Transcript Tobias " New Methods and Drugs for Sedation in

New Methods and Drugs for
Sedation in the Pediatric ICU
Joseph D. Tobias MD
Departments of Anesthesiology & Pediatrics
The University of Missouri
Columbia, Missouri
Pain and Anxiety in the PICU
• pain
• anxiety
– procedure-related
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central line placement
arterial line placement
lumbar puncture
chest tube insertion
mechanical ventilation
– postoperative
– acute illness
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burn, trauma
sickle cell crisis
pleuritis
respiratory insufficiency, dyspnea
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disruption of the day-night cycle
constant noise
sleep interruption
unfamiliar faces
new environment
fear of death or unknown
PICU Sedation: New
Methods and Drugs
• medications
– propofol
– dexmedetomidine
– remifentanil
• techniques
– alternative routes of delivery
– BIS monitoring
Propofol
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intravenous anesthetic agent
alkyl phenol
amnesia, anxiolysis, no analgesia
GABA system
– increased occupancy time of GABA
• advantages
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rapid onset and offset
short half-life, easy to titrate
anti-emetic effect
anti-convulsant
decreases CMRO2 and ICP
cerebral protection
blunts airway reactivity
ICU Sedation: Midazolam vs. Propofol
Sanchez-Izquierdo-Riera JA et al, Crit Care Med 1998;86:1219
• prospective study in 106 adult trauma patients
• three groups
– midazolam starting at 0.1 mg/kg/hr up to 0.35 mg/kg/hr
– propofol starting at 1.5 mg/kg/hr up to 6 mg/kg/hr
– midazolam starting at 0.1 mg/kg/hr up to 0.2 mg/kg/hr, propofol added
• findings
– no difference in hemodynamics or CNS dynamics
– equal efficacy in achieving desired level of sedation
– wake-up (minutes)
• midazolam
• propofol
• midazolam + propofol
660 + 400
110 + 50
90 + 220
Propofol: CNS Effects
Tobias JD, J Intensive Care Med 2000;15:237
• animal studies
– lowered ICP
– decreased CMRO2 and CBF
– intact autoregulation
• MAP, PaCO2
– EEG slowing
– reduction in infarct size
• vascular occlusion, hypoxemia
– anti-oxidant effects
• human studies
– conflicting effects on ICP
• dependent on MAP
• ICP controlled if MAP maintained
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decreased CBF
increased CVR
decreased CMRO2
intact autoregulation (PaCO2)
no effect on SjO2 during CPB
Propofol: Disadvantages
• cardiovascular effects
– hypotension, bradycardia
• respiratory depression
• bacterial contamination
– EDTA, sodium metabisulfite
• neurologic sequelae
– opisthotonus, myoclonus, seizure-like activity
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pain with injection
anaphylactoid reactions
hyperlipidemia (2 mg/kg/hr = 0.5 gm/kg/day)
cost
Increased Propofol (2% vs. 1%)
Barrientos-Vega R et al, Crit Care Med 2001;29:317
• ICU sedation (1% propofol vs. 2% propofol)
– decreased hyper-triglyceridemia (3.9% vs. 20.4%, p=0.016)
Increased Propofol (2% vs. 1%)
Camps AS et al, Crit Care Med 2000;28:3612
• ICU sedation (midazolam vs. 1% propofol vs. 2% propofol)
– 2% solution may be less effective
Propofol: Decreased Lipid
Song D et al, Anesthesiology 2004;100:1072
• anesthetic induction study with propofol 1% vs. Ampofol®
– Amphastar Pharmaceuticals, Rancho Cucamonga, CA
– 50% less soybean oil, egg lecithin
• 60 healthy adults, outpatient surgery
– midazolam premedication; fentanyl 0.5 mcg/kg and lidocaine 0.5 mg/kg
– propofol 0.75 mg/kg  50 mcg/kg/min
• no difference
– onset time, dose, BIS values, hemodynamics, recovery time, patient satisfaction
• increased incidence of pain on injection with Ampofol®
– overall:
– severe pain:
52% versus 28%
26% versus 7%, p<0.05
Propofol: EDTA vs. Metabisulfite
• antibacterial agent to prevent bacterial growth
– AstraZeneca (EDTA), Baxter (metabisulfite)
• lower pH with metabisulfite
– decreased pain on injection with metabisulfite
• potency
– MRI study: Lewis TC et al, Am J Anesthesiol 2000;27:30
• airway reactivity
– metabisulfite less effective: Chih-Chung L et al, Anesthesiology 1999;91:750
• allergic phenomena
• cracking with sodium metabisulfite
– separation of lipid and water phase
• differences with drug compatibility
Propofol Infusion Syndrome
• initial reports in the early 1990’s
• clinical symptoms
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brady-dysrhythmias, cardiac failure
metabolic acidosis
hepatomegaly, fatty infiltration
rhabdomyolysis
• no other apparent causative factor
• potential risk factors
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age
associated respiratory infection
high infusion rates
longer duration of infusion
Are you sure it’s the propofol?
US FDA Center for Drug Evaluation and Research
FDC Reports 1992;54:14
“propofol has no direct link to pediatric
deaths in hospital intensive care units and
no identifiable link to adverse cardiac
events in children and adults”
Propofol Infusion Syndrome
Bray RJ, Paediatr Anaes 1998;8:491
• review of 18 pediatric-aged patients
• clinical symptoms
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brady-dysrhythmias, cardiac failure
metabolic acidosis
hepatomegaly, fatty infiltration
rhabdomyolysis
• age range
– 2 months to 11 yrs, 13/18: 4 yrs or less
– only 1 older than 10
• risk factors
– age, respiratory infection
– infusion rate (> 4 mg/kg/hr)
– duration (> 48 hours)
Are you sure it’s the propofol?
Propofol bashing: The time to stop is now!
Reed MD, Blumer JL, Crit Care Med 1996;24:175
Propofol toxicity in critically ill pediatric
patients: Show us the proof
Susla GM, Crit Care Med 1998;26:1959
Propofol Infusion Syndrome
Cremer OL et al, Lancet 2001;357:117
• 5 adults with closed head injury
– unexplained cardiac death
• retrospective review of 1996 through 1999
– 67 patients sedated and ventilated
– 7 met inclusion criteria for propofol infusion syndrome
• progressive myocardial failure with dysrhythmias
• unexplained metabolic acidosis, hyperkalemia, rhabdomyolysis
– odds ratio for the syndrome
• 1.93 for every 1 mg/kg/hr above 5 mg/kg/hr
Propofol: Mitochondrial Function
• two year old boy (Wolf A et al, Lancet 2001;357:606)
– clinical features of propofol infusion syndrome
– increased plasma concentrations
• malonylcarnitine, C5-acylcarnitine
– disruption of mitochondrial fatty acid oxidation
• animal study (Schenkman KA et al, Crit Care Med 2000;28:172)
– perfused guinea pig heart
– propofol impairs
• mitochondrial oxygen utilization
• electron flow along the mitochondrial electron transport chain
“Dear Healthcare Provider”
• letter from Astra-Zeneca in March 2001
• may be safety issues when propofol used in PICU
• report of prospective trial of 2% propofol
– 327 patients (1% propofol, 2% propofol, standard agents)
– 25 deaths during the trial
• 12 (11%) with 2% propofol
• 9 (8%) with 1% propofol
• 4 (4%) with standard agents
“Dear Healthcare Provider”
“We would like to reemphasize that
propofol is currently not approved for
sedation in pediatric ICU patients in the
US and should not be used for this
purpose”.
Propofol: Where Are We Now?
• sufficient evidence to suggest a causal link
• limit use for short term sedation (less than 24 hrs)
– transition from other agents to extubation
• no need to restrict OR or procedural sedation use
• if used for therapeutic agent (control of ICP)
– monitor ABG’s every 6-8 hours, CPK every 12-24 hours
– discontinue immediately if base deficit develops
PICU Sedation: New
Methods and Drugs
• medications
– propofol
– dexmedetomidine
– remifentanil
• techniques
– alternative routes of delivery
– BIS monitoring
Dexmedetomidine
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Precedex®, Abbott Laboratories
intravenous formulation
alpha2 adrenergic agonist
alpha2 to alpha1 = 1600:1
– 7 times greater than clonidine
• hepatic metabolism
• shorter elimination half-life than clonidine
– 2-3 hours versus 8-12 hours
• dosing (adult literature)
– loading dose (0.5-1 mcg/kg over 15 minutes)
– infusion (0.2-0.7 mcg/kg/hr)
• FDA approved for ICU sedation in adults
– 24 hours
Mechanism of Action
• locus cereuleus  sedation, anxiolysis
• medullary vasomotor center  decreased HR, BP
– decreased norepinephrine turnover
• spinal cord 2 receptors  analgesia
– decreased release of substance P
•  renin, vasopressin + increased ANP  diuresis
• peripheral 1 receptors  vasoconstriction (variable)
Sedative Effects of Dexmedetomidine
Hall JE et al, Anesth Analg 2000;90:699
• 7 healthy, adult volunteers
• three sesssions, random order
– placebo
– dexmedetomidine 0.2 mcg/kg/hr
– dexmedetomidine 0.6 mcg/kg/hr
• Bispectral Index
– processed EEG monitor
• VASsedation
– patient reported
• OAA/S
– observer evaluated
Sedative Effects of Dexmedetomidine
Hall JE et al, Anesth Analg 2000;90:699
0.2 mcg/kg/min
0.6 mcg/kg/min
placebo
Dexmedetomidine: Adult ICU Patients
Venn RM et al, Anaesthesia 1999;54:1136
• adult ICU population
– 98 postoperative cardiac and general surgery patients
• dexmedetomidine versus placebo
– 1 mcg/kg over 10 minutes  0.2-0.7 mcg/kg/hr
• morphine and midazolam for rescue sedation
• dexmedetomidine vs. placebo (equal Ramsay scores)
– 80% less midazolam
• 4.9 + 5.8 vs. 23.7 + 27.5 mcg/kg/hr, p<0.0001
– 50% less morphine
• 11.2 + 13.4 vs. 21.5 + 19.4 mcg/kg/hr, p=0.0006
Dexmedetomidine: End-organ Effects
• cardiovascular
– hypotension (especially with loading dose)
– bradycardia
– hypertension (occasionally during loading dose)
• respiratory
– blunted airway reactivity
– depressed respiratory drive
• central nervous system
– sedation, anxiolysis, analgesia
– ICP, CBF
– seizure threshold, damage during ischemia
Dexmedetomidine: Adult ICU Patients
Venn RM et al, Anaesthesia 1999;54:1136
• dexmedetomidine versus placebo
– HR, systolic & diastolic BP lower during first hour
– no statistical difference after the first hour
• hypotension (MAP < 60 mmHg or > 30%  from start)
– 18/66 dexmedetomidine patients, 11 with loading dose
• hypertension with loading dose
– 6/66 dexmedetomidine patients
Dexmedetomidine: Cardiovascular Effects
Bloor BC et al, Anesthesiology 1992;77:1134
• cardiac output by thoracic bio-impedance
– expressed as percentage of baseline
– 37 healthy, male volunteers
– placebo, 0,25, 0.5, 1, 2 mcg/kg over 2 minutes
dose
placebo
0.25
0.50
1.0
2.0
0-1 min
98 + 12
95 + 22
84 + 39*
81 + 13*
58 + 32*, +
10 min
105 + 20
98 + 16
93 + 39
88 + 14*
76 + 33*
60 min
102 + 10
90 + 18
88 + 35*
91 + 11*
85 + 28*
* p<0.05 vs. baseline, + p<0.05 vs. placebo
Dexmedetomidine: Bradycardia
Berkenbosch JW & Tobias JD, Pediatr Crit Care Med 2003;4:203
• 5 week old, 3.6 kg infant, trisomy 21, viral pneumonia
– AV canal defect, digoxin and furosemide for chronic CHF
– intubated, mechanical ventilation
• enrolled in prospective randomized trial
– dexmedetomidine versus midazolam
• dexmedetomidine 0.5 mcg/kg  0.44 mcg/kg/min
• 12 hours after start of dexmedetomidine
– bradycardia with heart rate of 40-50 beats/minute, BP stable
– dexmedetomidine stopped, bradycardia resolved in 1 hour
Dexmedetomidine: Respiratory Effects
Belleville JP et al, Anesthesiology 1992;77:1125
• double blind, placebo controlled study, 37 adults
– dexmedetomidine: 0.25, 0.5, 1.0, 2.0 mcg/kg over 2 minutes
– findings of dexmedetomidine 2.0 mcg/kg/min group
parameter
baseline
10 minutes
60 minutes
VAS (mm) sedation
16.6 + 12.4
93.2 + 9.1*
72.4 + 15.9*
SpO2 (%saturation)
98.3 + 0.8
96.2 + 1.5*
95.4 + 1.2*
PaCO2 (mmHg)
41.9 + 2.3
46.1 + 5.0*
45.3 + 3.5*
ventilation (l/min)
8.73 + 0.71
7.14 + 3.04*
6.28 + 1.53*
VE vs. PETCO2
2.00 + 0.99
1.36 + 1.62
1.50 + 0.79
VE @ PETCO2 55 mmHg
22.50 + 7.32
13.82 + 8.01*
12.89 + 3.22*
Dexmedetomidine: Respiratory Effects
Groeben H et al, Anesthesiology 2004;100:359
• 5 mongrel dogs
– intubation and mechanical ventilation
• provocative challenge
– inhaled histamine
• protective effects
– IV and inhaled dexmedetomidine
Dexmedetomidine: End-organ Effects
• cardiovascular
– hypotension (especially with loading dose)
– bradycardia
– hypertension (occasionally during loading dose)
• respiratory
– blunted airway reactivity
– respiratory drive
• central nervous system
– sedation, anxiolysis, analgesia
– ICP, CBF
– seizure threshold, damage during ischemia
Dexmedetomidine and ICP
Talke P et al, Anesth Analg 1997;85:358
• adults (n = 16)
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transphenoidal surgery
lumbar CSF drain
placebo or dexmedetomidine
600 pg/mL
• highest clinically used concentration
• no change in ICP
– highest ICP
• control - 20 mmHg
• dexmedetomidine - 19 mmHg
• dexmedetomdine group
– HR:
– MAP:
– CPP:
77 + 12 to 64 + 7 bpm, p<0.05
103 + 10 to 86 + 6 mmHg, p<0.05
95 + 8 to 78 + 6 mmHg, p<0.05
Dexmedetomidine, ICP, and CBF
Zornow MH et al, Anesth Analg 1992;75:232
• 24 New Zealand white rabbits
– anesthetized with halothane
– mechanical ventilation to PaCO2 of 34-39 mmHg
– saline or dexmedetomidine (20, 80, 320 mcg/kg) over 10 minutes
• findings
– 20 mcg/kg   ICP (9.4 + 1.3 to 6.5 + 1.0 mmHg, p<0.05)
– 320 mcg/kg   BP and no change in ICP
• intracranial hypertension (cryogenic lesion, ICP 16.8 mmHg)
– no change in ICP with dexmedetomidine
– 320 mcg/kg  14% decrease in CBF
Dexmedetomidine and CBF
Prielipp RC et al, Anesth Analg 2002;95:1052
• nine adult volunteers
• dexmedetomidine: 1 mcg/kg  0.2 and 0.6 mcg/kg/hr
• PET scan/H215O for CBF
Parameter
baseline
CO (l/min)
7.3
MAP (mmHg)
92
PaCO2 (mmHg)
37
MAP (mmHg)
92
CBF
90.5
(mL/100 gm/min)
load
6.1*
91
NA
91
NA
low dex
6.3*
79*
42*
79*
63.9*
high dex
5.9*
81*
42*
81*
60.6*
dex off
6.0*
77*
39
77*
63.4*
Dexmedetomidine and Seizures
• Sprague Dawley rats, cocaine infusion
– 25.0 + 7.7 versus 49.3 + 14.8 min (saline vs. dexmedetomidine)
Whittington RA et al, Anesthesiology 2002;97:693
• Sprague Dawley rats, pentylenetetrazol (PTZ) infusion
– dexmedetomidine decreased EEG seizure and clonic activity dose
Mirski MAZ et al, Anesthesiology 1994;81:1422
• cats, enflurane
– dexmedetomdine decreased seizure threshold
Miyazaki Y et al, Br J Anaesth 1999;82:935
Dexmedetomidine & Brain Injury
• gerbils, bilateral carotid occlusion
– dexmedetomidine before and for 48 hr after reperfusion
– decreased number of damaged neurons compared to placebo
Kuhmonen J et al, Anesthesiology 1997;87:371
• rat, right common carotid occlusion + hemorrhage
– dexmedetomidine (10, 100 mcg/kg)
– improved neurologic and histologic outcome vs. saline
• despite increased serum glucose
– effect blocked by atipamezole
Hoffman WE et al, Anesthesiology 1991;75:328
• rat, middle cerebral artery occlusion
– dexmedetomidine decreased infarct size after transient occlusion
Kuhmonen J et al, J Neural Trans 2001;108:261
Dexmedetomidine: Pediatric Use
Tobias JD et al, South Med J (in press)
• prospective randomized trial
• infants and children requiring mechanical ventilation
– midazolam at 0.1 mg/kg/hr
– dexmedetomidine at 0.25  0.5 mcg/kg/hr
• morphine (0.1 mg/kg) prn agitation
• assessment of sedation
– BIS number
– 3 sedation scores
• Ramsay, PICU score, tracheal suction score
Dexmedetomidine: Pediatric Use
Tobias JD et al, South Med J (in press)
• midazolam (10), dexmedetomidine 0.25 (10), 0.5 (10)
• no difference
– age, weight, gender
– mean, median of the three sedation scores
– mean BIS number
• morphine needs (mg/kg/24 hours)
– 0.74 + 0.5
0.55 + 0.38
0.28 + 0.12, p<0.05 vs. midazolam
• Ramsay score = 1 (points, patients)
– 14 & 6/10
11 & 4/10
5 & 2/10, p = 0.08 vs. midazolam
• dexmedetomidine patients with Ramsay = 1
– 5 of 6 were < 12 months of age, p<0.05 vs. other dexmedetomidine patients
Dexmedetomidine: Procedural Sedation
Berkenbosch JW et al, submitted for publication
• dexmedetomidine for diagnostic imaging
• 48 pediatric patients, 6.9 + 3.7 years
– 15 failed sedation with chloral hydrate + midazolam
– 33 received primary sedation with dexmedetomidine
• dosing regimen
– bolus (mcg/kg)
– infusion (mcg/kg/hr)
0.92 + 0.36 (0.30 to 1.92)
0.69 + 0.32 (0.25 to 1.14)
• no adverse effects
– ETCO2 > 50 mmHg 1.7% of the time, highest 52 mmHg
• recovery time longer when used following other agents
– 117 + 47 versus 69 + 34 minutes, p=0.0001
PICU Sedation: New
Methods and Drugs
• medications
– propofol
– dexmedetomidine
– remifentanil
• techniques
– alternative routes of delivery
– BIS monitoring
Remifentanil
• synthetic opioid, mu agonist
• equipotent to fentanyl
• cardiorespiratory effects
– similar to other opioids
• short half-life: 5-10 minutes
– metabolism: plasma esterases
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•
effects dissipate rapidly
multiple applications intraoperatively
potential for procedural or ICU sedation
preservative precludes neuraxial use
Remifentanil in the Neonate
Davis PJ et al, Anesth Analg 2001;93:1380
Galinkin JL et al, Anesth Analg 2001;93:1387
• neonates and infants undergoing pyloromytomy
– normal preoperative pneumograms
– intravenous induction, cis-atracurium
– 60% N2O + halothane or remifentanil (0.4 mcg/kg/min)
• similar extubation times, PACU time
• postoperative apnea
– 3/13 with halothane vs. 0/22 with remifentanil (p=0.04)
Remifentanil in the Neonate
Kinder-Ross A et al, Anesth Analg 2001;93:1393
Remifentanil bolus of 5 mcg/kg.
Variable
0-2 mos
2 mo-2 y
Vd (mL/kg)
452.8 + 144.7
307.9 + 89
clearance
(mL/kg/min)
90.5 + 36.8
T1/2 (min)
range
5.4 + 1.8
3-8
92.1 + 25.8
3.4 + 1.19
2-6
2-6 yr
7-12 yr
240.1 + 130.5
248.9 + 91.4
76.0 + 22.4
59.7 + 22.5
3.6 + 1.19
1-6
5.3 + 1.4
3-7
Remifentanil: PICU Sedation
Tobias JD, Amer J Pain Manage 1998;8:114
• case series of 4 patients, sedation for mechanical ventilation
– airway issues (epiglottitis, croup, status post airway procedures)
– deep sedation, no NMBA, rapid awakening
• ages: 6 mo, 4 mo, 4 yr, 8 yr
• brief period of sedation: 1.5, 16, 18, 36 hours
• remifentanil dosing
– bolus: 0.5-1 mcg/kg  infusion 0.3-0.5 mcg/kg/min
– adjusted in increments of 0.1 mcg/kg/min
• comments
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–
–
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effective sedation with rapid awakening
do not use in patients at risk for withdrawal
cost ($120/day in 20 kg patient at 0.5 mcg/kg/min)
rapid development of tolerance
Remifentanil: Procedural Sedation
Litman RS, Arch Pediatr Adolesc Med 1999;153:1085
• brief, painful procedures in 20 children
– midazolam 0.05 mg/kg, remifentanil 1 mcg/kg  0.1 mcg/kg/min
– supplemental oxygen
• success in 17 of 20 patients
– remifentanil dose: 0.4 + 0.2 mcg/kg/min
– discharge time: 17.4 + 6.8 minutes
• adverse effects
– hypoxemia in 4, verbal or tactile stimulation
– apnea in 10, verbal prompting to breathe
– mask ventilation in 1
• conclusion
– not useful due to high incidence of respiratory depression
Remifentanil: Procedural Sedation
Reyle-Hahn M et al, Paediatr Anaesth 2000;10:59
• prospective study in 26 patients (3 to 14 years)
– bronchoscopy
• oral premedication + inhaled local anesthetic
• sedation procedure
– remifentanil infusion: 0.05 mcg/kg/min
– intermittent propofol: 0.5-1 mg/kg
• propofol requirements: 14.5 + 7 mg/kg/hr
• no adverse effects
• awake within 5 minutes, discharged at 60 minutes
Remifentanil: Procedural Sedation
Keidan I et al, Paediatr Anaes 2001;11:297
• prospective study, 80 children, BMA
• propofol/remifentanil or propofol
– propofol 3 mg/kg  300 mcg/kg/min
– remifentanil: 0.15 mcg/kg  0.1 mcg/kg/min
• propofol/remifentanil versus propfol
– eye opening
– home readiness
– RR < 10 or O2 sat < 90%
23 + 12 vs. 38 + 19 min (p<0.001)
33 + 15 vs. 52 + 24 min (p<0.001)
8 vs. 4 (p<0.05)
PICU Sedation: New
Methods and Drugs
• medications
– propofol
– dexmedetomidine
– remifentanil
• techniques
– alternative routes of delivery
– BIS monitoring
Non-Parenteral Routes
• inhalational
• oral
• rectal
– cancer-related pain, anesthetic premedication, procedural sedation
– limited number of opioid preparations
– acceptability issues
• transmucosal
– nasal, buccal, sublingual, endotracheal, respiratory (nebulized)
– preliminary although limited data show good efficacy
– limited preparations
• butorphanol, nasal fentanyl for PE tubes, aerosolized morphine, OTFC
• transdermal
Subcutaneous Sedatives & Analgesics
Tobias JD, Crit Care Med 1999;27:2262
• retrospective study of 9 children
– prolonged PICU sedation, 3-7 years, 11 to 31 kgs
• subcutaneous fentanyl + midazolam
– fentanyl 5-9 mcg/kg/hr, midazolam 0.15-0.3 mg/kg/hr
• slow weaning of agents to prevent withdrawal
• effective alternative to IV administration
• no need to maintain IV access
Subcutaneous Technique
• can use several medications (concentrated solutions)
– morphine, fentanyl, hydromorphone, midazolam, lorazepam
• infusion rate less than 3 mL/hr
• location
– subclavicular, abdomen, thigh, deltoid
• 23 gauge butterfly or angiocatheter
–
–
–
–
flushed with solution
EMLA® cream
covered with bio-occlusive dressing
change every 7 day
• standard infusion pump
– increase pressure limit
• start subcutaneous infusion, stop IV
PICU Sedation: Mode of
Administration
•
•
•
•
intermittent, prn
intermittent, fixed interval
continuous infusion
patient-controlled device
Opioids and sedatives should be
administered to maintain a steady
state serum concentration while
avoiding peaks and troughs
PCA or Patient-Controlled Anxiolysis
• patient-activated device
– can be used in patients as young as 5-6 years of age
– use for nurse activation at bedside
• time-saving, no need to access lines, improved sedation
• maintains steady-state serum concentration
• postoperative studies
– improved analgesia, decreased opioid needs
• can use with any medication
– new reports of patient-controlled anxiolysis in OR
• load with medication prior to starting PCA
– adjust dose as needed
PICU Sedation: New
Methods and Drugs
• medications
– propofol
– dexmedetomidine
– remifentanil
• techniques
– alternative routes of delivery
– BIS monitoring
Bispectral Index Monitoring
• modified EEG
• numerical readout
– 0 (isoelectric)  100 (awake, eyes open)
– amnesia  < 60-70
• predominant intraoperative use
4 month old, 5.4 kg infant: repair of AV canal with circulatory arrest
3 month old, 4.3 kg infant: mitral valve replacement
EEG Changes During Anesthesia
Descriptor
Awake EEG
Raw EEG
Clinical State
Awake

Beta Activation
Synchronized Slowing
Emerging Suppression
Isoelectric EEG
Sedated

Unconscious

Deep Anesthesia
Bispectral Index Monitoring
• Burst suppression
– suppression ratio
• Power
– spectral edge frequency
• Bispectrum
– correlation of phase between
different frequency components
Bispectral Index Monitoring
Probability of Response
Glass et al, Anesthesiology 1997;86:836
Struys et al, Anesthesiology 2002;96:803
1.0
Free Recall
OAA/S
Eyelash Reflex
Pk BIS
Predictive Probability
.93
.95
.2
BIS=60
Sensitivity
99%
96%
0
Specificity
.81
.62
8
Response to
Verbal
Command
.6
.4
0
20
40
60
80
Bispectral Index
100
Intraoperative Awareness
Ekman A et al, Acta Anaesthesiol Scand 2004;48:20
• prospective study of 4945 patients
• BIS maintained at 40-60
• compared to historical control group of 7826 patients
– same authors as previous study
• interviewed 3 times
– before discharge from PACU
– day 1 to 3
– day 7 to 14
• 2 cases of recall (0.04%)
– during intubation
– BIS number was > 60 for 4 & 10 minutes
BIS and Procedural Sedation
Motas D et al, Paediatr Anaesth 2004;14:256
• depth of sedation during procedural sedation
• pentobarbital or midazolam plus opioid
BIS number
Pentobarbital
Midazolam
plus opioid
Awake (>90)
0
8
Conscious sedation
(71-90)
Deep sedation
(61-70)
1
19
6
11
General anesthesia
(<60)
9
15
BIS
number
Number of
patients
Desaturation
Airway
events
Awake
(>90)
8
0
0
Conscious
sedation
(71-90)
20
1
0
Deep sedation
(61-70)
17
2
3
General
anesthesia
(<60)
24
4
4
P value
------
0.181
0.022
Motas D et al, Paediatr Anaesth 2004;14:256
BIS and PICU Sedation
Berkenbosch JW et al, Anesth Analg 2002;94:506
• prospective study, 24 pediatric patients
– sedation during mechanical ventilation
– 5.7 + 6.1 years, 428 sample sets, adult BIS probe
• correlation of the BIS with sedation scores
– Ramsay, PICU sedation score, tracheal suctioning score
• stepwise correlation of median BIS with sedation score
– wide ranges: EMG interference or natural sleep
• adequate sedation (BIS = 70)
– sensitivity 0.87-0.89, positive predictive value 0.68-0.84
• excessive sedation (BIS = 50)
– sensitivity 0.67-0.75, positive predictive value 0.07-0.52
BIS and PICU Sedation
Berkenbosch JW et al, Anesth Analg 2002;94:506
1
PICU
2
3
71
52
44
36-99 30-94 13-93
4
5
6
39
8-91
----
----
Ramsay
54
65
48
42
42
18-98 47-99 13-90 17-91 13-93
36
8-91
PICU
70
61
43
44
42
37-98 28-97 17-94 13-99 17-77
----
BIS and NMBA’s in the PICU
Tobias JD et al, submitted for publication
• prospective study, NMBA’s in the PICU
– BIS number recorded, not seen by RN
– titration of sedatives by clinical means
– midazolam or propofol + prn fentanyl, morphine
• data collected for 16 to 116 hours in 12 patients
– 476 hours, 161,893 BIS values
• BIS values
< 49
50 to 70
> 70
35%
57%
8%
• BIS values when prn doses given (104)
< 49
50 to 70
> 70
5%
31%
64%
• BIS value < 50 more likely with propofol than midazolam
QUESTIONS
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