Anesth Analg 2002;95:1031-1036
© 2002 International Anesthesia Research Society
CRITICAL CARE AND TRAUMA
Hypertonic-Hyperoncotic Solutions Reduce the Release of Cardiac Troponin I and S-100 After Successful Cardiopulmonary Resuscitation in Pigs
Heiner Krieter, MD DEAA*,
Christof Denz, MD*,
Christoph Janke, MD*,
Thomas Bertsch, MD
,
Thomas Luiz, MD*,
Klaus Ellinger, MD*, and
Klaus van Ackern, MD*
Institutes of *Anesthesiology and Intensive Care Medicine and Clinical Chemistry, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Mannheim, Germany
Address correspondence and reprint requests to Heiner Krieter, MD, DEAA, Postfach 10 19 42, 68019 Mannheim, Germany. Address e-mail to heiner.krieter{at}anaes.ma.uni-heidelberg.de
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Abstract
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In some patients, cardiopulmonary resuscitation (CPR) can revive spontaneous circulation (ROSC). However, neurological outcome often remains poor. Hypertonic-hyperoncotic solutions (HHS) have been shown to improve microvascular conductivity after regional and global ischemia. We investigated the effect of infusion of HHS in a porcine CPR model. Cardiac arrest was induced by ventricular fibrillation. Advanced cardiac life support was begun after 4 min of nonintervention and 1 min of basic life support. Upon ROSC, the animals randomly received 125 mL of either normal saline (placebo, n = 8) or 7.2% NaCl and 10% hydroxyethyl starch 200,000/0.5 (HHS, n = 7). Myocardial and cerebral damage were assessed by serum concentrations of cardiac troponin I and astroglial protein S-100, respectively, up to 240 min after ROSC. In all animals, the levels of cardiac troponin I and S-100 increased after ROSC (P < 0.01). This increase was significantly blunted in animals that received HHS instead of placebo. The use of HHS in the setting of CPR may provide a new option in reducing cell damage in postischemic myocardial and cerebral tissues.
IMPLICATIONS: Infusion of hypertonic-hyperoncotic solutions (HHS) after successful cardiopulmonary resuscitation in pigs significantly reduced the release of cardiac troponin I and cerebral protein S-100, which are sensitive and specific markers of cell damage. Treatment with HHS may provide a new option to improve the outcome of cardiopulmonary resuscitation.
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Introduction
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The modern algorithms for the treatment of cardiac arrest (CA) often make it possible to restore spontaneous circulation. Despite all efforts to accelerate the response to and improve the treatment of CA, the neurological outcome often remains poor (1). One unsolved problem after successful cardiopulmonary resuscitation (CPR) is the discrepancy between normalized hemodynamic variables and the still-compromised microcirculation (2). Periods of low blood flow, which notoriously occur during basic life support (BLS), contribute significantly to the cerebral no-reflow phenomenon (3).
The infusion of small amounts of hypertonic-hyperoncotic solutions (HHS) has proven to be successful in restoring macro- and microcirculation after shock (4–6) and regional ischemia and reperfusion (7). One common mechanism of action in those settings is the shift of fluid from endothelial cells into the intravascular space. This effect will not only increase blood volume, but will also markedly improve conductance of the microcirculation which, in turn, warrants a fast restoration of regional blood flow (6). This study was designed to investigate the effects of HHS in a porcine model of global ischemia and reperfusion as occurs after successful CPR.
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Methods
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The study protocol and all procedures were approved by the governmental and institutional Animal Care Committees. Guidelines and terminology of the Utstein style for laboratory CPR research (8) were followed. Sixteen domestic farm pigs (body weight for both sexes, 27 ± 3 kg) were studied. The animals were fasted for 24 h but had free access to water. The pigs were premedicated with 4 mg/kg IM of azaperone and were left in a dark and silent room for 30 min. Anesthesia was then induced with 0.3 mg/kg of midazolam and 10 mg/kg of S(+)-ketamine IV. Upon orotracheal intubation with a cuffed tracheal tube, the lungs were mechanically ventilated at a respiratory rate of 16 breaths/min with a mixture of oxygen and air (fraction of inspired oxygen, 0.4). The tidal volume was initially set to 10 mL/kg. On the basis of arterial blood gas analysis and the end-tidal concentration of carbon dioxide (CO2 Analyzer 930; Siemens-Elema, Solna/Sweden), ventilation was adjusted to keep the arterial PCO2 in a range of 38 to 40 mm Hg. Anesthesia was maintained by continuous IV infusion of pentobarbital (2 mg · kg-1 · h-1), piritramide (0.5 mg · kg-1 · h-1), and vecuronium (0.6 mg · kg-1 · h-1). A balanced electrolyte solution (ElomelTM; Delta Pharma, Pfullingen/Germany) was infused at a rate of 10 mL · kg-1 · h-1 to compensate for the basal loss of fluid. Body core temperature was monitored via a thermistor-tipped pulmonary artery catheter and maintained at 38°C ± 1°C by means of a heating pad and an infrared light.
A 2 x 2 cm area of the skull was exposed to place a Codman probe (ICP ExpressTM; Johnson & Johnson, Raynham, MA) 1 cm lateral from the sagittal and 1 cm rostral from the coronary suture to monitor intracranial pressure (ICP). Next, the animals were placed in the supine position. The probe was calibrated and connected to the monitoring system (Sirecust 1281; Siemens Medical Electronics, Danvers, MA). The right external jugular vein was exposed to place a multilumen central venous catheter (Arrows PN BR-14703-EK; Arrow Int., Reading, PA) and a 7F pulmonary artery catheter (Spectramed, Bilthoven/Netherlands). For monitoring of the aortic blood pressure and arterial blood sampling, another three-lumen catheter was inserted via the right femoral artery and advanced into the abdominal aorta. Finally, the correct placement of all catheters was verified by fluoroscopy, and the wounds were closed.
Central venous, arterial, and pulmonary arterial blood pressures were measured with fluid-filled catheters connected to calibrated pressure transducers. The zero-pressure level was adjusted to half the sagittal thoracic diameter. All pressure signals and one lead of an electrocardiogram (ECG) were digitized and stored on a personal computer for off-line data analysis. Cardiac output was estimated in triplicate at each time point by the thermodilution technique and averaged. The cardiac index (CI) was calculated as cardiac output/body weight. Coronary perfusion pressure (corPP) was calculated as the difference between diastolic aortic pressure and the central venous pressure. Cerebral perfusion pressure (cerPP) was calculated as the difference between mean aortic pressure and ICP.
Concentrations of hemoglobin (Hb), sodium, and potassium were determined according to standard laboratory methods. Blood gas analysis was performed with an automatic blood gas analyzer (ABL 300; Radiometer, Copenhagen, Denmark). Arterial blood samples were centrifuged and the serum stored at -80°C until analysis. Concentrations of cardiac troponin I (cTnI) was determined with an immunoassay from Dade Behring as described in detail previously (9). Another immunoassay was used to measure the serum levels of protein S-100 (S-100 immunoradiometric assay [IRMA]; AB Sangtec Medical).
Baseline values of all variables were recorded after a 30-min equilibration period. Ventricular fibrillation was then induced by a short transthoracic alternating current pulse of 60 V/50 Hz. The time line of the CPR is given in Figure 1. Onset of CA was verified by ventricular fibrillation (ECG) and rapidly decreasing nonpulsatile pressure readings of the aortic pressure. Artificial ventilation and all infusions were stopped. After 4 min of untreated ventricular fibrillation, BLS was begun: mechanical ventilation was resumed at the prearrest settings but with ambient air (fraction of inspired oxygen, 0.21). Closed-chest CPR was applied manually at a rate of 100 compressions per minute, with a duty cycle of 50%. In all experiments, chest compressions were performed by the same person, who was blinded to the type of solution used and the monitor readings. A metronome was used to ensure the correct compression rate. After 1 min of BLS (5 min of CA), advanced cardiac life support according to the algorithm published by the American Heart Association (10) was begun. In detail, closed-chest compression was continued as detailed previously while ventilation was switched to 100% oxygen. Every 3 min, epinephrine was injected at a dose of 50 µg/kg via the central venous line, which was then flushed with 20 mL of saline. External defibrillation was used at an energy of 200 J per shock. Return of spontaneous circulation (ROSC) was defined as the recurrence of cardiac contractile activity, indicated by a pulsatile aortic pressure tracing and a systolic aortic pressure of >60 mm Hg during the first 10 min (8).
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Figure 1. Time line of the resuscitation protocol. Cardiac arrest due to ventricular fibrillation was induced by a transthoracic alternating current (AC) pulse of 60 V/50 Hz. After 4 min of nonintervention, basic life support (BLS) was begun. Advanced cardiac life support (ACLS) was started after 5 min of ventricular fibrillation and continued until the return of spontaneous circulation (ROSC). During ACLS, epinephrine (50 µg/kg) and external defibrillation shocks (200 J) were applied (see Methods for details).
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Upon ROSC, the animals randomly received either placebo (n = 8; 125 mL of 0.9% saline at 12.5 mL/min) or HHS (n = 8; 125 mL 7.2% NaCl and 10% hydroxyethyl starch 200,000/0.5 at 12.5 mL/min). The type of solution and group assignment of each experiment were blinded for all persons involved in CPR and monitoring. Complete sets of measurements were recorded at 30, 60, 120, 180, and 240 min after ROSC. Finally, the animals were killed by injection of pentobarbital and saturated KCl solution.
All values are given as arithmetical mean ± 1 SD. Differences between groups were assessed with the Mann-Whitney U-test. For testing of different time points among the same group, the Wilcoxon test for paired samples was used. All descriptive and analytical procedures were implemented with SAS or JMP (SAS Institute, Cary, NC). A probability of P < 0.05 was considered statistically significant.
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Results
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All eight animals in the control group completed the protocol. One of the eight animals in the HHS group failed to reestablish a stable systolic aortic pressure of >60 mm Hg during the first 10 min upon ROSC. In accordance with the guidelines of the Utstein style (8), the data of this animal were excluded from further analysis.
The average time until ROSC, mean arterial blood pressure, corPP, cumulative dosage of epinephrine, and number and cumulative energy of electrical defibrillation shocks were similar in both groups (Table 1). Hemodynamic variables and Hb concentrations are summarized in Table 2. There were no significant differences between the groups. As the pulmonary capillary wedge pressure (PCWP) served as the target variable for volume replacement, no relevant changes over time were observed. Immediately after reversal of CA, CI and ICP increased significantly in both groups. The calculated cerPP never revealed significant differences between groups. Hb levels were slightly lower in HHS-treated animals but did not differ significantly as compared with placebo. Figure 2 depicts the time course of serum concentrations of protein S-100. The levels increased immediately after ROSC in both groups. This increase, however, was significantly blunted in animals treated with HHS. Figure 3 illustrates the time course of serum levels of cTnI. Again, there was a steep increase immediately after ROSC that was significantly reduced in animals that received HHS. In contrast to S-100, the maximal concentration of cTnI was not reached within the observation period. The values continuously increased in both groups until 240 min after ROSC.
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Figure 2. Time course of serum concentration of S-100 (mean ± SD) before and after cardiac arrest. Time points given are at baseline (Basis) and up to 240 min after the return of spontaneous circulation (ROSC 5 to ROSC 240). The animals received either hypertonic-hyperoncotic solution (HHS, n = 7; 7.2% NaCl/10% hydroxyethyl starch 200,000/0.5) or placebo (Pla, n = 8; 0.9% NaCl). *P < 0.05; **P < 0.01 versus placebo. CPR = cardiopulmonary resuscitation.
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Figure 3. Time course of serum concentrations of cardiac troponin I (mean ± SD) before and after cardiac arrest. Time points given are at baseline (Basis) and up to 240 min after the return of spontaneous circulation (ROSC 5 to ROSC 240). The animals received either a hypertonic-hyperoncotic solution (HHS, n = 7; 7.2% NaCl/10% hydroxyethyl starch 200,000/0.5) or placebo (Pla, n = 8; 0.9% NaCl). *P < 0.05; **P < 0.01 versus placebo. CPR = cardiopulmonary resuscitation.
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Discussion
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Despite the achievements in technical equipment, resuscitation algorithms, and drug therapy, the neurological outcome in patients who have been resuscitated from CA often remains poor (1). One of the pertinent problems that remain to be solved is fast and adequate reperfusion of vital organs after transient circulatory arrest. This is particularly true for brain tissue, which is prone to early functional and structural damage even after short periods of circulatory arrest. Moreover, despite ROSC, the no-reflow phenomenon is a notorious problem in postischemic tissue in general, but particularly after CA (11). Fischer et al. (12) have demonstrated that the use of thrombolytic drugs and heparin reduces no-reflow in the cat brain after resuscitation from CA. Böttiger et al. (13) have recently shown that the same concept increases the number of patients surviving initially unsuccessful CPR after out-of-hospital CA. Both concluded that this effect is at least in part is explained by improving the perfusion of postischemic tissues.
Our study also addresses the problem of no-reflow after CA, but we focused on another strategy. Rapid infusion of small amounts of HHS not only improves organ blood flow in hemorrhagic shock (4–6), but also improves microcirculation after regional and global ischemia (7,14). In contrast to conventional volume substitutes, HHS are able to drain water from endothelial cells (15), thus enlarging the vessel diameter and its hydraulic conductivity (15–17). The crucial point in such treatment is to produce a sufficiently high osmotic gradient, which requires a concentration of NaCl as high as 7.2%–7.5% wt/vol. Moreover, experimental studies using intravital microscopy revealed that hypertonic solutions may also decrease the number of leukocytes sticking to postischemic vessel walls, thus further improving organ blood flow and preventing the detrimental effects of leukocyte activation and migration on the microcirculatory level (18).
On the basis of these findings, this study was designed to clarify whether the use of HHS will also prove beneficial in the setting of successful CPR. The model is well established and was used in similar studies (19). One animal randomized for HHS had to be excluded from data analysis because it failed to meet the criteria of the Utstein style (8) for stable hemodynamics after ROSC. Because hemodynamic parameters of the remaining animals of the same group did not differ significantly from those of animals in the placebo group, it appears not very likely that this effect can be directly attributed to the infusion of HHS. However, detailed analysis of outcome will require a larger number of animals and should be addressed in future studies. Because morphological changes in postischemic tissue after 5 min of CA are very subtle and require a long follow-up to determine, we chose to assess tissue damage with a biochemical serum marker. Protein S-100 is located predominantly in the astroglial cells and is a very sensitive and specific marker for brain tissue injury and disruption of the blood-brain barrier (20–22). It has been shown to correlate well with the extent and prognosis of ischemic brain injury (20). In addition, we assessed the concentration of cTnI as a marker of myocardial damage. Release of cTnI is highly specific for cardiac cell damage (23) and correlates well with its extent (24). Both markers significantly increased after ROSC in our model of CPR. Whereas the concentration of S-100 peaked at 5 minutes after ROSC and approached baseline values at the end of the experimental protocol (240 minutes after ROSC), the levels of cTnI continuously increased throughout the experiment. This might indicate a larger structural damage during and after resuscitation in the heart. However, the levels of both S-100 and cTnI were significantly reduced in animals that received HHS. A Codman probe was used to monitor ICP and to estimate the cerPP. Because the mean arterial blood pressure and ICP, and thus the cerPP, did not differ significantly between the groups, the reduced release of S-100 cannot be explained by hemodynamic effects on cerebral perfusion. Hb levels did significantly increase in both groups after CA, indicating a loss of cell-free fluid from the intravascular space. Recruitment of pooled erythrocytes would also explain this phenomenon but, in contrast to that in dogs, the spleen of pigs is not known to mobilize considerable numbers of red blood cells under stress. Infusion of HHS led to a reduction of Hb levels that is far too small to explain the huge differences in S-100 or cTnI concentration by hemodilution alone. Moreover, the overall fluid regimen was adjusted to maintain a constant PCWP. Therefore, larger amounts of non-HHS were infused in control animals during the first 60 minutes, thus compensating, at least in part, for the loss of intravascular volume. Epinephrine increases metabolic demands during CPR (25,26) by its ß-adrenergic effect. An impaired balance between myocardial oxygen supply and demand might worsen the myocardial injury during and after CPR. Because the cumulative dosage of epinephrine did not differ between groups, this effect did not influence our results.
In conclusion, we showed that infusion of HHS in the setting of CPR can significantly reduce the release of two sensitive and specific markers of tissue damage in the brain and heart. In accordance with the known effects of HHS (i.e., the improved hydraulic conductivity and reduced leukocyte sticking in postischemic circulation), the use of HHS during CPR may provide a new option for minimizing tissue damage in the brain and heart. Taking into account the findings of Fischer et al. (12) on thrombolytic drugs, further studies should address the effects of a combined therapeutic regimen with HHS and thrombolytic drugs. This may offer a new approach to significantly enhance neurological outcome in patients after resuscitation from CA.
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Acknowledgments
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Supported in part by a grant of the Faculty for Clinical Medicine Mannheim of the University of Heidelberg.
The authors thank M. Lehmer, K. Salomon, J. T. Schulte, and A. Tapper for their skillful technical assistance.
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Footnotes
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Presented in part at the 7th annual meeting of the European Society of Anaesthesiologists, Amsterdam, The Netherlands, May 1999, and the 74th Congress of the International Anesthesia Research Society, Honolulu, HI, March 2000.
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Accepted for publication June 11, 2002.
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Abstract
Introduction
