Fehler und Gefahren Anaesthesist 2014 DOI 10.1007/s00101-014-2371-2 © Springer-Verlag Berlin Heidelberg 2014

D. Pehböck1 · H. Dietrich2 · G. Klima3 · P. Paal1 · K.H. Lindner1 · V. Wenzel1 1 Department of Anaesthesiology and Critical Care Medicine, Medical University of Innsbruck 2 Central Laboratory Animal Facilities, Medical University of Innsbruck 3 Division of Histology and Embryology, Medical University of Innsbruck

Redaktion

K. Markstaller, Wien

Anesthesia in swine Optimizing a laboratory model   to optimize translational research

Introduction In order to extrapolate novel therapies from the bench to the bedside (translational research), animal experiments are inevitable. While smaller animals, such as rodents are a valuable model for screening, they are often too low on the phylogenetic developmental scale to allow a careful extrapolation to humans [36]. For example, rats can breathe 50% carbon dioxide without problems [41] while humans quickly become unconscious and develop seizures while breathing 10% carbon dioxide [38] indicating significant differences in cardiorespiratory physiology and hence, extrapolation difficulties between rodents and humans. In our experience, rodents are frequently used in basic science research laboratories [9] while swine are more favored in translational research [27]. Swine are appropriate laboratory animals for cardiology and respiratory studies because the cardiorespiratory physiology is similar to humans. As swine with a 30–40 kg body weight have a similar relationship between cardiac size and body weight compared to humans, study results may be extrapolated better than with other laboratory animals [13]. Dogs have much heavier hearts than pigs in relation to the body weight and have a strong collateral blood supply [37] between the right and left coronary arteries in contrast to humans and pigs [16] rendering extrapolation of study results to humans more difficult. For example, while in our cardiopulmonary resuscitation experiments

a cardiac arrest interval of 4 min poses a significant ischemic stress in swine [45] this interval would have to be extended to approximately 10–15 min in dogs to achieve equivalent ischemic conditions [17]; however, employing dogs for physiological preparations such as local vascular control may be feasible. Furthermore, electrophysiological mechanism considerations are similar in humans and pigs, thus producing another argument in favor of employing pigs for cardiovascular studies [1]. However, pigs grow very fast and animals above 100 kg (approximately 8 months old) in weight are very difficult to handle in terms of weight, airway management and cardiovascular stress thus posing a certain limit on long-term experiments. Ruminants such as sheep have the advantage that the maximum weight of about 70 kg facilitates long-term experiments but induction of anesthesia is extremely difficult due to salivation, regurgitation, rumen paralysis and aspiration risk. Furthermore, studies in primates were often performed decades ago [10] but have become seldom due to legal guidelines, associated public outrage and high costs. Our working group has experience in conducting laboratory research with swine since the 1980s [26], thus optimizing many aspects over time. This porcine animal model was the backbone for extrapolation of improving blood pressure during cardiac resuscitation with vasopressin to a large prospective randomized clinical trial [43]. Also this model yielded reproducible data in laboratory studies

researching clinical investigations in hypothermia [15], uncontrolled hemorrhagic shock [23, 25] and septic shock [28]. This manuscript is intended to assist researchers in conducting laboratory investigations in porcine preparations in order to ensure ethical treatment of animals and reproducible results.

Transport conditions for swine As swine are extremely sensitive to stress, the primary goal is to provide a calm, stress-free environment in both housing and experimental facilities [12] and to minimize transport from one barn to another. If transport is inevitable it is recommended that the animal should be allowed an acclimatization period of a minimum of 1 week [19]. Any excessive or unnecessary stress has to be avoided at any time of the entire experiment because stressed pigs may respond to experimental inter-

Fig. 1 8 Intravenous cannulation of an ear vein Der Anaesthesist 2014 

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Fig. 2 8 Preoxygenation in ensured by applying 10 l oxygen per minute via a nose cone

ventions differently than unstressed animals, which are carefully handled and properly anesthetized. In contrast to cats and dogs, swine are not familiar with being lifted and touched by humans. Accordingly, transport boxes with sliding doors are useful to enable the pig to move between cages on its own. Before being transported, swine should be sedated irrespective of the mode of transport. We have made good experiences with a simultaneous intramuscular (i.m.) injection of azaperone (2 mg/kg body weight) and atropine (0.01 mg/kg i.m.) into the shoulder or buttock muscles for sedation [12]. Due to a different porcine hemoglobin structure and higher body temperature compared to humans (approximately 38.5°C in swine versus 37.0°C in humans) [13], correct control of temperature in porcine studies is extremely important and needs to be carefully controlled. As swine have a sparse body hair coat and a high metabolism rate, hyperthermia or hypothermia can develop quickly. For example, at a room temperature of 20°C the abdominal skin surface temperature in swine is 34°C but only 22–24°C in cats or dogs. Accordingly, transport containers for swine should provide adequate circulation to prevent heat accumulation, which could trigger hyperthermia. Thus, anesthetizing a pig without a heating blanket, an infrared heating lamp and warmed infusions almost automatically results in hypothermia, resulting in unexplainable

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Fig. 3 8 Sketch of a paramedian section through the head of a pig featuring the airway only. The epiglottis has to be picked up with the laryngoscope blade to optimize visualization of the trachea. Note the treacherous pouch recessus piriformis, which may result in a fatal intubation attempt

and mostly unrecognized confounding variables [34]. In one study [47] temperature was not reported in approximately 50% of the published reports, with the remaining experiments being conducted at temperature levels that were either physiologically normal or near normal for pigs. In order to provide an accustomed environment, bedding material of the pig barn should cover the bottom of the transport container. The transport container needs to be spacious in order to allow adequate movement and posture of the pig, especially in case of defecation and urination, when pigs arch their spine. In longterm experiments it is recommended to transfer pigs back to their former housing facilities during anesthesia or sedation. A change of the environment is thus obscured for the animal. After recovery from anesthesia the pig then easily acclimatizes to the given conditions. If a shipment of pigs is performed in a vehicle, proper space and air conditions are required to ensure well-being of the animal.

Anesthesia Well before the experiment, a test run of the experiment should be performed without the animal to ensure that all technical equipment is working, sufficient material is present, staff duty schedules are known and last minute questions can be addressed. After arrival of the sedated pig in the experimental facility, induc-

tion of anesthesia is prepared by injecting ketamine S (20 mg/kg i.m.). Due to the rapid porcine metabolism, even large ketamine doses are broken down quickly; furthermore, ketamine does not cause apnea which may occur quickly after propofol administration [5]. Approximately 5–15 min after injecting ketamine, the pig is positioned on its side to facilitate breathing and intravenous cannulation of an ear vein (. Fig. 1) can be performed. If multiple blood sampling or a large vascular access is required, femoral or jugular approaches are recommended [20]. Infusing 500 ml of lactated Ringer’s solution (1– 4 ml/kg/h) prevents hypovolemia. Measuring peripheral oxygen saturation is easily possible at the tail (preferably) or tongue. For swine weighing 30–50 kg an endotracheal tube with 5.5– 6.0 mm internal diameter is suggested, with increasing sizes thereafter. For intubation, a Miller laryngoscope (preferably extended by approximately 30% compared to those employed in humans) is advised due to the long distance between incisors and the larynx. Alternatively, a straight cystoscope may be employed. It is highly emphasized that endotracheal intubation is usually the most difficult maneuver during a porcine experiment. The essential prerequisites are careful preparation of equipment and adequate training to prevent the necessity of the fallback strategy tracheostomy. While surgical procedures can be quickly extrapo-

Abstract · Zusammenfassung Anaesthesist 2014 · [jvn]:[afp]–[alp]  DOI 10.1007/s00101-014-2371-2 © Springer-Verlag Berlin Heidelberg 2014 D. Pehböck · H. Dietrich · G. Klima · P. Paal · K.H. Lindner · V. Wenzel

Anesthesia in swine. Optimizing a laboratory model to optimize translational research Abstract In order to extrapolate novel therapies from the bench to the bedside (translational research), animal experiments are scientifically necessary. Swine are popular laboratory animals as their cardiorespiratory physiology is very similar to humans. Every study has to be approved by the local and/or national animal ethical committees. As swine are extremely sensitive to stress the primary goal is therefore to provide a calm, stress-free environment in both housing and experimental facilities. Swine should be properly sedated for transport and normothermia needs to be ensured. It is recommended to commence anesthesia by injecting ketamine and propofol followed by endotracheal intubation during

spontaneous breathing. After intubation, anesthesia maintenance is performed with morphine or piritramide, propofol and rocuronium and routine monitoring is applied analogue to a clinical operating theater for humans. Normothermia (38.5°C) needs to be ensured. While surgical procedures can be readily extrapolated from a human operating theater to swine, non-anesthesiologist scientists may lose the animal rapidly due to airway management problems. Vascular access can be secured by cut-downs or ultrasoundguided techniques in the inguinal and the neck region. For humane euthanasia of pigs, morphine, followed by propofol, rocuronium and potassium chloride are recommended.

As radical animal right groups may threaten scientists, it is prudent that animal laboratories have unmarked entrance doors, are located in buildings that are not accessible to the public and strictly controlled access of laboratory staff is enforced. In conclusion, swine are an excellent laboratory animal for bench to bedside research and can be managed properly when basic knowledge and adequate skills on careful handling, anesthesia and surgical considerations are present. Keywords Anesthesia · Animal experimentation · Euthanasia · Surgery · Translational research

Anästhesie bei Schweinen. Optimierung eines Labormodells zur Optimierung der translationalen Forschung Zusammenfassung Tierversuche sind wissenschaftlich notwendig, um das klinische Potenzial neuer Thera­ piemöglichkeiten zu bewerten und Studien vorzubereiten (translationale Forschung). Schweine sind gut als Versuchtstiere geeignet, da ihre kardiorespiratorische Physiologie der des Menschen sehr ähnlich ist. Je­ der Tierversuch muss von einer Ethikkommission bzw. den zuständigen Behörden genehmigt werden. Schweine sind sehr anfällig für Stress, das primäre Ziel ist daher eine ruhige, stressfreie Umgebung im Stall und For­schungslabor. Schweine sollten bereits vor dem Transport ins Forschungslabor sediert werden, und die Normothermie während des Transport ist sicherzustellen. Zur Narkose­ einleitung wird die Kombination aus Ketamin bzw. Propofol gefolgt von einer endotrachealen Intubation bei Spontanatmung emp-

lated from experience in a human operating room to swine, non-anesthesiologist scientists may lose the laboratory animal rapidly due to airway management problems, rendering the entire experiment and budget threatened due to a controllable intervention that became uncontrollable. We therefore recommend to have an expert in pig anesthesia permanently present during the most critical interventions to guarantee successful intubation and effective anesthesia. After placing the animal in a supine position with the head slightly placed

fohlen. Nach der Intubation wird die Anästhesie mit Morphium bzw. Piritramid, Propofol und Rocuronium geführt. Ein intraoperatives Routinemonitoring erfolgt wie beim Menschen. Normothermie (38,5°C) muss während der gesamten Untersuchung gewährleistet werden. Während chirurgische Techniken re­ lativ einfach von Operationen am Menschen auf das Schwein übertragbar sind, können nicht anästhesiologisch ausgebildete Wissenschaftler aufgrund ungewohnter anatomischer Verhältnisse rasch Probleme beim AtemManagement bekommen und ein Versuchs­ tier bereits vor der Untersuchung verlieren. Intravasale Zugänge lassen sich durch chirurgische Präparation oder ultraschallgestützte Techniken in der Leiste und am Hals schaffen. Für eine humane Euthanasie des Versuchs­ tiers wird eine Morphininjektion empfohlen,

over the edge of the operating table to facilitate maneuvering of the head, 10 l oxygen per minute should be administered via a nose cone (. Fig. 2) to ensure preoxygenation [33]. The depth of anesthesia can be easily ascertained by advancing the laryngoscope into the pharynx and endotracheal intubation should be performed during spontaneous breathing. Additional propofol (20–30 mg i.v. increments) [19] may further facilitate endotracheal intubation but can rapidly result in apnea as well. Mask ventilation in pigs is almost impossible [18]. After advancing the la-

gefolgt von Propofol, Rocuronium und Kaliumchlorid. Radikale Tierversuchsgegner können eine Bedrohung für Wissenschaftler sein; es ist daher ratsam, Forschungslabors nicht als solche zu kennzeichnen, sie in Gebäuden einzurichten, die nicht öffentlich zugänglich sind, und den Zugang der Mitarbeiter streng zu kontrollieren. Wenn Fachkenntnisse und entsprechende Kompetenzen bei der Haltung, Anästhesie und chirurgischem Vorgehen angewandt werden, eignen sich Schwei­ ne hervorragend für Bench-to-Bedside-Untersuchungen. Schlüsselwörter Anästhesie · Tierversuch · Euthanasie · Chirurgie · Translationale Forschung

ryngoscope into the pharynx the epiglottis has to be picked up with the laryngoscope blade to optimize visualization of the vocal cords (. Fig. 3). The endotracheal tube should be inserted during inspiration and the use of a guide wire facilitates this procedure. Subsequently, correct tube placement is verified by putting pressure on the chest resulting in exhalation via the tube and detection of end tidal carbon dioxide. Intubating a pig is much more difficult than intubating a human, especially when the pig weighs >100 kg. Pigs have deep blind ending pouches Der Anaesthesist 2014 

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Fig. 4 8 The main femoral vein and artery can be accessed by a 5 cm long skin incision followed by blunt preparation

around the larynx which increase the risk of inadvertent misplacement of the endotracheal tube. While a guide wire is usually sufficient to ensure endotracheal intubation, a tube exchanger may sometimes be helpful as well. Deep anesthesia is achieved by piritramide (30 mg i.v.) or morphine (20 mg i.v.) and propagated by infusion of propofol (6–8 ml/kg/h). The authors of this article have made good experiences with piritramide as a long-acting opioid. Piritramide works better than fentanyl, as it requires less bolus injections, accumulates less and facilitates weaning much better [6]. If a volatile anesthetic drug is chosen for maintenance of anesthesia, isoflurane provides the least cardiodepressant effects while ensuring a reliable level of anesthesia; swine are relatively resistant to the analgesic effects of nitrous oxide [39]. Volume-controlled ventilation [7 ml/kg, inspiratory oxygen fraction (FIO2) 0.3] is recommended but needs to be carefully controlled by capnography and blood gas analysis. Swine can well tolerate muscle relaxation with rocuronium (0.6 mg/kg) if required. Anesthesia in swine needs to be carefully monitored as in a clinical operating room. Pigs do not tolerate regional anesthesia without general anesthesia but neuroaxial techniques are possible if the pig is well sedated [14]. For epidural anesthesia the pig is placed in a prone position and a 19-gauge epidural catheter is inserted through a 17-gauge Tuohy needle into the epidural space at the L3–4 level and advanced under fluoroscopic guid-

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Fig. 5 8 The neck vasculature can be accessed preferably at the right anterior lateral neck region

ance until the tip reaches the T15/L1 interspace. In one study, 8 ml bupivacaine 0.5% resulted in thoracolumbar blockade of all vertebral segments with preganglionic sympathetic outflow in 35–45 kg pigs [22]. When ensuring that the degree of intervention enables a pain-free recovery, animal ethics committees usually allow survival and long-term experiments. After confirming normothermia, normovolemia, full neuromuscular recovery and painlessness, a pig can be quickly disconnected from the respirator. In order to prevent postoperative pain and suffering paracetamol (15 mg/kg i.v.) or metamizole (2 g iv) is usually well tolerated if intravascular access is maintained and kept sterile. Paracetamol and metamizole should be given at least 15–30 min before the animal recovers from anesthesia to be most effective [2]. In cases of insufficient analgesia, piritramide (15 mg s.c. every 4 h) or morphine (10 mg) is more potent. Cefuroxim (1.5 g), a second generation cephalosporin, is very effective in preventing infectious complications. If interventions are being performed that affect coagulation activity (e.g. central or cardiac catheters), heparin can be employed (150 IU/kg i.v.) to avoid blood clotting. If blood sampling is needed on a daily basis, not more than 0.07% of the calculated blood volume (6.5% of the body weight) should be withdrawn in order to ensure normal cardiovascular homeostasis [4, 42]. A longterm experiment requires a skilled individual to supervise the immediate weaning and recovery phase, especially in cas-

es of analyzing the survival time of the pig. Neurological recovery scores have been adapted for swine and can be easily applied by non-neurologists [46]. If the experiment is to be performed in spontaneous breathing, we recommend using ketamine S (20–50 mg/kg/h i.v.) and midazolam (0.2–0.5 mg/kg/h i.v.).

Surgical preparation As a standard procedure for skin disinfection the skin of the pigs needs to be carefully washed with a disinfection fluid to ensure asepsis. After an adequate level of anesthesia is ensured, the main femoral vein and artery can be accessed by an approximately 5 cm long skin incision (. Fig. 4), followed by a blunt preparation procedure using appropriate scissors. With the Seldinger technique, catheters or a 5F sheath can easily be inserted into the artery or vein to measure blood pressure and blood gases and to infuse blood, fluids or drugs. If blood transfusions are needed, full blood can be taken from another pig under strict sterile conditions and matched for compatibility before administration [35]. Processing porcine blood with normal hospital equipment is possible to isolate specific coagulation effects [11]. The neck vasculature can be accessed preferably at the right anterior lateral neck region but the vasculature is located deeper in the tissue than in the groin (. Fig. 5). However, the neck is the preferred entry port to place a pulmonary catheter. Each surgical incision should be

sutured after the intervention. For sampling of cerebral venous blood and determination of intracranial pressure, a burr hole needs to be drilled into the skull over the midline and a catheter can be inserted into the sagittal sinus [44]. After a midline abdominal incision the abdomen can be opened in order to access the intestines. In order to place flow measurement devices around blood vessels [40] a surgically experienced person needs to operate, as tissues are very sensitive to damage and discharge large amounts of lymph fluid after injury of vessel walls. After a sternotomy, thoracic organs can be accessed for experimental interventions [29]. One advantage in swine compared to smaller laboratory animals is that standard operating surgical tools fit perfectly. Catheter insertion may be assisted by an ultrasound unit. In an experimental model lasting several hours an easy way to drain a swine’s bladder is a suprapubic access with an 18G i.v. line. Furthermore, intraosseous drugs may be an alternative for administration, for example during cardiopulmonary resuscitation (CPR), when intravenous access is delayed or not available [45].

Termination Laboratory animals give their life to advance medical research, thus mandating a dignified treatment throughout laboratory investigations and upon conclusion of the experiment. If surgical preparation is too complex or postoperative painlessness cannot be ensured, pigs have to be sacrificed at the end of an experiment [30, 48]. While specially prepared commercially available euthanization drugs exist for household pets these are rarely used for laboratory animals. In our experience, it is recommended to inject a large dose of piritramide (1 mg/kg i.v.) or morphine (1 mg/ kg i.v.), followed 10 min later by propofol (10 mg/kg i.v.), rocuronium (1 mg/kg i.v.) and subsequently potassium chloride (40 mmol), which ensures a painfree death without any suffering. Euthanasia of animals without an opioid would be unethical [21]. Regardless of an experiment being a non-survival model or longterm observation, a post-mortem autopsy should be performed whenever possible. Although a given underlying prob-

lem may not always be identified in cases where unexpected phenomena occur, it is a chance to improve quality control and to detect the pathology which hampered the experiment.

Safety and security Each animal experiment needs to be based on an approved application to the appropriate animal ethics committee. A valid approval for an animal experiment by official authorities is the legal principle to avoid a legal indictment. Scientists should be aware that some people strongly oppose animal experimentation even if being performed within all legal boundaries; however, animal rights organizations probably exist in all industrialized countries and are usually very well organized and well connected to the media1. While some animal rights groups may conduct their business in a liberal manner which may even allow public discussion about animal research, other radical animal rights groups exist who do not shy away from violent actions, such as damaging laboratories, arson, bomb and death threats, public false accusations and phone terror [8]2. Therefore, it is prudent that animal laboratories have unmarked entrance doors, are located in buildings that are not accessible to the public, strict control of laboratory staff access is enforced and that investigators are not listed in the public phone book. For instance, when our physician scientists performed an approved simulated snow avalanche burial study using anesthetized pigs [32] the media appeared at the scene quickly followed by animal rights activists threatening personal attacks [7]. Subsequently, we had to stop the study the same day due to safety reasons. The principal investigators and associated institutions received more than 35,000 protest e-mails and letters, including threats of violence and death. The study team and the Austrian Federal Minister of Science were taken to court for violence and murder of animals by animal rights activists (all dismissed by the state

attorney). Additionally, two parliamentary enquiries were put forward in the Federal Austrian parliament [31]. Thus, it is recommended that a risk assessment should be performed before laboratory studies with animals are conducted. The approved application by the animal ethics committee should always be available in the home institution’s office as well as in the laboratory, the institutional press officer must be accurately briefed, a brief one page summary of the study for the public and the media should be available and a spare cellular phone including charge station should be ready for use in case of a sudden and massive media interest [3]. It is also recommended that scientists are able to explain the goals of a given laboratory animal project in lay terms to the public and to the media, otherwise incorrect accusations cannot be addressed properly. Public action needs to be taken as well as when other scientists or institutions are being attacked to protect medical science [24]3. Lastly, investigators need to be aware that their descriptions of anesthesia and surgical protocols of laboratory investigations in scientific publications may be critically reviewed by skilled animal rights activists possibly resulting in embarrassing questions about insufficient levels of anesthesia to authors and journals, which may subsequently fundamentally threaten laboratory investigations. Each researcher should be the greatest advocate for a dignified and ethical treatment of laboratory animals.

Conclusion Swine are excellent laboratory animals and can be managed properly when basic knowledge and adequate skills on careful handling, anesthesia, and surgical considerations are present and a welltrained staff is at hand.

1 Der Standard 14.01.2010; Die Zeit 22.01.2010;

Frankfurter Allgemeine Zeitung 14.01.2010; Die Welt 14.01.2010. 2 Telegraph 30.08.2010.

3 Daily Mail 28.05.2010.

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Fehler und Gefahren Corresponding address Prof. V. Wenzel Department of Anaesthesiology and Critical Care Medicine, Medical University of Innsbruck Anichstr. 35, 6020 Innsbruck Austria [email protected]

Compliance with ethical guidelines Conflict of interest.  D. Pehböck, H. Dietrich, G. Klima, P. Paal, Karl H. Lindner and Volker Wenzel state that there are no conflicts of interest. All national guidelines on the care and use of laboratory animals have been followed and the necessary approval was obtained from the relevant authorities.

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34. Radde GR, Hinson A, Crenshaw D, Toth LA (1996) Evaluation of anaesthetic regimens in guineapigs. Lab Anim 30:220–227 35. Raedler C, Voelckel WG, Wenzel V et al (2004) Treatment of uncontrolled hemorrhagic shock after ­liver trauma: fatal effects of fluid resuscitation versus improved outcome after vasopressin. Anesth Analg 98:1759–1766 36. Safar P (1993) Cerebral resuscitation after ­cardiac arrest: research initiatives and future directions. Ann Emerg Med 22:324–349 37. Schaper W, Jageneau A, Xhonneux R (1967) The development of collateral circulation in the pig and dog heart. Cardiologia 51:321–335 38. Sechzer PH, Egbert LD, Linde HW et al (1960) Effect of carbon dioxide inhalation on arterial pressure, ECG and plasma catecholamines and 17-OH corticosteroids in normal man. J Appl Physiol 15:454– 458 39. Swindle MM, Smith AC, Hepburn BJ (1988) Swine as models in experimental surgery. J Invest Surg 1:65–79 40. Voelckel WG, Lindner KH, Wenzel V et al (1999) Effect of small-dose dopamine on mesenteric blood flow and renal function in a pig model of cardiopulmonary resuscitation with vasopressin. Anesth Analg 89:1430–1436 41. Planta I von, Weil MH, Planta M von et al (1991) Hypercarbic acidosis reduces cardiac resuscitability. Crit Care Med 19:1177–1182 42. Weiss JB, Becker K, Bernsmann E et al (2014) Tier­ pflege in Forschung und Klinik, 4. Aufl. Enke, Stuttgart 43. Wenzel V, Krismer AC, Arntz HR et al (2004) A comparison of vasopressin and epinephrine for out-ofhospital cardiopulmonary resuscitation. N Engl J Med 350:105–113 44. Wenzel V, Linder KH, Augenstein S et al (1998) Vasopressin combined with epinephrine decreases cerebral perfusion compared with ­vasopressin alone during cardiopulmonary resuscitation in pigs. Stroke 29:1462–1467 (discussion 1467–1468) 45. Wenzel V, Lindner KH, Augenstein S et al (1999) ­Intraosseous vasopressin improves coronary perfusion pressure rapidly during cardiopulmonary resuscitation in pigs. Crit Care Med 27:1565–1569 46. Wenzel V, Lindner KH, Krismer AC et al (2000) Survival with full neurologic recovery and no cerebral pathology after prolonged cardiopulmonary resuscitation with vasopressin in pigs. J Am Coll Cardiol 35:527–533 47. Wenzel V, Padosch SA, Voelckel WG et al (2000) Survey of effects of anesthesia protocols on hemodynamic variables in porcine cardiopulmonary resuscitation laboratory models before induction of cardiac arrest. Comp Med 50:644–648 48. Close B, Baumans V, Bromage N et al (1996) Recommendations for euthanasia of experimental ­animals: part 1. Lab Anim 30:293–316