DIABETES TECHNOLOGY & THERAPEUTICS
Volume 11, Number 2, 2009
© Mary Ann Liebert, Inc.
Preventing Hypoglycemia Using Predictive Alarm
Algorithms and Insulin Pump Suspension
Bruce Buckingham, M.D.,1Erin Cobry, B.S.,2Paula Clinton, R.D.,1Victoria Gage, R.N.,2
Kimberly Caswell, A.P.R.N., B.C.,1Elizabeth Kunselman, N.P.,1
Fraser Cameron, M.S.,3and H. Peter Chase, M.D.2
Background: Nocturnal hypoglycemia is a significant problem. From 50% to 75% of hypoglycemia seizures oc-
cur at night. Despite the development of real-time glucose sensors (real-time continuous glucose monitor [CGM])
with hypoglycemic alarms, many patients sleep through these alarms. The goal of this pilot study was to as-
sess the feasibility using a real-time CGM to discontinue insulin pump therapy when hypoglycemia was pre-
Methods: Twenty-two subjects with type 1 diabetes had two daytime admissions to a clinical research center.
On the first admission their basal insulin was increased until their blood glucose level was ?60 mg/dL. On
the second admission hypoglycemic prediction algorithms were tested to determine if hypoglycemia was pre-
vented by a 90-min pump shutoff and to determine if the pump shutoff resulted in rebound hyperglycemia.
Results: Using a statistical prediction algorithm with an 80 mg/dL threshold and a 30-min projection horizon,
hypoglycemia was prevented 60% of the time. Using a linear prediction algorithm with an 80 mg/dL thresh-
old and a 45-min prediction horizon, hypoglycemia was prevented 80% of the time. There was no rebound hy-
perglycemia following pump suspension.
Conclusions: Further development of algorithms is needed to prevent all episodes of hypoglycemia from oc-
tinuous glucose monitor (CGM) controls delivery of insulin
via an insulin pump. The system requires an accurate CGM,
an accurate insulin delivery system, and algorithms to ad-
just insulin delivery. Although CGM values are now ap-
proaching adequate accuracy1and insulin pumps deliver in-
sulin with precision, there have been relatively few clinical
studies of algorithms to adjust insulin delivery.2,3
It is likely that initial CLP systems will be “partial” sys-
tems focusing on a particular aspect of diabetes manage-
ment. Hypoglycemia is one of the major rate-limiting factors
in diabetes management.4In the Diabetes Control and Com-
plications Trial, 55% of severe hypoglycemia (SH) occurred
during sleep,5and in children, approximately 75% of SH
episodes occur during sleep.6Although alarms for pending
hypoglycemia are a part of many CGM systems, an initial
HE TERM “CLOSED LOOP PANCREAS” (CLP) as used in this
study refers to a system in which a subcutaneous con-
study showed that 71% of alarms were not responded to dur-
ing sleep.7SH episodes are a well-recognized cause of death
in people with diabetes.8,9It is thus not unreasonable to ex-
pect that an early partial CLP might be aimed at preventing
SH episodes during sleep. The purpose of this pilot study
was to evaluate algorithms to discontinue insulin delivery
when pending hypoglycemia was predicted.
Research Design and Methods
Subjects for this pilot study were recruited at the Barbara
Davis Center (Aurora, CO) and the Stanford Medical Center
(Stanford, CA). The protocol was approved by the local in-
stitutional review boards, and all subjects and parents
and/or guardians signed an informed consent form and an
assent form if necessary.
Twenty-two subjects with type 1 diabetes (T1D) were en-
rolled in the initial phase of this pilot study. All subjects had
been diagnosed with T1D for at least 1 year and had used
Departments of 1Pediatric Endocrinology and 3Aeronautics and Astronautics, Stanford University, Stanford, California.
2Barbara Davis Center, University of Colorado Denver, Aurora, Colorado.
an insulin pump for at least 3 months. Potential subjects who
had an SH event in the previous 18 months were excluded
from the study.
Subjects were trained on the use of the FreeStyle Naviga-
tor®(Abbott Diabetes Care, Alameda, CA) and given two
systems to be worn during their admissions to the Clinical
Research Center (CRC). Subjects were admitted in the morn-
ing to the CRC on two occasions and had at least one func-
tioning and calibrated Navigator at the time of their admis-
sion. During the initial visit, the basal insulin infusion rates
were increased by approximately 25% increments to induce
a steady decline in blood glucose (BG) level to ?60 mg/dL.
BG was measured from an intravenous line every 15–30 min
depending on the BG level and the rate of fall. Patients were
treated with oral glucose when their venous BG level was
?60 mg/dL. Based on their insulin sensitivity from the first
admission, basal rates were again increased on the second
admission to produce a similar glucose rate of fall and a pro-
jected BG of ?60 mg/dL. One-minute glucose readings from
the Navigator receiver display were manually entered into
an Excel (Microsoft, Redmond, WA) spreadsheet. The
spreadsheet contained two hypoglycemic prediction algo-
rithms. One was a modification of the current Navigator
alarm, which uses a short-term linear extrapolation and un-
certainty threshold to predict hypoglycemia (linear predic-
tion [LP] alarm). The modification from the alarm on current
receivers allowed for greater uncertainty, and therefore it
was more sensitive in predicting hypoglycemia. The second
algorithm was developed at Stanford and is based on mul-
tiple empirical, statistical models that are used to estimate
future glucose values (statistical prediction [SP] alarm). From
these models a probability of hypoglycemia is generated to
produce an alarm. For each subject only one of the hypo-
glycemia prediction algorithms was used during the second
admission. When the hypoglycemia prediction algorithm
predicted a future BG of ?80 mg/dL the insulin pump was
suspended for 90 min. After 90 min, the pump basal insulin
infusion was resumed at the usual infusion rate, and sub-
jects were observed for 2 h in a fasting state to assess for sub-
sequent hyperglycemia. Serum ketones were measured
every 1/2h during the pump suspension and for the 2 h af-
ter basal insulin infusion was resumed. During the pump
suspension, BG levels were measured from a venous line
every 10 min.
To determine how long basal insulin caused a negative
rate of change in glucose levels after basal insulin was sus-
pended, we measured the glucose rate of change after pump
suspension in those subjects who did not require treatment
for hypoglycemia. The time from when the pump was sus-
pended until the rate of change reached 0 was considered
the duration of the basal insulin hypoglycemic effect.
Twenty-two subjects with a mean age of 20 years (range
6–38 years) and a mean duration of diabetes of 12 years
(range 2–24 years) completed both CRC admissions. Their
mean body mass index was 22 kg/m2(range 15–29 kg/m2).
During the first CRC admission the basal rate was increased
by a mean of 180% to induce hypoglycemia. During this ad-
mission, 18 of the 22 subjects (82%) reached a BG value of
?60 mg/dL. The nadir glucose values for the four subjects
not achieving a BG of ?60 mg/dL were 61 mg/dL, 63
mg/dL, 66 mg/dL, and 91 mg/dL after 4–6 h of increasing
basal rates up to 200% above their usual basal rate. Figure 1
is an example of glucose values from one study subject on
the first admission. Her hypoglycemia was treated with 16
g of carbohydrate. During these admissions, the 30-min hy-
BUCKINGHAM ET AL.94
Time in Minutes
Basal Insulin Infusion Rate (units/hr)
100 200300400 500
Graph of results from a first admission.
poglycemic prediction alarm that is integrated into the
FreeStyle Navigator was set to 80 mg/dL and a 30-min pro-
jection horizon. This internal projection alarm failed to alarm
in the first three subjects before their hypoglycemic thresh-
old was reached. There after, only the LP or SP alarms were
used to trigger pump suspension.
During the second admission, increases in the basal in-
sulin infusion rate generated a predicted hypoglycemic
alarm in 21 of 22 subjects. Figure 2 is an example of glucose
values during the second admission from the same subject
as in Figure 1. For the first 16 subjects, the alarm threshold
was set to 80 mg/dL, and the projection horizon was set to
30 min. Of these subjects, the SP alarm was used with 15,
and the LP alarm was used with one. Results are presented
in Table 1. Nine of the 16 subjects (56%) had prevention of
hypoglycemia, whereas the other seven had a BG level ?60
mg/dL in the 90 min following pump suspension. One sub-
ject (clearly having T1D with three positive insulin autoan-
tibodies at diagnosis, but with a body mass index of 29
kg/m2) was insulin resistant, and a predicted hypoglycemic
alarm was unable to be generated despite a 200% increase in
basal insulin rate (his lowest BG value was 98 mg/dL dur-
ing his first admission and 78 mg/dL during his second ad-
mission). For the last five subjects studied, the LP alarm hori-
zon was set to 45 min (with the same threshold of 80 mg/dL),
and four out of the five subjects (80%) did not develop hy-
poglycemia following pump suspension. There were no SH
events in any of the subjects.
Following 90 min of pump suspension, there was no hy-
perglycemia (BG level ?180 mg/dL) in the subsequent 2 h.
The maximum BG level was 139 mg/dL (mean, 94 mg/dL;
range, 72–139 mg/dL). Three subjects developed transient
ketonemia (0.7–1.0 mmol/L) following pump suspension.
This mild ketonemia occurred after 17–20 h of fasting and
following 90 min of basal insulin suspension. Ketones re-
solved in all subjects with resumption of the basal insulin in-
fusion and carbohydrate ingestion, and additional insulin
was not required. No subject was symptomatic.
The mean duration of effective insulin action following
pump suspension (time when the glucose rate of change
reached 0 mg/dL-min) was 75 min based on venous BG read-
ings and 80 min based on Navigator glucose readings (Fig.
3). The rate of change at the time of pump suspension was
consistent with changes in the basal rate and was not as high
as might be seen following an insulin bolus. The mean ? SD
rate of change was ?0.56 ? 0.44 mg/dL-min.
REAL-TIME CGM/PUMP STOPPAGE FOR HYPOGLYCEMIA95
Time in Minutes
Basal Insulin Infusion Rate (units/hr)
TABLE 1.EFFECTIVENESS OF PREDICTION ALGORITHMS IN PREVENTING HYPOGLYCEMIA
(BG ? 60 MG/DL) DURING THE 90 MIN OF PUMP SUSPENSION
Second admission with pump shutoff on projected alarm.
For these pilot studies we initially used the “Projected
Alarm” that is in the current version of the Navigator
FreeStyle receiver with a threshold of 80 mg/dL and a pro-
jection horizon of 30 min. Using these settings, we did not
generate a predictive alarm with our first three subjects. This
is because the current model of the FreeStyle Navigator is
set to provide a low frequency of false-positive alarms. Since
this tuning of the alarm was not appropriate for our studies
of preventing hypoglycemia by suspension of basal insulin
infusion, we evaluated the use of two additional alarm al-
gorithms. Using these alarms, we were still unable to pre-
vent some subjects from decreasing to ?60 mg/dL. With a
projection horizon of 30 min and a glucose threshold of 80
mg/dL, pump suspension for 90 min prevented hypo-
glycemia 56% of the time. When the projection horizon was
increased to 45 min, hypoglycemia was prevented 80% of the
It is clear that further development of algorithms to sus-
pend insulin infusion is needed to prevent all episodes of
hypoglycemia from occurring. Some additional modifica-
tions to future alarms could include: (1) consideration of the
remaining “insulin-on-board” from both basal insulin and
previous boluses of insulin; (2) using a longer prediction
horizon so that the insulin infusion can be suspended ear-
lier; (3) recalibration of the Navigator immediately before
bed if BG levels are stable and showing greater than a 15%
difference from the bedtime capillary BG readings; and (4)
adding a user input to account for changes in insulin sensi-
tivity. The latter might include vigorous activity earlier in
the day. These were not taken into account in the current
study. In our current studies we did have greater success in
preventing hypoglycemia when we increased the alarm
horizon to 45 min.
We were encouraged that we did not see rebound hyper-
glycemia in the 2 h following restoration of the usual basal
infusion rates after pumps had been suspended for 90 min.
These studies involved a prolonged fast for many subjects,
from 9 p.m. until 4 p.m. the following day, and it was there-
fore not surprising that a few subjects developed mild ke-
tonemia. This was transient and asymptomatic and resolved
quickly once they received oral carbohydrates and insulin.
Two of the subjects who did not experience hypoglycemia
during the 90-min pump suspension did experience a BG
?60 mg/dL in the ensuing 2 h. Thus, additional protective
measures may be important.
One of the critical factors in determining when to suspend
the insulin infusion to prevent hypoglycemia is the duration
of action of basal insulin. Because only small amounts of in-
sulin are given every few minutes, the pharmacodynamics
of basal insulin action may be different when compared to
a standard meal bolus. At the time of pump suspension, there
was a negative rate of change of glucose levels, and this ini-
tial negative rate of change was maintained for about 30 min
following pump suspension. Seventy-five minutes after
pump suspension, the rate of change reached zero, indicat-
ing there was no longer sufficient insulin to lower BG lev-
els. This time roughly correlates with the clinical finding that
changes in basal insulin infusion rates need to occur about
1 h prior to the desired effect.
These pilot studies were conducted in a clinical research
center during a daytime admission to determine the success
of the hypoglycemic prediction algorithms in preventing hy-
poglycemia and to assess for rebound hyperglycemia after
stopping basal insulin for 90 min. A larger study with proper
BUCKINGHAM ET AL. 96
Time from Pump Shut Off (Minutes)
Rate of Change of Glucose (mg/dL-min)
Usual Basal Insulin Infusion Rate
Rate of change of glucose levels following pump shutoff.
sample size calculations now needs to be conducted in the Download full-text
home environment prior to applying similar algorithms to
clinical practice. Some additional work also needs to be done
on the hypoglycemic algorithm development to completely
prevent hypoglycemic episodes from occurring. This may re-
quire initiating pump suspension 40–50 min before projected
hypoglycemia or raising the alarm threshold above 80
mg/dL. There were no significant adverse events from sus-
pending the basal insulin for 90 min. It remains to be deter-
mined if multiple episodes of pump suspension in a single
night in the home environment would result in sustained hy-
This research was supported by the Juvenile Diabetes Re-
search Foundation. Abbott Diabetes Care provided the
FreeStyle Navigator Continuous Glucose Monitoring Sys-
tems. Karmeen Kulkarni, M.S., R.D., B.C.-A.D.M., C.D.E.,
Kerstin Rebrin, M.D., Ph.D., Marc Taub, Ph.D., and Geoff V.
McGarraugh from Abbott Diabetes Care provided technical
and device support. The Clinical Research Center studies
were supported in part by grants MO1 RR-00070 and
RR000051 and 5 MO1 RR00069 from the National Center for
Research Resources, National Institutes of Health.
Author Disclosure Statement
B.B. and H.P.C. have received research support from Ab-
bott Diabetes Care in the form of devices and sensors for do-
ing these studies. B.B. is also a consultant for Abbott Dia-
1. Wilson DM, Beck RW, Tamborlane WV, Dontchev MJ, Koll-
man C, Chase P, Fox LA, Ruedy KJ, Tsalikian E, Weinzimer
SA; DirecNet Study Group: The accuracy of the FreeStyle
Navigator continuous glucose monitoring system in children
with type 1 diabetes. Diabetes Care 2007;30:59–64.
2. Weinzimer SA, Steil GM, Swan KL, Dziura J, Kurtz N, Tam-
borlane WV: Fully automated closed-loop insulin delivery
versus semi-automated hybrid control in pediatric patients
with type 1 diabetes using an artificial pancreas. Diabetes
3. Steil GM, Rebrin K, Darwin C, Hariri F, Saad MF: Feasibility
of automating insulin delivery for the treatment of type 1 di-
abetes. Diabetes 2006;55:3344–3350.
4. Cryer PE: Hypoglycemia is the limiting factor in the man-
agement of diabetes. Diabetes Metab Res Rev 1999;15:42–46.
5. Diabetes Control and Complications Trial: Adverse events
and their association with treatment regimens in the Diabetes
Control and Complications Trial. Diabetes Care 1995;18:
6. Davis EA, Keating B, Byrne GC, Russell M, Jones TW: Hy-
poglycemia: incidence and clinical predictors in a large pop-
ulation-based sample of children and adolescents with
IDDM. Diabetes Care 1997;20:22–25.
7. Buckingham B, Block J, Burdick J, Kalajian A, Kollman C,
Choy M, Wilson DM, Chase P; Diabetes Research in Children
Network: Response to nocturnal alarms using a real-time glu-
cose sensor. Diabetes Technol Ther 2005;7:440–447.
8. Heller S: Dead in bed. Diabet Med 1999;16:782–785.
9. Nystrom L, Dahlqvist G: ‘Dead in bed’ in Norway. Diabet
Address reprint requests to:
Bruce Buckingham, M.D.
Department of Pediatric Endocrinology
G-313, Medical Center
Stanford, CA 94305-5208
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