n.liu@hopital-foch.org33(1)-46-25-27-67

Service d’AnesthésieHôpital Foch Suresnes

France

Closed-Loop Control of General Anesthesia: “My Clinical Experience”

Ngai LIU, M.D.

JAMA 1950, 144 (13)

50 patients, ETHER“Major Surgical procedures

varying age, both sexesWithout untoward effect “

-Mortier/Struys: Anaesthesia 1998 “Closed-loop controlled administration of propofol using BIS” -Morley: Anaesthesia 2000 “Closed-loop control of anaesthesia: An assessment of the BIS…”-Struys: Anesthesiology 2001 “Comparison of closed-loop controlled administration of propofol..”-Leslie/Absalom: Anaesthesia 2002 “Closed-loop … colonoscopy using the BIS”-Absalom: Anesthesiology 2002 “Closed-loop control…under combined general and regional anesthesia”-Absalom : BJA 2003 “Closed-loop control of propofol using the BIS …minor surgery”-Ihmsen/ Naguib: BJA 2007 “Teletherapeutic drug administration by long distance closed-loop control of propofol”-Puri: Anaesth. Intensive Care 2007 “Closed-loop anaesthesia delivery system using bispectral index”-Haddad : IEEE Neural Network 2007 “Neural Network Adaptive Output Feedback …for Intraoperative Anesthesia 

Feasibility of Feedback control of Propofol

During GA MaintenanceUsing the BIS monitor

Proportional-Differential + TCI propofol (Schnider) + Feed-forward

June 2006, pp 470-475

Prospective randomized study20 patients/group

Manual vs Automated induction

We wanted to compare our closed-loop controller to the manual TCI Titration in varying conditions of routine clinical anesthesia. Including minor and major surgery.

The titration of remifentanil TCI during the surgical procedure was decided by the physician in charge of the patient in both groups.

End point : 40 < BIS < 60 during maintenance.

Percentage BIS 40-6050

40

30

20

10

0

161817

6

11

55

100908070605040302010

50

40

30

20

10

0

46

21

12

3

1009080706040302010 50

70 ± 21 vs 89 ± 9, p = 0.0001

Adequate anesthesia was more frequent in the Closed-loop group

Manual (n=81) Closed-loop (n=83)

Hypnosis

AnalgesiaHR, MAP, Pupillometry

Paralysis

Hypnotic

NMBA

Surgery

Opioid ?DynamicBalance

Gray Br Med J 1952

Case report

Male 72 yearsHistory of coronary disease (CABG and Angioplasty)Beta-blocker

Tympanoplasty

General AnesthesiaClosed-loop

PropofolManual TCI of RemifentanilBolus of Atracurium

Instability !Oscillation !

TI draping Incision Arousal

Remi (ng/ml) 6 4 8 12 14 16 20

Propofol Target

Movement

Your hypothesis ?

Anesthesia depth

Dynamic Balance between

Hypnosis and Analgesia

Poor Analgesia

BIS Instability (oscillation) !

With a Closed-loop BIS-Propofol system, we obtain a stable level of hypnosis and the BIS can also reflect the degree of inhibition of response to noxious stimuli.

If BIS suddenly increases in response to noxious stimuli, this could be a deficit in the analgesic component of anesthesia, and this requires an increase of analgesia.

We have implemented a second closed-loop controller between Remifentanil and BIS using a Proportional-

differential algorithm

GA = LOC + Inhibition of noxious stimuliP. Glass Anesthesiology 1998, 88; 5-6T. Bouillon et al Anesthesiology 2004

With a Closed-loop BIS-Propofol system, we obtain a stable level of hypnosis and the BIS can also reflect the degree of inhibition of response to noxious stimuli.

If BIS suddenly increases in response to noxious stimuli, this could be a deficit in the analgesic component of anesthesia, and this requires to increase analgesia.

We have implemented a second closed-loop controller between Remifentanil and BIS using a Proportional-

differential algorithm

GA = LOC + Inhibition of noxious stimuliP. Glass Anesthesiology 1998, 88; 5-6T. Bouillon et al Anesthesiology 2004

We learn from failureNot from success.

Kidney Tx

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20

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120

1 301 601 901 1201 1501 1801 2101 2401

Time (secondes)

Bis

grefferénale

Male 27 years, Kidney Transplantation, HTA

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120

1 301 601 901 1201 1501 1801 2101 2401

Time (Seconds)

Bis

-1

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3

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15

grefferénalepropofol

Male 27 years, Kidney Transplantation, HTA

0

20

40

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80

100

120

1 301 601 901 1201 1501 1801 2101 2401

Temps (en secondes)

Bis

-1

1

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11

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15

grefferénalepropofol

Male 27 years, Kidney Transplantation, HTA

Incision Retractor

Titre du graphique

0

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100

120

1 301 601 901 1201 1501 1801 2101 2401

Temps (en secondes)

Bis

0

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12

14

16

grefferénaleremifentanilpropofol

Male, Kidney Transplantation, HTA

Incision Retractor

Propofol and Remifentanil guided solely by the BIS : Manual vs Closed-loop

• Prospective Randomized, MulticenterAfter informed consentEthical Committee and AFSSAPS approval

• Foch, Argenteuil, Angers, Besançon.• Manuel vs Dual-loop• 100 patients per group• End points

– Percentage 40-60– Movement, HD– Behavior of the controller during all types of surgery– ASA IV

A854 ASA Meeting Chicago 2006

ASA Meeting Chicago 2006

Manual Dual-loop

100 %908070605040302010

50

40

30

20

10

0

Number of patients

Dual-loop (n=83)

Manual (n=84)

Percentage of Time 40-60

71 % ± 19 vs 82 % ± 12 (p < 0.0001)

State Entropy : irregularity (1-32 Hz) : Depth of hypnosis Response Entropy (1-47 Hz)

(RE-SE) represents (32-47 Hz) : Facial EMG activity or adequacy of anti-nociception

ASA MeetingSan Francisco

2007A 1881

Feedback control of

Propofol-SE

Remifentanil-(RE-SE)

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80

1000

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100

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Manual (n=31) Dual-loop (n=27)

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100

0 20 40 60 80 100 120 140 160 1800

50

100

0 20 40 60 80 100 120 140 160 180 minutes

SE

RE

% of patients 50

100

0

2D Graph 12

1 2

nom

bre

de m

odifi

catio

ns d

e ci

bles

/h

0

20

40

60

80

100

40 < BIS < 60 BIS < 40 BIS > 60

Dual-loop in ICU, Prospective randomized study (E. Bourgeois SFAR 2007)

Manual (n=14) vs Dual-loop sedation (n=15)

% 67 ± 22 vs 38 % ± 21

50 % PropofolDual-loop Manual

What did the Closed-loop controller teach me ?

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160

12:00:07 AM 12:05:12 AM 12:10:12 AM 12:15:12 AM 12:20:12 AM 12:25:12 AM 12:30:12 AM 12:36:07 AM 12:41:07 AM 12:46:07 AM 12:51:07 AM

Tim e

Entropy

BIS

Female 20 years, 1.70 m, 50 kg, PK SchniderClosed-loop propofol, Remi fixed (4 ng/ml)

0

20

40

60

80

100

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140

160

12:00:07 AM 12:05:12 AM 12:10:12 AM 12:15:12 AM 12:20:12 AM 12:25:12 AM 12:30:12 AM 12:36:07 AM 12:41:07 AM 12:46:07 AM 12:51:07 AM

Tim e

Entropy

BIS

Female 20 years, 1.70 m, 50 kg, PK SchniderClosed-loop propofol (1%), Remi fixed (4 ng/ml)

0

20

40

60

80

100

120

140

160

12:00:07 AM 12:05:12 AM 12:10:12 AM 12:15:12 AM 12:20:12 AM 12:25:12 AM 12:30:12 AM 12:36:07 AM 12:41:07 AM 12:46:07 AM 12:51:07 AM

Tim e

Entropy

BIS

Female 20 years, 1.70 m, 50 kg, PK SchniderClosed-loop propofol, Remi fixed (4 ng/ml)

Piglet 22 Kg3 month !

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140

160

00:00:07 00:05:12 00:10:12 00:15:12 00:20:12 00:25:12 00:30:12 00:36:07 00:41:07 00:46:07 00:51:07

temps

EntropyBIS

Propofol 2 %

9-years-old boy 25 kgGiant lobar emphysemaSpO2 = 85 % with 10 l/min O2

Dual-loop Propofol-RemifentanilInduction and MaintenanceIntrathecal morphineRight postero-lateral thoracotomyMiddle lobectomy Lower lobe atypical resection

Paediatr Anaesth. 2007 Sep;17(9):909-10.

Closed-loop administration of propofol and remifentanil guided by the Bispectral Index for transsphenoidal surgery in a patient

with extreme gigantism

Age : 24Weight : 125 kgHeight : 2.48 m !

Blade # 6

0

10

2030

40

50

60

7080

90

100Bis

Induction MaintenancePropofol 0.9 mg/kg 5.2 mg/kg/hRemifentanil 1.9 µg/kg 0.30 µg/kg/min

40-60 : 83 % < 40 : 15 % > 60 : 2 %GS : 23Extubation : 7 min

Female, 69 years, 1.60 m, 85 kgAortic StenosisAortic valve repair

Bis

0

20

40

60

80

100

120

140

160

180

0:00:00 0:05:11 0:10:22 0:15:33 0:20:44 0:25:55 0:31:06

Bis

Female, 69 years, 1.60 m, 85 kgAortic StenosisAortic valve repair

0

20

40

60

80

100

120

140

160

180

0:00:00 0:05:11 0:10:22 0:15:33 0:20:44 0:25:55 0:31:06

BisSys

Female, 69 years, 1.60 m, 85 kgAortic StenosisAortic valve repair

0

20

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60

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100

120

140

160

180

0:00:00 0:05:11 0:10:22 0:15:33 0:20:44 0:25:55 0:31:060

2

4

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10

12

BisSyspropofolremifentanil

Propofol : 0.8 mg/kgRemifentanil : 2.6 µg/kg

Feedback controlContinuous Titration to effect

compensates for most of PK Errors !

ModelConcentration

Drug

Safety +++

The impact of the PK model in a controller is low

BIS Propofol Concentration (ng/ml)

0 50 100 150 200 250 300 350 400 450 500

20

40

60

80

100

0,5

1,0

1,5

2,0

2,5

Minutes

Safety

Closed-loop controller during cardiac arrest

BIS Propofol Concentration (ng/ml)

0 50 100 150 200 250 300 350 400 450 500

20

40

60

80

100

0,5

1,0

1,5

2,0

2,5

Minutes

Safety

Closed-loop controller during cardiac arrest

Conclusion

• Feasibility of Dual-loop• Reliable and safe

• Closed-loop controller could fundamentally change the practice of Anesthesia !!!

“The clinician will always hold the ultimate responsibility for patient safety”O’Hara Anesthesiology 92

n.liu@hopital-foch.org Service d’Anesthésie Hôpital Foch Suresnes

France

Open loop TCI

Semi-closed loop TCI

Closed-loop

What is the best for the physician ?

Emergence

0.0177 ± 4 10 ± 7Extubation Time (min)

pClosed-loop(n = 83)

Manual TCI (n = 81)

min

4035302520151050

1009080706050403020100

Manual TCI

Closed-loop group

Greater predictability and better planning of the recovery phase

Prof. Manfred MORARI

0

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1 721 1441 2161 2881 3601 4321 5041

Time (h)

0

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12

BISSRpropofolremifentanil

%<40 4%<45 23%>60 2%>70 0

%30 50 59%45 60 75%40 60 94

Norepinephrine (mg/h)

1 1.6 1.5 1 0.61

Main events Fibero TEEnursing nursing

Case male 59 y

40-600

20

40

60

80

100

Manual TCI

Closed-loop

%

<45 < 40 >60

Figure 3. Efficiency of the system during maintenance of anesthesia. 40 < BIS < 60 = percentage of time in which the BIS value was between 40 and 60 during the maintenance. BIS < 45 = percentage of time in which the Bispectral index (BIS) value was below 45. BIS < 40 = percentage of time in which the BIS value was below a value of 40. BIS > 60 = percentage of time in which the BIS value was greater a value of 60. Manual TCI: Manual TCI group guided by the BIS. Closed-loop: Closed-loop group. # p < 0.0001, ns: not significant.

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Closed-loop Anesthesia decreases the incidence of Too Deep AnesthesiaWeldon Anesthesiology 2002 : A1097Lennmarken ASA 2003 : A303Monk, ASA 2004 : A1361

Prolonged deep anesthesia was associated with increased risk of one year mortality !