Convulsions following rapid ceftazidime administration for preinduction antibiotic prophylaxis during neurosurgical procedure.

Ceftazidime is a widely used antibiotic with broad spectrum activity against Gram-positive and Gram-negative microbes and is used prophylactically in neurosurgical patients prior to surgery. Neurotoxicity is a recognized complication of ceftazidime use but is reported predominantly after repeated administration in patients with impaired renal status. We encountered a patient with an intracranial tumor who developed generalized convulsions following a single dose of ceftazidime, which was infused rapidly and attempt to provide an explanation of this uncommon occurrence.

INTRODUCTION

Prophylactic antibiotics are often administered prior to neurosurgical procedures to minimize or eliminate potential postoperative infections such as wound infection, meningitis or abscess. Ceftazidime is a potent 3rd generation cephalosporin with beta-lactamase resistance, antistaphylococcal activity and pseudomonal coverage which is employed for prophylactic antimicrobial therapy in neurosurgical procedures.[123] We report a case where a patient posted craniotomy and excision of intracranial tumor developed generalized convulsions following rapid intravenous administration of ceftazidime preoperatively. Written consent was obtained prior to reporting this event.

CASE REPORT

A 14-year-old male patient (30 kg weight) with the diagnosis of fourth ventricular ependymoma was posted for suboccipital craniotomy and excision of tumor in the prone position. Preoperative assessment did not reveal any other comorbidities, previous seizures episodes, drug allergies, and normal laboratory values (including renal functions). The patient was conscious, alert, and cooperative. However, examination showed that the patient was emaciated (due to poor nutrition) and had been bed ridden due to the primary disease for 1 month.

In the operation theater, after connection of monitors, intravenous access with an 18 gauge cannula was established. To compensate for any hemodynamic disturbances caused following anesthesia induction and prone positioning it was decided to preload the patient with 500 ml of 0.9% sodium chloride over 15 min. Preloading started and about 300 ml of 0.9% normal saline was infused over the next 10 min. When about 200 ml of the fluid was remaining in the fluid bag, 1.5 g injection ceftazidime (preinduction antibiotic prophylaxis as per departmental protocol) was diluted and added in the fluid bag for simultaneous administration before induction of anesthesia. 200 ml of this fluid was rushed within 5 min and just as the infusion completed the patient developed generalized convulsions. A Guedel's airway was immediately inserted inside the patient's oral cavity to prevent tongue bite. The seizures did not subside in the succeeding 20 s and injection midazolam (4 mg) was administered. The seizures abated with the administration of midazolam, and the patient could be ventilated with a face mask. Blood samples were sent promptly for estimation of blood gases, electrolytes, sugar, and serum albumin levels. Vital parameters of the patient were stable and remained so, thereafter. The reports of investigations meanwhile showed slight acidosis (pH - 7.24), hypercarbia (49 mmHg), and hypoalbuminemia (albumin-3 mg/dL). Blood sugar and electrolytes were within normal levels. By the time the laboratory reports (which were not grossly abnormal) had arrived, the patient had regained consciousness with a Glasgow coma scale of 14/15 (eye opening to speech). After mutual discussions with the surgeons, we decided to continue with the surgery after making provisions for elective postoperative ventilation. Injection thiopentone sodium (120 mg) and a nondepolarizing muscle relaxant (injection rocuronium, 30 mg) were now administered and the patient was intubated. Invasive lines (arterial and central venous catheters) were placed for stringent monitoring of hemodynamics and regular intraoperative sampling.

Subsequently, the patient was turned prone for surgery. The surgical course lasted for 4 h and was uneventful. Postoperatively, the patient was transferred to the Intensive Care Unit (ICU) for overnight elective ventilation in view of the perioperative adverse event (convulsions). He could be safely extubated the following morning. Injection ceftazidime was omitted from the postoperative antibiotic schedule and replaced with Ciprofloxacin. He was vigilantly monitored for recurrence of convulsions, which, however, did not occur. His postoperative stay in ICU (for 2 days) and ward (for 6 days) was unremarkable and after making a satisfactory recovery, he was discharged on the 10th day after surgery.

DISCUSSION

Previously described adverse neurological effects attributed to ceftazidime include hallucinations, absence status, encephalopathy, confusion, sore throat, chest tightness, wheezing, and myoclonus.[45] Predisposing factors for antibiotic induced neurotoxicity includes reduced renal clearance, excessive dose, increased cerebral penetration, and increased unbound antibiotic levels.[6] Renal insufficiency influences development of neurotoxicity as ceftazidime is not metabolized and excreted exclusively by the kidneys. The mechanism of neurotoxicity and convulsions caused by cephalosporins involves the inhibition of binding of gamma amino butyric acid with their receptors. Electroencephalography changes consistent with seizure activity can arise such as polyspike discharges, rhythmic slow waves or irregular spikes or sharps, which initially may be confined to one region, then become widespread and subsequently involve both the cerebral hemispheres.[5] Resulting in overt convulsions or continuous subclinical seizures. Benzodiazepines are the first line drugs used to terminate such episodes.[6] Readministration of ceftazidime could again have deteriorated the neurological status.[5]

Majority of the previously reported cases of adverse effects related to central nervous system (CNS) had been reported in patients with deranged renal profiles and receiving multiple doses of ceftazidime. In contrast, our patient had normal renal functions and had received a single dose of the drug. His preoperative biochemical and electrolyte profiles were within normal limits, and there was no antecedent history of seizures in spite of the existence of the intracranial lesion. No drug was administered concurrently which might have precipitated cephalosporin cross reaction. We hypothesized that the following conditions would have been the reason for generation of convulsions in our patient. First, due to the rapid bolus of the drug infused intravenously, there would have been a sudden peak in the plasma concentration of the drug in spite of administering the prescribed dosage (30–50 mg/kg). Typically 1 g dosage of ceftazidime results in a peak serum concentration of 55 µg/ml. However, high peak levels (185 µg/ml) have been reported to have been reached in patients whose renal functions were normal.[7] Measurement of serum ceftazidime concentration during the event would have clinched the diagnosis, which was missed due to the emergent situation. Even though serum ceftazidime concentrations were not measured at that point of time, it is likely to be elevated because of the rapid rate of administration.

Second, the relationship of serum ceftazidime concentration and neurotoxicity is not established but cerebrospinal fluid (CSF) concentration of ceftazidime is estimated to average 23% of concurrent blood levels.[8] It has been found that the CSF penetration of ceftazidime in patients with diseased meninges is higher than in those with normal meninges.[9] Due to the presence of a preexisting intracranial pathology, the structure of blood-brain barrier was probably altered leading to an increase CSF concentration of the drug. Concentration of seizure causing drugs can increase not only by large doses but also due to changes in blood-brain barrier permeability.[10] Existence of an intracranial tumor might also have reduced the seizure threshold in the patient.

Finally, a slight increase in the free form of drug expected in this patient due to hypoalbuminemia would also have contributed to the rise in plasma concentration and consequently, the CSF concentration. Even though this effect is negligible considering the plasma protein binding of ceftazidime is only 17%.[11]

Though convulsions in neurosurgical patients can be multifactorial, in our patient the temporal association of rapid ceftazidime administration and seizure generation makes it the likely culprit for the occurrence in view of its known neurotoxicity and the alteration in the CNS physiology due to the tumor. There was no recurrence of seizures in the postoperative period after the drug was withdrawn. Thus, ceftazidime administration in neurosurgical patients should proceed with utmost caution. Apart from the patient's renal profile, the presence of concurrent CNS pathology should be considered during therapy with ceftazidime. Infusion rate of the drug must be very slow with constant monitoring of the mental status and seizure control measures should be readily available whenever antimicrobial therapy with ceftazidime is undertaken.