archildrens.org uams.edu arpediatrics.org 3 lessons learned from a pam survivor w. matthew linam,...
TRANSCRIPT
archildrens.org uams.eduarpediatrics.org
3Lessons Learned from a PAM Survivor
W. Matthew Linam, MD, MS
archildrens.org uams.eduarpediatrics.org
Objectives
1. Discuss factors that likely contributed to the survival of our patient
2. List the recommended medications for treatment of Naegleria fowleri primary amebic meningoencephalitis (PAM)
3. Discuss the potential benefits of therapeutic hypothermia in the management of patients with N. fowleri PAM
archildrens.org uams.eduarpediatrics.org
MOTHER KNOWS BESTLesson 1
archildrens.org uams.eduarpediatrics.org
Case
• A previously healthy 12-year-old female who presented to the emergency department with a 2-day history of headache and a 1-day history of fever (39.4°C)
• Additional symptoms: nausea, vomiting and somnolence.
• She was fully oriented and had a normal neurologic exam.
• She reported swimming in a freshwater water park 7 days prior to symptom onset.
Linam WM, et al. Pediatrics. Volume 135, Number 3, March 2015. e744-48
archildrens.org uams.eduarpediatrics.org
archildrens.org uams.eduarpediatrics.org
Case
• Not an uncommon presentation to our ED in the summer
• In many ways seemed consistent with viral meningitis
• Lumbar puncture not indicated for every febrile child with a headache
archildrens.org uams.eduarpediatrics.org
Initial Laboratory Evaluation
• Peripheral white blood cell count of 18.4 cells/µL (77% segmented and 13% banded neutrophils).
• Cerebrospinal fluid (CSF) revealed a white blood cell count of 3675 cells/µL (86% segmented neutrophils), red blood cell count of 53 cells/µL, protein of 374 mg/dL and glucose of 22 mg/dL
• Computed tomography scan of her brain was normalLinam WM, et al. Pediatrics. Volume 135, Number 3, March 2015. e744-48
archildrens.org uams.eduarpediatrics.org
The Lesson
• The mother was concerned and she expressed those concerns to the medical team.
• The doctor listened.
• Parents know their children better than anyone. They have expertise that we as a medical team should draw upon.
archildrens.org uams.eduarpediatrics.org
KNOWING IS HALF THE BATTLELesson 2
archildrens.org uams.eduarpediatrics.org
Naegleria fowleri
• Thermophilic free-living ameba • Found in warm freshwater• Lives in temperatures above 30°C • Tolerates temperatures up to 45°C
Three stages: the infective trophozoite, a transient non-dividing flagellate stage, and the cystic stage www.cdc.gov
archildrens.org uams.eduarpediatrics.org
PAM Clinical Presentation
• Early symptoms indistinguishable from bacterial meningitis– High fever, – Severe headache, – Photophobia, – Nausea and vomiting, – Seizures– Altered mental status– Smell and taste
alterations
• Symptoms progress rapidly– Severe mental status
alterations– Seizures– Cranial nerve palsies– Coma– Herniation – Death
archildrens.org uams.eduarpediatrics.org
The Laboratory Technician
• The spinal fluid specimen was sent to the lab for analysis• Present that evening was one of our experienced
technologists. She was not on duty and only there to complete an annual competency review.
• She was available to look and the microscope slides of the fluid and saw the Naegleria organisms.
• This was not her first patient with Naegleria.• She quickly called the emergency department and me.
archildrens.org uams.eduarpediatrics.org
archildrens.org uams.eduarpediatrics.org
archildrens.org uams.eduarpediatrics.org
The Lesson• Our patient
– Symptom onset 7 days after exposure– Hospital presentation 30 hours after symptom onset– Recommended therapy started 36 hours after symptom onset
• Median time for other PAM patients1
– Symptom onset to hospital presentation 2 days– Symptom onset to recommended therapy 3 days
• Quick identification of N. fowleri is a crucial step for patient survival.
1. CDC, unpublished data
archildrens.org uams.eduarpediatrics.org
THE POWER OF TEAMWORKLesson 3
archildrens.org uams.eduarpediatrics.org
archildrens.org uams.eduarpediatrics.org
The Lesson
• We were a TEAM fighting to save a girl’s life.• Everyone did their best at what they do best.• AND we were in constant communication with each
other.
• When healthcare professionals work together as a high-functioning team there is really no limit to what can be accomplished!!!
archildrens.org uams.eduarpediatrics.org
AN OLD DRUG WITH A NEW USELesson 4
archildrens.org uams.eduarpediatrics.org
PAM TreatmentU.S. California Survivor 2, 3 (1978) Mexico Survivor 4 (2003)
Amphotericin B Amphotericin BRifampicin Rifampicin
Miconazole – no longer available in US Fluconazole
Dexamethasone Dexamethasone
Sulfisoxazole (IV) – discontinued after Naegleria diagnosed
Ceftriaxone
Phenytoin Seidel JS, et al. N Engl J Med. 1982;306:346-8. Visvesvara GS, et al. FEMS Immunol Med Microbiol. 2007;50:1-26. Vargas-Zepeda J, et al. Arch Med Res. 2005;36:83-6.
archildrens.org uams.eduarpediatrics.org
PAM Treatment• Conventional amphotericin1
– Lower MIC compared to the liposomal formulation– Preferred even though the liposomal form has better CSF penetration
• Drugs with activity against N. fowleri1-3: – Fluconazole– Voriconazole– Azithromycin
• Azithromycin synergistic with Amphotericin4
1. Goswick SM, Brenner GM. Antimicrob Agents Chemother. 2003;47(2):524-528.2. Schuster FL, Guglielmo BJ, Visvesvara GS. J Eukaryot Microbiol. 2006;53(2):121-126.3. Tiewcharoen S, Junnu V, Chinabut P. Southeast Asian J Trop Med Public Health. 2002;33(1):38-41.4. Soltow SM, Brenner GM. Antimicrob Agents Chemother. 2007;51(1):23-27.
archildrens.org uams.eduarpediatrics.org
Recommended Treatment for N. fowleri PAM
Linam WM, et al. Pediatrics. Volume 135, Number 3, March 2015. e744-48
archildrens.org uams.eduarpediatrics.org
Miltefosine• Investigational breast cancer drug
• Antiparasitic agent– Treatment of Leishmaniasis– In vitro activity against free-living amebae
• Successful treatment of other free-living amebae infections– Balamuthia mandrillaris1
– Acanthamoeba sp.2 1. Martinez DY, et al. Clin Infect Dis. 2010;51(2):e7-11.
2. Aichelburg AC, et al.. Emerg Infect Dis. 2008;14(11):1743-1746.
archildrens.org uams.eduarpediatrics.org
Miltefosine
• Until recently miltefosine was not available in the U.S.• In August 2013, the CDC obtained expanded access to
miltefosine – Investigational new drug (IND) protocol in effect with the Food and
Drug Administration– Miltefosine is now directly from CDC for treatment of FLA in the U.S.
MMWR Morb Mortal Wkly Rep. 2013;62(33):666.
archildrens.org uams.eduarpediatrics.org
The Lesson
• Treatment of N. fowleri PAM requires a combination of antimicrobials
• These medicines must be started quickly
• Early administration of miltefosine may play an important role in the treatment of PAM
archildrens.org uams.eduarpediatrics.org
STAYING COOL UNDER PRESSURELesson 5
archildrens.org uams.eduarpediatrics.org
Linam WM, et al. Pediatrics. Volume 135, Number 3, March 2015. e744-48
archildrens.org uams.eduarpediatrics.org
PAM: Management of Increased ICP
• N. fowleri causes direct cellular damage: 1,2
– Direct cell-to-cell interaction– Release of a number of cytotoxic proteins– The combined effect causes a cascade of proinflammatory
cytokines resulting in hyperinflammation and further injury
• Management of cerebral edema included: 3 – EVD drainage of CSF – hyperosmolar therapy: mannitol and 3% saline – Moderate hyperventilation (pCO2 30-35 mmHg) – Induced hypothermia (32-34°C)– Goal ICP below 20 mmHg
1. Visvesvara GS, et al. FEMS Immunol Med Microbiol. 2007;50(1):1–26
2. Rojas-Hernández S et al. Parasitol Res. 2004;94(1):31–363. Linam et al. Pediatrics. Volume 135, Number 3, March 2015.
e744-48
archildrens.org uams.eduarpediatrics.org
Hypothermia• The goal of neuroprotective management of brain injuries involves:
– Maintaining adequate perfusion– Limiting oxygen consumption– Controlling intracranial pressure (ICP)
• Mild to moderate hypothermia (32°C-34°C) may have neuroprotective effects1,2
– Lowering ICP– Reducing reactive oxygen and nitrogen– Reducing proinflammatory cytokines
• Clinical results remain mixed3-6 – Traumatic brain injury– Bacterial meningitis
1. Irazuzta JE, et al. Brain Res. 2000; 881(1):88–972. Polderman KH. Crit Care Med. 2009; 37(suppl 7):S186–S2023. Lepur D, et al. J Infect. 2011; 62(2):172–1774. Clifton GL, et al. N Engl J Med. 2001;344(8):556–5635. McIntyre LA, et al. JAMA. 2003;289(22):2992–29996. Mourvillier B, et al. JAMA. 2013;310(20): 2174–2183
The Relationship Between Mean Arterial Pressure, Cerebral Perfusion Pressure, Intracranial Pressure and Core Body Temperature During the Management of a Twelve-Year-Old Female with N. fowleri PAM
Linam WM, et al. Pediatrics. Volume 135, Number 3, March 2015. e744-48
archildrens.org uams.eduarpediatrics.org
The Lesson
• Cerebral edema is an important cause of morbidity and mortality in patient with PAM
• Rapidly administering the correct medications is only part of the treatment
• Tight control of ICP is just as important in the management of PAM
• Therapeutic hypothermia may play a beneficial role in the management of PAM
archildrens.org uams.eduarpediatrics.org
MIRACLES DO HAPPENLesson 6
archildrens.org uams.eduarpediatrics.org
Back to the Case
• PICU care: 3 weeks
• Total hospitalization: 55 days
• 6- months after discharge: back to her baseline state of health
• Almost 2 years later she remains fully recovered
archildrens.org uams.eduarpediatrics.org
archildrens.org uams.eduarpediatrics.org
The Lesson
• Miracles do happen, but often times they are the countless small things that go well.
– Trusting a mother’s instincts– Identifying N. fowleri quickly so correct therapy can be
started– Working as a healthcare TEAM– Rapidly starting a combination of antimicrobials, including
miltefosine– Excellent control of increased intracranial pressure
including using hypothermia
archildrens.org uams.eduarpediatrics.org
On December 27, 2014, Traci Hardig passed away after a long struggle with Stage IV breast cancer.