Measure for Measure Consequences, Detection and ...

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SOURCE (OR PART OF THE FOLLOWING SOURCE): Type Dissertation Title Measure for measure: consequences, detection and treatment of hyperglycaemia Author J. Hermanides Faculty Faculty of Medicine Year 2010 Pages 228 ISBN 978-90-9025313-8

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UITNODIGING Measure for Measure

Consequences, Detection and Treatment of Hyperglycaemia

Jeroen Hermanides

Jeroen Hermanides

Measure for Measure Consequences, Detection and Treatment of Hyperglycaemia Op vrijdag 4 juni 2010 om 14:00 in de Agnietenkapel, Oudezijds Voorburgwal 231, Amsterdam Receptie ter plaatse na afloop van de verdediging

“Pissing Evil”

Paranimfen Bas van Geldere [email protected]

Jeroen Hermanides

That is how sir Thomas Willis in the 17th century described the high concentrations of glucose found in the urine of patients. The sweet urine described by dr. Willis was the result of pathologically elevated concentrations of glucose in the blood called hyperglycaemia. In those days, hyperglycaemia would eventually mean certain death. Since then we have come a long way, but are still left with questions on the consequences of hyperglycaemia and how we best measure it in order to take the appropriate measures. In this thesis, several studies are presented that investigated the consequences, detection and treatment of hyperglycaemia.

Measure for Measure

Voor het bijwonen van de openbare verdediging van het proefschrift van

Wietse Eshuis [email protected] Jeroen Hermanides Tugelaweg 139F 1091VX Amsterdam [email protected]

Measure for Measure


Jeroen Hermanides

Author: Cover:

Jeroen Hermanides Design of a perpetuum mobile by Johann Joachim Becher, adapted from Technica Curiosa (Casper Scott, 1664)

Printed by:

Gildeprint Drukkerijen B.V.

ISBN/EAN

978-90-9025313-8

The printing of this thesis was financially supported by: Abbott Diabetes Care, B. Braun Medical B.V., Bayer B.V., Boehringer Ingelheim B.V., Eli Lilly Nederland B.V., GlaxoSmithKline, J.E. Jurriaanse Stichting, Menarini Diagnostics Benelux, Merck Sharp & Dohme B.V., NovoNordisk B.V., sanofi-aventis Netherlands B.V., Stichting Amstol, Stichting Asklepios, and the Universiteit van Amsterdam.

Copyright© 2010, J. Hermanides, Amsterdam, The Netherlands No part of this thesis may be reproduced, stored in a retrieval system or transmitted in any form or by any means, without prior written permission of the author

Measure for Measure


Academisch proefschrift

ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof.dr. D.C. van den Boom ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op vrijdag 4 juni 2010, te 14.00 uur

door

Jeroen Hermanides

Geboren te Amsterdam

PROMOTIECOMMISSIE Promotor

Prof.dr. J.B.L. Hoekstra

Co-promotor

Dr. J.H. de Vries

Overige leden

Prof.dr. H.R. Büller Prof.dr. J.C. Pickup Prof.dr. F.R. Rosendaal Prof.dr. W.S. Schlack Prof.dr. D.F. Zandstra

Faculteit der Geneeskunde

Financial support by the Netherlands Heart Foundation and the Dutch Diabetes Research Foundation for the publication of this thesis is gratefully acknowledged.

TABLE OF CONTENTS Chapter 1

Introduction

7

PART I Consequences of Hyperglycaemia Chapter 2

Glucose: a prothrombotic factor?

15

Chapter 3

Venous thrombosis is associated with

31

hyperglycaemia at diagnosis: a case–control study Chapter 4

Hip surgery sequentially induces stress

43

hyperglycaemia and activates coagulation Chapter 5

Stress-induced hyperglycaemia and venous

53

thromboembolism following total hip or total knee arthroplasty Chapter 6

Early postoperative hyperglycaemia is associated with

67

postoperative complications after pancreatoduodenectomy PART II Detection and Treatment of Hyperglycaemia Chapter 7

Sense and nonsense in sensors

87

Chapter 8

Sensor augmented pump therapy

97

lowers HbA1c in suboptimally controlled type 1 diabetes; a randomised controlled trial Chapter 9

Sensor augmented insulin pump

117

therapy to treat hyperglycaemia at the coronary care unit; a randomised clinical pilot trial Chapter 10

No apparent local effect of insulin on microdialysis continuous glucose-monitoring measurements.

133

Chapter 11

Algorithm to treat postprandial glycaemic

141

excursions using a closed-loop format: a pilot study Chapter 12

Glucose variability is associated with ICU mortality

151

Chapter 13

Hypoglycaemia is associated with ICU mortality

165

Mean glucose during ICU admission is

179

Chapter 14

related to mortality by a U-shaped curve; implications for clinical care Chapter 15

Summary and future considerations

197

Samenvatting en toekomstperspectief

205

List of publications

213

Biografie

217

Co-authors

221

Dankwoord

225

Introduction

J Hermanides

,QWURGXFWLRQ

„Pissing Evil‰

1

That is how sir Thomas Willis, the famous London physician, described the high concentrations of glucose found in the urine of his patients.1 For this, the underlying illness became known as „diabetes mellitus‰, translated as „flowing sweetness‰. The sweet urine described by dr. Willis was the result of pathologically elevated concentrations of glucose in the blood called hyperglycaemia. With no

2 3

treatment available at that time, patients with hyperglycaemia would eventually face certain death. Nowadays in the Western world insulin and other glucose lowering agents have become available to treat hyperglycaemia and life expectancy of patients with diabetes continues to increase.2 However, patients with diabetes mellitus type 1 still face intensive, bothersome and lifelong treatment, trying to

4 5

prevent complications.3;4 Recently the growing epidemic of diabetes mellitus type 2 has put this form of diabetes in the spotlight.5 Even more since morbidity and mortality are worrying.6 In 2001 another form of hyperglycaemia drew everyoneÊs attention (at least in the medical world) when Greet van den Berghe in Leuven showed that strict glycaemic control in the Intensive Care Unit (ICU) reduced mortality by a relative

6 7

43%.7

Especially patients without known diabetes, but with transient hyperglycaemia because of severe illness, benefitted from this intervention.8 This so-called „diabetes of injury‰ or „stress-hyperglycaemia‰ turned out to be a risk factor for poor outcome in a variety of acute- and severe illnesses.9;10

8 9

But what exactly is the harm of hyperglycaemia? It is known to cause micro-, macrovascular and neural damage in longstanding diabetes.3;4;6 Another major cause of morbidity and mortality is the influence of hyperglycaemia on the coagulation system11, thereby causing arterial and venous thrombosis, leading to stroke, myocardial infarction and pulmonary embolism. The consequences of stress

10 11

hyperglycaemia in different patient groups remain unclear. In general it is thought to have its impact on the immune system, the endothelium and the coagulation system.9 The exact effects seem to vary between patient groups and many research questions remain unanswered. In PART I of this thesis the effects of hyperglycaemia on the coagulation system are investigated in venous thrombosis

12 13

and after orthopaedic surgery. Chapter 2 gives a review of the current evidence on hyperglycaemia and thrombosis. The association between venous thrombosis and hyperglycaemia is investigated in Chapter 3, whereas Chapter 4 and 5 study the influence of orthopaedic surgery on glucose metabolism, coagulation activation and

9

14 15

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postoperative

venous

thrombosis.

Furthermore,

the

consequences

of

hyperglycaemia after pancreatoduodenectomy are studied in Chapter 6. With developing technologies, new possibilities have become available to target hyperglycaemia. After advancing from bulky insulin needles to the delicate pens today, the development of the insulin pump made it possible to continuously administer and adjust insulin administration.12 This flexible insulin dosing proved beneficial in treating diabetes mellitus.13 Hereafter, new ways of measuring glucose became available with the continuous glucose sensors. Instead of the snapshot glucose values gained with fingerstick measurements, there was now a continuous stream of data available.14 Only recently, these two devices have been combined in one integrated sensor augmented insulin pump15, a major step towards the development of a closed-loop system or artificial pancreas. Clearly, the detection and treatment of hyperglycaemia is being modernised and provides a source for interesting research questions in PART II. Chapter 7 comments on the development of the glucose sensors so far. In Chapter 8 the results of a randomised controlled trial investigating the efficacy of sensor augmented pump therapy are presented. In Chapter 9 the application of sensor augmented pump therapy in patients with acute myocardial infarction and hyperglycaemia is studied. Also further steps towards the closed-loop system have been studied and described by infusing insulin in the close proximity of subcutaneous glucose sensors in Chapter 10 and the development of a closed-loop algorithm in Chapter 11. After the first Leuven study by Greet van den Berghe, following trials could not reproduce her impressive results. Even more, the evidence from the recent NICESUGAR study implies that strict glycaemic control in the ICU does more harm than good.16 Whether or not strict glycaemic control in the ICU should be common practice and what guidelines to follow is being heavily debated. Factors not yet studied could be involved and explain the differences between the trials. We therefore used a different approach in measuring hyperglycaemia, by taking glucose variability into account, which is done in Chapter 12. A major side effect of treating hyperglycaemia and important factor in interpreting study results is hypoglycaemia. The consequence of hypoglycaemia in the ICU has been investigated in Chapter 13. Finally, the implications for clinical care resulting from our data and the Leuven and NICE-SUGAR trials are discussed in Chapter 14. The title of this thesis refers to the Shakespeare play „Measure for Measure‰, which means that every action is followed by a reaction or every upside has its downside. As with ShakespeareÊs play, this thesis is about searching for „truths‰ and

10

,QWURGXFWLRQ

questioning methods of measuring as these will directly influence the measures that are taken. The bad guy in this thesis is however not a harsh judge from ancient

Vienna

named

Angelo,

but

a

pathological

phenomenon

1

called

hyperglycaemia.

2 3 4 5 6 7 8 9 10 11 12 13 14 15 11

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REFERENCES (1)

12

Willis T. Pharmaceutice rationalis. 1679.

(2)

Gale EA. How to survive diabetes. Diabetologia 2009; 52(4):559-567.

(3)

The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993; 329(14):977-986.

(4)

Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained Effect of Intensive Treatment of Type 1 Diabetes Mellitus on Development and Progression of Diabetic Nephropathy: The Epidemiology of Diabetes Interventions and Complications (EDIC) Study. JAMA 2003; 290(16):2159-2167.

(5)

Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP. The Continuing Epidemics of Obesity and Diabetes in the United States. JAMA 2001; 286(10):1195-1200.

(6)

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352(9131):837-853.

(7)

Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001; 345(19):13591367.

(8)

Van den Berghe G, Wilmer A, Milants I, Wouters PJ, Bouckaert B, Bruyninckx F et al. Intensive insulin therapy in mixed medical/surgical intensive care units: benefit versus harm. Diabetes 2006; 55(11):3151-3159.

(9)

Dungan KM, Braithwaite SS, Preiser JC. Stress hyperglycaemia. Lancet 2009; 373(9677):1798-1807.

(10)

Vriesendorp TM, de Vries JH, Hoekstra JB. [Hyperglycaemia during hospitalisation]. Ned Tijdschr Geneeskd 2007; 151(23):1278-1282.

(11)

Carr ME. Diabetes mellitus: a hypercoagulable state. J Diabetes Complications 2001; 15(1):44-54.

(12)

Pickup JC, Keen H, Parsons JA, Alberti KG. Continuous subcutaneous insulin infusion: an approach to achieving normoglycaemia. Br Med J 1978; 1(6107):204-207.

(13)

Retnakaran R, Hochman J, DeVries JH, Hanaire-Broutin H, Heine RJ, Melki V et al. Continuous Subcutaneous Insulin Infusion Versus Multiple Daily Injections: The impact of baseline A1c. Diabetes Care 2004; 27(11):2590-2596.

(14)

Wentholt IM, Hoekstra JB, DeVries JH. Continuous glucose monitors: the long-awaited watch dogs? Diabetes Technol Ther 2007; 9(5):399-409.

(15)

Mastrototaro JJ, Cooper KW, Soundararajan G, Sanders JB, Shah RV. Clinical experience with an integrated continuous glucose sensor/insulin pump platform: a feasibility study. Adv Ther 2006; 23(5):725-732.

(16)

Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009; 360(13):12831297.

CONSEQUENCES OF HYPERGLYCAEMIA

Glucose: a prothrombotic factor?

J Hermanides, BA Lemkes, JH DeVries, F Holleman, JCM Meijers and JBL Hoekstra

Submitted for publication

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ABSTRACT Evidence is mounting that both diabetes and stress induced hyperglycaemia contribute

to

coagulation

activation

and

hypofibrinolysis,

resulting

in

a

procoagulant state that predisposes patients to thrombotic events. Hyperglycaemia is often accompanied by hyperinsulinaemia and their combined effects may be even stronger. In this review we discuss the current evidence regarding the role of glucose as prothrombotic factor, not only in relation to diabetes, but also with regard to acute hyperglycaemia. Furthermore, the effects of glucose lowering therapies to prevent hypercoagulability are considered.

16

*OXFRVHDSURWKURPERWLFIDFWRU"

INTRODUCTION

1

Patients with diabetes are notorious for their risk of vascular events. Apart from the effects of diabetes and its prerequisite hyperglycaemia on the development of atherosclerosis, this high risk may also be caused by the procoagulant state found in diabetes.1;2 In recent years hyperglycaemia per se, even without overt diabetes, has gained

2 3

interest as a potential target to improve clinical outcomes in hospitalised patients with acute illness.3 In this setting the effects of hyperglycaemia on the coagulation system may be of greater importance than previously considered. Here we discuss the current evidence regarding potentially harmful changes in the coagulation system and subsequent risk of thrombotic disease, not only caused by diabetes but

4 5

also by acute hyperglycaemia.

6

CHRONIC HYPERGLYCAEMIA

7

Type 2 diabetes Type 2 diabetes (DM2) is defined by hyperglycaemia, but often accompanied by hyperinsulinaemia, dyslipidaemia, hypertension and obesity. Its effects on the coagulation system can therefore not easily be attributed to either one of these entities4, but the impact of glucose on coagulation in diabetes has been studied extensively.

Markers of fibrinolysis and coagulation Both parameters of increased coagulability as well as a fibrinolytic impairment have been found in DM2, although there are many different markers in the circulation

to

measure

these

abnormalities.

Platelet-dependent

thrombin

8 9 10 11

generation, for instance, was measured in patients with poor glycaemic control, good glycaemic control and healthy controls. In vitro induced thrombin generation was found to be increased in platelet-rich plasma from diabetes patients compared to healthy controls and a significant elevation of thrombin levels was also demonstrated in plasma from poorly controlled DM2 when compared to well controlled

patients.5

12 13

In a placebo controlled trial using troglitazone combined with

diet modification a significant association was shown between improved glycaemic control and blood thrombogenicity as reflected by a reduction in ex-vivo thrombus formation in a Badimon perfusion chamber. Improved glycaemic control was the only significant predictor of a decrease in blood thrombogenicity irrespective of

17

14 15

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treatment allocation.6 In a group of poorly controlled DM2 patients (HbA1c 10%) extraordinarily high concentrations of plasminogen activator inhibitor-1 (PAI-1), indicating hypofibrinolysis, were detected leading the authors to conclude that profound hyperglycaemia is accompanied by profound increases in PAI-1. Subsequent treatment of hyperglycaemia by either glipizide or metformine as monotherapy comparably decreased PAI-1, which argues for an effect of glucose lowering rather than a specific medication effect.7 This state of hypofibrinolysis was recently confirmed in a case-control study; patients with DM2 were found to have a prolonged clot lysis time as well as elevated levels of PAI-1 and von Willebrand factor (vWf).8 The impairment in the fibrinolytic system in DM2 of interest since these impairments are independent primary risk factors for myocardial infarction.9;10 In addition to hypofibronolysis, the levels of prothrombin fragment 1+2 (F1+2) were also found to be associated with the presence of proven cardiovascular disease in DM2 patients.8

Hyperinsulinaemia To disentangle the effects of glucose and insulin in type 2 diabetes, Boden et al studied the effects of acute correction of hyperglycaemia with insulin followed by either 24 hours of experimently induced normo-insulinaemic euglycaemia, 24 hours of euglycaemic hyperinsulinemia or 24 hours of combined hyperinsulinaemia and hyperglycaemia, in DM2 patients as well as healthy controls. They found baseline elevations of tissue factor procoagulant activity (TF-PCA), monocyte TF mRNA and plasma factor VII, factor VIII and thrombin-antithrombin (TAT) complexes in patients with DM2 compared to healthy controls. Normalizing glucose significantly decreased TF-PCA. Increasing insulin levels raised TF-PCA and elevating glucose and insulin levels together resulted in a much larger rise of TF-PCA, which was associated with increases in TAT and F1+2.11 Thus glucose and insulin both seem to play a role in the pathogenesis of the prothrombotic state in type 2 diabetes.

Effect of glucose lowering therapies The effects of improved glycaemic control on PAI-1 levels in DM2 have been demonstrated for different oral antidiabetic therapies, such as metformin alone12 or in combination with pioglitazone or rosiglitazone13 and glimepiride in combination with pioglitazone or rosiglitazone.14 Metformin, which already had proven beneficial cardiovascular effects in the United Kingdom Prospective Diabetes Study trial, also reduced factor VII and fibrinogen levels and shortened clot lysis time.15 When metformin was added to a sulphonylurea derivate in poorly controlled elderly

18


DM2 patients, the resulting substantial improvement in glycaemic control was accompanied by beneficial changes in markers of platelet function (platelet factor 4

1

and beta-thromboglobulin), thrombin generation (fibrinopeptide A, F1+2, and Ddimer) and fibrinolysis (PAI-1 activity and antigen).16 In the Diabetes Prevention Program, which studied the stages preceding diabetes, i.e. impaired glucose tolerance, lifestyle interventions even more than metformin treatment showed a modest, but significant, amelioration in fibrinogen levels.17

2 3

Data on the effects of insulin therapy on coagulation and fibrinolysis markers in DM2 are scarce, and more conflicting than for the oral antidiabetic treatments. Although some authors report beneficial effects of insulin18, others were unable to find improvements with insulin therapy.19;20

4 5

Type 1 Diabetes

6

Markers of fibrinolysis and coagulation In type 1 diabetes (DM1) patients the specific contribution of hyperglycaemia to the prothrombotic state is clearer as they lack the other risk factors which confound the

7

relationship in DM2 patients. In a long term follow up study, a highly significant correlation was found between mean HbA1c in DM1 patients over the course of 18 years and impaired fibrinolysis as represented by elevated PAI-1 and decreased tissue plasminogen activator (t-PA).21 In a smaller setting, eight DM1 patients on continuous subcutaneous insulin infusion therapy were withheld treatment for the

8 9

duration of four hours which caused a rise of PAI-1 and plasma TF. Although the authors conclude that early ketogenesis causes a prothrombotic change in DM1 patients, the effects of acute hyperglycaemia in this setting cannot be excluded.22 Platelet function tests, including aggregation and platelet adhesion tests, did not improve with intensive glycaemic control in DM1. However, platelet function tests

10 11

are notoriously variable and the authors may not have included a sufficient number of patients to overcome this disadvantage.23 Finally, despite the abundant evidence of fibrinolytic impairment in diabetes, not all markers of fibrinolysis are abnormal. Thrombin-activatable fibrinolysis inhibitor (TAFI) for instance, showed no difference between patients with DM1 and healthy controls24 a finding which was recently confirmed in DM2

12 13

patients.8

14

Diabetes and thrombosis DM2 and, maybe to a lesser extent, DM1 are known for a high risk of developing atherothrombotic events. This is at least partly explained by hyperglycaemia, given

19

15

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the continuous relationship between the development of cardiovascular disease and glycaemic control, also in DM2.25 Moreover, intensive blood glucose control in the early stages of the disease proved effective in lowering the long term incidence of cardiovascular disease in both disease entities.26;27 Recently it has become clear that not only atherothrombotic events are seen more often in patients with diabetes but that venous thromboembolism (VTE) is also more frequent in this patient group. Movahed found an odds ratio (OR) of 1.27 (95% CI 1.19 to 1.35) for the occurrence of pulmonary embolism in DM patients.28 Earlier, Tsai et al also found diabetes to be a risk factor for VTE with a hazard ratio (HR) of 1.46 (95% CI 1.03 to 2.05), even after adjusting for BMI, a known predictor of VTE.29 A recent meta-analysis on cardiovascular risk factors for VTE showed DM to be an independent risk factor with an OR of 1.41 (95%CI 1.12 to 1.77).30 Although the effect of glucose lowering on VTE risk remains to be established, the overrepresentation of both venous as well as atherothrombosis in diabetes is highly suggestive of a prothrombotic effect of its main component, hyperglycaemia, in addition to its more established effects on atherosclerosis. ACUTE HYPERGLYCAEMIA Apart from chronic hyperglycaemia, it is important to consider the role of acute hyperglycaemia. Frequently, this is transient hyperglycaemia resulting from metabolic deterioration during (severe) illness.31 Although this may result from pre-existing and undiagnosed diabetes, 30-40% of patients with „stresshyperglycaemia‰ will revert to normoglycaemia with follow-up.32;33 Transient hyperglycaemia will usually be accompanied by transient hyperinsulinaemia.

Markers of fibrinolysis and coagulation The effect of hyperglycaemia and hyperinsulinaemia on the coagulation system in subjects without diabetes has been studied rather extensively. Already in 1988, Ceriello showed that experimentally increased glucose levels activated the coagulation system in non-diabetic subjects by increasing factor VII.34 Stegenga and co-workers demonstrated in healthy volunteers that hyperglycaemia (12 mmol/l), irrespective of insulin levels, activates coagulation, marked by an increase in TAT complexes and soluble tissue factor (sTF).35 In contrast, hyperinsulinaemia inhibited fibrinolysis by increasing PAI-1 levels. This was even more profound when systemic inflammation was induced.36 In vitro, studies with endothelial cells from pig aortas exposed to increasing glucose concentrations indicated that PAI-1

20


secretion and synthesis increased in parallel to glucose levels. Activation of the tissue factor pathway following induction of hyperglycaemia in healthy volunteers

1

was also observed in by Rao and colleagues.37 In a subsequent study, 29 healthy volunteers were exposed to combinations of euglycaemia or hyperglycaemia with normoinsulinaemia

or

hyperinsulinaemia.38

They

found

that

selective

hyperglycaemia and hyperinsulinaemia activated the coagulation system, but the combination of both showed the largest increase in sTF procoagulant activity, TF

2 3

expression on monocytes and TF mRNA in monocytes, TAT, factor VII, factor VIII and platelet activation, measured by platelet expression of soluble CD40 ligand. Finally, Nieuwdorp and co-workers discovered that hyperglycaemia in healthy volunteers concomitantly reduced the protective glycocalyx of the endothelium and the function of the endothelium itself and increased prothrombin fragment 1+2 and

4 5

D-dimer levels.39

6

Acute hyperglycaemia and coagulation in the ICU Two studies have attempted to elucidate the role of the coagulation system in relation to strict glycaemic control. In the first Leuven trial, van den Berghe

7

successfully implemented strict glycaemic control in the ICU, showing a clear mortality benefit.3 She published a subanalysis, investigating the effect of strict glucose control on coagulation and fibrinolysis.40 Although a variety of parameters was assessed, no differences were found between the intensively treated group and the control group. However, samples were obtained only at 5 and 10 days after

8 9

admission and an acute effect within the first 5 days could have been missed. Savioli and coworkers investigated the effect of strict glucose control on coagulation and fibrinolysis in patients with septic shock on admission and up to 28 days after admission.41 They found that strict glucose control reduced the impairment of the fibrinolytic system, as measured by PAI-1. However, strict glucose control in the

10 11

ICU is now being heavily debated because of the recently published NICE-SUGAR trial, which showed increased mortality in the intervention group.42

12

Acute hyperglycaemia and thrombosis Several thrombotic conditions are associated with acute hyperglycaemia, most

13

importantly myocardial infarction (MI), stroke and venous thromboembolism (VTE). During MI, admission hyperglycaemia predicts morbidity and mortality in patients without previously diagnosed diabetes.43-47 Furthermore, elevated admission glucose levels are directly related to the infarct size and reductions in coronary flow

21

14 15

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after stent implantation in non-diabetic patients.48;49 This might be related to intravascular thrombotic events. Patients with acute coronary syndrome and admission glucose >7.0 mmol/l had elevated values of thrombin-antithrombin complexes and platelets activation, measured by soluble CD40 ligand levels, as compared to patients admitted with glucose 11.1 mmol/l) is associated with an OR of 3.2 for pulmonary embolism after orthopaedic surgery.59 However, this might reflect undiagnosed and uncontrolled diabetes. Recently, we published data on glucose levels at presentation for suspected VTE and showed that higher glucose levels at presentation are associated with actually having VTE, in a clear doseresponse fashion.60 During hip surgery, glucose levels rise in patients without diabetes and this precedes a rise in factor VIII, vWF and F1+261, but whether this is a causal relation needs further investigation. Unfortunately, clinical trials in patients with MI and stroke have not been able to reach their targets and trials aiming to prevent VTE are awaited. After proven beneficial in patients with DM in the DIGAMI study, the value of glucose-insulinpotassium (GIK) infusion on outcome after MI in patients without diabetes was investigated, but no significant contrast in glucose control between the intervention and control groups was achieved,62-65 The GIST-UK trial randomised stroke patients to GIK infusion or saline infusion to investigate the effect of glucose modulation with GIK. In this trial no clinical benefit was observed, however the trial was underpowered and the glucose lowering effect of GIK was small and patients were treated for only 24 hours.66

22


POSSIBLE MECHANISMS

1

Many theories on how hyperglycaemia leads to hypercoagulability have already been proposed and studied.67 First, on a cellular level, hyperglycaemia and also hyperinsulinaemia increases the expression of PAI-1 on vascular smooth muscle cells in vitro, thereby increasing its concentration and activity. As a result, the activity of t-PA is reduced thereby decreasing the fibrinolytic potential.68 The

2 3

authors suggested that a direct effect of glucose and insulin on gene transcription could be responsible. Indeed, hyperglycaemia in the presence of insulin increases the activity of transcription factor nuclear factor kappa-B (NF-kB) in human hepatocyte cells and the gene transcription of PAI-1 in vitro, which suggests that PAI-1 transcription is increased via NF-kB.69 Because this effect disappeared when

4 5

an antioxidant was added to the medium, hyperglycaemia-induced oxidative stress was hypothesised to be the major activator of NF-kB. Khechai and coworkers studied the effect of advanced glycation end products (AGE) on TF expression in human monocytes and concluded this AGE-induced TF expression at the mRNA level, which could be diminished by adding antioxidants. The effect of AGEs on

6 7

coagulation activation was also seen when human umbilical vein endothelial cells were exposed to AGEs70 and AGEs dose-dependently increased procoagulant activity and TF levels. Withholding insulin in patients with DM1 increased TF and PAI-1 levels, which was accompanied by a rise in malondialdehyde (MDA) and protein carbonyl groups (PCG), both markers of oxidative stress.22

8 9

Next, hyperglycaemia directly influences the vulnerability of the vascular endothelium by affecting the glycocalyx, a protective layer of proteoglycans covering the vessel wall. This results in enhanced platelet-endothelial cell adhesion and release of coagulation factors harboured within the endothelial glycocalyx.71 Finally, hyperglycaemia exerts its effects also extracellular by direct glycation of

10 11

proteins involved in coagulation. Verkleij et al. showed that glycated TAFI looses its fibrinolytic properties in vitro, although this could not be reproduced in vivo.8 Fibrin clots from patients with diabetes type 2 are more dense as compared to controls and displayed an altered structure, resulting in longer clot lysis time.72 In

vivo glycaemic control was directly correlated to the clot density from the patients. A likely explanation for this is the possible non-enzymatic glycation of

fibrin.73

12 13

It is

conceivable that other coagulation proteins are also glycated, altering their activity. Thus, multiple complex pathways are likely to be involved in the induction of hypercoagulability by hyperglycaemia, and its effect is more profound in combination with hyperinsulinaemia.

23

14 15

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SUMMARY In

summary,

the

evidence

is

compelling

that

both

chronic

and

acute

hyperglycaemia contribute to coagulation activation and hypofibrinolysis, resulting in a procoagulant state that predisposes patients to thrombotic events (Figure 1). What is more, hyperglycaemia is often accompanied by hyperinsulinaemia and their combined effects may result in an even stronger hypercoagulable state. Although we separately discussed the effects of chronic and acute hyperglycaemia on coagulation, the current evidence gives no reason to assume that the underlying mechanisms differ. Intensive glycaemic control in patients with diabetes reduces the incidence of thrombotic diseases such as myocardial infarction and stroke in the long run. Whether intensive glucose control during acute hyperglycaemia during acute MI, stroke and VTE could prevent hypercoagulability and thereby improve outcome awaits further investigation in randomised controlled trials.

24


1 2 3 4 5 6 7 8 9 Figure 1- A simplified impression of the relations between hyperglycaemia, hyperinsulinaemia and coagulation, leading to clinical outcome.

10 11 12 13 14 15 25

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REFERENCES

26

(1)


(2)

Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med 2007; 262(2):157172.

(3)


(4)

Nieuwdorp M, Stroes ES, Meijers JC, Buller H. Hypercoagulability in the metabolic syndrome. Curr Opin Pharmacol 2005; 5(2):155-159.

(5)

Aoki I, Shimoyama K, Aoki N, Homori M, Yanagisawa A, Nakahara K et al. Plateletdependent thrombin generation in patients with diabetes mellitus: effects of glycemic control on coagulability in diabetes. J Am Coll Cardiol 1996; 27(3):560-566.

(6)

Osende JI, Badimon JJ, Fuster V, Herson P, Rabito P, Vidhun R et al. Blood thrombogenicity in type 2 diabetes mellitus patients is associated with glycemic control. J Am Coll Cardiol 2001; 38(5):1307-1312.

(7)

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14

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Kosiborod M, Rathore SS, Inzucchi SE, Masoudi FA, Wang Y, Havranek EP et al. Admission Glucose and Mortality in Elderly Patients Hospitalized With Acute Myocardial Infarction: Implications for Patients With and Without Recognized Diabetes. Circulation 2005; 111(23):3078-3086.

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Kosiborod M, Inzucchi SE, Krumholz HM, Masoudi FA, Goyal A, Xiao L et al. Glucose Normalization and Outcomes in Patients With Acute Myocardial Infarction. Arch Intern Med 2009; 169(5):438-446.

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Undas A, Wiek I, Stepien E, Zmudka K, Tracz W. Hyperglycemia Is Associated With Enhanced Thrombin Formation, Platelet Activation, and Fibrin Clot Resistance to Lysis in Patients With Acute Coronary Syndrome. Diabetes Care 2008; 31(8):1590-1595.

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Minatoguchi SM, Zhang ZM, Bao NM, Kobayashi HM, Yasuda SM, Iwasa MM et al. Acarbose Reduces Myocardial Infarct Size by Preventing Postprandial Hyperglycemia and Hydroxyl Radical Production and Opening Mitochondrial KATP Channels in Rabbits. Journal of Cardiovascular Pharmacology 2009; 54(1):25-30.

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Fuentes B, Castillo J, San JB, Leira R, Serena J, Vivancos J et al. The prognostic value of capillary glucose levels in acute stroke: the GLycemia in Acute Stroke (GLIAS) study. Stroke 2009; 40(2):562-568.

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Parsons MW, Barber PA, Desmond PM, Baird TA, Darby DG, Byrnes G et al. Acute hyperglycemia adversely affects stroke outcome: a magnetic resonance imaging and spectroscopy study. Ann Neurol 2002; 52(1):20-28.

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Bruno A, Levine SR, Frankel MR, Brott TG, Lin Y, Tilley BC et al. Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology 2002; 59(5):669674.

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Poppe AY, Majumdar SR, Jeerakathil T, Ghali W, Buchan AM, Hill MD. Admission hyperglycemia predicts a worse outcome in stroke patients treated with intravenous thrombolysis. Diabetes Care 2009; 32(4):617-622.

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Ribo M, Molina C, Montaner J, Rubiera M, gado-Mederos R, Arenillas JF et al. Acute hyperglycemia state is associated with lower tPA-induced recanalization rates in stroke patients. Stroke 2005; 36(8):1705-1709.

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Mraovic B, Hipszer BR, Epstein RH, Pequignot EC, Parvizi J, Joseph JI. Preadmission Hyperglycemia is an Independent Risk Factor for In-Hospital Symptomatic Pulmonary Embolism After Major Orthopedic Surgery. J Arthroplasty 2008.

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van der Horst I, Zijlstra F, van 't Hof AW, Doggen CJ, de Boer MJ, Suryapranata H et al. Glucose-insulin-potassium infusion inpatients treated with primary angioplasty for acute myocardial infarction: the glucose-insulin-potassium study: a randomized trial. J Am Coll Cardiol 2003; 42(5):784-791.

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Gray CS, Hildreth AJ, Sandercock PA, O'Connell JE, Johnston DE, Cartlidge NE et al. Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK). Lancet Neurol 2007; 6(5):397-406.

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Ceriello A. Coagulation activation in diabetes mellitus: the role of hyperglycaemia and therapeutic prospects. Diabetologia 1993; 36(11):1119-1125.

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Iwasaki Y, Kambayashi M, Asai M, Yoshida M, Nigawara T, Hashimoto K. High glucose alone, as well as in combination with proinflammatory cytokines, stimulates nuclear factor kappa-B-mediated transcription in hepatocytes in vitro. J Diabetes Complications 2007; 21(1):56-62.

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Min C, Kang E, Yu SH, Shinn SH, Kim YS. Advanced glycation end products induce apoptosis and procoagulant activity in cultured human umbilical vein endothelial cells. Diabetes Res Clin Pract 1999; 46(3):197-202.

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Dunn EJ, Philippou H, Ariens RA, Grant PJ. Molecular mechanisms involved in the resistance of fibrin to clot lysis by plasmin in subjects with type 2 diabetes mellitus. Diabetologia 2006; 49(5):1071-1080.

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Brownlee M, Vlassara H, Cerami A. Nonenzymatic glycosylation reduces the susceptibility of fibrin to degradation by plasmin. Diabetes 1983; 32(7):680-684.

Venous thrombosis is associated with hyperglycaemia at diagnosis: a case-control study

J Hermanides, DM Cohn, JH DeVries, TPW Kamphuisen, R Huijgen, JCM Meijers, JBL Hoekstra and HR Büller

Journal of Thrombosis and Haemostasis 2009 June;7(6):945-9

&KDSWHU ABSTRACT Background Patients with (undiagnosed) diabetes mellitus, impaired glucose tolerance or stress-induced hyperglycaemia may be at greater risk for venous thrombosis and present with relative hyperglycaemia during the thrombotic event. Objectives To assess whether venous thrombosis is associated with hyperglycaemia at diagnosis. Patients/methods We performed a case-control study, derived from a cohort of consecutive patients referred for suspected deep vein thrombosis. Cases were patients with confirmed symptomatic venous thrombosis of the lower extremity. Controls were randomly selected in a 1:2 ratio from individuals in whom this diagnosis was excluded. We measured plasma glucose levels upon presentation to the hospital. Results In total, 188 patients with thrombosis and 370 controls were studied. The glucose cut-off level for the first to fourth quartiles were as follows: first quartile =6.6 mmol/l. When adjusted for body mass index, a known history of diabetes mellitus, age, sex, ethnicity and whether known risk factors for deep vein thrombosis were present, the odds ratios for deep vein thrombosis in the second, third and fourth quartiles of glucose levels compared with the first quartile were 1.59 (95% confidence interval [CI] 0.89 to 2.85), 2.04 (95 % CI 1.15 to 3.62) and 2.21 (95% CI 1.20 to 4.05), respectively, p for trend =0.001. Conclusions Increased glucose levels measured at presentation were associated with venous thrombosis. Experimental evidence supports a potential causal role for hyperglycaemia in this process. As this is the first report on the association between (stress) hyperglycaemia and venous thrombosis, confirmation in other studies is required.

32

9HQRXVWKURPERVLVLVDVVRFLDWHGZLWKK\SHUJO\FDHPLDDWGLDJQRVLV INTRODUCTION Venous thromboembolism (VTE) is a common disease with an annual incidence of 2-3 per 1000 inhabitants.1 Both acquired and inherited risk factors are known to play a role in the development of thrombosis.2 Nevertheless, in approximately 25%

1 2

of patients with VTE neither an acquired nor an inherited risk factor can be demonstrated.3;4 Evidence is growing that classic risk factors for arterial disease are also involved in the development of VTE.5;6 Hyperglycaemia is associated with arterial thrombosis7-9 and, indeed, patients with diabetes mellitus or the metabolic syndrome also have an increased risk of VTE.10-12 This increased risk of VTE can in

3 4

part be explained by the platelet activation and hypercoagulability present in diabetes mellitus.13 Activation of the coagulation system has also been observed in acute experimentally induced hyperglycaemia in healthy male volunteers.14 During acute illness such as myocardial infarction, a phenomenon called stress hyperglycaemia may occur independently of the presence of known diabetes.

5 6

As hyperglycaemia stimulates coagulation, we hypothesised that higher glucose levels -independent of known diabetes mellitus- would be more common in patients

7

presenting with acute VTE.

8

METHODS A case-control study was performed. Cases and controls were selected from the

9

Amsterdam Case-Control Study on Thrombosis, which was initiated in 1999 to identify new risk factors for deep vein thrombosis (DVT). All consecutive outpatients older than 18 years referred to the Academic Medical Centre in

10

Amsterdam between September 1999 and August 2006 with clinically suspected DVT of the lower extremity were eligible for this study. The study protocol was

11

approved by the Medical Ethics Review Committee and all participants provided written informed consent. At presentation, the patientÊs medical history was obtained through a standardised questionnaire including specific questions about

12

symptom duration, presence of known risk factors (concomitant malignancy, pregnancy, use of hormonal replacement therapy, oral contraceptives or selective

13

oestrogen receptor modulators, recent trauma (within last 60 days), being bedridden for >3 days, uncommon travel (>6hrs) within the last 3 months, paralysis of the symptomatic leg, or surgery within the last 4 weeks), concomitant diseases

14

and medication use. In addition, body mass index (BMI) was calculated. Cases were patients with thrombosis of the lower extremity confirmed by compression

33

15

&KDSWHU ultrasonography, including proximal DVT (i.e. proximal thrombosis of the iliac or superficial femoral vein, calf vein thrombosis, involving at least the upper third part of the deep calf veins), symptomatic calf vein thrombosis, and superficial thrombophlebitis. The diagnosis was confirmed following a diagnostic management strategy, based on the WellsÊ criteria15 and a Tinaquant D-dimer assay (Roche Diagnostics, Basel, Switzerland), followed by compression ultrasound if indicated as validated and described previously.16 Controls were selected in a 1:2 ratio from those individuals in whom thrombosis was ruled out using the above mentioned strategy. Selection was performed randomly, only taking into account the male/female ratio of the cases. Sample storage and laboratory analysis On admission and prior to diagnostic testing, blood samples were drawn and collected in tubes containing 0.109 mmol/l trisodium citrate. Within one hour after collection, platelet poor plasma was obtained by centrifugation twice for 20 min at 1600 x g and 4°C. The plasma was stored in 2 ml cryovials containing 0.5 ml of plasma at -80° C. Glucose was measured using the HK/G-6PD method (Roche/Hitachi, Basel, Switzerland) and corrected for the 10% dilution with sodium citrate. To assess whether elevated glucose levels were related to an acute phase response induced by the thrombotic event itself, we analysed C-reactive protein (CRP) levels from 20 cases and 20 controls, randomly selected from each quartile, giving a total of 160 patients. Statistical analysis Results are presented as mean standard deviation or median with interquartile range (IQR), depending on the observed distribution. The primary objective of this study was to assess the relationship between glucose levels at presentation and VTE, which was expressed as odds ratios (ORs), with 95% confidence intervals. Glucose levels of the controls were divided into quartiles, as glucose levels are typically non-normally distributed. Subsequently, the cases were assigned to these quartiles according to their admission glucose values. Binary logistic regression was used. The regression model was created on the basis of clinically relevant potential confounders (BMI, concomitant known diabetes mellitus, sex, ethnicity, age at diagnosis, and whether known risk factors for VTE were present). Furthermore, ORs were calculated for cases in which the diagnosis of thrombosis was restricted to DVT only, excluding calf vein thrombosis and superficial

34

9HQRXVWKURPERVLVLVDVVRFLDWHGZLWKK\SHUJO\FDHPLDDWGLDJQRVLV thrombophlebitis. To assess the correlation between glucose levels and CRP levels a scatter plot was performed and the correlation (expressed in r) coefficient was

1

calculated. All statistical analyses were performed in SPSS version 15.0 (SPSS Inc., Chigaco, IL, USA).

2

RESULTS

3

In total 188 patients with confirmed thrombosis and 370 controls were included in this study, as blood samples were not available for two cases and 10 controls. The baseline characteristics of the two study groups are shown in Table 1. Mean age and gender distribution were comparable. The control group consisted of a smaller proportion of white patients and a greater proportion of black patients as compared

4 5

with the cases. The mean BMI was higher in the control group, as tended to be the number of patients with known diabetes mellitus. Median glucose levels were 5.9 mmol/l (IQR 5.3 to 6.6) in patients with thrombosis, and 5.6 mmol/l (IQR 5.2 to 6.6) in the controls. In thrombosis patients, 38% had one or more acquired risk factors and the distribution of thrombosis was as follows: 82% had DVT, 6% had calf vein

6 7

thrombosis, and the remaining 12% had superficial thrombophlebitis. The cut-off glucose levels were as follows: first quartile =6.6 mmol/l (n=144) (Table 2). After adjustment for BMI, concomitant known diabetes mellitus, sex, ethnicity, age

8 9

at diagnosis, and whether known risk factors for VTE were present, the ORs for thrombosis in the second, third and fourth quartiles of glucose levels as compared with the first quartile were 1.40 (95% CI 0.82 to 2.85), 1.69 (95 % CI 1.00 to 2.87) and 1.94 (95% CI 1.12 to 3.39), respectively; p for trend =0.01. The same trend of an increasing OR could be observed when adjusting only for BMI, age, sex and known

10 11

diabetes mellitus. As most risk factors predominantly relate to DVT a separate analysis was planned for DVT only, thus excluding patients with superficial thrombophlebitis or calf vein thrombosis, leaving 154 cases and 370 controls. Here also, the OR increases with glucose levels: 1.59 (95% CI 0.89 to 2.85), 2.04 (95% CI 1.15 to 3.62) and 2.21 (95% CI 1.20 to 4.05) for the second, third and fourth quartile

12 13

of glucose levels, respectively (see Table 2, p for trend =0.001). Finally, the Spearman rank correlation coefficient for CRP and plasma glucose was 0.09, with a

p-value of 0.27.

14 15

35

36 Controls (n=370) 56±16 58.1 69.2 18.1 4.2 8.5 27.2 (24.2 to 31.3) 10.0 5.6 (5.2 to 6.6)

Cases (n=188) 57±17 57.4

78.7 10.1 2.7 8.5 26.6 (23.9 to 29.1) 3.7 5.9 (5.3 to 6.6)

46 52 51

88 87 93

102

Controls reference 1.40 (0.82 to 2.38) 1.69 (1.00 to 2.87) 1.94 (1.12 to 3.39) p for trend = 0.01

p for trend = 0.14

Adjusted OR* (95% CI)

reference 1.37 (0.82 to 2.28) 1.56 (0.94 to 2.59) 1.43 (0.87 to 2.37)

Crude OR (95% CI) 37 46 43

28

Cases†

88 87 93

102

Controls†

* adjusted for BMI, known diabetes mellitus, sex, age, ethnicity and known risk factors †analyses for deep venous thrombosis only ††analyses for deep venous thrombosis only, adjusted for BMI, diabetes mellitus, sex, age, ethnicity and known risk factors CI=confidence interval

39

2nd : 5.3 to 5.7 3rd : 5.7 to 6.6 4th : 6.6

Cases

1st : < 5.3

Quartile (glucose mmol/l)

Table 2- odds ratios (ORs) for venous thromboembolism.

Known risk factors: concomitant malignancy, pregnancy, use of hormonal replacement therapy, oral contraceptives or selective estrogen receptor modulators, recent trauma (within last 60 days), bedridden > 3 days, uncommon travel (> 6hrs) within the last 3 months, paralysis of the symptomatic leg, or surgery within the last 4 weeks

Age, years (mean ±SD) Female (%) Ethnicity (%) White Black Asian/Pacific islander Other BMI kg/m² (median, IQR) Diabetes type 1 or 2 (%) Glucose mmol/l (median, IQR)

Table 1- baseline characteristics of the two study groups

p for trend = 0.05


Crude OR† (95% CI)

p for trend = 0.001


Adjusted OR†† (95% CI)

&KDSWHU

9HQRXVWKURPERVLVLVDVVRFLDWHGZLWKK\SHUJO\FDHPLDDWGLDJQRVLV DISCUSSION

1

In this case-control study, increased glucose levels measured at the time of presentation were associated with venous thrombosis. This could be a relevant clinical concept as the general population is becoming increasingly glucose intolerant. The relationship between glucose and DVT was not readily explained by an acute phase reaction due to the thrombotic event itself.

2 3

Whereas our results indicate that increased glucose levels and VTE coincide, it is impossible with the current design to demonstrate a causal relationship. However, a causal relationship seems plausible. To assess this one can apply the diagnostic criteria for causation.17 A causal relationship is supported by the available biological evidence from experiments in humans. Stegenga et al. showed that

4 5

experimentally induced acute hyperglycaemia activates the coagulation system in healthy volunteers.14 From a pathophysiologic point of view, hyperglycaemia is known to induce coagulation activation through glycocalyx damage18, up regulation of tissue factor19;20, non-enzymatic glycation and the development of increased oxidative stress.21 Long term exposure to hyperglycaemia such as occurs in diabetes mellitus, is a known risk factor for

VTE.22

6 7

In addition, the effect of

hyperglycaemia on coagulation seems to be modifiable in diabetes patients, as treating hyperglycaemia among these patients led to down regulation of coagulation activation in several randomised controlled trials.23;24 Furthermore, our results are in line with the findings by Mraovic et al. who demonstrated that

8 9

hyperglycaemia increases the risk of pulmonary embolism after major orthopaedic surgery.25 Thus, direct and indirect evidence supports a possible association for acute and chronic hyperglycaemia in the development of VTE. Furthermore, the association is consistent from this study to other studies, which is in line with the criterion for repetitive demonstration of causality.

10 11

In this study, an adjusted OR of 2.21 (95 % CI 1.20 to 4.05) for DVT was observed in the highest quartile which suggests a strong relationship. In comparison, the OR for the well established risk factor for VTE, the prothrombin 20210A mutation is 2.8 (95% CI 1.4 to 5.6).26 The OR for venous thrombosis increases with increasing glucose levels, from 1.40 (95% CI 0.82 to 2.38) in the second quartile to 1.69 (95%

12 13

1.00 to 2.87) in the third quartile and 1.94 (95 % CI 1.12 to 3.39) in the fourth quartile. We tested for differences in ORs among the quartiles of glucose levels and found a significant linear trend (p=0.01). This is in concordance with a doseresponse gradient, another criterion for causality.

14 15

37

&KDSWHU The question arises of whether elevated glucose levels during a VTE result from the inflammatory and counter regulatory hormone action initiated by the VTE event itself, or whether hyperglycaemia preceded the VTE event. Although a significant proportion of the patients with hyperglycaemia during an episode of VTE will have an undisturbed glucose tolerance at follow-up27,

undiagnosed impaired glucose

tolerance is likely to have been present in a proportion of patients before the VTE event itself, and may therefore have contributed to the development of thrombosis. We therefore suspect a temporal relationship. In addition, no correlation was found between the acute phase reaction, measured by CRP, and glucose levels. The presence of stress hyperglycaemia during a thrombotic event, independent of its cause, could be relevant: it has been shown to have evident clinical consequences in patients with myocardial infarction and patients admitted to the intensive care unit (especially without known diabetes mellitus)28;29, although results from recent intervention trials have been disappointing.30;31 Interestingly, we found a greater proportion of patients with diabetes in the control group than in the case group. In fact, this higher rate can be caused by referral bias. Patients with diabetes are usually under chronic medical care and are prone to leg- and foot problems that can resemble DVT, such as erysipelas. Thus, they are more easily referred for suspicion of DVT. We had no information on the use of anti-diabetic drugs. Differences in the distribution of diabetes treatment in both cases and controls could be a source of bias. However, we believe this effect to be limited. The model was adjusted for diabetes mellitus as a potential confounder. Our study has several limitations. First, the control group consisted of patients with complaints of their legs instead of healthy controls. Consequently, it may be possible that glucose levels were increased in the controls because of an underlying disease such as infection. However, this would have led to an underestimation of the association between glucose and DVT. Second, the glucose levels were measured on admission, and it was unknown whether these were fasting or nonfasting samples. However, owing to the study design there were no differences between cases and controls with respect to the time of presentation and larger dispersion of glucose levels would therefore have affected cases as much as controls. Third, citrated plasma is not the plasma of choice for determining glucose and CRP levels, because of the dilution with sodium citrate. Also, sodium citrate does not inhibit ex vivo glycolysis. However, we corrected glucose levels for the dilution and the obtained blood samples were centrifuged and stored within one hour thereby minimizing glycolysis. Again, as blood samples of both cases and controls were obtained and processed in the same manner, the results for glucose levels were

38

9HQRXVWKURPERVLVLVDVVRFLDWHGZLWKK\SHUJO\FDHPLDDWGLDJQRVLV affected equally. Because this is the first report on the association between stress hyperglycaemia and VTE, confirmation in other studies is required.

1

In conclusion, our findings suggest that higher glucose levels are a risk factor for the development of venous thrombosis. It will therefore be of importance to analyse whether disturbed glucose homeostasis persists after the acute phase of venous thrombosis.

2 3

ACKNOWLEDGEMENTS We would like to acknowledge M.M. Levi for assessing the manuscript and for his significant intellectual contribution. In addition we would like to acknowledge the „vasculists‰, a group of medical students responsible for execution of this study,

4 5

ranging from design of the study to recruitment and data collection.

6 7 8 9 10 11 12 13 14 15 39

&KDSWHU REFERENCES

40

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Cushman M, Kuller LH, Prentice R, Rodabough RJ, Psaty BM, Stafford RS et al. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004; 292(13):1573-1580.

(2)

Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353(9159):11671173.

(3)

Lensing AW, Prandoni P, Prins MH, Büller HR. Deep-vein thrombosis. Lancet 1999; 353(9151):479-485.

(4)

Spencer FA, Emery C, Lessard D, Anderson F, Emani S, Aragam J et al. The Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism. J Gen Intern Med 2006; 21(7):722-727.

(5)

Eliasson A, Bergqvist D, Bjorck M, Acosta S, Sternby NH, Ogren M. Incidence and risk of venous thromboembolism in patients with verified arterial thrombosis: a population study based on 23,796 consecutive autopsies. J Thromb Haemost 2006; 4(9):1897-1902.

(6)

Sorensen HT, Horvath-Puho E, Pedersen L, Baron JA, Prandoni P. Venous thromboembolism and subsequent hospitalisation due to acute arterial cardiovascular events: a 20-year cohort study. Lancet 2007; 370(9601):1773-1779.

(7)

Bruno A, Levine SR, Frankel MR, Brott TG, Lin Y, Tilley BC et al. Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology 2002; 59(5):669674.

(8)

Laakso M. Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes 1999; 48(5):937-942.

(9)

Malmberg K, Ryden L, Hamsten A, Herlitz J, Waldenstrom A, Wedel H. Effects of insulin treatment on cause-specific one-year mortality and morbidity in diabetic patients with acute myocardial infarction. DIGAMI Study Group. Diabetes Insulin-Glucose in Acute Myocardial Infarction. Eur Heart J 1996; 17(9):1337-1344.

(10)

Ay C, Tengler T, Vormittag R, Simanek R, Dorda W, Vukovich T et al. Venous thromboembolism a manifestation of the metabolic syndrome. Haematologica 2007; 92(3):374-380.

(11)

Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005; 112(17):27352752.

(12)

Petrauskiene V, Falk M, Waernbaum I, Norberg M, Eriksson JW. The risk of venous thromboembolism is markedly elevated in patients with diabetes. Diabetologia 2005; 48(5):1017-1021.

(13)

Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med 2007; 262(2):157172.

(14)

Stegenga ME, van der Crabben SN, Levi M, de Vos AF, Tanck MW, Sauerwein HP et al. Hyperglycemia stimulates coagulation, whereas hyperinsulinemia impairs fibrinolysis in healthy humans. Diabetes 2006; 55(6):1807-1812.

(15)

Wells PS, Anderson DR, Bormanis J, Guy F, Mitchell M, Gray L et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. The Lancet 350(9094):1795-1798.

(16)

Kraaijenhagen RA, Piovella F, Bernardi E, Verlato F, Beckers EA, Koopman MM et al. Simplification of the diagnostic management of suspected deep vein thrombosis. Arch Intern Med 2002; 162(8):907-911.

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How to read clinical journals: IV. To determine etiology or causation. Can Med Assoc J 1981; 124(8):985-990.

9HQRXVWKURPERVLVLVDVVRFLDWHGZLWKK\SHUJO\FDHPLDDWGLDJQRVLV (18)

Nieuwdorp M, van Haeften TW, Gouverneur MC, Mooij HL, van Lieshout MH, Levi M et al. Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo. Diabetes 2006; 55(2):480-486.

(19)

Khechai F, Ollivier V, Bridey F, Amar M, Hakim J, de PD. Effect of advanced glycation end product-modified albumin on tissue factor expression by monocytes. Role of oxidant stress and protein tyrosine kinase activation. Arterioscler Thromb Vasc Biol 1997; 17(11):2885-2890.

(20)

Min C, Kang E, Yu SH, Shinn SH, Kim YS. Advanced glycation end products induce apoptosis and procoagulant activity in cultured human umbilical vein endothelial cells. Diabetes Res Clin Pract 1999; 46(3):197-202.

1 2 3

(21)

Ceriello A. Coagulation activation in diabetes mellitus: the role of hyperglycaemia and therapeutic prospects. Diabetologia 1993; 36(11):1119-1125.

(22)

Ageno W, Becattini C, Brighton T, Selby R, Kamphuisen PW. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation 2008; 117(1):93-102.

(23)

Caballero AE, Delgado A, guilar-Salinas CA, Herrera AN, Castillo JL, Cabrera T et al. The Differential Effects of Metformin on Markers of Endothelial Activation and Inflammation in Subjects with Impaired Glucose Tolerance: A Placebo-Controlled, Randomized Clinical Trial. J Clin Endocrinol Metab 2004; 89(8):3943-3948.

(24)

De Jager J, Kooy A, Lehert P, Bets D, Wulffele MG, Teerlink T et al. Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med 2005; 257(1):100-109.

6

(25)


7

(26)

Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3'untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88(10):3698-3703.

8

(27)

Ishihara M, Inoue I, Kawagoe T, Shimatani Y, Kurisu S, Hata T et al. Is admission hyperglycaemia in non-diabetic patients with acute myocardial infarction a surrogate for previously undiagnosed abnormal glucose tolerance? Eur Heart J 2006; 27(20):2413-2419.

9

(28)

Ishihara M, Kojima S, Sakamoto T, Asada Y, Tei C, Kimura K et al. Acute hyperglycemia is associated with adverse outcome after acute myocardial infarction in the coronary intervention era. Am Heart J 2005; 150(4):814-820.

(29)

Whitcomb BW, Pradhan EK, Pittas AG, Roghmann MC, Perencevich EN. Impact of admission hyperglycemia on hospital mortality in various intensive care unit populations. Crit Care Med 2005; 33(12):2772-2777.

(30)


(31)

Mehta SR, Yusuf S, Diaz R, Zhu J, Pais P, Xavier D et al. Effect of glucose-insulinpotassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA randomized controlled trial. JAMA 2005; 293(4):437-446.

4 5

10 11 12 13 14 15

41

Hip surgery sequentially induces stress hyperglycaemia and activates coagulation

J Hermanides, R Huijgen, CP Henny, N Haj Mohammad, JBL Hoekstra, MM Levi and JH DeVries

The Netherlands Journal of Medicine, 2009 June;67(6):226-9

&KDSWHU

ABSTRACT Background A frequent complication of orthopaedic procedures is venous thromboembolism (VTE). Hyperglycaemia has been shown to activate the coagulation system and is associated with postoperative morbidity and mortality. Therefore we hypothesised that glucose levels increase during orthopaedic surgery and are associated with an activation of the coagulation system. Methods Nine adult patients undergoing elective hip replacement were included. Venous blood samples were taken before, during and after surgery. Plasma glucose levels, factor VIII clotting activity (fVIII:c), von Willebrand ristocetin cofactor activity, von Willebrand factor antigen and prothrombin fragment 1+2 were measured. Results Immediately after induction of anaesthesia, plasma glucose levels started to increase until the second day postoperatively (peak 8.0 mmol/l). After seven weeks glucose values had returned to baseline (6.1 mmol/l), p0.5. The level of significance was p2.2 1661 14 2.8 (1.0 to 7.7) 2.6 (0.9 to 7.3) 1197 64 1.9 (1.3 to 3.0) 1.8 (1.2 to 2.8)

VTE=venous thromboembolism; OR=Odds Ratio, LR test=Likelihood Ratio test for testing whether increase in glucose levels (in quartiles) has a significant influence on the occurrence of VTE. Total VTE is the composite of symptomatic VTE, asymptomatic DVT and all cause mortality. *mmol/l

60

6WUHVVLQGXFHGK\SHUJO\FDHPLD 97(IROORZLQJWRWDOKLSRUNQHHDUWKURSODVW\ Table 3- odds ratio for glucose levels measured at day 0, day 1 and difference in glucose levels between day 1 and day 0 in relation to symptomatic VTE and total VTE in knee surgery patients (RECORD 3&4)

1

a) quartiles glucose levels measured at day 0*

5.5 to 6.4

>6.4

all patients (N) symptomatic VTE (n) crude OR (95%CI) adjusted OR (95%CI) LR test patients valid for the modified intention to treat analyses (N) total VTE (n) crude OR (95%CI) adjusted OR (95%CI) LR test

1216 12 1 (ref) 1 (ref)

1480 18 1.2 (0.6 to 2.6) 1.2 (0.6 to 2.5)

1417 19 1.4 (0.7 to 2.8) 1.5 (0.7 to 3.1)

813 72 1 (ref) 1 (ref)

996 115 1.3 (1.0 to 1.8) 1.2 (0.9 to 1.7)

1320 11 0.8 (0.4 to 1.9) 0.8 (0.4 to 1.9) p=0.46 878 93 1.2 (0.9 to 1.7) 1.1 (0.8 to 1.5) p=0.14

b) quartiles glucose levels measured at day 1*

6.8 to 8.3

>8.3


1476 10 1 (ref) 1 (ref)

1300 22 2.5 (1.2 to 5.3) 2.6 (1.2 to 5.6)

1281 14 1.6 (0.7 to 3.7) 1.8 (0.8 to 4.1)

1005 103 1 (ref) 1 (ref)

876 93 1.0 (0.8 to 1.4) 1.1 (0.8 to 1.4)

1266 12 1.4 (0.6 to 3.3) 1.5 (0.6 to 3.4) p=0.07 846 99 1.2 (0.9 to 1.6) 1.2 (0.9 to 1.6) p=0.37

c) quartiles difference in glucose levels day 1 - day 0*

-0.2

>-0.2 to 1.1

>1.1 to 2.6

>2.6


1331 13 1 (ref) 1 (ref)

1304 21 1.7 (0.8 to 3.3) 1.6 (0.8 to 3.3)

1290 10 0.8 (0.3 to 1.8) 0.8 (0.3 to 1.8)

887 100 1 (ref) 1 (ref)

899 100 1.0 (0.7 to 1.3) 1.0 (0.8 to 1.4)

1347 13 1.0 (0.5 to 2.1) 1.0 (0.5 to 2.2) p=0.26 902 102 1.0 (0.7 to 1.3) 1.1 (0.8 to 1.4) p=0.98

903 124 1.6 (1.2 to 2.2) 1.4 (1.0 to 2.0)

831 107 1.3 (1.0 to 1.7) 1.3 (1.0 to 1.8)

840 95 1.0 (0.7 to 1.4) 1.1 (0.8 to 1.4)

VTE=venous thromboembolism; OR=Odds Ratio, LR test=Likelihood Ratio test for testing whether increase in glucose levels (in quartiles) has a significant influence on the occurrence of VTE. Total VTE is the composite of symptomatic VTE, asymptomatic DVT and all cause mortality.

2 3 4 5 6 7 8 9 10 11 12

*mmol/l

13 14 15 61

&KDSWHU

DISCUSSION This study shows an association between stress-induced hyperglycaemia and total VTE in patients undergoing total hip arthroplasty. This was not observed in knee surgical patients, in whom only glucose levels prior to surgery were associated with total VTE. An association between preoperatively elevated glucose levels and VTE in patients undergoing orthopaedic surgery has previously been reported.16 Mraovic and colleagues found that preadmission glucose levels exceeding 11.1 mmol/l independently increased the risk of pulmonary embolism (OR 3.19, 95%CI 1.25 to 8.10) when compared to glucose levels of less than 6.1 mmol/l in patients who underwent hip or knee arthroplasty. We did not find a relation between preoperative hyperglycaemia and VTE in patients undergoing hip surgery. However, 11.1 mmol/l is well above the cut-off value of the highest quartile in the hip surgery cohort, 8.0 mmol/l, and is likely to reflect patients with undiagnosed diabetes

mellitus

complications.17

before

surgery,

a

known

risk

factor

for

postsurgical

We also assessed the influence of post-surgical stress-induced

glucose increase in relation to the development of VTE to investigate whether stress-hyperglycaemia is an independent risk factor for VTE following orthopaedic surgery. Available pathophysiological evidence supports the relation between (acute) hyperglycaemia and hypercoagulability. In patients with diabetes mellitus, the concentration of several procoagulant factors are increased (fibrinogen, von Willebrand antigen, factor VII antigen, factor VIII) and antifibrinolytic factors are decreased, such as plasminogen activator inhibitor-1 (PAI-1).18 Furthermore, hip surgery has been shown to induce hyperglycaemia, which preceded a rise of factor VIII clotting activity, von Willebrand ristocetin cofactor activity, von Willebrand factor antigen and prothrombin fragment 1+2.7 In healthy volunteers, acute hyperglycaemia activates the coagulation system in an experimental setting.4 In this study, only those patients in the highest quartile of post-surgical stressinduced hyperglycaemia were at increased risk for VTE, instead of a linear increase in risk. This implies that glucose levels apparently need to exceed a certain threshold to reach a significant association with VTE. Interestingly, the cut-off between the third and fourth quartiles in hip surgery patients, 7.9 mmol/l, is close to the classic cut-off for impaired glucose tolerance following the glucose tolerance test, 7.8 mmol/l.19

62

6WUHVVLQGXFHGK\SHUJO\FDHPLD 97(IROORZLQJWRWDOKLSRUNQHHDUWKURSODVW\

Hyperglycaemia was not clearly associated with VTE in patients undergoing total knee replacement as in patients undergoing total hip replacement. This

1

discrepancy cannot be explained by major differences in patients characteristics, as these were included as covariates in the regression model. The most important factor may concern the surgical procedure. Total knee replacement is performed with application of a tourniquet, occluding arterial and venous flow.20 Tourniquet use is related to the formation of thrombi.21-24 It is thus possible that the effect of

2 3

hyperglycaemia is in part outweighed by other risk factors for VTE in patients undergoing total knee arthroplasty. Although preoperative glucose samples were drawn at predefined time points, patients were not mandatory in the fasting state. We have, however, no reason to assume that there was a difference in distribution in fasting/non-fasting samples in

4 5

patients with- or without VTE. Furthermore, this substudy involved a nonprespecified analysis. Nevertheless, we have investigated a prospective database, with a very large sample size. In addition, the most important assessments, VTE and glucose, were collected prospectively and comprehensively. The outcome „total VTE‰ not only included symptomatic VTE and asymptomatic DVT, but also „all

6 7

cause mortality‰. As the number of subjects who died during the treatment phase is very low in the four RECORD studies (n=23/8512, 0.3%), it is not likely that the inclusion of the latter outcome measure affected the results.

8 9

CONCLUSION Stress-induced post-surgical hyperglycaemia is associated total VTE following total hip replacement. Likely due to the surgical procedure, this was not found in patients undergoing total knee arthroplasty. Future studies should assess whether

10 11

the risk of VTE can be decreased by glucose lowering therapy in patients with

12

stress-induced hyperglycaemia.

13 14 15 63

&KDSWHU

REFERENCES

64

(1)

Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrom J. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007; 5(4):692-699.

(2)

Lensing AW, Prandoni P, Prins MH, Büller HR. Deep-vein thrombosis. Lancet 1999; 353(9151):479-485.

(3)

Spencer FA, Emery C, Lessard D, Anderson F, Emani S, Aragam J et al. The Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism. J Gen Intern Med 2006; 21(7):722-727.

(4)

Stegenga ME, van der Crabben SN, Levi M, de Vos AF, Tanck MW, Sauerwein HP et al. Hyperglycemia stimulates coagulation, whereas hyperinsulinemia impairs fibrinolysis in healthy humans. Diabetes 2006; 55(6):1807-1812.

(5)

Stegenga ME, van der Crabben SN, Blumer RM, Levi M, Meijers JC, Serlie MJ et al. Hyperglycemia enhances coagulation and reduces neutrophil degranulation, whereas hyperinsulinemia inhibits fibrinolysis during human endotoxemia. Blood 2008; 112(1):8289.

(6)


(7)

Hermanides J, Huijgen R, Henny CP, Mohammad NH, Hoekstra JB, Levi M et al. Hip surgery sequentially induces stress hyperglycaemia and activates coagulation. Neth J Med 2009; 67(6):226-229.

(8)

Hermanides J, Cohn DM, Devries JH, Kamphuisen PW, Huijgen R, Meijers JC et al. Venous thrombosis is associated with hyperglycemia at diagnosis: a case-control study. J Thromb Haemost 2009; 7(6):945-949.

(9)

Galster H, Kolb G, Kohsytorz A, Seidlmayer C, Paal V. The pre-, peri-, and postsurgical activation of coagulation and the thromboembolic risk for different risk groups. Thromb Res 2000; 100(5):381-388.

(10)

Warwick D, Friedman RJ, Agnelli G, Gil-Garay E, Johnson K, FitzGerald G et al. Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events: findings from the Global Orthopaedic Registry. J Bone Joint Surg Br 2007; 89(6):799-807.

(11)

Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358(26):2765-2775.

(12)

Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008; 372(9632):31-39.

(13)

Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358(26):2776-2786.

(14)

Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373(9676):1673-1680.

(15)

Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg 1972; 104(2):134-144.

(16)


6WUHVVLQGXFHGK\SHUJO\FDHPLD 97(IROORZLQJWRWDOKLSRUNQHHDUWKURSODVW\ (17)

Marchant MH, Jr., Viens NA, Cook C, Vail TP, Bolognesi MP. The impact of glycemic control and diabetes mellitus on perioperative outcomes after total joint arthroplasty. J Bone Joint Surg Am 2009; 91(7):1621-1629.

(18)


(19)

Diagnosis and classification of diabetes mellitus. Diabetes Care 2008; 31 Suppl 1:S55S60.

(20)

Sharrock NE, Go G, Sculco TP, Ranawat CS, Maynard MJ, Harpel PC. Changes in circulatory indices of thrombosis and fibrinolysis during total knee arthroplasty performed under tourniquet. J Arthroplasty 1995; 10(4):523-528.

3

(21)

Parmet JL, Horrow JC, Pharo G, Collins L, Berman AT, Rosenberg H. The incidence of venous emboli during extramedullary guided total knee arthroplasty. Anesth Analg 1995; 81(4):757-762.

4

(22)

Parmet JL, Horrow JC, Berman AT, Miller F, Pharo G, Collins L. The incidence of large venous emboli during total knee arthroplasty without pneumatic tourniquet use. Anesth Analg 1998; 87(2):439-444.

(23)

Westman B, Weidenhielm L, Rooyackers O, Fredriksson K, Wernerman J, Hammarqvist F. Knee replacement surgery as a human clinical model of the effects of ischaemia/reperfusion upon skeletal muscle. Clin Sci (Lond) 2007; 113(7):313-318.

(24)

Carles M, Dellamonica J, Roux J, Lena D, Levraut J, Pittet JF et al. Sevoflurane but not propofol increases interstitial glycolysis metabolites availability during tourniquetinduced ischaemia-reperfusion. Br J Anaesth 2008; 100(1):29-35.

1 2

5 6 7 8 9 10 11 12 13 14 15

65

Early postoperative hyperglycaemia is associated with postoperative complications after pancreatoduodenectomy

WJ Eshuis, J Hermanides, JW van Dalen, G van Samkar, ORC Busch, TM van Gulik, JH DeVries, JBL Hoekstra and DJ Gouma


&KDSWHU

ABSTRACT Background Perioperative hyperglycaemia is associated with complications after various

types

of

surgery.

This

relation

was

never

investigated

for

pancreatoduodenectomy. Aim of this study was to investigate the relation between perioperative hyperglycaemia and complications after pancreatoduodenectomy. Methods

In

a

consecutive

pancreatodoudenectomy,

glucose

series values

of were

330

patients

collected

from

undergoing the

hospital

information system during three periods: pre-, intra- and early postoperative. The average glucose value per period was calculated for each patient and divided in duals according to the median group value. Odds ratios for complications were calculated for the upper versus lower dual, adjusted for age, gender, ASAclassification, BMI, diabetes mellitus, intraoperative blood transfusion, duration of surgery, intraoperative insulin administration and octreotide use. The same procedures were carried out to assess the consequences of increased glucose variability, expressed by the standard deviation. Results Average glucose values were 7.5 (preoperative), 7.4 (intraoperative) and 7.9 mmol/l (early postoperative). Pre- and intraoperative glucose values were not associated with postoperative complications. Early postoperative hyperglycaemia (>7.8 mmol/l) was significantly associated with complications (OR 2.9, 95%CI 1.7 to 4.9). Overall, high glucose variability was not significantly associated with postoperative complications, but early postoperative patients who had both high glucose values and high variability had an OR for complications of 3.6 (95%CI 1.9 to 6.8) compared to the lower glucose dual. Conclusions Early postoperative hyperglycaemia is associated with postoperative complications after pancreatoduodenectomy. High glucose variability may enhance this risk. Future research must demonstrate whether strict glucose control in the early postoperative period prevents complications after pancreatoduodenectomy.

68

(DUO\SRVWRSHUDWLYHK\SHUJO\FDHPLDLVDVVRFLDWHGZLWKFRPSOLFDWLRQVDIWHU3'

INTRODUCTION

1

Although mortality of pancreatoduodenectomy (PD) is well below 5% in high volume centres, complications occur in up to 50% of patients. Most prevalent surgical

complications

include

delayed

gastric

emptying,

leakage

of

pancreaticojejunostomy or hepaticojejunostomy and infectious complications. Complications that are not directly related to surgery are mostly of cardiac, pulmonary or urogenital

2 3

origin.1-4

Numerous studies have been carried out to identify risk factors for the development of complications after PD. Factors reported to be associated with morbidity after PD include high body mass index, diabetes mellitus, high preoperative blood urea nitrogen and low preoperative serum albumin, longer duration of surgery,

4 5

intraoperative blood transfusion and a small, non-dilated main pancreatic duct.5-11 Higher perioperative glucose levels have been shown to be associated with complications after various types of cardiac, general, vascular and orthopaedic surgery.12-18 This effect is generally attributed to an impaired immune response, in combination with an excessive release of stress hormones and inflammatory cytokines resulting in diminished insulin

action.12;15;17

6 7

However, perioperative

hyperglycaemia does not increase postoperative morbidity in all types of surgery: in oesophageal resection no relation was found between early postoperative hyperglycaemia and postoperative complications.19 The relation between perioperative glucose levels and postoperative complications

8 9

after PD has never been investigated. Apart from surgical stress hyperglycaemia, patients undergoing PD might be extra susceptible to disarrangement of glucose levels: pancreatic cancer - the main indication for PD - is associated with progressive hyperglycemia and (new onset) diabetes mellitus in 20% to 30% of patients before diagnosis.20-22 The operation itself involves manipulation and

10 11

resection of pancreatic tissue, and resection of the duodenum, one of the enteric regions where the incretin hormone GIP (glucose-dependent insulinotropic polypeptide) is released, which assists in maintaining glucose homeostasis. Together, this may render patients hyperglycaemic.23;24 Aiming for near-normal glucose levels (4.4 to 6.1 mmol/l) in a surgical intensive care unit (ICU) significantly reduced

mortality.25

12 13

Although subsequent studies on

such strict glucose control has yielded conflicting results in various populations, it seems to reduce mortality and morbidity in surgical ICU patients.26 Because patients undergoing PD are at risk for hyperglycaemia, it seems important to establish whether increased perioperative glucose levels are associated with poor

69

14 15

&KDSWHU

outcome, especially since strict glucose control may be beneficial in this population.26 The aim of the present study was therefore to investigate the association of perioperative glucose levels with postoperative complications after PD.

70


METHODS

1

Patients and study outline In a consecutive series of 330 patients undergoing elective PD between July 2000 and December 2006 for suspected pancreatic or periampullary malignancy, clinicopathologic

data,

demographics

and

postoperative

outcomes

were

prospectively registered. Glucose values were analysed retrospectively. Since the

2 3

present study involved a retrospective analysis of anonymised data, the Dutch Ethical Review Board regulations do not require informed consent.

4

Surgical Procedure The standard surgical procedure was the pylorus-preserving PD with removal of

5

lymph nodes at the right side of the portal vein, as earlier described.27 In case of tumor ingrowth in pylorus or duodenum, a classic WhippleÊs resection was performed. If minimal tumor ingrowth in the portal or superior mesenteric vein was found, a segmental or wedge resection was carried out.28 Reconstruction was performed by retrocolic hepaticojejunostomy and pancreaticojejunostomy and

6 7

retrocolic or antecolic duodenojejunostomy, without Roux-Y reconstruction. One silicone drain was left in the foramen of Winslow near the hepaticojejunostomy and pancreaticojejunostomy.27 Feeding jejunostomy was not standard.29 Octreotide was routinely administered for 7 days until 2002, and afterwards on indication of soft pancreatic tissue or small pancreatic duct. Postoperatively, patients stayed at the

8 9

recovery room until the morning of the first postoperative day, before returning to

10

the surgical ward. Measures of glucose The most recent venous plasma glucose level within 4 months before surgery was

11

collected from the clinical information system or patient chart. Details about fasting or non-fasting state were mostly unknown. All available intraoperative and early postoperative glucose values (from operation until the end of the first postoperative day) were collected. During surgery and in the early postoperative period (defined as the period at the recovery room, or in case of extended stay at the

12 13

recovery room, until postoperative day 1), all blood glucose values were fasting. They were measured by a blood gas/pH analyzer (Ciba Corning 865, Chiron Diagnostics, Medford, MA, USA) in blood samples obtained from an arterial catheter, and automatically stored in the hospital information system. We calculated the mean intraoperative and early postoperative glucose value per

71

14 15

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patient. Furthermore, as a measure of glucose variability, the standard deviations (SD) of intraoperative and early postoperative glucose values in each patient were calculated. Outcome measures Primary outcome measure was whether the patient experienced any postoperative complication. All surgical complications and non-surgical complications were taken into account. Secondary outcome measures were the occurrence of a surgical complication, the occurrence of an infectious complication, a score of IIIa or higher in the DindoClavien

classification

of

complications,

delayed

gastric

emptying

and

pancreaticojejunostomy leakage (grade B or C according to the International Study Group of Pancreatic Surgery criteria), relaparotomy, admission to intensive or medium care unit or readmission to the recovery room, length of hospital stay, and hospital readmission within 30 days.30-32 Statistical analyses Results are presented as mean SD or median with interquartile range (IQR), depending on the distribution of the data. All glucose variables (the preoperative value, mean and SD of intraoperative and early postoperative values) were divided into duals of equal group size. Using multivariate binary logistic regression, we calculated Odds Ratios (OR) for all dichotomous outcome measures for patients in the upper versus the lower dual. Correlation with length of hospital stay (Natural log (Ln)-transformed) was calculated using linear regression. Calculations were carried out separately for each period (preoperative, intraoperative and early postoperative). Analyses were adjusted for age, gender, ASA-classification, body mass index (BMI), diabetes mellitus, intraoperative blood transfusion, duration of surgery, intraoperative insulin administration and octreotide use. Analyses of SD were also adjusted for the mean glucose value in the respective period. Finally, secondary outcomes analyses were corrected for multiple testing according to Benjamini and Hochberg.33 p-values below 0.05 were considered statistically significant. All analyses were performed in SPSS version 16.0 (SPSS Inc.,Chicago, IL, USA).

72


RESULTS

1

Patient population Patient and operative characteristics are summarised in Table 1. Mean age of the cohort was 62 (SD 12); 56% was male and 16% had diabetes mellitus. A preoperative glucose value was available in 79% of patients. At least one intraoperative glucose value was available in 97% of patients and at least one early

2 3

postoperative glucose value was available in 99% of patients (Table 2).

4

Table 1-baseline and operative characteristics of 330 patients undergoing pancreatoduodenectomy in the period July 2000 – December 2006 Baseline characteristics Age, years (mean, SD) Male sex, n (%) ASA I, n (%) ASA II, n (%) ASA III, n (%) Body Mass Index, n (%) -Underweight (1 value available, n (%) -No. of samples per patient (mean, SD) -Intraoperative value, mmol/l (mean, SD) -Standard deviation mmol/l (mean, SD) Early postoperative -At least 1 value available, n (%) ->1 value available, n (%) -No. of samples per patient (mean,SD) -Postoperative value, mmol/l (mean, SD) -Standard deviation, mmol/l (mean, SD)

259 7.5

(79) (4.2)

320 263 2.9 7.4 1.0

(97) (80) (1.6) (1.9) (1.2)

329 328 4.3 7.9 1.1

(100) (99) (1.9) (1.5) (0.9)

SD, standard deviation

Mean preoperative glucose was 7.5 (SD 4.2) mmol/l and mean intraoperative glucose 7.4 (SD 1.9) mmol/l. Intraoperative insulin was administered in 14% of patients. During stay at recovery, mean glucose was significantly higher as compared to the intraoperative period: 7.9 (SD 1.5) mmol/l (p III

Readmission

ICU admittance

Relaparotomy

DGE

PJ leakage

Infectious complications

Surgical complications

Any complication

1 0,1

4

5

0.9 (0.5-1.5) 1.1 (0.7-1.9) 1.0 (0.6-1.8) 1.7 (0.8-3.9)

1.1 (0.3-3.8)

1.5 (0.8-2.7)

10

2.7 (0.9-7.7)

1.6 (0.7-3.8)

1.3 (0.6-2.4)

Odds ratio with 95% CI

1

Mean Preoperative Glucose

3

Figure 2A-odds ratios (ORs) for all outcomes comparing patients with preoperative glucose of >=6.30 mmol/l to patients III

0,1

8

9

10

0.8 (0.5-1.4) 0.8 (0.5-1.4) 0.8 (0.5-1.3) 0.5 (0.2-1.2)

0.9 (0.3-2.9)

1.2 (0.7-2.2)

0.4 (0.2-1.0)

0.9 (0.5-1.7)

0.6 (0.2-1.5)

Odds ratio with 95% CI

1

10

Mean Intraoperative Glucose

7 Figure 2B-odds ratios (ORs) for all outcomes comparing patients with intraoperative glucose of >=7.06 mmol/l to patients III

6.2 (1.6-24.3), P=0.01

1

2.9 (1.7-4.9), P=7.78 mmol/l to patients 7.8 mmol/l) after pancreatoduodenectomy was significantly associated with the development of a postoperative complication, possible confounders taken into account. This was reflected by a higher risk of surgical and infectious complications, delayed gastric emptying, Dindo-Clavien complication score >=III and relaparotomy. Also length of stay was significantly longer in these patients. When elevated postoperative glucose was accompanied by high glucose variability, the risk of a postoperative complication seemed to increase. These novel findings were all adjusted for age, gender,

ASA-classification,

BMI,

diabetes

mellitus,

intraoperative

blood

transfusion, duration of surgery, intraoperative insulin administration and use of octreotide. Mean glucose levels before and during PD were comparable and significantly lower as compared to early postoperative levels. Elevated preoperative and intraoperative glucose and higher glucose variability were not associated with the development of complications. Our findings that early postoperative higher glucose levels are associated with complications after PD are in line with previous studies investigating this relation in other types of surgery. Ramos and coworkers identified postoperative hyperglycaemia as a significant risk factor for postoperative infections in general and vascular surgery.13 Vriesendorp et al observed an OR of 5.1 (95% CI 1.6 to 17.1) for postoperative infections when early postoperative glucose values were 8.4 mmol/l or above in peripheral vascular surgery.12 Also the seemingly additional detrimental effect of high glucose variability was described before in populations of critically ill and surgical intensive care unit patients.34;35 Although it is difficult to elucidate whether hyperglycaemia results from postoperative complications or indeed contributes to their development, we believe the latter mechanism is might be most plausible, but should be proven in the future by early regulation and control. As the increase in glucose levels preceded the development of complications and possible confounders were accounted for in the analyses, a causal relation between

elevated

glucose

levels

postoperatively

and

the

development

of

complications is suspected. Early postoperative hyperglycaemia was associated with the most prevalent complication in our cohort, delayed gastric emptying. Besides being a common complication

after

pancreatoduodenectomy,

gastroparesis

is

a

well-known

complication of longstanding diabetes mellitus. It has also been associated with acute hyperglycaemia.36

78


Several explanations for the harmful effects of both stress hyperglycaemia and glucose variability have been proposed, such as glucose toxicity and oxidative

1

stress, stimulating intracellular pathways that lead to detrimental tissue effects such as mitochondrial dysfunction and immune dysregulation.22;37 Although the application of strict glucose control has led to conflicting results in a variety of populations, a recent meta-analysis suggests that surgical ICU patients benefit from strict glucose control.26 Okabayashi and coworkers recently showed that strict

2 3

control of perioperative blood glucose following pancreatic resection is possible, and may reduce postoperative infection rates.38;39 We found that in PD, intraoperative glucose levels were comparable to preoperative levels, and that pre- and intraoperative glucose values and variability were not a risk factor for postoperative complications after PD. Intraoperative glucose values

4 5

have earlier been described as risk factor for adverse outcomes in cardiac surgery and liver transplantation.14;15;40;41 Contrary to PD, these operations involve substantial ischemia and reperfusion injury, which may explain these seemingly contradictory different findings. Interestingly, the mean glucose in patients with diabetes decreased after surgery as

6 7

compared to the intraoperative values, indicating a different glucose response to surgery. Diabetes patients did not have more complications than non-diabeties patients in our series, whereas diabetes mellitus has been described as a risk factor for intra-abdominal complications after PD.8 Our cohort was however too small to draw firm conclusions about the diabetes subpopulation.

8 9

Using an ROC-curve analysis we found that the cut-off value of 7.8 mmol/l early postoperatively was the most discriminatory value when predicting complications. This was comparable to our population mean and median value. Perhaps not coincidentally, normal healthy subjects will not peak above 7.8 mmol/l when challenged with oral glucose, supporting the strength of this cut-off value.42

10 11

Our study was limited by the retrospective collection of glucose values. Preoperative values were not available in 21% of patients. However, postoperative morbidity in these patients was not different from patients who did have a preoperative value available (59% versus 58%, data not shown). Glucose sampling was not standardised, leading to differences in timing, amount and indication of

12 13

glucose samples. To minimise these sources of error, the average glucose value per period was taken. Also, intraoperative and postoperative glucose values were available in nearly all patients, showing that frequent perioperative sampling was common, irrespective of the condition of the patient.

14 15

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Our study is the first to investigate the effect of perioperative glucose levels in this specific patient group with pancreatic disease. It was performed in a large consecutive series of elective patients. Patient characteristics and hospital course were prospectively scored. In conclusion, early postoperative glucose levels above 7.8 mmol/l are significantly associated with postoperative complications after PD. Future research must clarify the underlying mechanisms and pathways of this relation. Treatment of hyperglycaemia is possible and strict glucose control may be favourable in surgical patients.26 A randomised clinical trial should be conducted to investigate whether a strategy of strict glucose control (versus glucose correction on indication) in the early postoperative period is beneficial in this patient group.

80


REFERENCES

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Bassi C, Falconi M, Salvia R, Mascetta G, Molinari E, Pederzoli P. Management of complications after pancreaticoduodenectomy in a high volume centre: results on 150 consecutive patients. Dig Surg 2001; 18(6):453-457.

(2)

de Castro SM, Busch OR, van Gulik TM, Obertop H, Gouma DJ. Incidence and management of pancreatic leakage after pancreatoduodenectomy. Br J Surg 2005; 92(9):1117-1123.

(3)

van Heek NT, Kuhlmann KF, Scholten RJ, de Castro SM, Busch OR, van Gulik TM et al. Hospital volume and mortality after pancreatic resection: a systematic review and an evaluation of intervention in the Netherlands. Ann Surg 2005; 242(6):781-8, discussion.

(4)

Yeo CJ, Cameron JL, Sohn TA, Lillemoe KD, Pitt HA, Talamini MA et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg 1997; 226(3):248-257.

(5)

House MG, Fong Y, Arnaoutakis DJ, Sharma R, Winston CB, Protic M et al. Preoperative predictors for complications after pancreaticoduodenectomy: impact of BMI and body fat distribution. J Gastrointest Surg 2008; 12(2):270-278.

(6)

Su Z, Koga R, Saiura A, Natori T, Yamaguchi T, Yamamoto J. Factors influencing infectious complications after pancreatoduodenectomy. J Hepatobiliary Pancreat Surg 2009.

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(7)

Williams TK, Rosato EL, Kennedy EP, Chojnacki KA, Andrel J, Hyslop T et al. Impact of obesity on perioperative morbidity and mortality after pancreaticoduodenectomy. J Am Coll Surg 2009; 208(2):210-217.

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(8)

Cheng Q, Zhang B, Zhang Y, Jiang X, Zhang B, Yi B et al. Predictive factors for complications after pancreaticoduodenectomy. J Surg Res 2007; 139(1):22-29.

(9)

Fathy O, Wahab MA, Elghwalby N, Sultan A, EL-Ebidy G, Hak NG et al. 216 cases of pancreaticoduodenectomy: risk factors for postoperative complications. Hepatogastroenterology 2008; 55(84):1093-1098.

(10)

Muscari F, Suc B, Kirzin S, Hay JM, Fourtanier G, Fingerhut A et al. Risk factors for mortality and intra-abdominal complications after pancreatoduodenectomy: multivariate analysis in 300 patients. Surgery 2006; 139(5):591-598.

(11)

Winter JM, Cameron JL, Yeo CJ, Alao B, Lillemoe KD, Campbell KA et al. Biochemical markers predict morbidity and mortality after pancreaticoduodenectomy. J Am Coll Surg 2007; 204(5):1029-1036.

10

(12)

Vriesendorp TM, Morelis QJ, Devries JH, Legemate DA, Hoekstra JB. Early postoperative glucose levels are an independent risk factor for infection after peripheral vascular surgery. A retrospective study. Eur J Vasc Endovasc Surg 2004; 28(5):520-525.

11

(13)

Ramos M, Khalpey Z, Lipsitz S, Steinberg J, Panizales MT, Zinner M et al. Relationship of perioperative hyperglycemia and postoperative infections in patients who undergo general and vascular surgery. Ann Surg 2008; 248(4):585-591.

12

(14)

Gandhi GY, Nuttall GA, Abel MD, Mullany CJ, Schaff HV, Williams BA et al. Intraoperative hyperglycemia and perioperative outcomes in cardiac surgery patients. Mayo Clin Proc 2005; 80(7):862-866.

13

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Park C, Hsu C, Neelakanta G, Nourmand H, Braunfeld M, Wray C et al. Severe intraoperative hyperglycemia is independently associated with surgical site infection after liver transplantation. Transplantation 2009; 87(7):1031-1036.

(16)

Olsen MA, Nepple JJ, Riew KD, Lenke LG, Bridwell KH, Mayfield J et al. Risk factors for surgical site infection following orthopaedic spinal operations. J Bone Joint Surg Am 2008; 90(1):62-69.

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Vilar-Compte D, Alvarez dI, I, Martin-Onraet A, Perez-Amador M, Sanchez-Hernandez C, Volkow P. Hyperglycemia as a risk factor for surgical site infections in patients undergoing mastectomy. Am J Infect Control 2008; 36(3):192-198.

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Ambiru S, Kato A, Kimura F, Shimizu H, Yoshidome H, Otsuka M et al. Poor postoperative blood glucose control increases surgical site infections after surgery for hepato-biliary-pancreatic cancer: a prospective study in a high-volume institute in Japan. J Hosp Infect 2008; 68(3):230-233.

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Vriesendorp TM, Devries JH, Hulscher JB, Holleman F, van Lanschot JJ, Hoekstra JB. Early postoperative hyperglycaemia is not a risk factor for infectious complications and prolonged in-hospital stay in patients undergoing oesophagectomy: a retrospective analysis of a prospective trial. Crit Care 2004; 8(6):R437-R442.

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Pannala R, Leibson CL, Rabe KG, Timmons LJ, Ransom J, de AM et al. Temporal association of changes in fasting blood glucose and body mass index with diagnosis of pancreatic cancer. Am J Gastroenterol 2009; 104(9):2318-2325.

(21)

Chari ST, Leibson CL, Rabe KG, Timmons LJ, Ransom J, de AM et al. Pancreatic cancerassociated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology 2008; 134(1):95-101.

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Freeman JS. Role of the incretin pathway in the pathogenesis of type 2 diabetes mellitus. Cleve Clin J Med 2009; 76 Suppl 5:S12-S19.

(24)

Slezak LA, Andersen DK. Pancreatic resection: effects on glucose metabolism. World J Surg 2001; 25(4):452-460.

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Griesdale DE, de Souza RJ, van Dam RM, Heyland DK, Cook DJ, Malhotra A et al. Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data. CMAJ 2009; 180(8):821-827.

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Gouma DJ, Nieveen van Dijkum EJ, Obertop H. The standard diagnostic work-up and surgical treatment of pancreatic head tumours. Eur J Surg Oncol 1999; 25(2):113-123.

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van Geenen RC, ten Kate FJ, de Wit LT, van Gulik TM, Obertop H, Gouma DJ. Segmental resection and wedge excision of the portal or superior mesenteric vein during pancreatoduodenectomy. Surgery 2001; 129(2):158-163.

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Heslin MJ, Latkany L, Leung D, Brooks AD, Hochwald SN, Pisters PW et al. A prospective, randomized trial of early enteral feeding after resection of upper gastrointestinal malignancy. Ann Surg 1997; 226(4):567-577.

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Bassi C, Dervenis C, Butturini G, Fingerhut A, Yeo C, Izbicki J et al. Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery 2005; 138(1):8-13.

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Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004; 240(2):205-213.

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Wente MN, Bassi C, Dervenis C, Fingerhut A, Gouma DJ, Izbicki JR et al. Delayed gastric emptying (DGE) after pancreatic surgery: a suggested definition by the International Study Group of Pancreatic Surgery (ISGPS). Surgery 2007; 142(5):761-768.

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Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: a Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society 1995; 57(1):289300.

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Dossett LA, Cao H, Mowery NT, Dortch MJ, Morris JM, Jr., May AK. Blood glucose variability is associated with mortality in the surgical intensive care unit. Am Surg 2008; 74(8):679-685.

(DUO\SRVWRSHUDWLYHK\SHUJO\FDHPLDLVDVVRFLDWHGZLWKFRPSOLFDWLRQVDIWHU3' (35)

Hermanides J, Vriesendorp TM, Bosman RJ, Zandstra DF, Hoekstra JB, Devries JH. Glucose variability is associated with intensive care unit mortality. Crit Care Med 2010; 38(3):838-42

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De Block CE, De L, I, Pelckmans PA, Van Gaal LF. Current concepts in gastric motility in diabetes mellitus. Curr Diabetes Rev 2006; 2(1):113-130.

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Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005; 54(6):1615-1625.

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Hanazaki K, Okabayashi T, Maeda H. Hepatectomized PatientsTight Glycemic Control Using an Artificial Pancreas to Control Perioperative Hyperglycemia Decreases Surgical Site Infection in Pancreatectomized or Hepatectomized Patients. Ann Surg 2009; 250(2):351.

(39)

Okabayashi T, Nishimori I, Yamashita K, Sugimoto T, Maeda H, Yatabe T et al. Continuous postoperative blood glucose monitoring and control by artificial pancreas in patients having pancreatic resection: a prospective randomized clinical trial. Arch Surg 2009; 144(10):933-937.

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Ammori JB, Sigakis M, Englesbe MJ, O'Reilly M, Pelletier SJ. Effect of intraoperative hyperglycemia during liver transplantation. J Surg Res 2007; 140(2):227-233.

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Doenst T, Wijeysundera D, Karkouti K, Zechner C, Maganti M, Rao V et al. Hyperglycemia during cardiopulmonary bypass is an independent risk factor for mortality in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg 2005; 130(4):1144.

6

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American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes care 2008; 31(Suppl. 1):S55-S60.

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DETECTION AND TREATMENT OF HYPERGLYCAEMIA

Sense and nonsense in sensors

J Hermanides and JH DeVries

Diabetologia, 2010 April;53:593-596

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ABSTRACT Continuous subcutaneous glucose monitoring (CGM) is a developing technology in the treatment of diabetes mellitus. The first randomised controlled trials on its efficacy have been performed. In several studies, CGM lowered HbA1c in adult patients with suboptimally type 1 diabetes mellitus, when selecting compliant patients who tolerate the device. However, as a preventive tool for hypoglycaemia, CGM has not fulfilled the great expectations. Increasing reimbursement of CGM is expected in the near future, awaiting studies on cost-effectiveness.

88

6HQVHDQGQRQVHQVHLQVHQVRUV

INTRODUCTION

1

Pioneering work of artificially replacing the glucose-monitoring function of the pancreas started in the 1970s.1 With the introduction of the microdialysis technique in the early 1990s, the future of continuous subcutaneous glucose monitoring (CGM) seemed bright and shiny.2;3 The great expectation was that, by providing the patient with a continuous stream of data and alarms for otherwise

2 3

unrecognised (nocturnal) hypo- and hyperglycaemia, the HbA1c target of =8.1% on intensive treatment).9 There was a difference in HbA1c reduction of 0.6% after 3 months in favour of patients who were instructed to use the device continuously, as compared with patients using conventional treatment. In a third arm, patients used CGM biweekly, and this did not result in a significant

12 13

HbA1c improvement. A subsequent 26 week randomised treat-to-target study performed by Hirsch and coworkers (the STAR 1 trial) yielded disappointing results.10 There was no significant difference in change in HbA1c between type 1 diabetes patients using CSII randomised to either augmenting their current therapy with CGM or continuing with their standard self-monitoring of blood

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glucose (SMBG). In both groups, there was a decrease in HbA1c of 0.6 to 0.7%. That the decreases in HbA1c were comparable in both groups was attributed to intensification of the treatment in both the control and intervention groups. It seems that in an attempt to assure equal attention times in both groups, the control group was treated more intensively than would be feasible in daily practice. In the Juvenile Diabetes Research Foundation (JDRF) study, three different age groups (º25, 15 to 24 and 8 to 14 years) were randomised to either CGM or SMBG continuation.11 All patients had type 1 diabetes and the vast majority were already using CSII. The mean difference in HbA1c change was 0.5% after 26 weeks in favour of patients using CGM, but this was only in those aged 25 years and older. No significant difference in HbA1c change was detected in the other age groups. In both the STAR 1 and the JDRF trials, the frequency of sensor usage was strongly correlated to the decrease in HbA1c. This is in line with the study from Deiss et al.9 and the recently published RealTrend study12. In this latter study, patients administering multiple daily injections and with an HbA1c >=8% at inclusion started with either CSII therapy or sensor-augmented pump therapy for 26 weeks. From a predefined analysis, HbA1c improved compared with the CSII group only in patients using the sensor >70% of the time. Unfortunately, patients in the sensoraugmented pump group had already used CGM for 9 days before the baseline HbA1c measurement was performed and therefore the observed HbA1c difference, 0.41%, may have been underestimated. The combination of CGM and CSII has also been investigated in the recently presented Eurythmics trial, where a difference in HbA1c improvement of 1.21% in favour of the sensor-augmented pump group was found when type 1 diabetes patients (HbA1c at entry >=8.2%), who were using multiple daily injection therapy and SMBG, were randomised to continuing their current therapy or starting CGM-augmented insulin-pump therapy.13 It is interesting that the JDRF trial and the Eurythmics trial, both showing a significant HbA1c improvement in the intervention group, confronted patients with a short period of blinded CGM usage at baseline before randomisation. Patients who did not tolerate the device, and therefore would be likely to drop out or be noncompliant during the study course, were at least partly filtered out before randomisation. EFFECT ON SEVERE HYPOGLYCAEMIA The improvement in HbA1c in the different RCTs was not accompanied by a significant increase in severe hypoglycaemia.9;11-13 This seems reassuring, but

90


CGM did not fulfil the expectation that its use would reduce the frequency of severe hypoglycaemic events.14 Even more, in the STAR 1 trial, the use of CGM was

1

associated with a significant increase in severe hypoglycaemia. This is most likely related to the reduced awareness of auditory and vibratory alarms during hypoglycaemia and non-use of the device during high-risk activities, such as intensive sports. No study so far has shown a decrease in the frequency of severe hypoglycaemia in a CGM arm as compared with the control arm in type 1 diabetes.

2 3

Indeed, sensors have an inaccuracy of up to 21% when comparing plasma glucose values with subcutaneous glucose values.15 This inaccuracy is even more pronounced in the hypoglycaemic range. In addition, the usefulness of the CGM devices for detecting forthcoming hypoglycaemia is limited by a putative physiological delay between the blood glucose and glucose concentration in the

4 5

subcutaneous tissue, which is accompanied by an instrumental delay of the sensor.16 In other words, patients need more time to prevent hypoglycaemia, especially when they have hypoglycaemia unawareness. Perhaps the developing technology will result in an alarm function for predicting hypoglycaemia by using the rate of change in glucose in the lower euglycaemic range. For now, CGM is

6 7

insufficient for the prevention of severe hypoglycaemia.

8

COSTS AND REIMBURSEMENT Interestingly, it is the argument of possibly preventing severe hypoglycaemia that

9

has persuaded healthcare organisations in Israel to reimburse CGM use. Children with type 1 diabetes who have experienced more than two severe hypoglycaemic episodes within 1 year are entitled to CGM compensation. In addition, real-time CGM is now covered by the majority of health plans in the USA, including the federal Medicare program. Reimbursement is generally available for type 1

10 11

patients with severe hypoglycaemia or those who are not meeting American Diabetes Association HbA1c targets. In the Netherlands and part of Italy, retrospective CGM is currently reimbursed. The Czech Republic covers up to four sensors per year for retrospective CGM and in Sweden, real-time CGM is reimbursed for patients using CSII and having two or more severe hypoglycaemic

12 13

episodes per year, children who require at least ten plasma glucose tests per 24 h and patients with HbA1c >10% while receiving optimised insulin therapy. The reimbursement indication of hypoglycaemia illustrates that so far, coverage was based on feeling rather than the (scarce) evidence. This is not to say that CGM is not able to reduce severe hypoglycaemia, but we need randomised trials in patients

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at high risk for severe hypoglycaemia (i.e. those suffering from hypoglycaemia unawareness). From the results of the clinical trials to date, we can now argue that CGM offers a clear health benefit, expressed as HbA1c lowering, for type 1 diabetes patients with HbA1c values above 8%. The additional costs for sensors are US$4380 per person year compared with US$550-2740 when using SMBG.17 Consequently, we need to calculate whether the long-term health benefits of CGM following from ascertained lowering of HbA1c outweigh the costs when compared with standard care with multiple daily injections and/or insulin pumps. A similar comparison was performed by Roze and colleagues indicating that the cost-effectiveness of CSII is acceptable.18 A technical appraisal from the National Institute for Health and Clinical Excellence (England and Wales) seems timely. OTHER PATIENT GROUPS The application of CGM in patient groups other than those with type 1 diabetes is limited. No trials with adequate duration assessing HbA1c change have been performed for patients with type 2 diabetes.19 One particular patient group that warrants special attention is pregnant women with diabetes. CGM has proven effective in improving glucose control at the end of pregnancy.20 It resulted in fewer cases of macrosomia in the offspring, with an odds ratio of 0.36 (95% CI 0.13 to 0.98).21 As it concerns a limited time span, reimbursement of CGM in this group should impose no significant financial burden on the healthcare system. Finally, the use of CGM for treating in-hospital hyperglycaemia could be valuable, and the first randomised studies are awaited. However, the advantage of CGM in this setting may be less evident, as frequent blood sampling is standard practice in the intensive care unit and CGM accuracy may suffer if the circulation is compromised.22 CONCLUSION CGM with or without CSII has been proven to lower HbA1c in adult patients with type 1 diabetes mellitus and HbA1c values above 8%, when compliant patients who tolerate the device are selected. However, CGM is not the final answer to severe hypoglycaemia. Awaiting a cost-effectiveness analysis, increasing reimbursement of CGM is expected.

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ACKNOWLEDGDEMENTS

1

No funding was received for this commentary. We acknowledge N. Papo (Senior Reimbursement Manager, Medtronic International Trading Sárl, Tolochenaz Switzerland) for providing information on the current global reimbursement status of CGM.

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Bolinder J, Ungerstedt U, Arner P. Long-term continuous glucose monitoring with microdialysis in ambulatory insulin-dependent diabetic patients. Lancet 1993; 342(8879):1080-1085.

(3)

Bolinder J, Ungerstedt U, Arner P. Microdialysis measurement of the absolute glucose concentration in subcutaneous adipose tissue allowing glucose monitoring in diabetic patients. Diabetologia 1992; 35(12):1177-1180.

(4)

American Diabetes Association. Standards of Medical Care in Diabetes--2008. Diabetes Care 2008; 31(Supplement_1):S12-S54.

(5)

Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes 2008; 57(12):3169-3176.

(6)

Wentholt IM, Maran A, Masurel N, Heine RJ, Hoekstra JB, DeVries JH. Nocturnal hypoglycaemia in Type 1 diabetic patients, assessed with continuous glucose monitoring: frequency, duration and associations. Diabet Med 2007; 24(5):527-532.

(7)

Hanaire H. Continuous glucose monitoring and external insulin pump: towards a subcutaneous closed loop. Diabetes Metab 2006; 32(5 Pt 2):534-538.

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Gross TM, Bode BW, Einhorn D, Kayne DM, Reed JH, White NH et al. Performance evaluation of the MiniMed continuous glucose monitoring system during patient home use. Diabetes Technol Ther 2000; 2(1):49-56.

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Deiss D, Bolinder J, Riveline JP, Battelino T, Bosi E, Tubiana-Rufi N et al. Improved Glycemic Control in Poorly Controlled Patients with Type 1 Diabetes Using Real-Time Continuous Glucose Monitoring. Diabetes Care 2006; 29(12):2730-2732.

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Hirsch IB, Abelseth J, Bode BW, Fischer JS, Kaufman FR, Mastrototaro J et al. SensorAugmented Insulin Pump Therapy: Results of the First Randomized Treat-to-Target Study. Diabetes Technology & Therapeutics 2008; 10(5):377-383.

(11)

The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Continuous Glucose Monitoring and Intensive Treatment of Type 1 Diabetes. N Engl J Med 2008; 359(14):1464-1476.

(12)

Raccah D, Sulmont V, Reznik Y, Guerci B, Renard E, Hanaire H et al. Incremental value of continuous glucose monitoring when starting pump therapy in patients with poorly controlled type 1 diabetes: The RealTrend study. Diabetes Care 2009.

(13)

Hermanides J., NŒrgaard K., Bruttomesso D., Mathieu C., Frid A., Dayan C.M. et al. Sensor augmented pump therapy substantially lowers HbA1c. Diabetologia 52[Supplement I], S43. 2009. Abstract

(14)

Cryer PE. Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 2004; 350(22):2272-2279.

(15)


(16)

Wentholt IM, Hart AA, Hoekstra JB, DeVries JH. Relationship between interstitial and blood glucose in type 1 diabetes patients: delay and the push-pull phenomenon revisited. Diabetes Technol Ther 2007; 9(2):169-175.

(17)

Pham M. Medtronic Diabetes: Sizing the market for realtime, continuous blood glucose monitors from MDT, DXCM, and ABT. Available from www.research.hsbc.com/midas/Res/ RDV? p=pdf&key=ate2b8rygn&name=127057.PDF, accessed 28 September 2009

(18)

Roze S, Valentine WJ, Zakrzewska KE, Palmer AJ. Health-economic comparison of continuous subcutaneous insulin infusion with multiple daily injection for the treatment of Type 1 diabetes in the UK. Diabet Med 2005; 22(9):1239-1245.

6HQVHDQGQRQVHQVHLQVHQVRUV (19)

Yoo HJ, An HG, Park SY, Ryu OH, Kim HY, Seo JA et al. Use of a real time continuous glucose monitoring system as a motivational device for poorly controlled type 2 diabetes. Diabetes Res Clin Pract 2008; 82(1):73-79.

(20)

Landon MB, Gabbe SG, Piana R, Mennuti MT, Main EK. Neonatal morbidity in pregnancy complicated by diabetes mellitus: predictive value of maternal glycemic profiles. Am J Obstet Gynecol 1987; 156(5):1089-1095.

(21)

Murphy HR, Rayman G, Lewis K, Kelly S, Johal B, Duffield K et al. Effectiveness of continuous glucose monitoring in pregnant women with diabetes: randomised clinical trial. BMJ 2008; 337:a1680.

(22)

Sair MPMF, Etherington PJB, Peter Winlove CD, Evans TWM. Tissue oxygenation and perfusion in patients with systemic sepsis. Critical Care Medicine 2001; 29(7):1343-1349.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

95

Sensor augmented pump therapy lowers HbA1c in suboptimally controlled type 1 diabetes; a randomised controlled trial

J Hermanides, K NŒrgaard, D Bruttomesso, C Mathieu, A Frid, CM Dayan, P Diem, C Fermon, IME Wentholt, JBL Hoekstra, JH DeVries


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ABSTRACT Aims To investigate the efficacy of sensor augmented pump therapy vs. multiple daily injection therapy in patients with suboptimally controlled type 1 diabetes. Methods In this investigator initiated multicentre trial (Eurythmics Trial) in 8 outpatient centres in Europe we randomised 83 Diabetes type 1 patients (40 woman) currently treated with multiple daily injections, age 18-65 years and haemoglobin A1c (HbA1c)>=8.2% to 26 weeks of treatment with either a sensor augmented insulin pump (SAP, n=44) (Paradigm® REAL-Time) or multiple daily injections (MDI, n=39). Change in HbA1c between baseline and 26 weeks, sensor derived endpoints and patient reported outcomes were assessed. Results In the SAP group 43/44 (98%) patients completed the trial and in the MDI group 35/39 (90%). Mean HbA1c at baseline and 26 weeks changed from 8.46% (SD 0.95) to 7.23% (SD 0.65) in the SAP group and from 8.59% (SD 0.82) to 8.46% (SD 1.04) in the MDI group. Mean difference in change in HbA1c after 26 weeks was 1.21% (95% confidence interval -1.52 to -0.90, p60% of the time. In contrast with previous CGM trials, we could not find a relation between CGM use and change in HbA1c.11;19;20 This trial was however not

10 11

designed to investigate this relationship. It is noteworthy that the substantial improvement in glycaemic control with frequent sensor use was seen in a patient group not easy to reach, under treatment in experienced pump centres and failing on optimised MDI/SMBG therapy. In conclusion, these study results show that, as compared to MDI treatment, SAP

12 13

treatment in motivated but suboptimally controlled type 1 diabetes patients results in a considerable HbA1c reduction and improvement in quality of life, without increasing hypoglycaemia. The magnitude of the difference in change in HbA1c of 1.21% may be due to the combined effect of pump, sensor, Bolus Wizard® and the process of starting SAP therapy in this hard to reach population.

113

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Acknowledgements This trial was financially supported by Medtronic International Trading Sàrl. This was an investigator-initiated trial. The funding source had an advising role in trial design details and drafting of the report and was only involved in the collection of the sensor data. The funding source had no role in the conduct of the analyses, interpretation of the data or in the decision to approve publication. Chantal Mathieu is a clinical researcher of the FWO (Fund for Research Flanders). We further acknowledge the following people involved in the execution of the trial: Hilde Morobé, Peggy Callewaert, Marijke Carpentier, Conny Peeters, Kate Green, Dr. Danijela Tatovic, Dr. Silvana Costa, Dr. Andrea Egger, Dr. Andrea Lanker, Peggy Wentzel, Dorien Dragt, Dr. C.B. Brouwer, Merete Meldgaard, Ingrid Wetterholtz, and Hanna Söderling.

114

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REFERENCES

1

(1)

The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993; 329(14):977-986.

(2)

American Diabetes Association. Standards of Medical Care in Diabetes--2008. Diabetes Care 2008; 31(Supplement_1):S12-S54.

(3)

Bode BW, Schwartz S, Stubbs HA, Block JE. Glycemic Characteristics in Continuously Monitored Patients With Type 1 and Type 2 Diabetes: Normative values. Diabetes Care 2005; 28(10):2361-2366.

2 3

(4)

Cryer PE. The Barrier of Hypoglycemia in Diabetes. Diabetes 2008; 57(12):3169-3176.

(5)

Wentholt IM, Maran A, Masurel N, Heine RJ, Hoekstra JB, DeVries JH. Nocturnal hypoglycaemia in Type 1 diabetic patients, assessed with continuous glucose monitoring: frequency, duration and associations. Diabet Med 2007; 24(5):527-532.

(6)

Pickup J, Keen H. Continuous subcutaneous insulin infusion at 25 years: evidence base for the expanding use of insulin pump therapy in type 1 diabetes. Diabetes Care 2002; 25(3):593-598.

(7)


(8)

Pickup JC, Sutton AJ. Severe hypoglycaemia and glycaemic control in Type 1 diabetes: meta-analysis of multiple daily insulin injections compared with continuous subcutaneous insulin infusion. Diabet Med 2008; 25(7):765-774.

(9)

Jeitler K, Horvath K, Berghold A, Gratzer TW, Neeser K, Pieber TR et al. Continuous subcutaneous insulin infusion versus multiple daily insulin injections in patients with diabetes mellitus: systematic review and meta-analysis. Diabetologia 2008; 51(6):941-951.

(10)

Retnakaran R, Hochman J, DeVries JH, Hanaire-Broutin H, Heine RJ, Melki V et al. Continuous Subcutaneous Insulin Infusion Versus Multiple Daily Injections: The impact of baseline A1c. Diabetes Care 2004; 27(11):2590-2596.

(11)

The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Continuous Glucose Monitoring and Intensive Treatment of Type 1 Diabetes. N Engl J Med 2008; 359(14):1464-1476.

9

(12)

Mastrototaro JJ, Cooper KW, Soundararajan G, Sanders JB, Shah RV. Clinical experience with an integrated continuous glucose sensor/insulin pump platform: a feasibility study. Adv Ther 2006; 23(5):725-732.

10

(13)

Hanaire H. Continuous glucose monitoring and external insulin pump: towards a subcutaneous closed loop. Diabetes Metab 2006; 32(5 Pt 2):534-538.

(14)

Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained Effect of Intensive Treatment of Type 1 Diabetes Mellitus on Development and Progression of Diabetic Nephropathy: The Epidemiology of Diabetes Interventions and Complications (EDIC) Study. JAMA 2003; 290(16):2159-2167.

4 5 6 7 8

11 12

(15)

Ware JEJP. SF-36 Health Survey Update. Spine 2000; 25(24):3130-3139.

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Polonsky WH, Anderson BJ, Lohrer PA, Welch G, Jacobson AM, Aponte JE et al. Assessment of diabetes-related distress. Diabetes Care 1995; 18(6):754-760.

13

(17)

Bradley C. The Diabetes Treatment Satisfaction Questionnaire:DTSQ. Handbook of Psychology and Diabetes: A Guide to Psychological Measurement in Diabetes Research and Practice. Chur, Switzerland: Harwood Academic Publishers; 1994. 111-132.

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(18)

Cox DJ, Irvine A, Gonder-Frederick L, Nowacek G, Butterfield J. Fear of hypoglycemia: quantification, validation, and utilization. Diabetes Care 1987; 10(5):617-621.

115

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&KDSWHU (19)

Hirsch IB, Abelseth J, Bode BW, Fischer JS, Kaufman FR, Mastrototaro J et al. SensorAugmented Insulin Pump Therapy: Results of the First Randomized Treat-to-Target Study. Diabetes Technology & Therapeutics 2008; 10(5):377-383.

(20)

Raccah D, Sulmont V, Reznik Y, Guerci B, Renard E, Hanaire H et al. Incremental value of continuous glucose monitoring when starting pump therapy in patients with poorly controlled type 1 diabetes: The RealTrend study. Diabetes Care 2009.

(21)

Hermanides J, DeVries JH. Sense and nonsense in sensors. Diabetologia 2010; Apr;53:593-596..

(22)

O'Connell M, Donath S, O'Neal D, Colman P, Ambler G, Jones T et al. Glycaemic impact of patient-led use of sensor-guided pump therapy in type 1 diabetes: a randomised controlled trial. Diabetologia 2009; 52(7):1250-1257.

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Cryer PE, Davis SN, Shamoon H. Hypoglycemia in Diabetes. Diabetes Care 2003; 26(6):1902-1912.

116

Sensor augmented insulin pump therapy to treat hyperglycaemia at the coronary care unit; a randomised controlled pilot trial

J Hermanides, AE Engström, IME Wentholt, KD Sjauw, JBL Hoekstra, JPS Henriques, JH DeVries

Diabetes Technology & Therapeutics, In Press

&KDSWHU

ABSTRACT

Background The relationship between admission hyperglycaemia and adverse outcome in myocardial infarction has been shown consistently. However, achieving and maintaining normoglycaemia in STEMI-patients has proven difficult. This study aimed to investigate the efficacy of sensor augmented insulin pump therapy (SAP) to treat hyperglycaemia. Methods In a randomised controlled pilot trial, we assigned 20 patients, aged 30-80 years, admitted with STEMI and hyperglycaemia (>=7.8 mmol/l) to receive either 48 hours of strict glycaemic control with an subcutaneous insulin pump augmented with a continuous glucose monitor (SAP group) or to treatment according to standard practice (Control group) with glucose measured by blinded CGM. The main outcome measure proportion of time spent in hyperglycaemia. Results The median treatment time was 47.0 hours (IQR 46.2 to 48.0) in the SAP group and 44.6 (IQR 22.0 to 48.6) in the Control group. The median proportion of time >=7.8 mmol/l was 14.6% (IQR 10.5 to 18.5) in the SAP group and 36.3% in the control group (IQR 26.0 to 80.4), p=0.006. The proportion of time =7.8 mmol/l) as measured by continuous subcutaneous glucose monitor (CGM) during 48 hours. Also we calculated the proportion of time spent in hypoglycaemia

121

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(7%, n=4, the median glucose concentration on day 1 was 12.6 mmol/l (range 9.2 to 14.7 mmol/l) compared to 8.7 mmol/l (range 8.5 to 8.8 mmol/l) on day 3, p=0.07. The AUC of the sensor glucose concentration of day 1 (2993 mmol/l x minutes, range 1900 to 4581) did not differ from day 3 (2746 mmol/l x minutes range 2426 to 3330), p=0.5. The venous peak and nadir glucose concentration on day 1 and day 3 were not different (Table 2). Figure 1-median venous glucose concentrations day 1 compared to day 3

Table 2-postprandial glucose values day 1 compared to day 3, n=5 Plasma glucose, mmol/l (median, range)

Day 1

Day 3

p-value

Overall t=120 min t=180 min Peak Nadir

11.4 (5.2 to 14.7) 12.3 (4.2 to 17.4) 13.4 (3.3 to 15.6) 14.1 (7.9 to 17.7) 10.4 (3.0 to 10.1)

8.7 (7.1 to 8.8) 8.1 (6.8 to 9.6) 4.5 (3.3 to 9.0) 14.5 (10.8 to 17.7) 3.8 (3.2 to 4.4)

0.14 0.23 0.08 0.5 0.08

146

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On day three, the patients tended to have a higher percentage of time spent in

1

euglycaemia measured by venous glucose measurements compared to day 1 (31% vs 60%, p=0.08). No significant differences were seen in time spent in hypoglycaemia or hyperglycaemia between day 1 and day 3. On day 3, three hypoglycaemic episodes occurred in two patients lasting 6, 9 and 30 minutes. During the period of 30 minutes, the corresponding venous blood glucose

2 3

level was 3.2 mmol/l. No venous measurements were taken during the other two periods. In addition, venous glucose measurements detected five other episodes of glucose levels below 3.9 mmol/l, in three patients, with values of 3.2, 3.6 (twice) and 3.8 mmol/l (twice). All hypoglycaemic periods occurred late postprandially, after 150 minutes or more.

4 5

On day 3, the algorithm was enabled to give alarms. The number of sound alarms and number of the glucagon responses are shown in table 3. In total the sound alarm went off 14 times, range 1-4 per patient. Glucagon boluses were given in two patients. No nausea was noted. The cumulative mealtime related insulin requirements on day 1 and day 3 are

6 7

shown in table 3. No significant differences were seen, p=0.14.

8

Table 3a-insulin need during the study, given as international units Day 1 Patient 1 2 3 4 6

Day 3

Bolus 14 4 4 4.5 5

Basal 6.1 3 5 5.8 6.1

Total 20.1 7 9 10.3 11.1

9

Total 41 26.5 9 40.5 9

10 11

Table 3b- number of sound alarms (glucose

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