Ann Thorac Surg 2006;81:183-190
© 2006 The Society of Thoracic Surgeons
Original article: Cardiovascular
Hypertonic Saline Dextran Improves Outcome After Hypothermic Circulatory Arrest: A Study in a Surviving Porcine Model
Timo Kaakinen, MD
a
,
Hanna Alaoja, MS
a
,
Janne Heikkinen, MD
a
,
Sebastian Dahlbacka, MS
a
,
Päivi Laurila, MD, PhD
b
,
Kai Kiviluoma, MD, PhD
b
,
Timo Salomäki, MD, PhD
b
,
Hannu Tuominen, MD, PhD
c
,
Pasi Ohtonen, MS
a
,
b
,
Fausto Biancari, MD, PhD
a
,
Tatu Juvonen, MD, PhD
a
,
*
a Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland
b Department of Anesthesiology, Oulu University Hospital, University of Oulu, Oulu, Finland
c Department of Pathology, Oulu University Hospital, University of Oulu, Oulu, Finland
Accepted for publication July 5, 2005.
* Address correspondence to Prof Juvonen, Division of Cardiothoracic and Vascular Surgery, Department of Surgery, Oulu University Hospital, PO Box 21, 90029 OYS, Finland (Email: tatu.juvonen{at}oulu.fi).
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Abstract
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BACKGROUND: Hypertonic saline dextran (HSD) has been shown to have neuroprotective properties. In the present study we have assessed its potential neuroprotective efficacy in the setting of hypothermic circulatory arrest in a surviving porcine model.
METHODS: Twenty-four pigs were randomized to receive two 5-minute intravenous infusions (4 mL/kg) of either HSD (7.5 % saline, 6% dextran 70) or normal saline immediately after and 4 hours after a 75-minute period of hypothermic circulatory arrest at a brain temperature of 18°C.
RESULTS: The 7-day survival was 75% in the HSD group and 66% in the control group (p > 0.9). Brain total histopathologic score was lower in the HSD group (p = 0.01). Postoperative behavioral scores were higher in the HSD group on the second day after surgery (p = 0.03). Intracranial pressure was lower in the HSD group from 45 minutes to 8 hours after hypothermic circulatory arrest (p = 0.03). Cerebral perfusion pressure was higher in the HSD group from 45 minutes to 3 hours after hypothermic circulatory arrest (p = 0.06). Brain lactate concentration was lower in the HSD group when compared with controls (p = 0.05). Furthermore, brain glucose levels tended to be higher and brain lactate-pyruvate ratio and lactate-glucose ratio were lower in the HSD group. Brain tissue oxygen partial pressures were somewhat higher in the HSD group (p = 0.08).
CONCLUSIONS: The use of HSD in experimental hypothermic circulatory arrest is associated with significantly better neurologic recovery, better histopathology, lower intracranial pressure, higher cerebral perfusion pressure, and better preservation of brain metabolism.
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Introduction
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Hypothermic circulatory arrest (HCA) results in global brain ischemia which is followed by ischemia-reperfusion injury. This leads to loss of wall integrity in microvasculature and fluid leakage; ie, fluid escaping the intravascular space into the brain tissue [1, 2]. The resulting brain edema and elevated intracranial pressure further decrease brain tissue perfusion by compressing and occluding small vessels. Adherent neutrophils and microvascular thrombosis blocking the small cerebral vessels may also play a role in the impairment of cerebral blood flow [1]. If not interrupted by appropriate interventions, this vicious circle eventually leads to cessation of blood flow and irreversible ischemia.
Hypertonic saline dextran (HSD) is used with encouraging results in the treatment of elevated intracranial pressure and head trauma with hypotension [2]. Its neuroprotective properties have been demonstrated in animal models of brain ischemic injury [3, 4]. Hypertonic saline dextran increases plasma osmolarity [5, 6], has an inotropic effect on the heart, causes vasodilation, is associated with better tissue perfusion and oxygenation [7–9], and attenuates the ischemia-reperfusion injury [10].
In cardiac surgery, administration of HSD is associated with near-zero fluid balance and more beneficial hemodynamic parameters than conventional fluid therapy [11]. Hypertonic saline dextran used with cardiopulmonary bypass lowers elevated intracranial pressure [12]. We have found no studies which have evaluated the potentially beneficial effects of hypertonic fluid therapy in the setting of deep HCA. Thus, we planned the present study to assess the potential neuroprotective effects of HSD during experimental HCA.
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Material and Methods
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Twenty-four female juvenile pigs (8 to 10 weeks old) from a native stock, with a median weight of 26.3 kg (25th and 75th percentiles, 24.3 to 28.9) were randomly assigned to receive, during a 5-minute period, two intravenous infusions of either 7.5%/6% HSD (n = 12) or 0.9% saline (n = 12) solution at 4 mL/kg. The first infusion was given immediately after a 75-minute period of HCA and the second one 4 hours after the start of reperfusion.
Preoperative Management
All animals received humane care in accordance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources, National Research Council (published by the National Academy Press, revised in 1996). The study was approved by the Research Animal Care and Use Committee of the University of Oulu.
Anesthesia and Monitoring
The animals were sedated with ketamine hydrochloride (350 mg intramuscularly) and midazolam (45 mg intramuscularly). A peripheral catheter was inserted into a vein of the right ear for administration of drugs and to maintain fluid balance with Ringer acetate. Anesthesia was deepened with an intravenous bolus injection of fentanyl (25 µg/kg). After endotracheal intubation, the anesthesia was maintained by a continuous infusion of fentanyl (25 µg/kg/hour), midazolam (0.25 mg/kg/hour), and pancuronium (0.2 mg/kg/hour), in addition to isoflurane (0.5%). Animals were kept in anesthesia throughout the whole experiment, but not during HCA. The animals were maintained on positive pressure ventilation with 50% oxygen. Cefuroxime (1.5 g) was administered intravenously at anesthesia induction and before extubation. Electrocardiographic, hemodynamic, intracerebral, electroencephalographic, systemic metabolic parameters monitoring, and histopathologic analysis as evaluation of behavioral outcome were accomplished as described in details in one of our previous studies [13].
Fluid Administration
Hypertonic saline dextran (RescueFlow®, Biophausia AB, Uppsala, Sweden) is a hypertonic solution containing 7.5 g NaCl and 6 g dextran 70 kDa in 100 mL of solvent. The preparation is unbuffered, its pH being 3.5–7.0. The osmolality of HSD is 2,567 mOsm/L. The control solution consisted of normal saline, 0.9 g NaCl in 100 mL. The osmolality of normal saline is about 290 mOsm/L and pH in unbuffered solution is 4.0–7.0. The study fluids were randomized and prepared by a nurse, blinded from the study setting. The colorless solutions were put into identical syringes. The dose was set at 4 mL/kg, the one most used in previous studies. The first 5-minute infusion was given just after the start of rewarming. The second infusion was given 4 hours after the start of rewarming. Both groups received Ringer acetate according to standard fluid therapy protocols in addition to the experimental fluids.
Experimental Protocol and Hypothermic Circulatory Arrest
Through a right thoracotomy done on the fourth intercostal space, the right thoracic vessels were ligated and cut, the pericardium was opened, and the heart and great vessels were exposed. A membrane oxygenator (Midiflow D 705, Dideco, Mirandola, Italy) was primed with 1 L of Ringer acetate and heparin (5,000 international units [IU]). After baseline measurements, systemic heparinization (500 IU/kg) was performed. The ascending aorta was cannulated with a 16 F arterial cannula, and the right atrial appendage was cannulated with a single 24 F atrial cannula. Cardiopulmonary bypass was initiated at a flow rate of 90 to 110 mL · kg · min, and the flow was adjusted to maintain an arterial pressure of 50 to 70 mm Hg. A 10 F intracardiac sump cannula was positioned into the left ventricle through the apex of the heart for decompression of the left side of the heart during cardiopulmonary bypass. A cooling period of 60 minutes was carried out to attain a brain temperature of 18°C. A heat exchanger was used for core cooling. The PaCO2
level was maintained at 5.3 kPa, corrected for temperature, by adding carbon dioxide to the inflowing gas; ie using pH-stat principles.
When the target temperature was reached, the ascending aorta was cross-clamped just distal to the aortic cannula, and cardiac arrest was induced by injecting potassium chloride (40 mmol) through the aortic cannula. The 75-minute period of HCA was then initiated. Cardiac cooling with topical ice slush was begun and maintained throughout the HCA period. Similarly, the intracerebral temperatures were controlled and maintained at a level of 18°C with ice packs placed over the head. After the HCA, reperfusion was started along with the first infusion of HSD or placebo. Five minutes after the start of rewarming, furosemide (40 mg), mannitol (15 g), methylprednisolone (80 mg), lidocaine (40 mg), and calcium bioglyconate (2.25 mmol Ca2+) were administered. The left ventricular sump cannula was removed after 50 minutes of rewarming, and weaning from cardiopulmonary bypass occurred about 60 minutes after the end of HCA. During rewarming and after weaning from cardiopulmonary bypass, heat-exchanger mattress, heating lamps, paracetamol infusions (1–2 g intravenously), and ice packs regulated the temperatures. If necessary, intravenous dopamine infusion was started if fluid therapy was insufficient to maintain mean arterial pressure above 65 mm Hg. The animals of both groups were extubated 16 hours after the start of rewarming and were then moved to a recovery room. The neurologic recovery was assessed on a daily basis until the seventh postoperative day by an experienced observer unaware of the experimental setting and graded with the following scoring system: mental status (0 = comatose, 1 = stuporous, 2 = depressed, and 3 = normal), appetite (0 = refuses liquids, 1 = refuses solids, 2 = decreased, and 3 = normal), and motor function (0 = unable to stand, 1 = unable to walk, 2 = unsteady gait, and 3 = normal) were summed to obtain a final score, with a maximum score of 9 reflecting apparently normal neurologic function and with lower values indicating substantial brain damage.
Statistical Analysis
Statistical analysis was performed using SPSS (SPSS, version 11.5, SPSS Inc, Chicago, IL) and SAS (version 8.02, SAS Institute Inc, Cary, NC) statistical softwares. Continuous and ordinal variables are expressed as the median with 25th and 75th percentiles. The SAS procedure Mixed was used for repeated measurements. Since the measurement intervals were uneven, spatial exponential covariance structure was defined in repeated statement. Complete independence was assumed across animals (by random statement). Reported p values are as follows: p-between groups, indicates a level of difference between the groups; p-time*group (p
time in figures), indicates behavior between the groups over time. Repeated measurement analysis was not utilized for lactate-pyruvate ratio and lactate-glucose ratio because of a huge variation of the variables, only cross-sectional analysis was performed. Either the Student's t test or Mann-Whitney U test were used to assess the distribution of variables between the study groups. The Fischer's exact test was used to determine the significance of mortality rates between the groups. Two-tailed significance levels are reported. A p less than 0.05 was considered statistically significant.
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Results
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Comparability of the Study Groups
The median weight of the pigs was 26.3 kg (24.6–28.2 kg) in the HSD group and 26.5 kg (25.1–30.6 kg) in the control group (p = 0.36). The median cardiopulmonary bypass cooling time was 59 minutes (56–61 minutes) in the HSD group and 60 minutes (57–60 minutes) in the control group (p > 0.9). The median cardiopulmonary bypass rewarming time was 60 minutes (60–64 minutes) in the HSD group and 60 minutes (60–64 minutes) in the control group (p = 0.89). The median total cardiopulmonary bypass time was 120 minutes (116–126 minutes) in the HSD group and 120 minutes (119–121 minutes) in the control group (p = 0.51). There were no statistically significant differences between the study groups in terms of intracerebral temperatures at any interval. Blood temperatures did not differ between the study groups. The rectal and epidural temperatures did not differ between the study groups except at the 30-minute interval after HCA, during which the values were significantly higher in the HSD group. Venous oxygen saturation was significantly higher in the HSD group at baseline (p = 0.03), which reflected significantly lower oxygen extraction in the same animals (p = 0.05). However, these changes were short-lasting and the overall differences between the groups in these parameters were not significant (p = 0.7 and p = 0.2, respectively). There were no other significant differences in study parameters at baseline (see Table 1).
Mortality and Behavioral Outcome
The 7-day survival rates were 75% (9 out of 12 animals) in the HSD group and 66.7% (8 out of 12 animals) in the control group (p > 0.9). The postoperative behavioral data are reported in Figure 1. Animals that died before the seventh postoperative day were excluded from the behavioral score analysis. The recovery of the HSD group was much faster, as indicated by significantly higher behavioral scores on the second postoperative day (p = 0.03). The cumulative behavioral score tended to be significantly better in the HSD group (p = 0.067).
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Fig 1. Postoperative behavioral scores in the study groups. * p = 0.03 vs control group (second postoperative day). Horizontal lines indicate median values. The cumulative behavioral score was also counted, it being the sum of all daily scores, representing overall recovery.
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Hemodynamic and Metabolic Data
After the administration of HSD, there was a significant increase of serum concentrations of sodium (Fig 2). Infusion of HSD caused hemodilution, which is reflected on significantly lower hemoglobin and hematocrit levels in the HSD group at 30 minutes and 2 hours after HCA. As blood glucose levels did not differ between groups (p = 0.23), increased sodium load alone led to increased osmolarity in the HSD group compared with controls.
Although the overall difference between the study groups in terms of cardiac index did not reach statistical significance (p = 0.11), a trend of higher values of cardiac index was seen in the HSD group after the second infusion. Mean arterial pressure did not differ between groups as a whole (p = 0.52), but the first administration of HSD was associated with significantly higher mean arterial pressure values at 60-minute and 1-hour-30-minute intervals after HCA (p = 0.002 and p = 0.007, respectively). At the 15-minute interval after the end of HCA, however, the HSD group had significantly lower values of mean arterial pressure (p = 0.014). At the same time, vascular resistance and cerebral perfusion pressure were significantly lower as well (p = 0.046 and p = 0.03, respectively). The overall vascular resistance did not differ between the study groups (p = 0.6), but at 5-hour, 5-hour-30-minute, and 6-hour intervals after the second infusion, HSD was associated with significantly lower vascular resistance than the control group (p = 0.05, p = 0.05, and p = 0.014, respectively). Central venous pressure did not differ between the groups (p = 0.65).
Intracranial Measurements
Intracranial measurements are presented in Figure 3. Intracranial pressure was significantly lower in the HSD group (p = 0.028). The difference was observed from 45 minutes to 8 hours after the end of HCA. Cerebral perfusion pressure was higher in the HSD group, the difference being of borderline significance (p = 0.059) from 45 minutes to 3 hours after HCA. Microdialysis revealed significantly lower brain lactate levels in the HSD group (p = 0.049). Brain glucose levels did not differ between the study groups, but a tendency towards higher values was observed in the HSD group during the whole postoperative period. Lactate-pyruvate ratio was significantly lower in the HSD group at 3-hour and 4-hour intervals (p = 0.049 and p = 0.027, respectively). Lactate-glucose ratio was lower in the HSD group, although the differences were not statistically significant. Brain glutamate, pyruvate, and glycerol levels did not differ between the study groups (p = 0.6, p = 0.8, and p = 0.4, respectively). Brain tissue oxygen partial pressure levels were somewhat higher in the HSD group (p = 0.08).
Histopathologic Data
Histopathologic findings are presented in Table 2. The statistical analysis was performed including all animals as well as only 7-day survivors. Total histopathologic score was significantly lower in the HSD group (mean, 7.0 vs 10.0, p = 0.01), as it was in the histopathologic score of the thalamus (p = 0.04), when all pigs were included. When early deaths were excluded, the total score was again significantly lower in the HSD group (mean, 7.0 vs 9.6, p = 0.049). With or without the early deaths, the differences in the scores from brainstem and cerebellum were of borderline significance in favor of the HSD group.
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Comment
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The use of hypertonic saline was introduced by Velasco and colleagues in 1980 [14], and it was initially used mostly in experimental models of hemorrhagic shock, with impressive results [14, 15]. Its rapid and powerful hemodynamic effects, however, last only 30 to 60 minutes [16]. Soon after the first studies, hypertonic saline was combined with a hyperoncotic substance such as dextran (HSD) or hydroxyethyl starch, yielding a more sustained effect which lasts up to 3 to 4 hours [6].
Hypertonic saline has a direct effect on the inflammatory response, suppressing neutrophil activation [17] and decreasing susceptibility to sepsis after hypovolemic shock [18]. Indeed, hypertonic saline has been shown to down-regulate the expressions of some key adhesion molecules of neutrophils [10]. Dextran may have its own beneficial immunomodulatory effects that hydroxyethyl starch is lacking, possibly making HSD superior to other hypertonic-hyperoncotic solutions [19]. This was the reason why, herein, we chose HSD over other available products.
Hypertonic saline dextran has neuroprotective effects as it lowers intracranial pressure after brain trauma. A randomized, controlled trial suggested that trauma patients with Glasgow Coma Scale (GCS) below 8 could benefit from HSD [20]. This was later confirmed by a meta-analysis, in which the subgroup of patients with severe head trauma (GCS < 8) and hypotension receiving HSD had significantly higher survival rates [2]. A recent trial was not able to reproduce such findings in patients with severe head trauma with hypotension. However, the hypertonic fluid chosen was 7.5% hypertonic saline (HTS), not HSD [21]. In animal models, HSD has been shown to reduce the sizes of brain infarctions in rats with cortical vein occlusion [3] and to lessen the morphologic damage in rats with experimental subarachnoid hemorrhage [4].
In a few pilot studies, the sodium levels did not rise adversely with two infusions than with a single one, which is the predominating regimen. Therefore, we chose to proceed with the protocol of two infusions. Figure 2 shows that the serum concentrations of sodium remained mostly below 150 mmol/L. The animals operated on herein were young with normal renal function. Even though there is suspicion of adverse effects due to hypernatremia related to repeated administration of HSD, evidence of poorer outcome compared with a single infusion is lacking [22]. Indeed, repeated administration of 7.5% HTS/6% hydroxyethyl starch has been successfully used in a small number of patients with refractory intracranial hypertension resistant to conventional therapy [23]. In any case, a limited capacity to excrete sodium due to renal failure may formally contraindicate the use of these solutions in the critically ill patient.
In our study, the decrease of intracranial pressure started at the end of the rewarming phase and extended up to the 8-hour time interval after the start of rewarming. This can be considered as an excellent, prolonged effect with therapeutic relevance [24]. After 8 hours, the decrease of intracranial pressure and the effect of improved hemodynamics wear off. It is likely that an initially larger dose prevents this rebound phenomenon. In a dose-response study by Wade and colleagues [25], HSD 11.5 mL/kg was slightly, but not significantly, more effective than the standard 4 mL/kg dose, resulting in 100% survival compared with 83% in a model of hemorrhagic shock in swine. Another approach could be a third rapid infusion of HSD 8 hours after the start of rewarming or a continuous slow infusion throughout the postoperative hours. Slow infusions have yielded promising results, although studies are few in number and lacking in methodology [26]. Solutions with higher sodium concentration (10%–23.4%) have also shown their efficacy in lowering intracranial pressure with poor-grade patients or in animal studies [27]. As mentioned above, repeated dosing has been successful in a noncontrolled small evaluation study, but resulting hypernatremia still remains a problem. In this model, the sodium levels remained, in most cases, below 150 mmol/L, thus suggesting the safety of our regimen with two infusions. Further studies are needed to evaluate, whether a single, large dose, repeated dosing, or a longer, slow infusion indeed are effective in sustained decrease in intracranial pressure and perhaps generating even better outcome than reported here. Additional research is also of great importance in finding out whether sustained hypernatremia actually complicates repeated HSD therapy.
The infusion of HSD resulted in a short period of significantly lower mean arterial pressure at the beginning of the rewarming period. This phenomenon is due to vasodilation caused by HSD. Afterward, the mean arterial pressure levels were briefly even higher in the HSD group. Previous studies on HSD have shown that during and immediately after the infusion of HSD, the blood vessels dilate and there may even be a short period of hypotension. However, as the plasma volume and cardiac contractility increase, the mean arterial pressure levels are quickly restored or even elevated from baseline values [7]. The administration of unbuffered HSD probably caused the significantly lower pH at the 5-minute interval after HCA. Vasodilation most likely also explains the significantly lower venous line temperatures in the HSD group at the 15-minute and 30-minute intervals, as well as higher rectal and epidural temperatures in the HSD group 30 minutes after HCA. Hypertonic saline dextran was associated with a temporary, significant decrease of hematocrit, which in turn has been shown to decrease mean arterial pressure and to increase cerebral blood flow [26]. However, low hematocrit is also associated with increased cerebral metabolism, thus with possible deleterious effects on the brain during HCA [26]. Despite this, HSD has, herein, shown its neuroprotective effects, and any adverse effect related to a temporary decrease of hematocrit should be assessed in a further study in which hematocrit is both left uncorrected and corrected to optimal levels.
With our present methods, we are not able to distinguish whether the evident beneficial effects of HSD on overall hemodynamics and cerebral perfusion are the only mechanisms leading to neuroprotection, or whether the immunomodulatory properties of HSD also play a role. Neither can we provide direct evidence of increased brain tissue perfusion. The results of the microdialysis technique, however, clearly indicate that HSD has supportive effects on cerebral aerobic metabolism, thus indicating improved tissue oxygenation and perfusion. This finding supports the results of previous studies suggesting an increased cerebral perfusion after ischemia associated with the use of hypertonic solutions [28].
In conclusion, two rapid intravenous infusions of HSD were associated with significantly better neurologic recovery, significantly lower intracranial pressure, and higher cerebral perfusion pressure after HCA. Hypertonic saline dextran also has supportive effects on brain metabolism.
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Acknowledgments
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This study was supported by grants and funding from the Oulu University Hospital, the Finnish Foundation for Cardiovascular Research, Emil Aaltonen Foundation, Aarne Koskelo Foundation, Finnish Medical Foundation, Research and Science Foundation of Farmos, Ida Montin Foundation, and the Sigrid Juselius Foundation. We express our gratitude to Seija Seljänperä, RN, for preparing the study solutions and her valuable everyday collaboration, and to Veikko Lähteenmäki and director Hanna-Marja Voipio, DVM, PhD, as well as the rest of the staff of the Animal Research Centre of Oulu University Hospital for technical assistance and providing the excellent facilities for completing this study. The sincerest thanks of the authors go to the personnel in the Department of Pathology, University of Oulu, for the preparation of the histopathologic material.
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M. Stecker
Invited commentary
Ann. Thorac. Surg.,
January 1, 2006;
81(1):
190 - 190.
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Abstract
Introduction
= HSD; 
= Control.)