Acta Anaesthesiol Scand 2014; 58: 620–629 Printed in Singapore. All rights reserved

© 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd ACTA ANAESTHESIOLOGICA SCANDINAVICA

doi: 10.1111/aas.12293

Adrenaline increases blood-brain-barrier permeability after haemorrhagic cardiac arrest in immature pigs E. Semenas, H. S. Sharma and L. Wiklund Department of Surgical Sciences/Anaesthesiology and Intensive Care, Faculty of Medicine, Uppsala University, Uppsala, Sweden

Background: Adrenaline (ADR) and vasopressin (VAS) are used as vasopressors during cardiopulmonary resuscitation. Data regarding their effects on blood–brain barrier (BBB) integrity and neuronal damage are lacking. We hypothesised that VAS given during cardiopulmonary resuscitation (CPR) after haemorrhagic circulatory arrest will preserve BBB integrity better than ADR. Methods: Twenty-one anaesthetised sexually immature male piglets (with a weight of 24.3 ± 1.3 kg) were bled 35% via femoral artery to a mean arterial blood pressure of 25 mmHg in the period of 15 min. Afterwards, the piglets were subjected to 8 min of untreated ventricular fibrillation followed by 15 min of open-chest CPR. At 9 min of circulatory arrest, piglets received amiodarone 1.0 mg/kg and hypertonic-hyperoncotic solution 4 ml/kg infusions for 20 min. At the same time, VAS 0.4 U/kg was given intravenously to the VAS group (n = 9) while the ADR group received ADR 20 μg/kg (n = 12). Internal defibrillation was attempted from 11 min of cardiac arrest to achieve restora-


esuscitation of trauma patients after severe haemorrhage that leads to a cardiac arrest (CA) is a clinical challenge1 and remains a major cause of death.2,3 Using a pig model of exsanguinations CA, our group has recently reported that female sex protects against cerebral and cardiac injury.4,5 In our previous studies, we used vasopressin (VAS) as the primary drug and adrenaline (ADR) as a rescue drug. However, current guidelines for the treatment of CA from ventricular fibrillation (VF) recommend administration of ADR after the third defibrillation attempt.6 We have previously provided histopathological evidence of blood–brain barrier (BBB) disruption as soon as 5 min after untreated CA in a porcine model.7,8 However, some studies indicated that immature animals might be more prone to a delayed increase in BBB permeability after CA and cardiopulmonary resuscitation (CPR)9 while other animal studies showed a biphasic nature of BBB disruptions.10

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tion of spontaneous circulation. The experiment was terminated 3 h after resuscitation. Results: The intracranial pressure (ICP) in the postresuscitation phase was significantly greater in ADR group than in VAS group. VAS group piglets exhibited a significantly smaller BBB disruption compared with ADR group. Cerebral pressure reactivity index showed that cerebral blood flow autoregulation was also better preserved in VAS group. Conclusions: Resuscitation with ADR as compared with VAS after haemorrhagic circulatory arrest increased the ICP and impaired cerebrovascular autoregulation more profoundly, as well as exerted an increased BBB disruption though no significant difference in neuronal injury was observed. Accepted for publication 29 January 2014 © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd

Thus, despite extensive experimental and clinical data about vasopressor effects during normovolaemic CA, there is a knowledge gap regarding vasopressor effects on BBB permeability and the neuronal damage after haemorrhagic CA in immature piglets. The current study was designed to evaluate whether resuscitation with ADR, compared with VAS, would have an impact on cerebral haemodynamic parameters, blood–brain permeability and the neuronal damage after haemorrhagic CA.

Methods The Regional Animal Review Board of Uppsala, Sweden, approved the experimental protocol (Institutional number: C13/9).

Animals Twenty-one immature male piglets ageing 11–16 weeks with a mean weight of 24.3 ± 1.3 kg were

Adrenaline after hypovolemic cardiac arrest

used in the study. All animals were kept fasting with unrestricted access to water during the night before the experiment. The piglets were randomised into groups by means of sealed envelopes.

Anaesthesia and fluid administration General anaesthesia was induced with an intramuscular injection of 6 mg/kg·tiletamine-zolazepam mixed with 2.2 mg/kg xylazine and 0.04 mg/kg atropine, and an intravenous injection of 20 mg morphine and 100 mg ketamine. Anaesthesia was maintained with intravenous infusions of pentobarbital at 8 mg/kg/h, pancuronium bromide at 0.25 mg/ kg/h and morphine at 0.5 mg/kg/h. Pancuronium was added to the regimen only after a stable surgical level of anaesthesia was achieved. The piglets were tracheotomised and mechanically ventilated with 30% oxygen at 25 breaths/min. Tidal volume was adjusted to yield arterial PaCO2 between 5.0 and 5.5 kPa. Fluid losses were compensated by infusion of 30 ml/kg·of acetated Ringer’s solution during the first hour of preparation, followed by a continuous infusion of 2.5% glucose-electrolytes solution 8 ml/ kg/h and acetated Ringer’s solution 10 ml/kg/h.

Surgical preparation A laser Doppler flowmetry probe (MT B500-43, Periflux PF 2B Laser-Doppler Flowmeter, Perimed, Stockholm, Sweden) was inserted through a 10-mm burr hole between the occipito-parietal and coronal sutures for continuous monitoring of cerebral blood flow. A Camino intracranial pressure (ICP) sensor (Camino Laboratories, San Diego, CA, USA) was inserted through a 3-mm burr hole opposite the laser Doppler flowmetry probe placement into the subarachnoid space for the continuous measurement of the ICP. An 18-gauge arterial catheter was advanced into the aortic arch via a branch of the right external carotid artery. A 14-gauge central venous catheter was inserted through the right external jugular vein. A 7 Fr Swan-Ganz catheter (Edwards Lifesciences, Irvine, CA, USA) was inserted into the pulmonary artery. The left internal jugular vein was cannulated and an 18-gauge catheter was advanced in the cephalad direction for blood sampling. The catheter position was confirmed by fluoroscopy. A 14-gauge catheter was inserted to the right femoral artery for blood withdrawal. A median sternotomy was performed for open-chest CPR.

Measurements and samples Haemodynamic parameters, including lead II and V5 electrocardiogram recordings, heart rate, sys-

temic arterial blood pressure, right atrial pressure and pulmonary artery pressure were monitored (Solar 8000 monitor, Marquette Medical System, Milwaukee, WI, USA) and recorded. Cardiac output was measured using a thermodilution technique. Coronary perfusion pressure was calculated as the difference between diastolic aortic pressure and the simultaneously measured right atrial pressure. Cerebral cortical blood flow was recorded every 5 s by a computer and presented as a fraction of the steadystate baseline flow. Haemodynamic variables, temperature and laser Doppler flow measurements and ICP measurements were recorded at baseline, after haemorrhage and once every minute during CPR, 5, 15, 30, 60, 120 and 180 min after restoration of spontaneous circulation (ROSC). Samples of arterial and internal jugular venous blood were taken for blood gas analysis and acid-base balance (ABL 300, Radiometer, Copenhagen, Denmark) at baseline, after haemorrhage and 5, 15, 30, 60, 120 and 180 min after ROSC. The cerebral pressure reactivity index was calculated as a correlation coefficient between mean arterial pressure and ICP averaged over 5–10 s.11 Coefficients were recorded at baseline, after haemorrhage and 5, 15, 30, 60, 120 and 180 min after ROSC. Cerebral perfusion pressure was calculated as the difference between mean arterial blood pressure and ICP. Cerebral oxygen extraction ratio was calculated as the ratio of arterial-jugular bulb oxygen content difference to arterial oxygen content [(CaO2 − CjO2)/CaO2]. The arterial blood and jugular venous blood samples were used to determine troponin I, protein S-100β, 8-iso-dihydroPGF2α and 15-keto-dihydro-PGF2α levels at baseline, 30, 60, 120 and 180 min after ROSC. Analytical methods for these compounds had been published earlier.12,13 Plasma glucose, lactate and electrolyte concentrations were determined (ABL 700, Radiometer) at baseline, 120 and 180 min after ROSC.

Experimental protocol (Table 1) After preparation, piglets were allowed to stabilise for 1 h, after which baseline measurements were made. Heparin (60 IU/kg) was injected intravenously, and haemorrhage was started from the catheter in the femoral artery. Blood was collected in 450-ml bags (Baxter Healthcare Corporation, Deerfield, IL, USA) containing the citrate-phosphatedextrose anticoagulant solution for a subsequent retransfusion. The speed of haemorrhage was controlled by adjusting the blood flow through the femoral catheter. Bleeding was stopped when a mean arterial blood pressure of 25 mmHg was reached.14


E. Semenas et al. Table 1 Experimental protocol. Time/duration


Preparation and stabilisation periods Anaesthesia, tracheotomy 1h Haemorrhage period 15–20 min Circulatory arrest period 0 min 0–8 min VF 0 1 min CPR

3 min CPR CPR up to 15 min

Arterial and venous cannulation Stabilisation

Drug administration Xylazine, atropine, tiletamine and zolazepam, morphine, ketamine Pentobarbital + morphine + pancuronium 30% oxygen in air

Baseline parameters before exsanguination Haemorrhage Heparine, 60 IU/kg Post-haemorrhagic measurements AC electric shock Increase oxygen concentration No intervention Start CPR Continue CPR

Direct DC shock, 20 J Advanced life support Direct DC shock, 40 J

Post-resuscitation period 0 ROSC Blood pressure control 5 min after ROSC Decrease oxygen concentration 20 min after the start of infusions Stop administration of HSD Administration of remaining blood 180 min after ROSC Completion of experiment

100% oxygen Both groups: Amiodarone 1.0 mg/kg HSD 4 ml/kg for 20 min Vasopressin group (n = 9): vasopressin, 0.4 units/kg Adrenaline group (n = 12): adrenaline, 20 μg/kg If needed: Vasopressin group: vasopressin, 0.4 units/kg Adrenaline group: adrenaline, 20 μg/kg Dobutamine, if SBP < 70 mmHg 30% oxygen in air Vasopressin and adrenaline groups: stop HSD infusion and remaining blood for 1 h KCl, 20 mmol

CPR, cardiopulmonary resuscitation (open-chest CPR performed by the same investigator); DC, defibrillatory chocks; HSD, hypertonic saline (7.5%)-dextran (6%) solution; ROSC, restoration of spontaneous circulation; SBP, systolic blood pressure; VF, ventricular fibrillation.

VF was induced in all animals after 5 min with a 50 Hz, 20–40V transthoracic alternating current application via two subcutaneous needles placed on both sides of thorax. FiO2 of 1.0 was delivered during both the CA and CPR. After 8 min of circulatory arrest, open-chest CPR was started with a compression rate of 60–80 per minute as it is almost impossible to have higher compression rate than 80 per minute and not to damage myocardium while handling heart (ES). After 1 min of CPR, VAS group piglets (n = 9) received 0.4 units/kg of VAS (Arg8vasopresin, PolyPeptide Laboratories, Wolfenbuttel, Germany), whereas ADR group piglets (n = 12) received ADR 20 μg/kg via the right atrial catheter.15,16 At the same time, all piglets received 1 mg/kg amiodarone and 4 ml/kg hypertonic saline (7.5%) with dextran (HSD) solution (RescueFlow®, Biophausia, Uppsala, Sweden), infused through the right atrial catheter over 20 min. In previous hypovolaemic 4 min CA study, 0.5 mg/kg amiodarone dose was given,17 but in the current study in order to increase defibrillation success and to avoid


negative inotropic effect, a dose of 1 mg/kg amiodarone was arbitrarily chosen. After 3 min of CPR, an internal monophasic counter-shock was delivered at the energy level of 20 J (Medtronic Physio-Control, Seattle, WA, USA). Subsequent defibrillatory shocks were increased to 40 J. If ROSC was not achieved after six shocks, a 20-μg/kg bolus of ADR (ADR group) or 0.4 units/kg VAS (VAS group) was administered through the right atrial catheter. CPR was continued up to 15 min. ROSC was defined as the return of coordinated electrical activity resulting in a pulsatile cardiac rhythm with a systolic blood pressure of > 60 mmHg for at least 10 consecutive minutes. Five minutes after ROSC, FiO2 was reset at 0.3. Twenty-three minutes after CA, infusion of HSD was stopped, and the exsanguinated blood was given over 1 h. Dobutamine was administered to maintain systolic blood pressure of > 70 mmHg. Three hours after ROSC, piglets received a lethal intravenous injection of potassium chloride. Within 5 min after death, the skull was opened in prone position in all

Adrenaline after hypovolemic cardiac arrest Table 2 Haemorrhage volume and time, and number of defibrillatory shocks and duration of cardiopulmonary resuscitation (CPR). Study group

Total number of animals

Duration of haemorrhage (min) until mean arterial pressure of 25 mmHg was reached

Bleeding volume (% of calculated total blood volume)

Number of defibrillatory shocks (DC)

Duration of CPR (min)

Number of animals receiving a second dose of adrenaline or vasopressin during CPR

Adrenaline Vasopressin

12 9

15.8 ± 2.1 15.4 ± 01.3

35.61 ± 4.04 34.97 ± 5.04

4 (1–6) 9 (2–11)

8 (4–15) 5.4 (3.5–9)

7 3

Haemorrhage volume and time data are presented as mean ± standard deviation (SD). Number of defibrillatory chocks (DC) and duration of CPR are presented as means (range, minimum – maximum).

animals, and the brain was taken out for the histopathological analysis. Immunohistochemistry and histology. Both brain hemispheres were immersed in 4% buffered formalin and stored at 4°C for 1 week before small tissue pieces (< 3 × 5 mm) from the parietal-temporal cerebral cortex were cut. The tissue pieces were embedded in paraffin according to a standard protocol.18 Multiple sections, approximately 3–5-μm thick, were cut from cerebral cortex and stained using a commercial protocol.18 Immunohistochemistry for albumin was performed using a sheep polyclonal antirat albumin antibody (Sigma, Sigma-Aldrich, St. Louis, MO, USA) and the streptavidin horseradish peroxidase biotin technique.7,19 Three-micrometer paraffin sections from identical tissue blocks from the cerebral cortex were cut and stained with haematoxylin and eosin or Nissl for light microscopy to analyse cellular changes. The number of distorted neurons in one whole section and albumin-positive cells were counted by the same investigator (H. S. S.) in one identical area of the cortex from each animal at least for three times and in a blinded fashion in order to determine leakage of BBB7,19 and neuronal injuries. The median value was used for the final calculation. Immunohistochemistry of nitric oxide synthase (NOS). Immuonostaining was performed on 3-μm thick paraffin sections using a monoclonal NOS antiserum as described earlier.20,21 The antibodies of inducible and neuronal NOSs (iNOS and nNOS, respectively) were diluted 1 : 5000 and applied for 48 h with a continuous shaking at room temperature. The immune reaction was developed using a peroxidase-antiperoxidase technique and visualised at light microscopes. The number of nNOS- and iNOS-positive cells in each group was counted in a blind fashion (H. S. S.).

Statistical analysis The following statistical software was used: StatView for Windows, SAS Institute Inc., version 5, Cary, NC, USA. We planned to have at least nine animals, which achieve ROSC and survive until the end of the study. From the previous studies, we knew that approximately 25% of animals do not achieve ROSC or survive the whole experiment; thus, we intended to have 12 animals in each group. All data are presented as a mean ± standard error of the mean. After the data were shown to be normally distributed, parameters were analysed with two-way repeated measures analyses of variance (ANOVAs). If significant groups’ effects were observed, the specific differences between groups were determined with one-way ANOVA and a Bonferroni–Dunn post hoc test. Cerebral cortical blood flow, histological and immunohistochemical data were analysed using Mann–Whitney test.

Results Resuscitability and survival No significant group differences were observed in the CPR duration, the number of defibrillatory shocks needed to achieve ROSC, bleeding time or haemorrhage (Table 2). ROSC was achieved in 9 of 9 piglets in VAS group and 9 of 12 piglets in ADR group. All resuscitated piglets survived until the end of the experiment.

Haemodynamic variables After ROSC, all piglets required dobutamine in order to maintain systolic blood pressure according to the protocol. No significant group differences were observed in dobutamine requirement or its dose. Heart rate was higher (P = 0.03) in the ADR group as compared with the VAS group (Fig. 1). In the VAS group, systolic blood pressure, diastolic blood pres-


E. Semenas et al.

Jugular venous 8-iso-PGF2α and 15-keto-dihydroPGF2α values were not significantly different (data not shown). Systemic and jugular bulb acid-base status. Jugular bulb pH and base excess was higher in the ADR group 15 and 30 min (P = 0.0003 and P = 0.0002) after ROSC in comparison with the VAS group (P = 0.02 and P = 0.001).

Electrolytes, lactate, glucose, temperature and myocardial injury No significant differences were observed between groups regarding plasma lactate, potassium, sodium, glucose concentrations, body temperature or troponin I (data not shown).

Fig. 1. Haemodynamic variables: heart rate and mean arterial blood pressure (MABP) at baseline, during cardiopulmonary resuscitation (CPR) and after restoration of spontaneous circulation (ROSC). Data provided as a mean ± standard error of the mean (SEM). Adrenaline group (ADR), n = 12; vasopressin group (VAS), n = 9. # denotes significant difference between VAS and ADR groups [two-way repeated measures analyses of variance (ANOVA), P = 0.03]. * denotes significant difference between the ADR and VAS groups (one-way ANOVA, P < 0.05, for MABP). VF, ventricular fibrillation.

sure, mean arterial blood pressure (Fig. 1) and coronary perfusion pressure were greater at 5 min (P = 0.04, P = 0.01, P = 0.03 and P = 0.02, respectively) after ROSC as compared with ADR group animals.

ICP, cerebral perfusion pressure, cerebral cortical blood flow and cerebral oxygen extraction ratio (Fig. 2), protein S-100β and cerebral pressure reactivity No significant differences were observed between groups regarding the cerebral cortical blood flow or protein S-100β levels. ICP after ROSC was higher (P = 0.003) in the ADR group as compared with the VAS group. In the VAS group, cerebral perfusion pressure was higher 5 and 15 min (P = 0.006 and P = 0.02), and oxygen extraction ratio was greater at 15 and 30 min (P = 0.03 and P = 0.003) after ROSC in comparison with ADR group. The cerebral pressure reactivity index was lower in the VAS group than in the ADR group (P = 0.002) (Table 3).


Neuronal injury and albumin reactivity. No differences were observed in the number of distorted neurons between groups (P = 0.2). Albumin reactivity was higher in the ADR group as compared with the VAS group (P = 0.009) (Fig. 3). iNOS and nNOS. There was a greater activation of nNOS in the ADR group as compared with the VAS group (P = 0.04). No differences were observed in iNOS activation between the groups (P = 0.38) (Fig. 4).

Discussion Using a clinically relevant model of severe haemorrhage and circulatory arrest, the study demonstrated that resuscitation with ADR resulted in a significantly impaired cerebral autoregulation, increased ICP and BBB disruption in immature piglets. Specifically, albumin permeability and nNOS expression in cerebral cortex was markedly more pronounced in the ADR group while no differences were observed in the histological cerebral injury following 3-h observation period between the groups. Systemic hypertension that occurs immediately after the successful CPR increases the cerebral blood flow.7,22 At the same time, cerebrovascular autoregulation is a vital initial cerebral adaptation to changes in the systemic haemodynamics, and a poor autoregulation correlates with worse outcomes in trauma.23 In the current study, we calculated the pressure reactivity index,11 which showed that the autoregulation was better preserved in the VAS group. The latter variable is relevant for the reperfusion period after CA as a mismatch between

Adrenaline after hypovolemic cardiac arrest

Fig. 2. Cerebral cortical blood flow (CCBF), cerebral perfusion pressure (CePP), intracranial pressure (ICP) and jugular venous oxygen extraction ration (jugular venous OER) at baseline and after restoration of spontaneous circulation (ROSC). Data provided as mean ± standard error of the mean (SEM) [for CCBF data provided as mean ± 95% confidence interval (CI)]. Adrenaline group (ADR), n = 12; vasopressin group (VAS), n = 9. # denotes significant difference between the ADR and VAS groups [two-way repeated measures analyses of variance (ANOVA), P = 0.003, for ICP]. * denotes significant difference between ADR and VAS groups (one-way ANOVA, P < 0.05, for jugular venous OER and CePP). CPR, cardiopulmonary resuscitation; VF, ventricular fibrillation.

Table 3 Cerebral pressure reactivity index at baseline and after restoration of spontaneous circulation (ROSC). Group/time point


After haemorrhage

5 min after ROSC

15 min after ROSC

30 min after ROSC

60 min after ROSC

120 min after ROSC

180 min after ROSC


0.17 ± 0.026 0.13 ± 0.017

0.59 ± 0.074 0.41 ± 0.052

0.42 ± 0.044 0.19 ± 0.026

0.41 ± 0.05 0.20 ± 0.029

0.3 ± 0.031 0.20 ± 0.029

0.72 ± 0.019 0.75 ± 0.031

0.29 ± 0.016 0.23 ± 0.028

0.36 ± 0.031 0.26 ± 0.033

The cerebral pressure reactivity index (PRx) has been calculated as a correlation coefficient between mean arterial pressure and intracranial pressure averaged over 5–10 s. Data are provided as mean ± standard error of the mean (SEM). Adrenaline group (ADR), n = 12. Vasopressin group (VAS), n = 9. PRx was lower in VAS group compared with ADR [P < 0.002, repeated measures analysis of variance (ANOVA)].

the cerebral oxygen delivery and oxygen consumption would augment the brain tissue injury, which can worsen the functional outcome.24 The VAS group had a higher cerebral perfusion pressure immediately (5 and 15 min) after ROSC. Somewhat later, 15 and 30 min after ROSC, the cerebral oxygen extraction ratio was greater in the same group. As no statistical correlation was observed between groups regarding haemodynamics during CPR and posthaemodynamic function, we can only speculate that

a shorter period of CPR in the VAS group compared with ADR was responsible for the early difference in coronary perfusion pressure and oxygen extraction ratio. It seems logical to assume that the greater perfusion pressure in the VAS group resulted in a better immediate reperfusion and that the greater oxygen extraction mirrored a greater cerebral oxygen uptake and subsequently somewhat better autoregulation of the cerebral blood flow. Moreover, the concomitant cerebral venous pH and base excess


E. Semenas et al.

Fig. 3. Representative examples of Nissl stained neurons (above) and albumin leakage (below) in the pig brain cortex following cardiac arrest treated with vasopressin (VAS, left) or adrenaline (ADR, right). Neuronal damages (arrows) are seen in the VAS group frequently. However, the incidence of neuronal damages with dark and condensed neuronal cytoplasm (arrowheads) is more frequent in the ADR-treated group. Lower panel: albumin-positive cells and mild staining of neuropil is seen in the VAS group (arrows). Most of the albuminpositive cells are neurons whereas some small round-shaped cells could be glial cells as well. Most neurons in the group showed intense albumin immunoreaction (arrows). In the ADR group, albumin-positive cells are largely neurons (arrowheads). However, in several neurons, a clear distinct nucleus is also seen whereas few neurons showed intense immunoreaction of albumin without any apparent cell nucleus or visible nucleolus. Bar: Nissl = 50 μm; albumin = 35 μm.

Fig. 4. Representative examples of neuronal nitric oxide synthase (nNOS, upper panel) and inducible NOS (iNOS, lower panel) immunostained cells in the cerebral cortex of pig brain after cardiac arrest following treatment with vasopressin (VAS) or adrenaline (ADR). nNOS-positive neurons show damage and distortion (arrows) in the VAS group. In the ADR group, intense immunoreaction is seen in neurons largely showing dark stained neurons showing shrinkage with perineuronal oedema (arrow heads). Neuropil is spongy in appearance in this group. Bar: 35 μm. iNOS staining is seen in both neurons as well as glial cells (arrows) in the VAS group. In the ADR group, many more iNOS-positive cells are apparent with spongy neuropil. Intense iNOS immunoreaction is seen in large number of glial cells and neurons showing distorted appearances (arrowheads). Bar: 50 μm.

was greater in ADR group, which fits well with this proposed explanation. Cerebral perfusion was less well regulated, and it resulted in less release and transport of acid (CO2 = carbonic acid and lactic


acid) from the cerebral tissue resulting in increased BBB disruption and nNOS activation. The recent finding by Ristagno et al.25 would, in our view, explain the less well-regulated reperfusion after

Adrenaline after hypovolemic cardiac arrest

CPR by ADR in comparison with VAS. Thus, animal studies demonstrated that VAS, as opposed to ADR, increased the blood flow in vital organs26 and improved the cerebral oxygen delivery,27 which is explained by the finding that ADR decreases the cerebral cortex microvascular flow,28 whereas VAS has a more favourable effect on the cerebral blood flow.25 Despite the aforementioned benefits of postresuscitation hyperaemia, in some studies it has been associated with an increased tissue injury. When BBB permeability increases, it allows extravasation of albumin and other high-molecular weight compounds29 into the extracellular compartment of the brain, with vasogenic oedema formation and subsequent cell injury.8 As BBB permeability is increased and cerebral oedema has formed, it may lead to increased ICP.30 However, there is limited evidence that elevated ICP exacerbate the post-CA brain injury.31 This view is supported by our finding of significantly higher ICP in ADR group with no differences in histological damage between the groups, possibly because of the relatively short duration of cerebral no-flow. However, the systemic hypertensive response may be a major contributor to BBB disruption32 that results in the vasogenic oedema. This effect as well as the cerebral hyperaemia observed after the global ischaemia may be caused by high levels of NO produced during ischaemia and the early reperfusion.33 Moreover, there is strong evidence that NO is involved in the mechanisms of neurotoxicity after the cerebral ischaemia.34 The early phase of the process leading to the ischaemic brain injury is initiated almost immediately after CA arrest by calcium overload of the cellular cytoplasm of the neural cells and glial cells.35 The calcium overload leads to an almost instantaneous activation of nNOS and, a few hours later, to that of iNOS.7,19 Our finding of significantly augmented activation of nNOS after ROSC is in agreement with Miclescu et al.’s7 study results. However, more unexpected was the finding that the neurologic injury did not differ between the groups despite significant differences in albumin leakage and ICP. The latter finding can be partly explained by a short period of the observation. Our study lasted just 3 h after ROSC, whereas significant changes in the neurologic injury may appear only after 24 h or even later.36 There are obvious limitations to the design of the present study, the most obvious being its short duration. However, the current study was not designed to evaluate the long-term survival. We chose to use a

VF model of CA, which is the most reliable arrhythmia model to be controlled experimentally. We also acknowledge that our study may lack the power to detect some additional differences due to a relatively small sample size. At the same time, the use of hypertonic saline, dobutamine and amiodarone may also have influenced BBB permeability. Thus, in conclusion, resuscitation with ADR after the haemorrhagic CA in immature piglets significantly increased the ICP, more profoundly impaired cerebrovascular autoregulation and exerted an increased BBB disruption, although no significant changes in the histological injury were observed.

Acknowledgements The research was supported by the Laerdal Foundation for Acute Medicine, Stavanger, Norway. Conflict of interest: The authors have no conflicts of interest.

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Address: Egidijus Semenas Department of Surgical Sciences/Anaesthesiology and Intensive Care Uppsala University Hospital 751 85 Uppsala Sweden e-mail: [email protected]

Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Table S1. Haemodynamic variables [systolic blood pressure (SBP) and mean arterial blood pressure (MABP)], intracranial pressure (ICP), esophageal temperature, laser Doppler cerebral blood flow measurements (LD-CBF) and coronary perfusion pressure (CPP) during cardiopulmonary resuscitation (CPR). Table S2. Indicators of brain peroxidation (8-isoPGF2α) and inflammation (15-keto-dihydro-PGF2α), and brain injury S-100β in jugular plasma at baseline and after restoration of spontaneous circulation. CPR, cardiopulmonary resuscitation. Data provided

Adrenaline after hypovolemic cardiac arrest

as a mean ± standard error of the mean (SEM). VAS, vasopressin, n = 9; ADR, adrenaline, n = 12. Table S3. Esophageal temperature and troponin I in plasma at baseline and after restoration of spontaneous circulation.

Table S4. Glucose, lactate, potassium and natrium plasma concentrations (mmol/l) at baseline and after restoration of spontaneous circulation.


Adrenaline increases blood-brain-barrier permeability after haemorrhagic cardiac arrest in immature pigs.

Adrenaline (ADR) and vasopressin (VAS) are used as vasopressors during cardiopulmonary resuscitation. Data regarding their effects on blood-brain barr...
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