Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection is estimated to affect 30 million people worldwide every year with significant attributed morbidity and mortality (1, 2). Although advancements in treatment protocols have reduced in-hospital mortality (3, 4), therapies that improve sepsis survival by reducing organ dysfunction are scarce (5).
The global prevalence of diabetes has doubled from 4.7% in 1980 to 8.5% in 2014, with an estimated 422 million adults worldwide currently living with diabetes (6). Hyperglycemia predisposes the host to infection by altering host immune responses (7). There is, however, conflicting evidence as to whether diabetes increases or decreases morbidity and/or mortality from sepsis (8, 9).
Metformin is a commonly prescribed antidiabetic drug. Its use is associated with lower all-cause mortality when compared with other hypoglycemics (10). Metformin reduces glucose absorption, improves insulin sensitivity, and inhibits hepatic gluconeogenesis (11). On a cellular level, metformin inhibits mitochondrial respiration at complex I, predominantly in the liver but also in the heart, kidneys, and muscles resulting in reduced fatty acid oxidation and increased lactate production (12–14). Although not contraindicated, metformin is usually stopped in patients with sepsis due to the risk of metformin accumulation and metformin- associated lactic acidosis (MALA) (14). A study by Christiansen et al (15), however, found that premorbid metformin use was associated with reduced mortality among intensive care patients with type 2 diabetes. Similarly, the outcome of patients with MALA is reported to be somewhat better than expected despite very low blood pH values (16, 17). Therefore, we set to systematically examine whether premorbid metformin exposure is associated with mortality, hyperlactatemia, and/or organ dysfunction in sepsis.
MATERIALS AND METHODS
This study was conducted in accordance with the Meta-analysis Of Observational Studies in Epidemiology guidelines (18) and registered with the international prospective register of systematic reviews (PROSPERO, CRD42018094435).
Data Sources and Searches
We employed a high sensitivity strategy with the search last updated on September 26, 2018. Two databases, PubMed and EMBASE (with Medline via Ovid), were used. Timeframe of the search was from 1946 on PubMed, and from 1974 on EMBASE and Medline via Ovid. Search results were restricted to human adult articles only. No language limitations were applied. A detailed search strategy is appended (Supplementary Fig. 1, Supplemental Digital Content 1, http://links.lww.com/CCX/A23; legend, Supplemental Digital Content 15, http://links.lww.com/CCX/A37).
All studies must have included adult patients with sepsis cared for in the emergency department (ED) or ICU and exposure to metformin prior to an episode of sepsis or septic shock. Observational studies or clinical trials were eligible. Pediatric studies, case studies/small series (< 20 patients overall), reviews, conference abstracts, and secondary studies were not eligible. Inclusion criteria follow the Patient, Population, or Problem, Intervention, Comparison, Outcome, Study Design or Setting framework (19) (Table 1). Two investigators (K.T., M.N.) conducted an independent screening of all the abstracts according to the eligibility criteria. Any disagreements were resolved through discussion with a third investigator (A.S.).
Data Extraction and Quality Assessment
The full-text articles of all eligible studies were obtained and the data were extracted by two investigators (K.T., M.N.) in tandem. Authors were contacted directly to kindly provide missing research data or summary of events data as required.
The quality of studies and quality of evidence were formally and independently assessed by two investigators (K.T., M.N.) using the Risk Of Bias In Nonrandomized Studies - of Interventions instrument (20) and GRADE approach (21), respectively.
Data Synthesis and Analysis
Data from different studies were combined to obtain a pooled (summary) odds ratio (OR) using the Mantel-Haenszel method for random effects model (22). Between-study heterogeneity was measured by Higgin’s and Thomson’s I2 (23). I2 between 25% and 50% indicates low between-study heterogeneity, and between 50% and 75% and greater than 75% indicate moderate and high heterogeneity, respectively (24). Small study effects were examined by funnel plots in order to distinguish publication bias from other causes (25). Sensitivity analysis was carried out using the leave-one-out-at-a-time approach and subgroup analysis as described below.
Results were expressed as OR or mean difference (MD) and 95% CI. Where appropriate, the p values are also shown with statistical significance denoted as p values of less than 0.05, unless otherwise stated. Analyses were carried out using Review Manager Version 5.3 (The Cochrane Collaboration: Copenhagen, Denmark, 2014).
Where data were reported as median values and interquartile range (IQR), we followed the recommendation by Greco et al (26) and equated medians to means, whereas SD was calculated as third quartile–first quartile (Q3–Q1); bias attributed to this assumption is generally conservative.
The initial search returned 310 abstract results. After removing 16 duplicates, 294 abstracts were manually screened. Twelve studies were selected for data analysis after meeting all inclusion criteria. Of the 12, seven studies did not report mortality data that clearly identified patients with sepsis from patients without sepsis or metformin users from nonusers. The corresponding authors were contacted to obtain the necessary data for analysis. Four authors replied and three of those were able to provide their unpublished data. The remaining authors could not be reached. The list of studies excluded is appended (Supplementary Table 1, Supplemental Digital Content 2, http://links.lww.com/CCX/A24). Overall, a total of eight studies were found to be eligible, comprising 4144 patients with sepsis, including 562 diabetic patients on metformin prior to the episode of sepsis (Fig. 1). The authors declare no affiliation with any of the included studies.
Characteristics and Type of Studies
All studies were retrospective cohort studies except one prospective observational study by Van Vught et al (27). No controlled or randomized trials were identified. Each study was conducted in a different country with data collected between 2005 and 2014. Four studies (15, 27–29) were conducted in ICU, three (30–32) in ED, and one (33) in both ICU and ED.
The study populations described adult sepsis or septic shock patients with a wide range of illness severity as documented by the severity scoring systems and initial lactate levels. The definitions of sepsis, septic shock, and premorbid metformin exposure varied slightly across the studies, however, were reasonable and comparable to current definitions (34).
Two studies (29, 32) included only patients with septic shock, two (30, 31) included patients with severe sepsis and septic shock, whereas four studies (15, 27, 28, 33) did not specifically distinguish sepsis patients with and without shock. Six studies included mixed populations of surgical and medical patients and two studies (28, 32) included only medical patients. The smallest study included 25 patients (28) and the largest included 1947 patients (31). The characteristics of the studies are appended (Supplementary Table 2, Supplemental Digital Content 3, http://links.lww.com/CCX/A25; and Supplementary Table 3, Supplemental Digital Content 4, http://links.lww.com/CCX/A26).
Risk of Bias Assessment for Primary Outcome
Five studies (15, 27, 29–31) were judged to be of moderate risk of bias for the primary outcome of mortality. Three (28, 32, 33) studies were judged as having serious risk of bias in at least one of the domains, mainly due to selection bias, as patients were included in the study based on plasma lactate levels greater than 5 mmol/L (28, 33) or greater than 10 mmol/L (32). The risk of bias assessment of each trial is appended (Supplementary Fig. 2, Supplemental Digital Content 5, http://links.lww.com/CCX/A27; legend, Supplemental Digital Content 15, http://links.lww.com/CCX/A37) with reasonings (Supplementary Table 4, Supplemental Digital Content 6, http://links.lww.com/CCX/A28).
The primary outcome analysis included mortality data of 4,144 patients from all eight included studies (28 d, 30 d, or hospital mortality). The absolute mortality rates were lower in patients on premorbid metformin in all eight studies. Accordingly, pooled meta-analysis revealed that premorbid metformin exposure was associated with improved survival in sepsis (OR, 0.57; 95% CI, 0.40–0.80; p = 0.001), with low heterogeneity (i2 = 43%; τ2 = 0.10; p = 0.09) (Fig. 2). Inspection of the funnel plot revealed that publication bias was unlikely (Supplementary Fig. 3, Supplemental Digital Content 7, http://links.lww.com/CCX/A29; legend, Supplemental Digital Content 15, http://links.lww.com/CCX/A37). Due to the observational nature of the studies, GRADE quality of evidence for mortality outcome is judged to be low to moderate (Supplementary Table 5, Supplemental Digital Content 8, http://links.lww.com/CCX/A30).
Using the leave-one-out-at-a-time approach did not significantly alter the results of the meta-analysis (Supplementary Fig. 4a, Supplemental Digital Content 9, http://links.lww.com/CCX/A31; legend, Supplemental Digital Content 15, http://links.lww.com/CCX/A37). Excluding three studies (28, 32, 33) that had a serious risk of bias from selecting patients based on initial plasma lactate levels did not significantly affect the OR analysis (OR, 0.64; 95% CI, 0.49–0.84; p = 0.001; Supplementary Fig. 4b, Supplemental Digital Content 9, http://links.lww.com/CCX/A31; legend, Supplemental Digital Content 15, http://links.lww.com/CCX/A37). Analysis of studies comparing diabetics to nondiabetics increased the strength of the association between premorbid metformin exposure and reduced mortality (OR, 0.42; 95% CI, 0.23–0.77; p = 0.005; Supplementary Fig. 4c, Supplemental Digital Content 9, http://links.lww.com/CCX/A31; legend, Supplemental Digital Content 15, http://links.lww.com/CCX/A37). All studies comparing diabetics to nondiabetics were also conducted in ED. Interestingly, the association was blunted when comparing diabetic metformin users to diabetics not on metformin (OR, 0.74; 95% CI, 0.53–1.03; p = 0.07; Supplementary Fig. 4d, Supplemental Digital Content 9, http://links.lww.com/CCX/A31; legend, Supplemental Digital Content 15, http://links.lww.com/CCX/A37). The findings may reflect the removal of confounding by the diagnosis of diabetes or may be related to the fact that these four studies were all done in ICU patients as discussed below.
The use of metformin is contraindicated in patients with advanced chronic renal failure (10). Consequently, the group of metformin users in three out of the eight included studies had significantly fewer patients with advanced chronic renal failure. Chronic renal failure may be an important source of confounding, as it is associated with poorer outcomes in patients with sepsis (35). Hence, we performed a sensitivity analysis including only studies without a significant difference in the presence of chronic renal failure between metformin users and nonusers. The result (OR, 0.44; 95% CI, 0.25–0.76; p = 0.003; Supplementary Fig. 4e, Supplemental Digital Content 10, http://links.lww.com/CCX/A32; legend, Supplemental Digital Content 15, http://links.lww.com/CCX/A37) suggests that the association between metformin and decreased mortality in sepsis was not significantly influenced by fewer patients with advanced chronic renal failure among the metformin users. Inspection of the funnel plots revealed that publication bias was unlikely (Supplementary Fig. 5a-c, Supplemental Digital Content 11, http://links.lww.com/CCX/A33—legend, Supplemental Digital Content 15, http://links.lww.com/CCX/A37; and Supplementary Fig. 5d, Supplemental Digital Content 12, http://links.lww.com/CCX/A34—legend, Supplemental Digital Content 15, http://links.lww.com/CCX/A37).
Initial Plasma Lactate Level.
Four studies (27, 29, 31, 32) reported lactate levels as median and IQR. Scale and Harvey (33) provided raw data from which median and IQR were derived. Overall, only two studies (29, 30) reported significantly higher plasma lactate level in premorbid metformin users, but one (30) had missing SD data, precluding it from meta-analysis. Three studies (27, 28, 31) reported lactate levels that trended higher in metformin users but the increase was not significant. Two studies (32, 33) reported no significant differences in lactate levels between both populations and one study (15) did not provide a comparison of lactate levels. Overall, meta-analysis of five studies (27, 29, 31–33) indicates that plasma lactate levels are not significantly elevated due to premorbid metformin exposure (MD, 0.39 [–0.50 to 1.28]; i2 = 0.72%; p = 0.39) (Fig. 3). Inspection of the funnel plot revealed that publication bias was unlikely (Supplementary Fig. 6, Supplemental Digital Content 13, http://links.lww.com/CCX/A35; legend, Supplemental Digital Content 15, http://links.lww.com/CCX/A37). The GRADE quality of evidence is low due to selection bias and inconsistency (Supplementary Table 5, Supplemental Digital Content 8, http://links.lww.com/CCX/A30).
Three studies reported initial glucose levels. In one study (27) that included only diabetics, the initial glycemia was higher in the nonmetformin users. In two studies that included nondiabetics in the control group (30, 31), initial glycemia was higher in the metformin users as expected. The GRADE quality of evidence is very low (Supplementary Table 5, Supplemental Digital Content 8, http://links.lww.com/CCX/A30).
The data on organ dysfunction and sepsis severity were very heterogeneous, precluding meaningful meta-analysis. The following paragraphs summarize the most important findings and the data are presented in Supplementary Table 3 (Supplemental Digital Content 4, http://links.lww.com/CCX/A26). The GRADE quality of evidence for organ dysfunction data is very low for all (Supplementary Table 5, Supplemental Digital Content 8, http://links.lww.com/CCX/A30).
Three studies (27, 29, 30) reported vasopressor usage comparing metformin users to nonusers. Two of those found significantly lower usage of vasopressors in premorbid metformin users (27, 30). Neither any significant differences in the maximum noradrenaline dose nor duration of noradrenaline administration were reported in the remaining study (29).
Three studies (27, 29, 30) reported ventilation requirements of premorbid metformin users and metformin nonusers. No significant differences were found between the groups.
Renal function was measured across six studies (27–32) via four different variables (Table 3). Renal replacement therapy was more common in metformin users in two studies (28, 29). Two studies (27, 29) reported no significant difference in acute kidney injury (AKI) rates, whereas one study (32) reported a significant decrease in AKI rates with metformin usage.
Five studies provided a comparison of sepsis severity scores between the groups, but each used a different score (Acute Physiology and Chronic Health Evaluation [APACHE] II, APACHE IV, Sequential Organ Failure Assessment, Predisposition, Infection [or Insult], Response and Organ dysfunction, and Simplified Acute Physiology Score II). Therefore, a meta-analysis linking sepsis severity and metformin exposure was impossible. Nonetheless, the five studies independently found that sepsis severity did not differ due to premorbid metformin exposure. The GRADE quality of evidence is low (Supplementary Table 5, Supplemental Digital Content 8, http://links.lww.com/CCX/A30).
To our knowledge, this is the first systematic review addressing the association between premorbid metformin exposure and mortality and organ dysfunction in sepsis. The main finding is that patients on premorbid metformin seem to have better odds of surviving sepsis. Our finding is relatively robust across a range of sensitivity analyses. Due to the observational nature of included studies, however, we cannot rule out potential confounding by various factors. Interestingly, secondary results suggest that in patients with sepsis, initial plasma lactate levels are not significantly associated with premorbid metformin exposure. Unfortunately, due to the variability in data reporting, we were unable to systematically analyze any association of premorbid metformin exposure with organ dysfunction in sepsis. Our results invite careful consideration regarding possible reasons for the association between decreased mortality in sepsis and prior metformin exposure.
First, hyperlactatemia or perceived risk of MALA could lead to an earlier and more aggressive treatment of sepsis, particularly, where Surviving Sepsis guidelines have been adopted. The guidelines use elevated lactate as one of the early triggers for the initiation of treatment protocols (36). However, the association between metformin exposure and increased lactate levels could not be confirmed by our systematic review.
Second, several pharmacodynamic effects of metformin could be protective in sepsis. The inhibition of mitochondrial enzymes of complex I of the respiratory chain and the mitochondrial isoform of glycerophosphate dehydrogenase at the time of increased inflammation may lead to reductions in mitochondrial electron transfer, oxygen consumption, generation of reactive oxygen species, and adenosine triphosphate (ATP) production and consumption. This is akin to hibernation, hence potentially affording mitochondrial protection (12, 37–40). Metformin also activates the cellular energy sensor adenosine monophosphate-activated protein kinase, which is otherwise induced by cellular stress (41, 42), switching off the ATP consuming pathways (38). This switch may improve cellular and organ function under the stressful conditions of initial sepsis, when the pharmacodynamic effect of premorbid metformin may still be present (43, 44).
Third, metformin has some antimicrobial properties that affect multiple bacterial and viral pathogens (45, 46). Metformin may facilitate bacterial eradication in sepsis by improving host neutrophil activation, chemotaxis, and phagocytosis and by inhibiting the differentiation of monocytes into macrophages, reducing their secretion of pro-inflammatory cytokines (49, 50). However, inhibition of cytokine secretion by metformin during protracted Candida albicans sepsis in mice led to reduced survival (47) and in mice with sepsis caused by Escherichia coli-induced peritonitis, metformin pretreatment had no effect on mortality (48).
The ability of metformin to improve insulin sensitivity, reduce hepatic gluconeogenesis, and improve blood sugar level control may also play a role during the initial stage of sepsis. Hyperglycemia, hypoglycemia, and large variability in blood sugar levels are associated with increased mortality, in particular, for nondiabetic patients with sepsis (49–52)..
The results of our meta-analysis are pertinent to critical care physicians, endocrinologists, and other practitioners. Metformin seems to confer overall survival benefit in the diabetic population and appears to be associated with reduced risk of developing sepsis and decreased mortality if sepsis develops (53–55). An association of metformin use with lower mortality in older patients with pneumonia was similarly reported in a preliminary study (56). Of interest, critically ill burned patients started on metformin instead of insulin displayed improved glycemic control and reduced inflammation (57). Our systematic review questions the often negatively perceived role of metformin use in patients with sepsis and in patients at risk of developing sepsis.
By nature of the subject, the eight included studies were all cohorts of patients with sepsis and did not include any randomized control trial. Thus, systematic confounding and risk of bias cannot be ruled out. In the sensitivity analysis, however, removing studies with a serious risk of bias did not affect our findings. The risk of bias can be minimized by adjusted analysis. Unfortunately, the six studies that provided adjusted analysis used different methods precluding direct comparison (15, 27, 29–32). An overview of adjusted risks is appended (Supplementary Table 6, Supplemental Digital Content 14, http://links.lww.com/CCX/A36). The relatively small number of included studies has reduced the power to detect any publication bias.
The sensitivity analysis also revealed that when only diabetic patients with sepsis are included in the control group, the certainty of the association between premorbid metformin exposure and decreased mortality is reduced. This may seem surprising as the higher prevalence of chronic renal failure in diabetics not exposed to metformin may have favored metformin users. The nonsignificant association in diabetics is likely explained by the relatively small number of patients in the four studies concerned; 700 diabetics, out of whom 243 patients were on metformin. Of note those studies were all conducted in the ICU. Other factors specific to diabetics, such as looser glycemia targets, less hypoglycemia, or the inclusion of type I diabetics in the control groups, could be responsible.
None of the studies were able to specify the duration or consistency of premorbid metformin exposure. The inconsistency could be a contributing factor to our finding regarding hyperlactatemia. A further reason could be the selection bias caused by the inclusion of patients with specific lactatemia threshold that may have obscured any differences in hyperlactatemia between the groups.
Another limitation of this review is the variability in the way sepsis severity and data on organ dysfunction variables were reported, which affected our ability to assess the influence of disease severity on patient outcome and to conduct meta-analysis on the prevalence and severity of specific organ dysfunctions. In the future, population-based studies or analysis of sepsis registries might be helpful to delineate whether premorbid metformin exposure is associated with specific organ protection in sepsis.
In conclusion, this systematic review and meta-analysis suggests that metformin exposure prior to an episode of sepsis may be associated with decreased mortality. We could not confirm that metformin significantly increases blood lactate levels in patients with sepsis. The association between premorbid metformin exposure and organ dysfunction in sepsis requires further investigation.
1. Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis
and septic shock (sepsis
2. Fleischmann C, Scherag A, Adhikari NKJ, et al. Assessment of global incidence and mortality
of hospital-treated sepsis
. Current estimates and limitations.Am J Respir Crit Care Med2016193259–272
3. Levy MM, Evans LE, Rhodes A. The Surviving Sepsis
Campaign bundle: 2018 update.Intensive Care Med201844925–928
4. Schorr CA, Dellinger RP. The Surviving Sepsis
Campaign: Past, present and future.Trends Mol Med201420192–194
5. Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus fludrocortisone for adults with septic shock.N Engl J Med2018378809–818
6. Mathers CD, Loncar D. Projections of global mortality
and burden of disease from 2002 to 2030.PLoS Med20063e442
7. Koh GCKW, Peacock SJ, Poll T, et al. The impact of diabetes on the pathogenesis of sepsis
.Eur J Clin Microbiol Infect Dis201231379–388
8. Tiwari S, Pratyush DD, Gahlot A, et al. Sepsis
in diabetes: A bad duo.Diabetes Metab Syndr Clin Res Rev20115222–227
9. Schuetz P, Jones AE, Howell MD, et al. Diabetes is not associated with increased mortality
in emergency department patients with sepsis
.Ann Emerg Med201158438–444
10. Ekström N, Schiöler L, Svensson A-M, et al. Effectiveness and safety of metformin
in 51 675 patients with type 2 diabetes and different levels of renal function: A cohort study from the Swedish National Diabetes Register.BMJ Open20122e001076
11. Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin
12. Owen MR, Doran E, Halestrap AP. Evidence that metformin
exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain.Biochem J2000348Pt 3607–614
13. Bridges HR, Jones AJY, Pollak MN, et al. Effects of metformin
and other biguanides on oxidative phosphorylation in mitochondria.Biochem J2014462475–487
14. DeFronzo R, Fleming GA, Chen K, et al. Metformin-associated lactic acidosis
: Current perspectives on causes and risk.Metabolism20166520–29
15. Christiansen C, Johansen M, Christensen S, et al. Preadmission metformin
use and mortality
among intensive care patients with diabetes: A cohort study.Crit Care201317R192
16. Kajbaf F, Lalau J-D. The prognostic value of blood pH and lactate and metformin
concentrations in severe metformin-associated lactic acidosis
.BMC Pharmacol Toxicol20131422
17. Friesecke S, Abel P, Roser M, et al. Outcome of severe lactic acidosis associated with metformin
18. Stroup DF. Meta-analysis of observational studies in epidemiology A proposal for reporting.JAMA20002832008
19. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration.PLoS Med20096e1000100
20. Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions.BMJ2016355i4919
21. Atkins D, Best D, Briss PA, et al; GRADE Working GroupGrading quality of evidence and strength of recommendations.BMJ20043281490
22. Emerson JD. Combining estimates of the odds ratio: The state of the art.Stat Methods Med Res19943157–178
23. Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis.Stat Med2002211539–1558
24. Higgins JPT. Measuring inconsistency in meta-analyses.BMJ2003327557–560
25. Peters JL, Sutton AJ, Jones DR, et al. Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry.J Clin Epidemiol200861991–996
26. Greco T, Biondi-Zoccai G, Gemma M, et al. How to impute study-specific standard deviations in meta-analyses of skewed continuous endpoints?World J Meta-Anal20153215
27. van Vught LA, Scicluna BP, Hoogendijk AJ, et al. Association of diabetes and diabetes treatment with the host response in critically ill sepsis
28. Hloch O, Charvat J, Masopust J, et al. Lactic acidosis in medical ICU - the role of diabetes mellitus and metformin
.Neuro Endocrinol Lett201233792–795
29. Jochmans S, Alphonsine J-E, Chelly J, et al. Does metformin
exposure before ICU stay have any impact on patients’ outcome? A retrospective cohort study of diabetic patients.Ann Intensive Care20177116
30. Park J, Hwang SY, Jo IJ, et al. Impact of metformin
use on lactate kinetics in patients with severe sepsis
and septic shock.Shock201747582–587
31. Green JP, Berger T, Garg N, et al. Impact of metformin
use on the prognostic value of lactate in sepsis
.Am J Emerg Med2012301667–1673
32. Doenyas-Barak K, Beberashvili I, Marcus R, et al. Lactic acidosis and severe septic shock in metformin
users: A cohort study.Crit Care20152010
33. Scale T, Harvey JN. Diabetes, metformin
and lactic acidosis: Lactic acidosis.Clin Endocrinol (Oxf)201174191–196
34. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis
Campaign: International Guidelines for management of severe sepsis
and septic shock, 2012.Intensive Care Med201339165–228
35. Maizel J, Deransy R, Dehedin B, et al. Impact of non-dialysis chronic kidney disease on survival in patients with septic shock.BMC Nephrol20131477
36. Casserly B, Phillips GS, Schorr C, et al. Lactate measurements in sepsis
-induced tissue hypoperfusion: Results from the Surviving Sepsis
Campaign Database.Crit Care Med201543567–573
37. Madiraju AK, Erion DM, Rahimi Y, et al. Metformin
suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase.Nature2014510542–546
38. Protti A, Lecchi A, Fortunato F, et al. Metformin
overdose causes platelet mitochondrial dysfunction in humans.Crit Care201216R180
39. Tang G, Yang H, Chen J, et al. Metformin
-induced brain injury by inhibiting apoptosis, oxidative stress and neuroinflammation via the PI3K/Akt signaling pathway.Oncotarget2017897977–97989
40. Singer M. Critical illness and flat batteries.Crit Care201721Suppl 3309
41. Hardie DG, Carling D. The AMP-activated protein kinase. Fuel gauge of the mammalian cell?Eur J Biochem1997246259–273
42. Sambandam N, Lopaschuk GD. AMP-activated protein kinase (AMPK) control of fatty acid and glucose metabolism in the ischemic heart.Prog Lipid Res200342238–256
43. Masoudi FA, Inzucchi SE, Wang Y, et al. Thiazolidinediones, metformin
, and outcomes in older patients with diabetes and heart failure: An observational study.Circulation2005111583–590
44. Shibata R, Ouchi N, Ito M, et al. Adiponectin-mediated modulation of hypertrophic signals in the heart.Nat Med2004101384–1389
45. Singhal A, Jie L, Kumar P, et al. Metformin
as adjunct antituberculosis therapy.Sci Transl Med20146263ra159
46. Xie W, Wang L, Dai Q, et al. Activation of AMPK restricts coxsackievirus B3 replication by inhibiting lipid accumulation.J Mol Cell Cardiol201585155–167
47. Cheng S-C, Scicluna BP, Arts RJW, et al. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis
48. Gras V, Bouffandeau B, Montravers PH, et al. Effect of metformin
on survival rate in experimental sepsis
49. Vandijck DM, Oeyen SG, Buyle EM, et al. Hyperglycaemia upon onset of ICU-acquired bloodstream infection is associated with adverse outcome in a mixed ICU population.Anaesth Intensive Care20083625–29
50. Marik PE, Raghavan M. Stress-hyperglycemia, insulin and immunomodulation in sepsis
.Intensive Care Med200430748–756
51. Van Cromphaut SJ, Vanhorebeek I, Van den Berghe G. Glucose metabolism and insulin resistance in sepsis
.Curr Pharm Des2008141887–1899
52. Ali NA, O’Brien JM, Dungan K, et al. Glucose variability and mortality
in patients with sepsis
.Crit Care Med2008362316–2321
53. Shih C-J, Wu Y-L, Chao P-W, et al. Association between use of oral anti-diabetic drugs and the risk of sepsis
: A nested case-control study.Sci Rep2015515260
54. Selvin E, Bolen S, Yeh H-C, et al. Cardiovascular outcomes in trials of oral diabetes medications: A systematic review
.Arch Intern Med20081682070
55. Simard P, Presse N, Roy L, et al. Association between metformin
adherence and all-cause mortality
among new users of metformin
: A nested case-control study.Ann Pharmacother201852305–313
56. Mortensen E, Alvarez C. Prior metformin
use is associated with lower mortality
for patients with diabetes who are hospitalised with pneumonia.J Gen Intern Med201833312
57. Jeschke MG, Abdullahi A, Burnett M, et al. Glucose control in severely burned patients using metformin
: An interim safety and efficacy analysis of a phase II randomized controlled trial.Ann Surg2016264518–527