Transcript SEROTONIN SYNDROME

VIRGINIA SOCIETY OF
PERIANESTHESIA NURSES
(VSPAN)
2016 ANNUAL CONFERENCE
THE HOTEL ROANOKE AND CONFERENCE CENTER
ROANOKE, VA
SATURDAY, OCTOBER 1, 2016
SEROTONIN SYNDROME
JAMES J. CRAWFORD, M.D.
ANESTHESIOLOGY CONSULTANTS OF
VIRGINA
CARILION CLINIC AND MEDICAL
CENTER
CONFLICTS OF INTEREST
• NOTHING TO DISCLOSE
• NO FINANCIAL RELATIONSHIPS TO ANYTHING
DISCUSSED
LECTURE GOALS
• TO DESCRIBE SEROTONIN SYNDROME
• TO DISCUSS ITS PREVALENCE
• TO PROVIDE CASE EXAMPLES FROM MY OWN
HOSPITAL SYSTEM
• TO DESCRIBE THE SYSTEM OF SEROTONIN
RECEPTORS IN HUMAN PHYSIOLOGY
• TO DISCUSS DRUGS AND DRUG INTERACTIONS
WHICH CAN CAUSE SERTONIN SYNDROME
LECTURE GOALS
• TO DISCUSS TREATMENT OF MILD,
MODERATE, AND SEVERE CASES OF
SEROTONIN SYNDROME
• TO DISCUSS PREVENTION
• TO DISCUSS WHY THE PERIANESTHETIC
ENVIRONMENT IS A PARTICULARLY HIGH RISK
ENVIRONMENT FOR THE OCCURRENCE OF
SEROTONIN SYNDROME
OUR CHEMICAL WORLD
WHAT IS SEROTONIN SYNDROME?
• SEROTONIN SYNDROME IS A CONSTELLATION
OF FINDINGS RELATING TO EXCESSIVE
STIMULATION OF SEROTONIN RECEPTORS
AND IS MANIFESTED BY MENTAL,
AUTONOMIC, AND NEUROMUSCULAR
CHANGES
SEROTONIN SYNDROME
• IS A POTENTIALLY LIFE THREATENING ADVERSE
DRUG REACTION
• IT HAS A MORTALITY RATE OF 2-12% IN
SEVERE CASES
THE TRIAD OF SEROTONIN SYNDROME
M-A-N: MENTAL, AUTONOMIC,
NEUROMUSCULAR
SEROTONIN SYNDROME
THREE FEATURES OF SEROTONIN
SYNDROME ARE IMPORTANT TO
REMEMBER
FIRST
• IT IS A PREDICTABLE CONSEQUENCE OF
EXCESS STIMULATION OF SEROTONIN
RECEPTORS IN THE BRAIN AND BODY
SECOND
• EXCESS SEROTONIN PRODUCES A SPECTRUM
OF CLINICAL FINDINGS FROM MILD TO SEVERE
THIRD
• BECAUSE THE CLINICAL MANIFESTATIONS CAN
RANGE FROM BARELY PERCEPTIBLE TO LETHAL
IT IS OFTEN NOT RECOGNIZED BY MEDICAL
PROFESSIONALS
WHY STUDY SEROTONIN SYNDROME?
• WE ARE SURROUNDED AND IN A VIRTUAL SEA
OF MEDICATIONS WITH ACTIONS AFFECTING
THE SEROTONIN SYSTEM AND WITH THE
POTENTIAL TO CAUSE SEROTONIN SYNDROME
WHY STUDY SEROTONIN SYNDROME?
• MANY PHYSICIANS AND HEALTH CARE
WORKERS ARE NOT AWARE OF THE
SYNDROME—A LARGE SURVEY OF DOCTORS
IN GREAT BRITAIN IN 1999 REVEALED THAT
85% OF DOCTORS DID NOT KNOW WHAT IT
WAS OR HOW TO DIAGNOSE IT
WHY STUDY SEROTONIN SYNDROME?
• THE DIAGNOSIS IS OFTEN MISSED AND IT
CAUSES HUNDREDS OF DEATHS IN THE
UNITED STATES EACH YEAR
• IT IS LIKELY THAT WE MISS MILDER CASES OF
SEROTONIN SYNDROME IN THE
PERIANESTHETIC ENVIRONMENT
EPIDEMIOLOGY: FEDERAL TOXIC
EXPOSURE SURVEILLANCE SYSTEM
• FOR SSRI IN 2002: 26,733 EXPOSURES WITH
7349 MODERATE OR SEVERE CASES OF
SEROTONIN SYNDROME WITH 93 DEATHS
• FOR SSRI IN 2004: 48,204 EXPOSURES WITH
8,871 MODERATE OR SEVERE CASES OF
SEROTONIN SYNDROME WITH 103 DEATHS
• 113 DEATHS FROM SEROTONIN SYNDROME IN
2005
MANY FATALITIES
• COME FROM COMBINATION OF DIFFERENT
CATEGORIES OF SEROTONERGIC DRUGS SUCH
AS THE COMBINATION OF SSRI AND MAO
INHIBITOR---• DEMEROL AND MAO INHIBITOR
• FENTANYL AND MAO INHIBITOR
• BUT THE SYNDROME CAN OCCUR WITH A
SINGLE DOSE OF A SEROTONERGIC DRUG
SUCH AS AN SSRI
WHY STUDY SEROTONIN SYNDROME?
• SERIOUS CASES INCLUDING DEATH HAVE
OCCURRED AT MY OWN HOSPITAL FROM
SEROTONIN SYNDROME
IN ROANOKE, VIRGINIA
A ROUTINE COLONOSCOPY
ELDERLY PATIENT UNDERGOES
COLONOSCOPY AT RMH
• PATIENT HAS PARKINSON’S DISEASE AND IS
ON CARBIDOPA-LEVODOPA
• CARBIDOPA (SINEMET) PREVENTS THE
BREAKDOWN OF LEVODOPA
• PATIENT IS ALSO ON ELDEPRYL (SELEGILINE)-IT
IS AN MAO-B INHBITOR WHICH IS USED TO
ENHANCE THE EFFECT OF CARBIDOPALEVODOPA IN THE TREATMENT OF
PARKINSON’S SYNDROME
DURING HIS COLONOSCOPY
• PATIENT RECEIVES FENTANYL AND VERSED AS
SEDATION FOR HIS COLONOSCOPY
• POST PROCEDURE HE DEVELOPS HIGH FEVER
AND OTHER SYMPTOMS
• A WORK UP APPARENTLY EMPHAZIZING
INFECTIOUS CAUSES OF FEVER AND
OVERLOOKING A DRUG REACTION PROBLEM
FAILS TO REVEAL A SOURCE OF THE FEVER
• COOLING MEASURES WERE UNDERTAKEN BUT
DESPITE THESE EFFORTS PATIENT DIES WITH A
TEMPERATURE OVER 110 DEGREES FAHRENHEIT
AT AUTOPSY
• THE PATHOLOGIST WHO REVIEWS THE
PATIENT’S DRUG HISTORY COMES TO THE
CONCLUSION THE PATIENT DIED OF
SEROTONIN SYNDROME FROM AN
INTERACTION BETWEEN FENTANYL AND
ELDEPRIL
AS A CONSEQUENCE
• MEDICAL EXECUTIVE COMMITTEE REVIEWS CASE
AND INSTITUTES A FULLER IMPLEMENTATION OF
MICROMEDEX AT ALL NURSING LOCATIONS
• WARNING SIGNS ARE PLACED AT ALL SEDATION
LOCATIONS REGARDING AWARENESS FOR
ADVERSE DRUG INTERACTIONS AND SEDATION
PIC REQUIRES TEMPERATURE MONITORING POST
PROCEDURE
FINALLY
• THE USE OF FENTANYL AND ITS STRUCTURAL
ANALOG MEPERIDINE (DEMEROL) IS
REVIEWED
• CONSIDERATION IS GIVEN TO REMOVING
MEPERIDINE FROM THE FORMULARY BUT A
DECISION IS MADE TO REDUCE ITS USAGE AT
THE HOSPITAL
CASE 2
• PATIENT HAS PARKINSONS DISEASE. SHE HAS
SUFFERED A MINOR STROKE BUT HAS
RECOVERED BUT IS DEPRESSED
• SHE HAS BEEN ON ELDEPRYL (MAO-B INHIBITOR)
AND CARBIDOPA/LEVODOPA.
• SHE IS GIVEN A SSRI (SEROTONIN RE-UPTAKE
INHIBITIOR)-ZOLOFT(SERTRALINE)-- TO TREAT
DEPRESSION
• SHE GOES TO PHARMACY—THEY DO NOT FILL
PRESCRIPTION SAYING SHE NEEDS TO BE OFF
ELDEPRYL
CASE 2
• SHE RETURNS A FEW DAYS LATER
• PHARMACY COMPUTER INDICATES SHE IS OFF
ELDEPRYL BUT IT IS NOT NOTICED THAT SHE HAS
NOT BEEN OFF THE NECESSARY 2 WEEKS
• SHE TAKES A SINGLE DOSE OF ZOLOFT AND VERY
QUICKLY FEELS FEVERISH, STIFF, UNWELL
• SHE GOES TO HER FAMILY DOCTOR AND IS
ADMITTED— IN SUCCESSION TO FLOOR, PCU, ICU
AS HER FEVER PROGRESSES TO 110 FAHRENHEIT
CASE 2
• HER PHYSICIAN MISTAKENLY DIAGNOSES
MALIGNANT HYPERTHERMIA
• HOWEVER NO HISTORY SUCCINYLCHOLINE
ADMINISTRATION
• NO HISTORY OF ISOFLURANE, SEVOFLURANE,
OR DESFLURANE ADMINISTRATION
CASE 2
• FACED WITH A PATIENT IN THE ICU WITH A
FEVER OVER 110 DEGREES FAHRENHEIT THE
PHYSICIAN ORDERS DANTROLENE—THE SPECIFIC
DRUG TREATMENT FOR MALIGNANT
HYPERTHERMIA
• OUR OPERATING ROOM PHARMACIST IS TASKED
WITH TAKING DANTROLENE TO THE ICU AND
ASKS ME ON THE WAY (I AM ANESTHESIA 1ST
CALL COORDINATOR) IF I KNOW ABOUT THE CASE
OF MH IN THE ICU
CASE 2
• THE PHARMACIST TAKES THE MALIGNANT
HYPERTHERMIA BOX TO THE ICU AND I
FOLLOW—WITH PACU NURSES FOLLOWING TO
THE ICU
• WE ADMINISTER DANTROLENE, I INTUBATE THE
PATIENT, PLACE AN ARTERIAL LINE AND CENTRAL
LINE WHILE WE PLACE A COOLING FAN, PACK THE
AXILLA AND GROINS WITH ICE, AND DO COOLING
GASTRIC LAVAGE
• LAB STUDIES ARE DONE
CASE 2
• OUR PHARMACIST CONTACTS THE DRUG
MANUFACTURERS FOR ZOLOFT AND
ELEDPRYL—ONE REPORTS THEY HAVE NOT
HAD A SURVIVOR OF THIS REACTION
• THE OTHER THINKS THAT DANTROLENE IS A
GOOD IDEA
• WE CALL THE FDA—GIVE THE REPORT—THEY
DO NOT ADVISE ON TREATMENT
• SEROTONIN REACTION DIAGNOSED
CASE 2
• PATIENT RECOVERS COMPLETELY-FEVER
RAPIDLY REDUCED
• THE NEUROLOGIST WHO DOES EEG DAY 2
SAYS SHE HAS OK EEG
• PATIENT EXTUBATED DAY 3 WITHOUT
SEQUELAE
SO WHAT IS SEROTONIN?
• IT IS 5- HYDROXYTRYPTAMINE
WHERE IS SEROTONIN MADE?
• ABOUT 90% OF SEROTONIN IS MADE AND
USED IN THE PERIPHERY ESPECIALLY THE GUT
AND ABOUT 10% OF SEROTONIN IS MADE IN
THE BRAIN
• IT IS MADE FROM DIETARY TRYPTOPHAN
• THE SEROTONIN MADE AND USED IN THE
BRAIN PLAYS THE MOST IMPORTANT ROLE IN
SEROTONIN SYNDROME
FOODS RICH IN TRYPTOPHAN
•
•
•
•
•
•
•
•
•
•
COTTAGE CHEESE
SPINACH
TOFU
LOBSTER
BANANAS
EGGS
TURKEY
SALMON
NUTS AND SEEDS
PINEAPPLES
AND----
•CHOCOLATE!!!
IT IS PRODUCED IN THE CNS PRIMARLY
IN THE MIDBRAIN, PONS AND
MEDULLA
THERE IS A FULL SEROTONERGIC
SYSTEM IN THE BRAIN
ACTIONS OF SEROTONIN
• THE SEROTONIN SYSTEM IS THE LARGEST AND
MOST EXTENSIVE NEUROCHEMICAL SYSTEM
IN THE BRAIN AND THE BODY
• IT INFLUENCES MOOD, BEHAVIOR, ANXIETY,
DEPRESSION, AGGRESSION, LEARNING AND
SLEEP
• IT PLAYS A KEY ROLE IN THE CENTRAL
CONTROL OF THERMOREGULATION
ACTIONS OF SEROTONIN
• IT INCREASES PERISTALSIS, CAUSES STOMACH
CONTRACTION, AND CAN PROVOKE NAUSEA,
VOMITING, AND DIARRHEA
• REMEMBER THAT ODANSETRON (ZOFRAN)—
OUR MOST POPULAR ANTI-EMETIC IS AN HT3
RECEPTOR SEROTONIN ANTAGONIST
ACTIONS OF SEROTONIN
• IT CAN CAUSE BOTH EXCITATION AND
INHIBITION IN THE NERVOUS SYSTEM AS WELL
AS STIMULATION OF NOCICEPTIVE NERVE
ENDINGS
• IT CAN ACT DIRECTLY AND INDIRECTLY ON THE
SYMPATHETIC NERVOUS SYSTEM TO CAUSE
VASOCONSTRICTION, DIAPHORESIS AND
MYDRIASIS
ACTIONS OF SEROTONIN
• IT CAUSES PLATELET AGGREGATION
• INCREASES MICROVASCULAR PERMEABILITY
• CAUSES PERIPHERAL VASOCONSTRICTION
ACTIONS OF SEROTONIN
• IT INFLUENCES MUSCULAR CONTROL AND
AND THE REGULATION OF LOCOMOTION
INCLUDING MUSCULAR TONE
• IT INFLUENCES NEURAL REFLEXES BY CAUSING
HYPERREFLEXIA
GUT AND PLATELETS IMPORTANT
SITES OF SEROTONIN ACTIVITY
SEROTONIN RECEPTORS: 7 MAJOR
TYPES AND AT LEAST 14 SUBTYPES
HOW DOES INCREASED
SEROTONERGIC ACTIVITY OCCUR?
•
•
•
•
•
INCREASED PRODUCTION OF SEROTONIN
DECREASED METABOLISM OF SEROTONIN
INCREASED RELEASE OF SEROTONIN
INCREASED SEROTONIN RECEPTOR AGONISM
INCREASED SEROTONIN RECEPTOR
SENSITIVITY
• DECREASED RE-UPTAKE OF SEROTONIN
• SEROTONIN ACTIVITY IMBALANCE
MECHANISMS OF SEROTONIN
SYNDROME
INCREASED PRODUCTION OF
SEROTONIN
• INCREASED DIETARY TRYPTOPHAN CAN LEAD
TO INCREASED PRODUCTION OF SEROTONIN
• THE WORLD AND THE WEB IS FULL OF DIETS
AND PROMOTERS ADVOCATING HIGH
SEROTONIN DIETS AS A “NATURAL”
“ORGANIC” WAY TO COMBAT DEPRESSION
DECREASED METABOLISM OF
SEROTONIN
•
•
•
•
•
•
•
•
MONOAMINE OXIDASE INHIBITORS
PHENYLZENE (NARDIL)
TRANSCYCLOPROMINE (PARNATE)
MOCLOBEMIDE (MANERIX)
SELEGELINE (ELDEPRYL)
ISOCARBOXAZID (MARPLAN)
LINEZOLID (ZYVOX)
METHYLENE BLUE
INCREASED RELEASE OF SEROTONIN
•
•
•
•
•
•
•
•
AMPHETAMINES
COCAINE
FENLURAMINE
PHENTERAMINE
DEXFENLURAMINE
SIBUTRAMINE
ECSTASY (METHYLENEDEOXYAMPHETAMINE)
PHENANTHERENE
INCREASED RELEASE OF SEROTONIN
•
•
•
•
•
OXYCODONE
BUPRENORPHINE (BUPRENEX)
TRAMADOL
LEVODOPA
CARBIDOPA/LEVODOPA (SINEMET)
INCREASED SEROTONIN RECEPTOR
AGONISM (DRUG DIRECTLY
STIMULATES SEROTONIN RECEPTOR)
•
•
•
•
BUSPIRONE (BUSPAR)
LSD
DIHYROERGOTAMINE
TRIPTANS--SUMATRIPTAN, ZOLMATRIPTAN,
ETC (ANTI MIGRAINE DRUGS)
• MIRTAZAPINE
INCREASED SEROTONIN RECEPTOR
SENSITIVITY
• LITHIUM
DECREASED RE-UPTAKE OF
SEROTONIN
• TRICYCLIC ANTIDEPRESSANTS (TCAs):
AMITRYPTALINE, IMIPRAMINE, DESIPRAMINE
CLOMIPRAMINE, DOXEPIN
• SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIs): PAROXETINE (PAXIL), SERTRALINE,
FLUVOXAMINE, FLUOXETINE (ZOLOFT),
CITALOPRAM (CELEXA), ESCITALOPRAM
(LEXAPRO)
DECREASED RE-UPTAKE OF
SEROTONIN
• SEROTONIN NOREPINEPHRINE REUPTAKE
INHIBITIORS (SSNRIs): VENLAFAXINE
(EFFEXOR), DULOXETINE(CYMBALTA),
MILNACIPRAN
• OTHER ANTIDEPRESSANTS: TRAZADONE,
NEFAZADONE
DECREASED RE-UPTAKE OF
SEROTONIN
• OPIOIDS: MEPERIDINE, FENTANYL,
METHADONE, TRAMADOL,
DEXTROMETHORPHAN, PENTAZOZINE
• MISCELLANEOUS: ODANSATRON (ZOFRAN),
GRANISTRON, ST. JOHN’S WORT, PANAX
GINSENG, SYRIAN RUE, METOCLOPRAMIDE,
VALPROIC ACID
SEROTONIN ACTIVITY IMBALANCE
• DOPAMINE AGONISTS: LEVODOPA,
BROMOCRIPTINE, AMANTADINE.
• INTERACTION WITH CYTOCHROME SYSTEMS IN
THE LIVER RESULTIING IN DECREASED
METABOLISM OF SSRIs: RETROVIR (HIV
ANTIVIRAL)
• COMPLEX CLASSES SDRIs (SEROTONIN DOPAMINE
REUPTAKE INHIBITORS), SMSs (SEROTONIN
MODULATOR STIMULATORS)-VORTIOXETINE(BRINTELLIX)
MECHANISMS OF SEROTONIN
SYNDROME
LINEZOLID (ZYVOX) ANTIBIOTIC FOR
VRE (VANCOMYCIN RESISTANT
ENTEROCOLITIS)
SEROTONIN RECEPTORS
MOST IMPORTANT RECEPTORS
INVOLVED IN SERTONIN SYNDROME
HOW DO YOU RECOGNIZE SEROTONIN
SYNROME?
• REMEMBER THE MNEMONIC—
• M-A-N: MENTAL, AUTONOMIC,
NEUROMUSCULAR SIGNS AND SYMPTOMS IN
SEROTONIN SYNDROME
THE TRIAD OF SEROTONIN
SYNDROME: M-A-N
SEROTONIN SYNDROME
CLONUS
HOW DOES A PATIENT DIE FROM
SEROTONIN SYNDROME?
• SEVERE HYPERTHERMIA—A “HEAT STROKE”
TYPE DEATH
• RHABDOMYOLYSIS
• DISSEMINATED INTRAVASCULAR
COAGULOPATHY (DIC)
• RENAL FAILURE
• METABOLIC ACIDOSIS
• MULTISYSTEM ORGAN FAILURE
HOW DO YOU TREAT SEROTONIN
SYNDROME?
•
•
•
•
•
FIRST DECIDE IF THE CASE IS MILD OR SEVERE
USE A DECISION TREE
CONTINUALLY RE-ASSESS THE PATIENT
ADMIT TO AN INTENSIVE CARE SETTING
EDUCATE THE NURSING AND MEDICAL STAFF TO
THE NATURE OF THE PROBLEM
• ESCALATE TREATMENT FROM BENZODIAZEPINES
TO CYPROHEPTADINE TO DANTROLENE
• PROVIDE ALL NECESSARY ADJUNCTIVE
TREATMENT MEASURES
SEROTONIN SYNDROME DECISION
TREES
• STERNBACH NOT USED ANYMORE---TOO MUCH
EMPHASIS ON COGNITIVE AND MENTAL ASPECTS,
NOT RECOMMENDED BECAUSE OF A LACK OF
SPECIFICITY AND SENSITIVITY
• HUNTER SEROTONIN SYNDROME DECISION TREE:
84% SENSITIVITY, 97% SPECIFICITY, DEVELOPED IN
AUSTRALIA AFTER A REVIEW OF OVER 2000
CASES
• RADOMSKI SYSTEM TRIES TO DISTINGUISH
BETWEEN MILD AND SEVERE SEROTONIN
SYNDROME TO HELP GUIDE MANAGEMENT
HUNTER SEROTONIN SYNDROME
DECISION TREE
RADOMSKI DIAGNOSTIC CRITERIA
SEROTONIN SYNDROME
RADOMSKI DIAGNOSTIC CRITERIA
SEROTONIN SYNDROME
MILD SEROTONIN SYNDROME:
TREATMENT
MODERATE SEROTONIN SYNDROME:
TREATMENT
SEVERE SEROTONIN SYNDROME:
TREATMENT
TREATMENT OF SEROTONIN
SYNDROME
• TRADITIONAL ANTIPYRETICS SUCH AS
ACETOMINOPHEN ARE NOT RECOMMENDED
• DO NOT RESTRAIN PATIENT— RESTRAINTS INCREASE
MUSCULAR ACTIVITY
• STOP OFFENDING AGENTS
• GIVE BENZODIAZEPINE
• GIVE CYPROHEPTADINE
• REMEMBER IT NEEDS TO BE CRUSHED AND MIXED
WITH WATER AND GIVEN ORALLY OR DOWN AN
OROGASTRIC TUBE 12 MG PO THEN 2 MG Q2H
TREATMENT OF SEROTONIN
SYNDROME
• DANTROLENE HAS BEEN USED SUCCESSFULLY TO
TREATSEVERE SEROTONIN SYNDROME ON 2 OF
MY PATIENTS
• SOME AUTHORS ON THE BASIS OF A FEW
ANIMAL STUDIES HAVE RECOMMENDED AGAINST
USING DANTROLENE BUT IT IS GREAT NONSPECIFIC ANTI-PYRETIC AND WORKS AT THE ONE
OF THE SITES—THE MUSCLES, THAT IS
GENERATING HYPERMETABOLISM AND FEVER
• MANY AUTHORS DO RECOMMEND IT
SEROTONIN SYNDROME- CASE 3
• A PATIENT HAS “COR CONCRETA”—CHRONIC
RESTRICTIVE PERICARDITIS—PATIENTS HEART
ENCASED IN AN INFLAMMATORY CALCIUM
SHELL GIVING HER RIGHT HEART FAILURE
SIGNS AND DYSPNEA
• I PROVIDE ANESTHESIA FOR OPEN CHEST
CARDIPULMONARY BYPASS CASE WITH ONE
OF OUR CARDIAC SURGEONS
CASE 3
• AFTER A AN EXTENSIVE PROCEDURE REMOVING
THE SCARRED AND CALCIFIED PERICARDIAL SAC
THE PATIENT’S HEART IS FUNCTIONING FINE BUT
SHE IS NOTED TO HAVE SEVERE TRICUSPID
INSUFFICIENCY ON MY TEE EXAM
• SURGEON DOES A TRICUSPID VALVULOPLASTY
• SHE AT THIS POINT BECOMES VASOPLEGIC AND
REQUIRES LARGE DOSES OF LEVOPHED AND
VASOPRESSIN AND IS TRANSPORTED TO CSICU
CASE 3
• LATER THAT NIGHT AFTER INCREASING DOSES OF
PRESSORS A DECISION IS MADE BY THE CARDIAC
NURSE PRACTIONER TO USE METHYLENE BLUE
TO IMPROVE THE RESPONSIVENESS OF THE BP TO
VASOPRESSORS
• WORKS BY BLOCKING GUANYLATE CYCLASE-THIS
REDUCES cGMP AND MAKES IT HARDER FOR THE
PRIMARY NATIVE VASODILATOR NITRIC OXIDE TO
CAUSE VASODILATION
CASE 3
• THIS RELATIVELY YOUNG PATIENT IS ON ZOLOFT—
SERTRALINE—AND SSRI DRUG—SHE WAS OFF
THE MEDICATION FOR JUST A COUPLE OF DAYS
• THE POSSIBLE DRUG INTERACTION IS NOTED—
AND ALERTED TO BY MICROMEDEX-THE NURSING
STAFF IS ON ALERT TO LOOK FOR THE POSSIBILTY
OF SEROTONIN SYNDROME DEVELOPING WITH
METHYLENE BLUE
• RISK/BENEFIT IS DISCUSSED AND DECISION IS
MADE TO PROCEED WITH METHYLENE BLUE
CASE 3
• IMMEDIATELY AFTER COMMENCING THE INFUSION OF
METHYLENE BLUE—AN MAO INHIBITIOR—THE
PATIENT INDICATES WITH GESTURES THAT SHE IS HOT
BY FANNING HERSELF-SHE HAS BEEN KEPT INTUBATED
SINCE SURGERY BUT IS AWAKE
• HER TEMPERATURE ACCELERATES
• SEROTONIN SYNDROME DIAGNOSED—METHYLENE
BLUE INFUSION STOPPED
• CYPROHEPTADINE AND DANTROLENE ARE GIVEN
• PATIENT RECOVERS AND IS EXTUBATED THE NEXT DAY
ABOUT METHYLENE BLUE
• IT HAS BEEN USED TO HELP IDENTIFY THE URETERAL
ORIFICE IN GYNECOLOGICAL SURGERY
• USED IN CARDIAC SURGERY TO TREAT VASOPLEGIC
SYNDROMES
• IT HAS BEEN USED IN LAST STAGES IN THE TREATMENT
OF CYANIDE INDUCE NITROPRUSSIDE TOXICITY
• CAN REVERSE METHEMOGLOBINEMIA AT LOW DOSES
AND CAUSE IT AT HIGH DOSES
• IT IS AN EXTREMELY POTENT MAO INHIBITOR!!
• GIVEN TOO FAST CAUSES HYPOXEMIA
FDA ALERT ON METHYLENE BLUE
• BECAUSE OF NATIONAL SHORTAGE OF INDIGO
CARMINE METHYLENE BLUE IS BEING USED
MORE FREQUENTLY DURING SURGERY
• AS OF JUNE 2015 14 CASES AND ONE DEATH
HAVE BEEN REPORTED INVOLVING
METHYLENE BLUE AND SEROTONIN
SYNDROME IN ASSOCIATION WITH SURGERY
• SUBJECT OF AN ANESTHESIA PATIENT SAFETY
FOUNDATION ALERT (JUNE, 2015)
METHYLENE BLUE
• ANYONE ON A SEROTONERGIC DRUG GETTING
METHYLENE BLUE IS AT RISK OF SEROTONIN
SYNDROME
• IF YOU HAVE A PATIENT IN THE PACU WITH
BLUISH URINE FROM METHYLENE BLUE BE ON
THE LOOKOUT FOR SEROTONIN SYNDROME IF
YOU GIVE FENTANYL OR DEMEROL—IN FACT I
WOULD AVOID DEMEROL COMPLETELY
ALTERNATIVES TO METHYLENE BLUE
FOR THE RECOGNITION OF URETERAL
DAMAGE
• INDOCYANIN GREEN
• FLORESCEIN
FEVER IN THE POST OP PERIOD
• LARGE DIFFERENTIAL
• MUST CONSIDER MH, SEROTONIN
SYNDROME, AND IF PATIENT HAS HAD
ATROPINE THEN ANTICHOLINERGIC
SYNDROME
• NEUROLEPTIC MALIGNANT SYNDROME (NMS)
UNLIKELY
• SEPSIS, ATELECTASIS MUST BE IN
DIFFERENTIAL
DIFFERENTIAL DIAGNOSIS
MALIGNANT HYPERTHERMIA
• 1000 CASES/YEAR U.S. 11% MORTALITY 35%
COMPLICATION RATE—DIC, RENAL FAILURE
RHABODMYOLYSIS, “HEAT STROKE” DEATH
• SUCCINYLCHOLINE, SEVOFLURANE,
DESFLURANE, ISOFLURANE
• CAN HAVE PRIOR UNEVENTFUL ANESTHETICS
• GENETIC BASIS 50-80%
• SUDDEN ONSET USUAL, DELAY IN TREATMENT
MEANS INCREASED MORTALITY/MORBIDITY
MH RECOGNITION SCORING
•
•
•
•
ET CO2>55 mmHG, PaCO2>60 (15 POINTS)
UNEXPLAINED TACHYCARDIA, VT, VF (3 PTS)
BASE DEFICIT> 8 MEQ/L (10 PTS)
GENERALIZED RIGIDIDITY, SEVERE MASSETER
MUSCLE RIGIDITY (15 PTS)
• MUSCLE BREAKDOWN (CPK> 20,000 UNITS/L ,
COLA URINE, MYOGLOBIN IN URINE OR
SERUM, K+ > 6 MEQ/L (15 PTS)
MH RECOGNITION SCORING
• RAPIDLY INCREASING TEMPERATURE, T > 38.8 (15
PTS)
• RAPID REVERSAL OF MH SIGNS WITH
DANTROLENE (5 PTS)
• ELEVATED RESTING SERUM CREATINE KINASE (10
PTS)
• POSITIVE FAMILY HISTORY CONSISTENT WITH
AUTOSOMAL DOMINANT INHERITANCE (15 PTS)
• SCORE > 50 MH FOR SUR
MANAGEMENT OF SYNDROMES
• MALIGNANT HYPERTHERMIA-DANTROLENE
• NEUROLEPTC MALIGNANT SYNDROMEBROMOCRIPTINE (DANTROLENE AS BACKUP)
• SEROTONIN SYNDROME-BENZODIAZEPINES,
CYPROHEPTANDINE, (DANTROLENE, OLAZAPINE,
CHLORPROMAZINE AS BACKUP)
• ANTICHOLINERGIC SYNDROME-PHYSOSTIGMINE
(ANTLIRIUM)
• DANTROLENE GOOD FOR ALL EXCEPT
ANTICHOLINERGIC SYNDROME
TREATMENT SUMMARY: SEROTONIN
SYNDROME
•
•
•
•
•
•
•
•
•
BENZODIAZEPINES
CYPROHEPTADINE
COOLING MEASURES
NO RESTRAINTS
THORAZINE OR OLAZOPINE
DANTROLENE FOR SEVERE CASES
INTUBATION, PARALYSIS (NOT SUX!) FOR SEVERE CASES
DIALYSIS IF RENAL FAILURE ENSUES
TREATMENT OF RHABODOMYOLYSIS WITH BICARB,
MANNITOL
• ANTICONVULSANTS IF NEEDED
FOOTNOTE: MANAGEMENT OF
POSTOPERATIVE SHAKING AND
SHIVERING
• IT IS A COMMON POSTOPERATIVE CONDITION
PARTICULARLY IN THE YOUNG
• THE LONG ESTABLISHED PRACTICE OF USING
DEMEROL (MEPERIDINE) TO TREATING
SHIVERING COULD ADD FUEL TO THE FIRE OF
AN EARLY CASE OF SEROTONIN SYNDROME
• PRECEDEX (DEXMETETOMIDINE) IN DOSES OF
8 TO 12 MCG IV MAY BE A BETTER
ALTERNATIVE TO DEMEROL (MEPERIDINE)
DEMEROL: ANOTHER FOOTNOTE
• THE ADMINISTRATION OF DEMEROL TO A
PATIENT IN 1984 REVOLUTIONIZED POST
GRADUATE MEDICAL EDUCATION IN THE
UNITED STATES AND EVENTUALLY THE WORLD
WHO IS THIS?
LIBBY ZION
“SHE SHOULD TOUCH THE WORLD IN
DEATH, THAT HER DEATH NOT BE IN
VAIN”
• TOM MOORE, ATTORNEY FOR THE PLAINTIFF
SIDNEY ZION IN THE CASE OF ZION VERSUS
NEW YORK HOSPITAL ---IN A STATEMENT
ABOUT THE DEATH OF LIBBY ZION FROM
SEROTONIN SYNDROME LESS THAN 8 HOURS
AFTER ADMISSION TO NYU MEDICAL CENTER
IN 1984
LIBBY ZION
• 18 YEAR OLD FRESHMAN AT BENNINGTON
COLLEGE IN VERMONT
• ADMITTED TO NEW YORK HOSPITAL AT ABOUT
11:30 PM MARCH 4, 1984
• UNDER CARE OF A PSYCHIATRIST AND HAD
BEEN PRESCRIBED PHENLZENE (NARDIL) AN
MAO INHIBITOR
LIBBY ZION
• IN LATE FEBRUARY SHE HAD A DENTAL
EXTRACTION AND HAD BEEN PRESCRIBED
PERCODAN (ASPIRIN/OXYCODONE)
• DURING THIS TIME SHE HAD BEEN PRESCRIBED
IMIPRAMINE, FLURAZEPAM, DIAZEPAM,
TETRACYCLINE, AND DOXYCYLINE
• ON MARCH 1 SHE BELIEVED SHE HAD A COLD
AND SAW HER PEDIATRICIAN WHO PRESCRIBED
CHLORAPHENIRAMNE AND ERYTHROMYCIN
NIGHT OF MARCH 4, 1984
• HER BROTHER CALLED HER PARENTS BACK FROM
A PARTY BECAUSE HIS SISTER SUDDENLY SEEMED
SICKER
• HER PARENTS RACED HOME—SHE HAD A FEVER
AND WAS AGITATED
• SHE HAD FLUSHED SKIN, ROVING EYE
MOVEMENTS, AND DILATED PUPILS
• PARENTS CALLED THEIR FAMILY PHYSICIAN—DR.
RAYMOND SHERMAN—WHO ADVISED THEM TO
GO TO NYU MEDICAL CENTER
DR. RAYMOND SHERMAN
NEW YORK HOSPITAL
HISTORY
• SHE HAD USED MARIJUANA AND COCAINE IN THE
PAST— IN A PAST LETTER SHE HAD STATED THAT
HER BRAIN IS IN A STATE OF “CONFUSION……DUE
TO INCREASED AMOUNTS OF A CERTAIN
POWDER ENTERING IT”
• SHE HAD SEEN AS MANY 7 PROVIDERS IN 1984
—INTERNIST, DENTIST, GYNECOLOGISIT,
PEDIATRICIAN, 2 SCHOOL PHYSICIANS, AND THE
PSYCHIATRIST
AT NYU MEDICAL CENTER
• SEEN IN THE ER WITH A TEMP OF 103.5, RAPID
PULSE AND RESPIRATION, WAS AGITATED BUT
ABLE TO ANSWER QUESTIONS
• ADMITTED BY AN INTERN DR. MAURICE
LEONARD-- THEN EXAMINED BY 1ST YEAR (PGY2)
RESIDENT DR. GREG STONE WHO RE-EXAMINED
HER AND DIAGNOSED “VIRAL” INFECTION ALONG
WITH “HYSTERICAL SYMPTOMS”
• DENIED RECENT ILLEGAL DRUG USE
• NARDIL, ERYTHROMYCIN, AND OTC COLD
MEDICINE ONLY MEDS ENTERED ON RECORD
DR. GREG STONE
CARE HANDED OFF
• DR. STONE ORDERED THAT INTRAMUSCULAR
DEMEROL BE GIVEN TO CONTROL LIBBY’S SHAKING
AND THAT SHE BE ADMITTED TO A WARD
• HE HAD CONFERRED WITH DR. SHERMAN BY PHONE
• AT 3 AM HE TOLD LIBBYS PARENTS THEY SHOULD GO
HOME BECAUSE THEIR PRESENCE MIGHT BE
CONTRIBUTING TO HER AGITATION
• CARE WAS HANDED OFF TO THE INTERN DR. LOUISE
WEINSTEIN WHO WAS COVERING 2 FLOORS AND
ABOUT 40 PATIENTS
DR. LOUISE WEINSTEIN
THROUGH THE NIGHT
• LIBBY BECAME SICKER AND THERE WERE
REPEATED CALLS FROM THE NURSES THAT
HER CONDITION WAS WORSENING
• AT 3:37 AM THE DEMEROL PREVIOUSLY
ORDERED WAS ADMINISTERED
• SHE BECAME INCREASINGLY AGITATED AND
STARTED TO CLIMB OUT OF BED
• SHE WAS PUT IN A STRAIGHT JACKET AND IN
RESTRAINTS
AT 430 AM
• HALDOL 1 MG WAS GIVEN IM ON THE PHONE ORDER
OF DR. WEINSTEIN WHO DID NOT COME TO SEE THE
PATIENT
• LIBBY SETTLED DOWN AND TOOK A DOSE OF
ACETAMINOPHEN BY MOUTH
• RESTRAINTS WERE REMOVED
• AT 630 AM HER TEMP WAS MEASURED AT 108
DEGREES
• COOLING MEASURES WERE INSTITUTED.
• SHE ARRESTED AND COULD NOT BE RESUSCITATED
AND WAS DECLARED DEAD AT 745 AM 8 HOURS AFTER
ADMISSION
HER FATHER--SIDNEY ZION—ACCUSED
THE HOSPITAL AND THE DOCTORS OF
MURDER
SIDNEY ZION
• HE WAS AN INFLUENTIAL COLUMNIST WITH THE NY DAILY
NEWS BUT HAD BEEN A PROSECUTING ATTORNEY IN THE
PAST
• A GRAND JURY FOUND NO BASIS FOR A CRIMINAL CHARGE
• IN A CIVIL CASE 10 YEARS LATER A MONETARY AWARD WAS
MADE BECAUSE DEMEROL WAS GIVEN
• THE AWARD WAS REDUCED BY HALF BECAUSE THE JURY
THOUGHT LIBBY HAD USED COCAINE TO TRIGGER THE
SEROTONIN SYNDROME
HIS DAUGHTERS DEATH WAS A
TRAGEDY, BUT SIDNEY ZION SPARKED
A REVOLUTION
• HE STARTED A CHAIN REACTION THAT CAUSED
A REVOLUTION IN POST GRADUATE MEDICAL
EDUCATION—INCLUDING REDUCED WORK
HOURS AND MORE SUPERVISION OF
RESIDENTS IN TRAINING
• “LIBBY ZION” RULES AND LAWS WERE
ENACTED THROUGHOUT THE UNITED STATES
LESSONS LEARNED FROM THE LIBBY
ZION CASE AND OTHERS
•
•
•
•
EXPAND YOUR DIFFERENTIAL DIAGNOSIS
AVOID THE USE OF DEMEROL
AVOID THE USE OF MAO INHIBITORS
REVIEW MEDICATIONS FOR THE POTENTIAL
OF DRUG INTERACTIONS
• DISTINGUISH BETWEEN SEROTONIN
SYNDROME AND OTHER DRUG TOXIDROMES
SUMMARY: SEROTONIN SYNDROME
REVIEW MECHANISMS OF SEROTONIN
SYNDROME
REVIEW-THE TRIAD OF SEROTONIN
SYNDROME: M-A-N
SEROTONIN SYNDROME
HUNTER SEROTONIN SYNDROME
DECISION TREE
TREATMENT SUMMARY: SEROTONIN
SYNDROME
•
•
•
•
•
•
•
•
•
BENZODIAZEPINES
CYPROHEPTADINE
COOLING MEASURES
NO RESTRAINTS
THORAZINE OR OLAZOPINE
DANTROLENE FOR SEVERE CASES
INTUBATION, PARALYSIS (NOT SUX!) FOR SEVERE CASES
DIALYSIS IF RENAL FAILURE ENSUES
TREATMENT OF RHABODOMYOLYSIS WITH BICARB,
MANNITOL
• ANTICONVULSANTS IF NEEDED
MAJOR REFERENCES
• BOYER, E, ET AL, THE SEROTONIN SYNDROME,
NEJM 352: 1112-1120, MARCH 17, 2005
• LOCKE, A, METHYLENE BLUE AND THE RISK OF
SEROTONIN TOXICITY, ASPF NEWSLETTER, VOL
30, NO.1, JUNE, 2015.
• COOPER, B, ET AL, SEROTONIN SYNROME:
RECOGNITION AND TREATMENT, AACN
ADVANCED CRITICAL CARE, VOL 24, NO. 1: 1520, JAN-MAR, 2013.
MAJOR REFERENCES
• BOYER, E, SERTONIN SYNDROME, UP TO DATE,
1-11, ONLINE, WOLTERS KLUWER, 2013.
• FRANK, C, RECOGNITION AND TREATMENT OF
SEROTONIN SYNDROME, CAN FAM PHYSICIAN,
54 (7): 988-992, JULY, 2008.
THANK-YOU!