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Outcomes from low versus high-flow cardiopulmonary resuscitation in a swine model of cardiac arrest
American Journal of Emergency Medicine (2010) 28, 195–202
www.elsevier.com/locate/ajem
Original Contribution
Outcomes from low versus high-flow cardiopulmonary resuscitation in a swine model of cardiac arrest☆,☆☆ Henry R. Halperin MD, MA, FAHAa,b,c,⁎, Kichang Lee PhDd , Menekhem Zviman PhDa , Uday Illindala MSd , Albert Lardo PhDa,c , Aravindan Kolandaivelu MDa , Norman A. Paradis MDd a
Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA Department of Radiology, Johns Hopkins University, Baltimore, MD 21287, USA c Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21287, USA d ZOLL Circulation and University of Southern California, Los Angeles, CA 90089, USA b
Received 1 September 2009; revised 15 October 2009; accepted 19 October 2009
Abstract Background: Return of spontaneous circulation (ROSC) is improved by greater vital organ blood flow during cardiopulmonary resuscitation (CPR). We tested the hypothesis that myocardial flow above the threshold needed for ROSC may be associated with greater vital organ injury and worse outcome. Methods: Aortic and right atrial pressures were measured with micromanometers in 27 swine. After 10 minutes of untreated ventricular fibrillation, chest compression was performed with an automatic, load-distributing band. Animals were randomly assigned to receive flows just sufficient for ROSC (low flow: target coronary perfusion pressure = 12 mm Hg) or well above the minimally effective level (high flow: coronary perfusion pressure = 30 mm Hg). Myocardial flow was measured with microspheres, defibrillation was performed after 3.5 minutes of CPR, and ejection fraction was measured with echocardiography. Results: Return of spontaneous circulation was achieved by 9 of 9 animals in the high-flow group and 15 of 18 in the low-flow group. All animals in the high-flow group defibrillated initially into a perfusing rhythm, whereas 12 of 15 animals achieving ROSC in the low-flow group defibrillated initially into pulseless electrical activity (P b .05, Fisher exact test). Compared with animals in the lowflow group, animals in the high-flow group had shorter resuscitation times, higher mean aortic pressures at ROSC, and higher ejection fractions at 2 hours post-ROSC (all P b .05). Conclusion: High-flow CPR significantly improved arrest hemodynamics, rates of ROSC, and postROSC indicators of myocardial status, all indicating less injury with higher flows. No evidence of organ injury from vital organ blood flow substantially above the threshold for ROSC was found. © 2010 Elsevier Inc. All rights reserved.
Abbreviations: CPP, coronary perfusion pressure; CPR, Cardiopulmonary Resuscitation; ECG, electrocardiogram; LDB, load-distributing band; ROSC, return of spontaneous circulation; VF, ventricular fibrillation. ☆
Supported by a grant from ZOLL Circulation, Sunnyvale, Calif. Disclosures: Drs. Halperin, Zviman, and Lardo are consultants for ZOLL Circulation. Financial interests are governed by policies of the Johns Hopkins University. Drs Lee and Paradis and Mr Illindala are employees of ZOLL. ⁎ Corresponding author. Johns Hopkins Hospital, Baltimore, MD 21287, USA. E-mail address: [email protected] (H.R. Halperin). ☆☆
0735-6757/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.ajem.2009.10.006
196
1. Introduction Of the estimated 300 000 victims of cardiac arrest each year in the United States [1,2], fewer than 15% of victims survive [3,4]. Although early defibrillation can improve outcome [5,6], most patients do not receive or are not candidates for early defibrillation. It is generally accepted that the outcome of patients who fail defibrillation or have non–ventricular fibrillation arrests is related to the vital organ blood flow generated by cardiopulmonary resuscitation (CPR) [7-9], which limits, and potentially reverses, ischemia from cardiac arrest [10]. Although it is well established that greater coronary perfusion pressure (CPP) and the resultant enhanced myocardial flow are strongly associated with increased rates of return of spontaneous circulation (ROSC), it is not as well established that greater CPP and myocardial flow during CPR are associated with better short-term outcomes, in particular lesser degrees of vital organ injury. Recently, it has been hypothesized that myocardial flow above the minimum threshold needed for ROSC may be associated with greater organ injury and worse outcome [11,12]. We undertook the present study to evaluate if improved vital organ blood flow from improved CPR is associated with greater degrees of myocardial injury as manifested by increased myocardial stunning [13,14]. We evaluated the outcomes of animals receiving the minimal CPP necessary for ROSC and a group who received CPR generating substantially greater CPP. Greater stunning would be expected to reduce the maximum positive and negative left ventricular dP/dt, increase the incidence of pulseless electrical activity (PEA), and reduce postresuscitation left ventricular ejection fraction. We made no attempt to distinguish ischemic injury from reperfusion injury because the important outcome is the overall amount of injury.
H.R. Halperin et al. data were not included in the results of this report). With 1 minute of untreated ventricular fibrillation followed by CPR and with a CPP less than 10 mm Hg generated during CPR, there was no ROSC. With a CPP of 10 to 15 mm Hg, 60% of the animals had ROSC and with a CPP higher than 22 mm Hg, all of the animals had ROSC (Fig. 1).
2.3. Relationship between CPP and myocardial blood flow Data from the above studies were analyzed. Prearrest myocardial blood flows were quantified, as were myocardial flows during CPR with CPP less than 10 mm Hg, with CPP 10 to 15 mm Hg, with CPP 22 to 30 mm Hg, and with CPP higher than 30 mm Hg (Fig. 1). With CPP less than 10 mm Hg, the flows were substantially less than 10% of baseline. With CPP 10 to 15 mm Hg, the flows were approximately 10% of baseline. These flows were similar to those reported with manual CPR in other animal models [9,16,17]. In addition, CPPs around 15 mm Hg were the minimum needed for ROSC in patients [18]. Thus, CPPs of 10 to 15 mm Hg can be considered the levels required to generate the minimum amount of flow sufficient for ROSC and will be referred to as those producing “low flow” in the studies below. With CPP of 22 to 30 mm Hg, myocardial flow was approximately 40% of baseline. This level of flow is substantially above the minimum level of flow needed for ROSC and, therefore, can be considered “high flow.”
2. Methods All studies were conducted in accordance with the guidelines of the American Physiological Society for the Care and Use of Laboratory Animals and with the approval of the Johns Hopkins University Institutional Animal Care and Use Committee.
2.1. Preliminary studies Preliminary studies were used to determine the minimum amount of CPP that was associated with ROSC and the relationship between CPP and myocardial blood flow, to assure that CPP gave a valid estimate of myocardial flow during CPR.
2.2. Relationship between CPP and ROSC Data from previous studies [15] were analyzed along with data from an additional eighteen 18-kg pigs (these
Fig. 1 Preliminary studies of 48 animals. Myocardial blood flows with SDs are shown at the prearrest baseline and for increasing levels of generated CPP. Rates of ROSC are shown at the respective levels of generated CPPs. None of these data were included in the other analyses.
Outcomes from low versus high-flow CPR
197 been shown that ejection fraction changes little after 2 hours postresuscitation [19].
2.4. Preparation Twenty-seven additional (beyond the preliminary studies) domestic Yorkshire swine weighing 16 to 18 kg were fasted overnight with free access to water and then sedated with an intramuscular injection of ketamine (30 mg/kg). After endotracheal intubation, anesthesia was maintained with isoflurane (0.5%-4 %) and oxygen (1-3 L/min). Ventilation was provided by a volume-controlled ventilator (Draeger EV-A, Lübeck, Germany) with 100 % O2 (tidal volume of 15-20 mL/kg and ventilation rate of 8 to 15 breaths/min). Ventilation rate and tidal volume were adjusted to maintain normocapnia (the end-expiratory partial pressure of CO2 between 35 and 45 mm Hg) as measured continuously by a capnometer (NPB-75; Nellcor Puritan Bennett, Boulder, Colo) placed in the airway. Arterial blood gases (ABL80; Radiometer, Denmark) were analyzed to confirm adequate baseline ventilation. At all times, the animals were monitored using electrocardiogram, end-tidal CO2, and arterial blood pressure. In addition, depth of anesthesia was continuously assessed. The animals were secured in a supine position and were given normal saline at a rate of 10 mL/kg per hour through a vein to maintain a central venous pressure of ∼5 mm Hg. Through percutaneous cannulations, 2 micromanometertipped single pressure sensors (SPC-350; Millar Instruments, Houston, Tex) and a pressure sensor with a lumen (SPC-471A, Millar Instruments) were placed into (1) the right atrium via the femoral vein, (2) the descending aorta through a femoral artery, and (3) the left ventricle via the carotid artery, for pressure measurements and microsphere injection. Also percutaneously, a pigtail catheter was placed into the descending aorta via a femoral artery, for blood withdrawal during microsphere injections. All catheters were positioned under fluoroscopic guidance, and unfractionated heparin 100 U/kg was given to prevent catheter clotting. A protocol then compared outcomes associated with low flow during CPR (target CPP = 12 mm Hg) with outcomes associated with high flow during CPR (target CPP = 30 mm Hg). Outcomes included the amount of time in CPR required for ROSC, numbers of animals defibrillating into PEA, positive and negative left ventricular dP/dt, and left ventricular ejection fraction 2 hours post-ROSC. It has
Fig. 2
2.5. Experimental protocol After instrumentation, baseline measurements were obtained for all variables, including an echocardiogram for cardiac function. After baseline data collection, blood was drawn for blood gas analyses, and then microspheres were injected to determine the control myocardial blood flow (Fig. 2). The animals were paralyzed using pancuronium (0.1 mg/kg) to minimize respiratory effect on blood pressure during CPR. Isoflurane was then weaned to 0%, and mechanical ventilation was discontinued. Ventricular fibrillation was then induced by 60 Hz, 25-mA alternating current applied to a pacing catheter placed in the right ventricle, and left untreated for 10 minutes, representing the time of untreated cardiac arrest. After 10 minutes of untreated cardiac arrest, pigs were randomly assigned to 2 different CPR protocols and received CPR for 3.5 minutes: group 1: high-flow (CPP ≈30 mm Hg) and group 2: low-flow (CPP ≈12 mm Hg). Nine animals were assigned to the high-flow group and 18 animals assigned to the low-flow group. The difference in the numbers between the 2 groups was due to the possible failure of ROSC in the low-flow group, which was found in the preliminary studies. Immediately after starting CPR, vasopressin (10 U) was administered intravenously, and ventilation was started asynchronously (tidal volume of 710 mL/kg, ventilation rate of 4, and 1:4 inspiration/ expiration ratio) with a mixture of 100% O2. Coronary perfusion pressure was monitored continuously and adjusted with an automated CPR device (AutoPulse) to maintain the desired CPP in each group. After approximately 30 seconds of CPR, arterial and venous blood was collected, and microspheres were injected. After 3.5 minutes of CPR, up to 2 counter shocks (120 J) were administered with a defibrillator (M-Series; ZOLL Med Corp, Chelmsford, Mass). Return of spontaneous circulation was defined as a stable pulse with a systolic arterial pressure of greater than 60 mm Hg. In animals with ROSC, postresuscitation care, including normal ventilation, was started. Animals without initial ROSC received CPR as per their group assignment for an additional 3 minutes, followed
The protocol for CPR and the protocol for post-ROSC.
198 by standard advanced cardiovascular life support, and then standard postresuscitation care. Additional defibrillation shocks were administered as needed. In addition to prearrest and during CPR, hemodynamic and blood gas data were analyzed at 15, 30, 60, and 120 minutes post-ROSC. Animals received standard critical care for 120 minutes post-ROSC. After completion of the protocol, the animals were euthanized with pentobarbital and potassium chloride. Postmortem examination was performed for identification of visceral and thoracic organ injuries and histology.
2.6. Load-distributing-band chest compression device The AutoPulse device (ZOLL Circulation, Sunnyvale, Calif) was modified for the animal study and built around a backboard that retracts a load-distributing band (LDB). The experimental device tightened or loosened a LDB around the chest at 80/min. The LDB conformed to the size of the subject being resuscitated while distributing the compressive load over the anterior chest to reduce local stresses. The AutoPulse device used in this study incorporated an LDB scaled down from the device designed for human use. This porcine-sized LDB allowed an analogous proportion of the porcine thorax to be compressed by the LDB. In addition, this experimental device was modified to allow investigators to manually adjust the compression depth to maintain the desired CPP.
H.R. Halperin et al. A relative decrease in maximum positive dP/dt would indicate a relative decrease in cardiac contractility, whereas a relative decrease in maximum negative dP/dt (less negative) would indicate a relative decrease in the rate of diastolic cardiac relaxation. Increased stunning is expected to reduce cardiac contractility and the rate of diastolic relaxation. Isovolumetric relaxation time (Tau) was determined as the time during isovolumetric relaxation required for the left ventricular pressure to decline from the point of maximal negative left ventricular dP/dt to the pressure point equal to the end-diastolic pressure. Doppler echocardiography was also used to assess left ventricular function by measuring systolic and diastolic left ventricular chamber diameters. Left ventricular ejection fraction was calculated from these latter measurements at the prearrest baseline and at 5, 15, 30, 60, and 120 minutes after ROSC.
2.9. Statistical analysis Data from the preliminary studies were included in Fig. 1 only. No data from the preliminary studies were included in the data analysis resulting in Figs. 2-5 or the tables. Data are
2.7. Measurements Analog outputs of the physiologic parameters were digitized and stored in data files on a personal computer for further analysis using a 16-channel computerized data-acquisition system at a sampling rate of 400 Hz (Powerlab 16SP; ADInstruments, Castle Hill, Australia). Raw data channels included electrocardiogram, aortic pressure, right atrial pressure, left ventricular pressure, end-tidal CO2, real-time CO2 level, and CPR depth. Coronary perfusion pressure was defined as the average difference between the aortic pressure and right atrial pressure during the release phase of chest compression and was calculated using Chart 5 software (ADInstruments). Myocardial blood flow was determined with neutron-activated microspheres (BioPhysics Assay Lab, Worcester, Mass), using methods previously described [15].
2.8. Left ventricular function Left ventricular pressure was measured continuously with a micromanometer-tipped catheter (SPC-471A; Millar Instruments). The left ventricular pressure waveforms were digitized, and left ventricular dP/dt (positive and negative) and end-diastolic pressure were calculated using Matlab software (The MathWorks, Natick, Mass).
Fig. 3 Typical hemodynamics during CPR aimed at generating high flow (A) and low flow (B). Aortic BP indicates aortic blood pressure; atrial BP, right atrial blood pressure.
Outcomes from low versus high-flow CPR
199
3. Results
Fig. 4 Left ventricular maximum positive dP/dt (A) and maximum negative dP/dt (B) showing mean and SDs for all animals in the low-flow and high-flow groups at baseline and at 15 to 120 minutes post-ROSC. *P b .05 versus baseline; †P b .05 highversus low-flow group.
presented as mean ± SD. Differences between group data were tested with 2-tailed t tests for continuous variables and with Fisher exact test for discrete variable. Continuous variables were compared by use of an analysis of variance with repeated measures. All calculations were performed using SAS (Cary, NC) statistical software. P b .05 was considered significant.
Fig. 5 Left ventricular ejection fractions showing mean and SDs for all animals in the low-flow and high-flow groups at baseline and at 5 to 120 minutes post-ROSC. ⁎P b .05 versus baseline; †P b .05 high- versus low-flow group.
Prearrest baseline hemodynamics and ejection fractions were similar for the animals in the low-flow and high-flow groups (Table 1). Return of spontaneous circulation was achieved by 9 of 9 animals in the high-flow group and 15 of 18 animals in the low-flow group. The 3 animals from the low-flow group that did not achieve ROSC were excluded from further analysis. All animals in the high-flow group defibrillated initially into a perfusing rhythm, whereas 12 of 15 animals achieving ROSC in the low-flow group defibrillated initially into PEA (Table 2, P b .05, Fisher exact test). Compared with animals in the low-flow group, animals in the high-flow group had similar numbers of defibrillation shocks but had shorter resuscitation times and less time required to achieve a stable blood pressure after ROSC (Table 2, all P b .05). Fig. 3 shows typical aortic, right atrial, and CPPs during CPR for the high-flow (Fig. 3A) and low-flow (Fig. 3B) groups. The target CPP of 12 versus 30 mm Hg was achieved for the low-flow and high-flow groups, respectively (Table 2), and produced myocardial flows similar to those from the preliminary studies (Table 2 and Fig. 1), verifying the achievement of low and high flows in the respective groups. Hemodynamics, end-tidal CO2, and Tau at the prearrest baseline and during the post-ROSC phase are shown in Table 3. Heart rate at 15 minutes post-ROSC was higher for the high-flow group compared with baseline and the lowflow group. Aortic blood pressures and left ventricular systolic pressures were lower at 15, 30, and 60 minutes postROSC in the low-flow group than at baseline. In addition, Tau was lower at 15 and 30 minutes post-ROSC in the lowflow group than at baseline. Table 1
Prearrest baseline parameters Low flow
High flow
Heart rate (beats/min) 106 ± 14 107 ± 17 Aortic systolic pressure 100 ± 13 101 ± 17 Aortic diastolic pressure 76 ± 12 76 ± 12 Aortic mean pressure 84 ±12 85 ± 13 Right atrial systolic pressure 9±2 9±2 Right atrial diastolic pressure 4±2 5±2 Right atrial mean pressure 6±2 6±2 Left ventricular 97 ±13 98 ± 16 systolic pressure Left ventricular diastolic 8±4 7±3 pressure End-diastolic pressure 11 ± 3 11 ± 3 Left ventricular dP/dt 1588 ± 725 1675 ± 669 Tau (ms) 49 ± 17 52 ± 9 Left ventricular 52 ± 12 45 ± 11 ejection fraction Myocardial blood 1.20 ± 0.46 0.94 ± 0.35 flow (mL min−1 g−1) Pressures are in mm Hg.
P .82 .85 .99 .97 .89 .27 .45 .90 .35 .83 .78 .65 .21 .32
200 Table 2
H.R. Halperin et al. Resuscitation parameters Low flow
High flow
Defibrillation shocks 2.1 ± 1.4 1.9 ± 0.8 PEA postdefibrillation 12/15 0/9 CPP (mm Hg) during CPR 13 ± 3 28 ± 8 CPR time (s) 438 ± 299 242 ± 27 Time to stable BP (s) 728 ± 394 432 ± 121 Myocardial flow during 0.12 ± 0.12 0.43 ± 0.25 CPR (mL min−1 g−1)
P .64 b.05 a b.05 b.05 b.05 b.05
4. Discussion
BP indicates blood pressure. a Fisher exact test.
Baseline maximum positive dP/dt (Fig. 4A) and baseline maximum negative dP/dt (Fig. 4B) were not different between the high-flow and low-flow groups. At 15 and 30 minutes post-ROSC, however, maximum positive dP/dt and maximum negative dP/dt were greater in the high-flow group than in the low-flow group (Fig. 4A and B). Those
Table 3
Hemodynamic parameters
Group
Baseline
ROSC 15 min
Heart rate (beats/min) High flow 107 ± 17 141 ± 24 ⁎ Low flow 106 ± 14 121 ± 20 † Aortic systolic blood pressure (mm Hg) High flow 101 ± 17 79 ± 10 ⁎ Low flow 100 ± 13 71 ± 14 ⁎ Aortic diastolic blood pressure (mm Hg) High flow 76 ± 12 61 ± 9 Low flow 76 ± 12 54 ± 12 ⁎ Mean aortic blood pressure (mm Hg) High flow 85 ± 13 67 ± 9 Low flow 84 ± 12 59 ± 12 ⁎ Mean atrial blood pressure (mm Hg) High flow 6±2 8 ± 2⁎ Low flow 6±2 8 ± 2⁎ Left ventricular systolic blood pressure (mm Hg) High flow 98 ± 16 78 ± 11 ⁎ Low flow 97 ± 13 69 ± 14 ⁎ Left ventricular diastolic blood pressure (mm Hg) High flow 7±3 10 ± 3 Low flow 8±4 12 ± 5 End-diastolic blood pressure (mm Hg) High flow 11 ± 3 12 ± 4 Low flow 11 ± 3 12 ± 3 End-tidal CO2 (%) High flow 36 ± 2 39 ± 5 Low flow 38 ± 4 38 ± 5 Tau (ms) High flow 52 ± 9 40 ± 11 Low flow 49 ± 17 30 ± 9 ⁎, † CI indicates confidence interval. ⁎ P b .05 versus baseline. † P b .05 versus high-flow group.
differences did not persist beyond 30 minutes, and at no times were the maximum dP/dt greater in the low-flow than in the high-flow group (Fig. 4A and B). Baseline ejection fractions were not statistically different between the high-flow and low-flow group animals (Fig. 5). Ejection fraction in the low-flow group animals, however, was lower than that in the high-flow group at 5 minutes postROSC and at 120 minutes post-ROSC.
In this clinically valid laboratory model of out-ofhospital cardiac arrest, we observed that the widely noted benefit of high-flow CPR with respect to increasing ROSC extends at least into the early postresuscitation period. We found that high-flow CPR, compared with low-flow CPR, is associated with better myocardial function after ROSC. Our results are consistent with previous studies in animals, and confirmatory studies in patients, which have
ROSC 30 min
ROSC 60 min
ROSC 120 min
95% CI
127 ± 22 112 ± 22
124 ± 20 109 ± 24
112 ± 26 103 ± 24
110-135 101-119
82 ± 8 73 ± 14 ⁎
84 ± 12 83 ± 16 ⁎
86 ± 14 86 ± 16
80-93 78-88
61 ± 6 55 ± 11 ⁎
63 ± 11 61 ± 14 ⁎
64 ± 14 65 ± 14
59-71 58-66
68 ± 7 61 ± 12 ⁎
70 ± 11 68 ± 15 ⁎
72 ± 14 72 ± 14
66-78 65-73
7±2 8 ± 2⁎
7±2 7 ± 3⁎
7±4 7±4
6-9 6-8
80 ± 9 71 ± 15 ⁎
82 ± 12 80 ± 16 ⁎
83 ± 14 84 ± 16
77-92 75-86
8±2 10 ± 2
7±2 8±2
7±3 7±2
6-10 8-10
11 ± 4 12 ± 2
9±3 10 ± 3
10 ± 4 10 ± 4
9-12 10-12
40 ± 3 38 ± 4
37 ± 1 38 ± 2
34 ± 2 37 ± 2
35-39 37-39
43 ± 11 31 ± 10 ⁎, †
47 ± 11 39 ± 11
41 ± 15 37 ± 12
37-51 32-42
Outcomes from low versus high-flow CPR demonstrated a strong correlation between ROSC and higher levels of CPP and myocardial blood flow [7,9,18]. We found no evidence that blood flows above the minimum threshold needed for ROSC are associated with greater vital organ injury and worse outcome. Traditionally, laboratory studies of CPR hemodynamics have focused on the minimum threshold of flow for ROSC. The theoretical possibility that vital organ blood flows in excess of that minimum threshold for ROSC might be associated with greater reperfusion injury has not previously been evaluated. We found no indication of increased myocardial stunning and thus potentially greater reperfusion injury, if the CPP was above the minimum threshold needed for ROSC. It has been hypothesized that myocardial blood flow during CPR in excess of the minimum threshold needed for ROSC may deliver more metabolic substrate than is needed and that this may exacerbate processes such as acidosis and free-radical production [12]. Our results do not support this conjecture. Our results do not indicate that blood flows just sufficient for ROSC improve outcome or prevent organ injury. Higher flows were associated with shorter resuscitation times, a lower incidence of PEA postdefibrillation (Table 2), and improved postresuscitation myocardial function (Figs. 4 and 5). If there was significant reperfusion injury from blood flows and the delivery of substrate above the minimum threshold for ROSC, it would be expected that our high-flow group would have increased myocardial stunning (as quantified by lower ejection fraction, reduced dP/dt, and increased incidence of PEA). Just the converse of this was observed, however (Figs. 4 and 5; Table 2), and the potential clinical benefits of greater myocardial flow during CPR seem to extend into the early postresuscitation phase. After ROSC, the maximum positive dP/dt of the animals in the high-flow group was always higher or equivalent to those of animals in the low-flow group (Fig. 4A), indicating increased or equivalent cardiac contractility for the high-flow group. The maximum negative dP/dt of the animals in the high-flow group was always increased or equivalent postROSC to those of animals in the low-flow group (Fig. 4B), indicating greater or equivalent rates of diastolic cardiac relaxation for the animals in the high-flow group. In addition, there was no PEA in the high-flow group compared with a substantial incidence in the low-flow group. Increased stunning would have been expected to reduce cardiac contractility and diastolic relaxation, as well as increase the incidence of PEA. Although we only survived animals for 2 hours, landmark studies by Kern et al [13] indicate that postarrest myocardial stunning remains at 24 hours, making it likely that this affects clinical outcomes in these patients. Our data may underestimate the effect because stunning is less in electrically induced models compared with those in which fibrillation is induced ischemically [14]. The theory that vital organs blood flow above the minimum threshold for ROSC might result in exacerbation
201 of reperfusion injury may have some plausibility from the perspective of cellular injury. After prolonged ischemia, tissues may have lost their stores of antioxidant molecules. The oxygen debt and resultant energy failure might theoretically render tissues unable to protect themselves from oxidant injury. We did not, however, obtain any data consistent with such an effect. Of particular importance, our results seem to identify a pattern in which CPR that generated just the minimum threshold flow for ROSC (low-flow group) resulted in PEA and a prolonged time to ROSC (Table 2). Possibly, the deleterious effect of minimum threshold flow on time to ROSC, in particular the prolonged ischemia related to the associated initial PEA, may have had a greater negative effect on the organ injury than any potential benefit associated with avoiding the increased substrate in the high-flow group. Thus, our data do not completely exclude the possibility that myocardial flow greater than the amounts sufficient to avoid initial PEA may be associated with increased reperfusion injury and subsequent postreperfusion myocardial dysfunction. If reperfusion injury was increased in the high-flow group, however, it was more than balanced out by the reduction in ischemic injury from the higher flow. Our results may highlight the importance of PEA in the setting of inadequate CPR hemodynamics. Although the CPP necessary for ROSC is a function of the preexisting coronary disease and the arrest interval, it is widely recognized that in a significant and increasing fraction of patients, standard therapy results in initial PEA [20]. Our results strongly suggest that this might be prevented in some patients if improved CPR is performed. We consider it likely that improved CPR, with its resultant increased CPP, and myocardial flow will be associated clinically with avoidance of initial PEA, earlier ROSC, and reduction of postresuscitation myocardial dysfunction.
4.1. Limitations of the present study We did not measure biochemical markers of reperfusion and myocardial injury. The relationships between these markers and actual outcome with respect to organ injury remain unclear, limiting their value in determining the actual presence of reperfusion injury [21,22]. Our current study does not address the possibility that blood flows in excess of a minimum threshold associated with immediate ROSC, in particular ROSC without initial PEA, might be associated with delayed organ injury.
5. Conclusions With respect to CPR hemodynamics and outcome, the greater the CPP and myocardial blood flow, the better the apparent outcome. Because survival from cardiac arrest, when initial defibrillation fails or is not indicated, is related to the amount of blood flow generated by CPR, it is likely
202 that high-flow CPR, such as from the LDB, might improve survival. No evidence of organ injury from vital organ blood flow substantially above the threshold for ROSC was found.
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www.elsevier.com/locate/ajem
Original Contribution
Outcomes from low versus high-flow cardiopulmonary resuscitation in a swine model of cardiac arrest☆,☆☆ Henry R. Halperin MD, MA, FAHAa,b,c,⁎, Kichang Lee PhDd , Menekhem Zviman PhDa , Uday Illindala MSd , Albert Lardo PhDa,c , Aravindan Kolandaivelu MDa , Norman A. Paradis MDd a
Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA Department of Radiology, Johns Hopkins University, Baltimore, MD 21287, USA c Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21287, USA d ZOLL Circulation and University of Southern California, Los Angeles, CA 90089, USA b
Received 1 September 2009; revised 15 October 2009; accepted 19 October 2009
Abstract Background: Return of spontaneous circulation (ROSC) is improved by greater vital organ blood flow during cardiopulmonary resuscitation (CPR). We tested the hypothesis that myocardial flow above the threshold needed for ROSC may be associated with greater vital organ injury and worse outcome. Methods: Aortic and right atrial pressures were measured with micromanometers in 27 swine. After 10 minutes of untreated ventricular fibrillation, chest compression was performed with an automatic, load-distributing band. Animals were randomly assigned to receive flows just sufficient for ROSC (low flow: target coronary perfusion pressure = 12 mm Hg) or well above the minimally effective level (high flow: coronary perfusion pressure = 30 mm Hg). Myocardial flow was measured with microspheres, defibrillation was performed after 3.5 minutes of CPR, and ejection fraction was measured with echocardiography. Results: Return of spontaneous circulation was achieved by 9 of 9 animals in the high-flow group and 15 of 18 in the low-flow group. All animals in the high-flow group defibrillated initially into a perfusing rhythm, whereas 12 of 15 animals achieving ROSC in the low-flow group defibrillated initially into pulseless electrical activity (P b .05, Fisher exact test). Compared with animals in the lowflow group, animals in the high-flow group had shorter resuscitation times, higher mean aortic pressures at ROSC, and higher ejection fractions at 2 hours post-ROSC (all P b .05). Conclusion: High-flow CPR significantly improved arrest hemodynamics, rates of ROSC, and postROSC indicators of myocardial status, all indicating less injury with higher flows. No evidence of organ injury from vital organ blood flow substantially above the threshold for ROSC was found. © 2010 Elsevier Inc. All rights reserved.
Abbreviations: CPP, coronary perfusion pressure; CPR, Cardiopulmonary Resuscitation; ECG, electrocardiogram; LDB, load-distributing band; ROSC, return of spontaneous circulation; VF, ventricular fibrillation. ☆
Supported by a grant from ZOLL Circulation, Sunnyvale, Calif. Disclosures: Drs. Halperin, Zviman, and Lardo are consultants for ZOLL Circulation. Financial interests are governed by policies of the Johns Hopkins University. Drs Lee and Paradis and Mr Illindala are employees of ZOLL. ⁎ Corresponding author. Johns Hopkins Hospital, Baltimore, MD 21287, USA. E-mail address: [email protected] (H.R. Halperin). ☆☆
0735-6757/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.ajem.2009.10.006
196
1. Introduction Of the estimated 300 000 victims of cardiac arrest each year in the United States [1,2], fewer than 15% of victims survive [3,4]. Although early defibrillation can improve outcome [5,6], most patients do not receive or are not candidates for early defibrillation. It is generally accepted that the outcome of patients who fail defibrillation or have non–ventricular fibrillation arrests is related to the vital organ blood flow generated by cardiopulmonary resuscitation (CPR) [7-9], which limits, and potentially reverses, ischemia from cardiac arrest [10]. Although it is well established that greater coronary perfusion pressure (CPP) and the resultant enhanced myocardial flow are strongly associated with increased rates of return of spontaneous circulation (ROSC), it is not as well established that greater CPP and myocardial flow during CPR are associated with better short-term outcomes, in particular lesser degrees of vital organ injury. Recently, it has been hypothesized that myocardial flow above the minimum threshold needed for ROSC may be associated with greater organ injury and worse outcome [11,12]. We undertook the present study to evaluate if improved vital organ blood flow from improved CPR is associated with greater degrees of myocardial injury as manifested by increased myocardial stunning [13,14]. We evaluated the outcomes of animals receiving the minimal CPP necessary for ROSC and a group who received CPR generating substantially greater CPP. Greater stunning would be expected to reduce the maximum positive and negative left ventricular dP/dt, increase the incidence of pulseless electrical activity (PEA), and reduce postresuscitation left ventricular ejection fraction. We made no attempt to distinguish ischemic injury from reperfusion injury because the important outcome is the overall amount of injury.
H.R. Halperin et al. data were not included in the results of this report). With 1 minute of untreated ventricular fibrillation followed by CPR and with a CPP less than 10 mm Hg generated during CPR, there was no ROSC. With a CPP of 10 to 15 mm Hg, 60% of the animals had ROSC and with a CPP higher than 22 mm Hg, all of the animals had ROSC (Fig. 1).
2.3. Relationship between CPP and myocardial blood flow Data from the above studies were analyzed. Prearrest myocardial blood flows were quantified, as were myocardial flows during CPR with CPP less than 10 mm Hg, with CPP 10 to 15 mm Hg, with CPP 22 to 30 mm Hg, and with CPP higher than 30 mm Hg (Fig. 1). With CPP less than 10 mm Hg, the flows were substantially less than 10% of baseline. With CPP 10 to 15 mm Hg, the flows were approximately 10% of baseline. These flows were similar to those reported with manual CPR in other animal models [9,16,17]. In addition, CPPs around 15 mm Hg were the minimum needed for ROSC in patients [18]. Thus, CPPs of 10 to 15 mm Hg can be considered the levels required to generate the minimum amount of flow sufficient for ROSC and will be referred to as those producing “low flow” in the studies below. With CPP of 22 to 30 mm Hg, myocardial flow was approximately 40% of baseline. This level of flow is substantially above the minimum level of flow needed for ROSC and, therefore, can be considered “high flow.”
2. Methods All studies were conducted in accordance with the guidelines of the American Physiological Society for the Care and Use of Laboratory Animals and with the approval of the Johns Hopkins University Institutional Animal Care and Use Committee.
2.1. Preliminary studies Preliminary studies were used to determine the minimum amount of CPP that was associated with ROSC and the relationship between CPP and myocardial blood flow, to assure that CPP gave a valid estimate of myocardial flow during CPR.
2.2. Relationship between CPP and ROSC Data from previous studies [15] were analyzed along with data from an additional eighteen 18-kg pigs (these
Fig. 1 Preliminary studies of 48 animals. Myocardial blood flows with SDs are shown at the prearrest baseline and for increasing levels of generated CPP. Rates of ROSC are shown at the respective levels of generated CPPs. None of these data were included in the other analyses.
Outcomes from low versus high-flow CPR
197 been shown that ejection fraction changes little after 2 hours postresuscitation [19].
2.4. Preparation Twenty-seven additional (beyond the preliminary studies) domestic Yorkshire swine weighing 16 to 18 kg were fasted overnight with free access to water and then sedated with an intramuscular injection of ketamine (30 mg/kg). After endotracheal intubation, anesthesia was maintained with isoflurane (0.5%-4 %) and oxygen (1-3 L/min). Ventilation was provided by a volume-controlled ventilator (Draeger EV-A, Lübeck, Germany) with 100 % O2 (tidal volume of 15-20 mL/kg and ventilation rate of 8 to 15 breaths/min). Ventilation rate and tidal volume were adjusted to maintain normocapnia (the end-expiratory partial pressure of CO2 between 35 and 45 mm Hg) as measured continuously by a capnometer (NPB-75; Nellcor Puritan Bennett, Boulder, Colo) placed in the airway. Arterial blood gases (ABL80; Radiometer, Denmark) were analyzed to confirm adequate baseline ventilation. At all times, the animals were monitored using electrocardiogram, end-tidal CO2, and arterial blood pressure. In addition, depth of anesthesia was continuously assessed. The animals were secured in a supine position and were given normal saline at a rate of 10 mL/kg per hour through a vein to maintain a central venous pressure of ∼5 mm Hg. Through percutaneous cannulations, 2 micromanometertipped single pressure sensors (SPC-350; Millar Instruments, Houston, Tex) and a pressure sensor with a lumen (SPC-471A, Millar Instruments) were placed into (1) the right atrium via the femoral vein, (2) the descending aorta through a femoral artery, and (3) the left ventricle via the carotid artery, for pressure measurements and microsphere injection. Also percutaneously, a pigtail catheter was placed into the descending aorta via a femoral artery, for blood withdrawal during microsphere injections. All catheters were positioned under fluoroscopic guidance, and unfractionated heparin 100 U/kg was given to prevent catheter clotting. A protocol then compared outcomes associated with low flow during CPR (target CPP = 12 mm Hg) with outcomes associated with high flow during CPR (target CPP = 30 mm Hg). Outcomes included the amount of time in CPR required for ROSC, numbers of animals defibrillating into PEA, positive and negative left ventricular dP/dt, and left ventricular ejection fraction 2 hours post-ROSC. It has
Fig. 2
2.5. Experimental protocol After instrumentation, baseline measurements were obtained for all variables, including an echocardiogram for cardiac function. After baseline data collection, blood was drawn for blood gas analyses, and then microspheres were injected to determine the control myocardial blood flow (Fig. 2). The animals were paralyzed using pancuronium (0.1 mg/kg) to minimize respiratory effect on blood pressure during CPR. Isoflurane was then weaned to 0%, and mechanical ventilation was discontinued. Ventricular fibrillation was then induced by 60 Hz, 25-mA alternating current applied to a pacing catheter placed in the right ventricle, and left untreated for 10 minutes, representing the time of untreated cardiac arrest. After 10 minutes of untreated cardiac arrest, pigs were randomly assigned to 2 different CPR protocols and received CPR for 3.5 minutes: group 1: high-flow (CPP ≈30 mm Hg) and group 2: low-flow (CPP ≈12 mm Hg). Nine animals were assigned to the high-flow group and 18 animals assigned to the low-flow group. The difference in the numbers between the 2 groups was due to the possible failure of ROSC in the low-flow group, which was found in the preliminary studies. Immediately after starting CPR, vasopressin (10 U) was administered intravenously, and ventilation was started asynchronously (tidal volume of 710 mL/kg, ventilation rate of 4, and 1:4 inspiration/ expiration ratio) with a mixture of 100% O2. Coronary perfusion pressure was monitored continuously and adjusted with an automated CPR device (AutoPulse) to maintain the desired CPP in each group. After approximately 30 seconds of CPR, arterial and venous blood was collected, and microspheres were injected. After 3.5 minutes of CPR, up to 2 counter shocks (120 J) were administered with a defibrillator (M-Series; ZOLL Med Corp, Chelmsford, Mass). Return of spontaneous circulation was defined as a stable pulse with a systolic arterial pressure of greater than 60 mm Hg. In animals with ROSC, postresuscitation care, including normal ventilation, was started. Animals without initial ROSC received CPR as per their group assignment for an additional 3 minutes, followed
The protocol for CPR and the protocol for post-ROSC.
198 by standard advanced cardiovascular life support, and then standard postresuscitation care. Additional defibrillation shocks were administered as needed. In addition to prearrest and during CPR, hemodynamic and blood gas data were analyzed at 15, 30, 60, and 120 minutes post-ROSC. Animals received standard critical care for 120 minutes post-ROSC. After completion of the protocol, the animals were euthanized with pentobarbital and potassium chloride. Postmortem examination was performed for identification of visceral and thoracic organ injuries and histology.
2.6. Load-distributing-band chest compression device The AutoPulse device (ZOLL Circulation, Sunnyvale, Calif) was modified for the animal study and built around a backboard that retracts a load-distributing band (LDB). The experimental device tightened or loosened a LDB around the chest at 80/min. The LDB conformed to the size of the subject being resuscitated while distributing the compressive load over the anterior chest to reduce local stresses. The AutoPulse device used in this study incorporated an LDB scaled down from the device designed for human use. This porcine-sized LDB allowed an analogous proportion of the porcine thorax to be compressed by the LDB. In addition, this experimental device was modified to allow investigators to manually adjust the compression depth to maintain the desired CPP.
H.R. Halperin et al. A relative decrease in maximum positive dP/dt would indicate a relative decrease in cardiac contractility, whereas a relative decrease in maximum negative dP/dt (less negative) would indicate a relative decrease in the rate of diastolic cardiac relaxation. Increased stunning is expected to reduce cardiac contractility and the rate of diastolic relaxation. Isovolumetric relaxation time (Tau) was determined as the time during isovolumetric relaxation required for the left ventricular pressure to decline from the point of maximal negative left ventricular dP/dt to the pressure point equal to the end-diastolic pressure. Doppler echocardiography was also used to assess left ventricular function by measuring systolic and diastolic left ventricular chamber diameters. Left ventricular ejection fraction was calculated from these latter measurements at the prearrest baseline and at 5, 15, 30, 60, and 120 minutes after ROSC.
2.9. Statistical analysis Data from the preliminary studies were included in Fig. 1 only. No data from the preliminary studies were included in the data analysis resulting in Figs. 2-5 or the tables. Data are
2.7. Measurements Analog outputs of the physiologic parameters were digitized and stored in data files on a personal computer for further analysis using a 16-channel computerized data-acquisition system at a sampling rate of 400 Hz (Powerlab 16SP; ADInstruments, Castle Hill, Australia). Raw data channels included electrocardiogram, aortic pressure, right atrial pressure, left ventricular pressure, end-tidal CO2, real-time CO2 level, and CPR depth. Coronary perfusion pressure was defined as the average difference between the aortic pressure and right atrial pressure during the release phase of chest compression and was calculated using Chart 5 software (ADInstruments). Myocardial blood flow was determined with neutron-activated microspheres (BioPhysics Assay Lab, Worcester, Mass), using methods previously described [15].
2.8. Left ventricular function Left ventricular pressure was measured continuously with a micromanometer-tipped catheter (SPC-471A; Millar Instruments). The left ventricular pressure waveforms were digitized, and left ventricular dP/dt (positive and negative) and end-diastolic pressure were calculated using Matlab software (The MathWorks, Natick, Mass).
Fig. 3 Typical hemodynamics during CPR aimed at generating high flow (A) and low flow (B). Aortic BP indicates aortic blood pressure; atrial BP, right atrial blood pressure.
Outcomes from low versus high-flow CPR
199
3. Results
Fig. 4 Left ventricular maximum positive dP/dt (A) and maximum negative dP/dt (B) showing mean and SDs for all animals in the low-flow and high-flow groups at baseline and at 15 to 120 minutes post-ROSC. *P b .05 versus baseline; †P b .05 highversus low-flow group.
presented as mean ± SD. Differences between group data were tested with 2-tailed t tests for continuous variables and with Fisher exact test for discrete variable. Continuous variables were compared by use of an analysis of variance with repeated measures. All calculations were performed using SAS (Cary, NC) statistical software. P b .05 was considered significant.
Fig. 5 Left ventricular ejection fractions showing mean and SDs for all animals in the low-flow and high-flow groups at baseline and at 5 to 120 minutes post-ROSC. ⁎P b .05 versus baseline; †P b .05 high- versus low-flow group.
Prearrest baseline hemodynamics and ejection fractions were similar for the animals in the low-flow and high-flow groups (Table 1). Return of spontaneous circulation was achieved by 9 of 9 animals in the high-flow group and 15 of 18 animals in the low-flow group. The 3 animals from the low-flow group that did not achieve ROSC were excluded from further analysis. All animals in the high-flow group defibrillated initially into a perfusing rhythm, whereas 12 of 15 animals achieving ROSC in the low-flow group defibrillated initially into PEA (Table 2, P b .05, Fisher exact test). Compared with animals in the low-flow group, animals in the high-flow group had similar numbers of defibrillation shocks but had shorter resuscitation times and less time required to achieve a stable blood pressure after ROSC (Table 2, all P b .05). Fig. 3 shows typical aortic, right atrial, and CPPs during CPR for the high-flow (Fig. 3A) and low-flow (Fig. 3B) groups. The target CPP of 12 versus 30 mm Hg was achieved for the low-flow and high-flow groups, respectively (Table 2), and produced myocardial flows similar to those from the preliminary studies (Table 2 and Fig. 1), verifying the achievement of low and high flows in the respective groups. Hemodynamics, end-tidal CO2, and Tau at the prearrest baseline and during the post-ROSC phase are shown in Table 3. Heart rate at 15 minutes post-ROSC was higher for the high-flow group compared with baseline and the lowflow group. Aortic blood pressures and left ventricular systolic pressures were lower at 15, 30, and 60 minutes postROSC in the low-flow group than at baseline. In addition, Tau was lower at 15 and 30 minutes post-ROSC in the lowflow group than at baseline. Table 1
Prearrest baseline parameters Low flow
High flow
Heart rate (beats/min) 106 ± 14 107 ± 17 Aortic systolic pressure 100 ± 13 101 ± 17 Aortic diastolic pressure 76 ± 12 76 ± 12 Aortic mean pressure 84 ±12 85 ± 13 Right atrial systolic pressure 9±2 9±2 Right atrial diastolic pressure 4±2 5±2 Right atrial mean pressure 6±2 6±2 Left ventricular 97 ±13 98 ± 16 systolic pressure Left ventricular diastolic 8±4 7±3 pressure End-diastolic pressure 11 ± 3 11 ± 3 Left ventricular dP/dt 1588 ± 725 1675 ± 669 Tau (ms) 49 ± 17 52 ± 9 Left ventricular 52 ± 12 45 ± 11 ejection fraction Myocardial blood 1.20 ± 0.46 0.94 ± 0.35 flow (mL min−1 g−1) Pressures are in mm Hg.
P .82 .85 .99 .97 .89 .27 .45 .90 .35 .83 .78 .65 .21 .32
200 Table 2
H.R. Halperin et al. Resuscitation parameters Low flow
High flow
Defibrillation shocks 2.1 ± 1.4 1.9 ± 0.8 PEA postdefibrillation 12/15 0/9 CPP (mm Hg) during CPR 13 ± 3 28 ± 8 CPR time (s) 438 ± 299 242 ± 27 Time to stable BP (s) 728 ± 394 432 ± 121 Myocardial flow during 0.12 ± 0.12 0.43 ± 0.25 CPR (mL min−1 g−1)
P .64 b.05 a b.05 b.05 b.05 b.05
4. Discussion
BP indicates blood pressure. a Fisher exact test.
Baseline maximum positive dP/dt (Fig. 4A) and baseline maximum negative dP/dt (Fig. 4B) were not different between the high-flow and low-flow groups. At 15 and 30 minutes post-ROSC, however, maximum positive dP/dt and maximum negative dP/dt were greater in the high-flow group than in the low-flow group (Fig. 4A and B). Those
Table 3
Hemodynamic parameters
Group
Baseline
ROSC 15 min
Heart rate (beats/min) High flow 107 ± 17 141 ± 24 ⁎ Low flow 106 ± 14 121 ± 20 † Aortic systolic blood pressure (mm Hg) High flow 101 ± 17 79 ± 10 ⁎ Low flow 100 ± 13 71 ± 14 ⁎ Aortic diastolic blood pressure (mm Hg) High flow 76 ± 12 61 ± 9 Low flow 76 ± 12 54 ± 12 ⁎ Mean aortic blood pressure (mm Hg) High flow 85 ± 13 67 ± 9 Low flow 84 ± 12 59 ± 12 ⁎ Mean atrial blood pressure (mm Hg) High flow 6±2 8 ± 2⁎ Low flow 6±2 8 ± 2⁎ Left ventricular systolic blood pressure (mm Hg) High flow 98 ± 16 78 ± 11 ⁎ Low flow 97 ± 13 69 ± 14 ⁎ Left ventricular diastolic blood pressure (mm Hg) High flow 7±3 10 ± 3 Low flow 8±4 12 ± 5 End-diastolic blood pressure (mm Hg) High flow 11 ± 3 12 ± 4 Low flow 11 ± 3 12 ± 3 End-tidal CO2 (%) High flow 36 ± 2 39 ± 5 Low flow 38 ± 4 38 ± 5 Tau (ms) High flow 52 ± 9 40 ± 11 Low flow 49 ± 17 30 ± 9 ⁎, † CI indicates confidence interval. ⁎ P b .05 versus baseline. † P b .05 versus high-flow group.
differences did not persist beyond 30 minutes, and at no times were the maximum dP/dt greater in the low-flow than in the high-flow group (Fig. 4A and B). Baseline ejection fractions were not statistically different between the high-flow and low-flow group animals (Fig. 5). Ejection fraction in the low-flow group animals, however, was lower than that in the high-flow group at 5 minutes postROSC and at 120 minutes post-ROSC.
In this clinically valid laboratory model of out-ofhospital cardiac arrest, we observed that the widely noted benefit of high-flow CPR with respect to increasing ROSC extends at least into the early postresuscitation period. We found that high-flow CPR, compared with low-flow CPR, is associated with better myocardial function after ROSC. Our results are consistent with previous studies in animals, and confirmatory studies in patients, which have
ROSC 30 min
ROSC 60 min
ROSC 120 min
95% CI
127 ± 22 112 ± 22
124 ± 20 109 ± 24
112 ± 26 103 ± 24
110-135 101-119
82 ± 8 73 ± 14 ⁎
84 ± 12 83 ± 16 ⁎
86 ± 14 86 ± 16
80-93 78-88
61 ± 6 55 ± 11 ⁎
63 ± 11 61 ± 14 ⁎
64 ± 14 65 ± 14
59-71 58-66
68 ± 7 61 ± 12 ⁎
70 ± 11 68 ± 15 ⁎
72 ± 14 72 ± 14
66-78 65-73
7±2 8 ± 2⁎
7±2 7 ± 3⁎
7±4 7±4
6-9 6-8
80 ± 9 71 ± 15 ⁎
82 ± 12 80 ± 16 ⁎
83 ± 14 84 ± 16
77-92 75-86
8±2 10 ± 2
7±2 8±2
7±3 7±2
6-10 8-10
11 ± 4 12 ± 2
9±3 10 ± 3
10 ± 4 10 ± 4
9-12 10-12
40 ± 3 38 ± 4
37 ± 1 38 ± 2
34 ± 2 37 ± 2
35-39 37-39
43 ± 11 31 ± 10 ⁎, †
47 ± 11 39 ± 11
41 ± 15 37 ± 12
37-51 32-42
Outcomes from low versus high-flow CPR demonstrated a strong correlation between ROSC and higher levels of CPP and myocardial blood flow [7,9,18]. We found no evidence that blood flows above the minimum threshold needed for ROSC are associated with greater vital organ injury and worse outcome. Traditionally, laboratory studies of CPR hemodynamics have focused on the minimum threshold of flow for ROSC. The theoretical possibility that vital organ blood flows in excess of that minimum threshold for ROSC might be associated with greater reperfusion injury has not previously been evaluated. We found no indication of increased myocardial stunning and thus potentially greater reperfusion injury, if the CPP was above the minimum threshold needed for ROSC. It has been hypothesized that myocardial blood flow during CPR in excess of the minimum threshold needed for ROSC may deliver more metabolic substrate than is needed and that this may exacerbate processes such as acidosis and free-radical production [12]. Our results do not support this conjecture. Our results do not indicate that blood flows just sufficient for ROSC improve outcome or prevent organ injury. Higher flows were associated with shorter resuscitation times, a lower incidence of PEA postdefibrillation (Table 2), and improved postresuscitation myocardial function (Figs. 4 and 5). If there was significant reperfusion injury from blood flows and the delivery of substrate above the minimum threshold for ROSC, it would be expected that our high-flow group would have increased myocardial stunning (as quantified by lower ejection fraction, reduced dP/dt, and increased incidence of PEA). Just the converse of this was observed, however (Figs. 4 and 5; Table 2), and the potential clinical benefits of greater myocardial flow during CPR seem to extend into the early postresuscitation phase. After ROSC, the maximum positive dP/dt of the animals in the high-flow group was always higher or equivalent to those of animals in the low-flow group (Fig. 4A), indicating increased or equivalent cardiac contractility for the high-flow group. The maximum negative dP/dt of the animals in the high-flow group was always increased or equivalent postROSC to those of animals in the low-flow group (Fig. 4B), indicating greater or equivalent rates of diastolic cardiac relaxation for the animals in the high-flow group. In addition, there was no PEA in the high-flow group compared with a substantial incidence in the low-flow group. Increased stunning would have been expected to reduce cardiac contractility and diastolic relaxation, as well as increase the incidence of PEA. Although we only survived animals for 2 hours, landmark studies by Kern et al [13] indicate that postarrest myocardial stunning remains at 24 hours, making it likely that this affects clinical outcomes in these patients. Our data may underestimate the effect because stunning is less in electrically induced models compared with those in which fibrillation is induced ischemically [14]. The theory that vital organs blood flow above the minimum threshold for ROSC might result in exacerbation
201 of reperfusion injury may have some plausibility from the perspective of cellular injury. After prolonged ischemia, tissues may have lost their stores of antioxidant molecules. The oxygen debt and resultant energy failure might theoretically render tissues unable to protect themselves from oxidant injury. We did not, however, obtain any data consistent with such an effect. Of particular importance, our results seem to identify a pattern in which CPR that generated just the minimum threshold flow for ROSC (low-flow group) resulted in PEA and a prolonged time to ROSC (Table 2). Possibly, the deleterious effect of minimum threshold flow on time to ROSC, in particular the prolonged ischemia related to the associated initial PEA, may have had a greater negative effect on the organ injury than any potential benefit associated with avoiding the increased substrate in the high-flow group. Thus, our data do not completely exclude the possibility that myocardial flow greater than the amounts sufficient to avoid initial PEA may be associated with increased reperfusion injury and subsequent postreperfusion myocardial dysfunction. If reperfusion injury was increased in the high-flow group, however, it was more than balanced out by the reduction in ischemic injury from the higher flow. Our results may highlight the importance of PEA in the setting of inadequate CPR hemodynamics. Although the CPP necessary for ROSC is a function of the preexisting coronary disease and the arrest interval, it is widely recognized that in a significant and increasing fraction of patients, standard therapy results in initial PEA [20]. Our results strongly suggest that this might be prevented in some patients if improved CPR is performed. We consider it likely that improved CPR, with its resultant increased CPP, and myocardial flow will be associated clinically with avoidance of initial PEA, earlier ROSC, and reduction of postresuscitation myocardial dysfunction.
4.1. Limitations of the present study We did not measure biochemical markers of reperfusion and myocardial injury. The relationships between these markers and actual outcome with respect to organ injury remain unclear, limiting their value in determining the actual presence of reperfusion injury [21,22]. Our current study does not address the possibility that blood flows in excess of a minimum threshold associated with immediate ROSC, in particular ROSC without initial PEA, might be associated with delayed organ injury.
5. Conclusions With respect to CPR hemodynamics and outcome, the greater the CPP and myocardial blood flow, the better the apparent outcome. Because survival from cardiac arrest, when initial defibrillation fails or is not indicated, is related to the amount of blood flow generated by CPR, it is likely
202 that high-flow CPR, such as from the LDB, might improve survival. No evidence of organ injury from vital organ blood flow substantially above the threshold for ROSC was found.
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