Phaedra Dowell, MD PGY2 Neurology Resident

Transcription

1 Phaedra Dowell, MD PGY2 Neurology Resident

2 CC: Abnormal Movements 73 y.o. F - Transferred from an OSH for valve replacement for paravalvular leak with CHF, Group B Strep Bacteremia, and AKI requiring CRRT. - Initially required pressors, but at time of consult, she is metabolically and hemodynamically stable - Neurology consulted for 5 hours of encephalopathy with abnormal movements

3 Mechanical AVR and MVR, 16 years prior, secondary to Rheumatic Heart Failure Afib CHF with AICD Pulmonary HTN Pacemaker

4 Argatroban gtt (HIT) Risperidone Hydrocortisone Cefepime Levaquin Vancomycin Historical Review of medications did not reveal any additional significant meds

5 Vitals 24 hours: Afebrile, O %, Pulse , BP: (96-121)/(50-61) General/Mental Status: Eyes Open, Follows Simple Commands, nonverbal, tracks around room CN: blinks to threat, PERRL, no nystagmus, symmetrical face, strong gag reflex, tongue midline Motor: Diffuse bilateral asynchronous tremor/myoclonic movements, moves all four extremities Sensory: withdraws to painful stimuli equally Reflexes: 1+ bilateral and symmetric. Negative Babinsky.

6 Where? What?

7 Metabolic: liver failure, renal failure, hyponatremia, hypoglycemia, Hashimotos encephalopathy Medication Induced: opioids, anticovulsants, TCAs, SSRI, antipsychotics, anesthestics, multiple antibiotics, ifosfamide Encephalitis Hypoxic/post-hypoxic Seizure

8 Basic labs stable CK wnl, risperidone held anyway. TSH wnl CT head unremarkable EEG: diffuse encephalopathy Could not obtain LP secondary to Argatroban/Hypotension Cefepime was held. Continued on Vanc, Levaquin, Zosyn Myoclonus/tremor resolved 3 days later, Encephalopathy improved

9 Started again requiring pressors. Still afebrile. Hypotension worsened, required intubation. Zosyn changed to Meropenum. Micafungin added. Hypotension worsened to the point that CRRT had to be held. Electrolytes became unregulated. Family agreed to make her DNR. She coded and passed away.

10 Altered Level of Consciousness, Myoclonus, Tremor, Seizure (Especially NCSE), Psychosis, Global Aphasia. All reports are with renal failure (though not all on dialysis) All reported are >50 yo Mean onset was 3-5 days (Range 1-10 days) Most are renally dosed

11 1945: Epileptogenic activity of beta lactam antibiotics. Seizures in experimental animals after intraventricular injections of penicillin 2012 FDA safety announcement: dose adjust Cefepime in patients with renal impairment secondary to seizures, specifically NCSE. At this time, 60 cases were reported. One cases series suggests that NCSE is rare compared to other neurologic manifestations

12 4 th generation cephalosporin; Broad Spectrum Normally, CSF concentration is low. It is not lipophilic, and there is active transport from CSF to back to the blood. In renal failure, there is inhibition of the active transport by accumulation of toxic organic acids which increases the CSF concentration Sepsis can also increase the permeability of the BBB Reduced clearance: 1/2 life normally hours. If creatinine clearance is <10ml/min, half life is hours

13 Build up of drug itself or metabolite: N-methylpyrrolidine metabolite Competitive antagonism of GABA by a portion of antibiotic molecule. May also decrease GABA release from nerve terminals Exact mechanism of neurotoxicity not completely understood

14 Low drug-protein binding, enables efficient removal of unbound fraction by hemodialysis 70% can be removed by dialysis Blood and dialysate flow determine characteristics of dialysis difficult to determine individual pharmacokinetics Unclear evidence if intensive dialysis would decrease mortality/morbidity

15 Not well known Some reports, early diagnosis = better prognosis Some studies suggest partial/complete recovery following withdraw One series, all patients died (range 1-42 days). Many of these patients had some improvement and then neurologic tableau Mortality of sepsis in ICU = 20-50% Even higher with renal failure

16 Abanades, S. (2004). Reversible Coma Secondary to Cefepime Neurotoxicity. Annals Of Pharmacotherapy, 38, Al-Awar, G. N. (2003). Cefepime-induced encephalopathy. International Journal of Infectious Diseases,, Bragatti, J. (2008). Cefepime-Induced Neurotoxicity. Central Nervous System Agents in Medicinal Chemistry, 8, Coleman, T. (2011). Cefepime neurotoxicity despite renal adjusted dosing. Scandinavian Journal of Infectious Diseases, 43, Gomolin, I. H. (2006). Cefepime Neurotoxicity: Case Report, Pharmacokinetic Considerations, and Literature Review. Pharmacotherapy, 26, Jardine, D. (2012). Cefepime: a rare cause of encephalopathy. Internal Medicine Journal,, Lee, J. (2012). Cefepime Neurotoxicity in Patients with Renal Insufficiency. Annals of Rehabilitation Medicine, 36, 159.

17 Li, P. K. (2003). Retrospective Review of Neurotoxicity Induced by Cefepime and Ceftazidime.Pharmacotherapy, 23, Moreillon, P. (2010). Prospective monitoring of cefepime in intensive care unit adult patients.critical Care, 14, R51. Pease, S. (2008). Cefepime overdosage with neurotoxicity recovered by high-volume haemofiltration. Journal of Antimicrobial Chemotherapy, 18, Rabinstein, A. A. (2013). Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy. Critical Care, 17, R264. Sonick. J. (2008). Neurotoxicity and death after treatment with cefepime in patients with kidney failure.nature Clinical Practice Nephrology, 23, Verbeelen, D. (2008). The neurotoxicity and safety of treatment with cefepime in patients with renal failure. Nephrology Dialysis Transplantation, 23,