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a Department of Pediatrics, Pediatric Intensive Care Unit, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
b Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
c Department of Cardiac Surgery, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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METHODS. The children were randomly assigned to 2 groups of 25. The hypertonic-hyperoncotic solution group received Poly-(O-2)-hydroxyethyl-starch 60.0 g, with molecular weight of 200 kDa, Na+ 1232 mmol/L and osmolality of 2464 mOsmol/L (7.2% sodium chloride with 6% hydroxyethyl-starch 200 kDa). The isotonic saline solution group received isotonic saline solution (0.9% sodium chloride). Atrial and ventricular septal defects were corrected using a homograft patch. Monitoring consisted of an arterial, a central venous, and a thermodilution catheter (PULSIOCATH). Cardiac index, extravascular lung water index, stroke volume index, mean arterial blood pressure, and systemic vascular resistance index were measured (Pulse Contour Cardiac Output technique). Immediately after surgery, patients were loaded either with hypertonic-hyperoncotic solution or with isotonic saline solution (4 mL/kg). Blood samples (sodium concentration, osmolality, thrombocyte count, fibrinogen, and arterial blood gases) were drawn directly before; immediately after; 15 minutes after; and, 1, 4, 12, and 24 hours after the end of volume loading. Hemodynamic parameters were registered at the same time. The total amount of dobutamine required was documented, as well as the 24- and 48-hour fluid balances.
RESULTS. In the hypertonic-hyperoncotic solution group, cardiac index was 3.6 ± 0.26 L/min per m2 before volume administration and increased to 5.96 ± 0.27 after the administration of the study solution (64%). Fifteen and 60 minutes after administration, the cardiac index remained significantly elevated (5.55 ± 0.29 L/min per m2 and 4.65 ± 0.18 L/min per m2, respectively) and returned to preadministration values after 4 hours. In the isotonic saline solution group, the cardiac index did not change during the entire observation period (3.39 ± 0.21 before and 3.65 ± 0.23 L/min per m2 after isotonic saline solution). The systemic vascular resistance index decreased in the hypertonic-hyperoncotic solution group after administration from 1396 ± 112 to 868 ± 63 dyn/sec per cm–5/m2. The decrease of systemic vascular resistance index in the hypertonic-hyperoncotic solution group was transiently significant within 60 minutes after administration but stayed lower than before volume load (999 ± 70 dyn/sec per cm–5/m2). In the isotonic saline solution group, we found no statistically relevant change in systemic vascular resistance index. Stroke volume index significantly increased after hypertonic-hyperoncotic solution infusion (53.9 ± 3.0 mL/m2 directly after, 48.8 ± 2.46 mL/m2 15 minutes after, and 41.4 ± 2.2 mL/m2 60 minutes after) when compared with stroke volume index before administration (32.4 ± 2.6 mL/m2). In the hypertonic-hyperoncotic solution group, an increase in mean arterial blood pressure remained transiently significant within 60 minutes after administration when compared with the isotonic saline solution group, in which the mean arterial blood pressure remained unchanged. Both central venous pressure and heart rate were unchanged during the whole time of observation in both groups. In the hypertonic-hyperoncotic solution group, extravascular lung water index decreased from 10.6 ± 1.2 to 5.6 ± 1.2 mL/kg and remained significantly decreased 15 minutes after (6.5 ± 1.2 mL/kg) when compared with before volume administration. In the isotonic saline solution group, extravascular lung water index increased from 12.3 ± 1.1 mL/kg to 18.1 ± 1.7 mL/kg directly after administration and remained elevated for 60 minutes after volume loading (15.6 ± 1.5 mL/kg). In all patients, no hypoxia (PaO2<60 mm Hg) or hypercapnia (PaCO2 >60 mm Hg) was observed. Arterial blood gas analysis showed pH and base excess within physiologic range, and this did not change throughout the whole period of observation. After infusion of hypertonic-hyperoncotic solution, sodium concentration increased from 139.2 ± 0.7 to 147.5 ± 0.7 mmol/L. The maximum sodium concentration was 153 mmol/L, measured immediately after hypertonic-hyperoncotic solution in 1 patient. The total amount of fluid infused was similar in both groups. The postoperative need for infused dobutamine in the patients in the hypertonic-hyperoncotic solution group was decreased compared with the isotonic saline solution group (46.9 ± 8.8 µg/kg vs 308.2 ± 46.6 µg/kg). No patient presented with severe bleeding. Short- and long-term cardiac and neurologic outcome was not reduced and all patients left the hospital in a clinically sufficient state.
DISCUSSION. This study demonstrates a profound increase of cardiac index after the administration of hypertonic-hyperoncotic solution in children after uncomplicated open-heart surgery, suggesting a positive inotropic effect. The total amount of catecholamine was lower, assuming that hypertonic-hyperoncotic solution reduces the need for positive inotropic support. The observed positive cardiac effect of hypertonic-hyperoncotic solution may even be intensified by the decreased afterload (decreased systemic vascular resistance index). According to the Frank-Starling relation, an effective tool in the treatment of low cardiac output are an elevated preload while afterload is diminished. Therefore, we postulate that hypertonic-hyperoncotic solution may be helpful in preventing or attenuating low cardiac output failure in childhood. Capillary leakage syndrome also is a frequent problem after cardiopulmonary bypass. For quantification of edema formation, extravascular lung water index measurement is a useful tool. Using this approach, we provided evidence that the infusion of hypertonic-hyperoncotic solution is transiently able to reduce extravascular lung water index. This reduction was transient but might prevent the triggering of a clinically relevant capillary leakage syndrome. This is in line with in vitro studies demonstrating that hypertonic-hyperoncotic solution improves microcirculation by reducing vascular permeability. The single administration of hypertonic-hyperoncotic solution infusion was safe, and no adverse effects, such as hemostatic disturbances, were observed.
CONCLUSIONS. A single infusion of hypertonic-hyperoncotic saline solution after cardiac surgery is safe despite the hypertonicity and the colloid component of the hypertonic-hyperoncotic saline solution. In children after cardiopulmonary bypass surgery, the administration of hypertonic-hyperoncotic saline solution increased cardiac index by elevating stroke volume index in combination with a lowered systemic vascular resistance index. Extravascular lung water index transiently decreased, suggesting that hypertonic-hyperoncotic saline solution effectively counteracts the capillary leakage that often occurs after cardiac surgery in children. Additional investigations might elucidate whether the temporary effects of hypertonic-hyperoncotic saline solution are beneficial in the treatment of severe capillary leakage after complicated cardiac surgery. It has to be shown that hypertonic-hyperoncotic saline solution is a long-lasting, effective treatment strategy for low cardiac output failure in children that is caused by sepsis, multiorgan failure, and endothelial edema. We have provided evidence to pediatric intensive care clinicians that the single administration of hypertonic-hyperoncotic saline solution might be a useful and safe treatment in the amelioration of contractility, inotropy, and the possible treatment of early-onset capillary leakage.
Key Words: hypertonic-hyperoncotic solutions • pediatrics • capillary leakage • low-output failure • cardiopulmonary bypass
Abbreviations: HHS—hypertonic-hyperoncotic saline solution • HES—hydroxyethyl starch • ASD—atrial septal defect • VSD—ventricular septal defect • TC—thrombocyte count • ISS—isotonic saline solution • CI—cardiac index • ELWI—extravascular lung water index • HR—heart rate • SVI—stroke volume index • MAP—mean arterial blood pressure • SVRI—systemic vascular resistance index • PiCCO—Pulse Contour Cardiac Output • CVP—central venous pressure • CO—cardiac output
Hypertonic-hyperoncotic solutions (HHSs) have been used in controlled clinical studies for stabilization of micro- and macrocirculation in adult patients with various types of shock.1,2 This concept, termed small-volume resuscitation, has been used for almost 20 years.2–4 Nowadays, small-volume resuscitation usually is performed by the rapid administration of a small dose (4 mL/kg) of 7.2% to 7.5% sodium chloride in combination with a colloid solution (6%–10% hydroxyethyl starch, molecular weight 200 kDa).
The pharmacologic effects of HHS are widely known. The increase of an osmotic gradient causes a fluid shift from the intracellular and extravascular spaces into the vascular compartment and mainly is responsible for the hemodynamic effects. Possibly, the increase in plasma osmolality may cause a positive inotropic effect.5,6 Until now, it has remained unclear whether the preload effect or direct inotropy is the reason for the amelioration of hemodynamic function. A significant influence of HHS is on the human atrial natriuretic peptide and its second messenger cyclic guanosine monophosphate, which leads to a decrease in systemic and pulmonary vascular resistance. An additional beneficial effect is the amelioration of cardiac, renal, and mesenterial blood flow that stabilizes micro- and macrocirculation, reducing postischemic reperfusion injury. HHS significantly reduces endothelial swelling by the attenuation of leukocyte adhesion to the postcapillary venules’ endothelium. Therefore, the use of HHS in severe sepsis or multiorgan failure as a result of systemic inflammatory response syndrome is established.3,7–11
Potential adverse effects of HHS have been reported. The infusion of HHSs may provoke imbalances of the electrolyte state.3,12,13 Severe hypernatremia as a result of HHS has been reported in a large cohort of emergency patients.14 In several clinical trials, arterial hypotension was seen initially after the rapid infusion of hypertonic saline.15 Kreimeier et al16 postulated anaphylactic reactions against hydroxyethyl starch (HES) by demonstrating HES antibodies. Coagulation disorders, such as reduced fibrinogen levels and thrombocyte count (TC), may be explained by the potential interference of HES with the coagulation system.3
Experience in using HHS in pediatric intensive care patients is scarce.17–19 To our knowledge, only 2 studies in the literature have reported on the safety and the efficacy of HHS in pediatric open-heart surgery.20,21
We hypothesized that HHS may improve cardiac function in children. Therefore, the primary objective of this controlled, randomized, blinded study was to evaluate the hemodynamic effects and the safety of HHS infusions in children shortly after open-heart surgery for congenital cardiac disease. The secondary objective was whether the administration of HHS could be a potential and effective therapeutic option for preventing a probable capillary leakage syndrome that occurs frequently in children after open-heart surgery.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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All patients underwent cardiac surgery with cardiopulmonary bypass. None received an intraoperative hyperoncotic solution (eg, Mannitol). The only fluid given was isotonic sodium chloride. No patient had modified ultrafiltration after the end of cardiopulmonary bypass. Atrial (ASDs) and ventricular septal defects (VSDs) were corrected using a homograft patch. In all patients, invasive monitoring consisted of an arterial catheter placed in the radial artery, a central venous catheter placed in the superior vena cava, and a thermodilution catheter (PULSIOCATH thermodilution catheter; PULSION Medical Systems, Munich, Germany) placed in the femoral artery. After bolus injection of ice-cooled sodium chloride solution (1 mL/kg), cardiac index (CI), extravascular lung water index (ELWI), heart rate (HR), stroke volume index (SVI), systemic arterial blood pressure (mean arterial pressure [MAP]), and systemic vascular resistance index (SVRI) were measured and calculated (Pulse Contour Cardiac Output [PiCCO] technique; PULSION Medical Systems). The central venous pressure (CVP) was measured by the central venous catheter in the superior vena cava. ST deviations were evaluated on-line with limb and precordial leads in the electrocardiogram monitored by Siemens (Erlanger, Germany) SC 8000 software (Einthoven I to III).
Immediately after arrival to the PICU, patients were volume loaded either with HHS or with ISS. All staff members who were treating the patient remained blinded to the solution, which was administered at a dosage of 4 mL/kg over 15 minutes. Blood samples were drawn directly before; immediately after; then 15 minutes and 1, 4, 12, and 24 hours after the end of volume loading. Hemodynamic parameters were registered at the same time. Postoperative maintenance fluids consisted of isotonic saline (60 mL/kg per 24 hours). The need for and the total amount of dobutamine required (the only vasoactive substance used in the study) were documented, as was the total volume load after 24 and 48 hours (as 24/48-hour fluid balance), the duration of stay on PICU, and the time to discharge from hospital.
Sodium concentration, osmolality, TC, fibrinogen, and an arterial blood gas analysis were analyzed before and 15 minutes and 1, 4, 12, and 24 hours after the administration of study or control solution. The analysis of these parameters was performed by standard laboratory methods and measurements.
Statistical Analysis
Values are shown as the mean ± SEM. All groups of data passed normality tests and showed a Gaussian distribution. In the case of multiple tests, data were compared using 1-way analysis of variance for repeated measurements within 1 group. Different groups were compared using 2-way analysis of variance. P values were corrected according to Bonferroni. P < .05 was considered statistically significant. All tests were conducted using GraphPad Prism 3.0 software package (GraphPad Software, San Diego, CA).
Limitations of the Method
The patient population used in this study was highly selected to avoid harm to our pediatric patients. This was necessary because there were no sufficient data for the use of HHS; in fact, it is not yet approved by the German National Drug Board. The data that were collected within this study helped to provide information on the safety issues when using HHS in pediatric patients. Because the safety issue always was paramount, we chose to use this selected population.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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In the HHS group, the CI was 3.6 ± 0.26 L/min per m2 before volume administration and increased to 5.96 ± 0.27 L/min per m2 after the administration of the study solution (64%, P < .001). Fifteen and 60 minutes after administration, the CI remained significantly elevated (5.55 ± 0.29 L/min per m2 and 4.65 ± 0.18 L/min per m2, respectively) and returned to preadministration values after 4 hours. In the ISS group, the CI did not change during the entire observation period (3.39 ± 0.21 L/min per m2 before and 3.65 ± 0.23 L/min per m2 after ISS administration; Fig 1).
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The ELWI was altered in both groups. In the HHS group, ELWI decreased from 10.6 ± 1.2 mL/kg to 5.6 ± 1.2 mL/kg (P < .01) and remained significantly decreased 15 minutes after (6.5 ± 1.2 mL/kg) when compared with before volume administration (P < .05). In the ISS group, ELWI increased from 12.3 ± 1.1 mL/kg to 18.1 ± 1.7 mL/kg directly after administration (P < .001) and remained elevated for 60 minutes after volume loading (15.6 ± 1.5 mL/kg), when it then returned to preadministration values. Between the 2 study groups, data were significantly different during the first 60 minutes of measurement (P < .001). Four hours after administration, no difference between the 2 groups was noted (Fig 3). Before and then 1 to 12 hours after extubation, arterial blood gases were analyzed. In both groups, PaO2 and PaCO2 were not significantly altered 4 hours after extubation. In all patients, no hypoxia (PaO2 <60 mm Hg) or hypercapnia (PaCO2 > 60 mm Hg) was observed; no patient required reintubation. Arterial blood gas analysis showed pH and base excess in physiologic ranges, and this did not change throughout the whole period of observation (detailed data not shown).
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The total amount of fluid infused was similar in both groups. There was no difference in the 2 groups concerning the dobutamine dosage when arriving in PICU from theater. However, the total postoperative need for infused dobutamine in the HHS patients was statistically decreased compared with the ISS group (46.9 ± 8.8 µg/kg vs 308.2 ± 46.6 µg/kg; P < .001; Table 4). There was no difference in the need for dobutamine between the ASD patients and the VSD patients in either group.
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The number of adverse events, related and unrelated to the administration of the study medication, was not different in either group (data not shown). We found no evidence of cardiac or neurologic instability. Short- and long-term cardiac and neurologic outcome was not reduced, and all patients left the hospital in a clinically sufficient state (data not shown).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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A ventricle with a predominantly low compliance might be a contraindication for the use of HHSs. However, in these patients, rapid volume administration generally leads to clinically relevant problems: when given too much or too quickly, it can end in severe cardiac failure that cannot be compensated. In contrast, when using vasoactive drugs instead, one might run the risk of worsening a poorly compliant ventricle, which itself can lead to a fatal outcome.
The filling pressures of all patients, expressed as CVP, measured directly after cardiac surgery were equal. Therefore, severe hypovolemia can be excluded. A significant elevation of MAP could be demonstrated in children who are treated with HHS, too. This increase is the consequence of the increased CI. In addition, the total amount of catecholamine that had to be infused to maintain a stable blood pressure was lower in the HHS group than in the ISS group, suggesting that the administration of HHS reduces the need for positive inotropic support. CI values directly after cardiac surgery always were in the upper ranges. One might speculate that the administration of vasoactive drugs intra- or postoperatively was not indicated. The clinical experience with children after uncomplicated or complicated cardiac surgery shows that shortly after admission to PICU, their cardiac output (CO) can rapidly decrease. Therefore, the catecholamine therapy is a form of safety treatment to avoid a sudden, often unpredictable cardiac depression.
A reduction in the SVRI occurred in children after the infusion of HHS. In contrast, this reduction could not be demonstrated in the ISS group. Therefore, one might speculate that the observed positive cardiac effect of HHS may even be intensified by the decreased afterload.
Restoration from low CO failure that often occurs in children who undergo cardiac surgery with cardiopulmonary bypass is of great clinical importance.25,26 According to the Frank-Starling relation, the most effective tools in the treatment of low CO are an elevated preload while afterload is diminished.27–29 Therefore, we postulated that the infusion of HHS may be helpful to prevent or attenuate low CO failure after cardiac surgery in childhood. Of course, in our patients after ASD or VSD repair, we cannot really comment on the effects on low CO. Indeed, patients after complicated cardiac surgery (eg, Norwood I procedure) were excluded. However, from what our data have demonstrated in a "healthy" cohort of patients, we cannot find any pathophysiologic reasons for why HHS should not be hemodynamically effective in these groups of patients as well.
Hemodynamic parameters all were determined by using the transpulmonary thermodilution method. Its use in children is well studied and described by Cecchetti et al.22 Levy and colleagues24,30 pointed out that the PiCCO technique compared with noninvasive CO measurements was clinically acceptable only in children with >0.6 m2 body surface area. In smaller children, Levy performed a noninvasive CO measurement using partial rebreathing via the Fick principle for carbon dioxide. However, this method rarely is used to determine CO and is not accepted as a clinical standard.
Capillary leakage syndrome is a frequent problem in children who undergo cardiac surgery with cardiopulmonary bypass and is difficult to treat. There is clinical and experimental evidence that capillary leakage is attributable to endothelial swelling that is caused by an endothelial dysfunction that often is induced by circulating endotoxins, cytotoxins, and complement activation.31–34 Different pathophysiologic mechanisms have been described.31,33 For clinicians, it is of great use to measure weight trends for assuming the edema state. In all children in the PICU, the weight generally is measured once a day, especially after cardiac surgery. Because we did not find any clinically relevant capillary leakage, it is not surprising that we did not find statistically relevant changes in the body weight. However, for quantification of edema formation, measurement of ELWI is a useful tool.22,35 Using this approach, our data provide evidence that in children, the infusion of HHS is transiently able to reduce ELWI significantly after cardiac surgery. Of course, the reduction of ELWI was transient, but this initial reduction might prevent a consequent triggering of a clinically relevant capillary leakage syndrome. ELWI was worse after ISS, although there was no difference in the time on the ventilator. However, despite increased ELWI, clinically relevant capillary leakage syndrome was not detected, and oxygen saturation was stable in all patients before and after extubation. Therefore, we postulate that ELWI measurements are a sensitive parameter in detecting a possible, although clinically not obvious, endothelium-derived cell edema, and the administration of HHS might protect against capillary leakage. This is in line with in vitro studies that demonstrate that HHS improves microcirculation by reducing vascular permeability.36 Our finding opens a new therapeutic approach in children for the capillary leakage syndrome by administration of HHS. A possible limitation of this treatment strategy for avoiding capillary leakage is the knowledge that hypertonic solutions cannot be applied in several repetitive dosages because of the high and accumulating sodium load, consequently leading to severe hypernatremia. Also for consideration are the other principles in influencing capillary leakage, such as volume restriction or the administration of C1-esterase inhibitor.34 However, the administration of HHS could be a useful supplementary treatment in the future.
The data from the present study showed a significant transient increase of serum sodium concentrations of 
6% after the administration of HHS in children. The average sodium increase remained below 147.5 mmol/L. We did not see any short-lasting cases of severe hypernatremia.12 The maximum sodium concentration was 153 mmol/L in 1 patient, measured immediately after the administration of HHS. In all other patients, sodium levels did not exceed 151 mmol/L at any time after administration. Sodium concentrations dropped back to within normal values at least 24 hours after the administration of HHS.13,14 Electrolyte imbalances as a result of severe hypernatremia and elevated serum osmolality have been described in children, leading to neurologic dysfunctions that may even be life threatening and so may limit the use of HHS.37,38 Therefore, it is important to demonstrate that in a pediatric cohort of patients, the single administration of HHS does not induce severe hypernatremia. The neurologic state of all children after their stay in the hospital was not altered, and no neurologic dysfunction was seen.
Furthermore, the single administration of HHS infusion was safe, and no adverse effects were observed in our study. In adults, arterial hypotension after the administration of hypertonic saline solutions has been described.39 This was not observed in our study population; none of our patients developed blood pressure or cardiac decompensation or even signs of a hypertensive emergency or crisis.
The HES component of HHS may negatively affect the coagulation system, particularly plasma fibrinogen. In adults, there also is evidence of a decreased TC.40–42 In the present study, fibrinogen levels were not altered. None of the children required replacement of coagulation factors, and no severe bleeding occurred. However, the TC fell slightly 1 hour after the administration of hypertonic saline and returned to baseline levels after 24 hours.
If the platelet count is low or if platelets are dysfunctional, then this can lead to severe bleeding, especially in cases of disseminated intravascular coagulation, which can be predominant in multiorgan failure or severe low CO. This bleeding situation has to be treated by platelet transfusions, fresh-frozen plasma, or even the transfusion of single coagulation parameters. However, to our knowledge, no data in the literature have reported that such bleeding as a result of disseminated intravascular coagulation can be made worse by the administration of HHSs. Therefore, this may be a "theoretical" adverse event that clinically is no longer of relevance. In our study, the single administration of HHS in children did not cause any hemostatic disturbances.
No deviations were observed in the continuous ST segment monitoring. During the total period of observation, no anaphylactic or allergic reactions were documented.
Limitations of the Study
The aim of the study was to demonstrate the hemodynamic effects of HHS under optimized monitoring conditions. Of course, patients after uncomplicated cardiac surgery (VSD and ASD) will not present major postoperative problems. Therefore, these patients were optimal in demonstrating clearly hemodynamic and physiologic alterations. One could assume that the need for inotropic agents would be higher in VSD patients than in ASD patients. However, evaluation of our data revealed no difference between these 2 diagnostic groups. Therefore, the requirement of the HHS group to receive less dobutamine than the ISS group probably is not attributable to the surgical procedure or diagnosis. For future investigations, it is recommended that the demonstrated hemodynamic and fluid mobilizing effects be reproduced in severe and critically ill children who present with manifest low CO or even clinically obvious capillary leakage syndrome.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Additional investigations are needed to investigate whether the temporary effects of HHS are beneficial in the treatment of severe capillary leakage after complicated cardiac surgery. It has to be shown that HHS is a safe and long-lasting effective treatment strategy for low CO failure in children. However, we also conclude that the administration of HHS might be a treatment strategy in cases of low CO that is caused by sepsis, multiorgan failure, and endothelial edema. We have provided evidence to pediatric intensive care clinicians that the single administration of HHS might be a useful and safe treatment in the amelioration of contractility and inotropy and in the possible treatment of early-onset capillary leakage. We also have provided clinical information and data particularly when managing situations when invasive monitoring (eg, in invasive cardiac monitoring) technically cannot be performed.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address correspondence to Michael Schroth, MD, Kinder- und Jugendklinik, Friedrich-Alexander-University Erlangen-Nuremberg, Loschgestraße 15, D-91054 Erlangen, Germany. E-mail: michael_schroth{at}yahoo.de
The authors have indicated they have no financial relationships relevant to this article to disclose.
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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) and in the ISS group (
). Data are shown as mean ± SEM. aP < .001 and bP < .05 between study groups; cP < .001 and dP < .05 in the same study group (versus baseline value).
