All vår början bliver svår…
Extern closed loop
Ragnar Hanås, Barn- och Ungdomskliniken, Uddevalla och NÄL
MAT
➠ Den första
insulinpumpen från
Indiana, USA 1963.
➠ Pumpen kunde även
ge glukagon!
Håller den blodsockerbalansen automatiskt?
Low Glucose Suspend i praktiken
Pump, sensor + LGS (Low Glucose Suspend
21 pat. 1-18 år, diabetes duration ≥ 12 mån., CSII 3 ≥ mån.
2 veckor med Sensor-Augmented Pump (SAP) jämfördes med
6 veckor med SAP + Low Glucose suspend (LGS)
Hypoglykemi-larm vid 4,2 mmol/l, LGS vid 3,9 mmol/l
Hannes, 8 år, 29 kg
Diabetes sedan1½ år
Pump, 0.7 E/kg/dag
HbA1c 41 mmol/l (4,9%)
Frukost-problem:
Hyper-, sedan hypoglykemi
Pumpen stänger av med LGS
(Low Glucose Suspend)
Resultat
➠
Hypo < 4.2
Hypo < 2.2
SAP
SAP+LGS
1.27/dag
0.28/dag
0.95/dag
0.13/dag
Tid i hypo
101 min/dag 58 min/dag
< 4.2mmol/l
Medel-BG
8.1 mmol/l 8.2 mmol/l
Danne, T. Diab Tech Ther 2011;13, 1129-34.
Danne, T. Diab Tech Ther 2011;13, 1129-34.
Pump, sensor + LGS (Low Glucose Suspend)
Closing the loop - InfuLink
50 pat. 17-58 years, diabetes duration > 1 year., CSII 3 ≥ months.
Exercise sessions until BG < 4.7 mmol/l
LGS set at 3.9 mmol/l, stopped basal for 120 min.
134 sessions, 36 not included as BG > 16.7 or < 2.8 mmol/l
5 mmol/l
Exercise until
4.7 mmol/l
5 mmol/l
3.9 mmol/l
Produkten finns inte!
Children with Diabetes website
Garg S. DiabTechTher 2012;14:205-09
1
Closed loop algoritmer
S.c. sensor och s.c. pump hos barn och ungdomar
17 tonåringar med typ 1 diabetes, ålder 13-20 år
MiniMed ePID pump och CGMS sänder radiosignaler till en laptop
➠ PID – proportional integral derivative
- används mycket i kontrollsystem inom industrin
- P: justerar i förhållande till aktuella PG-nivåer
- I: arean under kurvan mellan uppmätt och target PG
- D: hastigheten i PG-förändringen över tid
8 patienter fick allt insulin automatiskt enligt algorithm (FCL).
9 fick en liten manuell bolus före måltider (HCL).
mmol/l 16,7
➠ MPC – model predictive control
- bättre på fördröjningar associerade med insulin-absorption
- inkluderar måltider och måltidsdoser
➠ Fuzzy logic
- baserad på läkarens sätt att ta beslut (“fuzzy logic“)
- bygger på tidigare individuella patientdata
- använder inte direkta fysiologiska modeller eller linjära
11,0
5,6
Medelvärde för BG på dagen var 8,3 ± 2,6 i HCL gruppen vs. 8,8 ±
3,3 i FCL gruppen (P = 0.03)
matematiska beräkningar
Hypoglykemi (<3,3 mmol/l) inträffade x1 i FCL & x2 HCL gruppen
Kumareswaran K. Discov Med. 2012 Feb;13(69):159-70.
Weinzimer SA. Diabetes Care. 2008; 31:934-9.
Overnight closed loop in young children
Overnight closed loop in adults
8 children, 6-13 years
77g carb. at 18:00h and 21g carb. at 21:00 (manual bolus)
Navigator sensor + Deltec pump
MPC algorithm, insulin dose adjusted automatically
Results
12 adults consumed a medium sized meal (60g carb.)
12 adults consumed a larger meal (100g carb.) + wine (5 dl)
Navigator sensor + Deltec pump
MPC algorithm, insulin dose
adjusted manually by nurse.
Results
➠ Closed loop time in target
(3.9-8.0 mmol/l) was 52% if
started at 18:00 and 70% if
stared at 21:00 (p=n.s.)
➠ Closed loop increased time in
target (3.9-8.0 mmol/l) by 15%
in medium meal and 28% in
large meal
➠ Time < 3.9 mmol/l was
0% vs. 8% (p=n.s.)
➠ Closed loop decreased time in
hypoglycemia (≤ 3.9 mmol/l)
and eliminated time < 3.0
➠ No rescue carbs for
mmol/l after midnight
hypoglycemia were needed
Elleri D. DiabTechTher 2011;13:419-24.
Hovorka R. BMJ 2011;342:d1855.
Meta-analysis of Cambridge closed loop studies
4 randomized crossover studies in 17 children and adolescents and 24
adults (37.5 +/- 9.1 years) on 45 closed-loop and 45 CSII visits
PG 3.9-8 mmol/l
➠ Results
Time in target
Time < 3.9
SD of PG
CL
CSII
60%
2.1%
1.5
40% 0.002
4.1% 0.01
2.1 0.07
100g carb. meal + 5 dl wine
60g carb. meal
p
Closed loop based on in silico design
Algorithms based on in silico experiments (computer simulation), n=300
Clinical experiments with 20 adults from France, USA and Italy
22h of closed loop compared with 22h of open loop (dosing by patient
under a physician’s supervision)
Results
➠ Less nocturnal
hypoglycemia
PG
PG>8.0
< 3.9
mmol/l
mmol/l
➠ More time in target
(3.9-7.8 mmol/l)
➠ No change during
meal control
Kumareswaran K. J Diabetes Sci Technol 2011;5:1352-62.
Kovatchev B. J Diabetes Sci Technol 2010;4:1374-81.
2
Overnight closed loop in adolescents
Att minimera riskerna
Pilot study with 2 adolescents
2 Enlite sensors, Medtronic Veo pump
Blackberry with Proportional-Integrative-Derivative (PID)
ISM-to-Bluetooth radiofrequency (RF) translator
SG #1
Results
➠ No investigator
intervention
Glucose (mg/dL)
280
➠ Sensor glucose
3.4-8.4 mmol/l
mmol/l
SG (Control)
Day (OL)
MBG
Night #2 (CL)
240
10 mmol/l
200
160
120
80
40
0
ePID Infusion
Rate (U/h)
➠ YSI glucose 3.4-7.8
SG #2
Night #1 (CL)
5
4
3
2
1
0
20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54
20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54
Time (h)
O’Grady MJ. ATTD 2012 Abstract.
Closed loop in adults with fuzzy logic
➠ Returned to < 10
mmol/l (180 mg/dl)
within 2.6 hours
%
3.9-10.0
PID
73
MPC 79
EMPC 84
mmol/l
mean BG
8.4
8.7
8.2
BB
7.8
92
Too high Extra insulin given
Insulin dose given
by algorithm
(mean at minimal risk)
Don´t give too much
insulin quickly!
Span of ± 75 mg/dl (4.2 mmol/l)
Too low Wait for endogenous glucose production
(takes much longer time to correct)
Cameron F. J Diabetes Sci Technol 2011;5(2):368-379.
Bi-hormonal closed loop USA
Fuzzy logic theory to imitate the line of reasoning of diabetes caregivers
7 adults in Israel, 14 closed loop sessions of 8 and 24 hours
Dexcom or Navigator sensors, Omnipod pumps
Results
➠ Postprandial peak
12.5 mmol/l (224
mg/dl)
Asymmetrisk risk för kliniska komplikationer med höga och låga BG
Irreversibel verkan av insulin när bara insulin används
Modellen testad i en silico simulator
PID = proportional-integral-derivative
MPC = model predictive control
EMPC = enhanced MPC
BB = basal/bolus controller (retrospective)
Results
1 case report
2 Medtronic sensors, 2 Omnipod pumps and a laptop
At calibration, the sensor that is most correct will be used until next
calibration.
Example patient
10 mmol/l
Bolus dose
➠ 73% of sensor
values 3.9-10
mmol/l (70-180
Basal
insulin
mg/dl), 0% < 3.9
Atlas E. Diabetes Care 2010;33:1072-6.
Bi-hormonal closed loop USA
11 patients
2 pumps and a laptop, IV BG every 5 min.
27 hour experiments with 3 meals. No premeal announcements.
MPC algorithm with PK model of lispro, PK model for glucagon
Jacobs_Conf Proc IEEE Eng Med Biol Soc. 2011;2011.397-400.
Bi-hormonal closed loop USA
10 mmol/l
10 mmol/l
3.9 mmol/l
2.82.8
mmol/l
mmol/l
10
10mmol/l
mmol/l
3.9 mmol/l
3.9mmol/l
mmol/l
3.9
2.8 mmol/l
2.8 mmol/l
Results
➠ Time to peak 117 min. in
group with hypoglycemia vs.
64 min with no hypo
➠ Time in algorithm was set to
31 min!
No
hypoglycemia
treatment
needed
adjusted
settings
lispro in same patients!
Hypoglycemia
treatment
needed
withwith
standard
PKPK
settings
for for
lispro!
➠ Better results with no hypo in
either group after adjustment
of lispro PK to give peak after
65 min.
El-Khatib FH. Sci Transl Med 2, 27ra27 (2010)
10 mmol/l
El-Khatib FH. Sci Transl Med 2, 27ra27 (2010)
3
Uppkopplad i bilen…!
Future product concept not currently available for investigational use. Has not been reviewed by the U.S. FDA.
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