Journal of Veterinary Emergency and Critical Care 24(2) 2014, pp 221–225 doi: 10.1111/vec.12123
Bispectral index analysis during cardiac arrest and cardiopulmonary resuscitation in a propofol-anesthetized calf Francesco Aprea, VMD, DECVAA, MRCVS; Olga Martin-Jurado, Dr Vet Med; Simon Jenni, Dr Vet Med and Martina Mosing, Dr Vet Med, DECVAA Abstract
Objective – To describe bispectral index (BIS) findings and compare them with cardiovascular and respiratory trends during cardiac arrest and successful CPR in a propofol-anesthetized calf. Case Summary – A 3-month-old calf was anesthetized as part of a research project. A thromboxane analog drug (U46619) was administered IV to induce pulmonary hypertension. Within 10 minutes following U46619 administration, cardiac activity deteriorated, leading to asystole. At this point, BIS and suppression rate were 0 and 100, respectively. Anesthetic drug delivery was discontinued and external chest compressions were initiated. During CPR, end-tidal CO2 concentration decreased and BIS increased, but no spontaneous cardiac activity was noted, thus IV epinephrine was administered. Return of spontaneous circulation was achieved and systemic arterial hypertension developed, while BIS briefly decreased and then increased during the following 2 minutes. The calf’s cardiopulmonary variables returned to physiological ranges within 10 minutes after the return of spontaneous circulation and remained stable. Unique Information Provided – This is the first report in which BIS is documented together with standard monitoring techniques during cardiopulmonary arrest and resuscitation in a calf. BIS varied with cardiovascular performance, and may be indicative of cerebral blood flow in this context. Further research may be warranted to define the role of BIS for monitoring cerebral activity during CPR. (J Vet Emerg Crit Care 2014; 24(2): 221–225) doi: 10.1111/vec.12123 Keywords: BIS, CPR, bovine, anesthesia, TIVA
BIS CPP CVR CPA CVP DAP EEG EMG
bispectral index cerebral perfusion pressure cerebral vascular resistance cardiopulmonary arrest central venous pressure diastolic arterial blood pressure electroencephalogram electromyography
HR IBP MAP ROSC SAP SPAP SVR TP TxA2
partial pressure of expired (end-tidal) carbon dioxide heart rate invasive arterial blood pressure mean arterial blood pressure return of spontaneous circulation systolic arterial blood pressure systolic pulmonary arterial pressure systemic vascular resistance thromboxane receptor thromboxane A2
From the Dick White Referrals, Station Farm, Cambridgeshire, CB8 0UH, UK (Aprea); AO Foundation, Preclinical Services Focus Area Surgery, 7270 Davos, Switzerland (Martin-Jurado); Division of Small Animal (Jenni); and ¨ Division of Anaesthesiology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland (Mosing). The work was carried out at the Veterinary Hospital, Vetsuisse Faculty, Uni¨ versity of Zurich, Winterthurerstrasse 260, 8057 Zurich, Switzerland. Dr. Aprea’s current address is MRIVets, c/Maghalaes 3 B, Palma de Mallorca 07014, Spain. The authors declare no conflict of interest. Address correspondence and reprint requests to Francesco Aprea, MRIVets, c/Maghalaes 3 B, Palma de Mallorca 07014, Spain. Email: [email protected]
Submitted June 27, 2012; Accepted October 24, 2013. C Veterinary Emergency and Critical Care Society 2014
Introduction Effective CPR is essential during cardiopulmonary arrest (CPA) to maintain adequate cerebral and coronary perfusion until spontaneous cardiac activity returns. During CPR, cardiac output is generally assessed by presence of a palpable pulse and indirectly, by measuring the endtidal CO2 (ETCO2 ) or invasive arterial blood pressure 221
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(IBP).1 The bispectral index (BIS) is a complex parameter derived from a multivariate analysis of the electroencephalogram (EEG) signal. The BIS monitor displays a single number that ranges from 0 (silent, flat EEG) to 100 (normal awake state). Clinically, BIS can be employed to examine corticocerebral activity and to estimate the degree of consciousness in anesthetized patients.2 Assessment of cerebral activity during CPA and CPR is a novel application of this monitor and thus far has only been described as case reports in the human medicine literature.3–8 Post-CPA BIS values in human patients following the return of spontaneous circulation (ROSC) may be correlated to neurologic outcomes.9 A downside of the use of BIS during CPR is that the time needed for the computer to process the algorithm and to display a number (generated from integration of power spectral parameters, burst suppression, frequency, and phase coupling of the EEG) causes an intrinsic delay in the display of the BIS value.10 The BIS has been investigated in veterinary medicine to monitor the degree of hypnosis and the effects of anesthetic and sedative agents in different species,2 but BIS findings during CPA and CPR have not been described in the veterinary literature. This case report describes the BIS findings during CPA and CPR in an anesthetized calf.
Case Summary A 3-month-old male Holstein-Friesian calf weighing 107 kg, bred for experimental purposes, and judged healthy by clinical examination, was anesthetized. This procedure was part of a research project to evaluate the presence of anatomic shunt within the pulmonary vasculature in ruminants. The study was performed with ethical and governmental approval (Cantonal Veterinary Office 18/2010). The animal was withheld from food for 24 hours prior to anesthesia, with free access to water. Following cannulation of the left jugular vein, midazolama (0.3 mg/kg) was administered IV as preanesthetic medication. General anesthesia was induced with IV propofolb (6 mg/kg). The trachea was intubated with an 11 mm outer diameter cuffed silicone tube. General anesthesia was maintained with a propofol constant rate infusion (CRI; 0.5 mg/kg/min IV), and boluses of propofol (0.1–0.2 mg/kg) were administered to deepen the anesthetic plane if necessary. Lungs were mechanically ventilated with air using a large-animal ventilatorc in a volume-controlled mandatory mode targeting normocapnia (ETCO2 between 4.6 and 6 kPa [35–45 mm Hg]). The ventilator was initially set to deliver a tidal volume of 15 mL/kg and a respiratory rate of 10/min. Monitoring included ECG, inspired and expired par222
tial pressures of airway gases, esophageal temperature, IBP, central venous pressure (CVP), and systolic pulmonary arterial pressure (SPAP) by means of a SwanGanz catheter.d Needle electrodes were positioned over the frontal region of the scalp, as previously described in goats,11 in order to monitor BIS.e An IV CRI of fentanylf (0.01 mg/kg/h) was initiated following a loading dose of fentanyl (0.002 mg/kg). Isotonic crystalloid solutiong was infused at 2 mL/kg/h throughout the procedure. During general anesthesia vital parameters were continuously monitored and automatically downloaded and recorded into a computerized data sheet at 5-second intervals. Monitored variables were within the physiologic reference intervals apart from hypothermia (34◦ C). The mean value calculated by the BIS monitor was 45. Two hours following induction of general anesthesia, a thromboxane A2 (TxA2 ) analog drug (U46619h ) was administered IV (0.12 mg/kg/h) as part of the experimental protocol. An overview of the changes in relevant monitored variables following U46619 administration is listed in Figure 1. Following U46619 administration, systolic PAP (SPAP) increased from 43 to 85 mm Hg and CVP from 4 to 7 mm Hg. At the same time, systolic, mean, and diastolic arterial blood pressures (SAP, MAP, and DAP, respectively) increased from 87, 67, and 45 mm Hg to 189, 164, and 146 mm Hg, respectively. The ETCO2 increased from 5.7 to 6.2 kPa (43–47 mm Hg). Subsequently, SPAP, SAP, MAP, and DAP decreased; within 10 minutes SPAP dropped to 41 mm Hg and SAP, MAP, and DAP to 39, 30 and 21 mm Hg, respectively, while CVP increased to 12 mm Hg. Heart rate (HR) initially had ranged from 80 to 100/min, but 10 minutes following U46619 administration, the calf developed bradycardia, progressing to asystole. Prior to CPA, the ECG showed broadening of the complexes and an idioventricular rhythm. At time of asystole, ETCO2 was 3.4 kPa (26 mm Hg). No peripheral pulse was palpable and reflexes were absent. Five minutes following the initiation of U46619 administration (6 minutes prior to CPA), the BIS value started to decrease and by 11 minutes following initiation it had decreased from 82 to 0 at time of asystole. Appropriate connection of BIS electrodes was checked and impedance confirmed. Infusion of U46619 was discontinued when arterial blood pressure started to decline, and the fraction of inspired oxygen was increased to 100% without modifying ventilator settings. Delivery of anesthetic drugs was interrupted after 3 minutes when monitored cardiovascular variables further deteriorated even though the TXA2 administration was interrupted. With the calf in sternal recumbency, chest compressions were initiated. One operator supported one side of the chest to prevent the animal from moving, while another investigator performed vigorous manual compression to the other side C Veterinary Emergency and Critical Care Society 2014, doi: 10.1111/vec.12123
BIS during CPR in a calf
Figure 1: Trends of HR (beats per minute), BIS, ETCO2 (mmHg), SAP, DAP, and MAP pressure (mm Hg) after the administration of U46619 (time 0) and during CPA and resuscitation in a propofol-anesthetized calf.
of the thorax at a rate of about 100/min. After 2 minutes of CPR, asystole persisted. At this time SPAP was 27 mm Hg, CVP 20 mm Hg, and SAP, MAP, and DAP were 31, 26, and 24 mm Hg, respectively, with an ETCO2 of 1.7 kPa (13 mm Hg). The displayed BIS values increased from 0 to 11 during CPR. Suppression ratio and signal quality index were 100. Epinephrinei (0.028 mg/kg) was administered IV while compressions continued. Following administration of epinephrine, an abrupt increase of arterial blood pressure above physiological ranges (SAP, MAP, and DAP of 262, 227, 194 mm Hg, respectively) occurred, with ROSC. The ECG monitor displayed a sinus cardiac rhythm with a HR of 147/min. At this time, SPAP was 39 mm Hg, CVP was 7 mm Hg and ETCO2 6.6 kPa (50 mm Hg) and CPR was discontinued. During the 2 minutes following the administration of epinephrine, the BIS value dropped from 35.4 to 30 and then increased to 81 (Figure 1). Ten minutes after cessation of CPR, SPAP was 33 mm Hg, CVP 7 mm Hg, and SAP, MAP, and DAP were 130, 122, 110 mm Hg, respectively. The HR was 120/min in a regular sinus rhythm, and ETCO2 was 6 kPa (45 mm Hg). Variables remained stable within the normal ranges for a further 15 minutes, and the BIS was also stable, at 80. Following this period, general anesthesia was resumed as previously described. The experiment was continued and the calf was euthanized at end of the procedure.
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Discussion Several reports in human medicine describe changes in BIS during CPA and CPR, and this is the first report describing BIS performance during CPA and CPR in a calf. Losasso17 described EEG changes during asystole and CPR in an anesthetized human being. EEG activity showed generalized suppression to isoelectricity with CPA and normalized following effective resuscitation and ROSC. Two other cases, where human patients were monitored using BIS and where BIS values dropped to zero during episodes of cerebral hypoperfusion or CPA have been described.5, 6 In 2 human patients with CPA for whom the BIS was lower than 35 during CPR, neurological deficits secondary to ischemic brain injury occurred.8 In the calf in this report, BIS was lower than 20 for about 5 minutes. Evaluation of neurologic function was not possible in this case because the calf was euthanized at the end of the procedure. A metabolite of arachidonic acid, TxA2 is a thromboxane receptor (TP) agonist that elicits platelet aggregation and contraction of smooth muscle, and is released in pathological events such as acute respiratory distress syndrome and pulmonary thromboembolism.12 By inhibiting voltage-gated potassium channels, L-type calcium channels are activated, resulting in pulmonary arterial vasoconstriction.13 The TxA2 analog U46619 (9, 11dideoxy-9 alpha, 11 alpha-methanoepoxy prostaglandin
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F-2␣) also binds to TP and causes primarily pulmonary but also systemic hypertension.12 In this calf, an initial increase in SPAP and CVP was observed following U46619 administration. The IBP sharply increased over a brief period, most likely because of an increase in systemic vascular resistance, and then decreased. The circulatory collapse observed in this calf was possibly caused by an excessive increase in pulmonary resistance,14 leading to right-sided myocardial overload and subsequent failure (as suggested by the marked increase in CVP). The authors suspect that right-sided myocardial failure was the most likely reason for CPA; however, other contributing factors exist. With an increase in CVP, an increase in arterial blood pressure was also observed, which may have triggered the observed bradycardia through baroreceptor stimulation. In addition, the calf was hypothermic and the administration of anesthetics continued for 9 minutes following U46619 infusion. Hypothermia can augment anesthesia-related cardiovascular and neurologic depression and in combination with bradycardia and continued anesthetic administration, it may have contributed to CPA. Poor gas exchange, caused by pulmonary hypertension,14 and hypoxemia might have enhanced the systemic derangement as well. Five minutes after U46619 administration was initiated BIS, had already started to decrease; other monitored variables were still within normal limits and a peripheral pulse was palpable. It is likely that U46619 administration resulted in increased afterload and reduced cardiac output. Within 5 minutes of initiating the U46619 infusion, cardiovascular performance deteriorated and in another 5 minutes asystole occurred. Cerebral blood flow depends on the ratio between cerebral perfusion pressure (CPP) and cerebrovascular resistance (CVR). The CPP is the difference between MAP and intracranial pressure, or (when CVP is greater than intracranial pressure) the difference between MAP and CVP. U46619 has only a moderate constriction effect on the cerebral vasculature, which is inhibited by hypoxia and hypercania in both rat and rabbit models.15 The initial decrease in BIS might have been due to cerebral arteriolar vasoconstriction secondary to the rapid increase in MAP following U46619 infusion; in specific circumstances (eg, hyperdynamic circulatory states) sympathetic stimulation causes constriction of cerebral arteries in order to prevent the transmission of high systemic blood pressures to smaller arteries, decreasing the chance of intracranial hemorrhage.16 An acute increase in CVR can cause a decrease in CPP and consequent reduction of brain neuronal activity. Sympathetic influence on cerebral vascular tone is primarily a protective mechanism rather than a direct means of controlling blood flow and several differences are found among species.16
During CPA, autoregulatory mechanisms are impaired and cerebral perfusion is compromised. To prevent neuronal ischemia cerebral electrical activity is inhibited to minimize metabolic demands, which would be expected to cause a decrease in BIS.7 In the described case, BIS constantly decreased and reached zero during asystole. At this time ETCO2 was 3.4 kPa (26 mm Hg). The partial pressure of expired carbon dioxide decreased during CPA but the negative trend was not as steep as expected (Figure 1). The BIS appeared to be an indicator of decreased cerebral activity (possibly caused by reduced CPP). The calf described herein was anesthetized as part of an experimental study to evaluate the presence of pulmonary shunting vessels in ruminants. In order to minimize bias and create a more physiologic scenario, lungs were ventilated with medical air during general anesthesia. To assure that the animal did not become hypoxemic, hemoglobin saturation with oxygen was monitored throughout the procedure by means of a pulse oximeter. Once asystole occurred chest compressions were performed with the calf in sternal recumbency. This position is not ideal to maximize compression efficacy but the subject was connected to a variety of monitors and equipment and positioned on a table for computerized tomography, therefore changing the position was not possible. Chest compressions continued for approximately 2 minutes, during which BIS increased to a maximum of 20 while the electromyography (EMG) remained stable (Figure 1). A value of BIS of at least 35 may be considered optimal during CPR in human patients.8 Following epinephrine administration, BIS briefly decreased and then increased (Figure 1). The initial decrease was likely due to a sudden increase in systemic vascular resistance and CVR with subsequent reduction in CBF and cerebral electrical signaling; once spontaneous circulation resumed BIS started to increase. A similar pattern has been reported in human patients following successful CPR.5, 6, 17 The increase in BIS might have been related to an increase in MAP and thus CPP (in presence of normal CVR), resulting in the reperfusion of brain parenchyma and restoration of neuronal activity. A direct binding of catecholamine on ␤ receptors at the level of the brain reticular activating system (stimulating alertness and consciousness) may also have contributed to the increased BIS.3 Following restoration of cardiac activity, the rate of increase in BIS was less steep than that of IBP and HR. This lag between the restoration in blood pressure and increase in BIS following ROSC has been reported.18 This feature is likely caused by the intrinsic delay of the BIS device that is more apparent when abrupt
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physiologic changes occur.18 The marked increase in IBP observed after epinephrine administration was possibly exacerbated by the synergistic action of U46619 and catecholamines. Trachte19 showed that U46619 potentiates norepinephrine efflux from adrenergic nerves in isolated rabbit vas deferens by stimulating both TP and non-TP type of receptors; more recently U46619 has been shown to potentiate epinephrine-induced vasoconstriction in a dose-dependent manner in isolated human umbilical veins by acting on TP receptors expressed on the vessel endothelium.20 Considering the nature of this report, there are several limitations. The BIS monitor only assesses the electrical activity of the frontal cortex while other parts of the CNS (eg, the brainstem) were not evaluated. In addition, moving artifacts can increase BIS, and it is possible that chest compressions affected the EMG signal, increasing artifact, and making the BIS value unreliable. In this case, EMG values remained stable and did not change during external chest compressions. Prior reports of BIS use during CPA and CPR described human patients, and BIS monitoring on a calf might be not directly comparable with the human ones. Specific differences including brain and skull conformation may lead to differences in EEG recording. In this patient, a postmortem exam was not performed thus neurological outcome and clinical relevance of the described event cannot be assessed. BIS is not validated in any species for use during CPA and CPR and the use of BIS during CPR is not included in official human resuscitation guidelines.1 Following ischemic brain injury, autoregulation of blood flow is disrupted and perfusion of damaged areas varies with CPP. Following ROSC, cerebral electrical activity is initially not coordinated and burst suppression patterns and epileptiform discharges are often recorded on EEG.21 The effect of these phenomena on BIS has not been fully elucidated. Further research may be warranted to better define the role of BIS during CPA and CPR in human and veterinary medicine.
Footnotes a b c d e f g h i
Dormicum, Roche Pharma AG, Switzerland. Propofol 2%, Fresenius Kabi, Switzerland. Tafonius, Vetronic, UK. S5, Datex, Switzerland. BISR TM Monitor A 200; Aspect Medical System, MA. Sintenyl, Sintetica, Switzerland. Ringer Lactate, Fresenius Kabi. U46619, Chemie Brunschwig AG, Switzerland. Adrenaline Sintetica, Sintetica.
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References 1. Nolan JP, Soar J, Zideman DA, et al. ERC guidelines writing group. European Resuscitation Council guidelines for resuscitation 2010 section 1. Executive summary. Resuscitation 2010; 81:1219–1276. 2. March PA, Muir WW. Bispectral analysis of the electroencephalogram: a review of its development and use in anesthesia. Vet Anaesth Analg 2005; 32:241–255. 3. Kluger MT. The bispectral index during an anaphylactic circulatory arrest. Anaesth Intens Care 2001; 29:544–547. 4. Chakravarthy M, Patil T, Jayaprakash K, et al. Bispectral index is an indicator of adequate cerebral perfusion during cardiopulmonary resuscitation. J Cardiothorac Vasc Anesth 2003; 17:506–508. 5. Azim M, Wang CY. The use of bispectral index during a cardiopulmonary arrest: a potential predictor of cerebral perfusion. Anaesthesia 2004; 59:610–612. 6. Morimoto Y, Monden Y, Ohtake K, et al. The detection of cerebral hypoperfusion with bispectral index monitoring during general anesthesia. Anesth Analg 2005; 100:158–161. 7. Pawlik MT, Seyfried TF, Riegger C, et al. Bispectral index monitoring during cardiopulmonary resuscitation repeated twice within 8 days in the same patient: a case report. Int J Emerg Med 2008; 1:209–212. 8. Goodman PG, Mehta AR, Castresana MR. Predicting ischemic brain injury after intraoperative cardiac arrest during cardiac surgery using the BIS monitor. J Clin Anesth 2009; 21:609–612. 9. Leary M, Fried DA, Gaiesk DF, et al. Neurologic prognostication and bispectral index monitoring after resuscitation from cardiac arrest. Resuscitation 2010; 81:1133–1137. 10. Rosow C, Menberg PJ. Bispectral index monitoring. Anesthesiol Clin North America 2001; 19:947–966. 11. Antognini JF, Wang XW, Carstens E. Isoflurane anaesthetic depth in goats monitored using the bispectral index of the electroencephalogram. Vet Res Commun 2000; 24:361–370. 12. Carrithers JA, Brown D, Liu F, et al. Thromboxane A2 mimetic U-46619 induces systemic and pulmonary hypertension and delayed tachypnea in the goat. J Appl Physiol 1994; 77:1466–1473. 13. Cogolludo A, Moreno L, Bosca L, et al. Thromboxane A2 -induced inhibition of voltage-gated K+ channels and pulmonary vasoconstriction: role of protein kinase Czeta. Circ Res 2003; 93:656–663. 14. Lotvall J, Elwood W, Tokuyama K, et al. A thromboxane mimetic, U-46619, produces plasma exudation in airways of the guinea pig. J Appl Physiol 1992; 72:2415–2419. 15. Haberl RL, ML Heizer ML, Ellis EF. Effect of the thromboxane A2 mimetic U46619 on pial arterioles of rabbits and rats. Stroke 1987; 18:796–800. 16. Bevan JA, Duckworth J, Laher I, et al. Sympathetic control of cerebral arteries: specialization in receptor type, reserve, affinity, and distribution. FASEB J 1987; 1:193–198. 17. Losasso TJ, Muzzi DA, Meyer FB, et al. Electroencephalographic monitoring of cerebral function during asystole and successful cardiopulmonary resuscitation. Anesth Analg 1992; 75:1021–1024. 18. England MR. The changes in bispectral index during a hypovolemic cardiac arrest. Anesthesiology 1999; 91:1947–1949. 19. Trachte GJ. Thromboxane agonist (U46619) potentiates norepinephrine efflux from adrenergic nerves. J Pharmacol Exp Ther 1987; 237:473–477. 20. Errasti AE, Luciani LI, Cesio CE, et al. Potentiation of adrenaline vasoconstrictor response by sub-threshold concentrations of U-46619 in human umbilical vein: involvement of smooth muscle prostanoid TP (alpha) receptor isoform. Eur J Pharmacol 2007; 562:227–235. 21. Sundgreen C, Larsen FS, Herzog TM, et al. Autoregulation of cerebral blood flow in patients resuscitated from cardiac arrest. Stroke 2001; 32:128–132.