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Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Appendix

Background: Therapeutic hypothermia (TH) after cardiac arrest protects from neurological sequels and death and is recommended in guidelines. The Hypothermia Registry was founded to the monitor outcome, performance and complications of TH.

Methods: Data on out-of-hospital cardiac arrest (OHCA) patients admitted to intensive care for TH were registered. Hospital survival and long-term outcome (6–12 months) were documented using the Cerebral Performance Category (CPC) scale, CPC 1–2 representing a good outcome and 3–5 a bad outcome.

Results: From October 2004 to October 2008, 986 TH-treated OHCA patients of all causes were included in the registry. Long-term outcome was reported in 975 patients. The median time from arrest to initiation of TH was 90 min (interquartile range, 60–165 min) and time to achieving the target temperature (≤34 °C) was 260 min (178–400 min). Half of the patients underwent coronary angiography and one-third underwent percutaneous coronary intervention (PCI). Higher age, longer time to return of spontaneous circulation, lower Glasgow Coma Scale at admission, unwitnessed arrest and initial rhythm asystole were all predictors of bad outcome, whereas time to initiation of TH and time to reach the goal temperature had no significant association. Bleeding requiring transfusion occurred in 4% of patients, with a significantly higher risk if angiography/PCI was performed (2.8% vs. 6.2%P=0.02).

Conclusions: Half of the patients survived, with >90% having a good neurological function at long-term follow-up. Factors related to the timing of TH had no apparent association to outcome. The incidence of adverse events was acceptable but the risk of bleeding was increased if angiography/PCI was performed.

Mortality after a sudden and unexpected cardiac arrest (CA) is high, and the chance of survival to hospital discharge has, until recently, remained unchanged.1–3 Outcomes after an out-of-hospital cardiac arrest (OHCA) show large differences between regions,2,4 and for patients hospitalised alive, the survival rate has been reported to vary between 34% and 56%.3–6 Further, the incidence of persistent neurological deficits varies considerably.5–9 The post-resuscitation period was previously regarded as the missing link in the chain of survival,10 but this has changed after the publication of two landmark studies,11,12 supporting the use of therapeutic hypothermia (TH) after OHCA. The subsequent publication by the International Liaison Committee on Resuscitation (ILCOR),13 recommending the use of TH after ventricular fibrillation (VF) and OHCA, made it imperative to monitor implementation of TH in clinical practice. Safety issues like infection, coagulopathy, metabolic and electrolyte disorders associated with TH have been poorly studied. There have also been questions about the timing, depth and duration of TH treatment.14 As a consequence, the Hypothermia Network Registry was formed in 2004 for registration of unconscious CA victims admitted to intensive care. The main purpose of this registry was to evaluate the safety aspects, treatment performance and outcome associated with TH in CA patients and to identify key areas for future research. In the present study, we have used registry data to present treatment and outcome data, predictors of outcome and adverse events in TH-treated OHCA patients.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Appendix

Patients

This was a prospective and observational study. The national Data Security Systems within each country approved the registry when required. The Regional Ethical Review Board in Lund, Sweden, approved the study (no. 272/2007). Patients regaining consciousness and/or next of kin were informed about the registration according to the legislation on a national level.

The participating centres reported consecutively all unconscious [Glasgow Coma Scale (GCS)<8] CA patients with return of spontaneous circulation (ROSC) admitted to their intensive care units (ICU). There were no formal exclusion criteria for registration. The centres treated the patients according to their own treatment protocol and any kind of temperature management equipment could be used. Reporting centres were responsible for, and owners of, the data they entered into the registry.

Data set

Data entry regarding patient characteristics, comorbidity, OHCA-related factors and time points followed the Utstein recommendations.15,16 OHCA data were accessed from the ambulance and emergency medical services (EMS) records. Core data on TH treatment, general ICU data, cardiac interventions and adverse events were recorded. Cardiogenic shock was defined as a systolic blood pressure <90 mmHg in spite of inotropics/vasopressors, or the use of an Intra Aortic Balloon Pump (IABP). Serious arrhythmias were defined as ventricular tachycardia (VT), VF, bradycardia <40/min or tachycardia >130/min. Metabolic and electrolyte disorders were defined as sustained hyperglycaemia (>8 mmol/l for>4 h), hypoglycaemia (<3 mmol/l), hypokalaemia (<3.0 mmol/l), hypophosphataemia (<0.7 mmol/l) and hypomagnesaemia (<0.7 mmol/l). Data from a limited number of patients in the registry have already been published in reports from single centres.17,18

Outcome

Outcome was recorded at ICU discharge, at hospital discharge and after 6–12 months, using the Cerebral Performance Category scale (CPC):19 CPC 1 – conscious, no neurological disability; CPC 2 – conscious, moderate neurological disability, can work; CPC 3 – conscious, severe neurological disability, dependent; CPC 4 – coma or vegetative state; and CPC 5 – dead. A CPC of 1–2 was reported as a good outcome and a CPC of 3–5 as a bad outcome. Long-term follow-up was performed by a neurologist, a behavioural therapist, a cardiologist or by the intensive care investigator, either in the outpatient clinic or by a telephone call.

Statistics

Proportions are expressed as percentages and continuous data as medians with interquartile range if not specified else. Continuous and categorical data were compared using the Wilcoxon Mann–Whitney and Fischer's exact test as appropriate. Two-tailed tests of significance were used, and a P-value of <0.05 was considered significant. The best predictive model for outcome at follow-up (dichotomized into good and bad outcome) was obtained using logistic regression with smooth functions, i.e. a generalised additive model.20 A particular covariate was added to the existing model, in an attempt to always include interactions with terms already present, when the largest decrease in the Akaike Information Criterion was achieved.21 To avoid overfitting, the best model was defined as the model with the lowest AIC and fewer parameters than the minimum of patients with a good or a bad outcome, divided by 20.22 Having the best predictive model with the above constraint, each covariate involving TH procedures (time to initiation of TH, time to achievement of the target temperature, time on target temperature, depth and duration of TH treatment and rate of rewarming) was entered one at a time for evaluation of trends. Patients with missing data in any of the selected covariates were excluded. Statistics were calculated using R: A Language and Environment for Statistical Computing ver. 2.8.1 2008 (R Foundation for Statistical Computing, Vienna, Austria) and the mcgv 1.5–0 package.20

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Appendix

From October 2004 to October 2008, 994 adult patients (≥18 years) with OHCA of all causes and treated with TH were entered in the registry, representing 38 centres in seven countries (see Appendix 1). Four centres (eight patients) were excluded due to poor data entry. Hence, 986 patients from 34 centres were included in the final analysis. Forty-five per cent of the centres were university hospitals, registering 73% of the patients. The background characteristics are presented in Tables 1 and 2.

Table 1.  Patient and cardiac arrest characteristics.
 n=986
  1. Age (years) is presented as median (inter quartile range)

  2. All other data are presented as absolute numbers (percentage)

  3. CPR, cardiopulmonary resuscitation; IDDM, insulin-dependent diabetes mellitus; NIDDM, non-insulin-dependent diabetes mellitus; PEA, pulseless electrical activity; TH, therapeutic hypothermia; VT/VF, ventricular tachycardia/ventricular fibrillation.

Age63 (53–73)
Male sex733 (74)
Out-of-hospital cardiac arrest986 (100)
Cardiac cause of arrest817 (83)
Witnessed arrest850(86)
Bystander CPR614 (62)
Asystole217 (22)
PEA66 (7)
VT/VF686(70)
Previously healthy226 (23)
Coronary disease351 (36)
Congestive heart failure196 (20)
IDDM67 (7)
NIDDM67 (7)
Renal impairment46 (5)
Neurological disease103 (10)
Hepatic disease19 (2)
Pulmonary disease125 (13)
Malignancy51 (5)
Hypertension307 (31)
Alcohol/drug abuse113 (11)
Table 2.  Cardiac arrest and TH time point characteristics.
 n=986
  1. Data (minutes) presented as median and interquartile range

  2. CPR, cardiopulmonary resuscitation; EMS, emergency medical services; ROSC, return of spontaneous circulation; TH, therapeutic hypothermia.

Emergency call to arrival of EMS team6 (4–10)
Cardiac arrest to start of CPR7 (5–11)
Cardiac arrest to defibrillation9 (6–14)
Cardiac arrest to ROSC20 (14–30)
Cardiac arrest to initiation of hypothermia90 (60–165)
Cardiac arrest to goal temperature (<34°C)260 (178–400)

Outcome at ICU, hospital discharge and at long-term follow-up

At ICU discharge, 676 patients (69%) were alive, of whom 401 (41%) had a good outcome. At hospital discharge, 556 patients (56%) were alive, 434 (44%) with a good outcome.

Long-term follow-up was reported in 975 of the 986 patients (99%); 490 patients (50%) were alive, 447 (46%) with a good outcome. Thus, 91% of the survivors had a good outcome. Among the 43 patients alive with a bad outcome at long-term follow-up, 39 had CPC 3 and four had CPC 4. Patients discharged alive from the ICU who died during follow-up had a median time from CA to death of 1 week (1–3). Outcomes related to initial rhythms are presented in Fig. 1. In 293 patients, time to ROSC exceeded 25 min (range 25–240 min), with an overall good outcome of 23% at long-term follow-up.

image

Figure 1.  Utstein template of the 986 out-of-hospital cardiac arrests (OHCA) included in the study divided into initial rhythm of ventricular tachycardia/ventricular fibrillation (VT/VF), asystole, Pulseless Electrical Activity (PEA) and unknown rhythm. Survival and good outcome rates (Cerebral Performance Category 1 or 2) are presented as numbers and percentages at intensive cars unit (ICU) discharge, at hospital discharge and at long-term follow-up.

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Treatment data

The median ICU length-of-stay was 100 h (65–165). Inotropes and/or vasopressors were administered to 764 patients (77%). Renal replacement therapy was used in 38 patients (4%).

The initial temperature on admission was 35.9 °C (35.1–36.5 °C). Time to initiation of TH was 90 min (60–165 min) and to achievement of the target temperature (≤34 °C) was 260 min (178–400 min) (Table 2). Methods for TH are presented in Table 3. Combinations of methods were common. All centres used 32–34 °C as the target temperature and 814 patients (85%) were treated at 33 °C. TH was maintained for 12, 24 and 48 h in 53 patients (5%), 896 patients (93%) and 15 patients (2%), respectively. The duration of rewarming ranged from 4 h (6% of the patients) to 12 h or more (14%). Six hours was used in 41%, 8 h in 32% and 10 h in 7% of the patients.

Table 3.  Techniques for initiating and maintaining hypothermia.
 Initiation of THMaintenance of TH
  1. Data presented as absolute numbers and percentages.

  2. TH, therapeutic hypothermia.

Ice-packs420 (43)171 (17)
Cold fluid infusion788 (80)N/A
Air cooling93 (9)78 (8)
Circulating water blankets460 (47)625 (63)
Intravascular device98 (10)157 (16)
Other61 (6)78 (8)

Cardiac interventions and cardiogenic shock

Acute myocardial infarction was present in 617 patients (63%). Among the 479 patients (49%) who underwent emergency coronary angiography, 303 (63%) survived, of whom 278 (58%) had a good outcome at long-term follow-up. Percutaneous coronary intervention (PCI) was performed in 299 patients (62% of those who underwent coronary angiography), with 197 survivors (66%), 180 survivors (60%) with a good outcome. Few patients received thrombolysis or coronary artery bypass grafting (Table 4).

Table 4.  Coronary interventions, AMI and cardiogenic shock.
 n=986
  1. Data presented as absolute numbers and percentages.

  2. AMI, acute myocardial infarction; CABG, coronary artery bypass grafting; IABP, intra-aortic balloon pump; PCI, percutaneous coronary intervention; TH, therapeutic Hypothermia.

Emergency angiography479 (49)
PCI299 (30)
Thrombolysis54 (5)
CABG13 (1)
AMI617 (63)
Cardiogenic shock176 (18)
IABP123 (12)

The 176 patients (18%) with cardiogenic shock at ICU admittance had an overall lower chance of a good outcome than patients who were not in shock in a univariate comparison (39% vs. 47%, respectively, P<0.049), but shock was not a predictor in the final multivariate model. Among survivors, there was no difference in good outcome if cardiogenic shock was present or not (87% vs. 92%, respectively, P=0.26).

Predictors of outcome

The best model of prediction revealed increased time to ROSC (P<0.0001) (Fig. 2), higher age (P<0.0001) (Fig. 3), low GCS at admittance (P=0.0002) and unwitnessed arrest (P=0.0001) as predictors of a bad outcome. There was an interaction between the initial rhythm and coronary angiography (χ2=12.4, df=2, P=0.002). VT/VF as the initial rhythm was predictive of a favourable outcome if coronary angiography was performed (P=0.0008), whereas asystole was only predictive for a bad outcome if coronary angiography was not performed (P=0.0007) (Table 5). Neither time to initiation of TH (P=0.48), time to achievement of target temperature (P=0.91), depth of TH (P=0.50), duration of TH (P=0.19) nor rewarming time to normothermia (P=0.73) had an association with outcome.

image

Figure 2.  Odds ratios for a good outcome at follow-up, related to time to return of spontaneous circulation (ROSC) in minutes with 95% confidence intervals. (χ2=68.5, df=4.72, P<0.0001), 16 observations in the model had times longer than 60 min (not shown).

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image

Figure 3.  Odds ratios for a good outcome at follow-up, related to age in years with 95% confidence intervals. (χ2=56.6, df=1.58, P<0.0001).

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Table 5.  Odds ratios for non-continuous predictors of outcome.
 ORCIP-value
  1. CI, confidence interval; OR, odds ratio; VT/VF, ventricular tachycardia/ventricular fibrillation.

VT/VF with angiography1.561.20–2.020.0008
Asystole without angiography0.190.07–0.500.0007
Unwitnessed arrest0.300.16–0.550.0001

Adverse events

Adverse events and complications are presented in Table 6. Severe arrhythmias were present in 33% of the patients and pneumonia was the most frequent infection (41%). Bleeding requiring transfusion occurred in 4% of all patients and the risk was significantly higher if angiography/PCI was performed (2.8% vs. 6.2%, respectively, P=0.02). Hypokalaemia, hypomagnesaemia and hypophosphataemia were present in approximately 20% of the patients.

Table 6.  (a) Adverse events: all 34 centres and (b) adverse events: 22 reporting centers.
 n=986
(a)
Bradycardia <40 beats/min127 (13)
Tachycardia >130 beats/min57 (6)
Atrial fibrillation88 (9)
VT89 (9)
VF71 (7)
Any combination of arrhythmia325 (33)
Pneumonia407(41)
Sepsis35 (4)
Other infection41 (4)
Bleeding requiring transfusion44 (4)
Intracerebral bleeding2 (0.2)
Seizures233 (24)
 n=760
  1. Data presented as absolute numbers and percentages.

  2. TH, therapeutic hypothermia; VT, ventricular tachycardia; VF, ventricular fibrillation.

(b)
Hypoglycaemia <3 mmol/l42 (6)
Sustained hyperglycaemia >8 mmol/l>4 h278 (37)
Hypokalaemia (<3.0 mmol/l)133 (18)
Hypomagnesaemia (<0.7 mmol/l)132 (18)
Hypophosphataemia (<0.7 mmol/l)143 (19)

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Appendix

In this registry study, we have evaluated the outcome, treatment performance and safety aspects related to TH in a large OHCA population admitted to intensive care. Half of the patients survived, >90% with a good neurological function. Higher age, longer time to ROSC, lower GCS at admission, unwitnessed arrest and initial rhythm asystole were all predictive factors for a bad outcome at follow-up, whereas we found no significant relation between the timing of TH and outcome. The overall incidence of adverse events was acceptable compared with previous findings, but the risk of bleeding was increased if coronary angiography/PCI was performed.

After the ILCOR recommendations from 2003,13 two meta-analyses,23,24 several single centre reports, retrospective analyses17,25–30 and two registry-based publications31,32 have reported outcome in TH-treated CA patients, all comparable with our findings. In the ERC-HACA registry, also including patients with in-hospital CA, the number of patients with severe neurological disability (CPC 3 and 4) was much higher at outcome evaluation, compared with our data (36% vs. 4%, respectively).31 There may be several reasons for this, one being the difference in the follow-up time (hospital discharge vs. 6–12 months in the present study). The majority of the comatose patients discharged from hospital in the present study died within a few weeks. One important finding in our study is that TH does not appear to be associated with making a large group of patients vegetative, with only four patients in coma at follow-up.

None of the factors directly related to TH treatment were significantly associated with outcome. However, the target temperature and the duration of TH had a very concentrated distribution, with the majority of the patients treated for 24 h at 33 °C, which limits the interpretation. The benefits from early TH shown in animal studies33,34 and a recent observational human study35 could not be confirmed by us. This should not be interpreted as it is equally good to delay the start of TH treatment, cool slower or rewarm faster, but it certainly indicates that factors other than timing may be more important for the final outcome. Previous animal experiments have shown that a delayed start of cooling is still effective in mitigating neuronal damage.36 This is consistent with the present results, but also with the HACA study, where the target temperature was reached at a median of 8 h.11 We could not show any harm or benefit related to the rate of rewarming; 80% of the patients were rewarmed between 6 and 10 h. Other reports, however, indicate that a slow rewarming should be advocated.37,38

Because the reperfusion injury develops over days after ROSC,39 the duration and depth of TH should probably be given priority in future studies.

There is an increasing use of emergency coronary angiography and revascularisation with PCI in unconscious patients post CA.25,27,28,30 In the present study, 49% of the patients received emergency coronary angiography, and 30% subsequent PCI. Most centres combine early PCI with early initiation of TH, which also has been shown to be feasible without delaying the door-to-balloon time.40 Further, 18% of our patients were in cardiogenic shock, receiving inotropic drugs, vasopressors and/or IABP. Patients with cardiogenic shock had a lower survival rate than those who were not in shock, but survivors had comparable CPC scores. This is in line with recent reports17,28,29,41 supporting the statement that cardiogenic shock should not disqualify for active treatment.

Most centres in the registry treat CA patients with TH irrespective of initial rhythm if active treatment is decided. Although TH has not been proven to be beneficial for non-VF patients, ILCOR stated in 2003 that: ‘for any other rhythm, or cardiac arrest in hospital, such cooling may also be beneficial’.13 In the present study, 29% of the patients had an initial rhythm of asystole or PEA, with an overall long-term survival with a good outcome of 22%, which is better than what was reported from the pre-TH era.3,5,8 Resuscitated patients remaining in coma suffer from an ischaemic–reperfusion brain injury, referred to as the post-CA syndrome.42 This injury ought to be dependent on the cause of the arrest, anoxia time and quality of CPR, rather than the nature of the initial rhythm, and it is therefore reasonable to offer TH to non-VF patients as well, in spite of the more pessimistic prognosis.43

The outcome for patients with time to ROSC >30 min is dismal.44 In a recent study with TH-treated OHCA patients,45 there were no survivors with a good outcome if time to ROSC exceeded 25 min. This is contrasted by our results, where survival with a good outcome remained at 23% when time to ROSC exceeded 25 min. Even if a longer time to ROSC was a predictive factor for a bad outcome, the absolute numbers demonstrate that it could not be utilised as a sole predictor of outcome because other factors like the quality of CPR may be equally important.

Bleeding related to TH has not been identified as a clinical problem.11,25,29–31 Consistent with these reports, we found an overall low risk of bleeding. However, there was an increased risk if coronary angiography with or without PCI was performed. CA per se affects coagulation,46 and hypothermia may, depending on the depth and duration, also induce coagulopathy.39 Moreover, patients receive heparin before coronary angiography and platelet inhibitors in association with PCI. All these factors combined may explain the increased risk of bleeding requiring transfusion when an invasive procedure is performed. Further, we did not control for confounding factors such as transfusion triggers or the concurrent use of volume therapy.

Arrhythmia is common in the post-resuscitation period4 and is inherently related to the nature of the underlying disease. In our material, one third of the patients had arrhythmias, which is comparable to both the intervention and the control group in the HACA study.11

We report 41% of the patients diagnosed with pneumonia, again comparable with previous findings,11,29,31 but also with cardiac-arrested patients not treated with TH47 and with patients comatose due to other causes.48

Electrolyte disorders were common, as hypothermia induced electrolyte shifts and a tubular dysfunction, leading to increased diuresis with subsequent losses.49 Because these disorders are easily preventable, frequent control of serum levels is recommended during TH treatment.

This study has the limitations of an observational and descriptive registry. All patients may not have been reported. Furthermore, the background material of OHCA patients in the EMS and Emergency Department setting is unknown. The majority of the patients were from university hospitals, indicating a selection bias because some are referral centres for coronary angiography and cardiac interventions. However, the inclusion of patients has been prospective and the centres have been urged to report all consecutive patients treated in their ICUs. The patient population was similar to previous reports on OHCA cohorts,3,5 indicating that our data were representative. This is, until now, the largest material presented in an OHCA population after the implementation of TH, with an almost 100% long-term follow-up rate. Even though 70% of the patients were from university hospitals, more than half of the registering centres were non-university clinics, indicating that our material represents a cross section of ICUs and may well represent the current state of the art in the participating countries.

Conclusion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Appendix

Half of the patients survived, with >90% having a good neurological function at long-term follow-up. Factors related to the timing of TH had no apparent association to outcome. The incidence of adverse events was acceptable but the risk of bleeding was increased if coronary angiography/PCI was performed.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Appendix

The Scandinavian Critical Care Trials Group and the Scandinavian Society of Anaesthesiology and Intensive Care, the Stig and Ragna Gorthon Foundation, the Torsten Birger Segerfalk Foundation, Region Skåne and the governmental funding of clinical research within the Swedish National Health Service (ALF) supported this study.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Appendix
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Appendix

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Appendix

Appendix 1: Members of the hypothermia network

Hospital, City (local investigator, patients enrolled)

Denmark: Rigshospitalet, Copenhagen (M. Wanscher, 57); Aarhus University Hospital, Aarhus (H.M. Betsch, 17); Germany: Charite Campus Virchow, Berlin (D. Hasper, 11); Evangelisches Krankenhaus, Bonn (M. Födisch, 10); Iceland: Landspitali University Hospital (F. Valsson, 63); Luxembourg: Centre Hospitalier de Luxembourg, Luxembourg (P. Stammet, 57); Norway: Buskerud Hospital, Drammen (S. Balsliemke, 7); Rikshospitalet, Oslo (J. Hovdenes, 82); Ullevål University Hospital (T. Draegni, 113); Sweden: Academic Hospital, Uppsala (S. Rubertsson, 47); Danderyd Hospital, Stockholm (E. Oddby, J Lindahl, 20); Falu Hospital, Falun (P. Guldbrand, M. Sellert-Ryding, 33); Halmstad Hospital, Halmstad (J. Undén, 19); Helsingborg Hospital, Helsingborg (N. Nielsen, 35); Jönköping Hospital, Jönköping (K. Johansson, 11); Centralsjukhuset, Karlstad (K. Edqvist, 26); Karlskrona Hospital, Karlskrona (S. Juhl-Andersen, 11); Karolinska Hospital, Solna, Sweden (Å. Bengtsson, 8); Kungälv Hospital, Kungälv, Sweden (R. Zätterman, 1); Lidköping Hospital, Lidköping (I. Lindström, 17); Lund University Hospital, Lund (M. Rundgren, 105); Malmö University Hospital, Malmö (T. Karlsson, 35); Mälarsjukhuset, Eskilstuna (A. Lifbom, 8); Vrinnevi Hospital, Norra Älvsborgs Läns sjukhus, Trollhättan-Vänersborg, Sweden (Andreas G. larsson, 1); Norrköping (R. Svensson, 6); Örebro University Hospital, Örebro (S. Persson, 18); Östersund Hospital, Östersund (M. Schindele, 12); PiteåÄlvdal Hospital, Piteå (K. Lindgren, 2); Kärnsjukhuset, Skövde (B. Gardell, A. Paulsson, 26); Södersjukhuset, Stockholm (S. Forsberg, 13); Sahlgrenska University Hospital, Östra, Göteborg (R. Sarbinowski, 23); Värnamo Hospital, Värnamo (A. Dynebrink, 3); Ystad Hospital, Ystad (U. Hyddmark, 11); United States of America: Maine Medical Center, Maine (R. Riker, D. Sedar, 78)