and Patients admitted to Intensive Care Unit (ICU) and died (group IIIb).
Every selected patient was subjected to thorough history taking and clinical examination. The investigations which were done for each patient include: Electrocardiography (ECG), arterial blood gases (PH, HCO3, PO2, and PCO2), routine investigations (Serum glucose, Na, K), renal profile (BUN, serum creatinine), hepatic profile (AST, ALT, and serum bilirubin), CBC (WBCs, hematocrit value), CPK and CK-MB levels.
Calculation of APACHE II score for all patients as well as SAPS II (original and expanded) for ICU patients only were done. The results were then represented in tables, pie charts and histograms and discussed.
In the present study, age of the patients ranged from 16 to 69 years with mean age between 28.84 and 34.97 years. Males represented the majority of cases (78.7%) while females represented (21.3%). The mean delay time for reaching hospital was between 3.44 hours and 3.72 hours in group I and II while it was between 4.69 hours and 6.00 hours in group IIIa and IIIb. The mean dosage of tramadol taken ranged between 837.67 mg (group I) and 2856.25 mg (group IIIb). The majority of patients (81.7%) were addict on tramadol and showed accidental toxicity, 15.8% attempted suicide and only 2.5% due to iatrogenic manner. Duration of hospitalization of patients in the current study ranged between 1 to 6 days with most of them discharged within 1-2 days.
Regarding the vital data, almost all studied patients had tachycardia. There was non significant difference between group I, II and IIIa regarding systolic and diastolic blood pressure as well as the mean arterial pressure while there was significant decrease in group IIIb. Respiratory rate was within normal range in patients of group I and II while it was decreased in patients of group IIIa and increased in patients of group IIIb. group IIIb showed significant increase in body temperature when compared with group I, II and IIIa.
As regards skin examination, sweating was found in more than half of patients of group I (54.8%), 46.9% of group II and most of patients of group IIIa and IIIb (75% and 66.7% respectively). Cyanosis was seen in about all patients of group IIIa and IIIb while it was not observed in any patient of group I or II.
Regarding the pupil size, miosis was observed in most of patients of group IIIa and IIIb while mydriasis was observed in less than half of patients of group II (45.3%) and IIIb (44.4%).
Examination of the respiratory system revealed respiratory failure which occurs in most of patients of group IIIa (94.6%) and all patients of group IIIb (100%). Pulmonary oedema was observed in all patients of group IIIb (100%) and 21.4% of group IIIa.
Regarding the cardiovascular system, most of the studied patients had minor cardiovascular effects such as palpitation which occurred in 47.94% of patients of group I, 75% of group II and 41.1% of group IIIa. On the other hand, severe cardiovascular effects such as shock and cardiac arrest occurred in patients of group IIIa and IIIb as 7.1% of group IIIa and 77.8% of group IIIb suffered shock while 33.3% of patients of group IIIb presented with cardiac arrest.
Concerning the gastrointestinal manifestations, almost all cases of group I, II and about half of cases of group IIIa suffered nausea. Vomiting occurred in all patients of group II and most of patients of group I, IIIa and IIIb. Most of cases of group IIIb (77.8%) suffered diarrhea which was noticed in only 1.6% of cases of group II and 7.3% of cases of group IIIa.
Regarding the neurological manifestations, headache occurred in near half of patients of group I, II and IIIa. Dizziness was observed in 24.7% of group I and 45.3% of group II. Agitation was noticed in most of patients of group I, II and about half of group IIIa. All patients of group II (100%), 85.7% of group IIIa and 44.4% of group IIIb had seizures.
As regards coma, none of patients of group I presented with it which was seen in more than half of patients of group II and all patients of group IIIa and IIIb and it was commonly grade I. The mean glascow coma score (GSC) was between 13.91 and 14.95 in group I and II while it was between 3.00 and 8.76 in group IIIa and IIIb.
Arterial blood gas analysis (ABG) revealed metabolic acidosis in patients of group I and II while mixed metabolic and respiratory acidosis with hypoxemia was observed in severe cases (group IIIa and IIIb) which necessitate their admission to ICU.
Serum glucose was within the normal range for patients of group I and group II while it was slightly increased in patients of group IIIa and IIIb where half of studied patients (50%) had normal glucose level, 31.2% had hyperglycemia and only 18.8% of patients had hypoglycemia. As regards serum Na, it was within the normal range in almost all studied patients. On the other hand, serum potassium was within the normal range in patients of group I and II while it was decreased in patients of group IIIa and increased in patients of group IIIb.
As regards liver function tests, AST and ALT were within the normal range for patients of group I and II while they were increased in patients of group IIIa and IIIb. Regarding kidney function tests, serum urea was within the normal range for patients of group I, II and IIIa while it was increased in patients of group IIIb. Serum createnine was within the normal range for patients of group I and II while it was increased in patients of group IIIa and IIIb.
Total CPK and CK-MB were within normal levels in patients of group I and II while they were slightly increased in patients of group IIIa and markedly increasd in group IIIb.
The total leukocytic count was within the normal range for patients of group I and II while it was increased in patients of group IIIa and IIIb. The hematocrit value was within normal value in patients of group I and II while it was slightly increased in patients of group IIIa and IIIb.
As regards the electrocardiographic changes of tramadol intoxication, most of patients had sinus tachycardia (56.9%), 37.1% had prolonged QTc, 1.5% had elevated ST segment, 3% had depressed ST segment and 3% of patients had inverted T wave.
Concerning the outcome of patients, results indicated that death occurred in 9 (4.45%) out of 202 studied cases.
As regards the mean APACHE II Score, group IIIb showed statistically significant highest worse score (recorded to be 35.67) when compared with group I, II and IIIa. The area under the ROC curve for APACHE II score was 0.993, the best cut-off point was 11 with a sensitivity of 98.44% and specificity of 98.55%.
Out of the 14 parameters which constituted the APACHE II score, mean arterial pressure, serum createnine, pH, total leukocytic count and Glascow coma score were more often disturbed in patients who had a complicated outcome by multiple linear regression statistical analysis.
On comparison between APACHE II, SAPS II (Original) and SAPS II (Expanded) scores to estimate the discriminative power of the scores by the area under the ROC curve, the current study found non statistical significant difference.
By using discriminant analysis, the current study has discovered 15 variables, which best discriminate between the four studied groups. These variables are manner of poisoning, respiratory rate, cyanosis, respiratory failure, pulmonary oedema, shock, cardiac arrest, seizures, coma, ST segment changes, PH, HCO3, K, ALT and CK-MB.
The current study constructs and assesses a new score for prediction of prognosis of tramadol intoxicated patients from clinical and laboratory results obtained from the most predictive parameters affecting the APACHE II score by the multiple linear regression and the most important variables that differentiate best between the studied groups obtained from the discriminant analysis.
This predictive score depends on manner of poisoning, blood pressure, respiratory rate, skin manifestations (cyanosis), CNS manifestations (coma and seizures), cardiovascular manifestations (shock and cardiac arrest), pulmonary manifestations (respiratory failure and pulmonary edema) and ECG findings (ischemic changes as elevated or depressed ST segment, flat or inverted T wave, deep Q). In addition to investigational parameters which are simple, routine and readily available in most hospitals (PH, HCO3, serum K, createnine, ALT, total leukocytic count and CK-MB).
The area under the ROC curve for the predictive score was 0.996, the best cut-off point was 26 with a sensitivity of 98.46% and specificity of 95.62%.
The current clinical study concluded that patients with predictive score (which obtained from the current study) >26 on admission considered as mild cases and can be discharged from the hospital after observation for 6 hours while Patients with predictive score <26 on admission considered as moderate or severe cases and need careful monitoring in ICU until full recovery.
The experimental study was designed to deduce the mechanism of death of tramadol intoxication. It was carried out in the Medical Research Center, Ain Shams University on groups of adult albino rats. They were divided into 4 groups, every group comprised 15 rats. group I was the control group, groups II was the normal saline group, group III was the acute toxicity group and group IV was the dependence group.
The acute toxicity group (group III) was given a single dose of double the calculated LD50 of tramadol orally by gavage. The dependence group (group IV) received tramadol in gradually increasing doses until it reached the dependent dose in one month.
At the end of the experiment, surviving animals of group III (acute toxicity group) were sacrificed by cervical dislocation at 24 hours after a single dose for group III (acute toxicity group) and after the last dose at the end of the month for group IV (dependence group). Histopathological exanination of brain, heart, lung, liver and kidney were done for all animals of the all groups.
The current experimental study concluded that tramadol has the potential to cause major acute changes and irreversible damages to the brain, heart, lung, liver and kidney as documented by histopathological examination.
The present study recommended the need for governmental support and law enforcement mechanisms with restriction from the medicolegal side to deal with tramadol abuse in the whole country and limitation of approachability and distribution especially in younger ages as the findings of the present study showing an increase in tramadol morbidity and mortality.