Song 2014
Song 2014
Song 2014
Review Article
Intensive Insulin Therapy for Septic Patients:
A Meta-Analysis of Randomized Controlled Trials
Fang Song,1 Liu-Jun Zhong,2 Liang Han,2 Guo-Hao Xie,2 Cheng Xiao,3
Bing Zhao,2 Yao-Qin Hu,4 Shu-Yan Wang,2 Chao-Jin Qin,4 Yan Zhang,2
Deng-Ming Lai,4 Ping Cui,2 and Xiang-Ming Fang2
1
School of Medicine, Zhejiang University, Yuhangtang Road 866, Hangzhou 310058, China
2
Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Qingchun Road 79,
Hangzhou 310003, China
3
Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Qingchun Road 79,
Hangzhou 310003, China
4
Department of Surgery, Children’s Hospital, School of Medicine, Zhejiang University, Zhuganxiang 57, Hangzhou 310003, China
Copyright © 2014 Fang Song et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background. Studies on the effect of intensive insulin therapy (IIT) in septic patients with hyperglycemia have given inconsistent
results. The primary purpose of this meta-analysis was to evaluate whether it is effective in reducing mortality. Methods. We
searched PubMed, Embase, the Cochrane Library, clinicaltrials.gov, and relevant reference lists up to September 2013 and including
randomized controlled trials that compared IIT with conventional glucose management in septic patients. Study quality was
assessed using the Cochrane Risk of Bias Tool. And our primary outcome measure was pooled in the random effects model. Results.
We identified twelve randomized controlled trials involving 4100 patients. Meta-analysis showed that IIT did not reduce any of the
outcomes: overall mortality (risk ratio [RR] = 0.98, 95% CI [0.85, 1.15], 𝑃 = 0.84), 28-day mortality (RR = 0.66, 95% CI [0.40, 1.10],
𝑃 = 0.11), 90-day mortality (RR = 1.10, 95% CI [0.97, 1.26], 𝑃 = 0.13), ICU mortality (RR = 0.94, 95% CI [0.77, 1.14], 𝑃 = 0.52),
hospital mortality (RR = 0.98, 95% CI [0.86, 1.11], 𝑃 = 0.71), severity of illness, and length of ICU stay. Conversely, the incidence of
hypoglycemia was markedly higher in the IIT (RR = 2.93, 95% CI [1.69, 5.06], 𝑃 = 0.0001). Conclusions. For patients with sepsis,
IIT and conservative glucose management show similar efficacy, but ITT is associated with a higher incidence of hypoglycemia.
investigate intensive insulin therapy for septic patients, found 1842 records identified by database
no significant reduction in mortality [10]. Then, further search
randomized controlled trials failed to replicate the mortality 646 PubMed
benefit in septic patients [16, 17]. Despite this continuing 938 Embase
debate, the Surviving Sepsis Campaign included an upper 171 Cochrane Library
87 clinicaltrials.gov
limit for blood glucose of 180 mg/dL in their guidelines based
upon systematic reviews of studies involving critically ill
patients [18]. Although sepsis is the chief cause of death in 1816 excluded after abstract screening
ICUs, whether the impact and safety of intensive insulin
therapy in septic patients are the same as those in critically 26 full text retrieved for evaluation
ill patients is uncertain.
In order to clarify this matter, we conducted a meta- 13 excluded after full text screening
analysis to assess the use of intensive insulin therapy in 3 reviews
managing glycemic control for septic patients. The primary 6 wrong population
purpose was to evaluate the effects of tight glycemic control 3 wrong comparison
1 outcomes of interest not reported
on mortality stratified into four subgroups (90-day and 28-
day mortality and hospital and ICU mortality).
13 studies met the inclusion criteria
Cochran’s 𝑄-test (𝑃 < 0.10 for statistical significance) and the 3. Results
𝐼2 statistic (𝐼2 value >50% for substantial heterogeneity). To 3.1. Literature Search. Our predefined search strategy yielded
eliminate the heterogeneity, we conducted either a sensitivity a total of 1,842 abstracts (Figure 1). After reviewing the
analysis or subgroup analysis. titles and abstracts, we excluded 1,816 studies because they
4 BioMed Research International
were nonrandomized controlled trials, not specific to septic glycemic subcategories: 80–110 mg/dL or 120–150 mg/dL [23].
patients or pertained to interventions other than intensive Because our inclusion criterion was an intensive insulin ther-
insulin therapy. We checked the full text of the remaining apy group targeting a glucose concentration of ≤150 mg/dL,
26 articles. One trial that met our inclusion criteria was we combined the data of the two glycemic subcategories
excluded because the data were presented in diagrams from for mortality analysis. The mean glucose concentration of
which we were unable to abstract values [22]. No additional included patients varied significantly among eligible trials,
studies were found in the screened reference lists. Finally, from 130 mg/dL to 216 mg/dL. The proportion of patients with
12 randomized controlled trials were included in our meta- septic shock ranged widely (32.7–100%). In 3 trials, the base-
analysis [10–14, 16, 17, 23–27]. One trial was only an abstract, line parameters of the septic patients were undocumented in
despite contacting the authors to request a copy of the full the intensive and the control groups [17, 23, 24]. Most of the
article [23]. included trials used a specific method of random sequence
generation (Table 2). None of the trials met the “blinding of
participants and personnel” bias criterion and thus were rated
3.2. Study Characteristics. The 12 randomized controlled
as high-risk. On the contrary, all studies were identified as low
trials included 4,100 patients in all, of whom 2,094 were
risk because they did not have “incomplete outcome data.”
assigned to the intensive insulin group and 2,006 to the
control group. The details of the included studies are listed in
Table 1. For the intervention, all the trials used tight glycemic 3.3. Primary Outcome: Mortality. The all-cause mortality was
control (80–110 mg/dL) except for one trial used that used two reported in the 12 randomized controlled trials [10–14, 16, 17,
BioMed Research International 5
Figure 2: Forest plot with all-cause mortality showing no significant difference between IIT and control group (RR = 0.98, 95% CI [0.85,
1.15]). IIT: intensive insulin therapy. CI: confidence interval. M-H: Mantel-Haenszel.
23–27]. There were 681/2,094 (32.5%) deaths in the intensive II), and MODS (Multiple Organ Dysfunction Score) to
insulin intervention group and 661/2,006 (33%) in the control evaluate severity of illness after intensive insulin therapy. Five
group. Meta-analysis showed that the rate of death did not trials reported SOFA score [10–13, 16], two studies reported
differ significantly between the two groups (RR = 0.98, 95% APACHE II score, and only the MODS [23] and SAPS II
CI [0.85, 1.15], 𝑃 = 0.84) (Figure 2). [27] scores were reported in only one study each. The data
In the subgroup analysis, there was no significant differ- about SOFA score could only be extracted from two trials
ence in 28-day mortality (RR = 0.66, 95% CI [0.40, 1.10], that included 578 participants [10, 11]. The pooled estimate in
𝑃 = 0.11), 90-day mortality (RR = 1.10, 95% CI [0.97, 1.26], the intensive insulin group was similar to that in the control
𝑃 = 0.13), ICU mortality (RR = 0.94, 95% CI [0.77, 1.14], group (SMD = 0.05, 95% CI [−0.12, 0.21], 𝑃 = 0.57) with
𝑃 = 0.52), or hospital mortality (RR = 0.98, 95% CI [0.86, no statistical heterogeneity (𝐼2 = 0%; 𝑃 = 1.00) (Figure 4).
1.11], 𝑃 = 0.71) (Figure 3). Similarly, there was no significant difference in APACHE II
The statistical heterogeneity was substantial for all-cause score (𝑃 = 0.46) and SAPS II (𝑃 = 1.00). The MODS was
mortality (𝐼2 = 51%; 𝑃 = 0.03) and for 28-day mortality lower in the intensive insulin group, but its methodological
(𝐼2 = 74%; 𝑃 = 0.02). Because we could not acquire the full quality was low. This suggests that intensive insulin therapy
text of the study by Jin and Guolong [23], we did not have does not reduce the severity of sepsis.
sufficient information to evaluate its methodological quality. Five trials reported the length of ICU stay as an outcome
Therefore, we excluded this trial and the heterogeneity for [10, 11, 16, 23, 26]. It should be noted that in four of the
all-cause mortality was resolved (𝐼2 = 0%; 𝑃 = 0.51). The trials the data were presented as the median (interquartile
heterogeneity was still significant for 28-day mortality. We range) [10, 11, 16, 26], each with no statistically significant
noted that the Cappi trial had a wide confidence interval difference between the intensive insulin and control groups.
due to its small sample size [14]. Thus, we identified this The remaining trial with unclear methodological quality
trial as an outlier in the 28-day mortality. Even with this found that intensive insulin therapy resulted in a shorter
adjustment, the results of all-cause mortality (RR = 1.05, ICU stay, but the result was dubious [23]. We did not
95% CI [0.96, 1.14], 𝑃 = 0.33) and 28-day mortality merge the medians (interquartile range), because we could
(RR = 0.95, 95% CI [0.71, 1.27], 𝑃 = 0.74) did not change not determine whether they had a normal distribution
significantly. [19].
For the occurrence of hypoglycemia, we extracted data
3.4. Secondary Outcomes: Severity of Illness, Length of ICU from seven trials including 2,213 participants [10, 11, 13, 14, 16,
Stay, and Hypoglycemic Events. The included trials used 25, 27] (Figure 5). There were 196/1,093 (17.9%) hypoglycemic
the SOFA (Sequential Organ Failure Assessment) score, events in the intensive insulin group and 55/1,120 (4.9%) in
APACHE II (Acute Physiology and Chronic Health Evalu- the control group. The intensive insulin group had a higher
ation II) score, SAPS II (Simplified Acute Physiology Score rate of hypoglycemia than the control group (RR = 2.93,
6 BioMed Research International
Figure 3: Meta-analysis showing no significant difference between IIT and control groups, with mortality being stratified into 28-day, 90-day,
ICU, and hospital mortality. IIT: intensive insulin therapy. CI: confidence interval. M-H: Mantel-Haenszel.
Study or subgroup IIT Control Weight Standard mean difference Standard mean difference
Mean SD Total Mean SD Total IV, random, 95% CI IV, random, 95% CI
4.1.1 SOFA score
Brunkhorst et al. 2008 7.8 3.9 232 7.7 3.8 274 87.5% 0.03 [−0.15, 0.20]
Iapichino et al. 2008 7.4 3.6 36 6.7 3.5 36 12.5% 0.20 [−0.27, 0.66]
Subtotal (95% CI) 268 310 100.0% 0.05 [−0.12, 0.21]
Heterogeneity: 𝜏2 = 0.00; 𝜒2 = 0.45, df = 1 (P = 0.50); I2 = 0%
Test for overall effect: Z = 0.56 (P = 0.57)
−1 −0.5 0 0.5 1
Favours IIT Favours control
Figure 4: Forest plot with severity of illness showing no significant difference between IIT and control groups in SOFA, APACHE II, and
SAPS II scores, with a reduction of MODS score with IIT. IIT: intensive insulin therapy. SD: standard deviation. CI: confidence interval. IV:
inverse variance.
observational studies indicate that hyperglycemia is associ- compared with other ICU patients. Therefore, the effect of
ated with a higher mortality rate, in particular, sepsis-induced intensive insulin therapy for ICU patients is not necessarily
hyperglycemia rather than mortality due to preexisting congruent with the effect for septic patients. In addition,
diabetes mellitus [6]. The landmark randomized controlled we classified the outcome of mortality into four subgroups
trial showed that intensive insulin therapy (targeting 80– (90-day, 28-day, hospital, and ICU mortality) and added the
110 mg/dL) reduced hospital mortality in septic patients [15], outcome of severity of illness and the length of ICU stay that
so clinicians enthusiastically received it as an effective therapy were not evaluated in the prior reviews.
for these patients. Unfortunately, subsequent randomized We included one specific study [25] that contained a
controlled trials failed to confirm this beneficial effect. database of two randomized controlled trials [15, 32], which
Several prior reviews investigated the effect of intensive used identical protocols and were implemented at the same
insulin therapy (IIT) for a general population of ICU patients center but one year apart. Thus, we treated these studies as
[29–31]. Though we obtained similar results regarding the a consecutive study. This study [25] showed that intensive
effect of IIT on mortality and risk of hypoglycemia, there insulin therapy reduced the ICU mortality in septic patients
are some differences in our findings compared with the prior who stayed in the ICU for at least three days, but there
reviews. The previous reviews concentrated on a general was no statistically significant difference in septic patients
population of ICU patients. Solyemez Wiener et al. [29], who stayed for less than three days. They performed this
Kansagara et al. [30], and Griesdale et al.’s [31] trials were subgroup analysis to specifically consider patients whose
grouped by type of ICU (medical ICU, surgical ICU, and intensive care was limited or who were withdrawn from
mixed ICU). Kansagara et al.’s [30] trials were also grouped by intensive care within 3 days of admission to the ICU. Another
type of patients (myocardial infarction and stroke); however, trial, the Brunkhorst et al. trial [10], showed no effect of
we focused on patients with sepsis. Even though septic intensive insulin on mortality in septic patients who stayed
patients are intermixed with other ICU patients, they possess in the ICU at least three or five days. The remaining trials
distinct treatment and prognostic and clinical outcomes as did not stratify by the length of stay in the ICU. Taking
8 BioMed Research International
Figure 5: Forest plot showing that IIT increased the risk of hypoglycemia. IIT: intensive insulin therapy. CI: confidence interval. M-H:
Mantel-Haenszel.
the authentic clinical practice environment into considera- does not reduce mortality, the use of IIT as a strategy to
tion, we pooled the overall ICU stay and found no significant maintain normoglycemia remains unclear.
difference. Septic patients are apt to suffer from a striking increase
Perhaps the failure to find a benefit with intensive insulin in blood glucose variability, which causes endothelial dys-
therapy can be attributed to several factors. It remains unclear function, oxidative stress, and organ dysfunction [6, 9,
whether hyperglycemia is a cause of increased mortality or 36, 37]. Though the mean blood glucose concentration is
is just a marker of an increased risk of death; it may even similar among trials, the degree of glucose variability may
be a normal response [6]. Finfer’s [33] latest review states be quite different. Several observational studies have shown
that “Until quite recently stress hyperglycemia was seen as that blood glucose variability is independently associated
a normal and possibly beneficial physiological response to with an increased mortality rate, even more than continuous
promote cellular glucose uptake” (pp: 1–6). hyperglycemia [9, 35]. The glycemic lability index, which is
In agreement with previous studies, our meta-analysis calculated from continuous glucose monitoring, reveals the
demonstrated that intensive insulin therapy carries a inherent variability better than the standard deviation of the
markedly increased risk of hypoglycemia. Hypoglycemia mean blood glucose value [35]. The included trials mainly
has been reported to have an independent association used sampling at a predefined time, rather than monitoring
with increased mortality in patients with sepsis [34, 35]. 24-hour continuous glucose levels, resulting in insufficient
Considering the increased risk of death due to increased data to determine the relationship between glucose variability
hypoglycemia and the findings that intensive insulin therapy and mortality rate.
BioMed Research International 9
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Conflict of Interests intensive insulin therapy for septic shock in adults-a ran-
The authors declare that there is no conflict of interests domized controlled trial,” Journal of the American Medical
regarding the publication of this paper. Association, vol. 303, no. 17, pp. 341–348, 2010.
[17] The NICE-SUGAR Study Investigators, “Intensive versus con-
ventional glucose control in critically ill patients,” The New
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