University of Groningen Treatment of cardiac patients and ......the ventilator, he rediscovered the...

University of Groningen

Treatment of cardiac patients and complications on the ICUBergman, Remco

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Treatment of cardiac patients

and complications on the ICU

Remco Bergman

Bergman, R.Treatment of cardiac patients and complications on the ICU

PhD, dissertation, University of Groningen, The Netherlands

ISBN: 978-94-6233-728-2ISBN (electronic version): 978-94-6233-729-9

© Copyright 2017 Remco Bergman, Groningen, The NetherlandsAll rights reserved. No part of this thesis may be reproduced, stored in a retrieval system, or transmitted in any former by any means without prior permission of the author or, when appropriate, of the publishers of the published articles.

Cover design: Angela WangLay-out: Remco BergmanPrinted by: Gildeprint, Enschede ~ www.gildeprint.nl

Financial support:

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

This research was also financially supported by:ABN/AMRO bank & CSL Behring

Treatment of cardiac patients and complications on the ICU

PhD thesis

to obtain the degree of PhD at the University of Groningen on the authority of the

Rector Magnificus Prof. E. Sterken and in accordance with

the decision by the College of Deans.

This thesis will be defended in public on

Monday 30 October 2017 at 14:30 hours

by

Remco Bergman

born on 6 June 1980in Apeldoorn

Supervisors

Prof. A.R. Absalom

Prof. J. van der Naalt

Co-supervisor

Dr. I.C.C. van der Horst

Assessment committee

Prof. C. Boer

Prof. J.C. ter Maaten

Prof. T.W. Scheeren

Voor mijn lieve Eva Sophie

Contents

Chapter One

General introduction and scope of the thesis

9

Chapter Two A

Haemodynamic consequences of mild therapeutic hypothermia after cardiac arrest

17

Chapter Two B

Unexpected fatal neurological deterioration after successful cardio-pulmonary resuscitation and therapeutic hypothermia

31

Chapter Three

Early lactate decrease in patients after cardiopulmonary resuscitation after out of hospital cardiac arrest

41

Chapter Four

Long-term outcome of patients after out-of-hospital cardiac arrest in relation to treatment: a single centre study

53

Chapter Five

Short- and long-term outcome after OHCA in patients aged 75 years and older

75

Chapter Six

Long-term outcome in patients requiring mechanical ventilation after ST-segment elevation myocardial infarction

93

Chapter Seven

The frequency of electrocardiographic changes, arrhythmias and sudden cardiac death in severe traumatic brain injury

111

Chapter Eight

Summary, discussion and future directions

129

Chapter Nine

Samenvatting, discussie en toekomstperspectieven

147

Dankwoord

167

Curriculum Vitae

171

Publications

175

Abbreviations

181

Chapter One

General introduction and scope of the

thesis

11


The beginnings of CPRThough Cardiopulmonary Resuscitation (CPR) may date back hundreds or even thousands of years, the first instance of CPR being medically cited occurred in 1740 when the Paris Academy of Science first recommended mouth-to-mouth resuscitations as a means of restoring life to drowning victims. Somewhat later, in August 1767 wealthy and civic-minded citizens in Amsterdam gathered to form the Society for Recovery of Drowned Persons.1 This society was the first organized effort to respond to sudden death.2 Some techniques this society propagated are still used today:

■ warming the victim; ■ removing swallowed or aspirated water by positioning the victim’s head

lower than feet; ■ applying manual pressure to the abdomen; ■ respirations into the victim’s mouth, either using a bellows or with a

mouth-to-mouth method;However other arguable less usefull measures were abandoned, such as;

■ tickling the victim’s throat; ■ ‘stimulating’ the victim by such means as rectal and oral fumigation with

tobacco smoke; bellows were used to drive tobacco smoke, a known irritant, into the intestine through the anus, as this was thought to be enough of a stimulant to engender a response in the “almost” dead;

■ and bloodletting.

In modern medicine the first publications and more scientifically based methods came in the 1950’s when Peter Safar, an anesthesiologist, wrote about mouth to mouth resuscitation & chest compressions.3 Together with James Elam, who also pioneered the ventilator, he rediscovered the airway, head tilt, chin lift (Step A) and the mouth-to-mouth breathing (Step B) components of CPR. Safar began to work on cardiopulmonary resuscitation (CPR) in 1956 at Baltimore City Hospital. In several experiments where he administered a muscle relaxant to awake volunteers, he demonstrated that “rescuer exhaled air” mouth-to-mouth breathing could maintain satisfactory oxygen levels in the non-breathing “victim”.3,4 He combined the A (Airway) and the B (Breathing) of CPR with the C (chest compressions) 5, and wrote the book “ABC of Resuscitation” in 1957.6 This work was instrumental in the establishment of mass training of CPR. This A-B-C system for CPR training of the public was later adopted by the American Heart Association, which propagated standards for CPR in 1973.7 In 1961 Safar extended CPR to include cerebral resuscitation in recognition of the fact that cerebral recovery is dependent on arrest and cardiopulmonary resuscitation times, and numerous factors related to basic, advanced, and prolonged life support.8

Mild therapeutic hypothermiaLike CPR hypothermia was already in use long before modern medicine employed it. Already described by Hippocrates 9 and the ancient Romans 10 for treating wounded soldiers on the battle field, the first modern research into hypothermia was published by William & Spencer in 1958 describing a case series of 4 patients that were treated

12

Chapter One

successfully after cardiac arrest.11

In the early nineties animal experiments showed that inducing and prolonging hypothermia increased the positive results, and that cooling during resuscitation could further improve outcome.12 Towards the end of the nineties five clinical trials were held throughout the world, which all showed positive results.

The beginning of mass use of mild therapeutic hypothermia after OHCA was after two large studies performed in Europe and Australia in 2002 showed improved outcome.13,14 The utilization of mild therapeutic hypothermia has now gained widespread following at least in Europe 15, but implementation has not been instantaneous.16 While the larger hypothermia trials have focused mainly on patients with ventricular tachycardia (VT) or ventricular fibrillation (VF) as the initial rhythm, preliminary results indicate favourable effects also in other causes such as asystole or pulseless electrical activity (PEA), though these had not been researched extensively. However in 2010 an analysis from the NICE (Netherlands Intensive Care Evaluation) database showed a definite improvement in outcome when implementing MTH after cardiac arrest.17 More recently the effectiveness of this treatment option has been questioned.18 Nielsen et al. found no difference in outcome between patients cooled to 33 °C vs. 36 °C. This has raised the supposition that prevention of fever rather than hypothermia itself is the mechanism in improving outcome in patients after OHCA.19 Today the optimum temperature of treating patients after OHCA has not been firmly established.

Relationship between the heart & the brainBesides the advances in the field of CPR & mild therapeutic hypothermia, there are also other factors, which can improve outcome in OHCA.20-23 The outcome after OHCA is related to the initial rhythm, the presence of witnesses and the organization of care. Mainly patients with ventricular fibrillation (VF) as the initial rhythm survive.24 A myocardial infarction due to coronary artery disease (CAD) is the main cause for VF.24 In patients with an initial rhythm other than VF, CAD is less common. During the last few years, evidence has been emerging showing a definite role of cardiac intervention in improving outcome of patients after OHCA. PCI has been shown to improve chances of survival.25,26

In the early years of the previous decade thrombolytic therapy was employed during cardiac arrest and STEMI. This has been superseded by percutaneous coronary intervention (PCI). Good cardiac function has been shown as an independent predictor of survival in our recent study.26 In current guidelines and recommendations, the use of reperfusion therapy, i.e. either primary percutaneous coronary intervention (PCI) or thrombolytic therapy is recommended irrespective of the Glasgow coma score.27-29 Studies on the effect of primary PCI as part of a ST elevation myocardial infarction (STEMI) study protocol are increasingly common.30-34 Cerebral perfusion may be the key to prevent further ischemic damage alongside mild therapeutic hypothermia.26,34,35 Arrhythmia and sudden cardiac death have been correlated with traumatic brain injury.36-38

13


A number of case studies concerning arrhythmia and ECG changes in patients after traumatic brain injury are present although patient numbers are limited.39,40 ECG abnormalities in traumatic brain injury are described in combination with autonomic disturbances, elevation of cardiac enzymes 41, cardiac arrhythmias and disturbances in blood pressure regulation and cerebrogenic pulmonary oedema.42 A role of the insula is suggested although the volume of research is quite low and understanding of these phenomena is illusive.41

These same phenomena have been described in the setting of acute stroke or intracranial haemorrhage. Concomitant elevations of cardiac troponin levels and ischemic ECG changes have also been described leading to erroneous diagnosis of ischemic heart disease. In one series of 149 patients with symptoms of acute stroke, 27% were found to have elevated serum cTnI. Elevated troponin levels were also noted in two case series of patients with subarachnoid haemorrhage (SAH).43,44 Troponin elevations were seen to correlate with severity of neurologic injury and cardiovascular abnormalities including left ventricular dysfunction, pulmonary oedema, and hypotension requiring vasopressors. And in one of the studies, elevations in cTnI also predicted a higher likelihood of in-hospital death or severe disability at discharge, although this relationship was no longer significant at three months.44

Scope of this thesisOver the past decade there have been many improvements in the management of patients after cardiac arrest. In this thesis we investigated what these changes were and what their effect on outcome was for all patients after cardiac arrest. In chapter two we researched the consequences of treatment with mild hypothermia; it’s physiological and metabolic effects. In chapter three we evaluate the clearance of lactate, a by-product of anaerobic metabolism, after return of spontaneous circulation (ROSC) after OHCA. We compare these values to patients treated for sepsis as well as athletes. In chapter four we investigated the relationship between initial rhythm, coronary intervention and outcome.

In chapter five we delved deeper into the treatment results for a group, which is specifically at risk, the elderly. In chapter six we compare the latest treatment results with the outcome for patients with STEMI. In chapter seven we look at the reverse relationship between traumatic brain disease and cardiac function. Finally in chapter eight the results of this thesis and the value of future developments are discussed.

14

Chapter One

References1. Johnson A. An account of some societies at Amsterdam and Hamburg for the recovery of drowned persons, 1773.2. Cary RJ. A brief history of the methods of resuscitation of the apparently drowned. Bulletin of the Johns Hopkins Hospital 1913;24:243-51.3. Berman RA, Safar P. Mouth-to-mouth resuscitation. Anesthesiology. 1958;19(5):685- 87.4. Safar P, Escarraga LA, Elam JO. A comparison of the mouth-to-mouth and mouth-to-airway methods of artificial respiration with the chest-pressure arm- lift methods. N Engl J Med. 1958;258(14):671-77. 5. Safar P, Brown TC, Holtey WJ, et al. Ventilation and circulation with closed- chest cardiac massage in man. JAMA. 1961;176:574-76.6. Soar J, Perkins GD, Nolan J. ABC of Resuscitation: John Wiley & Sons 2012.7. Srikameswaran A. Srikameswaran: Dr. Peter Safar: A life devoted to. - Google Scholar2003.8. Safar P. Community-wide cardiopulmonary resuscitation. Journal of the Iowa Medical Society. 1964;54:629-35.9. Hippocrates. De Vetere Medicina. 46010. AC C. De Medicina. 10011. Williams GR, Spencer FC. The clinical use of hypothermia following cardiac arrest. Annals of surgery. 1958;148(3):462-68.12. Sterz F, Safar P, Tisherman S, et al. Mild hypothermic cardiopulmonary resuscitation improves outcome after prolonged cardiac arrest in dogs. Crit Care Med. 1991;19(3):379-89.13. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out- of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557-63. 14. Group HaCAS. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549-56. 15. Skulec R, Truhlár A, Knor J, et al. The practice of therapeutic mild hypothermia in cardiac arrest survivors in the Czech republic. Minerva anestesiologica. 2010;76(8):617-23.16. Laver SR, Padkin A, Atalla A, et al. Therapeutic hypothermia after cardiac arrest: a survey of practice in intensive care units in the United Kingdom. Anaesthesia. 2006;61(9):873-77. 17. van der Wal G, Brinkman S, Bisschops LL, et al. Influence of mild therapeutic hypothermia after cardiac arrest on hospital mortality. Crit Care Med. 2011;39(1):84-88. 18. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33 °C versus 36 °C after cardiac arrest. N Engl J Med. 2013;369(23):2197- 206. 19. Bergman R, Tjan DHT, Adriaanse MW, et al. Unexpected fatal neurological deterioration after successful cardio-pulmonary resuscitation and therapeutic hypothermia. Resuscitation. 2008;76(1):142-45.

15


20. Holmberg M, Holmberg S, Herlitz J, et al. Survival after cardiac arrest outside hospital in Sweden. Swedish Cardiac Arrest Registry. Resuscitation. 1998;36(1):29-36. 21. Herlitz J, Engdahl J, Svensson L, et al. Decrease in the occurrence of ventricular fibrillation as the initially observed arrhythmia after out-of-hospital cardiac arrest during 11 years in Sweden. Resuscitation. 2004;60(3):283-90. 22. Martinell L, Larsson M, Bang A, et al. Survival in out-of-hospital cardiac arrest before and after use of advanced postresuscitation care: a survey focusing on incidence, patient characteristics, survival, and estimated cerebral function after postresuscitation care. Am J Emerg Med. 2010;28(5):543-51. 23. Nichol G, Aufderheide TP, Eigel B, et al. Regional systems of care for out-of- hospital cardiac arrest: A policy statement from the American Heart Association. Circulation. 2010;121(5):709-29. 24. Silfvast T. Cause of death in unsuccessful prehospital resuscitation. J Intern Med. 1991;229(4):331-35. 25. Spaulding CM, Joly LM, Rosenberg A, et al. Immediate coronary angiography in survivors of out-of-hospital cardiac arrest. N Engl J Med. 1997;336(23):1629- 33. 26. Bergman R, Hiemstra B, Nieuwland W, et al. Long-term outcome of patients after out-of-hospital cardiac arrest in relation to treatment: a single centre study. Eur Heart J Acute Cardiovasc Care. 2016 Aug;5(4):328-38.27. 2005 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Part 1: introduction. Resuscitation. 2005;67(2-3):181-86. 28. Cummins RO, Chamberlain DA, Abramson NS, et al. Recommended guidelines for uniform reporting of data from out-of-hospital cardiac arrest: the Utstein Style. A statement for health professionals from a task force of the American Heart Association, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, and the Australian Resuscitation Council. Circulation. 1991;84(2):960-75. 29. Nolan JP, Soar J, Zideman DA, et al. European Resuscitation Council Guidelines for Resuscitation 2010 Section 1. Executive summary. Resuscitation. 2010;81(10):1219-76. 30. Bendz B, Eritsland J, Nakstad AR, et al. Long-term prognosis after out-of hospital cardiac arrest and primary percutaneous coronary intervention. Resuscitation. 2004;63(1):49-53. 31. Hovdenes J, Laake JH, Aaberge L, et al. Therapeutic hypothermia after out-of- hospital cardiac arrest: experiences with patients treated with percutaneous coronary intervention and cardiogenic shock. Acta Anaesthesiol Scand. 2007;51(2):137-42. 32. Knafelj R, Radsel P, Ploj T, et al. Primary percutaneous coronary intervention and mild induced hypothermia in comatose survivors of ventricular fibrillation with ST-elevation acute myocardial infarction. Resuscitation. 2007;74(2):227- 33. Garot P, Lefevre T, Eltchaninoff H, et al. Six-month outcome of emergency percutaneous coronary intervention in resuscitated patients after cardiac arrest complicating ST-elevation myocardial infarction. Circulation.

16

Chapter One

2007;115(11):1354-62. 34. Dumas F, Cariou A, Manzo-Silberman S, et al. Immediate percutaneous coronary intervention is associated with better survival after out-of-hospital cardiac arrest: insights from the PROCAT (Parisian Region Out of hospital Cardiac ArresT) registry. Circ Cardiovasc Interv. 2010;3(3):200-07. 35. Dumas F, Rea TD. Long-term prognosis following resuscitation from out-of- hospital cardiac arrest: role of aetiology and presenting arrest rhythm. Resuscitation. 2012;83(8):1001-05. 36. Hersch C. Electrocardiographic changes in head injuries. Circulation. 1961;23:853-60. 37. Walder LA, Spodick DH. Global T wave inversion. J Am Coll Cardiol. 1991;17(7):1479-85. 38. Oppenheimer SM, Cechetto DF, Hachinski VC. Cerebrogenic cardiac arrhythmias. Cerebral electrocardiographic influences and their role in sudden death. Archives of neurology. 1990;47(5):513-19. 39. Rabinstein AA. Paroxysmal sympathetic hyperactivity in the neurological intensive care. Neurological research. 2007;29(7):680-82. 40. Keren O, Yupatov S, Radai MM, et al. Heart rate variability (HRV) of patients with traumatic brain injury (TBI) during the post-insult sub-acute period. Brain injury : [BI]. 2005;19(8):605-11. 41. Cheshire WPJ, Saper CB. The insular cortex and cardiac response to stroke. Neurology. 2006;66(9):1296-97. 42. Gajic O, Manno EM. Neurogenic pulmonary edema: another multiple-hit model of acute lung injury. Crit Care Med. 2007;35(8):1979-80. 43. Tung P, Kopelnik A, Banki N, et al. Predictors of neurocardiogenic injury after subarachnoid hemorrhage. Stroke; a journal of cerebral circulation. 2004;35(2):548-51. 44. Naidech AM, Kreiter KT, Janjua N, et al. Cardiac troponin elevation, cardiovascular morbidity, and outcome after subarachnoid hemorrhage. Circulation. 2005;112(18):2851-56.

Chapter Two A

Haemodynamic consequences of mild

therapeutic hypothermia after cardiac

arrest

Remco Bergman, Annemarije Braber, Marlies A. Adriaanse, Roel van Vugt, David H.T.

Tjan and Arthur R.H. van Zanten

Eur J Anaesthesiol. 2010 Apr; 27(4):383-7.

19


AbstractBackground and objective Mild therapeutic hypothermia (MTH) is used after out-of-hospital cardiac arrest (OHCA) to minimize cerebral damage. Induced hypothermia may further interfere with cardiac function and influence haemodynamics after OHCA.

Methods This was a prospective study of haemodynamic variables in 50 consecutive patients with OHCA treated with MTH. Patients were cooled to a core body temperature of 32 °C for 24 hours. Induction and maintenance of cooling was accomplished via infusion of 2 litres of cold isotonic saline (4 °C) and a cooling blanket. Rewarming was performed to 36 °C at a rate of 0.3 °C per hour. Haemodynamic data were analysed and compared in individual patients during different temperature phases.

Results Heart rate dropped from a mean of 85 to 60 beats per min (P = 0.001) during hypothermia. Mean arterial pressure dropped from 79 to 72 mmHg, despite a rise in vasopressors and inotropes. Lactate levels were elevated throughout the induction (mean ± SD) and maintenance phase (mean ± SD); however, this did not correlate with a decrease in SVO2. Pulmonary artery pressures decreased during induction of hypothermia despite rapid infusion.

Conclusion MTH after OHCA lowered the heart rate. Despite induction of hypothermia with cold fluids, filling pressures decreased. Lower mean arterial pressure and cardiac output were observed during MTH, without deleterious effect on ScVO2. Lactate levels were elevated during MTH; however, levels did not correlate with outcome. Although the need for vasopressors and inotropes increases, this hypothermia-induced metabolic b-blocker-like effect seems to have no negative effect on oxygen consumption and only temporarily affects anaerobic metabolism. No association of haemodynamic changes during MTH with outcome was found.

20

Chapter Two A

IntroductionIn 1961 cardiopulmonary resuscitation (CPR) was extended to also include cerebral resuscitation.1 In the early 1990s, animal experiments showed that induction or prolongation of hypothermia after cardiac arrest positively influenced survival and that cooling during resuscitation could further improve outcome.2

Since then, three prospective randomized clinical trials on humans have been performed.3-5 All showed improved survival and neurological outcome. A recent meta-analysis observed that the mean number needed to treat to allow one additional patient to be discharged from hospital with favourable neurological recovery was six [95% confidence interval (CI) 4-13].6

Although the larger hypothermia trials have so far mainly focused on patients with ventricular tachycardia or ventricular fibrillation as the initial rhythm, preliminary results also indicate favourable effects in other causes such as asystole or pulseless electrical activity (PEA), although these have not been researched extensively. The application of hypothermia in this group, however, may provide benefits, as has been suggested by a more recent study.7

Reviewing the evidence, there seems to be an abundance of reasons for implementing mild therapeutic hypothermia (MTH) in clinical practice. There are, however, side effects. Much of the knowledge on side effects of hypothermia has been gained from observations in accidental hypothermia. It can lead to loss of electrolytes (potassium, magnesium and phosphate) due to both increased urinary excretion and intracellular shift. These findings also have been confirmed in clinical studies on MTH.8,9 Electrolyte abnormalities may further affect cardiac performance.

Hypothermia remains underused in Dutch ICUs; for example, only around 50% of hospitals in the Netherlands currently treat comatose patients following cardiac arrest according to the guidelines of the Netherlands Society of Intensive Care Medicine.10 In Britain, a recent survey showed only 26% application of therapeutic hypothermia after cardiac arrest.11 A reason for these low rates may be fear of potential side effects, as has recently been described.12

A large percentage of patients with out-of-hospital cardiac arrest (OHCA) have acute coronary syndromes and myocardial infarction. This may include cardiac function. Induced hypothermia may further interfere with cardiac function and influence haemodynamics after OHCA. As information on haemodynamic variables during MTH is scarce, we studied these in patients with OHCA admitted to our ICU.

Patients & methodsPatients Our hospital is a teaching non-university hospital and the primary hospital for 250,000 people in a rural area in the Netherlands. Emergency care is provided by ambulance services, with each ambulance being staffed by a registered nurse with additional training

21


in emergency care and a driver. The hospital response team consists of an intensive care and internal medicine physician backed up by staff from the coronary care unit (CCU) and emergency department.

Our standard care hypothermia protocol includes all adult patients (> 18 years of age) after cardiac arrest with return of spontaneous circulation (ROSC), both in-hospital cardiac arrest (IHCA) and OHCA with a Glasgow coma score less than 8 at presentation in the emergency department or on admission to the ICU.

Patients who had cardiac arrest were treated according to advance cardiac life support (ACLS) guidelines.

Treatment protocol Hypothermia was induced via rapid infusion of 2 litres of cold isotonic saline (4 °C) followed by further induction and maintenance of cooling with the patient positioned between two water-cooled blankets (Blanketroll II, CSZ, Cincinnati, Ohio, USA). Temperature was measured continuously with an oesophageal temperature probe and used as feedback for the cooling device. After reaching the target temperature of 32 °C, patients were maintained at this temperature for 24 hours. After the maintenance phase, patients were rewarmed at a controlled rate of 0.3 °C per hour to reach a target temperature of 36 °C and sedation was discontinued. The complete protocol is depicted in figure 1.

22

Chapter Two A

Rewarming phase Rewarming rate of 0.3 °C per hour to target temperature of 36 °C Discontinuation of sedation after reaching normal temperature (propofol) or when starting rewarming (morfine/midazolam) Preservation of normothermia for 24 hours using cooling mattress and/or antipyretics

Induction phase Sedation with propofol or midazolam and morfine, in case of severe shivering add bolus rocuronium Rapid infusion of 2 litres cold saline (4 °C) Two cooling mattresses (Blanketroll II, CSZ) underneath and on top of patient temperature set on 4 °C until temperature 34 °C is reached, then set at 32,5 °C Supplementation of 2g magnesium sulphate i.v.

Hypothermia maintenance phase Maintenance of therapeutic hypothermia with cooling mattresses set at temperature 32.5 °C for 24 hours Continuation of sedation

Laboratory investigation during therapeutic hypothermia During first 6 hours every 2 hours, thereafter every 4 hours: potassium, calcium, magnesium, phosphate, glucose, arterial blood gas Once daily; complete blood count, renal functions, amylase, liver enzymes, prothrombin time, activated partial thromboplastin time

Figure 1. Treatment protocol.

Haemodynamic disturbances in patients were treated and monitored according to the discretion of the attending intensivist using inotropes and vasopressors to influence blood pressure, heart rate and ScVO2 or SVO2, if necessary. Pulmonary artery catheters are not routinely used; however, in case of insertion, data were collected and analysed. All patients were treated with cefotaxime prophylactically with the intent to prevent aspiration pneumonia. Furthermore, sedation with midazolam and morphine was used for deep sedation until rewarming.

Study design A total of 50 consecutive patients were enrolled into the hypothermia protocol as part of standard care. During MTH, we analysed haemodynamic data from four phases both continuously and at set intervals: induction (T = 0 h), maintenance (T = 24 h), rewarming (T = 36 h) and normothermia (T = 52 h). Data were collected using medical records, monitoring charts and laboratory tests. ScVO2 and SVO2 were summarized in one dataset.

23


ScVO2 was diminished by 5% to add data to pulmonary artery catheter measurements of SVO2. Statistical analysis was performed by SAS software. Results are presented as mean ± SD. Student’s unpaired t-test and χ2 test were used for comparisons, and Welch corrections were made when appropriate. Statistical significance was accepted as a P-value of less than 0.05.

ResultsPatients’ characteristics are shown in table 1. The mean time to reach the target temperature was 151.8 ± 74.5 min. The treatment protocol was ended prematurely in only two cases due to death from multiple organ dysfunction syndrome (MODS) (4%). Forty-eight patients completed the induction, maintenance, rewarming and normothermia phase.

Table 1. Clinical characteristics of studied patients.

Mean ± SD

Age (years) 70.8 ± 15.4

Male sex (n/%) 31 (62)

APACHE-II score 23.3 ± 8.8

ICU LOS (days) 7.0 ± 5.2

HLOS (days) 13.1 ± 13.8

ICU mortality (n/%) 31 (62)APACHE II = Acute Physiology And Chronic Health Evaluation II. HLOS = Hospital Length Of Stay. LOS = Length Of Stay.

During induction of hypothermia, heart rate dropped from a mean of 85 to 60 beats per min (P = 0.001) during the hypothermia maintenance phase (figure 2). This lower heart rate was accompanied by a decrease in the cardiac index as compared with normothermia (2.64 ± 0.87 vs. 2.45 ± 0.59; P = 0.03; figure 3). Mean arterial pressure (MAP) decreased during MTH from 79.5 ± 19.36 to 72.08 ± 10.05. This was also accompanied by an increase in vasopressor use. Almost all patients (92%) required norepinephrine from a mean of 0.45 mg/h during induction to 0.6 mg/h during the maintenance phase (P = 0.004) and rising to 0.8 mg/h during the rewarming phase (P = 0.00023). In the normothermia phase, in all patients, all vasoactive medications could be stopped.

24

Chapter Two A

Figure 2. Heart rate during mild therapeutic hypothermia.

Figure 3. Cardiac index during mild therapeutic hypothermia.

25


Figure 4. PAP pressures during mild therapeutic hypothermia.

Figure 5. Urine production during mild therapeutic hypothermia.

26

Chapter Two A

Thirteen patients (27%) were given a pulmonary artery catheter at the discretion of the attending intensivist. Mean pulmonary artery pressures decreased during induction of hypothermia from 18.6 ± 6.58 to 11.8 ± 3.49, despite the fact that induction was carried out by infusion of ice-cold isotonic saline (P = 0.02; see figure 4).

Urine output during MTH is depicted in figure 5. After an initial increase in urine output, normal urine flow can be seen.

Lactate measurements were taken at all time points in 20 patients. Levels are shown in figure 6.

Figure 6. Arterial lactate levels during mild therapeutic hypothermia.

Lactate levels were elevated during induction (6.68 ± 3.64; 0.5–1.7 mmol /l) and during the maintenance phase (3.29 ± 2.44). During rewarming, levels normalized. In total, 46 measurements of ScVO2 (n = 17) and SVO2 (n = 29) were available. Combined data are shown in table 2.

27


Table 2. Mixed venous oxygen levels during Mild Therapeutic Hypothermia.

Time Induction Maintenance Rewarming Normothermia

T °C (± SD) 35,4 (1,1) 32,6 (0,5) 35,9 (0,6) 37 (0,5)

Mean SVO2 (± SD) 72.5(12,3)

78(9,4)

78(11,9)

80(13,2)

DiscussionWe demonstrated marked haemodynamic consequences in a cohort of 48 patients treated with MTH using a rigorous protocol. We found a marked reduction in heart rate. This b-blocker-like effect may positively affect ischaemia or myocardial damage size. Lowering heart rate is a cornerstone of treatment in patients with acute coronary syndromes.13,14 However, in many patients after OHCA, b-blockers cannot be used, as low blood pressures are common in this group, for example comprising 55% of patients in a large hypothermia study after cardiac arrest.2 Animal data also suggest a modulating effect of MTH on myocardial infarction 15,16, but this may be protective only during ischaemia and not reperfusion.17 In our study group, 92% of patients needed vasoconstrictors. Therefore, this adverse effect (bradycardia) of mild hypothermia may in fact be a beneficial factor in patients with MTH-treated OHCA. No patients needed pacemaker stimulation and in some patients (27 of 48 patients) norepinephrine was temporarily exchanged for dopamine (which exerts positive chronotropic effects and vasoconstriction in higher dosages).

In several animal experiments, it has been suggested that rapid induction is of pivotal importance to improve outcome.18 As induction of cooling may take some time for central body temperature to drop, infusion of cold isotonic saline is commonly used. Our data show that, despite this fluid induction, filling pressures decrease, suggesting this does not present relevant clinical problems such as fluid overloading.

Despite induction of hypothermia with 2 litres of cold isotonic saline (4 °C), pulmonary artery pressures decreased. This is in line with previous research addressing the safety of infusion of ice-cold isotonic saline.18,19 This may suggest that many patients initially are hypovolaemic.

We found an initial rise in urine output during MTH. This is often explained as cold diuresis, caused by peripheral vasoconstriction promoting subsequent higher central filling pressures.20 Others have suggested this could be due to nephrogenic diabetes insipidus due to decreased renal collecting tubular function during hypothermia.21

However, we feel these explanations are not very likely as diuresis was not excessive during the hypothermia maintenance phase. Another explanation may be that our rapid fluid induction had some influence only on early phase urine output. Marked cold diuresis

28

Chapter Two A

during ongoing hypothermia treatment was not seen. It is difficult to analyse whether these results may have been influenced by acute tubular necrosis after cardiac arrest. We may conclude that high urine output or cold diuresis does not pose a relevant clinical problem.

Although a drop in cardiac index (10%) may lead to inadequate organ perfusion, during induced hypothermia, we could not demonstrate that this lower cardiac output caused lower mixed venous oxygen saturation. This suggests that, parallel to the drop in cardiac output, oxygen consumption was also lower due to the lower body temperature. In other words, during MTH, the workload for the injured heart may be lower due to lower resting energy metabolism required at a lower body temperature.22

The findings of elevated lactate levels during hypothermia that normalize during rewarming could suggest tissue hypoperfusion. In contrast to this, we found normal mixed venous oxygen saturation levels. In addition, we could not find any correlations of elevated lactate levels during hypothermia with outcome.

We hypothesize that hyperlactataemia may be related to hypothermia and is not deleterious or prognostic per se as hyperlactataemia has also been described during hypothermia in cardiac surgery patients.23

Raper et al. 23 published data on a subgroup of cardiac bypass surgery patients with type B lactic acidosis who had longer duration of cardiopulmonary bypass, more frequent requirement for vasopressor agents and greater intraoperative hypothermia. Haemodynamic variables, including cardiac index, were remarkably similar in both the lactic acidotic and non-acidotic groups. All of the acidotic patients, in both parts of this study, recovered from their acidosis. Occurrence of type B lactic acidosis was frequent in this subgroup of patients undergoing cardiopulmonary bypass. They stated that the pathogenesis of this disorder is uncertain, but it appeared not to relate to inadequate oxygen delivery and that systemic vasodilatation and reduced oxygen extraction appear to be features of this disorder, which has an excellent prognosis.

This suggests that some lactate elevation may be normal during hypothermia; at least it does not predict poor outcome. Therefore, we feel that no conclusions about whether to continue treatment should be based on these elevated lactate findings.

In conclusion, we have shown that MTH causes haemodynamic consequences. The hypothermia-induced metabolic b-blocker-like effect on lowering heart rate and possibly cardiac output seems to have no negative effect on oxygen consumption. Blood pressures are lower in many patients and vasopressors are used frequently. Although there is an increase in lactate levels, it is unclear whether this is caused by increased anaerobic metabolism and it is not associated with poor outcome in MTH patients. Cold diuresis is not an important clinical problem. Induction with cold isotonic saline up to 2 litres does not cause relevant negative haemodynamic consequences or fluid overload.

29


References1. Safar P. Heart-lung resuscitation (cardiopulmonary-cerebral resuscitation). J Iowa Med Soc. 1964; 54:629–635.2. Sterz F, Safar P, Tisherman S, et al. Mild hypothermic cardiopulmonary resuscitation improves outcome after prolonged cardiac arrest in dogs. Crit Care Med. 1991; 19:379-389.3. The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurological outcome after cardiac arrest. N Engl J Med. 2002; 346:549-556.4. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002; 346:557-563.5. Hachimi-Idrissi S, Corne L, Ebinger G, et al. Mild hypothermia induced by a helmet device: a clinical feasibility study. Resuscitation. 2001; 51:275-281.6. Holzer M, Bernard SA, Hachimi-Idrissi S, et al. Hypothermia for neuroprotection after cardiac arrest: systematic review and individual patient data meta- analysis. Crit Care Med. 2005; 33:414-418.7. Holzer M, Mullner M, Sterz F, et al. Efficacy and safety of endovascular cooling after cardiac arrest: cohort study and Bayesian approach. Stroke. 2006; 37:1792-1797.8. Tokutomi T, Miyagi T, Morimoto K, et al. Effect of hypothermia on serum electrolyte, inflammation, coagulation, and nutritional parameters in patients with severe traumatic brain injury. Neurocrit Care. 2004; 1:171-182.9. Polderman KH, Girbes AR. Severe electrolyte disorders following cardiac surgery: a prospective controlled observational study. Crit Care. 2004; 8:R459-R466.10. Bergman R, Polderman KH, van Zanten ARH. First National Therapeutic Hypothermia Symposium: a narrative report. Neth J Crit Care. 2007; 11:111- 115.11. Laver SR, Padkin A, Atalla A, Nolan JP. Therapeutic hypothermia after cardiac arrest: a survey of practice in intensive care units in the United Kingdom. Anaesthesia. 2006; 61:873-877.12. Polderman KH. Application of therapeutic hypothermia in the intensive care unit. Opportunities and pitfalls of a promising treatment modality. Part 2: Practical aspects and side effects. Intensive Care Med. 2004; 30:757-769.13. Avezum A, Piegas LS, Goldberg RJ, et al. Magnitude and prognosis associated with ventricular arrhythmias in patients hospitalized with acute coronary syndromes (from the GRACE registry). Am J Cardiol. 2008; 102:1577-1582.14. Corbelli JC, Janicke DM, Cziraky MJ, et al. Acute coronary syndrome emergency treatment strategies: improved treatment and reduced mortality in patients with acute coronary syndrome using guideline-based critical care pathways. Am Heart J. 2009; 157:61-68.15. Babu PP, Suzuki G, Ono Y, Yoshida Y. Attenuation of ischemia and/or reperfusion injury during myocardial infarction using mild hypothermia in rats: an immunohistochemical study of Bcl-2, Bax, Bak and TUNEL. Pathol Int.

30

Chapter Two A

2004; 54:896–903.16. Hale SL, Dae MW, Kloner RA. Hypothermia during reperfusion limits ‘no- reflow’ injury in a rabbit model of acute myocardial infarction. Cardiovasc Res. 2003; 59:715-722.17. Maeng M, Mortensen UM, Kristensen J, et al. Hypothermia during reperfusion does not reduce myocardial infarct size in pigs. Basic Res Cardiol. 2006; 101:61-68.18. van Zanten AR, Polderman KH. Early induction of hypothermia: will sooner be better? Crit Care Med. 2005; 33:1449-1452.19. Polderman KH, Rijnsburger ER, Peerdeman SM, et al. Induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous fluid. Crit Care Med. 2005; 33:2744- 2751.20. Knight DR, Horvath SM. Urinary responses to cold temperature during water immersion. Am J Physiol. 1985; 248 (5 Pt 2):R560-R566.21. Granberg PO. Human physiology under cold exposure. Arctic Med Res. 1991; 50 (Suppl 6):23-27.22. Yenari M, Kitagawa K, Lyden P, Perez-Pinzon M. Metabolic downregulation: a key to successful neuroprotection? Stroke. 2008; 39:2910-2917. 23. Raper RF, Cameron G, Walker D, . Type B lactic acidosis following cardiopulmonary bypass. Crit Care Med. 1997; 25:46-51.

Chapter Two B

Unexpected fatal neurological

deterioration after successful cardio-

pulmonary resuscitation and therapeutic

hypothermia

Remco Bergman, David H.T. Tjan, Marlies W. Adriaanse, Roel van Vugt, Arthur R.H. van

Zanten

Resuscitation. 2008 Jan;76(1):142-5.

33


AbstractA 77-year-old woman was admitted to the intensive care unit after successful cardiopulmonary resuscitation for out-of-hospital cardiac arrest due to pulseless electrical activity. She was treated with mild therapeutic hypothermia to minimise secondary anoxic brain damage.

After a 24 hour period of therapeutic hypothermia with a temperature of 32.5 °C, the patient was rewarmed and sedation discontinued. Neurological evaluation after 24 hours revealed a maximum Glasgow Coma Score of E4M4Vt with spontaneous breathing. However the patient developed a fever reaching 39 °C for several hours that was unresponsive to conventional cooling methods. In the subsequent 24 hours the patient developed apnoea, hypotension and bradycardia with deterioration of the coma score. Diabetes insipidus was confirmed. Cerebral CT was performed which showed diffuse brain oedema with herniation and brainstem compression. The patient died within hours.

Autopsy showed massive brain swelling and tentorial herniation. Hyperthermia possibly played a pivotal role in the development of this fatal insult to this vulnerable brain after cardiac arrest and therapeutic hypothermia treatment. The acute histopathological alterations in the brain, possibly caused by the deleterious effects of fever after cardiac arrest in human brain, may be considered a new observation. © 2007 Elsevier Ireland Ltd. All rights reserved.

34

Chapter Two B

IntroductionImportant factors determining outcome after out-of-hospital cardiac arrest (OHCA) are primary and secondary brain damage. Neurological complications account for two thirds of deaths after initial resuscitation of OHCA patients.1 Recently, the use of mild hypothermia to lower body metabolism and decrease mechanisms of secondary brain damage has been advocated as a standard of care.2 We present a case in which uncontrolled fever; even after a 36 hours hypo- and normothermic window, possibly caused secondary brain injury and negated the positive effects of mild hypothermia.

Case reportA 77-year-old woman with a history of aortic valve stenosis and left ventricular hypertrophy became increasingly dyspnoeic at home. No immediate life support was started when she collapsed. Paramedics arrived at the scene 10 min later and pulseless electrical activity was noted. The patient was intubated and resuscitated according to ACLS guidelines. Return of spontaneous circulation was noted after a total of 12 min.

On arrival at the emergency room, she was still comatose (GCS = 1-1-T) with midrange dilated pupils unresponsive to light. On ICU admission, her vitals signs were as follows: temperature 33.9 °C, heart rate 65 beats/min, blood pressure 120/60 mmHg, and intubated with controlled mechanical ventilation. The initial arterial blood gas showed pH 7.29 (7.37-7.45), pCO2 4.4 kPa (4.5-6.0 kPa), pO2 14.2 kPa (9.5-13.0 kPa), HCO3 15.6 mmol/l (22-26 mmol/l), BE -9.4 mmol/l (-2.0 to +2.0 mmol/l), SaO2 97% (92-99%). Laboratory examination revealed an initial lactate of 14.8 mmol/l (0.5-1.7 mmol/l). Troponin-I levels were only mildly elevated: 1.8 mcg/l (0-0.48 mcg/l). Cardiac ultrasound revealed severe left ventricular hypertrophy with reduced LV function and aortic valve stenosis with a gradient of 50-70 mmHg.

Mild therapeutic hypothermia was initiated and the patient was sedated and actively cooled to a core temperature of 32.5 °C. Target temperature was reached within 2 hours of admission. Cooling was performed with a 2 liter cold saline infusion (4 °C) in combination with an external cooling mattress.

Hypothermia was maintained for 24 hours. During this period, no significant haemodynamic instability occurred. Her mean arterial pressure was above 70 mmHg at all times with low doses of norepinephrine (noradrenaline) (dose range up to 0.05 mcg/kg/min) and intravenous fluids with a target central venous pressure between 8 and 10 mmHg. Venous mixed oxygen saturation (ScvO2) was 89% at the start of cooling. After 24 hours the patient was slowly rewarmed at a controlled rate of 0.3 °C/h until she reached a core body temperature of 36 °C. Sedation was stopped at that time. Over the next day, the neurological condition of the patient improved. Spontaneous breathing started and GCS improved to E4M4Vt. However, during the following 24 hours, the patient developed high fever, reaching body temperature of a maximum of 39 °C. All devices used to induce hypothermia were unavailable at that moment. Fever was treated with paracetamol and intravenous cefotaxime was started for suspected pulmonary infection. However, she remained hyperthermic for 34 hours.

35


The patient had episodes of bradypnoea which ultimately required renewed controlled mechanical ventilation. Subsequently, she developed hypertension, followed by hypotension and relative bradycardia. Pupils were fixed and dilated and a deterioration of GCS to E1M1Vt was noted. She developed polyuria (> 300 ml urine/h) and diabetes insipidus was diagnosed subsequently.

A cerebral CT-scan was performed showing massive and diffuse cerebral oedema. Complete compression of the fourth ventricle and supratentorial herniation was confirmed. Clinical brainstem death was reported after a neurological examination. The patient died in a matter of hours.

Post-mortem examination of the brain confirmed acute massive brain oedema with ischaemic changes, unlikely caused by the initial cardiac arrest. Furthermore, signs of congestive heart failure such as pulmonary oedema and bilateral pleural effusions were noted.

DiscussionSudden cardiac death (SCD) is a term used to describe cardiac arrest with cessation of cardiac functions regardless of the mechanism. Most common causes are ventricular fibrillation (VF), pulseless ventricular tachycardia (PVT), pulseless electrical activity (PEA) or asystole. PEA accounts for almost 25% of all cases of SCD.3 Resuscitation techniques and guidelines have improved over the last decade which resulted in improved survival after cardiac arrest.2,3 However, some survivors become vegetative and die from complications.

The development of mild therapeutic hypothermia as a treatment strategy has demonstrated the potential to improve neurological outcome.4,5 In 2002, two major studies were published that compared normothermia and therapeutic hypothermia in out-of-hospital cardiac arrest patients who were comatose on admission. One large European trial which targeted a temperature of 32-34 °C showed a relative risk of 1.4 in favour of the hypothermia group in terms of favourable neurological outcome (able to live independently and work at least part-time). The number needed to treat was six to achieve one additional surviving patient with good neurological function.2

The Australian study although smaller showed similar results; a relative risk reduction of 1.85 in favour of the hypothermia group.5 Although evidence for other initial rhythms than VF in case of SCD is scarce, some series and case reports do suggest positive effects in non-VF cases.6,7

We present a case of a patient with PEA and aortic valve stenosis, who was treated with mild hypothermia according to our local cooling protocol for patients for out-of-hospital cardiac arrest patients. Apart from the evidence supporting hypothermia treatment as brain protection there is also overwhelming evidence suggesting that hyperthermia may be deleterious and can increase ischaemic damage to the brain following a primary insult.

36

Chapter Two B

Animal experiments show that even delayed hyperthermia (up to 24 h) can result in very enhanced neurological damage after ischemic insults.8,9 Prospective trials in stroke victims have also shown that fever (T > 37.9 °C) is an independent predictor of poor outcome (odds ratio 3.4).10 Another trial in a similar patient group showed an increase of 2.2-fold (95% confidence interval, 1.4-3.5) for every 1 °C elevation of body temperature.11 To add to that evidence in cardiac arrest in 2001 results were published on patients with a favourable neurological outcome that showed a lower peak temperature (37.7 °C versus 38.3 °C; P = 0.001).12 The risk of unfavourable neurological outcome increased 2.2-fold per 1 °C elevation of body temperature.

This study did not focus on the causes of fever; however there were no statistical differences in markers of infection (white blood cell level, fibrinogen levels, C-reactive protein) or infiltrative disorders on chest X-ray. Higher temperatures were also shown to be associated with a higher incidence of brain death in another study of pyrexia following cardiac arrest.13 Comparing the weighted mean temperature (the area under the curve > 37 °C, divided by the time it was elevated) patients with a favourable neurological outcome had lower temperatures than in patients with an unfavourable neurological outcome (P = 0.002). Although it cannot be excluded that the rise in body temperature resulted from brain damage rather than that it may have caused it, there is ample evidence to conclude that pyrexia is detrimental in neurological injury. It has been shown to increase the release of excitatory neurotransmitters.14,15 Free radical production has been shown to increase 4-5-fold in hyperthermic ischaemia compared to a 2-3-fold increase in normothermia.16,17 In addition, adenosine triphosphate depletion and less complete recovery of the levels may occur during hyperthermia.18 Furthermore, calpain activation and spectrin proteolysis in cortical pyramidal neurons is enhanced during hyperthermia and associated with morphological evidence of irreversible neuronal injury.19

It is important to consider that while most temperatures are measured rectally to assess systemic temperature, brain temperatures following an insult are often higher. During direct measurement of brain temperature, brain temperatures exceeded body temperature in 90% of cases with the maximal gradient being 2.3 °C.20 Other studies have shown focal differences in brain temperature after focal insults.21

While the clinical applications of these findings may not be completely clear, one can hypothesize that when measuring modest systemic temperature elevations in patients with vulnerable brains due to ischaemia and reperfusion, brain temperature may already be at a dangerous level.

Experimental data have shown that even days after cardiac arrest some of the pathological processes in the brain may still persist stressing the importance of avoiding temperature rises in this period as fever can fuel this deleterious effects.22 Based on pathological post-mortem examinations, this case in our view suggests that fever may have caused late and ultimately fatal neurological deterioration after successful cardio-pulmonary resuscitation and therapeutic hypothermia.

37


ConclusionsFever is a risk factor for poor neurological outcome after cardiac arrest. How long this vulnerability of the brain lasts and the risk for neurological deterioration persists is not known. However our observations suggest that hyperthermia should be aggressively treated for several days after return to normothermia. In our ICU we try to control temperature after OHCA in the normothermic range up to 72 hours after the cessation of mild hypothermia in order to minimise damage by secondary mechanisms. Beware of the comatose patient with fever after out-of-hospital cardiac arrest even after therapeutic hypothermia!

Conflict of interestNone to declare.

38

Chapter Two B

References1. Laver S, Farrow C, Turner D, Nolan J. Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med. 2004;30(November (11)):2126-8. 2. The Collaborative Group on Induced Hypothermia for Neuroprotection After Cardiac Arrest. Hypothermia for neuroprotection after cardiac arrest: systematic review and individual patient data meta-analysis. Crit Care Med. 2005;33(February (2)):414-8. 3. Parish DC, Dinesh Chandra KM, Dane FC. Success changes the problem: why ventricular fibrillation is declining, why pulseless electrical activity is emerging, and what to do about it. Resuscitation. 2003;58:31. 4. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurological outcome after cardiac arrest. N Engl J Med. 2002;346:549-56. 5. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out- of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557-63. 6. Fink EL, Marco CD, Donovan HA, et al. Brief induced hypothermia improves outcome after asphyxial cardiopulmonary arrest in juvenile rats. Dev Neurosci. 2005;27(March-August (2-4)):191-9. 7. Silfvast T, Tiainen M, Poutiainen E, Roine RO. Therapeutic hypothermia after prolonged cardiac arrest due to non-coronary causes. Resuscitation. 2003;57(April (1)):109-12. 8. Kim Y, Busto R, Dietrich WD, et al. Delayed postischemic hyperthermia in awake rats worsens the histopathological outcome of transient focal cerebral ischemia. Stroke. 1996;27: 2274-81. 9. Baena RC, Busto R, Dietrich WD, et al. Hyperthermia delayed by 24 h aggravates neuronal damage in rat hippocampus following global ischemia. Neurology. 1997;48(March (3)):768-73. 10. Azzimondi G, Bassein L, Nonino F, et al. Fever in acute stroke worsens prognosis. A prospective study. Stroke. 1995;26(November (11)):2040-3. 11. Reith J, Jorgensen HS, Pedersen PM, et al. Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Lancet. 1996 ;347(February (8999)):422-5. 12. Zeiner A, Holzer M, Sterz F, et al. Hyperthermia after cardiac arrest is associated with an unfavorable neurologic outcome. Arch Intern Med. 2001;161(September(16)):2007-12. 13. Takasu A, Saitoh D, Kaneko N, et al. Hyperthermia: is it an ominous sign after cardiac arrest? Resuscitation. 2001;49(June (3)):273-7. 14. Busto R, Globus MY, Dietrich WD, et al. Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke. 1989;20:904-10. 15. Hachimi-Idrissi S, Van Hemelrijck A, Michotte A, et al. Postischemic mild hypothermia reduces neurotransmitter release and astroglial cell proliferation during reperfusion after asphyxial cardiac arrest in rats. Brain Res.

39


2004;1019:217-25. 16. Globus MY, Busto R, Lin B, et al. Detection of free radical activity during transient global ischemia and recirculation: effects of intraischemic brain temperature modulation. J Neurochem. 1995;65(September (3)):1250-6.17. Kil HY, Zhang J, Piantadosi CA. Brain temperature alters hydroxyl radical production during cerebral ischemia/reperfusion in rats. J Cereb Blood Flow Metab. 1996;16(January (1)):100-6. 18. Madl JE, Allen DL. Hyperthermia depletes adenosine triphosphate and decreases glutamate uptake in rat hippocampal slices. Neuroscience. 1995;69(November (2)):395-405. 19. Morimoto T, Ginsberg MD, Dietrich WD, et al. Hyperthermia enhances spectrin breakdown in transient focal cerebral ischemia. Brain Res. 1997;746(January (1-2)):43-51. 20. Mellergard P, Nordstrom CH. Intracerebral temperature in neurosurgical patients. Neurosurgery. 1991;28(May (5)):709-13. 21. Verlooy J, Heytens L, Veeckmans G, et al. Intracerebral temperature monitoring in severely head injured patients. Acta Neurochir (Wien). 1995;134(1-2):76-8. 22. van Zanten ARH, Polderman KH. Early induction of hypothermia: will sooner be better? Crit Care Med. 2005;33(June (6)): 1449-52.

40

Chapter Three

Early lactate decrease in patients after

cardiopulmonary resuscitation after out

of hospital cardiac arrest

Pedro Freire Jorge, Rohan Boer, Gert-Jan C. Zwart, Anthony Absalom, Remco Bergman,

Maarten W. Nijsten.

Submitted to Resuscitation.

43


AbstractAim Increased lactate levels and impaired lactate clearance are associated with adverse outcomes in critically ill patients. After resuscitation for out of hospital cardiac arrest (OHCA), lactate levels commonly exceed 8 mmol/L. In patients with sepsis, a decrease of at least 10% per hour in blood lactate levels is associated with favourable outcome. Immediate changes in lactate concentrations after OHCA however have not been studied to date, and so it is unclear if this criterion applies to OHCA patients. The goal of our study was to measure the early dynamics of lactate levels directly after return of spontaneous circulation (ROSC).

Methods We studied patients presented to the emergency department after OHCA and initial ROSC. Arterial lactate levels were determined with point-of-care blood gas analyzers. Patients with an initial lactate of > 8 mmol/L were included. Lactate values taken during the first two hours after ROSC were studied. Both absolute and relative lactate concentration decreases were determined.

Results We studied 324 blood samples from patients with a mean age of 61 ± 12 years. The mean (± SD) initial lactate level was 12.1 (3.5) mmol/L and mean relative lactate decrease was 41 (19) %/h over the first 2 hours. Hospital survivors and non-survivors had lactate decreases of 46 and 37 %/h respectively (P = 0.01).

Conclusions Lactate decrease in the first hours after ROSC is considerably higher than the 10 %/h seen in patients with sepsis who respond favourably to treatment. Thus a lactate decrease of 10 %/h after an OHCA should not be considered sufficient.

44

Chapter Three

IntroductionUnder physiological stress, such as a bout of intense exercise which generates large amounts of lactate, healthy patients are able to rapidly clear large amounts of lactate, so that elevations are only seen in extreme situations.1,2 In critically ill patients, elevated blood lactate concentrations are more common and are caused by a variety of factors involving increased production and diminished clearance. In these patients sustained blood lactate level elevations are strongly associated with adverse outcome.3 During the recovery phase from critical illness the restoration of normal lactate levels and the rate at which this occurs is also correlated with outcome.4,5,6,7 In patients with sepsis presenting with a lactate level of > 4 mmol/L, a decrease in lactate levels of 10 %/h is associated with favourable outcome.8,9

In the setting of return of spontaneous circulation (ROSC) after a out-of-hospital cardiac arrest (OHCA) the same target for lactate decrease of 10 %/h per hour has been suggested as a prognostic factor and guide to the adequacy of therapy.8,10 As there has been limited research regarding early serial lactate levels in patients after OHCA, it is unclear how appropriate this target is. The goal of our study was to determine lactate dynamics in the first two hours following ROSC after an OHCA.

Patients & MethodsData from patients presenting to the emergency department (ED) after OHCA (2006-2014), at the University Medical Center Groningen (UMCG), were analysed. Arterial blood samples were routinely collected at the ED, cardiac catheterization lab and intensive care unit (ICU) and immediately analyzed on a Radiometer 700/800 series system. Patients, who achieved ROSC, had an initial arterial lactate > 8 mmol/L and a minimum of two lactate measurements within the first two hours were included. Time 0 was taken as the first lactate measurement after ROSC. The absolute decrease in mmol/L/h and the relative lactate decrease as in %/h, related to the initial lactate level over the first two hours, were determined for each patient using regression analysis. Data from patients who displayed an initial rise in lactate after the first measurement were not utilized in the calculations of relative or absolute lactate decreases. This study complies with the Declaration of Helsinki; the local medical ethics committee approved the study (METC 2011.374) and waived the requirement for consent from patients or relatives to use their data. Statistical analyses were performed with SPSS 22 for Windows (IBM, Chicago, IL, USA).

ResultsA total of 135 patients, 81% male and of mean age of 60, matched our inclusion criteria. In 103 (76%) patients the initial rhythm was ventricular fibrillation or tachycardia (VF/VT). Fifty-nine patients (44%) survived to hospital discharge. Fourteen (10%) patients displayed a secondary rise in lactate after the first measurement after ROSC. Population characteristics are summarised in table 1.

45


Table 1. Characteristics & outcome of the included patients.n = 135

Age (± SD) 60 (12)Male (%) 109 (80%)Cause of OHCA

pVT/VF 103 (76%)No VF 32 (24%)

Hospital survival 59 (44%)Initial lactate (± SD) mmol/L 12.4 (3.4)Secondary rise in lactate 14 (10%)

OHCA = Out-of-Hospital Cardiac Arrest. pVT = pulseless Ventricular Tachycardia. VF = Ventricular Fibrillation.

The mean (± SD) lactate level immediately after ROSC was 12.4 (3.4) mmol/L, the mean absolute lactate decrease was 5.0 mmol/L per hour and the mean relative lactate decrease was 40% per hour (table 2). As shown in figure 1 the early relative lactate decrease in survivors and non-survivors was considerably higher than the previously suggested prognostic value of 10 %/h (for sepsis and post-cardiac arrest patients), but was lower than the rate observed in athletes after heavy exertion.11 While there was no significant difference in the initial lactate level between survivors and non-survivors, there was a higher relative lactate decrease was associated with hospital survival (Table 2).

Table 2. Lactate & outcome.Whole group n = 123

Survivors n = 55

Non-survivors n= 68

P-value

Initial lactate (± SD) mmol/L 12.3 (3.5) 12.3 (3.2) 12.3 (3.7) 0.96

Absolute decrease (mmol/L/h) 5.1 (2.9) 5.5 (2.6) 4.7 (3.0) 0.14

Fractional decrease (% of initial lactate/h

40 (19) 46 (19) 37 (18) 0.01

Characteristics of patients with no secondary rise in lactate. The P-value refers to the comparison between survivors and non-survivors. The absolute and relative decreases were calculated over the first two hours after ROSC.

46

Chapter Three

Figure 1. Time course of recovery of lactate in different conditions. Time course of lactate after ROSC in patients studied, after a bout of intense exercise 10

and a 10% decrease per hour as considered desirable in

sepsis 7,11 and in OHCA.8

DiscussionThe lactate decrease early after OHCA was much higher than the 10 %/h goal advised for septic patients as well as the 10 %/h that has been advised for an OHCA.8-10 Furthermore although a significant difference in relative lactate decrease (P = 0.01) between survivors and non-survivors was found, the relative lactate decrease in most non-survivors was still much higher than 10 %/h (supplemental material figure 2G) This indicates that if lactate is used to guide therapy in the setting of cardiac arrest, a higher target for lactate decrease is required. After OHCA the body has sustained a large oxygen deficit with an accompanying accumulation of lactate resulting from anaerobic metabolism. In contrast during sepsis lactate production is often not the result of generalized hypoxia but rather of increased adrenergic stress.1

Restoration of appropriate circulation enables many tissues to clear

lactate by conversion back to glucose or direct metabolism. After maximal exertion athletes can consume lactate at extremely high rates. It seems reasonable to assume that the post-exertional decrease of lactate in athletes reflects the upper range of physiological lactate consumption.12 Lactate dynamics after OHCA with ROSC also have similarities with the lactate recovery levels observed after a grand mal seizure. In such patients lactate can rapidly increase to very high levels due to generalized muscular contractions.

47


After cessation of seizures, lactate decrease can reach 50 %/h. This demonstrates the rapidity by which lactate can be cleared after a very energy-demanding period such as a seizure in patients with otherwise intact hemodynamics.13 As indicated in figure 1 the time course of lactate decrease in the setting of OHCA is intermediate between that of athletes recovering from severe exertion and the goal for septic patients.

We found a significant difference in relative but not in absolute lactate decrease between survivors and non-survivors of OHCA. As expected survivors had higher decrease rates than non-survivors. Importantly, there was no difference between the initial lactate levels of both groups corroborating results reported elsewhere.4,5 The early changes in lactate levels after CPR have to our knowledge not been documented before. A recent prospective trial that successfully applied ‘lactate-decrease’ as a central goal in patients with sepsis suggested that 10 %/h in these patients population was a realistic target.9

This study clearly shows that directly after ROSC lactate levels can decrease much faster than the goal of 10 %/h suggested by Ward et al. 10 for patients recovering from OHCA and for management of patients with sepsis in the LACTATE trial.9

Whereas we have focussed on early lactate clearance, Kliegel et al. previously investigated serial lactate measurements between 4 and 48 hours after admission as a predictor of outcome in successfully resuscitated patients after cardiac arrest.4 They found that during this period lactate clearance differed significantly between survivors and non-survivors.4 In this context, it is also not surprising that a 12-hour lactate decrease of < 10% was associated with an increased in-ICU mortality in patients with cardiogenic shock following ST-elevation myocardial infarction (STEMI). This latter study also did not evaluate lactate levels within the first 2 hours after the incident.5

Clinicians consider achieving ROSC early after resuscitation and subsequent hemodynamic stability as key therapeutic goals. Prediction of neurological outcomes is not realistic at the early stage. However indicators that can help to identify patients at high risk for complications are useful. Indicators such as cardiac output, blood pressure and urine output may serve as surrogate variables of the adequacy of systemic perfusion. Although these variables may return to normal, lactate levels may remain elevated, and thus possibly point to ongoing circulatory and metabolic derangements.14 In fact, the time needed for lactate normalization has been shown to be a useful prognostic variable.15

Indeed, current clinical practice should consider lactate decrease as an important measurement when assessing the effectiveness of therapy. Our study indicates a mean relative lactate decrease after ROSC of 40.1 %/h in the overall group and 46 %/h in the survivors. We therefore consider that the current recommended 10 %/h decrease rate should be revised upward to at least 40 %/h.

Conventional theories regarded lactate as a consequence of anaerobic respiration caused by cellular hypoxia. It is now known however, that this glycolytic product is extensively produced and used under aerobic conditions in a diverse range of cells in the context of cell-cell and intracellular shuttles.3,16 During exercise or stress responses, lactate has been proven to be a primary fuel for especially the heart 17 and working skeletal

48

Chapter Three

muscles.18 In this context lactate can be the preferred substrate over glucose.19,20 In our patients a comparison of the recovery curves of glucose and lactate over the first 6 hours (supplementary material) suggest that after ROSC the lactate excess is cleared sooner than the glucose excess.

Our study has several limitations. The number of lactate measurements within 2 hours varied, with some patients having only two measurements. Determining the early time course with linear regression may be considered less appropriate for a time course that is known to be non-linear. However, as pointed out earlier, our focus was to determine the early changes in lactate levels on the basis of real patient data acquired in an emergency context. Another related issue is that the interval between lactate measurements differed between patients.

In conclusion the lactate decrease after successful cardiopulmonary resuscitation after OHCA is much higher than the 10% per hour that is considered desirable in sepsis and that has been proposed for OHCA patients. We believe that during the initial two hours a rate of 40 %/h may be considered appropriate as a prognostic marker and guide to the adequacy of therapy after ROSC after OHCA.

AcknowledgementsNone

Conflict of interestThe authors have no conflict of interest to declare

49


Supplemental material

Supplemental figures A. pH in time. B. glucose in time C. Potassium in time. D. Lactate in time. E. PaCO2 in time. F. pH versus PaCO2.

50

Chapter Three

G. L

acta

te in

tim

e re

lativ

e to

initi

al le

vel.

51


References1. Kemppainen J, Fujimoto T, Kalliokoski KK, et al. Myocardial and skeletal muscle glucose uptake during exercise in humans. J Physiol. 2002;542 (Pt 2):403–12. 2. Goodwin ML, Harris JE, Hernández A, Gladden LB. Blood lactate measurements and analysis during exercise: a guide for clinicians. J Diabetes Sci Technol. 2007;1(4):558–69. 3. Bakker J, Nijsten MW, Jansen TC. Clinical use of lactate monitoring in critically ill patients. Ann Intensive Care. 2013;3(1):12. 4. Kliegel A, Losert H, Sterz F, et al. Serial lactate determinations for prediction of outcome after cardiac arrest. Medicine (Baltimore). 2004;83(5):274–9. 5. Attaná P, Lazzeri C, Chiostri M, et al. Lactate decrease in cardiogenic shock following ST elevation myocardial infarction: a pilot study. Acute Card Care. 2012;14(1):20–6. 6. Kruse O, Grunnet N, Barfod C. Blood lactate as a predictor for in-hospital mortality in patients admitted acutely to hospital: a systematic review. Scand J Trauma Resusc Emerg Med. 2011;19:74. 7. Donnino MW, Andersen LW, Giberson T, Gaieski DF, Abella BS, Peberdy MA, Rittenberger JC, Callaway CW, Ornato J, Clore J et al: Initial lactate and lactate change in post-cardiac arrest: a multicenter validation study. Crit Care Med. 2014, 42(8):1804-1811. 8. Vincent JL, Dufaye P, Berre J, Leeman M, Degaute JP, Kahn RJ: Serial lactate determinations during circulatory shock. Crit Care Med. 1983, 11(6):449-451. 9. Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010, 182(6):752-761.10. Ward KR BJ: Cardiac arrest resuscitation monitoring. In: Paradis N, Halperin H, Kern K, Wenzel V, Chamberlain D (eds) Cardiac Arrest - The Science and Practice of Resuscitation Medicine. Camridge University Press, 2nd Edition 2007:703.11. Astrand PO, Hultman E, Juhlin-Dannfelt A, Reynolds G: Disposal of lactate during and after strenuous exercise in humans. J Appl Physiol. (1985) 1986, 61(1):338-343.12. Brooks, George A, Thomas D. Fahey, and Kenneth M. Baldwin. Exercise Physiology: Human Bioenergetics and Its Applications. Boston: McGraw-Hill, 2005. 13. Orringer CE, Eustace JC, Wunsch CD, Gardner LB. Natural history of lactic acidosis after grand-mal seizures. A model for the study of an anion-gap acidosis not associated with hyperkalemia. N Engl J Med. 1977;297(15):796– 9. 14. James JH, Luchette FA, McCarter FD, Fischer JE. Lactate is an unreliable indicator of tissue hypoxia in injury or sepsis. Lancet. 1999;354(9177):505–8. 15. Lee TR, Kang MJ, Cha WC, et al. Better lactate clearance associated with good neurologic outcome in survivors who treated with therapeutic hypothermia after out-of-hospital cardiac arrest. Crit Care. 2013 Oct 31;17(5):R260.

52

Chapter Three

16. Brooks GA. Cell-cell and intracellular lactate shuttles. J Physiol. 2009;587(Pt 23):5591–600. 17. Gertz EW, Wisneski J a, Stanley WC, Neese R a. Myocardial substrate utilization during exercise in humans. Dual carbon-labeled carbohydrate isotope experiments. J Clin Invest. 1988;82(6):2017–25. 18. Gladden LB. Net lactate uptake during progressive steady-level contractions in canine skeletal muscle. J Appl Physiol. 1991;71(2):514–20. 19. Jacobs RA, Meinild A-K, Nordsborg NB, Lundby C. Lactate oxidation in human skeletal muscle mitochondria. Am J Physiol Endocrinol Metab. 2013;304(7):E686–94. 20. Schurr A. Lactate: a major and crucial player in normal function of both muscle and brain. J Physiol. 2008;586(Pt 11):2665–6.

Chapter Four

Long-term outcome of patients after out-

of-hospital cardiac arrest in relation to

treatment: a single centre study

Remco Bergman, Bart Hiemstra, Wybe Nieuwland, Eric Lipsic, Anthony Absalom, Joukje

van der Naalt, Felix Zijlstra, Iwan C.C. van der Horst, Maarten W.N. Nijsten.

Eur Heart J Acute Cardiovasc Care. 2016 Aug;5(4):328-38.

55


Abstract Introduction Outcome after out-of-hospital cardiac arrest (OHCA) remains poor. With the introduction of automated external de brillators, percutaneous coronary intervention (PCI) and mild therapeutic hypothermia (MTH) the prognosis of patients after OHCA appears to be improving. The aim of this study was to evaluate short and long-term outcome among a non-selected population of patients who suffered OHCA and were admitted to a hospital working within a ST-elevation myocardial infarction (STEMI) network.

Methods All patients who achieved return of spontaneous circulation (ROSC) (n = 456) admitted to one hospital after OHCA were included. Initial rhythm, reperfusion therapy with PCI, implementation of MTH and additional medical management were recorded. Primary outcome measure was survival (hospital and long-term). Neurological status was measured as Cerebral Performance Category (CPC). The inclusion period was January 2003 till August 2010. Follow-up was complete until April 2014.

Results Mean patient age was 63 ± 14 years, and 327 (72%) were males. The initial rhythm was ventricular brillation (VF), pulseless electrical activity (PEA), asystole and pulseless ventricular tachycardia (pVT) in 322 (71%), 58 (13%), 55 (12%), and 21 (5%) of the 456 patients respectively. Treatment included PCI in 191 (42%) and MTH in 188 (41%). Overall in-hospital and long-term (5-year) survival was 53% (n = 240) and 44% (n = 202) respectively. In the 170 patients treated with primary PCI, in-hospital survival was 112/170 (66%). After hospital discharge these patients had a 5-year survival rate of 99% and CPC was good in 92%.

Conclusions In this integrated STEMI network survival and neurological outcome of selected patients with ROSC after OHCA and treated with PCI was good. There is insufficient evidence about the outcome of this approach, which has a significant impact on utilization of resources. Good quality RCT’s are needed. In selected patients successfully resuscitated after OHCA of presumed cardiac aetiology, we believe that a more liberal application of primary PCI may be considered in experienced acute cardiac referral centres.

56

Chapter Four

IntroductionDespite several advances in the field of resuscitation, the management of patients after out of hospital cardiac arrest (OHCA) can still be improved.1-4,5 Factors influencing outcome after OHCA are the initial rhythm, whether the arrest was witnessed or not, early good quality cardiopulmonary resuscitation (CPR), early defibrillation and organization of care. Efforts have been undertaken to improve outcome after OHCA. Organisational measures, such as teaching of CPR in courses and other initiatives to promote early bystander CPR 6-8, optimisation of emergency medical systems responses 9 and systems to ensure very rapid access to automated external defibrillators (AEDs) 10, have been shown to improve outcome.11 Survival is most likely if the initial rhythm was ventricular fibrillation (VF) 12, which is most frequently caused by myocardial infarction due to coronary artery disease (CAD).12, 13

In our region an ST elevation myocardial infarction (STEMI) network was created in conjunction with ambulance services, the emergency, cardiology and intensive care departments. It involves a defined treatment plan for patients with return of spontaneous circulation (ROSC), whose goal is to allocate definitive care as expediently as possible guided on the clinical signs and electrocardiographic (ECG) or echocardiographic signs of acute myocardial ischemia. In guidelines and recommendations the use of reperfusion therapy, either primary percutaneous coronary intervention (PCI) or thrombolysis, is recommended regardless of Glasgow coma score.14-17

Studies on the effect of primary PCI as treatment of a ST-segment elevation myocardial infarction (STEMI), in the setting of OHCA, are increasingly common.18-23 Despite this, data on the effect of primary PCI after OHCA on the (long-term) outcome among all patients admitted to hospital are sparse. We aimed to evaluate short- and long-term outcome among consecutive patients treated after OHCA within a regional STEMI network.

MethodsSettingThe University Medical Center Groningen is a tertiary referral hospital, which serves the North Eastern part of the Netherlands. In our region we are the only hospital, which performs PCI. With referral hospitals, this centre provides 24/7 emergency care in a region with 750,000 inhabitants.24 In the case of an emergency, the closest ambulance is sent to the scene and when resuscitation is necessary a second ambulance is always sent as backup. Patients are then preferentially transported to our centre, especially when there is suspicion of coronary occlusion (e.g. VF or STEMI). There resuscitation is continued or post-resuscitation care is given following Advanced Cardiovascular Life Support (ACLS) guidelines.25 Ambulance services in our area have the discretion to discontinue CPR in case of a non-shockable rhythm if it persists after 20 minutes in adult patients. And as a consequence, these patients were not presented to our centre.Upon arrival at the hospital, stable patients with STEMI were transferred directly to the catheterization laboratory. Unresponsive patients were admitted to the emergency department and following stabilization transferred directly to the catheterization laboratory

57


in case of STEMI. In patients without STEMI the decision to go to the catheterization laboratory was made by the attending cardiologist and based on hemodynamic stability and echocardiographic signs of ischemia. At the catheterization laboratory PCI was performed if a culprit was identified according to the current guidelines.26,27

Patients underwent delayed PCI based on the discretion of the attending physician. Reasons not to perform immediate coronary angiography were hemodynamic instability and absence of ST segment elevation on the electrocardiogram. If during the course after admission patients were more stable and when it was anticipated that myocardial ischemia due to coronary artery stenosis was present delayed coronary angiography and PCI was performed.

In all patients with a Glasgow Coma Scale (GCS) of ≤ 8 or patients with insufficient oxygenation and ventilation endotracheal intubation was performed. Mechanical ventilation was no contraindication for early coronary intervention, neither was time of day. If the GCS did not immediately improve to a score of > 8 or if the patient was sedated and could not be scored and already was on mechanical ventilation, mild therapeutic hypothermia (MTH) was initiated, irrespective of early coronary intervention. Hemodynamic instability would preclude MTH. MTH aimed to cool patients to 32-34 °C for approximately 24 hours at the ICU. Sedation was given according the local protocol. After 24 hours the patients’ body temperature was allowed to return to normal spontaneously. At a temperature of 36 °C sedatives were stopped. Thereafter, the attending intensivist and the neurologist scored the patient neurologically. Somatosensory evoked potentials (SSEP) and electroencephalogram (EEG) were performed in comatose patients. After ICU treatment the patients were transferred to the cardiology ward. Outpatient follow-up was done at the cardiology, neurology or rehabilitation departments. Patients with a higher GCS (> 8) and without respiratory problems were transferred to either the ICU or the coronary care unit.

PatientsWe retrospectively studied all consecutive patients over 18 years of age admitted to our hospital after out of hospital cardiac arrest (OHCA) between January 2003 and August 2010. All patients were included in our analysis unless it was impossible to confirm OHCA or to define the initial rhythm (figure 1). We collected baseline demographic and clinical characteristics that were anonymously entered in a dedicated database. Gathering information from the ambulance registry and the hospital information system comprising all medical records completed data collection.

Data from additional investigations being ECG, echocardiography, SSEP, EEG and laboratory values, were recorded and subsequently added to our cohort. Left ventricular function measured by echocardiography was scored as poor, moderate (< 45%), reasonable and normal.

58

Chapter Four

Figure 1. Flow-chart of all patients presented at the Emergency Department after out-of-hospital cardiac arrest.After each step total percentage is set as 100%.

Outcome measuresPrimary outcome measures were in hospital and long-term survival at 1 and 5 years. In hospital cause of death was noted (based on the judgment of at least two physicians). The neurological status after discharge was the secondary outcome measure. Neurological status was derived from information of the outpatient control visits of cardiologists, neurologists or rehabilitation specialists. Outcome was scored by the cerebral performance score (CPC) comprising five categories; (1) Conscious and alert with normal function or only slight disability, (2) Conscious and alert with moderate disability, (3) Conscious with severe disability, (4) Comatose or persistent vegetative state, (5) Brain dead or death from other causes.

Survival status and neurological outcome was determined until April 2014. This study complies with the declaration of Helsinki; the local medical ethics committee approved the study (METC 2011.374) and waived the requirement for consent from patients or relatives to use their data.

59


Statistical analysisContinuous data are presented as either means ± standard deviation (SD) for normally distributed variables or medians and interquartile ranges (IQR) for skewed data or as group percentages for categorical variables. Statistical analysis was performed using the Chi square test for categorical and the Mann Whitney or independent sample t-test for skewed continuous and normal distributed variables, respectively. We determined outcome in subgroups, given initial rhythm (VF vs. no-VF), implemented treatment (PCI vs. no PCI, MTH vs. no MTH) and systolic left ventricular ejection fraction (LVEF) (LVEF < 45% vs. ≥ 45%). A Kaplan-Meier survival analysis was used for our primary endpoint. We used hazard ratios (HR) and associated 95% confidence intervals by Cox regression analysis to compare the relative odds of survival after OHCA after hospital discharge imputing age and gender, and known factors associated with outcome: initial rhythm, in hospital treatment (PCI and MTH) and left ventricular function. A univariate two-sided p-value of < 0.10 was required for inclusion in our multivariate model, which was constructed using a stepwise backward selection. Statistical significance was defined as a two-sided p-value of < 0.05. Propensity scoring was used to correct for age, sex, rhythm (VF vs. No VF), performance of BLS and GCS-score at admission. We conducted a successful match of the variables age, sex, rhythm (VF vs. No VF) and performance of BLS; GCS-score at admission could not be matched in our population. All statistical analyses were performed using Stata version 12.0 (StataCorp).

ResultsBaseline demographic and clinical characteristicsDuring the study period 695 patients were admitted after suspected OHCA (figure 1). Of these patients 34 (5%) were excluded because of a final diagnosis other than OHCA (n = 24) or if their initial rhythm was undeterminable (n = 10). Successful ROSC occurred in 322/425 (76%) of VF patients compared to 134/236 (57%) in the group without VF (P < 0.001), thus excluding 205 (29%) patients that failed to achieve ROSC.The 456 patients with ROSC were included in the analyses. Mean ± SD age of these patients was 63 ± 14 years and 72% were male (table 1).A total of 322 (71%) patients presented with VF as the initial rhythm. Of the non-VF patients (n = 134), pulseless electrical activity (PEA) was the initial rhythm in 58 patients (43%); 55 patients (41%) presented with asystole, and 21 patients (16%) with pulseless ventricular tachycardia (pVT).

Coronary angiography, reperfusion therapy and mild therapeutic hypothermiaCoronary angiography after admission was performed in 257/456 (56%) patients, delayed in 63/456 (14%) patients (table 1). Median time to CAG was 111 (IQR 62 – 180) minutes. Most patients undergoing immediate CAG were receiving mechanical ventilation: 62% vs. 71% in VF vs. non-VF, respectively. Primary CAG was performed in 170/322 (53%) of patients with VF and in 24/134 (18%) of patients without VF (P < 0.001). Primary PCI was performed in 170/194 (88%) of these cases and 3/170 patients (2%) underwent emergency coronary bypass surgery after immediate CAG. In 21/257 (8%) patients delayed PCI was performed during hospitalization.

60

Chapter FourTa

ble

1. C

linic

al c

hara

cter

istic

s of

stu

died

pat

ient

s.

Tota

ln

= 45

6VF

n =

322

No

VFn

= 13

4P

Pri

mar

y C

AG

n =

194

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prim

ary

CA

Gn

= 26

2

PP

rim

ary

PC

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= 17

0

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Age*

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66 ±

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5<

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± 1

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± 1

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957

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154

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re (%

)

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)

36 (8

%)

285

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117

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ROSC

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322

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134

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194

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262

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61

Long-term outcome of patients after out-of-hospital cardiac arrest in relation to treatment: a single centre studyTa

ble

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istic

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62

Chapter FourTa

ble

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hara

cter

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s of

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died

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ient

s (c

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.

Tota

ln

= 45

6VF

n =

322

No

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= 13

4P

PR

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o P

R C

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n =

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C

x

LM

G

raft

U

nkno

wn

(mul

tiple

)

No

Culp

rit

59 (2

3%)

99 (3

9%)

39 (1

5%)

13 (5

%)

4 (2

%)

24 (9

%)

19 (7

%)

51 (2

3%)

89 (4

0%)

34 (1

5%)

10 (4

%)

4 (2

%)

21 (9

%)

16 (7

%)

8 (2

5%)

11 (3

5%)

5 (1

6%)

3 (1

0%)

0 (0

%)

1 (3

%)

3 (1

0%)

0.88

951

(26%

)87

(45%

)28

(14%

)11

(6%

)1

(1%

)7

(4%

)8

(4%

)

8 (1

3%)

12 (1

9%)

11 (1

8%)

2 (3

%)

3 (5

%)

15 (2

4%)

11 (1

8%)

< 0.

001

49 (2

9%)

85 (5

0%)

25 (1

5%)

9

(5%

)0

(0%

)1

(1%

)0

(0%

)

3 (1

4%)

9 (4

3%)

9 (4

3%)

0 (0

%)

0 (0

%)

0 (0

%)

0 (0

%)

0.04

5

PCI (

%)

P

rimar

y

Sec

onda

ry

191

(42%

)17

0 (3

7%)

21 (5

%)

171

(53%

)15

4 (4

8%)

17 (5

%)

20 (1

5%)

16 (1

2%)

4 (3

%)

< 0.

001

< 0.

001

0.09

2

170

(88%

)17

0 (8

7%)

0 (0

%)

21 (8

%)

0 (0

%)

21 (8

%)

< 0.

001

< 0.

001

170

(100

%)

170

(100

%)

0 (0

%)

21 (1

00%

)0

(0%

)21

(100

%)

CABG

(%)

6 (1

%)

6 (2

%)

0 (0

%)

0.18

73

(2%

)3

(1%

)0.

710

3 (2

%)

0 (0

%)

0.53

9

* =

Mea

n ±

SD, # =

med

ian

(IQR)

. VF

= Ve

ntric

ular

Fib

rilla

tion.

CVD

= C

ardi

oVas

cula

r Dis

ease

. BLS

= B

asic

Life

Sup

port

. PEA

= P

ulse

less

Ele

ctric

al A

ctiv

ity. V

F =

vent

ricul

ar ta

chyc

ardi

a. R

OSC

= Re

turn

Of S

pont

aneo

us C

ircul

atio

n. S

TEM

I = S

T-se

gmen

t Ele

vatio

n M

yoca

rdia

l Inf

arct

ion.

MTH

= M

ild T

hera

peut

ic H

ypot

herm

ia.

LVEF

= L

eft V

entri

cula

r Eje

ctio

n Fr

actio

n. W

MA

= W

all M

otio

n Ab

norm

aliti

es. M

B =

Myo

card

ial B

and.

CAG

= C

oron

ary

Angi

oGra

phy.

RCA

= Ri

ght C

oron

ary

Arte

ry. L

AD

= Le

ft An

terio

r Des

cend

ing.

Cx

= Ci

rcum

flex.

LM

= L

eft M

ain.

PCI

= P

ercu

tane

ous

Coro

nary

Inte

rven

tion.

CAB

G =

Cor

onar

y Ar

tery

Byp

ass

Gra

fting

. PR

= Pr

imar

y. SE

=

Seco

ndar

y. ∞

If CA

G p

erfo

rmed

; tot

al n

umbe

r 257

† If

PCI

per

form

ed; t

otal

num

ber 1

91

63


A total of 191 patients were eventually diagnosed with a significant coronary occlusion, of which 137/191 (72%) showed an ST-segment elevation on the initial ECG. Characteristics of patients who underwent emergent vs. delayed PCI are summarized in table 1. Mild therapeutic hypothermia was instituted in 188/456 (41%) patients with ROSC. Of these 80/188 (43%) patients also underwent a PCI. Survival for these patients who underwent PCI was 42/80 (53%) vs. 46/108 (43%). However this difference did not reach statistical significance (P = 0.12).

In-hospital survival after ROSCHospital survival was 240/456 (53%) in all patients. A total of 193/322 (60%) in the VF group and 47/134 (35%) in the non-VF group survived to hospital discharge (P < 0.001). Patients undergoing primary PCI had a good hospital survival rate, with 112/170 (66%) of patients who underwent primary PCI surviving compared to 128/286 (45%) in the group that did not have primary PCI. A successfully matched population using propensity scoring was assessed for age, sex, rhythm (VF vs. no-VF) and performance of BLS. In this matched population of 286 patients, 62/143 (43%) survived in the group that did not have a primary PCI, versus 99/143 (69%) in the primary PCI population (P < 0.001). When examining subgroups; (VF ± primary PCI) and (no-VF ± primary PCI) we did not find statistically significant differences in outcome in these groups. Additionally there was no statistical difference in outcome between patients who had primary vs. secondary PCI 18/21 (86%) in the group that received secondary PCI (P = 0.251).

Unadjusted, MTH was associated with worse outcome: survival was 88 (47%) with MTH vs. 150 (56%) without MTH, P < 0.03 overall. This was true for patients treated with MTH after VF where survival was; 81/158 (51%) in patients treated with MTH vs. 111/164 (68%) not treated with MTH (P = 0.002). However when correcting for confounding factors (sex, age, performance of BLS and GCS score) through propensity analysis there was no significant difference in survival. Furthermore, MTH was not an independent predictor of mortality in our multivariate Cox regression model. In patients treated after non-VF survival also did not differ significantly between groups (P = 0.11). Outcome was also associated with systolic left ventricular ejection fraction (LVEF). Of the patients who regained ROSC, 225 underwent transthoracic echocardiography. Neurological outcome, as reflected by the CPC-score, differed markedly with a CPC score of 1-2 in the VF and no-VF groups 46% vs. 19% respectively (P < 0.001).

Factors associated with in-hospital mortality after ROSC were refractory cardiogenic shock (15%) and multiple organ failure (6%). In 144 patients (67%) the team of specialists (senior intensivists and neurologists) concluded that neurological injury was so severe that it was incompatible with survival. Decisions about withdrawal of treatment were based on clinical examination and additional assessment of SSEP or EEG at day 3 after CPR according to Dutch guidelines.28, 29

In case of absent brain stem reflexes (i.e. absent pupillary light response and corneal reflexes) and absent motor scores, treatment was stopped. In all other cases, additional SSEP was done and in case of absent bilateral N20 potentials treatment was withdrawn. An EEG was only performed when seizures or myoclonus were present. Seizures were

64

Chapter Four

treated with antiepileptic drugs; in case of myoclonus status epilepticus treatment was withdrawn. This information obtained by repetitive clinical evaluation, and sometimes additional EEG and SSEP recordings (EEG in 22 (15%) cases, SSEP 7 (5%) cases or SSEP and EEG combined 8 (6%) cases). In these patients active therapies (mechanical ventilation, endotracheal intubation, inotrope administration) were discontinued, whilst general end of life measures to maintain dignity were continued. Survival after hospital dischargeThe overall survival after hospital discharge was 93% and 84% at 1 and 5 years respectively. Survival after hospital discharge was 96% at 1-year and 91% at 5-year follow-up for the 193 patients after VF. The long-term survival among no-VF group of patients (n = 47) was 79% at 1 year and 57% at 5 years after hospital discharge (figure 2). The highest survival rate was observed in patients presenting with VF and treated with immediate PCI (1-year survival 99%, 5-year survival 99%) (figure 3).

Years 2 4 6 8 10

VF (n) 182 164 79 36 15

No VF (n) 33 27 15 8 2Figure 2. Kaplan Meier after discharge of the OHCA survivors comparing VF vs. no-VF with associated 95% confidence interval. Associated table showing the number of patients in follow-up.

65


Years 2 4 6 8 10

PCI (n) 118 108 44 17 8

No PCI (n) 64 56 35 19 7

Figure 3. Kaplan Meier after discharge of patients after OHCA presenting with VF comparing PCI vs. No-PCI with associated 95% confidence interval. Associated table showing the number of patients in follow-up.

Independent predictors of long-term survivalA multivariate Cox regression (including the factors age, sex, glucose and pH upon admission, door to balloon time, witnessed arrest, location, performance of basic life support, GCS, VF as initial rhythm, presence of a STEMI, MTH, performance of primary PCI, induction of MTH, need of mechanical ventilation and length of hospital stay) was performed to predict long-term mortality. Age (1 year step, HR 1.02, 95% CI 1.02 – 1.04, P < 0.000), GCS (HR 0.89, 95% CI 0.85 – 0.93, P < 0.001), myocardial infarct size (area under the curve of creatin kinase myocardial band, HR 1.24, 95% CI 1.08 – 1.42, P = 0.002), pH on admission (HR 0.19, 95% CI 0.07 – 0.51, P = 0.001), no initial rhythm of VF (HR 1.35, 95% CI 1.19 – 1.53, P < 0.001), performance of emergency PCI (HR 0.56, 95% CI 0.35 – 0.77, P = 0.006) and performance of basic life support (HR 0.56, 95% CI 0.41 – 0.77, P < 0.001) were independent predictors of long-term mortality after ROSC.

66

Chapter Four

DiscussionIn a large group of consecutive patients treated within a STEMI network, outcome after out of hospital cardiac arrest remained poor. However, in patients with an initial rhythm of ventricular fibrillation, who showed return of spontaneous circulation and were treated by immediate PCI outcome was good. In-hospital survival reached 66% and even more remarkable, survival after discharge was 99% after 5 years. Therewith the outcome is comparable to figures reported for patients with STEMI without a cardiac arrest treated with PCI.30

Patients with poor cardiac function and co-morbidities might not regain ROSC or survive to hospital discharge. For our patients we found that survival was higher in patients with higher left ventricular ejection fraction, a better GCS, higher pH values and lower glucose and lactate levels, in accordance with observations by others.31-33 Moreover, patients with an initial rhythm other than VF showed a lower rate of ROSC and decreased GCS scores at admission compared to patients with VF.

In spite of ROSC in both groups, primary CAG was performed in 53% of patients with VF and only in 18% of patients without VF (P < 0.001). STEMI on ECG, regional wall motion abnormalities (WMA) were drivers for CAG. There was a lower incidence of STEMI in the no-VF group, 43% (VF) vs. 15% (no-VF) P < 0.001. Additionally, of the patients in whom an echocardiogram was recorded 60/162 (37%) with VF had regional WMA. This in contrast to patients with no VF, were only 7/53 (13%) had regional WMA.Therefore, treatment within a STEMI network might especially benefit patients with VF as the first observed rhythm. Patients presenting with another initial rhythm might have an underlying mechanism other than myocardial ischemia due to significant coronary occlusion. This is supported by the lower levels of cardiac markers such as troponin, creatin kinase and creatin kinase-MB in the no-VF group. The lack of treatment options apart from defibrillation, MTH and supportive care may explain the poorer outcome of patients with another initial rhythm. Even after hospital discharge, survival is worse when compared to patients who presented with VF.

The same was apparently the case for patients who underwent PCI, as they had better in-hospital survival as shown in our propensity matched score. This improved survival continued after hospital discharge. It could be that patients who did not undergo PCI were not amenable to treatment, explaining their poorer survival.

In subgroup analysis however (VF ± primary PCI, no VF ± primary PCI) we could not demonstrate a survival benefit. This could be due to the low number of patients in the VF group who did not undergo primary PCI after primary catherization, as angioplasty was performed in 91% of these patients. In this latter group in-hospital survival was even somewhat lower in the group that underwent primary PCI while in contrast long-term survival was more favourable. However neither of these differences was statistically significant most likely due to the small number of patients in these groups.

Neurological function, our secondary outcome measure, was also more favourable in

67


these PCI treated patients. Thus, the chance of surviving after an initial VF in good quality is realistic. Several reasons may explain the favourable neurological outcome. Recent evidence in comatose survivors of cardiac arrest showed that combining primary PCI and MTH might improve the probability of survival with good neurological outcome.34-39 It might be that treatment with PCI preserves myocardial function and therefore provides sufficient cerebral perfusion. It might also prevent hemodynamic disturbances due to recurrent rhythm disturbances, especially during MTH. False negative ECG can occur during total coronary occlusion. The prevalence of coronary abnormalities is high in this group of patients. A recent prospective registry questioned the benefit of emergency CAG in comatose patients presenting without a STEMI pattern on ECG.40 In our study only 79% of the patients who underwent primary PCI met traditional STEMI criteria on initial ECG, but all had coronary occlusion as judged by TIMI criteria.41 The fact that only 79% of patients with a coronary artery occlusion had STEMI signs on the ECG is interesting and supportive of the notion that even patients without STEMI on the ECG may benefit from CAG. This is in agreement with a recently published study that showed a very high prevalence of coronary artery disease in patients who underwent CAG after OHCA.42 In patients who underwent catherization after OHCA based on VF/ VT prevalence of significant coronary artery disease was 100%. Additionally acute coronary occlusion was discovered in 26.2% of patients who underwent early CAG compared to 29.3% of patients treated with secondary CAG. There was no significant difference in the rate of PCI between the early and late CAG groups (32.8% vs. 39.0%, P = 0.628). In our studies most PCI were emergent but also 5% of successfully resuscitated patients underwent a PCI at a later date.

Furthermore, other diagnostic criteria such as a history reported by bystanders or laboratory results have only very limited clinical utility in this setting.22 More research will be needed in this area, possibly performing CAG on all patients regardless of neurological status and or regardless of ECG criteria.

Outcome in patients after OHCA has often been studied. Most results underline our observations although differences exist. Gorjup et al. showed that 36 percent of patients (n = 135) with ROSC and undergoing PCI had a good outcome.43 Cronier et al. studied 111 patients resuscitated successfully following OHCA with an initial shockable rhythm. The incidence of coronary artery occlusion was 73%, which is comparable to our findings. Although they studied a selected group of patients, they showed that PCI was associated with increased survival.36 Gräsner et al. studied 584 patients after OHCA. In normothermic patients (n = 405), PCI was independently associated with good neurological outcome.35 However this study primarily focused on outcome after 24 hours and lacked follow-up after this period. Zanuttini et al. could even observe that PCI was effective in unconscious patients (n = 79) after OHCA, still only for in-hospital outcome.44 Moreover, in an Australian study (n = 35) the effects of early invasive strategy on outcome were not confirmed.45 Dumas et al. studied patients (n = 5958) who survived to hospital discharge after OHCA and investigated the relationship between treatment (MTH or PCI) and long-term outcome.46 Their data showed a 5-year survival of 78.7% after PCI. A more recent study by Sideris et al. also showed similar survival rates after hospital discharge.47

68

Chapter Four

Our overall survival after 5-years was 85% regardless of intervention or rhythm. Combined MTH and PCI has been associated with better in-hospital outcome in cohort studies.48 This benefit of PCI and MTH has been questioned by some however.49, 50 A recent study showed no difference in outcome between patient cooled to 33 °C vs. 36 °C, leading to the question if MTH itself is beneficial at all or the main beneficial effect might only be prevention of fever. Upon first multivariate analysis MTH was an independent predictor of long-term mortality in our study. This is likely due to the fact that these patients had more severe neurological injury than patients not treated with MTH. When correcting for GCS at admission there was no significant difference in survival for patients treated with or without MTH. Regarding PCI, Weisner et al. recently showed in a prospective study of 492 STEMI patients that treatment with PCI was not related to neurologic outcome after 30 days.51 The prospective design allowed for multivariate analyses leading to this conclusion. Taken together, results from over the world vary on short- and long-term outcome. It is likely that difference in inclusion account for these differences. However, most studies confirm the benefit of an early invasive strategy.

In our region we have optimized treatment for STEMI patients; as a result an infrastructure is present that allows expedient treatment of all patients that are suspected of having an acute coronary occlusion. Relatively short distances in our region and an extensive ambulance network help in this expedient treatment allocation. Wnent et al. has already showed that admission to a centre with PCI facilities is associated with favourable outcome in patients after OHCA.52 As a result of this STEMI network it is likely that other patients who have an indication to undergo CAG have a better chance of survival. Based on these observations we changed our practice and more liberally accept patients for coronary angiography. Whether these patients benefit to the same degree from angiography and PCI still has to be elucidated.

Several limitations have to be mentioned. First, this concerns a retrospective study of patients admitted to our hospital. Therefore, detailed data is sometimes absent, such as the time to BLS, ALS and ROSC. Second, selection bias limits the external validity of the efficacy of PCI and MTH. As in other studies, among our patients the GCS score was the second most powerful predictor of outcome (after initial rhythm), and thus the beneficial outcomes of patients who underwent primary PCI might be attributable to better initial GCS scores than among those present in the non PCI group. This creates an interesting avenue for research and possible improvement of treatment. Finally, these results only relate to patients presenting to the emergency unit of a single centre. More patients were resuscitated in our region in the same period, but patients with poor prognostic signs could have been presented to peripheral hospitals and pronounced dead there. Since our centre is the only regional facility, which offers PCI, patients suspected of coronary occlusion are primarily presented at our centre. Additionally, in our region ambulance services have the discretion to stop CPR if there is a non-shockable rhythm present for more than 20 minutes. This might explain differences in patient population in comparison with other studies, such as the Arrest study.53, 54 In essence we have a higher percentage of patients presenting with VF and after ROSC. Therefore, the outcome data we present do not pertain to the total population of patients suffering OHCA. However, our purpose was to investigate outcome among patients who presented to the emergency

69


department, because they still have a chance of survival.

In conclusion, survival and neurological outcome in our patients resuscitated after VF and treated with PCI within a STEMI network was remarkably good. In our opinion these observations underscores that the current chain of treatment allows optimal patient survival. However there is insufficient good quality evidence about the outcome of immediate angiography and coronary intervention in patients with ROSC after OHCA of presumed cardiac aetiology. Since the impact of this strategy on utilization of resources is significant, good quality RCT’s are needed. In selected patients successfully resuscitated after OHCA of presumed cardiac aetiology, we believe that a more liberal application of angiography and coronary intervention may be considered in experienced acute cardiac referral centres.

Conflict of interestThe Author(s) declare(s) that there is no conflict of interest

70

Chapter Four

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Cardiovascular Care. Part 6: advanced cardiovascular life support: 7C: a guide to the International ACLS algorithms. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Circulation. 2000; 102: I142-57.28. Bouwes A, Binnekade JM, Kuiper MA, et al. Prognosis of coma after therapeutic hypothermia: a prospective cohort study. Annals of neurology. 2012; 71: 206-12.29. Wijdicks EF, Hijdra A, Young GB, et al. Quality Standards Subcommittee of the American Academy of N. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006; 67: 203-10.30. Fokkema ML, James SK, Albertsson P, et al. Population trends in percutaneous coronary intervention: 20-year results from the SCAAR (Swedish Coronary Angiography and Angioplasty Registry). Journal of the American College of Cardiology. 2013; 61: 1222-30.31. Adrie C, Cariou A, Mourvillier B, et al. Predicting survival with good neurological recovery at hospital admission after successful resuscitation of out-of-hospital cardiac arrest: the OHCA score. Eur Heart J. 2006; 27: 2840-5.32. Skrifvars MB, Varghese B and Parr MJ. Survival and outcome prediction using the Apache III and the out-of-hospital cardiac arrest (OHCA) score in patients treated in the intensive care unit (ICU) following out-of-hospital, in-hospital or ICU cardiac arrest. Resuscitation. 2012; 83: 728-33.33. Nielsen N, Hovdenes J, Nilsson F, et al. Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand. 2009; 53: 926-34.34. Marcusohn E, Roguin A, Sebbag A, et al. Primary percutaneous coronary intervention after out-of-hospital cardiac arrest: patients and outcomes. Isr Med Assoc J. 2007; 9: 257-9.35. Grasner JT, Meybohm P, Caliebe A, et al. Postresuscitation care with mild therapeutic hypothermia and coronary intervention after out-of-hospital cardiopulmonary resuscitation: a prospective registry analysis. Critical care. 2011; 15: R61.36. Cronier P, Vignon P, Bouferrache K, et al. Impact of routine percutaneous coronary intervention after out-of-hospital cardiac arrest due to ventricular fibrillation. Critical care. 2011; 15: R122.37. Batista LM, Lima FO, Januzzi JL, Jr., et al. Feasibility and safety of combined percutaneous coronary intervention and therapeutic hypothermia following cardiac arrest. Resuscitation. 2010; 81: 398-403.38. Choudry F, Weerackody R, Timmis A, et al. Importance of primary percutaneous coronary intervention for reducing mortality in ST-elevation myocardial infarction complicated by out of hospital cardiac arrest. European heart journal Acute cardiovascular care. 2014.39. Demirel F, Rasoul S, Elvan A, et al. Impact of out-of-hospital cardiac arrest due to ventricular fibrillation in patients with ST-elevation myocardial infarction admitted for primary percutaneous coronary intervention: Impact of ventricular

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fibrillation in STEMI patients. European heart journal Acute cardiovascular care. 2015 Feb;4(1):16-23.40. Bro-Jeppesen J, Kjaergaard J, Wanscher M, et al. Emergency coronary angiography in comatose cardiac arrest patients: do real-life experiences support the guidelines? European heart journal Acute cardiovascular care. 2012; 1: 291-301.41. Ganz W. The thrombolysis in myocardial infarction (TIMI) trial. N Engl J Med. 1985; 313: 1018.42. Hollenbeck RD, McPherson JA, Mooney MR, et al. Early cardiac catheterization is associated with improved survival in comatose survivors of cardiac arrest without STEMI. Resuscitation. 2014; 85: 88-95.43. Gorjup V, Radsel P, Kocjancic ST, et al. Acute ST-elevation myocardial infarction after successful cardiopulmonary resuscitation. Resuscitation. 2007; 72: 379- 85.44. Zanuttini D, Armellini I, Nucifora G, et al. Impact of emergency coronary angiography on in-hospital outcome of unconscious survivors after out-of- hospital cardiac arrest. The American journal of cardiology. 2012; 110: 1723- 8.45. Nanjayya VB and Nayyar V. Immediate coronary angiogram in comatose survivors of out-of-hospital cardiac arrest-an Australian study. Resuscitation. 2012; 83: 699-704.46. Dumas F and Rea TD. Long-term prognosis following resuscitation from out-of- hospital cardiac arrest: role of aetiology and presenting arrest rhythm. Resuscitation. 2012; 83: 1001-5.47. Sideris G, Voicu S, Yannopoulos D, et al. Favourable 5-year postdischarge survival of comatose patients resuscitated from out-of-hospital cardiac arrest, managed with immediate coronary angiogram on admission. European heart journal Acute cardiovascular care. 2014; 3: 183-91.48. Maze R, Le May MR, Hibbert B, et al. The impact of therapeutic hypothermia as adjunctive therapy in a regional primary PCI program. Resuscitation. 2013; 84: 460-4.49. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted Temperature Management at 33 degrees C versus 36 degrees C after Cardiac Arrest. N Engl J Med. 2013 Dec 5;369(23):2197-206.50. Rittenberger JC and Callaway CW. Temperature Management and Modern Post-Cardiac Arrest Care. N Engl J Med. 2013 Dec 5;369(23):2262-3.51. Weiser C, Testori C, Sterz F, et al. The effect of percutaneous coronary intervention in patients suffering from ST-segment elevation myocardial infarction complicated by out-of-hospital cardiac arrest on 30 days survival. Resuscitation. 2013; 84: 602-8.52. Wnent J, Seewald S, Heringlake M, et al. Choice of hospital after out-of- hospital cardiac arrest - a decision with far-reaching consequences: a study in a large German city. Critical care. 2012; 16: R164.53. Berdowski J, Berg RA, Tijssen JG and Koster RW. Global incidences of out-of- hospital cardiac arrest and survival rates: Systematic review of 67 prospective studies. Resuscitation. 2010; 81: 1479-87.

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54. van Alem AP, Chapman FW, Lank P, et al. A prospective, randomised and blinded comparison of first shock success of monophasic and biphasic waveforms in out-of-hospital cardiac arrest. Resuscitation. 2003; 58: 17-24.

Chapter Five

Short- and long-term outcome after OHCA

in patients aged 75 years and older

Remco Bergman, Bart Hiemstra, Anthony Absalom, Joukje van der Naalt, Pim van der

Harst, Ronald de Vos, Wybe Nieuwland, Maarten W Nijsten, Iwan CC van der Horst.

Submitted to Critical Care & Resuscitation.

77


AbstractIntroductionOver the past decade, pre-hospital and in-hospital treatment for out-of-hospital-cardiac arrest (OHCA) has improved considerably. Long-term outcome in younger survivors is frequently good. We studied whether elderly OHCA patients benefit to the same extent at long-term follow-up.

MethodsBetween 2001 and 2010 data from all patients presented to our hospital after OHCA were recorded in an electronic database. Patients aged ≥ 75 years were compared with younger patients. Neurological outcome was classified as cerebral performance category (CPC) and long-term survival was evaluated and compared with matched general population data from the Dutch Census Bureau.

ResultsOf the 810 patients admitted after OHCA, a total of 551 patients (68%) achieved return of spontaneous circulation including 125 (23%) elderly patients with a mean age of 81 ± 5 years. The elderly patients had initial laboratory derangements that were comparable to younger patients. Hospital survival was lower in elderly patients compared to younger patients with an in-hospital survival of 33% vs. 57% (P < 0.001). The majority of surviving elderly patients had a CPC score of 1 (71%). Elderly patients had a median survival of 6.5 compared to 8.2 years for a matched general population.

ConclusionThe survival rate after OHCA in elderly patients is approximately half that of younger patients. However the majority of elderly patients who survive to discharge have a long-term survival that compares favourably with the general population.

78

Chapter Five

IntroductionOutcome after out of hospital cardiac arrest (OHCA) has markedly improved in the past years.1-3 While the overall mortality rate is still considerable, the patients who do survive tend to have a good neurological outcome.4-6 Although many studies have focused on outcome after OHCA 7-10, only a few studies have focused on the elderly. Since older studies reported dismal outcomes in certain elderly patient groups after cardiopulmonary resuscitation (CPR) 11, there may be reluctance to institute maximal treatment in all patients for fear of only generating greater numbers of survivors with poor functional outcomes.12 In our regional care system, when patients present with ST-segment elevation myocardial infarction (STEMI) after OHCA we perform early reperfusion therapy, i.e. percutaneous coronary intervention (PCI), in patients with return of spontaneous circulation (ROSC), including elderly patients.

Recent studies in other fields also show encouraging results for the acute treatment of elderly patients 13,14, such as good outcomes in survivors after acute abdominal aneurysm.14 Although patients who are older had a lower chance of survival compared to younger patients, the patients who did survive had good long-term outcome. Moreover, multiple studies in intensive care patients demonstrate that elderly patients benefit from intensive treatment.15-18 Whether elderly OHCA patients admitted to our centre after cardiac arrest also benefit from early treatment was investigated in the current study.

MethodsSettingThe University Medical Center Groningen is a tertiary referral hospital for the North Eastern part of the Netherlands. It operates in combination with multiple ambulance services in this area. A driver with a paramedical background and a nurse staff each ambulance, and both have the training and permission to administer inotropic drugs and use a defibrillator when required. In case of resuscitation a backup ambulance is always sent. Patients are preferentially transported to our centre where resuscitation is continued or post-resuscitation care is given following advanced cardiac life support (ACLS) guidelines. Patients requiring continuous mechanical ventilation were transferred to the intensive care unit (ICU) for post-resuscitation care.

PatientsWe studied all adult patients who presented at our hospital after OHCA during the years 2001-2010. Data were collected retrospectively from the medical records of the Ambulance System. During the study period mild therapeutic hypothermia (MTH) was initiated if patients had a Glasgow Coma Score < 8. These patients were cooled to 32-34 °C for 24 hours and thereafter passively rewarmed to 36 °C. From this cohort we extracted the patients with an age of ≥ 75 years (‘elderly patients’) and used the younger patients for comparison of outcomes in both categories. Treatment was left at the discretion of the attending physicians. Laboratory analysis was undertaken in all patients who achieved ROSC.

79


Electrocardiography data (ECG), somatosensory evoked potentials (SSEP), electroencephalography (EEG) data and laboratory values were gathered from the hospital information system. Neurological status was obtained from the clinical patient notes made during outpatient follow-up assessments by cardiologists or rehabilitation specialists. Survival status was determined until August 2016.

Statistical analysisContinuous data are presented as either means ± standard deviation (SD) for normally distributed variables or medians and interquartile ranges (IQR) for skewed data or as group percentages for categorical variables. We determined outcome in subgroups dependent on initial rhythm (ventricular fibrillation (VF) vs. no-VF), implemented treatment (PCI vs. no PCI, MTH vs. no MTH) and systolic left ventricular ejection fraction (LVEF) (LVEF < 45% vs. ≥ 45%). We recorded age, gender and known factors associated with outcome; initial rhythm, in hospital treatment (PCI and MTH) and left ventricular function.

Statistical analysis was performed using the Chi-square test for categorical and the Mann-Whitney or independent sample t-test for skewed continuous and normal distributed variables, respectively. Kaplan-Meier survival analysis was used to assess and compare survival. For each OHCA patient the actual survival was matched with the predicted survival for persons of the same age, same sex and for the same calendar year, as predicted by the Dutch Census Bureau in 2015.19 Statistical significance was defined as a two-sided P-value of < 0.05. All statistical analyses were performed using commercially available software (SPSS 23.0, IBM, USA).

80

Chapter Five

Figure 1. Flowchart of study population. After each step total percentage is set as 100%.

ResultsCharacteristics of all admitted patientsFrom 2001 to 2010 a total of 810 patients were admitted after OHCA (figure 1). Of these, 188 (23%) patients were ≥ 75 years with a mean age of 81 ± 5 years. Baseline and clinical characteristics of patients < 75 years and ≥ 75 years are presented in table 1 and table 2. The location of arrest differed between both groups and elderly patients less often had an initial rhythm of VF. Patients aged ≥ 75 years had an increased incidence of prior cardiovascular disease (CVD) and risk factors. More specifically, elderly patients were more frequently known with a previous myocardial infarction, cerebrovascular accident, hypertension, diabetes, and concurrent malignancy (table 1). There were no differences in glucose, lactate, pH, and base excess between these groups.

81


Table 1. Baseline characteristics of all patients admitted after out of hospital cardiac arrest.Total

n = 810< 75 years

n = 622≥ 75 years

n = 188P-value

Cardiovascular risk factors

Hypertension (%) 196 (24%) 141 (23%) 55 (29%) 0.031

Hypercholesterolemia (%) 78 (10%) 65 (11%) 13 (7%) 0.180Diabetes (%) 108 (13%) 72 (12%) 36 (19%) 0.004

Cardiovascular history

Myocardial infarction (%) 148 (18%) 98 (16%) 50 (27%) < 0.001

STEMI (%) 131 (16%) 86 (14%) 45 (24%) < 0.001

PCI (%) 61 (8%) 46 (7%) 15 (8%) 0.680CABG (%) 57 (7%) 31 (5%) 26 (14%) < 0.001

Angina (%) 79 (10%) 49 (8%) 30 (16%) < 0.001

Cerebrovascular accident (%) 51 (6%) 33 (5%) 18 (10%) 0.024

History of VF (%) 16 (2%) 11 (2%) 5 (3%) 0.400Malignancy (%) 35 (4%) 16 (4%) 19 (10%) < 0.001

Medication history

Beta blocker (%) 185 (23%) 124 (20%) 61 (32%) < 0.001

ACE-inhibitor (%) 125 (15%) 80 (13%) 45 (24%) < 0.001

AT-II receptor antagonist (%) 56 (7%) 39 (6%) 17 (9%) 0.043

Diuretics (%) 142 (18%) 87 (14%) 55 (29%) < 0.001

Antiplatelet therapy (%) 126 (16%) 83 (13%) 43 (23%) < 0.001

Coumarin derivatives (%) 110 (14%) 72 (12%) 38 (20%) < 0.001

Statins (%) 150 (19%) 107 (17%) 43 (23%) 0.003

Antiarrhythmics (%) 33 (4%) 18 (3%) 15 (8%) < 0.001

Oral antidiabetic therapy (%) 57 (7%) 37 (6%) 20 (11%) 0.003

Insulin (%) 35 (4%) 30 (5%) 5 (3%) 0.390STEMI = ST-segment Elevation Myocardial Infarction. PCI = Percutaneous Coronary Intervention. CABG = Coronary Artery Bypass Grafting. VF = Ventricular Fibrillation. ACE = Angiotensin Converting Enzyme. AT = AngioTensin.

Characteristics of patients who achieved ROSCThere was no difference between the two age groups in the fraction of patients who achieved ROSC, although initially upon arrival at the emergency department younger patients more often had achieved ROSC (table 2). Table 3 summarizes the clinical characteristics, angiography data and outcome of the patients who achieved ROSC. Elderly patients were less often diagnosed with a STEMI, had smaller infarct sizes and presented with higher N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels. After ROSC the initial Glasgow Coma Scores were equally low in the elderly and younger cohort with median scores of 3 (3 - 9) and 4 (3 - 14), P = 0.451, respectively.

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Chapter Five

Table 2. Clinical characteristics of patients after arrival at the hospital.Total

n = 810< 75 years

n = 622≥ 75 years

n = 188P-Value

Clinical characteristics

Age* 63 ± 15 57 ± 12 81 ± 5 < 0.001

Male sex (%) 572 (71%) 448 (72%) 124 (66%) 0.110History of CVD (%) 257 (32%) 169 (27%) 88 (48%) < 0.001

Location (%) < 0.001

Home 374 (46%) 280 (45%) 94 (50%) Public place 190 (24%) 164 (26%) 26 (14%) Other 116 (14%) 91 (15%) 25 (13%) Ambulance 60 (7%) 47 (8%) 13 (7%) Unknown 70 (9%) 40 (6%) 30 (16%)Witnessed arrest (%) 642 (79%) 504 (81%) 138 (73%) 0.964BLS performed (%) 460 (57%) 366 (59%) 94 (50%) 0.160Initial rhythm (%) < 0.001

VF 518 (64%) 421 (68%) 97 (52%) PEA 149 (18%) 97 (16%) 52 (28%) Asystole 116 (14%) 84 (14%) 32 (17%) Pulseless VT 27 (3%) 20 (3%) 7 (4%)ROSC before ED arrival (%) 473 (58%) 374 (60%) 99 (53%) 0.013

ROSC (%) 551 (68%) 426 (69%) 125 (67%) 0.606Glasgow Coma Scale at admission# 3 (3, 6) 3 (3, 6) 3 (3, 5) 0.358

Acute lab markers

Glucose# 13.4 (10.2, 18.4) 13.3 (10.1, 18.3) 13.4 (10.4, 18.6) 0.469Lactate# 7.9 (3.7, 12.4) 8.2 (3.5, 13.0) 6.9 (4.0, 11.0) 0.169pH# 7.20 (6.97, 7.30) 7.19 (6.96, 7.30) 7.23 (7.00, 7.32) 0.060

Base excess# -11.8 (-18.4, -5.0)

-11.9 (-18.9, -5.2) -10.55 (-17.1, -4.6) 0.332

* = Mean ± SD, # = median (IQR). CVD = CardioVascular Disease. BLS = Basic Life Support. VF = Ventricular Fibrillation. PEA = Pulseless Electrical Activity. VT = Ventricular Tachycardia. ROSC = Return Of Spontaneous Circulation.

TreatmentOnly 32 patients from the older cohort underwent primary CAG vs. 185 in the younger group (P < 0.001). The percentages of patients who underwent primary CAG were similar with 84% in the elderly and 89% in the younger patients (P = 0.492). Mild therapeutic hypothermia was also similarly used in the elderly (33%) and younger (38%) patients (P = 0.280).

Outcome Survival to hospital discharge was lower in elderly patients with only 33% surviving compared to 57% in the younger group (P < 0.001; table 3). After initial ROSC, there was no significant difference in outcome related to initial rhythm (VF vs. non-VF) in the elderly: 25 patients (60%) with VF-survival vs. 17 patients (40%) with non-VF survival, P = 0.489,

83


respectively. In younger patients this relation was strong with an improved outcome in the VF group: 207 (86%) survivors vs. 35 (14%) survivors to hospital discharge (P < 0.001). Length of hospital stay was shorter in the elderly patients due to their lower survival (table 3); with similar a hospital stay for hospital survivors in both groups.

After hospital discharge, survival in elderly patients was worse in comparison with younger patients (figure 2). One-year survival in the overall OHCA group after hospital discharge was 94% and 5-year survival was still 84%. In contrast, in the patients aged ≥ 75 years 1-year survival was only 76% and 5-year survival dropped to 56%. When compared to sex-, age- and calendar year-matched controls, long-term survival was comparable to the general population (figure 3).19 The median survival of the elderly patients was 5.6 (± 4.1) years compared to 7.7 (± 0.1) years for a matched general population (P = 0.084).

P < 0.001

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

0

41 28 24 21 10 5> 75 years242 229 216 204 116 68< 75 years

Number at risk

0 2 4 6 8 10Follow−up after OHCA (years)

Patients aged < 75 years

Patients aged > 75 years

Figure 2. Survival curves of younger (< 75 years) and elderly (≥ 75 years) patients.

84

Chapter Five

P = 0.084

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

0 1 2 3 4 5 6 7 8 9 10Follow−up after OHCA (years)

Figure 3. Survival curve elderly vs. matched control population with 95% confidence intervals.

Cause of deathCauses of death did not vary substantially between age groups (table 3). The major cause of death was neurological damage that was not compatible with survival. If brain stem reflexes were absent (i.e. absent pupillary light response and corneal reflexes) and in case of absent motor scores, no further life-sustaining treatment was delivered. In all other cases, additional SSEP monitoring was done and in the case of absent bilateral N20 potentials active treatment was also withdrawn. EEG analysis was performed when seizures or myoclonus was present. Seizures were treated with antiepileptic drugs; in the case of myoclonus status epilepticus treatment was also stopped.20,21 In these patients active therapies were discontinued, and treatment was altered to comfort-care. Other important causes of death were secondary circulatory failure and multi-organ failure (table 3).

Neurological outcome at hospital dischargeThe younger cohort had a better neurological outcome as scored by the CPC (table 3). In the elderly 71% had a CPC of 1 compared to 86% in the younger patients (P = 0.014). The incidence of poor outcome (CPC > 2) was 7.1% in the elderly vs. 2.5% in the younger cohort. However this difference was not statistically significant (P = 0.111).

85

Short- and long-term outcome after OHCA in patients aged 75 years and olderTa

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87


DiscussionFrom the long-term follow-up of a cohort of 810 patients after OHCA two main observations can be drawn. First, despite similar percentages of patients regaining spontaneous circulation, in-hospital mortality was much higher in elderly compared to younger patients. Second, we add to the current literature, that elderly patients who were discharged had a long-term outcome with a median survival of 7.4 years, is similar to that of matched elderly controls in the general population. Moreover, in these elderly patients the neurological outcome was good in a high percentage of patients, with less than 10% with a poor neurological outcome.

Over the last years interest in the outcome of elderly patients has increased. In a study with 34,291 patients Wong et al. showed in 2014 that over time the outcome of the elderly at 1 year has improved.22 In this study no data on functional outcome were available. The favourable outcome trend for functional outcome was more recently showed by Inokuchi et al. In 8,964 cardiac arrest patients favourable 1-month neurological outcome increased from 1.6% in 2002 to 2.7% in 2012.23 Beesems et al. recently showed worse survival and equally favourable functional outcome in survivors compared to our study. In 1,332 patients aged ≥ 70 years 1 year survival in patients discharged alive was 88% and neurologic outcome, as defined by the Charlston Comorbidity Index, was good in 90% of patients. Compared to our study their follow-up was limited to 1 year.24 Also recently, Winther-Jensen et al. presented data on very elderly OHCA patients with 30-day follow-up. In 2,509 patients success of resuscitation in patients ≥ 80 was 30% and CPC scores 1 or 2 were achieved in 70% of the very elderly.25

In our study several factors were associated with both mortality and unfavourable neurological outcome.6,26-28 In line with observations of others, the elderly have a higher cardiovascular risk profile and more co-morbidities.24,29,30 We also observed a higher incidence of an initial rhythm other than ventricular fibrillation, which is associated with a poor outcome, in the elderly patients.31 In our study the initial rhythm was not associated with outcome in elderly. We think that this is due to the relatively small number of patients. When looking at acute laboratory markers for predicting outcome there were no differences in glucose, base excess and lactate levels.6,26-28

However, in contrast to other studies, the incidence of return of spontaneous circulation in the elderly in our population was high and almost equal to younger patients.32,33 Like in the study of Winther-Jensen et al. coronary angiography, and associated therewith percutaneous coronary intervention, was employed less frequently in the elderly patients.25 This is partly explained by acute myocardial infarction being less frequently the underlying cause of OHCA in the elderly, with lower cardiac biomarkers in the elderly and another initial rhythm than ventricular fibrillation. The higher incidence of previous myocardial infarction in the elderly might underlie secondary rhythm disturbances that cause OHCA. Their underlying pathology in elderly is less amenable to treatment and might also explain their worse survival after hospital discharge.6,34,35 Mild therapeutic hypothermia was employed equally in both groups.

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Chapter Five

Treatment decisions can be particularly difficult for clinicians caring for elderly patients. Cardiopulmonary resuscitation for older patients is a controversial issue.36-38 Initiating CPR in the elderly is a decision that is hampered by differing opinions for what is best for the patient and these opinions may vary from country to country. It does not only imply medical but also ethical decisions, especially when there are important associated co-morbidities that directly affect the patient’s prognosis.39 As shown in our study the incidence of malignancies is significantly higher in the elderly. Since we add to the current literature the life expectancy of our population as compared to the general population we could demonstrate that survival is reasonable with an average life span of 7.4 (± 1.6) years.19 Our data thus do not support the withholding of resuscitation based on age. Moreover, while overall mortality is higher in the elderly group, neurological outcome is usually good.

LimitationsThis study has several limitations. First, it was performed retrospectively on data of patients admitted to our hospital. Therefore, detailed data are lacking on the time frames of initial treatment, such as time to BLS, ALS and ROSC for instance. Secondly treatment was not standardized; thus various potential sources of unidentified bias in the care of older and younger patients may be present. However, highlighting this potential bias is also an important finding in this study. Finally, these results only relate to patients presenting to the emergency unit of a single centre. This limits the external validity of our findings. Some patients who were resuscitated in the same period in our region will not have been presented in our hospital, since for some patients PCI was not deemed indicated. Likewise, for other patients with very poor early prognostic variables, referral to our hospital may have been considered futile. The ambulance services in our region have the discretion to discontinue CPR if there is a non-shockable rhythm present for more than 20 minutes. This may explain differences in our patient population in compared to other studies, such as the Arrest study.40,41 As such, the outcome data we present do not pertain to the total population of patients suffering OHCA in our region.

ConclusionDespite similar rates of ROSC in elderly patients vs. younger patients, outcome after OHCA for elderly patients is worse with a hospital survival rate that is approximate half that of younger patients. However, the majority of elderly patients who survived had a CPC score of 1 and a life span that compared favourably with the general population at this age.

Conflict of interestNo competing financial interests.

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References1. Nolan JP. Optimizing outcome after cardiac arrest. Curr Opin Crit Care. 2011;17(5):520-526.2. Savastano S, Klersy C, Raimondi M, et al. Positive trend in survival to hospital discharge after out-of-hospital cardiac arrest: A quantitative review of the literature. J Cardiovasc Med (Hagerstown). 2014;15(8):609-615.3. Arrich J, Holzer M, Havel C, et al. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev. 2016;2:CD004128.4. Bro-Jeppesen J, Kjaergaard J, Horsted TI, et al. The impact of therapeutic hypothermia on neurological function and quality of life after cardiac arrest. Resuscitation. 2009;80(2):171-176.5. Kim WY, Giberson TA, Uber A, et al. Neurologic outcome in comatose patients resuscitated from out-of-hospital cardiac arrest with prolonged downtime and treated with therapeutic hypothermia. Resuscitation. 2014;85(8):1042-1046.6. Bergman R, Hiemstra B, Nieuwland W, et al. Long-term outcome of patients after out-of-hospital cardiac arrest in relation to treatment: A single-centre study. Eur Heart J Acute Cardiovasc Care. 2016;5(4):328-338.7. Hosmane VR, Mustafa NG, Reddy VK, et al. Survival and neurologic recovery in patients with ST-segment elevation myocardial infarction resuscitated from cardiac arrest. J Am Coll Cardiol. 2009;53(5):409-415.8. Lang ES. ACP journal club. review: Therapeutic hypothermia improves neurologic outcome and survival to discharge after cardiac arrest. Ann Intern Med. 2010; 152(4):JC-22.9. Hinchey PR, Myers JB, Lewis R, et al. Improved out-of-hospital cardiac arrest survival after the sequential implementation of 2005 AHA guidelines for compressions, ventilations, and induced hypothermia: The wake county experience. Ann Emerg Med. 2010;56(4):348-357.10. van der Wal G, Brinkman S, Bisschops LL, et al. Influence of mild therapeutic hypothermia after cardiac arrest on hospital mortality. Crit Care Med. 2011;39(1):84-88.11. Applebaum GE, King JE, Finucane TE. The outcome of CPR initiated in nursing homes. J Am Geriatr Soc. 1990;38(3):197-200.12. Nagappan R, Parkin G. Geriatric critical care. Crit Care Clin. 2003;19(2):253- 270.13. Ferrari E, Tozzi P, Hurni et al. Primary isolated aortic valve surgery in octogenarians. Eur J Cardiothorac Surg. 2010;38(2):128-133.14. Scheer ML, Pol RA, Haveman JW, et al. Effectiveness of treatment for octogenarians with acute abdominal aortic aneurysm. J Vasc Surg. 2011;53(4):918-925.15. van den Noortgate N, Vogelaers D, Afschrift M, Colardyn F. Intensive care for very elderly patients: Outcome and risk factors for in-hospital mortality. Age Ageing. 1999;28(3):253-256.16. Wood KA, Marik PE. ICU care at the end of life. Chest. 2004;126(5):1403- 1406.

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17. Nathanson BH, Higgins TL, Brennan MJ, et al. Do elderly patients fare well in the ICU? Chest. 2011;139(4):825-831.18. Sprung CL, Artigas A, Kesecioglu J, et al. The eldicus prospective, observational study of triage decision making in european intensive care units. part II: Intensive care benefit for the elderly. Crit Care Med. 2012;40(1):132- 138.19. Central Bureau for Statistics. Statistics Netherlands: life expectancy; gender and age from 1950 on (per year). Retrieved from http://Statline.cbs.nl/ StatWeb publication/?PA=37360ned. 2015.20. Wijdicks EF, Hijdra A, Young GB, et al. Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: Prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): Report of the quality standards subcommittee of the american academy of neurology. Neurology. 2006;67(2):203-210.21. Bouwes A, Binnekade JM, Kuiper MA, et al. Prognosis of coma after therapeutic hypothermia: A prospective cohort study. Ann Neurol. 2012;71(2):206-212.22. Wong MK, Morrison LJ, Qiu F, et al. Trends in short- and long-term survival among out-of-hospital cardiac arrest patients alive at hospital arrival. Circulation. 2014; 130(21):1883-1890.23. SOS-KANTO 2012 Study Group. Changes in treatments and outcomes among elderly patients with out-of-hospital cardiac arrest between 2002 and 2012: A post hoc analysis of the SOS-KANTO 2002 and 2012. Resuscitation. 2015;97:76-82.24. Beesems SG, Blom MT, van der Pas MH, et al. Comorbidity and favorable neurologic outcome after out-of-hospital cardiac arrest in patients of 70 years and older. Resuscitation. 2015;94:33-39.25. Winther-Jensen M, Pellis T, Kuiper M, et al. Mortality and neurological outcome in the elderly after target temperature management for out-of-hospital cardiac arrest. Resuscitation. 2015;91:92-98.26. McGill JW, Ruiz E. Central venous pH as a predictor of arterial pH in prolonged cardiac arrest. Ann Emerg Med. 1984;13(9 Pt 1):684-687.27. Mullner M, Sterz F, Domanovits H, et al. The association between blood lactate concentration on admission, duration of cardiac arrest, and functional neurological recovery in patients resuscitated from ventricular fibrillation. Intensive Care Med. 1997;23(11):1138-1143.28. Takasu A, Sakamoto T, Okada Y. Arterial base excess after CPR: The relationship to CPR duration and the characteristics related to outcome. Resuscitation. 2007; 73(3):394-399.29. Bagnall AJ, Goodman SG, Fox KA, et al. Influence of age on use of cardiac catheterization and associated outcomes in patients with non-ST-elevation acute coronary syndromes. Am J Cardiol. 2009;103(11):1530-1536.30. Mosier J, Itty A, Sanders A, et al. Cardiocerebral resuscitation is associated with improved survival and neurologic outcome from out-of-hospital cardiac arrest in elders. Acad Emerg Med. 2010;17(3):269-275.31. Wissenberg M, Lippert FK, Folke F, et al. Association of national initiatives to

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improve cardiac arrest management with rates of bystander intervention and patient survival after out-of-hospital cardiac arrest. JAMA. 2013;310(13):1377- 1384.32. Fukuda T, Ohashi-Fukuda N, Matsubara T, et al. Trends in outcomes for out- of-hospital cardiac arrest by age in japan: An observational study. Medicine (Baltimore). 2015;94(49):e2049.33. Andersen LW, Bivens MJ, Giberson T, et al. The relationship between age and outcome in out-of-hospital cardiac arrest patients. Resuscitation. 2015;94:49- 54.34. Hollenbeck RD, McPherson JA, Mooney MR, et al. Early cardiac catheterization is associated with improved survival in comatose survivors of cardiac arrest without STEMI. Resuscitation. 2014;85(1):88-95.35. Camuglia AC, Randhawa VK, Lavi S, Walters DL. Cardiac catheterization is associated with superior outcomes for survivors of out of hospital cardiac arrest: Review and meta-analysis. Resuscitation. 2014;85(11):1533-1540.36. Gordon M. Ethical challenges in end-of-life therapies in the elderly. Drugs Aging. 2002;19(5):321-329.37. Deasy C, Bray JE, Smith K, et al. Out-of-hospital cardiac arrests in the older age groups in melbourne, australia. Resuscitation. 2011;82(4):398-403.38. van de Glind EM, van Munster BC, van de Wetering FT, van Delden JJ, Scholten RJ, Hooft L. Pre-arrest predictors of survival after resuscitation from out-of- hospital cardiac arrest in the elderly a systematic review. BMC Geriatr. 2013; 13:68-2318-13-68.39. Edin MG. Cardiopulmonary resuscitation in the frail elderly: Clinical, ethical and halakhic issues. Isr Med Assoc J. 2007;9(3):177-179.40. van Alem AP, Chapman FW, Lank P, et al. A prospective, randomised and blinded comparison of first shock success of monophasic and biphasic waveforms in out-of-hospital cardiac arrest. Resuscitation. 2003;58(1):17-24.41. Berdowski J, Berg RA, Tijssen JG, Koster RW. Global incidences of out-of- hospital cardiac arrest and survival rates: Systematic review of 67 prospective studies. Resuscitation. 2010;81(11):1479-1487.

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Chapter Six

Long-term outcome in patients requiring

mechanical ventilation after ST-segment

elevation myocardial infarction

Bart Hiemstra, Geert Koster, Remco Bergman, Ruben J Eck, Wouter G Wieringa, Chris

PH Lexis, Erik Lipsic, Ronald de Vos, Frederik Keus, Anne Marie GA de Smet, Pim van

der Harst, Iwan CC van der Horst.

Submitted to Journal of Intensive Care.

95


AbstractBackground The need for mechanical ventilation after ST-segment elevation myocardial infarction (STEMI) is associated with increased mortality. Data on variables associated with mortality in this setting are sparse.

Methods From January 1, 2009, to May 26, 2013 we performed a single-centre, observational study that recorded all consecutive STEMI patients in a registry that ran along a clinical trial. We analyzed all patients who required mechanical ventilation with STEMI as primary reason for admittance. Our primary outcome was to identify independent predictors of 30-day mortality. Secondary outcomes were to identify independent predictors of mortality with solely early available clinical parameters, stratified by mortality reason, and at longest term follow-up.

Results Of all 2104 retrospectively registered STEMI patients 155 patients (7.4%) met our inclusion criteria. Mortality in the first 30-days was 50% (77 patients) of which 38 (25%) patients died due to severe cerebral damage and 34 (22%) patients due to refractory cardiogenic shock with multi-organ failure. At a median follow-up of 5 years, only an additional 13% (10 patients) had died. In multivariable analyses five factors were identified as independent predictors of mortality: an initial rhythm of pulseless electrical activity (PEA) or asystole (odds ratio [OR] 16.98, 95% confidence interval [CI] 2.31-124.73, P = 0.005), the development of cardiogenic shock (OR 3.67, 95% CI 1.21-11.11, P = 0.021), the maximum creatine kinase-myocardial band (CK-MB) level (OR 2.43, 95% CI 1.37-4.31, P = 0.002), older age (OR 1.25, 95% CI 1.00-1.54, P = 0.045) and a higher APACHE-IV score (OR 1.04, 95% CI 1.02-1.06, P < 0.001). Except for the maximum CK-MB level, these factors remained independently associated with mortality at maximum follow-up.

Conclusions A substantial number of patients with a STEMI need mechanical ventilation: approximately 1 out of every 14 patients. The 30-day mortality was high (50%), while only an additional 10 patients (13%) died after having survived 30 days, implicating that prognosis is fairly reasonable once having survived 30 days. Independent predictors of long-term mortality were older age, initial rhythm of PEA or asystole, admission with a cardiogenic shock, and a higher APACHE-IV score.Trial registration clinicaltrials.gov Identifier: NCT01217307.

96

Chapter Six

IntroductionAcute myocardial infarction (AMI) is a life-threatening event and a major cause of death.1 The diagnosis of ST-segment elevation myocardial infarction (STEMI) was found to be a predictor of early mortality in the overall AMI population.2, 3 Over the last decades, focus on the rapid percutaneous reperfusion of the occluded coronary vessel 4 resulted in a decrease in mortality.5, 6 In-hospital death of the overall STEMI population is estimated at 5-14% 5, 7, 8 and 1-year mortality at 10-20%.5, 6, 9, 10

Patients with a STEMI requiring mechanical ventilation have substantial higher in-hospital mortality rates (up to 50%) compared to patients with AMI that do not require mechanical ventilation.11-15 Mechanical ventilation in the setting of STEMI is often required for supportive treatment in critically ill patients with cardiogenic shock, cardiac arrest, arrhythmias, and acute pulmonary edema.13, 14

Little is known, however, about the risk factors for mortality in STEMI patients requiring mechanical ventilation, especially at long-term follow-up. Five cohort studies have identified predictors of mortality in the general AMI population 11, 12, 14-16, but nonetheless prediction of mortality among patients with a STEMI requiring mechanical ventilation remains difficult. The aim of this study was to identify risk factors for mortality both at short and long-term follow-up in patients presenting with a STEMI requiring mechanical ventilation.

MethodsStudy population and data collectionFrom January 1, 2009, to May 26, 2013, clinical and angiographic data of all patients presenting with a STEMI at the University Medical Center Groningen (UMCG) were recorded in a registry of a clinical trial.17 We combined data prospectively entered into the registry with the Dutch National Intensive Care Evaluation registry to identify the STEMI patients admitted to the intensive care unit (ICU). All consecutive mechanically ventilated patients with STEMI as primary reason for ICU admittance were included and patients admitted after (emergency) cardiothoracic surgery were excluded. The diagnosis of STEMI was set according to European Society of Cardiology (ESC) Guidelines.18 Cardiogenic shock was defined as severe hypotension with clinical signs of hypoperfusion and a serum lactate > 2 mmol/L despite fluid resuscitation.All patients underwent coronary angiography to determine the necessity of any intervention: primary percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or conservative treatment. Ambulance records, clinical ICU parameters, diagnoses and echocardiographic measurements and ICU treatment strategies were added to the database retrospectively.

Follow-up of all-cause mortality was acquired using the municipal personal records database. Long-term mortality was assessed up until August 1, 2016. The local institutional review board (Medisch Ethische Toetsingscomissie, UMCG) approved the study and waived the need for informed consent due to the observational nature of the

97


study.

Outcome measuresThe primary outcome of our study was to identify independent predictors of 30-day mortality. Secondary outcomes were to identify predictors of mortality with solely early available clinical parameters, predictors of mortality stratified by mortality reason and to evaluate the independent predictors of mortality at longest term follow-up.

Statistical analysisBaseline clinical and angiographic data were compared between survivors and non-survivors at 30-day follow-up. Continuous variables are summarized as means with standard deviations or medians with interquartile ranges (IQR), depending on normality. Dichotomous and categorical data are presented in percentages. Differences in baseline and angiographic data between survivors and non-survivors were evaluated using Student’s t-test or Mann-Whitney U test, depending on normality of data, whereas the Chi-squared test was used for categorical values. Only data that was more than 90% complete was used for further analyses.

We performed multivariable logistic and Cox regression analyses including all univariable predictors with a P < 0.1 after checking for correlations. To investigate predictors of mortality at both short and long-term, a logistic regression analysis was made at 30 days and a Cox regression analysis at maximal follow-up. In addition, we performed a multivariable Cox regression with only variables measured within the first 24 hours of ICU admission and we stratified according to reasons of mortality. To test the proportional hazard assumption of the covariates, the log minus log test and the scaled Schoenfeld residuals were performed. We included the independent predictors of mortality that have been described in literature, including age, inotropic dependence, Acute Physiology and Chronic Health Evaluation (APACHE)-scores, the ratio of arterial oxygen pressure to fractional inspired oxygen (PaO2/FiO2) and serum creatinine levels. Two-sided P-values < 0.05 were considered to indicate statistical significance. Statistical analyses were performed using Stata version 14.1 (StataCorp, CollegeStation, TX).

98

Chapter Six

Figure 1. Flow-chart of all STEMI patients that underwent coronary angiography. After the exclusion criteria the total percentage is set to 100%.

ResultsBaseline demographic and clinical characteristicsDuring the inclusion period, 208 (9.9%) of all 2104 registered STEMI patients were admitted to the ICU. A little more than a quarter of the admitted patients were excluded, mainly due to admittance after cardiothoracic surgery or ICU admittance due to other underlying illnesses, e.g. a perioperative developed a STEMI after repair of a ruptured abdominal aorta aneurysm, and one patient did not require mechanical ventilation but presented with hematemesis upon the start of anticoagulation therapy. Patients admitted to the ICU were less often known with hypercholesterolemia, more often had multiple vessel disease, a culprit lesion in the left main coronary artery and were less often treated with PCI (table 1).

For all mechanically ventilated ICU patients the mean age was 64.4 years (± 11.6) and a total of 121 patients (78%) were male (table 2). No significant differences in cardiovascular risk factors or history, culprit location, number of diseased coronary vessels, and performance of PCI were observed between survivors and non-survivors (additional file 1). Reasons for intubation are displayed in figure 1 and differed significantly between survivors and non-survivors (P < 0.01). A total of 53 patients (34%) had a cardiogenic shock during their ICU stay. In addition to the 11 patients admitted due to cardiogenic shock, it developed in 11 patients (50%) with an initial rhythm of pulseless electrical activity (PEA) or asystole, in 27 patients (25%) with ventricular fibrillation (VF) and in 4

99


patients (33%) presenting with acute pulmonary edema (P < 0.01). Patients that died more often developed a cardiogenic shock, had a lower ratio of arterial oxygen pressure to fractional inspired oxygen (PaO2/FiO2), lower systolic and mean arterial pressure, and a lower Glasgow Coma Scale on presentation (P < 0.01 for all). Routinely laboratory measurements at admission and peak levels were significantly different between both groups. Furthermore, non-survivors more frequently needed adrenalin, dobutamine and other inotropes, e.g. levosimendan or isoprenaline.(table 2).

Table 1. Clinical Characteristics and angiography data of all STEMI patients.No MV

(n = 1949)MV

(n = 155)P-value

Demographic

Age, mean ± SD 63.7 ± 13.3 64.9 ± 11.6 0.294Sex male, n (%) 1398 (72%) 121 (78%) 0.090Cardiovascular risk factors, n (%)

Hypertension 755 (39%) 59 (38%) 0.379Hypercholesterolemia 572 (29%) 31 (20%) 0.003

Diabetes 248 (13%) 20 (13%) 0.943Cardiovascular history, n (%)

Myocardial infarction 227 (12%) 24 (16%) 0.191PCI 174 (9%) 10 (7%) 0.272CABG 51 (3%) 7 (5%) 0.175Cerebrovascular accident 87 (5%) 11 (7%) 0.130Angiography

Door to balloon time (min)# 182 (122, 299) 160 (115, 250) 0.063Culprit location, n (%) Right coronary artery 753 (39%) 35 (23%) < 0.001

Left anterior descending artery 770 (40%) 70 (45%) 0.061 Circumflex artery 305 (16%) 28 (18%) 0.298 Left main coronary artery 24 (1%) 8 (5%) < 0.001

Unknown (multiple) 97 (5%) 14 (9%) 0.030

Multiple vessel disease, n (%) 909 (47%) 99 (64%) < 0.001

PCI performed, n (%) 1771 (91%) 133 (86%) < 0.001

Post-procedural TIMI score of 3, n (%) 1316 (68%) 90 (58%) 0.293MV = Mechanical Ventilation. PCI = Percutaneous Coronary Intervention. CABG = Coronary Artery Bypass Grafting. TIMI = Thrombolysis In Myocardial Infarction.

100

Chapter SixTa

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102

Chapter Six

Follow-upA total of 77 (50%) of the 155 patients died within 30 days, of which 38 (25%) patients died due to severe cerebral damage, 34 (22%) patients due multi-organ failure and 5 (3%) patients due to other reasons, i.e. secondary sepsis or sudden cardiac arrest. All but one patient died in the ICU and two patients were transferred to a hospice and died the next day. The majority of deceased patients with multi-organ failure died within 48 hours: 27/34 (79%), whereas patients with severe cerebral damage mainly died after 48 hours: 26/38 (68%). All 34 patients who died due to multi-organ failure suffered from cardiogenic shock. Patients who died at 30 days had a significant worse left (P < 0.01) and right (P = 0.03) ventricular function measured by transthoracic echocardiography (additional file 1).

Mortality increased to 50% (78 patients) at 90 days follow-up, to 53% (82 patients) at one year, and to 56% (87 patients) at maximal follow-up (median of 5.0 years (IQR 4.1 – 5.8). Figure 2 displays mortality rates stratified by reasons for intubation. Mortality rates at 30 days were similar in patients that underwent PCI compared to patients who received conservative treatment: 48% versus 57%, respectively (P = 0.443), however differed significantly at maximal follow-up: 53% versus 76% (P = 0.046) in favor of patients that underwent PCI.

Predictors of mortalityUnivariable significant variables relating ICU parameters to 30-day mortality can be found in additional file 2. Variables that are embedded in The Acute Physiology and Chronic Health Evaluation (APACHE) IV score were not used in the multivariable model to avoid overfitting. Table 3 displays a multivariable logistic regression analysis with independent predictors of 30-day mortality. The composite logistic model demonstrated a good accuracy with a C-statistic of 0.893.

When performing a multivariable Cox regression model with solely clinical parameters available within the first 24 hours of ICU admission, the following independent predictors of 30-day mortality were identified: the delta-pH with a pH of 7.40 as the normal or reference value (hazard ratio [HR] 36.76, 95% CI 3.26 – 414.40, P = 0.004), serum creatinine at admission (HR 4.22, 95% CI 2.05 – 8.70, P < 0.001), a Glasgow Coma Score of E1-M4-V1 or lower (HR 2.25, 95% CI 1.33 – 3.82, P = 0.003), a PaO2/FiO2 ratio < 200 mmHg (HR 1.94, 95% CI 1.13 – 3.34, P = 0.017), the maximum level of CK-MB (HR 1.84, 95% CI 1.36 – 2.48, P < 0.001), an initial rhythm of PEA or asystole (HR 1.77, 95% CI 1.03 – 3.06, P = 0.040) and age per 1 year step (HR 1.03, 95% CI 1.01 – 1.05, P = 0.006).

103


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104

Chapter Six

When stratifying for the 30-day mortality reasons multi-organ failure (n = 34) or severe cerebral damage (n = 38), the result of the Cox regression models differed substantially. Independent predictors 30-day mortality for multi-organ failure were: dependence on adrenalin (HR 13.17, 95% CI 5.72 – 30.31, P < 0.001), dependence on dobutamine (HR 3.77, 95% CI 1.66 – 8.60, P = 0.002), a PaO2/FiO2 ratio < 200 mmHg (HR 3.68, 95% CI 1.35 – 10.09, P = 0.011) and admission serum creatinine (HR 3.12, 95% CI 1.29 – 7.56, P = 0.012). For mortality due to severe cerebral damage, a Glasgow Coma Score of E1-M4-V1 or lower at admission (HR 7.74, 95% CI 2.73 – 21.96, P < 0.001), an initial rhythm of PEA or asystole (HR 2.59, 95% CI 1.22 – 5.46, P = 0.013) and the maximum level of CK-MB (HR 1.88, 95% CI 1.26 – 2.83, P = 0.002) were independent predictors of 30-day mortality.

Table 3. Multivariable logistic and Cox regression with predictors of short- and long-term mortality.Variable 95% CI P-value

Logistic regression – 30 day mortality Odds ratio

PEA or asystole 16.98 2.31 – 124.73 0.005

Cardiogenic shock during ICU stay 3.67 1.21 – 11.11 0.021

Peak CK-MB level < 24 hours* 2.43 1.37 – 4.31 0.002

Age (per 5 year increase) 1.25 1.00 – 1.54 0.045

APACHE-IV score (per 1 point increase) 1.04 1.02 – 1.06 < 0.001

Cox regression – end of follow-up (median 5.0 years) Hazard ratio

PEA or asystole 2.73 1.57 – 4.74 < 0.001

Cardiogenic shock during ICU stay 2.16 1.33 – 3.53 0.002

Peak CK-MB level < 24 hours* 1.27 0.96 – 1.67 0.089Age (per 5 year increase) 1.14 1.03 – 1.27 0.010

APACHE-IV score (per 1 point increase) 1.03 1.02 – 1.03 < 0.001* Log transformed data. CI = Confidence Interval. PEA = Pulseless Electric Activity. ICU = Intensive Care Unit. APACHE = Acute Physiology And Chronic Health Evaluation. CK-MB = Creatine Kinase-Myocardial Band. Logistic regression: R2 = 0.45 (Cox&Snell), 0.60 (Nagelkerke), Hosmer-Lemeshow goodness-of-fit test χ2 11.17, P = 0.192. Cox regression: 148 patients included of which 80 patients died.

Table 3 presents a multivariable Cox regression model including only the independent predictors of mortality at maximal follow-up: age, an initial rhythm of PEA or asystole, admission due to cardiogenic shock, the APACHE-IV score and maximum level of CK-MB. The maximum level of CK-MB < 24 hours was a significant predictor of mortality when recalculating the regression model until two year follow-up. Figure 2 presents displays the survival curves of the 4 independent predictors. Further, the performance of primary PCI was not found to be an independent predictor of both 30-day and long-term mortality.

105


DiscussionA considerable proportion of patients presenting with STEMI is admitted to the ICU; 208 (9.9%) out of 2104 patients, and 155 (7.4%) require mechanical ventilation with STEMI as primary reason for ICU admittance. With an observed 30-day mortality rate of 50% our study confirms that patients presenting with a STEMI who need mechanical ventilation have the poorest prognosis of all STEMI patients.15, 19 Our study presents detailed data and risk factors of mortality in mechanically ventilated STEMI patients and reveals that nearly half of the deceased patients die due to multi-organ failure and the other half due to severe neurologic damage. Surprisingly, only an additional 10 patients (13%) died at maximal follow-up with a median of 5.0 years.

The 30-day mortality of STEMI patients in need for mechanical ventilation (50%) is in line with other studies (39% to 67%) 11, 13, 15, 20-22 and show declining mortality rates over time. Improvements in treatment might account for decreases in mortality rates, however 22% of our population still died of multi-organ failure due to cardiogenic shock. In the future, this prognosis might improve when all these patients would be considered for extracorporeal membrane oxygenation 23, 24 and are treated in a hospital with high ICU use or even in specialized cardiac ICU.25, 26 To achieve maximum benefit circulatory support should be initiated on the ICU as quickly as possible and therefore early clinical predictors of mortality should be available to identify the patients at greatest risk for multi-organ failure. Several of our early clinical predictors of mortality, i.e. signs of renal failure, a PaO2/FiO2 ratio < 200 mmHg, maximum infarct size, admission pH and an initial rhythm of PEA, are in agreement with previous findings 11, 14, 27 and could aid in individual decision-making for starting extracorporeal membrane oxygenation.

In our population the majority of patients had suffered from cardiac arrest and a smaller group was admitted with cardiogenic shock. Not surprisingly patients that died due to severe cerebral damage more often presented with a lower GCS upon admission, had an initial rhythm of PEA or asystole and larger myocardial infarct sizes. STEMI patients admitted to the ICU have a high chance of developing cardiogenic shock (34% in our population) and dying of multi-organ failure.28 We observed that refractory shock with a PaO2/FiO2 ratio < 200 mmHg is frequently the cause of death, especially when these patients require adrenalin and dobutamine. This is in accordance with previous studies 11 and it is even suggested that dobutamine infusion is associated with mortality 29, 30, implicating that more effective circulatory support methods are needed.31-33

After 30-day survival, only ten more patients (13%) died until the maximal follow-up (median of 5 years), which implicates that patients have a fairly reasonable prognosis once they have been discharged from the hospital. This is in contrast with Lazzeri et al, who reported an additional mortality of 39% until follow-up at median 38 months 14, while total mortality at long-term follow-up in Zahger et al. was similar.12 Heterogeneity in selected populations could explain these differences: in our study 34% of patients suffered from a cardiogenic shock, while in other studies up to 60% of patients had a cardiogenic shock.14 Cardiogenic shock is associated with poor long-term outcome.34,35 Moreover, 71% of our patients were admitted after out of hospital cardiac arrest (OHCA)

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Chapter Six

with VF as initial rhythm, and long-term mortality in these patients is estimated at 9-23% 27, 36, which is in accordance with our long-term mortality rate of 10%.

Several limitations to our study have to be mentioned. Retrospective research inevitably involves missing data. Most of our predictors of mortality were also available to treating physicians; these parameters could have led to the decision of stopping supportive treatment instead of being the direct cause of mortality. Further, our prospective registry selected patients suspected for STEMI with such a condition that cardiac catheterization was thought feasible and therefore contains a selection bias. The actual proportion of patients with a STEMI in need for mechanical ventilation might even be higher since our selection criteria only included patients who underwent an urgent coronary angiography.

ConclusionsA substantial number of patients with a STEMI need mechanical ventilation; approximately 1 out of every 14 patients. 30-day mortality remains high (50%) and improvement of prognosis may lie in early recognition of imminent mortality and the start of extracorporeal membrane oxygenation. Surprisingly, only an additional 10 patients (13%) die at maximal follow-up (median of 5 years). Independent predictors of long-term mortality are older age, initial rhythm of PEA or asystole, admission with a cardiogenic shock and a higher APACHE-IV score.

AcknowlegdementsThe authors would like to thank Dr. W. Dieperink and Mr. A.J.G. Heesink for providing the queries and extracting data from our local NICE database.

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References1. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics--2013 update: a report from the American Heart Association. Circulation. 2013;127:e6-e245.2. Fox KA, Dabbous OH, Goldberg RJ, et al. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE). BMJ. 2006;333:1091.3. Fokkema ML, James SK, Albertsson P, et al. Outcome after percutaneous coronary intervention for different indications: long-term results from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). EuroIntervention. 2016;12:303-311.4. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC), Steg PG, James SK, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33:2569- 2619.5. Jernberg T, Johanson P, Held C, et al. Association between adoption of evidence-based treatment and survival for patients with ST-elevation myocardial infarction. JAMA. 2011;305:1677-1684.6. Fokkema ML, James SK, Albertsson P, et al. Population trends in percutaneous coronary intervention: 20-year results from the SCAAR (Swedish Coronary Angiography and Angioplasty Registry). J Am Coll Cardiol. 2013;61:1222-1230.7. Mandelzweig L, Battler A, Boyko V, et al. The second Euro Heart Survey on acute coronary syndromes: Characteristics, treatment, and outcome of patients with ACS in Europe and the Mediterranean Basin in 2004. Eur Heart J. 2006;27:2285-2293.8. Rogers WJ, Frederick PD, Stoehr E, et al. Trends in presenting characteristics and hospital mortality among patients with ST elevation and non-ST elevation myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006. Am Heart J. 2008;156:1026-1034.9. Chan MY, Sun JL, Newby LK, et al. Long-term mortality of patients undergoing cardiac catheterization for ST-elevation and non-ST-elevation myocardial infarction. Circulation. 2009;119:3110-3117.10. Bjorklund E, Lindahl B, Stenestrand U, et al. Outcome of ST-elevation myocardial infarction treated with thrombolysis in the unselected population is vastly different from samples of eligible patients in a large-scale clinical trial. Am Heart J. 2004;148:566-573.11. Lesage A, Ramakers M, Daubin C, et al. Complicated acute myocardial infarction requiring mechanical ventilation in the intensive care unit: prognostic factors of clinical outcome in a series of 157 patients. Crit Care Med. 2004;32:100-105.12. Zahger D, Maimon N, Novack V, et al. Clinical characteristics and prognostic factors in patients with complicated acute coronary syndromes requiring prolonged mechanical ventilation. Am J Cardiol. 2005;96:1644-1648.13. Kouraki K, Schneider S, Uebis R, et al. Characteristics and clinical outcome of 458 patients with acute myocardial infarction requiring mechanical ventilation Results of the BEAT registry of the ALKK-study group. Clin Res Cardiol. 2011;100:235-239.14. Lazzeri C, Valente S, Chiostri M, et al. Mechanical ventilation in the early phase of ST elevation myocardial infarction treated with mechanical revascularization. Cardiol J. 2013;20:612-617.15. Pesaro AE, Katz M, Katz JN, et al. Mechanical Ventilation and Clinical Outcomes in Patients with Acute Myocardial Infarction: A Retrospective

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Observational Study. PLoS One. 2016;11:e0151302.16. Lopez Messa JB, Andres De Llano JM, Berrocal De La Fuente CA, Pascual Palacin R, Analisis Retraso Infarto Agudo Miocardio. Characteristics of acute myocardial infarction patients treated with mechanical ventilation. Data from the ARIAM Registry. Rev Esp Cardiol. 2001;54:851-859.17. Lexis CP, van der Horst IC, Lipsic E, et al. Effect of metformin on left ventricular function after acute myocardial infarction in patients without diabetes: the GIPS-III randomized clinical trial. JAMA. 2014;311:1526-1535.18. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC), Steg PG, James SK, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33:2569- 2619.19. Peels HO, Jessurun GA, van der Horst IC, et al. Outcome in transferred and nontransferred patients after primary percutaneous coronary intervention for ischaemic out-of-hospital cardiac arrest. Catheter Cardiovasc Interv. 2008;71:147-151.20. Brezins M, Benari B, Papo V, et al. Left ventricular function in patients with acute myocardial infarction, acute pulmonary edema, and mechanical ventilation: relationship to prognosis. Crit Care Med. 1993;21:380-385.21. Eran O, Novack V, Gilutz H, Zahger D. Comparison of thrombolysis in myocardial infarction, Global Registry of Acute Coronary Events, and Acute Physiology and Chronic Health Evaluation II risk scores in patients with acute myocardial infarction who require mechanical ventilation for more than 24 hours. Am J Cardiol. 2011;107:343-346.22. Zobel C, Dorpinghaus M, Reuter H, Erdmann E. Mortality in a cardiac intensive care unit. Clin Res Cardiol. 2012;101:521-524.23. Allen S, Holena D, McCunn M, et al. A review of the fundamental principles and evidence base in the use of extracorporeal membrane oxygenation (ECMO) in critically ill adult patients. J Intensive Care Med. 2011;26:13-26.24. Napp LC, Kuhn C, Hoeper MM, et al. Cannulation strategies for percutaneous extracorporeal membrane oxygenation in adults. Clin Res Cardiol. 2016;105:283-296.25. Loughran J, Puthawala T, Sutton BS, et al. The Cardiovascular Intensive Care Unit-An Evolving Model for Health Care Delivery. J Intensive Care Med. 2016.26. Valley TS, Sjoding MW, Goldberger ZD, Cooke CR. ICU Use and Quality of Care for Patients With Myocardial Infarction and Heart Failure. Chest. 2016;150:524-532.27. Bergman R, Hiemstra B, Nieuwland W, et al. Long-term outcome of patients after out-of-hospital cardiac arrest in relation to treatment: a single-centre study. Eur Heart J Acute Cardiovasc Care. 2016;5:328-338.28. Harjola VP, Lassus J, Sionis A, et al. Clinical picture and risk prediction of short- term mortality in cardiogenic shock. Eur J Heart Fail. 2015;17:501-509.29. Tacon CL, McCaffrey J, Delaney A. Dobutamine for patients with severe heart failure: a systematic review and meta-analysis of randomised controlled trials. Intensive Care Med. 2012;38:359-367.30. von Scheidt W, Pauschinger M, Ertl G. Long-term intravenous inotropes in low- output terminal heart failure? Clin Res Cardiol. 2016;105:471-481.31. Koster G, Wetterslev J, Gluud C, et al. Effects of levosimendan for low cardiac output syndrome in critically ill patients: systematic review with meta-analysis and trial sequential analysis. Intensive Care Med. 2015;41:203-221.32. Koster G, Bekema HJ, Wetterslev J, et al. Milrinone for cardiac dysfunction in critically ill adult patients: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis. Intensive Care Med.

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2016;42:1322-1335.33. Ng R, Yeghiazarians Y. Post myocardial infarction cardiogenic shock: a review of current therapies. J Intensive Care Med. 2013;28:151-165.34. Lekston A, Slonka G, Gasior M, et al. Comparison of early and long-term results of percutaneous coronary interventions in patients with ST elevation myocardial infarction, complicated or not by cardiogenic shock. Coron Artery Dis. 2010;21:13-19.35. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization and long- term survival in cardiogenic shock complicating acute myocardial infarction. JAMA. 2006;295:2511-2515.36. Bunch TJ, White RD, Gersh BJ, et al. Long-term outcomes of out-of-hospital cardiac arrest after successful early defibrillation. N Engl J Med. 2003;348:2626-2633.

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Chapter Seven

The frequency of electrocardiographic

changes, arrhythmias and sudden cardiac

death in severe traumatic brain injury

Remco Bergman, Rosette Bremmer, Maarten W.N. Nijsten,Iwan C.C. van der Horst, Joukje van der Naalt

Submitted to Neurocritical Care.

113


AbstractBackground Data on the occurrence of cardiac abnormalities in traumatic brain injury (TBI) are sparse. We aimed to investigate the frequency of electrocardiographic (ECG) changes and arrhythmias in patients with severe TBI. Additionally, the relation of these cardiac abnormalities with intracranial pressure (ICP) treatment and outcome was determined.

Methods Patients with severe TBI who fulfilled criteria for ICP-monitoring admitted to our hospital were entered in a prospective cohort study. Retrospectively, ECG recordings obtained within 48 hours after admission were independently scored according to predefined criteria. Arrhythmias could be diagnosed on recording of continuous rhythm monitoring.

Results Data of 171 patients were analyzed. ECG changes were observed in 86% and arrhythmias in 20% of patients. Most frequently observed ECG changes were increased QT-intervals (57%) and T wave changes (53%). Bradycardia (13%) was the most common cause in arrhythmias. Arrhythmia was related to CT progression (P = 0.038), right-sided (P = 0.049) and frontotemporal injury (P = 0.025). Arrhythmias were also related to severity of brain injury reflected by frequency of elevated ICP (P = 0.004) and treatment levels (P = 0.008). ECG abnormalities were not associated with arrhythmia. Mortality during admission was 31%, with cardiac causes only present in 4 patients.

Conclusion In patients with severe TBI ECG abnormalities are often present, mostly consisting of T-wave changes and QT-time increase. Arrhythmias are less frequently observed, but related to severity of brain injury and not with ECG changes. The contribution of sudden cardiac death to mortality was negligible. Further research should elucidate whether ECG changes and arrhythmias are signs of cardiac dysfunction.

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IntroductionData on the occurrence of electrocardiographic (ECG) changes and arrhythmias in traumatic brain injury (TBI) patients are sparse.1-3 Most data are derived from case reports of patients with specific ECG changes, rather than data of populations of TBI patients.1,4-6 Hersch et al. described a series of 164 patients with TBI and observed that in comparison to controls TBI patients had an increased QT interval and an increased voltage of the P wave.1 Others reported changes in T waves, ST segments and U waves.7 Similar phenomena have also been described in the setting of acute stroke or intracranial hemorrhage suggesting a neurogenic mechanism with excessive catecholamine release.8-12 Very recently comparable cardiac abnormalities have been described in patients with isolated subdural hematoma although these were not associated with SDH characteristics or myocardial injury.13 These aforementioned studies describe a different group of patients and do not analyze the effects of these cardiac abnormalities on outcome.

It is therefore the aim of this study to analyze the frequency ECG changes and arrhythmias in patients with severe TBI. Furthermore, our secondary aim is to determine the association of ECG changes and arrhythmias with ICP treatment and outcome.

MethodsStudy populationAll patients with severe TBI admitted to the University Medical Center Groningen from January 2002 until December 2008 who fulfilled the criteria for Intracranial Pressure (ICP)-monitoring defined by the international guidelines 14 were included for analysis. These patients are part of a prospectively followed cohort of patients to determine predictive factors related to outcome.

Data collectionData was collected by retrospective data analysis of medical records and ambulance forms. Laboratory data were assessed at the emergency department and during ICU admission. Hypokalemia was defined by a potassium level of < 3.5 mmol/l, hyperkalemia by a potassium level of > 4 mmol/l and hypomagnesaemia by < 0.7 mmol/l. Cardiac biomarkers were considered as elevated when troponin I was > 0.01, or creatine kinase (CK)-MB was > 10% of CK and above 10 mmol/L.

Computer TomographyIn all patients a CT-scan was obtained directly after admission with a second CT-scan if clinical status deteriorated. All scans were classified according to the Marshall criteria.15 Focal lesions < 25 cc were recorded separately for frontal, temporal, occipital or brainstem region. The CT-scan with highest Marshall-score was used for analysis. CT-progression was defined as an increase of the Marshall-score or as an increase of volume of an existing lesions/development of new lesions in case of equal Marshall-scores on the second CT-scan.

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Monitoring Patients were monitored according to a standardized protocol including continuous blood pressure monitoring and pulse oximetry. For ICP-monitoring a ventricular catheter for simultaneous ICP reading and CSF drainage (neurovent-iFD-S from Raumedic) was used. Zero level for arterial pressure measurement was the left ventricle. ICP data were obtained by notating end-hour values in combination with ICP elevations necessitating change in therapy. Increased ICP was defined as at least two episodes of intracranial hypertension requiring treatment, with an increase of ICP > 20 mmHg lasting for more than 5 minutes.

ElectrocardiographyECGs were obtained within 48 hours of admission were analyzed with 12-leads ECGs recorded with Cardio Perfect equipment (Cardio Control, Delft, The Netherlands) and stored digitally after admission. The ECGs were examined for rate; intervals; ST deflection; T-wave inversions; presence of U-wave; and the magnitude and duration of the P, R, and T waves. Predefined criteria for abnormal ECG were rate < 60/min and > 100/min, PR interval > 210 ms, QRS duration > 120 ms, QT-interval > 450 ms in men and > 460 ms in women, ST deflection > 1mm and negative T wave. After admission to the ICU the heart rate and rhythm was continuously monitored. In case of a suspected rhythm change a 12-leads ECG was recorded. These ECGs were analyzed for the presence of asystole, pulseless electrical activity, bradycardia (and type), atrial tachycardia, atrial fibrillation, atrial flutter and ventricular tachycardia, ventricular fibrillation according standard criteria.16-18

TreatmentPatients were admitted to the ICU with a standard regimen of sedatives and analgesics for ventilatory support. The level of sedation was assessed according to the Sedation Agitation Scale (SAS), with the intended sedation level 1 (unarousable).19 Therapy for elevated ICP was applied according to the international guidelines.20 The patients were positioned with head in the midline position with slight elevation (20-30 degrees). With respiratory support pCO2 levels between 4-4.5 kPa were maintained. Normothermia was defined as temperature between 36.5-37.5 °C. Hypothermia was defined as temperature between 32-34 °C. Cerebral Perfusion Pressure minimum target value was 60 mmHg. Treatment of preexisting cardiovascular comorbidities and rhythm abnormalities was done according to ACLS guidelines. To estimate the intensity of ICP-therapy the TIL was used.21 With this scale the stepwise therapeutic approach of ICP elevation was monitored by recording points for each therapeutic measure applied to control ICP. The TIL-scores range from 2 (normal ventilation and sedation) to 15 (barbiturates). To evaluate this stepwise change in ICP therapy, four categories were formed with increasing intensity of therapeutic measures: (1) ventilation, sedation and analgesics, (2) CSF drainage, (3) mannitol or hypertonic saline, (4) barbiturates.

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Chapter Seven

OutcomeOutcome was determined one year after injury with the extended Glasgow Outcome Scale (GOSE) 22 in combination with a neurological examination. Favorable outcome was defined by complete recovery or moderate disability while unfavorable outcome comprised severe disability, vegetative state and death.

Statistical analysisData are presented as means with standard deviation (SD) for continuous variables, or as group percentages for categorical variables. Statistical analysis was performed using Student’s t for numerical values, Mann Whitney for numerical values comparing two independent groups and Fisher exact or Chi square (χ2) test for significance between variables. Statistical significance was defined as P < 0.05. All statistical analyses were performed using commercially available software (SPSS 17.0, SPSS, Chicago, Illinois).

ResultsPatient characteristicsIn total, 194 patients were admitted for ICP monitoring comprising 23 patients (12%) with an age < 16 years leaving 171 patients for analysis. Demographic and clinical characteristics of patients are shown in table 1. Seven patients had a history of cardiovascular disease.

Cardiac characteristicsECG changes and arrhythmiaECGs were obtained within 48 hours after admission in 100 patients (59%). No differences were present between patients in whom an ECG was obtained compared to those without an ECG registration, except for hypomagnesaemia (50 vs. 75% respectively, P = 0.005) (table 2). ECG changes were present in 86 of these patients (86%). An increased QT-interval was observed in 57% of patients. T-wave changes were noted in 53% (n = 46), mostly comprising negative T waves (n = 31, 36%). Pathological Q-formation was noted in 7% (n = 6) patients (table 3). Arrhythmia was seen in 34 patients (20%), with one in three patients showing multiple rhythm abnormalities (table 3). Rhythm abnormalities were not significantly related to ECG abnormalities as 27% of patients without ECG abnormalities developed arrhythmia vs. 35% with ECG abnormalities (χ2 = 0.4, P = 0.37).

ECG changes and arrhythmia related to laboratory valuesECG abnormalities were not related to electrolyte levels (Magnesium, Potassium). Potassium levels below 3.6 were present in 16% of patients with arrhythmia compared to 25% in those without arrhythmia (χ2 = 1.6, P = 0.45). Hypomagnesaemia was present in 63% vs. 45% of patients with or without arrhythmia (χ2 = 3.14, P = 0.06). In total 14% of patients showed elevated troponin levels and 11% showed elevated CK-MB-levels during ICU stay. These cardiac biomarkers were not significantly related to arrhythmia or ECG abnormalities.

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Table 1. Patient characteristics of study population.

No. of patients 171

Age (mean (± SD)) 38 (19)Cause of injury

Traffic collisionOf which Car (55%)Bicycle (21%)Motorcycle (16%)Pedestrian (8%)

Fall Violence Other

65%

31%1%3%

GCS (mean (± SD)) 6.2 (1.5)Bilateral reactive pupils 73%Marshall score

IIIIIIIVV

44%18%6%15%17%

Extracranial injuries 72%Alcohol involved 9%Known prior cardiovascular history 4%Laboratory characteristics Day 1

Troponin I (mean (± SD))Elevated troponin*)CK-MB (mean (± SD)) Hypokalemia*)Hyperkalemia*)Magnesium (mean (± SD))

0.6 (1.3)9.4%24 (17)9.1%7.8%0.7 (0.1)

Data are number (%) unless otherwise indicated. GCS = Glasgow Coma Scale. CK-MB = Creatine Kinase-Myocardial Band. *) cut off values are defined in the method section.

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Relation with CT findings Patients with arrhythmia showed more contusions and hemorrhage compared to those without arrhythmias 97% vs. 81% (χ2 = 5.27, P = 0.013) and 100% vs. 80% (χ2 = 7.96, P = 0.001) respectively). Characteristics of the CT findings are presented in table 4.Arrhythmia was also associated with right sided (χ2 = 9.55, P = 0.049) and frontotemporal injury (χ2 = 5.19, P = 0.025). In particular the progression of CT abnormalities was related to an increased incidence of arrhythmia (χ2 = 4.10, P = 0.038). Arrhythmia was present in 34% of patients with CT-progression compared to 10% in patients without CT-progression. These CT abnormalities comprised the progression of existing abnormalities and not the occurrence of new abnormalities on follow up CT. Arrhythmia was present in 40% of patients if existing abnormalities increased vs. 7.1% if there was no progression of existing lesions (χ2 = 8.86, P = 0.003). Baseline CT findings such as the presence of shift or cisternal compression did not correlate with ECG abnormalities or arrhythmia.

Table 2. Patient characteristics with or without ECG.

ECG in archives No ECG in Archives P-value

Age (yrs ± SD) 37 (19) 38 (18) 0.41Sex (male in %) 79 76 0.42GCS Mean (± SD) 6.54 (3) 6.59 (3.2) 0.92Bilateral reactive pupils (%) 84 74 0.43Extracranial injuries (% 72 73 0.51ITL Mean (± SD) 5 (2.7) 4.6 (2.2) 0.86Mortality (%) 36 30 0.27Increased Troponin (%) 18 7 0.06

Increased CK-MB (%) 10.6 20 0.105Hypomagnesaemia (%) 50 75 0.005

Hypokalemia (%) 13 21 0.28

Data are presented as numbers (%) unless otherwise indicated. Abbreviations: GCS = Glasgow Coma Scale. TIL = Therapy Intensity Level. CK-MB = Creatine Kinase-Myocardial Band. *) cut off values are defined in the method section.

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Table 3. ECG abnormalities and arrhythmias in severe TBI.

ECG abnormalities * n (%)

Increased QT interval 49 (57)T waves changes 46 (53)

T wave inversion 31 (36)Non specific T wave changes 15 (17)

ST Elevations 24 (28)Straight ST segment 18 (21)Axis change

4 Left, 4 right, & 5 vertical axis13 (15)

ST depression 7 (8)Q development 6 7)U-wave 2 (2)1st degree AV block 2 (2)2nd degree AV block (Wenckebach) 1 (1)Bundle branch block 6 (7)RBBB (2) iRBBB (2) LAFB (1) LBBB (1)

Arrhythmias n (%)

Bradycardia 13 (8)Atrial (non sinus) 8 (5)Atrial Fibrillation 8 (5)AV junctional 6 (4)Ventricular Tachycardia 6 (4)Atrial Tachycardia 3 (2)PEA 2 (1)Ventricular Fibrillation 2 (1)Atrial Flutter 1 (1)Asystole 1 (1)

Data are number (%). AV = AtrioVentricular. (i)RBBB = (incomplete) Right Bundle Branch Block. LAFB = Left Anterior Fascicular Block. LBBB = Left Bundle Branch Block. VF = Ventricular Fibrillation. VT = Ventricular Tachycardia, PEA = Pulseless Ectrical Activity.*) ECG available in 100 patients for analysis.

Relation with treatment Intensive care treatment Duration of mechanical ventilation varied from 2 to 50 days with a mean of 17 (± 10) days. The most common complication during ICU admission was pulmonary infection, occurring in more than half of patients. In total only 18% of patients with arrhythmias were treated with anti-arrhythmic agents. In 4 patients cardiopulmonary resuscitation was initiated during ICU admission and 2 of these patients did not recover spontaneous circulation. Two patients developed arrhythmia with ensuing cardiac shock necessitating brief CPR, one of these patients subsequently died. Another patient developed an AV junctional dissociation with untreatable cardiac shock during a barbiturate-induced coma.

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ICP Treatment levels and cardiac characteristicsIn 34% of patients acceptable ICP values were achieved by treatment with sedatives and analgesics, 22% needed additional CSF drainage, and 39% hyperosmolar therapy. Refractory ICP elevations were treated with barbiturates in 8 patients (5%) and with decompressive craniotomy in 7 patients (4%). Additional cooling was applied in 55 patients (34%) to normothermia and in 3 patients (2%) to hypothermia. Patients with arrhythmias showed more ICP elevations (87%) compared to patients without arrhythmia (60%) (χ2 = 7.6, P = 0.004). Arrhythmias were also related to treatment levels (χ2 = 11.8, P = 0.008) (figure 1). Cooling was also related to arrhythmia, occurring in all patients cooled to hypothermia vs. 24% in cooling to normothermia and 14% in uncooled patients. ECG abnormalities were not related to ICP elevations or treatment levels.

Relation with outcomeOverall outcome in patients comprised good recovery (16%), moderate disability (26%), severe disability (22%) and vegetative state (5%). In total 51 patients (31%) died during admission, mostly (in 92%) the neurological condition was considered to be the primary cause of death. Other patients died of MODS in combination with a poor neurological prognosis (2) and sepsis (1). Severe cardiac complications were considered as determining factor in the death of four patients. Both ECG abnormalities and arrhythmias were not significantly associated with mortality.

Table 4. Characteristics of cerebral lesions (n of patients 171).

Localisation n (%) of patients total n (%) arrhythmiaRight hemisphere Frontal

Tempero-parietalFronto-temporalOccipital

54 (32)34 (20)20 (12)8 (5)

9 (17)7 (21)7 (35)4 (50)

Left hemisphere FrontalTempero-parietalFronto-temporalOccipital

49 (32)36 (21)17 (10)6 (4)

8 (16)5 (14)7 (41)2 (33)

Brainstem 34 (20%) 7 (21)

N of lesions 0123

23 (14)48 (28)51 (30)49 (29)

2 (9)11 (23)11 (22)10 (20

Data are presented as numbers (%) unless otherwise indicated.

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Figure 1. Percentage of arrhyhtmia (A) and ECG abnormalities (B) in the different Therapy Intensity Level groups.

Mortality rate was 37% in patients without ECG abnormalities compared to 28% of patients with ECG abnormalities (χ2 = 0.52, P = 0.32). For patients with arrhythmia mortality was 38% compared to 31% in patients without arrhythmia (χ2 = 0.67, P = 0.27). Outcome as defined by the GOSE was not significantly related to arrhythmia (χ2 = 3.42, P = 0.49).

DiscussionIn our cohort of patients with severe TBI ECG changes were seen very often, in 86% of patients, and arrhythmias were observed in 1 out of 5 patients. In comparison to the existing literature we observed far more ECG abnormalities.1 Already in 1961 Hersch et al. observed in 164 patients an elevated ST segment in 14% and inverted T waves in 10% of cases and a 21% prevalence of U waves. The incidence of ECG abnormalities in our cohort is higher and the frequency of U waves is much lower. Several reasons might explain these differences. First, our patient population was more severely injured, as only 12% of patients were comatose in the Hersch study. Second, time between injury and admission is short in our study and we correct electrolyte disturbances, which are known to be related to the occurrence of U waves, rapidly. This could be an explanation for the low frequency of U waves.

In addition we observed more arrhythmias in our cohort. Hersch et al. described a 4% incidence of nodal arrhythmia and 1% incidence of atrioventricular block in patients with head trauma. More recently, an incidence of arrhythmia ranging from 6-8% for severe trauma patients was observed.23,24 However, these studies comprised mostly trauma patients without TBI. The higher incidence of arrhythmias in our cohort might be explained by the fact that all patients at the ICU are on continuous rhythm monitoring

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which is started directly after admission. Furthermore, our hospital is a level I trauma center to which all patients with severe TBI are referred.In patients with cerebrovascular disease more information on ECG abnormalities is available.2,3 The incidence of ECG changes and other cardiac sequelae is 20-81% after subarachnoid hemorrhage (SAH) 8,9,11,25 and ischemic stroke.10,12,25,26 Mainly T-wave changes and QT-interval increase were reported which were also related to arrhythmias. In our study of patients with severe TBI, T-wave changes and increased QT-interval were also most commonly seen. The T-wave changes consisted of T-wave inversion and the arrhythmias mostly concerned atrial rhythms and bradycardia. The ECG changes were not found to be related to the arrhythmias in our cohort. Very recently Busl et al. described a series of patients with isolated subdural hematoma with a frequency of ECG abnormalities similar to our findings.13 They did not comment on incidence of arrhythmias or sudden cardiac death. Since they did not present data on injury severity in detail it remains unclear whether the cohorts are comparable. Additionally their mean age was much higher explaining the large number of patients with a previous cardiovascular history.

An important question concerns the clinical significance of the reported ECG changes and whether these changes are related to concomitant to severity of TBI or to ischemic cardiac disease. Ischemic ECG changes with concomitant elevation of cardiac biomarker levels are suggestive of ischemic heart disease. However, increased troponin levels without confirmatory ECG changes have been described in cerebral hemorrhage 10 and in subarachnoid hemorrhage.8,9 A neurogenic mechanism of myocardial injury has been postulated with excessive catecholamine release from the cardiac sympathetic nerves.27-31 In these studies troponin elevations correlated both with severity of neurologic injury 8 and left ventricular dysfunction, pulmonary edema, and hypotension requiring vasopressors.9 Elevations in troponin also predicted a higher likelihood of in-hospital death or severe disability at discharge, although this relationship was no longer significant at 3 months follow-up.9 On the other hand, the presence of ECG changes suggesting ischemia without increased cardiac biomarkers have also been described leading to erroneous diagnosis of ischemic heart disease. In the current study no relation between biomarkers of ischemic heart disease (troponin, CPK) and the occurrence of ECG abnormalities was found. Since a few patients had a history of cardiovascular disease it is unlikely that all ECG abnormalities had a primarily cardiac cause. Furthermore, only 14% of patients showed elevated troponin levels and just 11% showed elevated CK-MB-levels during the ICU stay. In addition, these cardiac biomarkers were not related to arrhythmia or ECG abnormalities. Likewise the observed hypokalemia and hypomagnesaemia were not related to incidence of arrhythmia, and therefore the observed arrhythmia cannot be contributed to abnormal electrolyte levels.

In cerebrovascular disease arrhythmias and fatal cardiac outcome have been related to intracerebral infarct localization, and a role of the insula in the occurrence of arrhythmia has been postulated.26,32 We also explored this relationship and found an association between the right sided and frontotemporal regions with arrhythmia. This finding is partly comparable to studies in ischemic stroke that showed a definite correlation between lesions of the insular region and arrhythmia.26,33,34 Oppenheimer 35 demonstrated

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that stimulation of the left insular cortex caused parasympathetic cardiac responses with the right insular cortex showing sympathetic responses. The conclusion was that the resulting augmentation of intra cardiac sympathetic nerve activity could provoke arrhythmias, even in the absence of symptomatic coronary artery disease. In our cohort we found more arrhythmias in patients with contusions of the right hemisphere, although not significantly related to the insular region. An explanation for this absent relation of arrhythmia with specific regions of the right hemisphere in patients with TBI could be that in cerebrovascular disease primarily more circumscribed areas injured by ischemia or bleeding are present while in TBI the more global effects of blunt head injury might obscure the relationship between the insular region and arrhythmias.

In our cohort of TBI patients, an increase in the frequency of arrhythmia was found related to the progression of CT abnormalities, which are regarded to represent global brain injury severity. In addition brain injury severity is also reflected by the frequency of increased ICP, which were also found to be related to a higher incidence of arrhythmia in our study. We also examined the relation of arrhythmia with the treatment of these ICP-elevations. The Treatment Intensity Level (TIL) comprises the step-wise treatment of ICP and is therefore indirectly related to severity of brain injury. In the current study, increasing TIL was related to an increased incidence of arrhythmias but not the occurrence of ECG abnormalities. It is suggested that these arrhythmias occurring with intensified ICP treatment might represent severity of injury instead of specific cardiac complications. This is supported by the fact that there was no correlation between increasing TIL levels and increased levels of cardiac enzymes. Furthermore, a relation between the incidence of arrhythmia and the cooling of patients to hypothermia was found in accordance with other studies.36 Also a trend towards more arrhythmia in the group cooled to normothermia was seen. Other factors for increasing severity such as the GOSE did not show a relation with arrhythmia. This might be explained by the fact that CT-progression reflects secondary complications whereas the GOSE on admission reflects in particular primary brain injury at the moment of impact.

The relationship between the occurrence of arrhythmia and ECG abnormalities with outcome was also explored. We did not find any significant differences in mortality of patients with ECG abnormalities or arrhythmias compared to those without these cardiac abnormalities. Only 18% of the arrhythmias were treated with anti-arrhythmic agents. This is most likely due to the time limiting nature of some of these arrhythmias not leading to an instable hemodynamic situation. In our study only four patients received CPR; all but one of these patients had arrhythmia before CPR was necessary. The estimated incidence of sudden in-hospital-cardiac arrest of was 1%. Since additional factors were present in at least two patients, the estimated contribution of cardiac death to fatal outcome of traumatic brain injury in our study was 7%, a small but not insignificant number. Therefore, it is suggested that while cardiac complications of TBI are present they do not constitute a major contributing factor to mortality.Several limitations have to be mentioned. First, our study has a retrospective design. Therefore, the ECGs were not available for all patients, since they were not entered in a database but came available from medical records. Since no differences regarding patient characteristics were present between the populations of which the ECGs were

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analyzed, except for hypomagnesaemia, we feel it can be stated that ECG abnormalities occur often in patients with severe TBI. Moreover, the percentage of ECG changes and arrhythmias observed would only increase if on the missing recordings abnormalities were present. Another limitation is that in the group of patients included in the earlier years cardiac markers were not assessed routinely. Finally, despite the long period of inclusion and being a referral center, the number of patients is still modest to draw firm conclusions. To our knowledge few studies are available to compare our results with. Others could enhance the data by publishing their observations and together this would increase the knowledge on ECG changes, rhythm disturbances in relation to outcome in severe TBI patients. Other objectives of future studies could be to elucidate whether ECG changes and arrhythmias are signs of cardiac dysfunction as determined by cardiac imaging.

Conclusion In patients with severe TBI ECG abnormalities are very common, especially T-wave changes and increased QT-interval. Arrhythmias occur less frequently although still present in one in five patients. Arrhythmias are related to severity of injury. The contribution of sudden cardiac death to mortality was negligible. It appears that cardiac sequelae occur relatively frequently in patients with severe TBI although they are not a major contributing factor to mortality and outcome.

Conflict of interestNo competing financial interests.

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References1. Hersch C. Electrocardiographic changes in head injuries. Circulation. 1961;23:853-60.2. Walder LA, Spodick DH. Global T wave inversion. J Am Coll Cardiol. 1991;17:1479-85.3. Oppenheimer SM, Cechetto DF, Hachinski VC. Cerebrogenic cardiac arrhythmias. Cerebral electrocardiographic influences and their role in sudden death. Arch Neurol. 1990;47:513-9.4. Wittebole X, Hantson P, Laterre PF, et al. Electrocardiographic changes after head trauma. J Electrocardiol. 2005;38:77-81.5. McLeod AA, Neil-Dwyer G, Meyer CH, et al. Cardiac sequelae of acute head injury. Br Heart J. 1982;47:221-6.6. Greenspahn BR, Barzilai B, Denes P. Electrocardiographic changes in concussion. Chest. 1978;74:468-9.7. Lim HB, Smith M. Systemic complications after head injury: a clinical review. Anaesthesia. 2007;62:474-82.8. Tung P, Kopelnik A, Banki N, et al. Predictors of neurocardiogenic injury after subarachnoid hemorrhage. Stroke. 2004;35:548-51.9. Naidech AM, Kreiter KT, Janjua N, et al. Cardiac troponin elevation, cardiovascular morbidity, and outcome after subarachnoid hemorrhage. Circulation. 2005;112:2851-6.10. Maramattom BV, Manno EM, Fulgham JR, et al. Clinical importance of cardiac troponin release and cardiac abnormalities in patients with supratentorial cerebral hemorrhages. Mayo Clin Proc. 2006;81:192-6.11. van Bree MD, Roos YB, van der Bilt IA, et al. Prevalence and characterization of ECG abnormalities after intracerebral hemorrhage. Neurocrit Care. 2010;12:50-5.12. Henninger N, Haussen DC, Kakouros N, et al. QTc-Prolongation in Posterior Circulation Stroke. Neurocrit Care. 2013;19:167-75.13. Busl KM, Raju M, Ouyang B, et al. Cardiac abnormalities in patients with acute subdural hemorrhage. Neurocrit Care. 2013;19:176-82.14. Bratton SL, Chestnut RM, Ghajar J, et al. Guidelines for the management of severe traumatic brain injury. VI. Indications for intracranial pressure monitoring. J Neurotrauma. 2007;24 Suppl 1:S37-44.15. Marshall LF, Marshall SB, Klauber MR, et al. The diagnosis of head injury requires a classification based on computed axial tomography. J Neurotrauma. 1992;9 Suppl 1:S287-92.16. Rautaharju PM, Surawicz B, Gettes LS, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: endorsed by the International Society for Computerized Electrocardiology. Circulation. 2009;119:e241-50.

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17. Wagner GS, Macfarlane P, Wellens H, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part VI: acute ischemia/infarction: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology. J Am Coll Cardiol. 2009;53:1003-11.18. Surawicz B, Childers R, Deal BJ, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part III: intraventricular conduction disturbances: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: endorsed by the International Society for Computerized Electrocardiology. Circulation. 2009; 119:e235-40.19. de Wit M, Gennings C, Jenvey WI, Epstein SK. Randomized trial comparing daily interruption of sedation and nursing-implemented sedation algorithm in medical intensive care unit patients. Crit Care. 2008;12:R70.20. Maas AI, Dearden M, Teasdale GM, et al. EBIC-guidelines for management of severe head injury in adults. European Brain Injury Consortium. Acta Neurochir (Wien). 1997;139:286-94.21. Maas AI, Harrison-Felix CL, Menon D, et al. Standardizing data collection in traumatic brain injury. J Neurotrauma. 2011;28:177-87.22. Wilson JT, Pettigrew LE, Teasdale GM. Structured interviews for the Glasgow Outcome Scale and the extended Glasgow Outcome Scale: guidelines for their use. J Neurotrauma. 1998;15:573-85.23. Goodman S, Weiss Y, Weissman C. Update on cardiac arrhythmias in the ICU. Curr Opin Crit Care. 2008;14:549-54.24. Hadjizacharia P, O’Keeffe T, Brown CV, et al. Incidence, risk factors, and outcomes for atrial arrhythmias in trauma patients. Am Surg. 2011;77:634-9.25. Sakr YL, Ghosn I, Vincent JL. Cardiac manifestations after subarachnoid hemorrhage: a systematic review of the literature. Prog Cardiovasc Dis. 2002;45:67-80.26. Colivicchi F, Bassi A, Santini M, Caltagirone C. Prognostic implications of right- sided insular damage, cardiac autonomic derangement, and arrhythmias after acute ischemic stroke. Stroke. 2005;36:1710-5.27. Catanzaro JN, Meraj PM, Zheng S, et al. Electrocardiographic T-wave changes underlying acute cardiac and cerebral events. Am J Emerg Med. 2008;26:716 -20.28. Samuels MA. The brain-heart connection. Circulation. 2007;116:77-84.29. Abildskov JA, Millar K, Burgess MJ, Vincent W. The electrocardiogram and the central nervous system. Prog Cardiovasc Dis. 1970;13:210-6.30. Keren O, Yupatov S, Radai MM, et al. Heart rate variability (HRV) of patients with traumatic brain injury (TBI) during the post-insult sub-acute period. Brain Inj. 2005;19:605-11.31. Gajic O, Manno EM. Neurogenic pulmonary edema: another multiple-hit model of acute lung injury. Crit Care Med. 2007;35:1979-80.

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32. Cheshire WP, Jr., Saper CB. The insular cortex and cardiac response to stroke. Neurology. 2006;66:1296-7.33. Abboud H, Berroir S, Labreuche J, et al. Insular involvement in brain infarction increases risk for cardiac arrhythmia and death. Ann Neurol. 2006;59:691-9.34. Rincon F, Dhamoon M, Moon Y, et al. Stroke location and association with fatal cardiac outcomes: Northern Manhattan Study (NOMAS). Stroke. 2008;39:2425-31.35. Oppenheimer S. Cerebrogenic cardiac arrhythmias: cortical lateralization and clinical significance. Clin Auton Res. 2006;16:6-11.36. Bourdages M, Bigras JL, Farrell CA, et al. Cardiac arrhythmias associated with severe traumatic brain injury and hypothermia therapy. Pediatr Crit Care Med. 2010;11:408-14.

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Summary, discussion and future

directions

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SummaryChapter 1 General introduction and scope of the thesisIn this thesis the connection between the heart and the brain is investigated. This is done through the perspective of three medical disciplines: cardiology, neurology & critical care. While these are three very different specialisms, all three play a role in this interconnection. The main focus of this thesis is on out-of-hospital cardiac arrest with its associated treatment and underlying causes. We investigate the hemodynamic and metabolic consequences of the ailment and treatment. Outcome of this devastating mostly cardiac disease is closely linked with the brain as first described by Safar.1 We also take a side step to look at the reverse relationship between traumatic brain injury and the heart.

Chapter 2 A: Hemodynamic consequences of mild therapeutic hypothermia after cardiac arrest Reviewing the evidence, there seems to be an abundance of reasons for implementing mild therapeutic hypothermia (MTH) in clinical practice. There are, however, side effects. Much of the knowledge on side effects of hypothermia has been gained from observations in accidental hypothermia. It can lead to loss of electrolytes (potassium, magnesium and phosphate) due to both increased urinary excretion and intracellular shift. These findings also have been confirmed in clinical studies on MTH.2,3 Electrolyte abnormalities may further affect cardiac performance. A large percentage of patients with out-of-hospital cardiac arrest (OHCA) have acute coronary syndromes and myocardial infarction. This may include cardiac function. Induced hypothermia may further interfere with cardiac function and influence haemodynamics after OHCA. As information on haemodynamic variables during MTH is scarce, we studied these in patients with OHCA admitted to our ICU.

The treatment protocol that was implemented consisted of hypothermia induced via rapid infusion of 2 litres of cold isotonic saline (4 °C) followed by further induction and maintenance of cooling with the patient positioned between two water-cooled blankets (Blanketroll II, CSZ, Cincinnati, Ohio, USA). Temperature was measured continuously with an oesophageal temperature probe and used as feedback for the cooling device. After reaching the target temperature of 32.5 °C, patients were maintained at this temperature for 24 hours. After the maintenance phase, patients were rewarmed at a controlled rate of 0.3 °C per hour to reach a target temperature of 36 °C and sedation was discontinued.

We demonstrated marked haemodynamic consequences in a cohort of 48 patients treated with MTH using a rigorous protocol, and found a marked reduction in heart rate. This beta-blocker-like effect may positively affect the volume of myocardium suffering from ischaemia or ischaemic injury. Lowering heart rate is a cornerstone of treatment in patients with acute coronary syndromes.4,5 However, in many patients after OHCA, b-blockers cannot be used, as low blood pressures are common in this group, for example

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comprising 55% of patients in a large hypothermia study after cardiac arrest.6,7

Despite induction of hypothermia with 2 litres of cold isotonic saline (4 °C), pulmonary artery pressures decreased. This is in line with previous research addressing the safety of infusion of ice-cold isotonic saline.8,9 This may suggest that many patients initially are hypovolaemic. We found an initial rise in urine output during MTH. This is often explained as cold diuresis, caused by peripheral vasoconstriction promoting subsequent higher central filling pressures.10 Others have suggested this could be due to nephrogenic diabetes insipidus due to decreased renal collecting tubular function during hypothermia.11 However, we feel these explanations are not very likely as diuresis was not excessive during the hypothermia maintenance phase. Another explanation may be that our rapid fluid induction had some influence only on early phase urine output. Marked cold diuresis during on going hypothermia treatment was not seen. It is difficult to analyse whether these results may have been influenced by acute tubular necrosis after cardiac arrest. We may conclude that high urine output or cold diuresis does not pose a relevant clinical problem.

Although a reduction in cardiac index (10%) may lead to inadequate organ perfusion, during induced hypothermia we could not demonstrate that this lower cardiac output caused lower mixed venous oxygen saturation. This suggests that, parallel to the reduction in cardiac output, oxygen requirements and consumption were also lower due to the lower body temperature. In other words, during MTH, the workload for the injured heart may be lower due to lower resting energy metabolism associated with a lower body temperature.12 The findings of elevated lactate levels during hypothermia that normalize during rewarming could suggest tissue hypoperfusion. In contrast to this, we found normal mixed venous oxygen saturation levels. In addition, we could not find any correlations of elevated lactate levels during hypothermia with outcome. We hypothesize that hyperlactataemia may be related to hypothermia and is not deleterious or prognostic per se as hyperlactataemia has also been described during hypothermia in cardiac surgery patients.13

Chapter 2B: Unexpected neurological deterioration after mild therapeutic hypothermia Relevant to the subject of induced mild therapeutic hypothermia is what exactly the mechanism behind the beneficial influence is. MTH has been a standard treatment since 2003.14 Recent studies have shown no difference in outcome if patients are cooled to 33 °C or 36 °C. Important factors determining outcome after out-of hospital cardiac arrest (OHCA) are primary and secondary brain damage. Neurological complications account for two thirds of deaths after initial resuscitation of OHCA patients.15 The development of mild therapeutic hypothermia as a treatment strategy has demonstrated the potential to improve neurological outcome.6,7

Apart from the evidence supporting hypothermia treatment as brain protection there is also overwhelming evidence suggesting that hyperthermia may be deleterious and can increase ischaemic damage to the brain following a primary insult. Animal experiments show that even delayed hyperthermia (up to 24 hours) can result in very enhanced

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neurological damage after ischaemic insults.16,17 Prospective trials in stroke victims have also shown that fever (T > 37.9 °C) is an independent predictor of poor outcome (odds ratio 3.4).18

Fever is a risk factor for poor neurological outcome after cardiac arrest. How long this vulnerability of the brain lasts and the risk for neurological deterioration persists is not known. However our observations suggest that hyperthermia should be aggressively treated for several days after return to normothermia.

Chapter 3 Early lactate clearance in patients after cardiopulmonary resuscitation after out of hospital cardiac arrestDuring OHCA the body sustains a large oxygen deficit with an accompanying accumulation of lactate resulting from anaerobic metabolism. In contrast during sepsis lactate production is often not the result of generalized hypoxia but rather of increased adrenergic stress.19 Restoration of appropriate circulation enables many tissues to clear lactate by conversion back to glucose or by direct metabolism. After maximal exertion athletes can consume lactate at extremely high rates. It seems reasonable to assume that the post-exertional decrease of lactate in athletes reflects the upper range of physiological lactate consumption.20 In critically ill patients sustained elevated lactate levels are strongly associated with adverse outcome.21 The restoration of normal lactate levels and the rate at which this occurs is also correlated with outcomes.22-24 In septic patients presenting with hyperlactataemia (lactate level of > 4 mmol/L), a decrease in lactate levels of 10% after 6 hours has been shown to be associated with favourable outcomes.25,26 In the setting of out-of-hospital cardiac arrest (OHCA) and after return of spontaneous circulation (ROSC) a target for lactate clearance of 10% per hour has been suggested.25,26

However, the kinetics of lactate clearance in the setting of OHCA resembles more those of athletes than of septic patients.Patients presenting to the emergency department (ED) (2006-2014), at the University Medical Center Groningen (UMCG), after having experienced an OHCA were analysed. Arterial blood samples were routinely collected at the ED, cardiac catheterization lab and intensive care unit (ICU). Patients who achieved ROSC after CPR with an initial arterial lactate > 8 mmol/L and a minimum of two lactate measurements within the first two hours were included. Time 0 was taken as the first lactate measurement after ROSC. The absolute clearance in mmol/L per hour and the relative lactate clearance as a percentage of maximum lactate level in % per hour were determined for each patient with linear regression.

We found no significant difference in the initial lactate level between survivors and non-survivors. The mean absolute lactate clearance was 5.0 mmol/L per hour and the mean relative lactate clearance was 40.9% per hour. Both higher absolute and relative lactate clearance after ROSC were positively associated with hospital survival.

Early lactate clearance after OHCA was much faster than the 10 %/hour reduction reported in successfully recovered septic patients and also above the 10 %/hour suggested in

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the setting of cardiac arrest.25,27 Even though there was significant difference in lactate clearance between survivors and non-survivors, the overall relative lactate clearance was still shown to be much higher than 10% per hour. This indicates that if lactate is used to guide therapy in the setting of cardiac arrest, a higher target for lactate clearance is required.In addition, our findings demonstrate a significant difference in absolute lactate clearance and relative lactate clearance between survivors and non-survivors of OHCA. As expected, survivors had higher clearance rates than non-survivors. Importantly, there was no difference between the initial lactate levels of both groups corroborating results shown elsewhere.22,23

Chapter 4Long-term outcome of patients after out-of-hospital cardiac arrest in relation to treatment: a single centre studyDespite several advances in the field of resuscitation, the management of patients after out-of-hospital cardiac arrest (OHCA) can still be improved.28-32 Factors influencing outcome after OHCA are the initial rhythm, whether the arrest was witnessed or not, early good quality cardiopulmonary resuscitation (CPR), early defibrillation and organisation of care. Efforts have been undertaken to improve outcome after OHCA. Organisational measures, such as teaching CPR in courses and other initiatives to promote early bystander CPR 33-35, optimisation of emergency medical system responses 36 and systems to ensure very rapid access to automated external defibrillators 37, have been shown to improve outcome.38 Survival is most likely if the initial rhythm was ventricular fibrillation (VF) 39, which is most frequently caused by myocardial infarction due to coronary artery disease.39,40 In our region an ST-elevation myocardial infarction (STEMI) network was created in conjunction with ambulance services, the emergency, cardiology and intensive care departments. It involves a defined treatment plan for patients with return of spontaneous circulation (ROSC), the goal of which is to allocate definitive care as expediently as possible guided on the clinical signs and electrocardiographic (ECG) or echocardiographic signs of acute myocardial ischemia.

The University Medical Center Groningen is a tertiary referral hospital, which serves the northeastern part of the Netherlands. In this region it is the only hospital that performs PCI. With referral hospitals, this centre provides 24/7 emergency care in a region with 750,000 inhabitants.41 In the case of an emergency, the closest ambulance is sent to the scene and when resuscitation is necessary a second ambulance is always sent as back up. Patients are then transported to the centre, especially when there is suspicion of coronary occlusion (e.g. VF or STEMI). There resuscitation is continued or post-resuscitation care is given following advanced cardiovascular life support guidelines.42

We retrospectively studied all consecutive patients over 18 years of age admitted to our hospital after OHCA between January 2003 and August 2010. All patients were included in our analysis unless it was impossible to confirm OHCA or to define the initial rhythm. In a large group of consecutive patients treated within a STEMI network, outcome after OHCA remained poor. However, in patients with an initial rhythm of VF, who showed ROSC and were treated by immediate PCI outcome was good. In-hospital survival reached 66%

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and, even more remarkably, survival after discharge was 99% after five years. Therefore, the outcome is comparable to figures reported for patients with STEMI without cardiac arrest treated with PCI.43

Patients with poor cardiac function and co-morbidities might not regain ROSC or survive to hospital discharge. For our patients we found that survival was higher in patients with higher LVEF, a better GCS, higher pH values and lower glucose and lactate levels, in accordance with observations by others.44-46 Moreover, patients with an initial rhythm other than VF showed a lower rate of ROSC and decreased GCS scores at admission compared to patients with VF.

Therefore, treatment within a STEMI network might especially benefit patients with VF as the first observed rhythm. Patients presenting with another initial rhythm might have an underlying mechanism other than myocardial ischemia due to significant coronary occlusion. This is supported by the lower levels of cardiac markers such as troponin, creatine kinase and creatine kinase-MB in the no VF group. The lack of treatment options apart from defibrillation, MTH and supportive care may explain the poorer outcome of patients with another initial rhythm. Even after hospital discharge, survival is worse when compared to patients who presented with VF. The same was apparently the case for patients who underwent PCI, as they had better in-hospital survival as shown in the propensity matched score. This improved survival continued after hospital discharge. It could be that patients who did not undergo PCI were not amenable to treatment, explaining their poorer survival.

Neurological function, our secondary outcome measure, was also more favourable in these PCI treated patients. Thus, the chance of surviving after an initial VF with a good quality outcome is realistic.

In conclusion, survival and neurological outcome in our patients resuscitated after VF and treated with PCI within a STEMI network was remarkably good. In our opinion these observations underscore the fact that the current chain of treatment allows optimal patient survival. However, there is insufficient good quality evidence about the outcome of immediate angiography and coronary intervention in patients with ROSC after OHCA of presumed cardiac aetiology. As the impact of this strategy on the utilisation of resources is significant, good quality randomised controlled trials are needed. In selected patients successfully resuscitated after OHCA of presumed cardiac aetiology, we believe that a more liberal application of angiography and coronary intervention may be considered in experienced acute cardiac referral centres.

Chapter 5 Outcome after OHCA in the elderlyAlthough there have been many studies focused on outcome after OHCA.47-50 There have only been few studies that have focused on the elderly. Since older studies reported a dismal outcome in certain elderly patients groups after cardiopulmonary resuscitation (CPR) 51, there may be reluctance in instituting maximum treatment in this group for fear of generating greater numbers of survivors with bad functional outcomes.52 However

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recent studies in other fields have shown encouraging results for the acute treatment of elderly patients.53,54

Despite similar percentage of patients regaining spontaneous circulation in both age groups outcome after OHCA for patients over 75 years was worse when compared to the results of the younger cohort, with a hospital survival rate that is 42% lower. When looking at markers for predicting outcome there were no differences in glucose, base excess and lactate levels.55-58

Surprisingly there was no difference in outcome related to initial rhythm. In younger patients initial rhythm is a strong predictor of survival as patients who present after VF have a better outcome. Survival after hospital discharge was also worse in the elderly patients. Neurological outcome however in elderly was good and similar to that of younger patients. Once discharged from hospital, the elderly patients had a reasonable 50%-survival of 6.5 years, compared to matched controls.

Cardiac catherization was employed less frequently in the elderly patients. This may be explained partly by the lower cardiac markers found with CK, CK-MB and Troponin I levels being significantly lower in the elderly. This implies that acute coronary occlusion may be less important as a trigger for OHCA than in the younger cohort. This could be due to the higher incidence of secondary VF in this patient group. This is supported by the higher incidence of previous myocardial infarction in the group ≥ 75 were possible secondary rhythm disturbances may cause OHCA. This may also explain their poorer survival after hospital discharge, as their underlying pathology is less amenable to treatment.58,59

However when correcting for underlying factors performing a propensity matched analysis the use of CAG is lower in the higher age category, which could be due to bias.Mild therapeutic hypothermia was employed equally in both groups despite the small difference of GCS at admission. Neurological outcome was better in the younger cohort. This could be due to a more susceptible brain since the incidence of stroke was higher in the elderly. However the mean for both groups falls in what is accepted as good outcome. Furthermore, the outcome means that 67% of elderly who survive have a CPC score of 1 and can carry on leading an independent life.

Despite similar rates of ROSC in elderly patients vs. younger patients, outcome after OHCA for elderly patients is worse with a survival rate that is approximate half that of younger patients. However the majority of elderly patients who survive have a CPC score of 1 and can carry on leading an independent life. The average life span for the mean aged patient in our study is still 6.72-8.59 years 60 and was comparable to the general population at this age.

Chapter 6Mechanically ventilated STEMI patients; risk factors for mortalityAcute myocardial Infarction (AMI) is a life-threatening event and a major cause of death.61 The diagnosis of ST-segment elevation myocardial infarction (STEMI) was found to be a

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predictor of early mortality in the overall AMI population.43,62 Over the last decades, focus on the rapid percutaneous reperfusion of the occluded coronary vessel 63 resulted in a decrease in mortality.43,64 The in-hospital incidence of death in the overall STEMI population is estimated at 5-14% 64-66 and 1-year mortality at 10-20%.43,64,67,68 Patients with STEMI requiring mechanical ventilation have substantially higher in-hospital mortality rates (up to 50%) compared to patients with AMI that do not require mechanical ventilation.69-72 Mechanical ventilation in the setting of STEMI is often required for supportive treatment in critically ill patients with cardiogenic shock, cardiac arrest, arrhythmias, and acute pulmonary edema.

Little is known, however, about the risk factors for mortality in STEMI patients requiring mechanical ventilation, especially at long-term follow-up. Four cohort studies have identified predictors of mortality in the general AMI population 69-71,73, but nonetheless prediction of mortality among patients with STEMI requiring mechanical ventilation remains difficult. The aim of this study was to identify risk factors for mortality both at short and long-term follow-up in patients presenting with STEMI requiring mechanical ventilation.

From January 1st, 2009, to May 26th, 2013, clinical and angiographic data of all patients presenting with a STEMI at the University Medical Center Groningen (UMCG) were prospectively recorded in a dedicated registry. We combined the registry with the Dutch National Intensive Care Evaluation (NICE) registry to identify the STEMI patients admitted to the intensive care unit (ICU). All mechanically ventilated patients with STEMI as primary reason for ICU admittance were included.

The primary outcome of our study was to identify predictors of 30-day mortality. Secondary outcomes were to identify predictors of long-term mortality at 90 days, 1- and 2-year follow-up. During the inclusion period, 231 (9.7%) of all 2380 registered STEMI patients were admitted to the ICU. Nearly one third of the admitted patients were excluded, mainly due to admission after cardiothoracic surgery or a final diagnosis other than STEMI. In addition, long-term mortality was assessed up until May 23th, 2015.

A total of 77 (49%) of the 157 mechanically ventilated patients died within 30 days. Demographic data, coronary risk factors and cardiovascular history were similar between survivors and non-survivors. Initial presentation with pulseless electric activity (PEA) or asystole was more often observed in patients who died (30% versus 1% among survivors; P < 0.01) and patients who died received an intra-aortic balloon pump more often during coronary angiography (56% versus 32%; P < 0.01). Of the survivors, 71 patients (89%) had a primary PCI compared with 65 patients (84%) of the non-survivors (P = 0.43). A considerable proportion of patients presenting with STEMI are admitted to the ICU: 231 (9.7%) out of 2380 patients, and 157 (6.6%) required mechanical ventilation. Patient presenting with STEMI who need mechanical ventilation have the poorest prognosis of all STEMI patients and data of this these patients are scarce as they are usually excluded from randomised clinical trials. Our study presents detailed data regarding risk factors of mechanically ventilated STEMI patients. Mortality rate in these patients is 49% at 30 days and increases to 52% at one-year follow-up. Mortality rates were higher in older

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patients presenting with a severe arrhythmia (PEA or asystole), cardiogenic shock, a higher APACHE-IV score and larger myocardial infarct size.

ConclusionA substantial number of patients with STEMI need mechanical ventilation: approximately 1 out of every 15 patients with a STEMI. 30-day mortality is 49%, while only an additional 8 patients die (10%) after having survived 30-days. Independent predictors of mortality are older age, initial rhythm of PEA or asystole, and admission with a cardiogenic shock, a higher APACHE-IV score and a larger myocardial infarct size.

Chapter 7Incidence of arrhythmia and sudden cardiac death in traumatic brain injuryData on the occurrence of electrocardiographic (ECG) changes and arrhythmias in traumatic brain injury (TBI) patients are sparse.74-76 Most data are derived from case reports of patients with specific ECG changes, rather than data of populations of TBI patients.74,77-79 All patients with severe TBI admitted to the University Medical Center Groningen from January 2002 until June 2013 who fulfilled the criteria for Intracranial Pressure (ICP)-monitoring defined by the international guidelines 80 were included for analysis. These patients are part of a prospectively followed cohort of patients to determine predictive factors related to outcome.

In all patients a CT-scan was obtained directly after admission with a second CT-scan if clinical status deteriorated. All scans were classified according to the Marshall criteria.81 Patients were monitored according to a standardized protocol including continuous blood pressure monitoring and pulse oximetry. For ICP-monitoring a ventricular catheter for simultaneous ICP reading and CSF drainage (neurovent-iFD-S from Raumedic) was used. ECGs were obtained within 48 hours of admission were analyzed with 12-leads ECGs recorded with Cardio Perfect equipment (Cardio Control, Delft, The Netherlands) and stored digitally after admission. Patients were admitted to the ICU with a standard regimen of sedatives and analgesics for ventilatory support.

In our cohort of patients with severe TBI ECG changes were very often seen, in 70% of patients, and arrhythmias were observed in 1 out of 5 patients. In comparison to the existing literature we observed far more ECG abnormalities.74 In the current study no relation between biomarkers of ischaemic heart disease (troponin, CPK) and the occurrence of ECG abnormalities was found. Since only a few patients had a history of cardiovascular disease it is unlikely that all ECG abnormalities had a primarily cardiac cause. Furthermore, only 25% of patients showed elevated troponin levels and just 24% showed elevated CK-MB-levels during the ICU stay. In addition, these cardiac biomarkers were not related to arrhythmia or ECG abnormalities. Likewise the observed hypokalemia and hypomagnesaemia were not related to incidence of arrhythmia, and therefore the observed arrhythmia cannot be contributed to abnormal electrolyte levels. In the current study, increasing TIL was related to an increased incidence of arrhythmias but not the occurrence of ECG abnormalities. It is suggested that these arrhythmias occurring with intensified ICP treatment might represent severity of injury instead of specific cardiac

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complications. This is supported by the fact that there was no correlation between increasing TIL levels and increased levels of cardiac enzymes. We did not find any significant differences in mortality of patients with ECG abnormalities or arrhythmias compared to those without these cardiac abnormalities. The estimated incidence of sudden in-hospital-cardiac arrest of was 2%. Since additional factors were present in at least nine patients, the estimated contribution of cardiac death to fatal outcome of traumatic brain injury in our study was 11%, a small but not insignificant number. Therefore, it is suggested that while cardiac complications of TBI are present they do not constitute a major contributing factor to mortality.

Future directionsOutcome after OHCA is dependant on several factors both outside and inside our abilities of optimization. Fast ROSC, fast resolving of the underlying cause of OHCA and good post-resuscitation care are within the scope of opportunities for improvement of care. There has been continued interest in resuscitation courses for the general public. Additionally the widespread availability of AEDs coupled with systems that alert nearby members of the public to the occurrence of OHCA can lead to shorter response times and earlier start of BLS.

The implementation of a STEMI network can further lead to improvements in outcome. Expedient diagnostic procedures such as forwarding of ECG cut down on time to devising a treatment plan. (Post-) resuscitation care requires a multidisciplinary approach. (Post-) resuscitation care is started on scene by the ambulance services by ALS, safeguarding oh an airway and rapid transportation. After arrival in-hospital the interdepartmental organisation is also critical.82 Rapid transportation and /or diagnostic procedures coupled with rapid optimization of the clinical condition of the patient require cooperation between the emergency, anaesthesia / critical care, cardiology and sometimes neurology department. Outcome for patients with OHCA varies depending on the hospital to which they are admitted 83 and there is some evidence that mortality is lower among those admitted to hospitals that treat a high volume of post-cardiac arrest patients.84 And perhaps, since an ECG is not 100% predictive of STEMI, all patients should be relegated to hospitals that are best suited for caring for patients with OHCA, therapeutic hypothermia, 24/7 PCI facilities and advanced neurological investigations should al be on hand.31,41,58

This is already the case with the organization of trauma care. Patients with traumatic brain injury are automatically triaged to a level I trauma centre. Cerebral perfusion is one of the most important factors related to outcome in TBI patients as it probably is for patients after OHCA, research into this field has been few and suggestions have been made that there may be a state of hyperperfusion after OHCA 85 or hypoperfusion leading to bad outcome.86 Since these results seem to be diametrically opposed more research is needed to evaluate cerebral perfusion and devise if there is an optimum level in the individual patient to which treatment should be tailored. In TBI patients, cardiac sequlae are no linked to outcome, and more information is needed on possible concomitant echocardiographic abnormalities influencing outcome. More insight into ECG abnormalities coupled with data on cardiac function may yet lead to increased interest and necessity of more aggressive treatment in both patient categories.

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There have been multiple recent advances in the care of patients with OHCA. The development of STEMI networks advances in therapeutic hypothermia and emergency post-OHCA Coronary interventions has been shown to drastically improve the outcomes of patients after OHCA.

Questions that still remain are the optimum temperature management for post-resuscitation care. Perhaps in the future a study can be undertaken comparing 36 °C vs. fever control. More and more there is appreciation that OHCA is a survivable event with a good chance of neurologically intact survival.

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concussion. Chest. 1978;74(4):468-69. 80. Foundation BT, Surgeons AAoN, Surgeons CoN, et al. Guidelines for the management of severe traumatic brain injury. VI. Indications for intracranial pressure monitoring. Journal of neurotrauma. 2007;24 Suppl 1(supplement 1):S37-44. 81. Marshall LF, Marshall SB, Klauber MR, et al. The diagnosis of head injury requires a classification based on computed axial tomography. Journal of neurotrauma. 1992;9 Suppl 1:S287-92. 82. Nolan JP, Lyon RM, Sasson C, et al. Advances in the hospital management of patients following an out of hospital cardiac arrest. Heart (British Cardiac Society). 2012;98(16):1201-06. 83. Stub D, Smith K, Bray JE, et al. Hospital characteristics are associated with patient outcomes following out-of-hospital cardiac arrest. Heart (British Cardiac Society). 2011;97(18):1489-94. 84. Carr BG, Kahn JM, Merchant RM, et al. Inter-hospital variability in post- cardiac arrest mortality. Resuscitation. 2009;80(1):30-34. 85. Lemiale V, Huet O, Vigue B, Mathonnet A, et al. Changes in cerebral blood flow and oxygen extraction during post-resuscitation syndrome. Resuscitation. 2008;76(1): 17-24.86. Torgersen C, Meichtry J, Schmittinger CA, Bloechlinger S, et al. Haemodynam- ic variables and functional outcome in hypothermic patients following out-of-hospital cardiac arrest. Resuscitation. 2013;84(6): 798-804.

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Samenvatting, discussie en

toekomstperspectieven

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Inhoud:Hoofdstuk 1 Algemene inleiding en reikwijdte van het proefschriftIn dit proefschrift wordt de verbinding tussen het hart en de hersenen onderzocht. Dit wordt gedaan via het perspectief van drie medische disciplines, cardiologie, neurologie en intensive care. Deze drie totaal verschillende specialismen spelen alle drie spelen een rol in deze samenhang. De belangrijkste focus van dit proefschrift ligt op de reanimatie buiten het ziekenhuis met bijbehorende behandeling en onderliggende oorzaken. We onderzoeken de hemodynamische en metabole consequenties van de ziekte en de behandeling. De uitkomst van deze verwoestende ziekte is nauw verbonden met de hersenen en als eerste beschreven door Peter Safar.1 We nemen ook uitstap om te kijken naar de omgekeerde relatie, de behandeling van cardiale gevolgen van traumatisch hersenletsel.

Hoofdstuk 2A: Hemodynamische gevolgen van milde therapeutische hypothermie na een hartstilstandNa het evalueren van de literatuur, lijkt er een overvloed bewijsvoor de uitvoering van een milde therapeutische hypothermie (MTH) in de klinische praktijk. Er zijn echter bijwerkingen. Veel van de kennis over de neveneffecten van hypothermie is opgedaan uit waarnemingen bij accidentele onderkoeling. Het kan leiden tot verlies van elektrolyten (kalium, magnesium en fosfaat) als gevolg van zowel verhoogde urinaire excretie en intracellulaire shift. Deze bevindingen zijn eveneens bevestigd in klinische studies betreffende MTH.2,3 Elektrolyt afwijkingen kunnen verder invloed uitoefenen op de hartfunctie. Een groot percentage van de patiënten met een reanimatie buiten het ziekenhuis (OHCA) word veroorzaakt door acute coronaire syndromen of een myocardinfarct. Deze syndromen kunnen ook invloed hebben op de hartfunctie. Geïnduceerde hypothermie kan dit verder verstoren en beïnvloed de hemodynamiek na OHCA. Omdat informatie over de hemodynamische gevolgen tijdens MTH schaars is, bestudeerden we deze bij patiënten met OHCA toegelaten tot onze ICU.

Het behandelingsprotocol dat werd uitgevoerd bestonden uit hypothermie geïnduceerd via snelle infusie van 2 liter koude isotone zoutoplossing (4 °C), gevolgd door verdere inductie en handhaven van koeling met de patiënt tussen twee watergekoelde dekens (Blanketroll II, CSZ, Cincinnati , Ohio, USA). De temperatuur werd continu gemeten met een oesofagiale temperatuursonde welke werd gebruikt als terugkoppeling voor de koelinstallatie. Na het bereiken van de gewenste temperatuur van 32,5 °C, werden de patiënten op deze temperatuur gehouden gedurende 24 uur. Na de onderhoudsfase werden de patiënten opgewarmd met een geregelde snelheid van 0,3 °C per uur tot een doeltemperatuur van 36 °C was bereikt en de sedatie werd beëindigd.

We toonden duidelijke hemodynamische veranderingen aan in een cohort van 48 patiënten die met MTH werden behandeld. We vonden een duidelijke daling van de hartslag. Dit beta-blocker-achtig effect kan een gunstige invloed hebben op ischemie

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van het hart en/ of de grootte van myocardschade. Het verlagen van de hartslag is een hoeksteen van de behandeling bij patiënten met acute coronaire syndromen.4,5 Echter, in veel patiënten na OHCA, kunnen beta-blokkers niet gebruikt worden omdat patiënten een lage bloeddruk hebben, dit betrof 55% van de patiënten in een groot onderzoek naar hypothermie na een hartstilstand.6,7

Ondanks inductie van hypothermie met 2 liter koude isotone zoutoplossing (4 °C), nam de pulmonale arteriële druk af. Dit is in lijn met eerder onderzoek aangaande de veiligheid van de infusie van koud isotoon zout.8,9 Dit kan erop wijzen dat veel patiënten aanvankelijk hypovolemisch zijn. We vonden een aanvankelijke stijging in de urineproductie tijdens MTH. Dit wordt vaak uitgelegd als koude diurese, veroorzaakt doordat perifere vasoconstrictie hogere centrale vullingsdrukken bevorderd.10 Anderen hebben gesuggereerd dat te wijten zou zijn aan nefrogene diabetes insipidus. Dit zou veroorzaakt worden door verminderde tubulaire functie tijdens hypothermie.11 Echter, wij vinden deze verklaringen zijn niet erg waarschijnlijk gezien de diurese niet excessief was tijdens de onderhouds-fase van hypothermie. Een andere verklaring kan zijn dat onze snelle vloeistof inductie enkel invloed had op de vroege fase van de urineproductie. Aanzienlijke koude-diurese tijdens lopende hypothermie behandeling werd niet gezien. Het is moeilijk om te onderscheiden of deze resultaten beïnvloed kunnen zijn door acute tubulaire necrose na een hartstilstand. We kunnen wel concluderen dat hoge urineproductie of koude diurese geen relevante klinische problemen opleveren.

Hoewel een daling van de cardiale index (10%) kan leiden tot ontoereikende orgaanperfusie, tijdens geïnduceerde hypothermie, toonden wij aan dat dit lagere hartminuutvolume geen lagere gemengde veneuze zuurstofverzadiging veroorzaakt. Dit suggereert dat, parallel aan de daling van het hartminuutvolume, het zuurstofverbruik lager was vanwege de lagere lichaamstemperatuur. Met andere woorden, tijdens MTH, kan de werklast van het geblesseerde hart verminderd worden doordat een lager rust metabolisme nodig is bij een lagere lichaamstemperatuur.12 De bevinding van het verhoogde lactaat niveaus gedurende hypothermie welke normaliseerden tijdens het opwarmen kan het gevolg zijn van weefselhypoperfusie. Er was echter sprake van normale gemengde veneuze zuurstofsaturaties wat hiermee in tegenspraak is. Daarnaast konden we geen correlatie vinden van een verhoogd lactaat niveau tijdens hypothermie met de uitkomst. We veronderstellen dat hyperlactatiëmie verband zou kunnen houden met hypothermie en niet schadelijk of prognostische negatief is gezien hyperlactatiëmie ook tijdens hypothermie bij hartchirurgie patiënten is beschreven.13

B: Onverwachte neurologische achteruitgang na milde therapeutische hypothermieRelevant voor het onderwerp van geïnduceerde milde therapeutische hypothermie is wat precies het mechanisme achter de gunstige invloed is. MTH is de standaard behandeling sinds 2003.14 Recente studies hebben aangetoond dat er geen verschil in uitkomst als patiënten tot 33 °C of 36 °C werden gekoeld. Belangrijke factoren die de uitkomst na reanimatie buiten het ziekenhuis (OHCA) beïnvloeden zijn de primaire en secundaire hersenschade. Neurologische complicaties veroorzaken twee derde van de sterfgevallen na aanvankelijke resuscitatie van OHCA patiënten.15 Milde hypothermie therapeutische

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is aangetoond als behandelingsstrategie om neurologische prognose verbeteren.6,7

Afgezien van het bewijs dat hypothermie behandeling de hersenen bescherming biedt er is ook overweldigend bewijs dat suggereert dat hyperthermie schadelijk kan zijn en ischemische schade aan de hersenen na een eerste beschadiging kan verhogen. Dierproeven tonen aan dat zelfs vertraagde hyperthermie (tot 24 uur) neurologische schade na ischemische schade kunnen verergeren.16,17 Prospectieve studies bij slachtoffers van een beroerte hebben aangetoond dat koorts (T > 37,9 °C) een onafhankelijke voorspeller is van een slechte uitkomst (odds ratio 3.4).18

Koorts is een tevens risicofactor voor een slechte neurologische uitkomst na een hartstilstand. Hoe lang deze kwetsbaarheid van de hersenen duurt en het risico van neurologische verslechtering voortduurt is onbekend. Maar onze waarnemingen suggereren dat hyperthermie agressief moeten worden behandeld gedurende enkele dagen na terugkeer naar normothermie.

Hoofdstuk 3Vroege lactaat klaring bij patiënten na reanimatie buiten het ziekenhuisNa OHCA heeft het lichaam een grote zuurstof achterstand gegenereerd met bijbehorende ophoping van lactaat als gevolg van een puur anaeroob metabolisme. Tijdens sepsis daarentegen, is lactaatproductie vaak niet het gevolg van algemene hypoxie maar verhoogde adrenerge stress.19 Het herstel van normale circulatie maakt het voor weefsels mogelijk het lactaat te metaboliseren. We hebben de klaring van lactaat door atleten na een maximale inspanning ingevoegd om aan te geven wat in principe het bovenste bereik van lactaat klaring is omdat bij atleten bekend is dat lactaat duidelijk sneller word gemetaboliseerd.20

Bij ernstig zieke patiënten zijn aanhoudend verhoogde lactaat niveaus sterk geassocieerd met een slechtere uitkomst.21

Het herstel van normale lactaatniveaus en de snelheid waarmee dit gebeurt is ook gecorreleerd met de uitkomsten.22-24 Bij septische patiënten met hyperlactatemie (lactaat van > 4 mmol / l), en een daling van 10% na 6 uur is bewezen geassocieerd met een gunstige uitkomst.7 In het kader van de out-of-ziekenhuis hartstilstand (OHCA) en na terugkeer van spontane circulatie (ROSC) is ook een doel voor lactaat klaring van 10% per uur voorgesteld.26,27

Echter, de kinetiek van lactaat klaring na een OHCA lijkt meer op de klaring van atleten dan van septische patiënten.Patiënten op de afdeling spoedeisende hulp ED (2006-2014), in het Universitair Medisch Centrum Groningen (UMCG), na een OHCA werden geanalyseerd. Arteriële bloedmonsters werden routinematig verzameld op de Eerste hulp (ED), hartkatheterisatie lab en intensive care unit (ICU). Patiënten die ROSC bereikten na een reanimatie met daarbij een initieel arterieel lactaat > 8 mmol / L en ten minste twee lactaat metingen binnen de eerste twee uur werden meegenomen in het onderzoek. Tijd 0 werd gesteld als de eerste lactaat meting na ROSC. De absolute klaring in mmol / l per uur en de relatieve lactaat klaring als percentage van het maximale lactaat niveau in % per uur werden voor elke patiënt vastgesteld met lineaire regressie.Er werd geen significant verschil in het initiële lactaatgehalte tussen overlevenden en niet-overlevenden gevonden. De gemiddelde absolute lactaat klaring was 5,0 mmol

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/ L per uur en de gemiddelde relatieve lactaat klaring was 40,9% per uur. Zowel de hogere absolute en relatieve lactaat klaring na ROSC waren positief geassocieerd met ziekenhuis overleving.Vroege lactaat klaring na OHCA was veel sneller dan de 10 % / uur reductie gerapporteerd bij succesvol genezen septische patiënten en ook boven de 10 % / uur welke is voorgesteld in de setting van een hartstilstand.25,27 Naast het aanzienlijke verschil tussen lactaat metabolisatie in overlevenden en niet-overlevenden, werd aangetoond dat de totale relatieve lactaat klaring veel hoger is dan 10% per uur. Dit geeft aan dat wanneer lactaat wordt gebruikt om de behandeling te monitoren na een hartstilstand, een hogere streefwaarde voor lactaat vermindering nodig is.Bovendien, tonen onze bevindingen een significant verschil in absolute lactaat klaring en relatieve lactaat klaring tussen overlevenden en niet-overlevenden van een OHCA. Zoals verwacht, hadden overlevenden een hogere klaring dan niet-overlevenden. Vermeldenswaardig is dat er geen verschil is tussen het oorspronkelijke lactaat niveau van beide groepen, wat door de resultaten van andere studies wordt bevestigd.22,23

Hoofdstuk 4Lange-termijn uitkomst van patiënten na een reanimatie buiten het ziekenhuis gecorreleerd met de behandeling: een single center studieOndanks verschillende ontwikkelingen op het gebied van reanimatie, kan de behandeling van patiënten na een reanimatie buiten het ziekenhuis (OHCA) nog worden verbeterd.28-32 Factoren die de uitkomst na OHCA beïnvloeden zijn het eerste ritme, of er getuigen waren van de collaps, of er direct gestart werd met reanimeren, vroege defibrillatie en de organisatie van de zorg. Er zijn diverse initiatieven ondernomen om de uitkomsten te verbeteren na OHCA. Organisatorische maatregelen, zoals cursorisch onderwijs over reanimeren en daarnaast andere initiatieven om omstander CPR te bevorderen; 33-35 optimalisering van spoed interventie systemen 36, en snelle toegang tot de automatische externe defibrillatoren.37 Deze initiatieven verbeteren de uitkomst.38 Overleving is het meest waarschijnlijk als het eerste ritme ventrikel fibrilleren (VF) betreft.39 Dit wordt het vaakst veroorzaakt door een hartinfarct als gevolg van een verstopte kransslagader.39,40 In onze regio is een “ST-elevatie myocardinfarct infarct (STEMI)” netwerk opgericht in met de ambulancediensten, de afdeling cardiologie en intensive care. Het doel is om de behandeling voor patiënten met terugkeer van spontane circulatie (ROSC), zo doelmatig mogelijk toe te passen op geleide van de klinische tekenen en het elektrocardiogram (ECG) of echocardiografische tekenen van hart ischemie.

Het Universitair Medisch Centrum Groningen is een tertiair ziekenhuis, dat het noordoostelijke deel van Nederland bedient. In dit gebied is het enige ziekenhuis dat PCI uitvoert. Met referentieziekenhuizen, biedt dit centrum 24/7 spoedeisende hulp in een regio met 750.000 inwoners.41 In noodgevallen wordt de dichtstbijzijnde ambulance gezonden en indien reanimatie noodzakelijk is wordt een tweede ambulance verzonden als back-up. Patiënten worden vervolgens naar het centrum vervoerd, vooral wanneer er een vermoeden van coronaire occlusie (bijv. VF of STEMI). De reanimatie wordt voortgezet of post-reanimatie zorg gegeven volgens de richtlijnen voor specialistische reanimatie.42

We bestudeerden retrospectief alle opeenvolgende patiënten ouder dan 18 jaar

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opgenomen in ons ziekenhuis na OHCA tussen januari 2003 en augustus 2010. Alle patiënten werden opgenomen in onze analyse, tenzij het onmogelijk was om OHCA bevestigen of het oorspronkelijke ritme te definiëren. In deze grote groep van opeenvolgende patiënten behandeld binnen een STEMI netwerk, bleef de uitkomst na OHCA matig. Bij patiënten met een initieel ritme van VF, die ROSC vertoonden en werden behandeld door onmiddellijke PCI was het resultaat goed. De in het ziekenhuis bereikte overleving was 66% voor deze categorie patiënten en, nog opmerkelijker, voor degenen die levend het ziekenhuis verlieten, was de overleving na ontslag 99% na vijf jaar. Dit resultaat vergelijkbaar met gegevens gerapporteerd voor patiënten met STEMI zonder hartstilstand behandeld met PCI.43

Patiënten met een slechte hartfunctie en veel comorbiditeit verkrijgen wellicht geen ROSC of overleven niet tot ontslag uit het ziekenhuis. Voor onze patiënten vonden we dat overleving beter was bij patiënten met hogere linker ventrikel ejectie fractie (LVEF), een betere Glasgow Coma Schaal (GCS), hogere pH-waarden en lagere glucose en lactaat niveaus conform volgens bevindingen van anderen.44-46 Bovendien, patiënten met een initieel ritme anders dan VF toonden een lager percentage van ROSC en verminderde GCS scores bij opname in vergelijking met patiënten met VF.Daarom zouden vooral patiënten met VF als eerste waargenomen ritme van de behandeling binnen een STEMI netwerk profiteren. Patiënten met een ander initieel ritme hebben waarschijnlijk een onderliggend pathofysiologisch mechanisme dan myocardiale ischemie op basis van coronaire occlusie. Dit wordt ondersteund door de lagere concentratie van cardiale markers zoals troponine, creatinekinase en creatine kinase-MB in de niet VF groep. Het ontbreken van behandelopties afgezien van defibrillatie, MTH en ondersteunende zorg kan de slechtere uitkomst van patiënten met een andere initiële ritme verklaren. Zelfs na ontslag uit het ziekenhuis, is de overleving lager in vergelijking met patiënten die zich presenteerden met VF. Ditzelfde princpipe gold voor patiënten die een PCI ondergingen, bij hen werd een betere ziekenhuis overleving aangetoond in de propensity gecorrigeerde score. Deze verbeterde overleving zet zich voort na ontslag uit het ziekenhuis. Het kan zijn dat voor patiënten die geen PCI ondergingen geen effectieve behandeling was, wat de slechtere overleving zou kunnen verklaren.

Neurologische uitkomst, onze secundaire uitkomstmaat, was ook gunstiger in deze middels PCI behandelde patiënten. Zo is de overlevingskans met een goede functionele uitkomst na een OHCA op basis van initieel VF realistisch.Tot slot, de overleving en neurologische uitkomst bij patiënten gereanimeerd na VF en behandeld met PCI binnen een STEMI netwerk was opmerkelijk goed. Naar onze mening onderstrepen deze waarnemingen het feit dat de huidige keten van behandeling optimale kans geeft op overleving. Er zijn echter onvoldoende kwalitatief goede gegevens over het resultaat van directe angiografie en coronaire interventie bij patiënten met ROSC na OHCA van vermoedelijke cardiale etiologie om dit definitief te mogen concluderen. Aangezien de impact van deze agressieve strategie op het gebruik van middelen groot is, zijn kwalitatief goede studies nodig. In geselecteerde patiënten met succes gereanimeerd na OHCA van vermoedelijke cardiale etiologie, vinden wij echter dat een meer liberale toepassing van angiografie en coronaire interventie moet worden overwogen in ervaren hartcentra.

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Hoofdstuk VijfResultaat na OHCA bij ouderen boven de 75 jaarHoewel er veel studies gericht op de uitkomst na OHCA.47-50 geweest zijn er slechts enkele studies verricht die focussen op ouderen. Omdat oudere studies melding maakten van een sombere afloop bij bepaalde groepen oudere patiënten na reanimatie (CPR) 51, kan er terughoudendheid zijn bij het instellen van de maximale behandeling bij deze groep. Dit uit angst voor het genereren van een groter aantal overlevenden met een slechte functionele uitkomst.52 Recente studies in andere onderwerpen toonden bemoedigende resultaten voor de acute behandeling van oudere patienten.53,54

Ondanks dat een vergelijkbaar percentage patiënten opnieuw eigen circulatie krijgen in beide leeftijdsgroepen is de uitkomst na reanimatie voor patiënten ouder dan 75 jaar slechter in vergelijking met het jongere cohort met een overleving die 42% lager is bij ontslag uit het ziekenhuis. Wanneer we kijken naar voorspellers voor uitkomst waren er geen verschillen in glucose, de base-excess en lactaat niveaus.55-58

Verrassend genoeg was er geen verschil in uitkomst met betrekking tot het initiële ritme. Bij jongere patiënten is het eerste ritme is een sterke voorspeller van de overleving, patiënten die zich presenteren na VF hebben een betere uitkomst. De neurologische uitkomst bij ouderen was goed en vergelijkbaar met die van jongere patiënten. Overleving na ontslag uit het ziekenhuis was net als de intiele overleving slechter bij de oudere patiënten. Na ontslag uit het ziekenhuis hadden oudere patiënten had een redelijke 50%-overleving van 6,5 jaar, vergelijkbaar met een geslachts en leeftijds gematchte populatie van ouderen.

Cardiale catheterisatie werd minder vaak toegepast bij de oudere patiënten. Dit kan deels worden verklaard door de lagere cardiale markers. Laboratoriumwaarden voor CK, CK-MB en troponine I waren significant lager in de oudere groep. Dit suggereert dat acute coronaire occlusie minder belangrijk als een trigger voor OHCA dan in het jongere cohort zijn. Dit zou samenhangen met een hogere incidentie van secundair VF bij deze patiëntengroep. Dit wordt ondersteund door het vaker voorkomen van een eerder myocard infarct in de groep ≥ 75 jaar welke ritmestoornissen kunnen veroorzaken. Dit kan ook hun lagere overleving na ontslag uit het ziekenhuis verklaren, hun onderliggende pathologie biedt minder mogelijkheden voor behandeling.58,59

Echter ook na het corrigeren van de onderliggende factoren middels propensity analyse is de inzet van CAG lager in de hogere leeftijdscategorie, mogelijk veroorzaakt door bias.

Milde therapeutische hypothermie werd bij beide groepen evenveel toegepast, ondanks het kleine verschil van GCS bij opname. De neurologische uitkomst was beter in het jongere cohort. Dit kan worden veroorzaakt door een gevoeliger hersenen van de daar de incidentie van CVA’s hoger bij ouderen was. Echter het gemiddelde uitkomst van beide groepen was goed. Bovendien betekent deze uitkomst dat 67% van de ouderen die overleven een zelfstandig leven kunnen leiden.Ondanks vergelijkbare percentages van ROSC bij ouderen & jongere patiënten, zijn uitkomsten na OHCA voor oudere patiënten slechter met een overlevingspercentage dat is ongeveer de helft is van dat van jongere patiënten. De gemiddelde levensduur van

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patiënten na ontslag in ons onderzoek is nog 6,72-8,59 jaren 60 en is vergelijkbaar met de algemene populatie van deze leeftijd.

Hoofdstuk ZesMechanisch geventileerde STEMI patiënten; risicofactoren voor mortaliteitHet acuut myocardinfarct (AMI) is een levensbedreigende aandoening en een belangrijke oorzaak van overlijden.61 De diagnose van ST-segment elevatie myocardinfarct (STEMI) bleek een voorspeller van vroege sterfte in de totale AMI population.43,62 Over de laatste decennia, heeft de focus op de snelle percutane reperfusie van de afgesloten kransslagader 63 geresulteerd in een afname van sterfte.43, 64 Overlijden in het ziekenhuis van de totale STEMI bevolking wordt geschat op 5-14% 64-66 en 1-jaars mortaliteit is omstreeks 10-20%.43,64,67,68

Patiënten met STEMI die mechanische geventilateerd moeten worden hebben een aanzienlijke hoger in-ziekenhuis mortaliteit (tot 50%) in vergelijking met patiënten met een AMI die geen mechanische ventilatie nodig hebben.69-72 Mechanische ventilatie in de setting van STEMI is vaak nodig voor ondersteunende behandeling bij ernstig zieke patiënten met cardiogene shock, hartstilstand, hartritmestoornissen en acuut longoedeem.Er is weinig bekend over de risicofactoren voor mortaliteit in STEMI patiënten met mechanische ventilatie, met name op de lange termijn. Vier cohortstudies hebben voorspellers van sterfte geïdentificeerd in de algemene populatie van AMI.69-71,73 Maar toch blijft voorspelling van sterfte onder patiënten met STEMI met mechanische ventilatie moeilijk. Het doel van dit onderzoek was het identificeren van risicofactoren voor mortaliteit, zowel op korte als op lange termijn bij patiënten met STEMI met mechanische ventilatie.

Klinische en angiografische gegevens van alle patiënten met een STEMI in het Universitair Medisch Centrum Groningen (UMCG) werden vanaf 1 januari 2009, tot 26 mei 2013, prospectief vastgelegd in een speciaal register. We combineerden het register met het Nederlandse Nationale Intensive Care Evaluatie (NICE) register om STEMI patiënten opgenomen op de intensive care unit (ICU) te identificeren. Alle mechanisch geventileerde patiënten met STEMI als primaire reden voor de ICU toelating werdem geïncludeerd.Het primaire doel van de studie was om voorspellers van mortaliteit na 30 dagen te identificeren. Secundaire uitkomsten waren om voorspellers van lange termijn sterfte te identificeren na 90 dagen, 1- en 2-jaar follow-up.

Tijdens de inclusieperiode, werden 231 (9,7%) van in totaal 2380 STEMI patiënten opgenomen op de ICU. Bijna een derde van de opgenomen patiënten werden uitgesloten, voornamelijk als gevolg van opname na cardiothoracale chirurgie of een definitieve diagnose anders dan STEMI. Daarnaast werd de mortaliteit geëvalueerd tot 23 mei 2015. In totaal stierven 77 (49%) van de 157 mechanisch geventileerde patiënten binnen 30 dagen. Demografische gegevens, coronaire risicofactoren en cardiovasculaire voorgeschiedenis waren vergelijkbaar tussen overlevenden en niet-overlevenden. Een presentatie met polsloze elektrische activiteit (PEA) of asystolie werd vaker waargenomen

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bij patiënten die overleden (30% versus 1% bij overlevenden; P < 0,01) en bij overleden patiënten werd vaker een intra- aortale ballonpomp ingebracht tijdens coronaire angiografie (56 % versus 32%; P < 0,01). Van de overlevenden hadden 71 patiënten (89%) een primaire PCI vergeleken met 65 patiënten (84%) van de niet-overlevenden (P = 0,43). Een aanzienlijk deel van de patiënten met STEMI werd toegelaten tot de ICU: 231 (9,7%) van de 2380 patiënten en 157 (6,6%) hiervan hadden mechanische ventilatie. Patiënt met STEMI die mechanischegeventileerd werden hebben de slechtste prognose van alle STEMI patiënten en gegevens van deze deze patiënten zijn schaars, omdat ze doorgaans uit gerandomiseerde klinische studies zijn uitgesloten. Onze studie geeft gedetailleerde gegevens over de risicofactoren van mechanisch geventileerde STEMI patiënten. Mortaliteit bij deze patiënten is 49% bij 30 dagen en neemt toe tot 52% na één jaar follow-up. Sterftecijfers waren hoger bij oudere patiënten met een ernstige aritmie (PEA of asystolie), een cardiogene shock, een hogere APACHE-IV score en groter infarct.

ConclusieEen aanzienlijk deel van de patiënten met STEMI hebben mechanische ventilatie nodig; ongeveer 1 op de 15 patiënten. Dertig-dagen mortaliteit is 49%, maar slechts 8 additionele patiënten overlijden nadat ze 30 dagen overleefden. Onafhankelijke voorspellers van sterfte zijn oudere leeftijd, ernstige hartritmestoornissen (PEA of asystolie), opname met een cardiogene shock, een hogere APACHE-IV score en een grotere myocard infarct.

Hoofdstuk 7Incidentie van aritmie en plotselinge hartdood bij traumatisch schedelhersenletselGegevens over het optreden van het elektrocardiogram (ECG) veranderingen en aritmie in patiënten met traumatisch hersenletsel (TBI) zijn schaars.74-76 De meeste gegevens zijn afkomstig van case reports van patiënten met specifieke ECG veranderingen, in plaats van populatiegegevens van TBI patiënten.74,77-79 Alle patiënten met ernstige TBI toegelaten tot het Universitair Medisch Centrum Groningen van januari 2002 tot juni 2013, die aan de criteria voor intracraniële druk (ICP) -monitoring voldeden, gedefinieerd door de internationale richtlijnen 80 werden opgenomen voor analyse. Deze patiënten zijn onderdeel van een prospectief gevolgd cohort patiënten voorspellende factoren gerelateerd aan resultaat bepalen.

Bij alle patiënten werd een CT-scan verkregen direct na opname met een tweede CT-scan als de klinische toestand verslechterde. Alle scans werden ingedeeld volgens de Marshall criteria.81 De patiënten werden gecontroleerd volgens een gestandaardiseerd protocol met inbegrip van continue controle van de bloeddruk en pulsoximetrie. Voor ICP-monitoren werd een ventriculaire katheter voor het gelijktijdig lezen en ICP CSF drainage (neurovent-AEB-S van Raumedic) gebruikt. Twaalf-afleidingen ECG’s werden verkregen binnen 48 uur na opname en werden geanalyseerd met Cardio Perfect uitrusting (Cardio Control, Delft, Nederland) en digitaal opgeslagen na opname.Patiënten werden opgenomen op de ICU met een standaard regime van slaapmiddelen en pijnstillers voor ademhalingsondersteuning.

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In ons cohort van patiënten met ernstige TBI werden ECG veranderingen waargenomen in 70% van de patiënten. Daarnaast werden aritmieën waargenomen bij 1 van 5 patiënten. In vergelijking met de bestaande literatuur zagen wij meer ECG afwijkingen.74 In deze studie werd geen verband tussen biomarkers van ischemische hartziekte (troponine, CPK) en het voorkomen van ECG afwijkingen gevonden. Aangezien slechts enkele patiënten een voorgeschiedenis van hart- en vaatziekten hadden is het onwaarschijnlijk dat alle ECG afwijkingen een primaire cardiale oorzaak hadden. Bovendien, vertoonden slechts 25% van de patiënten een verhoogd troponine niveau en slechts 24% toonde een verhoogde CK-MB niveau tijdens het ICU verblijf. Bovendien hadden deze cardiale biomarkers geen verband met aritmie danwel ECG afwijkingen. Ook de waargenomen hypokaliëmie en hypomagnesiëmie waren niet gerelateerd aan de incidentie van aritmie en derhalve kan de waargenomen aritmie kan niet worden toegeschreven aan abnormale elektrolyten. In de huidige studie, was toename van de behandelintensiteit (TIL) gerelateerd aan een verhoogde incidentie van aritmieën, maar niet het voorkomen van ECG afwijkingen. Er wordt gesuggereerd dat deze hartritmestoornissen optredend bij geïntensiveerde ICP behandeling de ernst van de verwonding weergeven in plaats van specifieke cardiale complicaties vertegenwoordigen. Dit wordt ondersteund door het feit dat er geen correlatie is tussen toenemende TIL niveaus en verhoogde hartenzymen. Er zijn geen significante verschillen in sterfte van patiënten met ECG afwijkingen en/of ritmestoornissen in vergelijking met degenen zonder deze hartafwijkingen. De geschatte incidentie van acute hartstilstand was 2%. Omdat er bijdragende factoren aanwezig waren in ten minste negen patiënten, was de geschatte bijdrage van hartdood op de fatale afloop van traumatisch hersenletsel bij onze studie 11%, een klein maar niet onbelangrijke percentage. Derhalve stellen wij dat terwijl cardiale complicaties van TBI weliswaar veelvuldig aanwezig zijn, zij geen bepalende factor vormt voor mortaliteit.

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ToekomstperspectievenUitkomst na OHCA is afhankelijk van een aantal factoren, zowel binnen als buiten onze capaciteiten van optimalisatie. Snelle ROSC, het snel oplossen van de onderliggende oorzaak van OHCA en een goede post-resuscitatie zorg valt binnen de mogelijkheden tot verbetering van de zorg. Er is voortdurende interesse in reanimatie cursussen voor het grote publiek. Daarnaast is de ruime beschikbaarheid van AED’s in combinatie met systemen die nabijgelegen leden van het publiek alarmeren bij het optreden van een OHCA een mogelijkheid tot het verkorten van responstijden en eerdere start van de BLS.

Het opzetten van een STEMI netwerk kan leiden tot verdere verbeteringen in de uitkomst. Snelle diagnostische procedures, zoals het doorsturen van ECG verkorten de tijd tot het opstellen van een behandelplan. (Post-) reanimatie zorg vereist een multidisciplinaire aanpak. Deze zorg start reeds op straat door de ambulancediensten middels ALS, het veiligstellen van een luchtweg en snel vervoer. Na aankomst in het ziekenhuis is de interdepartementale organisatie ook uitermate belangrijk.82 Snel transport en / of diagnostische procedures gepaard met een snelle optimalisatie van de klinische toestand van de patiënt vereist nauwe samenwerking tussen de ambulancedienst, anesthesie/intensive care, cardiologie en soms de neurologie afdeling. Uitkomst van patiënten met een OHCA varieert afhankelijk van het opnemende ziekenhuis.83 Er zijn aanwijzingen dat de sterfte lager is, onder degenen die in een ziekenhuis opgenomen worden welke een grote hoeveelheid gereanimeerde patiënten behandeld.84 Aangezien een ECG niet 100% uitsluiting kan geven voor een STEMI, zouden wellicht wel alle patiënten worden vervoerd naar ziekenhuizen die het meest geschikt voor de zorg voor patiënten met een OHCA. In deze centra moeten therapeutische hypothermie, 24/7 PCI-faciliteiten en geavanceerde neurologische onderzoeken beschikbaar zijn.31,41,58

Dit is reeds het geval is met de organisatie van de traumazorg. Patiënten met traumatisch hersenletsel worden bijvoorbeeld automatisch getrieerd tot een niveau 1 trauma centrum. Cerebrale perfusie is een van de belangrijkste factoren gerelateerd aan de uitkomst van TBI patiënten net als waarschijnlijk voor patiënten na een OHCA. Er is op dit gebied nog weinig onderzoek gedaan. Er zijn aanwijzingen dat na het circulatoir arrest er een hyperperfusie zou onstaan 85 of juist hypoperfusie leidend to een slechte uitkomst.86 Aangezien deze uitkomsten diametraal tegengesteld lijken is meer onderzoek nodig om de cerebrale perfusie te evauaeren en om te zien of er een optimaal niveau van perfusie kan zijn bij de individuele patiënt. Bij TBI patienten zijn cardiale complicaties niet gekoppeld zijn aan uitkomst, maar er is meer informatie nodig over mogelijke gelijktijdige echocardiografische afwijkingen en hun eventuele invloed op de uitkomst.

Meer inzicht in ECG afwijkingen in combinatie met gegevens over de hartfunctie kan mogelijk leiden tot een toename in interesse en noodzaak om agressievere behandelingen bij deze patiënt categorie in te stellen.

Er zijn recentelijk meerdere verbeteringen in de behandeling van patiënten na een OHCA gerealiseerd. De ontwikkeling van STEMI netwerken, vooruitgang in therapeutische hypothermie en snelle post-OHCA coronaire interventies hebben aangetoond dat de

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resultaten van de patiënten na een OHCA drastische kunnen verbeteren.Vragen die nog resteren zijn de optimale temperatuur voor het management van post-reanimanten. Misschien dat in de toekomst een onderzoek kan worden uitgevoerd waarbij word vergeleken tussen 36 °C kerntemperatuur en voorkomen van koorts. Meer en meer word gezien dat een OHCA een overleefbaar event is met een goede kans op neurologisch intact overleven

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Dankwoord

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DankwoordGeen proefschrift is compleet zonder dankwoord. Een promotie draait misschien wel om één persoon, maar bij het schrijven van een proefschrift en het onderzoek dat daarvoor is vereist zijn vele mensen betrokken.

In de eerste plaats wil ik mijn co-promotor dr. I.C.C. van der Horst bedanken, beste Iwan, je bent een steun en toeverlaat geweest ook in tijden dat je het zelf wat moeilijker hebt gehad. Daarnaast heb je ook geholpen met de ideeën voor de artikelen. Tijdens de IC opleiding ben je ook een gewaardeerd collega geweest en maakte je tijd al had je naast het bieden van hulp aan mij nog vele andere taken.

Ten tweede ben ik ook dank verschuldigd aan mijn co-promotor prof. dr. J. van der Naalt, beste Joukje, bedankt voor je inzicht en al je hulp. Ik heb ontzettend veel gehad aan je commentaar op mijn artikelen.

Uiteraard wil ik ook graag mijn promotor bedanken, prof. dr. A.R. Absalom, dear Tony, thank you for the effort you have taken in reading my articles en the attention you gave to the english and the overall pitch of the articles.

Daarnaast wil ik dr. M.W.N. Nijsten bedanken, beste Maarten, zonder jouw hulp was dit proefschrift er nooit gekomen. Je bent denk ik een van de meest ondergewaardeerde mensen in het UMCG. Ik ben je dan ook veel dank verschuldigd voor alle goede ideeën, in het bijzonder ook het vele werk met de databases.

Graag wil ik de leescommissie prof. dr. C. Boer, prof. dr. J.C. ter Maaten & prof. dr. T.W. Scheeren bedanken voor de tijd die zij hebben gestoken in het lezen van dit proefschrift.

Aan Youlan Gu & Marthe Kampinga ben ik ook veel dank verschuldigd, het gebruik van data die jullie al hadden verzameld heeft mij ontzettend veel tijd gescheeld. Verder stonden jullie altijd open als ik weer vragen had over infocop. Ontzettend bedankt!

Ook dr. A.R. van Zanten wil ik graag bedanken, beste Arthur, in mijn tijd op de IC in Ede ben ik voor het eerst in aanraking gekomen met onderzoek, mede ook door de onderzoeksgerichte sfeer binnen de afdeling. Daardoor ben ik ook in het spoor gekomen om onderzoek te gaan doen binnen het veld waar ik uiteindelijk ook deze promotie heb afgemaakt.

Dank ben ik ook verschuldigd aan mijn mede-onderzoeker Bart Hiemstra, bedankt voor alle tijd die je ook in de artikelen hebt gestopt. Hopelijk kunnen we ook in de toekomst deze vruchtbare samenwerking voortzetten.

Ook al hebben ze niet direct bijgedragen aan dit proefschrift toch wil ik graag prof. F. Mahmood en assistant prof. R. Matyal bedanken. Dear Feroze and Robina during my time in Boston I learned a lot from both of you pertaining to setting up research drafting a manuscript and generally working very hard. You are an inspiration for how I myself would

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Dankwoord

like to function during the rest of my career.

I also want to thank Angela Wang, dear Angela thank you for agreeing to make such a beautiful cover for this manuscript, and thank you for always brightening the days in the Echo office.

Ook wil ik graag mijn vrienden uit Nijmegen bedanken, beste Haantjes, ondanks mijn vertrek naar Groningen nu alweer enkele jaren geleden hebben jullie er altijd weer voor gezorgd dat als ik weer terugkwam in Nijmegen ik gelijk het gevoel had weer thuis te zijn.

Tot slot wil ik graag mijn vrouw bedanken. Lieve Kristel, bedankt voor alle steun die jij me gegeven hebt tijdens het schrijven van dit proefschrift, jouw promotie was een voorbeeld voor mij. Na het voltooien van dit proefschrift gaan wij samen verder bouwen aan onze toekomst!

Curriculum Vitae

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Curriculum Vitae

Curriculum vitaeRemco Bergman was born on June 6th, 1980 in Apeldoorn, The Netherlands. He completed secondary education (“Atheneum”) in 1998, which he followed at “de Heemgaard” in Apeldoorn, the Netherlands. That same year he started the study of Medicine at the “Katholieke Universiteit Nijmegen”, later renamed “Radboud University”, Nijmegen, The Netherlands.

He graduated in June 2006 and started working in the hospital ”de Gelderse Vallei” in Ede, The Netherlands. After a stint in general surgery he started working at the intensive care department. Here he started his first scientific research, which resulted in several publications. In 2007 he moved to Groningen, where he worked at the Neurosurgical intensive care department in the “University Medical Center Groningen” (UMCG), Groningen, The Netherlands.

Later that year he started his residency in Anesthesiology. His 2nd and peripheral year of the residency program was spent at hospital “de Tjongerschans”, Heerenveen, The Netherlands.

From June to December 2012, during his last months of residency, he travelled to Boston, Massachusetts, USA and enrolled in a research fellowship Advanced Echocardiography at “Beth Israel Deaconess Medical Center”, Harvard Medical School, Harvard University, Cambridge, Massachusetts, USA.

After his graduation as Anesthesiologist he started working as fellow of Intensive Care at the UMCG. After finishing his fellowship and graduating to Anesthesiologist-Intensivist he was employed as an Anesthesiologist at the department of Anesthesiology in the UMCG.

In November 2014 he started another fellowship in Cardiac Anesthesia at the UMCG and is currently working as Cardiac Anesthesiologist at this department. During all these years he combined his education with research leading to his promotion.

Remco is married to Kristel, they have a daughter and they live together in the city of Groningen.

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Publications

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Publications

ArticlesDiagnose in beeld (246) Een man met fecale naveluitvloedR. Bergman en C.E.J. Sloots, Medische vignetten NTvG2005; 149(35); 1940

A surprising cause of a spontaneous pleural empyema R. Bergman, D.H.T. Tjan, M.A. Schouten and A.R.H. van ZantenInfection. 2009 Feb; 37(1):56-9.

One Big Burp; R. Bergman, H.K. Jap-A-JoeNeth J Crit Care, volume 10, no 6, December 2006

First therapeutic hypothermia congressR. Bergman, K.H. Polderman, ARH van ZantenNeth J Crit Care, volume 11, no 2, April 2007

Unexpected neurological deterioration following therapeutic hypothermia R. Bergman, D.H.T. Tjan, ARH van Zanten Resuscitation. 2008 Jan;76(1):142-5.

Haemodynamic consequences of mild therapeutic hypothermia after cardiac arrest.R. Bergman, A. Braber, M.A. Adriaanse, R. van Vugt, D.H.T. Tjan, A.R. van Zanten.Eur J Anaesthesiol. 2010 Apr; 27(4):383-7.

Major Surgery, Hemodynamic Instability, and a Left Atrial Appendage Clot: What to Do?R. Bergman, O. Shakil, B. Mahmood, R. Matyal.J Cardiothorac Vasc Anesth. 2012 Nov 2.

Anesthesiologists and Transesophageal Echocardiography: Echocardiographers or Echocardiologists?R. Bergman, F. Mahmood.J Cardiothorac Vasc Anesth. 2012 Nov 2.

AAA in women; is it time to start screening? R. Bergman, R. Matyal SCA bulletin; volume 11, number 6, december 2012

Percutaneous closure of atrial septal defects and 3-dimensional echocardiography-Ingenuity and improvisationH. Kim, R. Bergman, F. MahmoodJ Cardiothorac Vasc Anesth. 2012 Dec 21.

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Publications

Three-dimensional echocardiography and en face views of the aortic valve: technical communication.H. Kim, R. Bergman, R. Matyal, K.R. Khabbaz, F. Mahmood.J Cardiothorac Vasc Anesth. 2013 Apr;27(2):376-80.

Tricuspid annular geometry: a three-dimensional transesophageal echocardiographic study.F. Mahmood, H. Kim, B. Chaudary, R. Bergman, R. Matyal, J. Gerstle, J.H. Gorman 3rd, R.C. Gorman, K.R. Khabbaz.J Cardiothorac Vasc Anesth. 2013 Aug;27(4):639-46.

Impact of aortic valve replacement for aortic stenosis on dynamic mitral annular motion and geometry.H.J. Warraich, R. Matyal, R. Bergman, P.E. Hess, K.R. Khabbaz, W.J. Manning, F. Mahmood.Am J Cardiol. 2013 Nov 1;112(9):1445-9.

Tricuspid valve: an intraoperative echocardiographic perspective.M. Montealegre-Gallegos, R. Bergman, L. Jiang, R. Matyal, B. Mahmood, F. Mahmood.J Cardiothorac Vasc Anesth. 2014 Jun;28(3):761-70.

In-vivo analysis of selectively flexible mitral annuloplasty rings using three-dimensional echocardiography.K. Owais, H. Kim, K.R. Khabbaz, R. Bergman, R. Matyal, R.C. Gorman, J.H. Gorman 3rd, P.E. Hess, F. Mahmood.Ann Thorac Surg. 2014 Jun;97(6):2005-10.

Sutureless management of left ventricle wall rupture; a series of three cases.R. Bergman, J.S. Jainandunsing, B.D. Woltersom, I.J. den Hamer, E. Natour.J Cardiothorac Surg. 2014 Sep 2;9:136.

Ventriculo-atrial defect after bioprosthetic aortic valve replacement.J.S. Jainandunsing, R. Bergman, J. Wilkens, A. Wang, G. Michielon, E. Natour.J Cardiothorac Surg. 2014 Oct 2;9:137.

Erratum: Ventriculo-atrial defect after bioprosthetic aortic valve replacement.J.S. Jainandunsing, R. Bergman, J. Wilkens, A. Wang, G. Michielon, E. Natour.J Cardiothorac Surg. 2015 May 29;10:77.

Long-term outcome of patients after out-of-hospital cardiac arrest in relation to treatment: a single-centre study.R. Bergman, B. Hiemstra, W. Nieuwland, E. Lipsic, A.R. Absalom, J. van der Naalt, F. Zijlstra, I.C.C. van der Horst, M.W.N. Nijsten.Eur Heart J Acute Cardiovasc Care. 2016 Aug;5(4):328-38.

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Publications

Manual Skill Acquisition During Transesophageal Echocardiography Simulator Training of Cardiology Fellows: A Kinematic Assessment.R. Matyal, M. Montealegre-Gallegos, J.D. Mitchell, H. Kim, R. Bergman, K.M. Hawthorne, D. O’Halloran, V. Wong, P.E. Hess, F. Mahmood.J Cardiothorac Vasc Anesth. 2015 Dec;29(6):1504-10.

Imaging skills for transthoracic echocardiography in cardiology fellows: The value of motion metrics.M. Montealegre-Gallegos, F. Mahmood, H. Kim, R. Bergman, J.D. Mitchell, R. Bose, K.M. Hawthorne, T.D. O’Halloran, V. Wong, P.E. Hess, R. Matyal.Ann Card Anaesth. 2016 Apr-Jun;19(2)

TextbooksKlinische anesthesiologie P.G. Noordzij, dr. M. Klimek, A.J. StamerHoofdstuk 12: Luchtwegmanagement R. Bergman, N. Koopmans, B. Molenbuur, J.L.G. Wietasch, G.B. Eindhoven

Klinische anesthesiologie (Revisie)P.G. Noordzij, dr. M. Klimek, A.J. StamerHoofdstuk 13: Luchtwegmanagement R. Bergman, N. Koopmans, B. Molenbuur, J.L.G. Wietasch, G.B. Eindhoven

Probleem georiënteerd denken in het management van de luchtweg Hoofdstuk 1 Systematisch onderzoek van de bovenste luchtweg G. Krenz, R. Bergman, G.B. Eindhoven

iBooksThe Boston Echo course Physics and Hemodynamics WorkshopsContributor

The Boston Echo course Trans Thoracic EchocardiographyEditor

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Publications

International presentationsBoston Echo Course 2012 Guest lecturer

Boston Echo Course 2013 Guest lecturer

Poster presentation SCA Miami 2013A Gerbode like defect after infective endocarditisMetrics as a means of evaluating TEE skills

Poster presentation SCA New Orleans 2014Correlation of vena contracta width with 3D Color Flow Area

Abbreviations

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Abbreviations

AbbreviationsACLS Advanced Cardiac Life Support. AED Automated External Defibrillator.AMI Acute Myocardial Infarction.APACHE Acute Physiology And Chronic Health Evaluation.ATLS Advanced Trauma Life Support.AV AtrioVentricular.CABG Coronary Artery Bypass Grafting.CAG Coronary AngioGraphy. CK Creatine Phosphokinase.CK-MB Creatine Phosphokinase Myocardial Band iso-enzyme. CPB CardioPulmonary Bypass. CPC Cerebral Performance Score. CPCR CardioPulmonary Cerebral Resuscitation. CPR CardioPulmonary Resuscitation. CT Computed Tomography. cTnI Cardiac Troponin I.CT-scan Computed Tomography. ECG ElectroCardioGram. ED Emergency Department.ESC European Society of Cardiology.GCS Glasgow Coma Scale. GOSE Glasgow Outcome Scale Extended .hs-Troponine T high sensitivity Troponine T.ICP Intra-Cranial Pressure.ICU Intensive Care Unit.IHCA In Hospital Cardiac Arrest. (i)RBBB (incomplete) Right Bundle Branch Block.LAFB Left Anterior Fascicular Block. LBBB Left Bundle Branch Block. LVEF Left Ventricular Ejection Fraction. MAP Mean Arterial Pressure. MODS Multiple Organ Dysfunction Syndrome. MTH Mild Therapeutic Hypothermia. NICE National Intensive Care Evaluation.NSTEMI Non ST-Elevated Myocardial Infarction.OHCA Out-of-Hospital-Cardiac-Arrest. PCI Percutaneous Coronary Intervention. PEA Pulseless Electrical Activity. pVT pulseless Ventricular Tachycardia. RBBB Right Bundle Branch Block.ROSC Return Of Spontaneous Circulation. SAH SubArachnoid Haemorrhage. SCD Sudden Cardiac Death. ScVO2 Central venous oxygen saturation.

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Abbreviations

STEMI ST-Elevated Myocardial Infarction. SVO2 Mixed venous oxygen saturation. SVT Supra Ventricular Tachycardia.TBI Traumatic Brain Injury.TIL Therapy Intensity Level.UMCG University Medical Center Groningen.VF Ventricular Fibrillation.VT Ventricular Tachycardia.

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