Z Sal?hoglu, S Dem?roluk, S Karaca, Y Kose
anaesthesia, midazolam, paradoxal reaction
Z Sal?hoglu, S Dem?roluk, S Karaca, Y Kose. Paradoxıcal Reactıon Wıth Mıdazolam. The Internet Journal of Anesthesiology. 2006 Volume 13 Number 2.
We report 4 cases of paradoxical reaction to midazolam after being used for sedation. The picture was characterized by a marked aggressiveness. In one case the reaction was treated with general anesthesia, whereas in the other two patients the clinical picture was rapidly reversed by administration of fentanyl. We describe the possible causative mechanisms of this reaction as well as their treatment.
Midazolam has sedative, anxiolytic, and anesthetic effects with proper doses. However even with normal doses excitation, aggression, disorientation, tachycardia, uncomfortable feeling can be seen. This phenomenon is called as paradoxical dishinibitory reaction. (1).
We report 4 cases of paradoxical reaction to midazolam after being used for sedation in our clinic during past 10 years. The picture was characterized by a marked aggressiveness. In one case the reaction was treated with general anesthesia, whereas in the other two patients the clinical picture was rapidly reversed by administration of fentanyl. We describe the possible causative mechanisms of this reaction as well as their treatment.
A 82 years old male was diagnosed with inguinal hernia. In preanesthetic examination signs of pulmonary infection was determined and expiratory time was longer than normal. He was consultated by respiratory diseases department. He had diagnosis of mixed type respiratory disease. Following three weeks treatment including antibiotics, corticosteroids, aminophylline, mucolitic and antitussive medication his respiratory tests were normal. Blood gas analysis was normal. In his medical history several antiulcer drug use was noted. Epidural anesthesia was chosen for the operation. In the operation room under standard monitorization 0.015 mg/kg iv midazolam was given the patient for sedative purpose. When we applied local anesthesia for epidural procedur we observed agitation. The patient calmed down and sedated with fentanil 1 ?gr/kg. The patient became stable and general anesthesia preferred for the operation under new circumstances. There were no extra problems during and after surgery. The patient was send his ward after the operation.
A 60 years old female patient was diagnosed with choledocholithiasis when she came to the emergency room with vomiting and abdominal distention. Laparoscopic cholecystectomy was planned. In the patient's medical history there was digoxine use over a year due to the heart failure and also H2 receptor antagonist (ranitidine). Her blood pressure was 160/60 mmHg and heart rate was 60 min-1. She was concultated by cardiologist and no additional treatment was suggested. All other laboratory tests were normal. In the operation room addition to standart monitorization for invasive blood pressure measurement placement of arterial canulla was planned. Local anesthetic applied for cannuluzation and 0.015 mg/kg iv midazolam was given for sedation. The patient showed agitatation after midazolam administration. Fentanil 1 µgr/kg iv was given for sedation. Later on, general anesthesia induction was started and she was successfully operated.
A 38 years old female patient was planned to have operation for breast cancer. All preanesthetic examinations and laboratory tests were normal. Midazolam 0.01 mg/kg iv was given for preoperative sedation. Agitation was observed after midazolam administration. General anesthesia induction was immediately statd. She was operated without any problem.
A 35 years old female patient was planned to have operation for breast cancer. All preanesthetic examinations and laboratory tests were normal. Midazolam 0.01 mg/kg iv was given for preoperative sedation. Agitation was observed after midazolam administration. General anesthesia induction was immediately statd. She was operated without any problem.
Midazolam is a frequently used drug which is belong to benodiazepins. Imidazol chain group provides water solubility and short acting time. Its effects like sedation,dizziness,sleep and anesthesia are dose dependent effects. Its first effects limbic system and it supplies muscle relaxation by central nervous system. Midazolam is anticonvulsan drug also decreases intracranial and intraocular pressures.(2)
However even with proper doses excitation,aggression,tachycardia, uncomfortable feeling and disorientation can be seen. This phenomenon is called as disinhibtory reaction or paradox reaction.(3,4).
Massanari et al reported that incidence of this phenomenon is (4) % 1.4. In a study by Pena and Krauss (5) in 7 children among 1180 showed this phenomenon after sedation with midazolam. In another study with dogs showed that ataxia and agitation can reverse in two our following midazolam administration (6). Oral midazolom intake can cause delirium in children (7).
It is not well understood what causes the paradoxical reaction. It is believed that some people who has personality problems and genetic characteristics shows this phenomenon. Hypoventilation, hypoxia, hypotension and other drugs can start or worsen the situation. Midazolam mainly effects benzodiazepin receptors in GABA receptor complex and it can also effect acetylcholine, seratonin or catecholamine mediator functions. Existing pain,fewer and constipation can cause the phenomenon. Lorezepam or clormetimazol can be used for agitation (8).
Senninger and Laxenaire (6) claimed that paradoxical reaction is dose dependant. Many different kind of drugs are used for treatment and flumazenil can reverse the signs of this phenomenon without blocking the sedation. (3,4,10). Opioids or haloperidol use can be another choice to treat the reaction (11). General anesthesia can be used for persisting reactions (3).
Massanari et al reported that paradoxical reaction (4) can be see in 17 minutes after midazolam administration and can reverse in 14 minutes after flumazenil administration.
In our clinic, we use midazolam mostly for preoperative sedation in the operation room and we start anesthesia induction in very short time after drug use.
In our two cases, one had heart problems and other had respiratory problems. The patient with respiratory problems had proper treatment in preoperative period and his SpO2 value could raise till %94. The patient with diagnosis of heart failure was using digoxcin. As we described above, both of this respiratory and cardiac problems can cause paradoxical reaction.
In our two cases, even there were no possible causes leading paradoxical reaction in patients' medical background we observed agitation in both patient after midazolam administration.
Midazolam is mainly eliminated in liver so that all changes in liver blood flow can effect its elimination time and influence. H2 receptor antagonists can change liver blood flow and also cause enzyme induction resulting in alteration of drug metabolisation. Cytochrom p 450 is one of the enzymes playing role of elimination of midazolam. The drugs inhibiting cytochrom p 450 can effect midazolam's metabolisation and influence. (12). In our first case the patient was using anti ulcer drugs and in our second case she was using H2 antagonist.
Midazolam is a watersoluble drug however in physiologic pH value it behaves like lyophilic drugs and it can pass through the blood brain barrier (13). This gives drug anterograd amnesia properties, which is a desired effect of midazolam, but also can cause agitation and aggression.
Midazolam is sedative, anesthetic and anxiolitic drug but it has no analgesic effects. In our two cases although we used the local anesthetics agitation was observed after painful procedures. We observed sedation after use of narcotic analgesics which possibly resulted in pain relief.
Ziya Salihoglu, MD 7-8 Kisim Ata sitesi, Deniz 9 Blok Daire no: 67, 34750 Ataköy-Istanbul/TURKEY Tel: +90 212 573 20 42 Fax: +90 212 529 56 00 E-mail: firstname.lastname@example.org