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Objective: To evaluate the literature and identify important monitoring system be designed to avoid and detect hypoglycemia
aspects of insulin therapy that facilitate safe and effective infusion (blood glucose ≤70 mg/dL) and to minimize glycemic variability.
therapy for a defined glycemic end point. Important processes of care for insulin therapy include use of a
Methods: Where available, the literature was evaluated using reliable insulin infusion protocol, frequent blood glucose monitor-
Grades of Recommendation, Assessment, Development, and Evalu- ing, and avoidance of finger-stick glucose testing through the use
ation (GRADE) methodology to assess the impact of insulin infu- of arterial or venous glucose samples. The essential components of
sions on outcome for general intensive care unit patients and an insulin infusion system include use of a validated insulin titration
those in specific subsets of neurologic injury, traumatic injury, and program, availability of appropriate staffing resources, accurate mon-
cardiovascular surgery. Elements that contribute to safe and effec- itoring technology, and standardized approaches to infusion prepa-
tive insulin infusion therapy were determined through literature ration, provision of consistent carbohydrate calories and nutritional
review and expert opinion. The majority of the literature supporting support, and dextrose replacement for hypoglycemia prevention and
the use of insulin infusion therapy for critically ill patients lacks treatment. Quality improvement of glycemic management programs
adequate strength to support more than weak recommendations, should include analysis of hypoglycemia rates, run charts of glucose
termed suggestions, such that the difference between desirable values <150 and 180 mg/dL. The literature is inadequate to support
and undesirable effect of a given intervention is not always clear. recommendations regarding glycemic control in pediatric patients.
Recommendations: The article is focused on a suggested glyce- Conclusions: While the benefits of tight glycemic control have
mic control end point such that a blood glucose ≥150 mg/dL trig- not been definitive, there are patients who will receive insulin infu-
gers interventions to maintain blood glucose below that level and sion therapy, and the suggestions in this article provide the struc-
absolutely <180 mg/dL. There is a slight reduction in mortality with ture for safe and effective use of this therapy. (Crit Care Med 2012;
this treatment end point for general intensive care unit patients 40:3251–3276)
and reductions in morbidity for perioperative patients, postopera- Key Words: critical care; glycemic control; glucose meter;
tive cardiac surgery patients, post-traumatic injury patients, and glucose monitoring; guideline; hyperglycemia; insulin; protocol;
neurologic injury patients. We suggest that the insulin regimen and stress hyperglycemia
From the Indiana University Health Methodist Supplemental digital content is available for this Glycemic Control. The remaining authors have not dis-
Hospital, Indianapolis, IN (JJ); University of Pittsburgh article. Direct URL citations appear in the printed text closed any potential conflicts of interest.
Medical Center, Pittsburgh, PA (NB); Stamford Hospital, and are provided in the HTML and PDF versions of this Listen to the iCritical Care podcasts for an
Stamford, CT (JK); Intermediate Care Unit, Children’s article on the journal’s Web site (http://journals.lww. in-depth interview on this article. Visit www.sccm.
Hospital Boston, Boston, MA (MA); Endocrine Consults com/ccmjournal). org/iCriticalCare or search “SCCM” at iTunes.
and Care, Evanston, IL (SSB); Critical Care and Surgery, Dr. Agus has consulted for the Diabetes Technology For information regarding this article, E-mail:
Perelman School of Medicine at the University of Society. He also has a pending patent on an ECMO- jjacobi@iuhealth.org
Pennsylvania, Philadelphia, PA (CD); PCC and Sleep based glucose, sensor, which is not connected to idea Copyright © 2012 by the Society of Critical Care
Medicine, University of Tennessee Health Science discussed in this article. Dr. Braithwaite has a U.S. pat- Medicine and Lippincott Williams and Wilkins
Center, Memphis, TN (AXF); University of Missouri ent. Dr. Kohl has received grant support from Amylin and The American College of Critical Care Medicine
Kansas City, Kansas City, MO (DG); University of Eli Lilly. Dr. Krinsley has performed consulting work for (ACCM), which honors individuals for their achievements
Pennsylvania, Philadelphia, PA (BK); SICU, Tufts/New Medtronic Inc., Edwards Life Sciences, Baxter, Roche and contributions to multidisciplinary critical care medi-
England Medical Center, Boston, MA (SAN); Pediatric Diagnostics, and Optiscan Biomedical and has received cine, is the consultative body of the Society of Critical
Critical Care, Riley Hospital For Children, Indianapolis, IN speaker’s fees from Edwards Life Sciences, Roche Care Medicine (SCCM) that possesses recognized exper-
(MR); Novant Health, Winston Salem, NC (KS); Barnes- Diagnostics and Sanofi-Aventis. Dr. Nasraway has con- tise in the practice of critical care. The College has devel-
Jewish Hosptial, St. Louis, MO (LS); Barnes Jewish sulted for Optiscan, Echo Therapeutics. Dr. Geehan has oped administrative guidelines and clinical practice pa-
Hospital, St. Louis, MO (BT); Emory University School received grant support from the Department of Defense rameters for the critical care practitioner. New guidelines
of Medicine, Atlanta, GA (GU); Washington University Research. Dr. Rigby has received consulting fees from and practice parameters are continually developed, and
St. Louis, St. Louis, MO (JM); McMaster University, Medtronic. Dr. Schallom has received honoraria/speak- current ones are systematically reviewed and revised.
Hamilton, Ontario, Canada (HS). ing fees from Roche Laboratories Speakers Bureau on DOI: 10.1097/CCM.0b013e3182653269
Study Quality
De La Rosa Medical and surgical Randomized 80–110 vs. 180–200 mg/dL Single center
et al (18) Bedside RN titrated per protocol Evaluated mean morning glucose, also
daily minimum and maximum values
Arabi et al (19) Medical and surgical Randomized 80–110 mg/dL vs. 180–200 mg/dL Single center, Evaluated daily average
Bedside RN titrated per paper protocol glucose
Farah et al (20) Medical with >3- day Randomized 110–140 mg/dL vs. 140–200 mg/dL Single center, reported overall average
length of stay glucose
Grey and Surgical, excluded patients Randomized 80–120 mg/dL vs. 180–220 mg/dL Single center, reported daily average
Perdrizet (21) with diabetes and overall average glucose
Mackenzie et al (22) Medical and surgical Randomized 72– 108 mg/dL vs. 180–198 mg/dL Two centers, multiple glucose end
points reported
Large cohort
Krinsley (23) Medical and surgical Observational cohort Single center
<140 mg/dL vs. historical control Evaluated all glucose values
Bedside RN titrated
Furnary et al (24) CV surgical, diabetic Observational Single center
patients IV–various goals (final <150 mg/dL) vs. SQ control Historical control
Bedside RN titrated per protocol Variable end points
Long study timeline
Evaluated average daily glucose for
three postoperative days
Treggiari et al (25) Medical, surgical, and Observational cohort Single center
trauma 80–110 mg/dL vs. 80–130 mg/dL vs. historical control Protocol utilization was optional
Bedside RN titrated per protocol Evaluated all glucose values
Krinsley (26) Medical, surgical, and Observational cohort Single center, includes patients
trauma <140 or <125 mg/dL vs. historical control in reference 12
Bedside RN titrated
Scalea et al (27) Trauma Prospective cohort, post-protocol goal <150 mg/dL Single center, Evaluated highest single
Bedside RN titrated, no dosing guidelines daily glucose and pattern of response
Furnary CV surgical, diabetics Observational Single center
and Wu (28) IV–various goals (final <110 mg/dL) vs. SQ control Historical control
Bedside RN titrated per protocol Variable end points
Long study timeline
Evaluated average daily glucose for
three postoperative days
Small cohort
Toft et al (29) Medical–surgical and no Prospective cohort, post-protocol goal Single center, Evaluated mean morning
CV surgical 80–110 mg/dL glucose
Bedside RN titrated per Van den Berghe protocol
IV, intravenous; IQR, interquartile range; CV, cardiovascular; SQ, subcutaneous; 3-blood glucose = 3-day average postoperative blood glucose.
Small trials included <1,000 patients; bhospital mortality unless otherwise specified; ctreatment not blinded.
a
783 765 Daily 153 ± 33 Daily 103 ± 19 0.64 [0.45, 0.91] Control glucose elevated with IV dextrose,
stopped early for benefit
605 595 Daily 153 ± 31 Daily 111 ± 29 0.89 [0.71, 1.13] Control glucose elevated with IV dextrose
542 536 144 (IQR 128–162) 117 (IQR 108–130) 1.27 [0.94, 1.7] Stopped early for hypoglycemia, many
median–all values median–all values protocol violations
3050 3054 144 ± 23 115 ± 18 28-day Glycemic control group did not achieve
1.09 [0.96, 1.23] target
90-day1.14 [1.02, 1.28]
290 247 Median daily 138 Median daily 130 28-day mortality Control target artificially elevated with IV
(IQR 111–184) (IQR 108–167) 0.94 [0.63, 1.38] dextrose. Study stopped early for hypo-
glycemia risk. Inadequate size to detect
difference in mortality
250 254 Median–all values Median–all values 28-day mortality Did not achieve target glucose, in-
149 (IQR 124–180) 120 (IQR 110–134) 1.08 [0.75, 1.54] adequate sample to detect mortality
difference
257 266 171 ± 34 115 ± 18 0.78 [0.53, 1.13] Small trial, inadequate size to show
mortality impact
48 41 174 ± 20 142 ± 14 1.37 [0.59, 3.16] Baseline imbalance in diabetes incidence
and admission glucose
27 34 179 ± 61 125 ± 36 mg/dL, 0.47 [0.12, 1.86] Lower nosocomial infection incidence
Daily mean value lower with glycemic control
on each day
119 121 8.4 ± 2.4 7.0 ± 2.4 0.73 [0.43, 1.24] Inadequate size to show mortality impact
800 800 152 ± 93 131 ± 55 0.45 [0.34, 0.60] High protocol adherence, subcutaneous
and IV insulin
942 2612 214 ± 41 177 ± 30 0.27 [0.19, 0.39] Remote historical controls on SQ insulin
p < .001 only
2366 <130 mg/dL, n = 3322 Mean all values Mean all values 1.07 [0.9, −1.21] Low protocol utilization, overlap in
<110 mg/dL n = 4786 147 ± 42 Goal < 130: 142 ± 37 glucose values actually achieved
Goal < 110:133 ± 31
2666 2699 Mean overall Mean overall 0.72 [0.62, 0.83] Includes patients in Krinsley above
154 ± 88 124 ± 51
1021 1108 Data not provided Data not provided 0.68 [0.52, 0.89] Changes in standard of care likely during
trial
1065 4469 Data not provided Data not provided 0.39 [0.28, 0.54] Includes patients in Furnary above
135 136 Median daily Median daily 0.77 [0.38, 1.55] Small trial, but trend to benefit with
133 (IQR 121–150) 110 (IQR 104–117) glycemic control
A. We suggest that there is no consis- was consensus that too many confound- surgery to achieve a reduced risk of
tently demonstrated difference in ing variables existed for this outcome. A deep sternal wound infection and
several morbidity measures (renal reduction in critical illness polyneurop- mortality.
failure, transfusion, bacteremia, athy was not analyzed as this potential
polyneuropathy, and ICU length of benefit was reported in only one study. [Quality of evidence: very low]
stay [LOS]) when evaluated in the Our analysis suggests that no evidence The only large-scale RCT to date evalu-
general adult ICU population. of benefit was found in ICU LOS with OR ating the impact of tight GC on morbid-
−0.05, 95% CI [−0.14, 0.05]; prevention ity and mortality in a population weighted
[Quality of evidence: very low] of bacteremia OR 0.81, 95% CI [0.58, with postoperative cardiac surgical
The following were considered as 1.11]; need for transfusion OR 1.06, 95% patients was published in 2001 (1). Almost
morbidity outcomes for evaluation, CI [0.90, 1.26]; or need for renal replace- two thirds of this study population under-
acute renal replacement therapy, inci- ment therapy OR 0.90, 95% CI [0.7, went cardiac surgery. Patients in the GC
dence of transfusion, bacteremia, criti- 1.16], but variable study design, popula- group (80–110 mg/dL) had lower ICU and
cal illness polyneuropathy, and ICU LOS. tions, and end points limit the analysis. hospital mortality rates compared with
To analyze ICU LOS in those studies in The forest and funnel plots are avail- conventional therapy (BG 180–200 mg/
which data were reported nonpara- able in Supplemental Digital Content 1 dL). Morbidity benefits for the GC group
metrically, the median value was used (http://links.lww.com/CCM/A589). included a reduced need for renal replace-
and interquartile range (IQR, 1.35) was ment therapy, less chance of hyperbiliru-
used as an estimate of sample standard B. We suggest implementation of mod- binemia, earlier cumulative likelihood of
deviation (sd). Duration of mechanical erate GC (BG < 150 mg/dL) in the weaning from mechanical ventilation, and
ventilation was not analyzed as there postoperative period following cardiac ICU and hospital discharge. A follow-up
Scalea Trauma Prospective data Single center, 1021 1108 NA NA Adjusted Reduced
et al (27) intensive collection, two reported outcomes: vent days
care unit patient series patterns Pre vs. post; and length
before and of glucose mortality of stay with
after protocol control in 1.4 [1.1, 10] improved
100–150 mg/dL week 1. pattern of
Over 51% glucose
had glucose control
>150 mg/dL
in first week
(poor protocol
effect)
Reed Surgical and Retrospective Single center, Not Not Reported by Reported by Estimated Lower mean
et al (47) trauma ICU, query of uncontrolled reported reported study year study year mortality glucose not
n = 7261 prospective protocol by group by group 2003: 141 2005: 129 ratio correlated
database, compliance. 2004: 134 2006: 125 measured with
pre- and Measured p < 0.01 as actual/ estimated
post-protocol glucose estimated mortality
implementation control by mortality risk
year. End point unchanged reduction.
was estimated Other factors
mortality ratio changed
measured during
as actual/ observational
estimated period (key
mortality personnel,
population,
quality
emphasis)
Collier Trauma, on Prospective Single center, 383 435 130 ± 11 124 ± 13 ≥1 Glucose Preprotocol,
et al (48) mechanical postprotocol Reported days above historical
ventilation (80–110 mg/dL) mean glucose 150 mg/dL: control, no
vs. historical Pre- vs. post- 2.16 [1.0, significant
control mortality not 4.6] reduction
reported p = .049 in mean
glucose pre
to post, did
not achieve
glucose
target
The NICE- Trauma Randomized, Multicenter, 465 421 Not reported Not reported 0.77 [0.5, Hypothesis-
SUGAR subset Tight 81–108 mg/ Reported mean for trauma for trauma 1.18] generating
Investiga- dL vs. control glucose and subset subset p = .07 for subset
tors (16) < 180 mg/dL time-weighted heterogene- analysis
mean overall ity 90-day
mortality
The impact of insulin-induced hypo- of vasoactive infusions, insulin therapy, liver disease, immune compromise, and
glycemia has varied among populations, and the use of continuous renal replace- medical or nonelective admissions are
and in some reports, hypoglycemia was ment therapy with a bicarbonate-based noted as potential risk factors for the
thought to be a marker for more serious replacement fluid (81). Some authors also occurrence of low BG (79). Physiologic
underlying illness (79, 80). Risk factors found that diabetes, mechanical ventila- changes increase the effect of insulin as
for SH include renal failure, interruption tion, female sex, greater severity of illness, renal failure prolongs the half-life of insu-
of caloric intake without adjustments in and longer ICU stays are associated with lin, leading to insulin accumulation, while
the insulin infusion, sepsis with the use increased risk of SH (80, 82). Additionally, also attenuating renal gluconeogenesis.
Hepatic failure can also lead to reduced trials to analyze the independent effects value to avoid overcorrection. The BG
hepatic gluconeogenesis. The reliability of of hypoglycemia and glycemic variability should be repeated in 15 mins with fur-
the insulin infusion therapy protocol and (GV) on the risk of mortality (88). The ther dextrose administration as needed
frequency of BG monitoring also appear to occurrence of one or more episodes of to achieve BG > 70 mg/dL with a goal to
influence the frequency of hypoglycemia. SH was independently associated with a avoid iatrogenic hyperglycemia.
Multivariate regression models dem- higher risk of mortality (OR 3.233, 95% [Quality of data: very low]
onstrate that even a single episode of SH CI [2.251, 4.644]; p < .0001). Although prevention of hypoglycemia
is independently associated with higher Morbidity impact of SH is difficult to is important during insulin therapy, epi-
risk of mortality (80–85). The OR for quantitate on critically ill patients as con- sodes of low BG may occur despite rea-
mortality associated with one or more current illness and sepsis may increase sonable precautions, and steps should be
episodes was 2.28, 95% CI [1.41, 3.70]; the risk of cognitive impairment, and it is taken to recognize and treat it promptly.
(p = .0008) among a cohort of 5,365 unknown how hypoglycemia may inter- With severe hypoglycemia, interruption of
patients admitted to a single mixed medi- act with other risk factors. Low BG levels the insulin infusion is a prudent first step.
cal–surgical ICU (82). Most other reports lead to nonspecific neurologic symptoms, This interruption may be adequate for a
similarly indicate a higher risk of mortal- although severe or prolonged glycopenia patient receiving exogenous dextrose, but
ity with hypoglycemia of varying severity may produce neurocognitive impairment, treatment with additional IV dextrose is
(Table 4). Early hypoglycemia has been seizures, loss of consciousness, perma- typical, although there is no adequate data
associated with longer adjusted ICU LOS nent brain damage, depression, and death to dictate the optimal dose. While the first
and greater hospital mortality, especially (89–91). A number of factors including priority is patient safety through restora-
with recurrent episodes (86). Further- sedation, medication, or underlying dis- tion of normoglycemia, rebound hyper-
more, patients with more severe degrees ease may mask symptoms of neuroglyco- glycemia due to excessive replacement
of hypoglycemia sustained higher ICU penia. To further complicate the analysis, should also be avoided, especially because
and hospital mortality (85, 86). A greater hyperglycemia has also been associated the resulting increase in GV may contrib-
risk of mortality (RR 2.18, 95% CI [1.87, with adverse effects on the brain (92). Fur- ute to adverse outcomes (82, 83, 88, 93).
2.53]; p < .0001) was similarly reported ther, the risk for neurologic injury may be An IV dextrose dose of 15–20 g has been
with mild to moderate hypoglycemia compounded by additional oxidative stress recommended by the American Diabetes
(BG 55–69 mg/dL) in a post hoc analy- associated with rapid correction of hypo- Association, with instructions to recheck
sis of prospective data collected in a glycemia with IV dextrose (93). BG in 5–15 mins and repeat as needed
randomized trial and two large cohorts (7). A dose of 25-g IV dextrose adminis-
(87). These data confirmed the results of 4. How should insulin-induced tered to nondiabetic volunteers produced
another cohort study that demonstrated hypoglycemia be treated in adult ICU significant but variable BG increases of
that mild–moderate hypoglycemia, BG patients? 162 ± 31 mg/dL and 63.5 ± 38.8 mg/dL
54–63 mg/dL, was independently asso- when measured 5 and 15 mins postinjec-
ciated with increased risk of mortality We suggest that BG < 70 mg/dL tion, respectively (94). BG returned to
(85). In each of these studies, the mor- (<100 mg/dL in neurologic injury patients) baseline by 30 mins, but the duration may
tality risk was greater with more severe be treated immediately by stopping be different in patients receiving exog-
hypoglycemia (85, 87). Finally, the Leu- the insulin infusion and administering enous insulin.
ven investigators have recently published 10–20 g of hypertonic (50%) dextrose, A formula to calculate a patient-
data pooling the two interventional adult titrated based on the initial hypoglycemic specific dose of dextrose has been used
Subsets of RCT
Van den Mixed, Randomized Single center 30 33 0.73 [0.21, 2.48] Control glucose
Berghe surgical, 80–110 mg/dL vs. Evaluated elevated with IV
et al (1) mechanical 180–200 mg/dL mean morning dextrose, stopped
ventilation Research RN titrated glucose early for benefit
insulin per protocol
Van den Mixed, Randomized Single center 31 30 1.05 [0.35, 3.15] Control glucose
Berghe medical Bedside RN titrated per Evaluated elevated with IV
et al (14) paper protocol mean morning dextrose
glucose
Small RCT or subset of small RCTb
Scott et al CVA Randomized Single center, 28 25 28-day mortality No difference in
(68) Fixed dose glucose- Evaluated 0.97 [0.29, 3.22] serum glucose at
potassium-insulin vs. glucose any point studied
saline infusion trajectory over
for 24 hrs treatment
period
Walters CVA Randomized Single center 12 13 3.00 [0.11, 80.95] AUC reduced
et al (71) Target 90–140 mg/dL vs. Evaluated
standard management glucose–time
curve AUC
Bilotta Aneurysmal Randomized Single center, 38 40 Six-month 83% of control
et al (60) subarachnoid Target 80–120 mg/dL vs. evaluated mortality and 69% of
hemorrhage 80–220 mg/dL percentage of 0.78 [0.24, 2.58] intensive therapy
glucose values in target range
in target range
Gray CVA Randomized, glucose- Multicenter, 469 464 90-day mortality Average difference
et al(72) potassium-insulin evaluated glu- 1.14 [0.86, 1.51] in glucose 10 mg/
infused to target cose every 8 hrs dL (p < .001)
72–126 mg/dL vs. using repeated
saline control measures analy-
sis of variance
Arabi et al Traumatic Randomized Single center, 39 55 1.43 [0.13, 16.39]
(19) brain injury 80–110 mg/dL vs. Evaluated aver-
180–200 mg/dL age glucose level
Bedside RN titrated per
paper protocol
Bilotta Traumatic Randomized, Target Single center, 49 48 1.02 [0.24, 4.35] Mean glucose
et al (73) brain injury 80–120 mg/dL vs. evaluated mean values 97 vs.
80–220 mg/dL glucose values 147 mg/dL
(p < .0001)
Bilotta Mixed, neuro- Randomized, Target Single center, 242 241 0.91 [0.61, 1.35] Difference in day
et al (74) surgical 80–110 mg/dL vs. evaluated mean 1 to day 14 mean
<215 mg/dL daily glucose glucoses: 92 mg/
values dL vs. 143 mg/dL
(p < .0001)
Cohort Studies
Krinsley (23) Mixed Observational co- Single center, 119 142 0.35 [0.17, 0.73] High protocol
hort<140 mg/dL vs. evaluated all adherence, sub-
historical control. glucose values cutaneous and IV
Bedside RN titrated insulin
Thiele et al Aneurysmal Retrospective postpro- Single center, 343 491 1.03 [0.67, 1.59] Median average
(75) subarachnoid tocol target 90–120 mg/ Evaluated glucose
hemorrhage dL. Bedside RN titrated median average 121 vs. 116 mg/dL
protocol glucose (p < .001)
RCT, randomized clinical trial; CVA, acute ischemic stroke; AUC, area under the curve.
a
Hospital mortality unless otherwise specified; bsmall trials included <1,000 patients.
Aside from Krinsley (23), every trial had an inadequate sample size to detect mortality differences. Treatment was not blinded in any study.
in several reports (50% dextrose dose in although additional testing of this inter- BG monitored at least every hour to allow
grams = [100 − BG] × 0.2 g), and it typi- vention appears warranted. rapid recognition of BG outside the goal
cally advises administration of 10–20 g Oral dextrose replacement (15 g) is range. More frequent reassessment is
of IV dextrose, an amount lower than that used in ambulatory patients with hypogly- needed after treatment of hypoglycemia,
in traditional dosing methods (95, 96). cemia, but is not tested for ICU patients. every 15 mins until stable.
This approach corrected the BG into the Fifteen grams of oral carbohydrate pro- A retrospective evaluation of data
target range in 98% within 30 mins for duced a BG increase of approximately from 6,069 insulin infusion episodes in
patients who had received IV insulin infu- 38 g/dL within 20 mins and provided 4,588 ICU patients suggested that delays
sions (95, 97). Similarly, titrated replace- adequate symptom relief in 14 ± 0.8 mins in measuring BG contributed to the risk
ment has been advocated for treatment of in hypoglycemic adult outpatients (101). of severe hypoglycemia. When a hypo-
adults in the prehospital setting. Adminis- If oral replacement is used, dextrose or glycemic episode occurred, the median
tration of 5-g aliquots of dextrose repeated sucrose tablets or solutions are preferred delay past the next hourly measurement
every minute, using either 10% (50 mL) for a more rapid or consistent response was 21.8 mins (IQR 12.2–29 mins) (97).
or 50% (10 mL) dextrose, restored mental compared with viscous gels or orange Modeling suggested SH was likely with as
status to normal in approximately 8 mins juice due to variable carbohydrate content little as a 12-min delay in the majority of
with both agents (IQR 5–15 and 4–11, in commercial juice (101). The impact of patients who developed hypoglycemia.
respectively), but the 50% dextrose group abnormal gastric emptying has not been Glucose checks every 4 hrs have been
received a larger median dose of dextrose, studied but may alter the response to used in some protocols; however, there
25 g (IQR 15–25) vs. 10 g (IQR 10–15), and therapy, especially in an ICU population. is a risk of unrecognized hypoglycemia
developed a higher median posttreatment with prolonged measurement intervals;
BG (169 mg/dL vs. 112 mg/dL [p = 003]), 5. How often should BG be monitored in so these intervals are not recommended
respectively (98). The authors recom- adult ICU patients? as a routine component of insulin infu-
mended titrating 10% dextrose in 50-mL sion protocols. The rates of hypoglyce-
IV (5-g) aliquots to treat the symptoms of We suggest that BG be monitored mia are above 10% for many protocols
hypoglycemia and to avoid overcorrec- every 1–2 hrs for most patients receiving using BG checks every 4 hrs (1, 14, 15,
tion of BG. The rate of administration of an insulin infusion. 17). One exception was reported with a
concentrated dextrose solutions may also [Quality of evidence: very low] computerized protocol that tested an
be important, as a report of cardiac arrest This is a consensus recommendation average of approximately six BG values
and hyperkalemia was associated with based on limited data, as this question has per day but produced SH in only 1%
rapid and repeated administration of 50% not been tested in a prospective fashion. of patients (102). With the higher rate
dextrose (99). The optimal frequency of BG testing has of hypoglycemia reported with every
A prehospital study comparing an not been established. Published protocols 4-hourly BG testing, this frequency is
intramuscular 1-mg injection of gluca- generally initiate insulin therapy with not suggested unless a low hypoglycemia
gon to a 25-g IV dose of dextrose demon- hourly BG testing, and then may liber- rate is demonstrated with the insulin
strated a rapid and potentially excessive alize the testing to every 4 hrs based on protocol in use.
BG response with dextrose, achieving the stability of the BG values within the
14–170 mg/dL increase in BG in the first desired range, as well as an assessment of 6. Are POC glucose meters accurate for
10 mins (100). The glucagon response was patient clinical stability. The personnel BG testing during insulin infusion
slower, achieving a final BG concentration time required for BG monitoring is the therapy in adult ICU patients?
of 167 mg/dL after 140 mins. Because vir- primary barrier to more frequent moni-
tually all ICU patients have venous access, toring. We suggest that unstable patients We suggest that most POC glucose
IV dextrose is preferred over glucagon, (e.g., titrating catecholamines, steroids, meters are acceptable but not optimal for
due to the delay in glucagon response, changing dextrose intake) should have routine BG testing during insulin infusion
Vriesendorp Retrospective 156 (245 events) Glucose <45 mg/dL, closed med- Risk factors: OR [95% CI]
et al (81) cohort 155 control surg ICU, University, teaching Nutrition interruption 6.6 [1.9, 23]
Diabetes mellitus 2.6 [1.5, 4.]
Sepsis 2.2 [1.2, 4.1]
Shock 1.8 [1.1, 2.9]
Renal replacement therapy with
bicarbonate fluids 14 [1.8, 106]
Insulin 5.4 [2.8, 10]
Vriesendorp Retrospective 156 Glucose <45 mg/dL, closed med- Cumulative in-hospital mortality:
et al (83) cohort 146 control surg ICU, University, teaching hazard ratio 1.03 [0.68, 1.56]; p = .88
Van den Berghe Post hoc 154 intensive Glucose ≤40 mg/dL, single Hypoglycemia frequency: control 1.8%,
et al (84) analysis of 25 control center, med-surg ICU intensive 11.3% (p < .0001)
two RCTs (2,748 total n) Hospital mortality: control 13 (52%),
intensive 78 (50.6%) (p = .9)
Mortality in 24 hrs: control 3 (12%),
intensive 6 (3.9%) (p < .0004)
Krinsley and Retrospective 102 cases Glucose <40 mg/dL, single- Hospital mortality: 55.9% vs. 39.5%
Grover (82) case-control 306 control center. Community med-surg (cases vs. controls) (p = .0057)
cohort (5,365 total in ICU. Insulin given to 72.5% of For the entire cohort, a single episode of
database) patients severe hypoglycemia
OR 2.28 [1.41–3.7]; p = .0008
(risk of hospital mortality)
Risk factors: OR [95% CI]
Diabetes 3.07 [2.03, 4.63]
Septic shock 2.03 [1.19, 3.48]
Mechanical ventilation 2.11 [1.28, 3.48]
Acute Physiology, Age and Chronic
Health Evaluation system II 1.07 [1.05,
1.10]Treatment in intensive insulin era
1.59 [1.05, 2.41]
Wiener et al (31) Meta-analysis 14 of 34 trials Intensive care patients, Hypoglycemia relative risk: 5.13
Tight glycemic International, glucose ≤40 mg/ (4.09, 6.43)
control vs. dL
control
Kosiborod Retrospective n = 7820, 482 Study of patients admitted with Higher mortality seen in patients with
et al (79) cohort hypoglycemia acute myocardial infarction; spontaneous hypoglycemia (OR 2.32
database from 40 U.S. medical [CI 1.31, 4.12]), but not in patients with
centers; hypoglycemia defined as insulin-related hypoglycemia (OR 0.92
glucose <60 mg/dL [CI 0.58, 1.45])
Arabi et al (80) Nested co- n = 523, 84 Med-surg ICU, RCT insulin Adjusted mortality hazard ratio, 1.31;
hort in RCT hypoglycemia infusion 80–110 mg/dL vs. con- 95% CI [0.70, 2.46]; p =.40
ventional 180–200 mg/dL Hypoglycemia rate 3.6 per 100 treat-
ment days
Risk factors: older age, higher Acute
Physiology, Age and Chronic Health
Evaluation system II score, longer LOS,
females, admitted for nonoperative
reasons, diabetics with higher admission
blood glucose, septic, m
echanically ven-
tilated, had received renal replacement
therapy intensive insulin protocol
Griesdale Meta-analysis 14 of 26 trials; Intensive care patients, Inter- Relative risk for hypoglycemia: 5.99
et al (32) tight glycemic national, glucose ≤40 mg/dL, (4.47, 8.03)
control vs. including NICE-SUGAR
control
Egi et al (85) Retrospective n = 4946, 1,109 Intensive care patients, two Higher unadjusted mortality: seen in
cohort hypoglycemia hospitals, 2000–2004 patients even with mild hypoglycemia,
54–80 mg/dL
CI, confidence interval; ICU, intensive care unit; med-surg, medical–surgical unit; OR, odds ratio; RCT, randomized controlled trial.
Karon Accu-Cheka comfort curve 20 coronary artery bypass grafts patients Bias 14 mg/dL (p = .02)
et al (129) GD 14 on pressors, none with systolic blood 56% of POC samples were within
Result is factored to agree with plasma results pressure <80 mm Hg 10% of laboratory
vs. plasma in laboratory No temperatures recorded
Kanji et al (130) Accu-Cheka Inform 30 ICU patients Overall: 69.9% agreement
GD 36 samples Vasopressor: 67.6% agreement over-
Result is factored to agree with plasma results Poor peripheral perfusion or vasopressor, all, 50% with glucose <80 mg/dL
vs. plasma in laboratory significant peripheral edema, postoperative Edema: 71.4% agreement, 55% with
glucose <80 mg/dL
Meex Accu-Cheka Inform 20 ICU samples Arterial and venous: ICU subset, no
et al (131) GD (plasma strips) difference between POC and blood
vs. whole blood gas analyzer gas analyzer (p > .05; r = .98)
Critchell Accu-Cheka Inform 80 consecutive ICU patients NA
et al (105) GD Pressors 25%
by trained technician vs. plasma in laboratory Edema 42%
Pressors and edema 48% 277 samples
Meynaar Accu-Chek Inform 32 ICU patients Bias 11 mg/dL
et al (123) GD 239 samples 90% of samples <75 mg/dL were
vs. serum in laboratory Glucose 25–288 mg/dL within 15 mg/dL of laboratory
90.4% of samples >75 mg/dL were
within 20% of laboratory
Ray et al (132) One Touch Profile, LifeScan 10 ICU patients Bias 0.7 mg/dL (95% confidence
GO Three in shock interval [−41, 40]), intraclass
vs. plasma in laboratory 105 samples correlation coefficient = 0.86,
Glucose 86–256 mg/dL p < .0001
Corstjens Precision PCx 19 ICU patients 93.7% values within the 95%
et al (133) GO 145 samples confidence interval (values
vs. blood gas analyzer not reported)
Few hypoglycemic values
Boyd et al (134) Medisense Precision Plus 20 ED patients NA
GO 20 samples
vs. whole blood in laboratory
POC, point-of-care; GO, glucose oxidase; ICU, intensive care unit; Hct, hematocrit; NA, not applicable/not available; LOA, limits of agreement (2 sd);
GD, glucose dehydrogenase.
Studies illustrate the variability of glucose meters in clinical use when measuring arterial or venous blood specimens compared with capillary specimens.
Error is increased in patients with peripheral edema, poor skin perfusion, or receiving vasopressors. Trials with exogenously spiked blood samples
were excluded.
a
Meters display plasma-equivalent glucose results.
3264 Crit Care Med 2012 Vol. 40, No. 12
Venous POC vs.
Venous POC vs. Laboratory Capillary POC vs. Laboratory Capillary POC Confounders
Bias 9.51 mg/dL Bias 9.54 mg/dL Bias 0.03 mg/dL Venous vs. finger stick No
Precision 8.44 mg/dL Precision 11.96 mg/dL No significant significant difference
21% samples >20 mg/dL difference 15% samples >20 mg/dL difference difference between Low Hct contributed to
LOA +26.5, −10.3 LOA +31.5, −12.5 samples difference between POC and
R2 = .288, p < .001 R2 = .280, p = .02 LOA +24.1, −24.0 laboratory
NA NA NA Overall agreement, but
potential error for individual
samples
Control: mean value 95.8% ± 1.1% of Control: mean value 91.8% ± 1.6% of NA Mean value from different
laboratory value laboratory methods were different
Hypotension: 99.2% ± 2.5% Hypotension: 67.5% ± 5.7%, p < .001 vs. (p < .05)
p < .05 vs. laboratory value laboratory
32% incorrectly diagnosed as hypoglycemic
NA 15% different from laboratory by >20% NA Perfusion index from Phillips
LOA 58.3, −55.3 monitor identified patients
with poor correlation