Hypertonic Solution Decreases Extravascular Lung Water in Cardiac Patients Undergoing Cardiopulmonary Bypass Surgery

Hypertonic Solution Decreases Extravascular Lung Water in Cardiac Patients Undergoing Cardiopulmonary Bypass Surgery Vladimir V. Lomivorotov, MD, PhD, Evgeniy V. Fominskiy, MD, Sergey M. Efremov, MD, PhD, Valeriy A. Nepomniashchikh, MD, PhD, Vladimir N. Lomivorotov, MD, PhD, Alexander M. Chernyavskiy, MD, PhD, Anna N. Shilova, MD, PhD, and Alexander M. Karaskov, MD, PhD Objective: To test the hypothesis that the infusion of hypertonic solution would decrease extravascular lung water postoperatively and thus improve pulmonary function. Design: Prospective, randomized, blinded trial. Setting: Tertiary cardiothoracic referral center. Participants: Twenty-six patients with coronary artery disease who underwent surgery with cardiopulmonary bypass (CPB). Interventions: Patients were allocated randomly to receive 4 mL/kg of 7.2% NaCl/hydroxyethyl starch, 200/0.5 (HSH group) or an equal volume of 0.9% NaCl (control group) for 30 minutes starting after anesthesia induction. The extravascular lung water index, hemodynamic and biochemical data, and the rate of complications were analyzed. Measurements and Main Results: The extravascular lung water index was significantly lower (7 v 9.5 mL/kg) in the HSH group at the first postoperative day (p < 0.01). The index of arterial oxygenation efficiency was significantly

higher at 5 minutes and 2 and 4 hours after cardiopulmonary bypass (CPB) in the HSH group (p < 0.05). The alveolararterial oxygen tension difference was significantly lower at 5 minutes and 2 and 4 hours after CPB in the HSH group (p < 0.01). The cardiac index was significantly higher at 5 minutes after infusion in the HSH group (p < 0.05). Conclusions: The infusion of HSH leads to significant decreases in the extravascular lung water index during and after cardiac surgery and is associated with better preservation of pulmonary function and transient increases in the cardiac index. Further trials are needed to clarify the clinical advantages of hypertonic solution administration in patients undergoing surgery with CPB. © 2013 Elsevier Inc. All rights reserved.

I

sible enrollment in the study. The exclusion criteria were emergency surgery, recent myocardial infarction (⬍6 months before surgery), left ventricular ejection fraction ⬍40%, diabetes mellitus, glomerular filtration rate ⬍90 mL/min, stroke or transient ischemic attack (⬍12 months before surgery), hematocrit ⬍30%, a body mass index ⬍18 and ⬎35 kg/m2, and current participation in other clinical trials. The primary end point was ELWI. The secondary endpoints were the CI, the index of arterial oxygenation efficiency (partial pressure of arterial oxygen [PaO2]/fraction of inspired oxygen [FIO2]), alveolar-arterial oxygen tension differences (AaDO2), the venous shunt fraction, the oxygen delivery index, and the duration of mechanical ventilation. This study was approved by the local hospital ethics committee, with written informed consent obtained from all patients before their inclusion in the study. Patients were allocated randomly to receive HSH (HSH group, n ⫽ 13) or 0.9% NaCl (placebo control or C group, n ⫽ 13) at a dose of 4 mL/kg for 30 minutes, starting after the first hemodynamic measurement was obtained and before the beginning of CPB (Fig 1). Randomization was based on a computer-generated code. Patients were kept blinded throughout the study. In addition to the study fluid, crystalloids, 3 mL/kg/h, routinely were administered intraoperatively in the 2 groups. In the intensive care unit (ICU), crystalloids also were administered to replace ongoing insensible losses, urinary losses, sweating losses, etc. The indication for colloid administration was hypovolemia, as determined by ⱖ1 of the following clinical signs: low cardiac filling pressures (pulmonary capillary wedge pressure [PCWP] ⬍12 mmHg and central venous pressure ⬍8 mmHg),

NCREASED CAPILLARY PERMEABILITY and decreased colloid osmotic pressure during cardiac surgery with cardiopulmonary bypass (CPB) have been shown to play a key role in fluid overload and an increased presence of extravascular water.1,2 Tissue edema can result in injury to many organs, including the lungs,3 heart,4 and brain,5 potentially leading to adverse outcomes.6 One of the primary strategies for decreasing excessive fluid extravasation in patients during cardiac surgery with CPB involves the use of hypertonic saline (HS). HS has been implemented widely during the prehospital care of trauma patients and has shown positive hemodynamic effects.7 In vitro studies have indicated that HS improves microcirculation by decreasing vascular permeability.8 The infusion of HS transiently can improve hemodynamics and decrease the extravascular lung water index (ELWI) after cardiac surgery in children.9 Numerous studies in adult cardiac patients have shown that the use of HS leads to a significant improvement in hemodynamics and a substantial decrease in a positive fluid balance.10-13 One of the possible explanations for this phenomenon is that HS creates an osmotic gradient across the cellular membrane, causing a fluid shift from the intracellular and the interstitial spaces of tissue to the intravascular compartment, thereby leading to plasma expansion.13 The authors hypothesized that the infusion of HS/hydroxyethyl starch (HSH) before the initiation of CPB would decrease ELWI postoperatively, improve pulmonary function, and increase the cardiac index (CI) in patients undergoing coronary artery bypass grafting (CABG). METHODS This prospective, randomized, blinded study investigated the influence of 7.2% NaCl plus 6% iso-oncotic hydroxyethyl starch, 200/0.5 (HyperHaes; Fresenius Kabi, Germany) on ELW in 26 patients who underwent CABG with CPB from November 2011 to February 2012. During this period, 283 eligible adult patients were assessed for pos-

KEY WORDS: hypertonic solution, extravascular lung water index, pulmonary function, coronary artery bypass grafting, cardiopulmonary bypass

From the Department of Anesthesiology and Intensive Care, Academician EN Meshalkin Novosibirsk State Budget Research Institute of Circulation Pathology, Novosibirsk, Russia. Address reprint requests to Evgeniy V. Fominskiy, MD, Department of Anesthesiology and Intensive Care, Academician EN Meshalkin Novosibirsk State Budget Research Institute of Circulation Pathology, Rechkunovskaya Street 15, Novosibirsk 630055, Russia. E-mail: [email protected] © 2013 Elsevier Inc. All rights reserved. 1053-0770/2702-0001$36.00/0 http://dx.doi.org/10.1053/j.jvca.2012.06.013

Journal of Cardiothoracic and Vascular Anesthesia, Vol 27, No 2 (April), 2013: pp 273-282

273

274

respiratory variation in systole or a mean arterial blood pressure ⬎5 mmHg, or a mean arterial pressure ⬍70 mmHg. In the 2 groups, the volume requirements were treated with a 4% solution of gelatin polysuccinate (Gelofusin; B. Braun, Melsungen, Germany). Packed red blood cells were administered when the hemoglobin level was ⬍9 g/dL, and fresh frozen plasma was administered when bleeding occurred (blood loss 150 mL/h over 2 h) with abnormal hemostatic values. The clinicians who treated the patients were unaware of the patients’ enrollment in this study. The trial was conducted during the routine treatment of other patients in the perioperative period. All surgeries were performed using a standardized anesthetic technique. Patients received premedication with diazepam in the evening and in the morning before surgery. Patients received ␤-blockers until the day of the surgery. The anesthesia induction was performed with fentanyl (3.0-5.0 ␮g/kg) and midazolam (0.1-0.15 mg/kg). Muscle relaxation was achieved using pipecuronium bromide (0.1 mg/kg). After tracheal intubation, the patients were ventilated to maintain normocapnia. A tidal volume of 8 mL/kg, a respiratory rate of 12-14 breaths/min, and an FIO2 content of 50% were used intra- and postoperatively. Anesthesia was maintained before and after CPB by an intermittent injection of fentanyl (total hourly dose, 2.5-3.5 ␮g/kg) and sevoflurane inhalation (1%-2%). Fentanyl (2.5-3.5 ␮g/kg/h) and propofol (2-4 mg/kg/h) were used during CPB. Pipecuronium bromide was added as necessary. Full median sternotomies were performed in all patients. CPB was initiated after cannulation of the right atrium and ascending aorta. The CPB circuit was primed with 500 mL of the modified gelatin (Gelofusin), 500 mL of crystalloids, 200 mL of 10% mannitol, and 150 mL of 4.2% sodium hydrocarbonate. The nasopharyngeal temperature was maintained at 36.0-36.7°C. Aminocaproic acid, 20 g, was used as an antifibrinolytic agent. An initial dose of heparin (300 U/kg) was administered to achieve an activated coagulation time of 480 seconds. Myocardial protection was achieved with an antegrade crystalloid

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cardioplegia solution at 4°C. During perfusion, nonpulsatile blood flow was maintained at 2.4-2.8 L/min/m2 and the mean arterial pressure was maintained at 50-70 mmHg by phenylephrine. The hematocrit was maintained at ⬎21% during CPB. The identical protocol of ultrafiltration was used in all patients during CPB. After the termination of CPB, the neutralization of heparin was achieved using protamine sulfate at a ratio of 1:1. All patients were admitted to the cardiac ICU after surgery and ventilator weaning was performed according to a standardized protocol. The extubation criteria were clear consciousness; stable hemodynamics; an absence of signs of excessive drainage loss; and stabilization of electrolyte, acid-base, and respiratory parameters. The decision of inotropic support (epinephrine and/or dopamine) was guided using hemodynamic data: CI ⬍2.2 L/min/m2 in the presence of PCWP ⬎15 mmHg. Norepinephrine was used for treatment vasodilatation, as defined by a systemic vascular resistance index (SVRI) ⬍600 dynes · s · cm⫺5/m2. Patients were transferred from the ICU to the wards after they met the following criteria: stable hemodynamics without inotropic and vasoactive support, urine output ⬎0.5 mL/kg/h, and minimal drainage. Heart rate, mean arterial pressure, and central venous pressure were monitored continuously. The ELWI, CI, stroke volume index, SVRI, and pulmonary vascular resistance index were monitored by a transcardiopulmonary thermodilution technique with the PiCCO Plus system (Pulsion Medical Systems AG, Munich, Germany). The femoral artery was used as the site for the catheter insertion in all patients. The arterial cannulation required for transcardiopulmonary thermodilution is considered safe, and no relevant drawbacks for using the femoral insertion site have been reported.14,15 Numerous experimental studies have shown a high correlation between the ELWI determined by a single thermodilution and gravimetric measurement over a wide range of changes.16,17 Clinical data have indicated that the ELWI determination using single thermodilution closely agrees with the corresponding values from the double-indicator technique.18 A Swan-Ganz catheter

Fig 1. Study design showing the analysis of the (C) extravascular lung water index, hemodynamics (except the 2nd POD); (M) respiratory parameters; (K) osmolarity and sodium. C, isotonic saline (control); CABG, coronary artery bypass grafting; CPB, cardiopulmonary bypass; HSH, hypertonic saline/hydroxyethyl starch; ICU, intensive care unit; POD, postoperative day.

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275

was used to monitor mean pulmonary artery pressure, PCWP, and oxygen content in mixed venous blood. The ELWI and hemodynamic parameters were evaluated after anesthesia induction (T0), 5 minutes after infusion (T1), 5 minutes after CPB (T2), 30 minutes after CPB (T3), at the end of surgery (T4), and then at 2 hours (T5), 4 hours (T6), 6 hours (T7), and 12 hours (T8) after CPB. An additional evaluation was performed on postoperative day 1 (T9). To assess lung function, PaO2/FIO2, AaDO2, and the venous shunt fraction were analyzed at T0, T2, T5, T6, and T9. The oxygen delivery index, oxygen consumption, and oxygen extraction index were analyzed at T0, T2, T5, T6, and T9. Plasma osmolarity was determined using Osmomat 030 (Gonotec, Berlin, Germany) after anesthesia induction (T0⬙), 5 minutes after infusion (T1⬙), 10 minutes of CPB (T2⬙), 5 minutes after CPB (T3⬙), 2 hours (T4⬙) and 4 hours (T5⬙) after CPB, and on postoperative day 1 (T6⬙). The perioperative fluid balance was analyzed at the end of surgery and on postoperative day 1 (Fig 1). The following clinical data were evaluated: mortality, the durations of ICU and hospital stays, the duration of mechanical ventilation, the occurrence of atrial fibrillation, acute myocardial infarction, the need for inotropic support, stroke, rethoracotomy for postoperative bleeding, and deep sternal wound infection. Mortality was defined as death from any cause in the hospital. The patients’ ICU stays were defined as the period from postsurgical admittance to the ICU to discharge from the ICU. The duration of mechanical ventilation was defined as the period from postoperative admission to extubation. Atrial fibrillation was defined as an irregular atrial rhythm without clear P-waves, confirmed by a 12-lead electrocardiogram. Inotropic support was defined as a need for the infusion of an inotrope (eg, dopamine, epinephrine) in a dosage

equivalent to dopamine ⬎5 ␮g/kg/min. Perioperative myocardial infarction was defined as the appearance of new ischemic Q-waves on an electrocardiogram. Before this research, a pilot study was conducted to predict an appropriate sample size. The eligibility criteria, study design, and treatment protocol were the same as in the present investigation. After the randomization of 15 patients (8 patients in the group with 0.9% NaCl and 7 patients in the group with 7.2% HSH), the ELWI as a preplanned primary endpoint was analyzed in all investigative stages. Based on data from the pilot study, a sample population of 12 patients per group was needed to provide 80% statistical power to detect a decrease in ELWI to 2 mL/kg (standard deviation, 1.8 mL/kg) using a 2-sided type-I error of 5%. To maintain a sufficient population in case of patient exclusion during the statistical analysis, 26 patients were included in the study. All medical records were collected and organized in a standardized manner using Excel (Microsoft, Redmond, WA). Nonparametric data were presented as median and interquartile range, and parametric quantitative data are presented as mean and standard deviation. Quantitative characteristics are described as the number and percentage for each category. Comparative analyses of nonparametric characteristics were performed using the Mann-Whitney test, and comparative analyses of parametric characteristics were performed using an independent-sample t test. Comparative analyses of qualitative characteristics were performed using the Fisher exact test. For all statistical analyses criteria, the type-I error was considered equal to 0.05. Null hypotheses were discarded if the probability (p) did not exceed type-I error. Statistical analyses were conducted according to standard methods19 using MedCalc 12.1.4 (MedCalc Software, Mariakerke, Belgium).

Table 1. Baseline Characteristics of Patients

Age (y) Women Body mass index (kg/m2) LVEF (%) History of myocardial infarction NYHA class Carotid artery stenosis History of stroke Angina class 0 I II III IV Unstable angina EuroSCORE Number of grafts 1 2 3 4 Endarterectomy Cardiopulmonary bypass time (min) Aortic cross-clamp time (min) Volume of cardioplegia (mL)

Group HSH (n ⫽ 13)

Group C (n ⫽ 13)

p Value

57.5 ⫾ 7.5 4 (31%) 29.6 ⫾ 4.0 62.2 ⫾ 8 11 (85%) 2.4 ⫾ 0.5 1 (8%) 0

55.3 ⫾ 7.2 1 (8%) 31.0 ⫾ 3.4 57.8 ⫾ 7.7 10 (78%) 2.6 ⫾ 0.7 4 (31%) 2 (15%)

0.445 0.322 0.325 0.161 1 0.323 0.322 1

1 (8%) 0 2 (15%) 8 (62%) 2 (15%) 0 2.2 ⫾ 1.6

0 0 1 (8%) 8 (62%) 0 4 (31%) 3.5 ⫾ 2.9

0 7 (54%) 6 (46%) 0 3 (23%) 61.0 ⫾ 18.2 34.7 ⫾ 9.8 1,119 ⫾ 218

0 3 (22%) 8 (62%) 2 (14%) 0 62.8 ⫾ 17.6 34.8 ⫾ 9.6 1,112 ⫾ 209

0.119

0.173

0.052

0.219 0.811 0.984 0.928

NOTE. Data are presented as mean ⫾ standard deviation, median (25th-75th percentiles), or number of patients (percentage). Abbreviations: C, isotonic saline (control); EuroSCORE, European System for Cardiac Operative Risk Evaluation; HSH, hypertonic saline/ hydroxyethyl starch; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.

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Table 2. Postoperative Complications and Clinical Course

Ventilation (h) Blood loss on postoperative day 1 (mL/kg) Inotropic support Atrial fibrillation ICU stay (d) Hospital stay (d)

Group HSH (n ⫽ 13)

Group C (n ⫽ 13)

p Value

6.0 (5.8-7.5)

7.0 (5.8-8.3)

0.408

4.8 (3.6-5.8) 1 (8%) 3 (23%) 1 (1-2) 14 (12-18)

5.1 (2.6-5.7) 5 (38%) 1 (8%) 2 (1-2) 16 (14-18)

0.626 0.160 0.593 0.473 0.396

NOTE. Data are presented as median (25th-75th percentiles) or number of patients (percentage). Abbreviations: C, isotonic saline (control); HSH, hypertonic saline/ hydroxyethyl starch; ICU, intensive care unit.

RESULTS

No patient was excluded during the study. The major demographics and baseline characteristics were similar in the 2 groups (Table 1). There were no significant differences in the mean values of age, left ventricular ejection fraction, number of grafts, aortic cross-clamp time, or CPB time between the 2 groups. Lengths of ICU and hospital stays were comparable (Table 2). The hospital mortality was 0 in the 2 groups. The assessment of the ELWI values is presented in Fig 2. At baseline, the ELWI was comparable in the 2 groups. However, in the HSH versus the C group, the ELWI values were significantly lower at 5 minutes after infusion (8 v 10 mL/kg; p ⬍ 0.05), at 5 minutes after CPB (9 v 10 mL/kg; p ⬍ 0.05), at 30 minutes after infusion (8 v 9.5 mL/kg; p ⬍ 0.05), at the end of surgery (8 v 9.5 mL/kg; p ⬍ 0.05), at 2 hours after CPB (7 v 9 mL/kg; p ⬍ 0.01), at 4 hours after CPB (7 v 9 mL/kg; p ⬍ 0.01), at 6 hours after CPB (6 v 9.5 mL/kg; p ⬍ 0.001), at 12 hours after CPB (7 v 9.5 mL/kg; p ⬍ 0.01), and on the first postoperative day (7 v 9.5 mL/kg; p ⬍ 0.01). The ELWI ranges are presented in Table 3. For the respiratory parameters, there was no difference between the groups at baseline. Nevertheless, the PaO2/FIO2 was significantly higher at 5 minutes (p ⬍ 0.01), 2 hours (p ⬍ 0.05), and 4 hours (p ⬍ 0.05) after CPB in the HSH group (Fig 3). The AaDO2 was significantly lower at 5 minutes, 2 hours, and 4 hours after CPB (p ⬍ 0.01 for all points) in the HSH group (Fig 4). There was no significant difference in the values of the venous shunt and the duration of mechanical ventilation between the groups (Table 4). The evaluation of hemodynamic data indicated that the CI at 5 minutes after infusion was increased in the HSH group and was significantly higher compared with the C group (3.18 L/min/m2, 2.74-3.67, with HS v 2.73 L/min/m2, 2.39-2.92; p ⬍ 0.05; Fig 5). At this point in the HSH group, the SVRI significantly decreased (p ⬍ 0.01; Fig 6). The other hemodynamic parameters were comparable, with few singular exceptions (Table 3). Compared with the control group, the plasma osmolarity and sodium concentration in the HSH group were significantly higher (p ⬍ 0.001) at most stages of the investigative period (Table 5).

The perioperative fluid balance is presented in Table 6. The net fluid balance was significantly lower (p ⬍ 0.001) in the HSH group than in the C group at the end of surgery. DISCUSSION

The use of CPB causes profound alterations of physiologic fluid homeostasis, which often result in interstitial fluid accumulation.20 At present, there are few studies that have investigated the influence of HS solutions on the ELW increase in patients undergoing cardiac surgery with CPB. Schroth et al9 infused hypertonic-hyperoncotic saline immediately postoperatively in children who underwent septal defect correction and detected a transient decrease in ELWI, suggesting that this solution effectively counteracts the fluid shift into the interstitial space. Kvalheim et al13 found no significant intergroup differences in the ELWI when HSH was administered in patients who underwent elective CABG. In contrast, Farstad et al21 observed that an infusion of the same solution resulted in a significant decrease in the tissue water content of the lungs during CPB in an animal study. Thus, the published evidence is conflicting and the independent influence of HS on the ELW is unclear.

Fig 2. Perioperative changes in the extravascular lung water index (ELWI; normal, 3-7 mL/kg). Values are presented as median and 25th-75th percentiles (error bars); *p < 0.05, †p < 0.01, ‡p < 0.001 significance level according to the Mann-Whitney test. C, isotonic saline (control); CPB, cardiopulmonary bypass; HSH, hypertonic saline/hydroxyethyl starch; POD, postoperative day.

Baseline

ELWI (mL/kg) Group HSH Group C HR (beats/min) Group HSH Group C MAP (mmHg) Group HSH Group C PCWP (mmHg) Group HSH Group C mPAP (mmHg) Group HSH Group C CVP (mmHg) Group HSH Group C PVRI (dynes · s · cm⫺5/m2) Group HSH Group C SVI (mL/m2) Group HSH Group C

5 min After Infusion

5 min After CPB

30 min After CPB

After CPB End of Surgery

9 (7-9) 8.5 (8-10)

8 (7-10)* 10 (8-11)

9 (8-9)* 10 (9-11)

8 (7.8-9)* 9.5 (9-12)

8 (7-9)* 9.5 (8-11)

64 (56-70) 72 (58-76)

79 (67-82) 70 (60-75)

86 (80-91) 83 (78-92)

79 (78-82) 85 (80-89)

83 (75-89) 80 (78-89)

79 (76-84) 86 (78-88)

80 (77-86) 77 (73-82)

11 (9-11) 9 (8-11)

13 (11-14) 12 (11-14)

17 (14-18) 17 (16-18) 7 (5-8) 7 (7-8)

2h

4h

6h

12 h

POD1

6 (6-7)‡ 9.5 (7-10)

7 (5.8-7.0)† 9.5 (7-11)

7 (6.8-7.3)† 9.5 (7-10)

7 (7-8)† 9 (8-11)

7 (6-7)† 9 (8-10)

82 (78-87) 87 (83-94)

86 (81-93) 86 (75-95)

80 (72-90) 84 (70-95)

78 (77-90) 81 (74-92)

85 (78-89) 79 (76-90)

85 (76-97) 81 (77-90)

73 (70-82) 80 (78-85)

78 (75-84) 79 (72-84)

79 (73-85) 80 (71-84)

78 (75-81) 72 (70-77)

83 (77-86) 73 (67-83)

83 (80-86)* 77 (70-80)

86 (79-93) 82 (80-89)

12 (11-12) 13 (11-13)

11 (10-13) 12 (11-13)

11 (11-12) 12 (11-14)

10 (8-11) 12 (9-13)

11 (8-12)† 13 (12-15)

12 (9-13) 13 (12-14)

11 (11-12) 12 (10-14)

12 (10-13) 13 (10-13)

19 (19-20) 19 (18-20)

18 (17-21) 19 (16-21)

18 (16-22) 19 (19-20)

19 (16-20) 19 (19-20)

19 (14-21) 18 (16-20)

19 (17-20) 20 (17-22)

20 (18-22) 20 (19-22)

20 (18-21) 20 (17-22)

20 (18-22) 21 (20-22)

8 (7-10) 8 (7-8)

9 (9-10) 9 (8-10)

9 (9-11) 10 (9-11)

9 (9-11) 11 (10-12)

8 (7-9) 8 (8-10)

9 (8-9)* 10 (9-12)

11 (9-12) 11 (9-11)

10 (9-10) 10 (9-11)

10 (8-11) 11 (10-12)

229 (178-263) 238 (157-280)

157 (119-197) 183 (168-259)

149 (112-177) 140 (112-210)

186 (136-228) 175 (150-211)

197 (143-230) 183 (141-214)

176 (163-253) 184 (143-264)

189 (156-236) 173 (119-224)

198 (159-268) 200 (164-233)

187 (170-235) 220 (155-237)

200 (144-231) 227 (190-250)

37 (32-42) 36 (30-39)

41 (39-51) 42 (32-45)

45 (39-48) 42 (38-45)

37 (35-42) 39 (34-43)

38 (34-41) 35 (33-39)

36 (32-40) 31 (28-35)

37 (33-41) 35 (30-40)

37 (32-44) 38 (31-45)

38 (32-46) 40 (35-44)

35 (33-42) 36 (33-46)

EXTRAVASCULAR LUNG WATER IN CARDIOPULMONARY BYPASS

Table 3. ELWI and Hemodynamic Data

NOTE. Data are presented as median (25th-75th percentiles). Abbreviations: C, isotonic saline (control); CPB, cardiopulmonary bypass; CVP, central venous pressure; ELWI, extravascular lung water index; HR, heart rate; HSH, hypertonic saline/hydroxyethyl starch; MAP, mean arterial pressure; mPAP, mean pulmonary artery pressure; POD1, postoperative day 1; PCWP, pulmonary capillary wedge pressure; PVRI, pulmonary vascular resistance index; SVI, stroke volume index. *p ⬍ 0.05, †p ⬍ 0.01, ‡p ⬍ 0.001 significance level accordingly to the Mann-Whitney test.

277

278

Fig 3. Perioperative changes in the index of arterial oxygenation efficiency (PaO2/FIO2). Values are presented as median and 25th-75th percentiles (error bars); *p < 0.05, †p < 0.01 significance level according to the Mann-Whitney test. C, isotonic saline (control); CPB, cardiopulmonary bypass; HSH, hypertonic saline/hydroxyethyl starch; POD, postoperative day.

The main result of the present study showed that an HSH infusion before CPB leads to a significant decrease in the presence of ELW during and after CABG. Edema has adverse consequences on the function of various tissues because it impairs tissue perfusion and oxygen transfer.22 Minimizing interstitial fluid accumulation in the lungs using HSH in the present study had beneficial effects on pulmonary function as assessed by measuring PaO2/FIO2 and AaDO2. These variables were deteriorated in the 2 groups but were significantly better preserved in patients using HSH. The edema formation during CPB with the subsequent organ dysfunction clearly is multifactorial. Changes in flow,23 arterial and venous pressures,24,25 precapillary and postcapillary resistances, and viscosity26 during CPB have effects on fluid extravasation, but the relative importance of each factor in edema is unknown. High flow rates,27 hemodilution,28 and hypothermia29 have been found to increase fluid extravasation, but the clinical relevance of these effects is not understood completely. In the present study, aside from the HSH infusion, the identical protocol of CPB, normothermia, and conventional ultrafiltration was used in the 2 groups to decrease effects of the factors described earlier. Some investigators have reported that HS induces several modulatory effects on neutrophils after ischemia and reperfusion injury by attenuating their ability to be sequestered in the lung and by attenuating their adherence and migration through the endothelium.30 It is apparent that the infusion of HSH during cardiac surgery with CPB not only contributes to fluid mobilization from the interstitial space, but also can decrease ischemia and

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reperfusion injury in the lung, which together may account for the effectiveness of the HSH administration in cardiac patients undergoing surgery with CPB. The present results regarding ELWI changes differed from those of Kvalheim et al13 who did not report any significant intergroup differences in the ELWI throughout the study when comparing the infusion of HSH with a placebo control of Ringer’s solution. Moreover, no significant difference in respiratory function was observed, but a lower positive fluid balance was observed in the HSH group compared with the C group. In the study by Kvalheim et al, patients received HSH, 1 mL/kg/h, for 4 hours from the beginning of the surgery, whereas in the present study, patients received 4 mL/kg for 30 minutes before the beginning of CPB. In this clinical study, the authors found that the use of HSH improved the contractile function of the heart. This was shown by the increase in CI at 5 minutes after infusion in the HSH group compared with the C group. The increase in preload and the decrease in SVRI may account for the increase in CI seen in the HSH group. The direct effects of HS on cardiac contractility remain controversial. Despite the declaration of a proper positive inotropic effect of increased serum osmolarity on the myocardium,31 no increases in myocardial contractility in isolated hearts have been reported in several studies.32,33 The vasodilatory effect of hypertonicity on smooth vascular muscles has been reported by other investigators. The vascular

Fig 4. Perioperative changes in alveolar-arterial oxygen tension differences (AaDO2). Values are presented as median and 25th-75th percentiles (error bars); †p < 0.01 significance level according to the Mann-Whitney test. C, isotonic saline (control); CPB, cardiopulmonary bypass; HSH, hypertonic saline/hydroxyethyl starch; POD, postoperative day.

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279

Table 4. Respiratory Parameters After CPB Baseline

Qs/Qt (%) Group HSH Group C DO2I (mL/min/m2) Group HSH Group C VO2I (mL/min/m2) Group HSH Group C O2EI (%) Group HSH Group C

8.6 (7.9-9.4) 10.5 (8-11.7) 414.7 (372.3-485.9) 457.6 (395.8-497.9)

5 min

18 (13.9-27.8) 21.5 (19.6-26.2) 451 (387.9-601.2) 361 (316.4-421.9)

2h

14.8 (10.8-16.5) 15.1 (13.3-18.2)

4h

10.6 (8.8-12.1) 12 (9.5-14.5)

POD1

11.8 (8.3-12.9) 12.3 (9.4-22.8)

647 (488.3-717.7) 518.7 (463.1-621.4)

504 (377-541.6) 459.2 (413.9-560.5)

502.6 (392.9-517) 404.1 (364.2-449.8)

111.8 (98.1-151.3) 130.7 (93.3-168.2)

113.2 (81.8-140.5) 93 (88.2-112.6)

161.3 (148.2-179.7) 180.1 (140-206.7)

146.2* (110.9-151.7) 163.1 (134.1-194.7)

168.5 (146.6-195.4) 157.3 (120.2-172.4)

27.5 (23.5-32.2) 29.5 (22.4-32.4)

22.6 (21.2-28.7) 27.6 (24.1-32.2)

29.2 (24.4-31.6) 32.4 (26.9-40.5)

30* (25.3-31.5) 35 (31.8-38.9)

36.5 (32.6-41.3) 37 (32.1-41)

NOTE. Data are presented as median (25th-75th percentiles). Abbreviations: C, isotonic saline (control); CPB, cardiopulmonary bypass; DO2I, oxygen delivery index; HSH, hypertonic saline/hydroxyethyl starch; O2EI, oxygen extraction index; POD1, postoperative day 1; Qs/Qt, venous shunt fraction; VO2I, oxygen consumption index. *p ⬍ 0.05 significance level accordingly to the Mann-Whitney test.

resistance is decreased by the neurohumoral effect, which decreases the serum level of vasoconstricting mediators.34 The main effect of HSH is the fluid shift from the interstitial to the intravascular compartment by an osmotic gradient, leading to plasma volume expansion.35 One of the potential mechanisms of the improvement of CI by HSH is a decrease of excess myocardial water content.4 As excess

fluid accumulates in the myocardial interstitium, the interstitial fluid pressure increases, which decreases myocardial compliance and leads to increasing demands on the energy resources of the heart.36 One of the results of the present study was a significantly lower net fluid balance at the end of surgery in the HSH group.

Fig 5. Perioperative changes in the cardiac index (CI; normal, 2.5-5 L/min/m2). Values are presented as median and 25th-75th percentiles (error bars); *p < 0.05 significance level according to the MannWhitney test. C, isotonic saline (control); CPB, cardiopulmonary bypass; HSH, hypertonic saline/hydroxyethyl starch; POD, postoperative day.

Fig 6. Perioperative changes in the systemic vascular resistance index (SVRI; normal, 600-1,600 dynes · s · cmⴚ5/m2). Values are presented as median and 25th-75th percentiles (error bars); †p < 0.01 significance level according to the Mann-Whitney test. C, isotonic saline (control); CPB, cardiopulmonary bypass; HSH, hypertonic saline/hydroxyethyl starch; POD, postoperative day.

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Table 5. Osmolarity and Sodium

Osmolarity (mOsmol/L) Group HSH Group C Sodium (mmol/L) Group HSH Group C

After CPB

Baseline

5 min After Infusion

10 min of CPB

5 min

2h

307 (304-314) 309 (305-314)

332 (326-339)† 309 (306-315)

336 (332-340)† 323 (319-325)

337 (334-340)† 322 (317-324)

337 (332-341)* 326 (321-328)

335 (333-337) 330 (322-354)

323 (321-328) 321 (313-326)

138 (136-140) 137 (136-137)

147 (144-149)† 137 (135-138)

143 (140-147)† 136 (133-137)

144 (142-146)† 137 (135-137)

149 (147-152)† 140 (139-142)

149 (146-150)† 141 (139-143)

146 (142-148)* 142 (139-144)

4h

POD1

NOTE. Data are presented as median (25th-75th percentiles). Abbreviations: C, isotonic saline (control); CPB, cardiopulmonary bypass; HSH, hypertonic saline/hydroxyethyl starch; POD1, postoperative day 1. *p ⬍ 0.01, †p ⬍ 0.001 significance level accordingly to the Mann-Whitney test.

This observation corresponds with the results of other studies.37,38 After the infusion of HSH, the fluid is shifted from the intracellular space (first from erythrocytes and endothelial cells) and interstitial fluids (by the osmotic gradient) to the intravascular compartment.39,40 One of the disadvantages of HS infusion in cardiac surgery is an increase in plasma sodium concentration. Typically, the clinical manifestation of cellular dehydration primarily resulting from hypernatremia should affect the central nervous system, but there have been no reported incidents of seizures or other neurologic disturbances in patients who were administered HS.41 In the present study, despite the rapid rate of HSH infusion, the sodium concentration did not exceed 160 mmol/L and osmolarity did not exceed 350 mOsmol/L, which are considered safe values42,43; no patients developed neurologic disturbances. The adverse effects associated with HSH infusion (eg, hypotension episodes, intensive increase of PCWP, ventricular arrhythmias) are observed infrequently during the rapid infusion of HSH.44 None of the present patients developed cardiac decompensation or signs of a hypertensive emergency. Thus, the single administration of HSH was found to be safe, and no adverse effects were observed in the present study.

The present research had several limitations. Because patients with a decreased left ventricular ejection fraction were excluded from the present study, these conclusions cannot be extrapolated to this category of patients. This study involved only uncompromised patients who underwent cardiac surgery with a short period of CPB. Because the degree of fluid extravasation and lung dysfunction are related directly to the duration of the CPB procedure, further investigations are warranted to support these results. Another limitation of the study was that the patients were not weighed after surgery. Moreover, hemostasis was not examined, although it has been reported that HSH administration is safe in patients undergoing cardiac surgery.13 The issues relating to the influence of HSH on renal function also require additional studies. Another limitation of the study was the infusion of standard saline in the C group instead of a balanced hydroxyethyl starch solution. The presence of a colloid component (hydroxyethyl starch, 200/0.5) in HSH could have favored an increase of colloid osmotic pressure in the HSH group compared with the C group. Further trials with larger samples are needed to clarify the clinical advantages of HSH administration in patients undergoing surgery with CPB.

Table 6. Data on Perioperative Fluid Balance End of Surgery

Crystalloid fluid balance (mL) Group HSH Group C Noncrystalloid fluid balance (mL) Group HSH Group C Net fluid balance (mL) Group HSH Group C Urine output (mL) Group HSH Group C

900 (900-1,138) 1,100 (900-1,600) 350 (288-388)* 500 (500-1,000)

POD1

1,900 (1,500-2,125) 1,550 (1,500-2,000) 500 (238-688) 500 (0-500)

⫺719 (⫺925 to ⫺735)† 150 (⫺50 to 400)

⫺810 (⫺1,150 to ⫺425) ⫺500 (⫺888 to ⫺65)

2,025 (1,700-2,300) 1,600 (1,300-2,000)

2,800 (2,000-3,045) 2,400 (2,150-2,500)

NOTE. Data are presented as median (25th-75th percentiles). The crystalloid fluid balance equals the sum of all crystalloid infusions. The noncrystalloid balance equals the sum of all noncrystalloid infusions. Net fluid balance at the end of surgery equals the sum of all infusions minus the urine output. Net fluid balance at postoperative day 1 equals the sum of all infusions minus the urine output and blood loss. Abbreviations: C, isotonic saline (control); CPB, cardiopulmonary bypass; HSH, hypertonic saline/hydroxyethyl starch; POD1, postoperative day 1. *p ⬍ 0.05, †p ⬍ 0.001 significance level accordingly to the Mann-Whitney test.

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In conclusion, the differences in the postoperative complications and clinical course between the HSH and C groups appear to be of minor clinical importance. The infusion of HSH

leads to significant decreases in the ELWI during and after CABG and is associated with a better preservation of lung function and transient increases in CI.

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