|Year : 2016 | Volume
| Issue : 3 | Page : 458-462
Levofloxacin: a rarely suspected cause of delirium
Vivek Chowdhry MD, PDCC, FCCS 1, B. B. Mohanty2
1 Department of Cardiac Anaesthesiology, Care Hospital, Bhubaneswar, Odisha, India
2 Department of CVTS, Care Hospital, Bhubaneswar, Odisha, India
|Date of Submission||12-Aug-2015|
|Date of Acceptance||03-Apr-2016|
|Date of Web Publication||31-Aug-2016|
Department of Cardiac Anaesthesiology, Care Hospital, Chandrasekharpur, Bhubaneswar - 751 024, Odisha
Source of Support: None, Conflict of Interest: None
Delirium or psychosis is a common entity in the postoperative period, affecting elderly ands well as middle-aged and young patients. Multiple factors predispose a patient to different forms of delirium. Postoperative delirium is associated with acute alteration in attention and cognitive impairment, which is responsible for significant increase in both morbidity and mortality. A wide range of drugs, including fluoroquinolones, can cause mental status changes in the postoperative period. Thus, a thorough knowledge of various drug actions and interactions as well as various risk factors can help an anesthesiologist counter the possible deleterious effects of delirium during the perioperative period. The side effects of fluoroquinolones on the central nervous system are well documented, although they are rarely suspected as the offending agents for delirium. We report the case of a middle-aged lady who after mitral valve replacement became delirious following levofloxacin administration in the postoperative period.
Keywords: delirium, fluoroquinolones, levofloxacin, neuropsychiatric symptoms, postoperative psychosis
|How to cite this article:|
Chowdhry V, Mohanty B. Levofloxacin: a rarely suspected cause of delirium. Ain-Shams J Anaesthesiol 2016;9:458-62
| Introduction|| |
Fluoroquinolones can cause adverse neuropsychiatric side effects, which, although more frequent in the elderly ,, have also been described in the young. Among the fluoroquinolones, levofloxacin is a widely used antimicrobial agent because of its broad spectrum of antibacterial activity, convenient once-daily dosing, lowest adverse drug reaction rates among all fluoroquinolones, and better tolerability profile. Despite well-documented side effects, fluoroquinolones are an under-recognized cause of changes in mental status.
A number of risk factors have been described to cause postoperative delirium and psychosis. As psychosis and delirium in the postoperative period are associated with increased risk for complications, increased medical costs, and death, prompt diagnosis and management are of paramount importance. With many risk factors interplaying, diagnosing a case of drug-induced psychosis is immensely challenging. We report a case of levofloxacin-induced postoperative acute psychosis in a middle-aged lady following mitral valve replacement that was successfully managed.
| Case history|| |
A 55-year-old lady with severe mitral valve stenosis and atrial fibrillation, New York Heart Association (NYHA) class III/IV, was scheduled for mitral valve replacement. The preanesthetic check-up, a day before the surgery, was found to be normal with no significant comorbidities, and her baseline blood pressure was 116/66 mmHg. In the operating room, the patient was monitored as per the American Society of Anesthesiologist standards. The patient was induced with 0.1 mg/kg midazolam and 10 μg/kg fentanyl; her trachea was intubated with a 7.0-mm cuffed endotracheal tube after administration of vecuronium bromide 0.2 mg/kg and she was put on mechanical ventilation with a mixture of 50% oxygen in air. Anesthesia was maintained with isoflurane and intermittent boluses of fentanyl and pancuronium bromide. After median sternotomy, cardiopulmonary bypass (CPB) was instituted with aortobicaval cannulation after achieving an activated clotting time of over 480 s. On CPB, a nonpulsatile flow was maintained, and the mean blood pressure was kept between 65 and 75 mmHg. The mitral valve was replaced through the left atrial approach with a 29-mm mechanical valve (St. Jude Medical Inc., Minnesota, USA). The patient weaned off CPB without any difficulty and had an aortic cross-clamp time of 46 min and CPB time of 64 min. Bleeding was checked thoroughly and heparin was reversed with protamine to normalize activated clotting time. Two units of fresh frozen plasma and 2 U of platelet concentrate were transfused after coming off CPB as per institutional protocol. The chest was closed over two chest drainage tubes, and the patient was transferred to the ICU and put on a ventilator with stable hemodynamics. Postoperative analgesia was maintained with 25 μg/h of fentanyl infusion for the first 24 h and then with intravenous paracetamol infusion. The patient was extubated in the morning after 14 h.
On the third postoperative day (POD), the patient was conscious, oriented, and stable hemodynamically, without any inotropic or vasopressor support. The arterial line, drainage tubes, and urinary catheter were removed, and intravenous antibiotics were stopped. On the fourth POD, the patient had a bout of fever and complained of burning sensation while micturition. The urine examination revealed many pus cells. As per our local sensitivity to urinary pathogens, oral levofloxacin 750 mg once daily was started empirically and a urine sample was sent for culture. In the night, the patient had difficulty in sleeping, and lorazepam 2 mg was given orally after which the patient slept for a few hours. In the morning on the fifth POD, the patient was anxious, restless, and complained of sleeplessness. Psychiatric assessment revealed the patient to be anxious, irritable, agitated, confused, and disoriented, having difficult recall of recent events, and confusion assessment method for ICU (CAM-ICU) was found to be positive. The patient was diagnosed to be suffering from hyperactive delirium, and as per the psychiatrist's advice tablet clozapine 5 mg twice daily was started. On the sixth POD, the patient was found to be drowsy, irritable, restless, and agitated. Suspecting cardiorespiratory complications, arterial blood gases analysis was done and found to be normal; transthoracic echocardiography revealed normal functioning prosthetic mitral valve, no pericardial collection, and good biventricular function. As there were no signs of low cardiac output, we did a computed tomography scan to rule out any cerebrovascular event as a cause of this mental irritability. However, the computed tomography scan was also found to be normal. At last, after excluding both brain and cardiovascular abnormality, we reviewed the patient's medication chart and stopped levofloxacin. Twenty-four hours after stopping levofloxacin, the patient's mental condition started improving and she had less difficulty in sleeping at night; hence, clozapine was stopped. After 48 h, the patient felt better, and the restlessness and agitation had reduced. For urinary tract infection, cefixime 200 mg was started twice daily as per the culture sensitivity report. After 72 h of stopping levofloxacin, the repeat psychiatric assessment found the patient to be alert, attentive, and oriented, with good recall of recent and remote memories. As the patient's mental condition became absolutely normal, she was discharged on the eighth POD.
| Discussion|| |
Delirium is defined as an acutely altered and fluctuating mental status with features of inattention and an altered level of consciousness. Delirium could be hyperactive, where the patient is aggressive and agitated, or hypoactive with signs of inattention and decreased awareness of the environment. However, some patients have a combination of both hyperactive and hypoactive delirium, which is called mixed delirium. The most common types of delirium in the ICU are mixed and hypoactive . The incidence of postoperative delirium ranges from 10 to 46% in the general surgical population and after cardiac surgery varies from 8 to 52% .
Delirium is a neuropsychiatric syndrome that is associated with cardiac surgery from the very beginning of CPB, described as postcardiotomy delirium . Cardiac surgery can lead to postoperative cognitive dysfunction or neuropsychiatric symptoms due to microembolization ,, hypoperfusion of the brain , systemic inflammatory response syndrome , anesthesia , preoperative or postoperative depression , and low cardiac output. Delirium can also be due to various pharmacological agents [Table 1]. As so many causes can give rise to neuropsychiatric symptoms after cardiac surgery, sometimes it becomes a difficult task to pinpoint a specific cause for these manifestations.
Fluoroquinolones are widely used in the treatment of various infections because of their broad spectrum of antibacterial activity. Levofloxacin, a third-generation fluoroquinolone, is an optically active l-isomer of the racemate ofloxacin. The l-isomer represents the active component of levofloxacin, with the d-isomer being inactive, making levofloxacin more potent in vitro against both Gram-positive and Gram-negative bacteria than ofloxacin. Levofloxacin works by inhibiting bacterial topoisomerase IV and DNA gyrase, preventing bacterial DNA replication, transcription, repair, and recombination . Almost all the fluoroquinolones have been reported to have neuropsychiatric manifestations; however, levofloxacin has better tolerance profile than most of the fluoroquinolones available. A European study in 2001, while assessing the side effects of levofloxacin, found the incidence of psychosis to be only one in six million prescriptions . The major reported adverse effects of fluoroquinolones are gastrointestinal (3–17%) and central nervous system (CNS)-related (0.9–11%) disturbances. The CNS-related side effects of levofloxacin are headache, dizziness, restlessness, tremor, insomnia, anxiety, psychosis, hallucinations, convulsions, and depression, which occurs with varying intensity ,,,,,. Seizures and hallucinations have been reported less commonly, but have been noted to occur with greater frequency in individuals with conditions that predispose them to CNS disorders, or in those who receive both quinolones and theophylline or a NSAID . Risk factors for neurotoxicity include renal insufficiency and underlying CNS disease  due to declined CNS as well as renal functions in older age. Elderly patients are highly prone to neurotoxicity.
The development of these CNS adverse effects correlates with the degree to which the fluoroquinolones bind to GABA and N-methyl-D-aspartate (NMDA) receptors. GABA is an inhibitory neurotransmitter of the brain. Quinolones prevent normal binding of GABA with their receptors  and directly activates NMDA and adenosine receptors. Thus, under specific conditions of sufficient CNS penetration, fluoroquinolones cause antagonism of inhibitory pathways (GABA) and stimulation of excitatory pathways (NMDA, adenosine) leading to excitatory CNS manifestations. This mechanism explains the pathogenesis of the acute anxiety and insomnia in the above case with levofloxacin therapy ,.
As per the clinical practice guidelines  delirium is an independent predictor of negative clinical outcomes in ICU patients. The baseline risk factors associated with postoperative delirium are pre-existing dementia, hypertension, alcoholism or drug abuse, and severe illness at admission. There are conflicting reports of association between delirium and use of drugs such as opioids, benzodiazepines, propofol, and dexmedetomidine. A number of delirium-monitoring tools are in practice, of which CAM-ICU and the Intensive Care Delirium Screening Checklist are the most valid and reliable tools in adult ICU patients.
Our patient did not have any baseline preoperative risk factors for delirium. She was recovering well in the postoperative period with stable hemodynamic and mental condition. From the fourth POD onward she had sudden deterioration of mental status with headache and insomnia, which gradually progressed to delirium. As there was no suggestive preoperative history or intraoperative event, we tried to exclude cardiorespiratory and cerebrovascular events. After careful exclusion of the most common causes and possibilities, we reviewed the drug chart and stopped levofloxacin. Within 48 h of discontinuing levofloxacin, the patient's condition improved symptomatically, and a repeat psychiatric evaluation found the patient to be alert and oriented with normal speech, concentration, and recall. Because clinicians may not always associate such findings with a pharmacotherapy, particularly an antibiotic, our case report serves to highlight the importance of considering the potential effects of the drugs when presented with such a clinical picture.
Neurotoxicity of fluoroquinolones is an important problem that has to be considered with this group of antibiotics. As the ICU psychosis or delirium in the postoperative period can inflate the medical cost, increase the hospital stay, and increase morbidity and mortality, we recommend the following:
- Patients having risk factors for postoperative delirium should be screened.
- Routine monitoring for delirium should be carried out in adult ICU patients.
- Nonpharmacological methods for decreasing the incidence of delirium, such as early mobilization, should be practiced whenever feasible.
- General measures such as exposure to daylight, reduction of noise, and minimization of the use of artificial lights at night and providing uninterrupted night-time sleep can decrease the incidence of delirium.
- Dehydration or hypovolemia, nonessential catheters, and multiple intravenous lines should be avoided because their presence is associated with an increased risk for delirium.
- Provide patients with their visual aids and hearing aids in the recovery area for better vision and hearing.
- The family should be encouraged to interact with the patient for psychological support and to maintain adaptive cognitive functions.
- Safety issues must be addressed for agitated patients against self-harm. Judicious clinical judgment and communication with the nursing team is essential. Restraints should be used only when other means of treating delirium have failed, as restraints can exacerbate delirium and lead to injuries.
- The intensivist should identify the cause promptly and should have thorough knowledge of adverse effects of the drugs used in the postoperative period.
- Dose of fluoroquinolones should be modified according to creatinine clearance in patients with renal dysfunction.
- In case of established postoperative delirium, a step-wise management strategy should be used [Figure 1] and atypical antipsychotics can be used to reduce the duration of delirium.
|Figure 1 Flow chart: strategy for the management of patients with postoperative delirium after cardiac surgery.|
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