Abstract
Background:
Emerging therapies for prolonged cardiac arrest (CA) include advanced circulatory interventions like emergency cardiopulmonary bypass (ECPB) and continuous venovenous hemofiltration (CVVHF). However, preclinical studies are limited because of the absence of a practical method of using CVVHF along with ECPB in rodents.
Methods:
We modified a CA model with ECPB resuscitation to include the CVVHF circuit. Adult rats were cannulated via the femoral artery or vein and the jugular vein for the ECPB circuit. A new circuit for CVVHF was added to allow ECPB and CVVHF to be started simultaneously. CVVHF blood flow at 3 mL/min could be controlled with a screw clamp during ECPB. After cessation of ECPB, the CVVHF flow was maintained using a roller pump. The filtration rate was controlled at 40 mL/h/kg in the standard volume of CVVHF and 120 mL/h/kg in the high volume (HV) of CVVHF. The driving force of hemofiltration was evaluated by monitoring transmembrane pressure and filter clearance (FCL).
Results:
Transmembrane pressure in both groups was stable for 6 h throughout CVVHF. FCL of blood urea nitrogen and potassium in the standard volume group was significantly less than the HV group (P < 0.01). FCL of blood urea nitrogen and potassium was stable throughout the CVVHF operation in both groups.
Conclusions:
We developed a method of CVVHF along with ECPB in rodents after CA. We further demonstrated the ability to regulate both standard and HV filtration rates.
Keywords: Hemofiltration, Cardiopulmonary bypass, Rodent, Cardiac arrest, Resuscitation
1. Introduction
Advanced therapies for the treatment of prolonged cardiac arrest (CA) include circulatory interventions such as emergency cardiopulmonary bypass (ECPB) and continuous venovenous hemofiltration (CVVHF). However, the studies of these advanced technologies are limited because of the absence of a practical method of using CVVHF along with ECPB in small animals.
ECPB, a system that pumps the oxygenated blood through a whole body, is thought to rescue a CA patient [1-3]. This system allows an extended window of time to determine the cause of CA and takes the necessary steps to restore adequate organ functions of patients [4].
CVVHF is a therapy for blood purification using a pump to pass the blood over a filter. The driving force of CVVHF is a pressure gradient rather than a concentration gradient. Several studies [5,6] have suggested that the use of CVVHF is associated with improved outcomes in CA. Therefore, CVVHF has been used in CA [5] and cardiac surgeries with cardiopulmonary bypass [7-9].
Although previous studies have shown the method for combination of ECPB with CVVHF, all of surgical sets has been done for the use of large animals [6,10,11]. It is difficult to operate two extracorporeal blood circuits in small animals because of the little blood volume. Therefore, there have been no rodent models to date.
For these reasons, we sought (a) to develop a practical method for dual extracorporeal circuits of CVVHF and ECPB in rats suffering CA, (b) to measure transmembrane pressure (TMP) and filter clearance (FCL) to evaluate the efficacy of CVVHF, and (c) to test the hypothesis that high-volume (HV) CVVHF was feasible in rats.
2. Materials and methods
The study protocol was approved by the Institutional Animal Care and Use Committee of the University of Pennsylvania. Sixteen adult male Sprague–Dawley rats (450–550 g; Charles River Laboratories, Wilmington, MA) were used.
2.1. Procedures
2.1.1. Surgical preparation
All the instrumentation was performed according to the previously described protocol [12,13]. In brief, animals were anesthetized with 4% isoflurane (Isosthesia; Butler-Schein AHS, Dublin, OH)/96% oxygen and intubated with a 14-gauge plastic catheter (Surflo; Terumo Medical Corporation, Somerset, NJ). Animals were mechanically ventilated (Ventilator Model 683; Harvard Apparatus, Holliston, MA), and anesthesia was maintained with isoflurane.
The left femoral artery was cannulated (sterile polyethylene-50 catheter inserted for 2 cm) for the continuous arterial pressure monitoring (MLT844; ADInstruments, Bridge Amplifiers ML221; ADInstruments, Colorado Springs, CO).
2.1.2. CA and resuscitation with cardiopulmonary bypass
After all the instrumentation, 2 mg/kg of vecuronium bromide (Hospira, Lake Forest, IL) was administered and asphyxia was induced for 12 min. Circulatory arrest was defined as a mean arterial pressure of <20 mm Hg. The ECPB circuit was primed with 10 mL of Plasma-Lyte A (Baxter, Deerfield, IL), 10 mL of 6% Hetastarch (Hospira), 0.8 mL of 0.406 mEq/mL magnesium sulfate (APP Pharmaceuticals, Schaumburg, IL), and 0.3 mL of 3.3 mmol/mL THAM Solution (XVIVO Perfusion AB, Göteborg, Sweden). Additional 8 mL of Plasma-Lyte A and 4 mL of 6% Hetastarch, a total volume of 12 mL, was added to the venous reservoir to maintain a stable circulating volume during ECPB. After 12 min of asphyxia, resuscitation was started with the initiation of the ECPB blood flow. Activated coagulation time (ACT) was maintained with heparin (SAGENT Pharmaceuticals) at >250 s during ECPB. At the end of 30 min ECPB, the remaining blood in the ECPB circuit was collected for a retransfusion into the animal. The rate of the transfusion was 6 mL/kg/h through the postresuscitation care period.
2.1.3. Development of CVVHF during and after cardiopulmonary bypass
The left femoral vein was cannulated with a 20-gauge catheter cannula (Insyte-W; BD, Franklin Lakes, NJ) for blood inflow to the CVVHF circuit. The right femoral artery was cannulated with a 20-gauge catheter cannula for blood inflow to ECPB. The right internal jugular vein was cannulated for the venous outflow of ECPB and CVVHF with a modified 4 hole 14-gauge catheter (Surflo; Terumo Medical Corporation), which was advanced to the vena cava. This catheter was heparin locked with 300 UI of heparin.
CVVHF was started simultaneously with the resuscitation by ECPB. The blood flow of both circuits was supplied from the same roller pump. A flow sensor (TS410; Transonic Systems, Ithaca, NY) was placed on the tube to monitor the rate of blood flow (Fig. 1A), which was controlled at 3 mL/min (5.5–6.5 mL/min/kg). The rate of blood flow was adjusted by a screw clamp placed on a tube (inside diameter 1.4 mm) for the inflow of CVVHF (Fig. 1A). The screw clamp was carefully adjusted according to the flow rate measured by the flow sensor throughout ECPB (Fig. 1A and C).
Fig. 1 –
(A) Schematic of the rodent CVVHF circuit combined with emergency cardiopulmonary bypass circuit. The letters indicate the location of monitoring and circuit components; A, outflow tube for two extracorporeal circuits; B, venous reservoir; C, roller pump; D, oxygenator of emergency cardiopulmonary bypass; E, inflow tube for emergency cardiopulmonary bypass; F, outflow for CVVHF; G, flow sensor; H, pressure sensor at PBi; I, pressure sensor at side hole; J, filtration (effluent) pump; K, screw clump; L, inflow tube for CVVHF; and M, replacement infusion pump. The flow rates shown in schematic were typical settings of two extracorporeal circuits. The filtration and replacement rates in hemofiltration group were 20 mL/h and those in HV HF group were 60 mL/h. (B) Schematic of the rodent CVVHF circuit. The letters indicate the location of monitoring and circuit components; A, roller pump; B, outflow for CVVHF; C, pressure sensor at PBi; D, pressure sensor at side hole; E, filtration (effluent) pump; F, screw clump; G, inflow tube for CVVHF; and H, replacement infusion pump. The flow rates shown in schematic were typical settings of continuous hemofiltration circuits. The filtration and replacement rates in hemofiltration group were 20 mL/h and those in HV HF group were 60 mL/h.
At the end of 30 min ECPB, the ECPB circuit was removed (Fig. 1B and D). And then, the roller pump in the CVVHF circuit was started at the blood flow rate of 3 mL/min (5.5–6.5 mL/min/kg). CVVHF was operated for 6 h in all animals.
2.1.4. Two settings of hemofiltration volume
The filtration rate was controlled at 20 mL/h (35–45 mL/h/kg) for the standard volume CVVHF and 60 mL/h (110–135 mL/h/kg) for the HV CVVHF. Animals were randomly assigned into each group. The effluent was drawn from a side hole of the hemofilter using a drawing pump (Genie Touch Syringe Pump; Kent Scientific, Torrington, CT). A replacement fluid, added at the same rate as the effluent was drawn, was infused through a pump using a three way stopcock placed between a catheter inserted into the left femoral vein and a tube for the inflow of CVVHF (Fig. 1, post-dilution, zero-balanced filtration). For CVVHF, a hollow-fiber hemofilter, AN69ST (GAMBRO Industries, Meyzieu, France; Table 1), was used. PrismaSATE BGK 4/2.5 (Gambro Renal Products, Daytona Beach, FL) was used as the replacement fluid. Priming volume of the CVVHF circuit was 6.9 mL. A total of 50 UI of heparin was injected between 2 and 3 h after the start of CVVHF, and then ACT was maintained at >180 s during CVVHF.
Table 1 –
Physical characteristics of hemofilter.
| Material | Copolymer of acrylonitrile and sodium methallylsulfonate |
|---|---|
| Surface, m2 | 0.048 |
| SC | |
| BUN (MM 60 Da) | 1 |
| Potassium (MM 39 Da) | 1 |
| Myoglobin (MM 17 kDa) | 0.58 |
| Albumin (MM 66 kDa) | <<0.01 |
| Fiber diameter, μm | 240 |
| Fiber wall thickness, μm | 50 |
| Total volume of column, mL | 5.7 |
| Maximum TMP, mm Hg | 500 |
MM = molecular mass.
2.2. Measurements and calculations
2.2.1. Pressure measurements
Two pressure sensors were placed at prefiltration points (PBi); one on the blood flow (Transpac IV Monitoring Kit; Hospira) and the second at a side hole on the effluent flow (844-28 Dome sterile; Memscap AS, Skoppum, Norway). The second sensor was placed between the side hole of a hemofilter column and an effluent pump, to monitor TMP throughout the CVVHF operation (Fig. 1).
2.2.2. Transmembrane pressure
Simplified TMP (sTMP) was calculated as
2.2.3. Laboratory data of blood and effluent samples
After a surgical preparation, a baseline blood sample (0.5 mL) was obtained from the arterial line and then ACT, blood urea nitrogen (BUN), potassium levels (i-STAT; Heska, East Windsor, NJ), and a hematocrit (Stat Spin MP; Iris Sample Processing, Westwood, MA) were measured immediately after blood sampling. Arterial blood samples (0.5 mL) were drawn at 1, 2, 3, and 6 h after the start of CVVHF. The effluent samples from CVVHF were collected at 1, 2, 3, and 6 h after CVVHF, which contained the cumulative amount of the effluent during 0–1, 1–2, 2–3, and 3–6 h, respectively. BUN and potassium levels of the blood and effluent samples were measured immediately after the sampling.
2.2.4. FCL of CVVHF
FCL of BUN and potassium was calculated in each group of CVVHF. FCL in our study was calculated as
| (1) |
where Qf was the rate of the filtration, which was 20 mL/h in the standard volume of CVVHF and 60 mL/h in the HV CVVHF. SCn (sieving coefficient) was calculated as
| (2) |
where Cf was the concentration measured in the effluent samples and Cb was that in the blood samples. Blood Cn is the mean value, which is calculated by Cn plus Cn−1 divided by two, whereas n = 0 indicated that samples were obtained at baseline; n = 1, at 1 h; n = 2, at 2 h; n = 3, at 3 h; and n = 4, at 6 h after the start of CVVHF.
2.3. Statistical analysis
Continuous data that were normally distributed were reported as mean and standard deviation. Data that were not normally distributed were reported as median and interquartile range. Group comparisons were made with one-way analysis of variance, and Scheffe test was used as a post hoc test. Continuous data were analyzed by the unpaired t-test. A two-tailed P value of <0.05 was considered statistically significant. All calculations were performed with SPSS Statistics version 21 for Mac (IBM SPSS Statistics, Chicago, IL).
3. Results
In total, 16 animals were randomized to receive standard volume CVVHF (n = 8) and HV CVVHF (n = 8). Basal characteristics and resuscitation data are shown in Table 2. There were no significant differences between the two groups. All animals were successfully resuscitated by ECPB. CVVHF was successfully performed for 6 h in all animals.
Table 2 –
Basal characteristics and resuscitation data of randomized animals.
| Characteristic | CVVHF | |
|---|---|---|
| Hemofiltration n = 8 |
HF hemofiltration n = 8 |
|
| Weight, g | 481 ± 17 | 489 ± 33 |
| Hematocrit, % | 43 ± 1 | 42 ± 1 |
| BUN, mEq/L | 27 ± 3 | 26 ± 1 |
| K, mEq/L | 4.5 ± 0.5 | 4.5 ± 0.4 |
| Asphyxia to CA time, s | 224 ± 14 | 217 ± 23 |
| Start ECPB to ROSC time, s | 44 (36–98) | 47 (36–150) |
ROSC = return of spontaneous circulation.
Blood samples were obtained from arterial line before asphyxia (baseline).
CA was defined to occur when mean arterial pressure dropped below 20 mm Hg. ROSC time was defined as the first time when spontaneous pulse pressure appeared.
Values are expressed as mean ± standard deviation and median and interquartile range unless otherwise indicated.
A hematocrit at the end of CVVHF was 28.6 ± 3.8% in the standard volume CVVHF group and 26.6 ± 2.2% in the HV CVVHF group. There were no cases of massive bleeding in either group during CVVHF.
3.1. sTMP measurements
sTMP is depicted in Figure 2. There were no significant differences of sTMP for 6 h sTMP in both groups were stable throughout CVVHF.
Fig. 2 –
(A) sTMP with time during ECPB in the two groups of animals. HF = hemofiltration. *P < 0.05, **P < 0.01 HF versus HV-HF. (B) sTMP with time after in the two groups of animals. HF = hemofiltration. *P < 0.05, **P < 0.01 HF versus HV-HF.
3.2. FCL of BUN and potassium
Mean FCL of BUN and potassium in the hemofiltration group was significantly lower than that in the HV CVVHF group (P < 0.01). Stability of FCL for two small molecules in both groups was maintained throughout the CVVHF operation (Fig. 3A and B).
Fig. 3 –
(A) FCL of BUN at each time point in the two groups of animals. HF [ hemofiltration. **P < 0.01 HF versus HV-HF. (B) FCL of potassium at each time point in the two groups of animals. HF = hemofiltration. **P < 0.01 HF versus HV-HF.
3.3. Blood levels of BUN and potassium
Blood levels of BUN and potassium increased with time during CVVHF in both groups (Fig. 4).
Fig. 4 –
(A) Blood BUN levels with time in the two groups of animals. HF= hemofiltration. *P < 0.05, **P < 0.01 HF versus HVHF; #P < 0.05, ##P < 0.01 compared with each time point. (B) Blood potassiumlevels with time in the two groups of animals. HF indicates hemofiltration. *P < 0.05, **P < 0.01 HF versus HV-HF; #P < 0.05, ##P < 0.01 compared with each time point.
4. Discussion
We have successfully developed a novel system designed for rats that will enable future functional studies using dual extracorporeal circuits, CVVHF and ECPB. ECPB was used for resuscitation of CA and then all animals were successfully resuscitated.
A major finding of our study was that stable TMP and FCL were achieved throughout CVVHF. These results supported that the driving force during CVVHF was adequately maintained, and small molecules were constantly removed for 6 h.
Miller et al. [14] showed that sTMP, calculated from two pressures (PB and PF), was a more practical method of estimating TMP calculated from four pressures. TMP was calculated as the classical form of [14]
We examined the differences between sTMP and TMP (Appendix A). Based on the result of this pilot study, we were certain that sTMP was able to be used instead of TMP.
In this study, we examined FCL of small molecules throughout CVVHF. FCL was calculated using [15,16],
| (1) |
and sieving coefficient (SC) was calculated using [17]
| (2) |
where Qf indicated filtrated volume; Cf, the concentration in an effluent; Ci, the blood levels at prefilter; Co, at post-filter. Because of little blood volume in rodents, collecting samples twice at each time point was not practical. Therefore, we examined Cb (concentration in the arterial blood), Ci, and Co of BUN or potassium at each time point (Appendix B and C). Based on this pilot study, Ci and Co could be replaced with Cb. Therefore, equation (2) was approximated by the following equation
| (3) |
When equation (3) was combined with equation (1), we had generated [18,19]
| (4) |
Because we collected effluent samples continuously for an hour (except the last period of 3 h) and measured Cf in each effluent sample, we used a mean value of Cb between two time points (n and n-1) for the calculation.
In addition, we found that HV CVVHF was feasible in small animals. The filtration rate of 110–135 mL/kg/h was higher than other groups [20,21]. To our knowledge, there has been no other study that achieves this rate for rat models. It is difficult to operate venovenous circuits because of the complexity of extracorporeal circuits. Therefore, most investigators use arteriovenous (AV) circuits for rats [22-25]. AV circuits will not allow sufficient blood flow. However, HV hemofiltration requires high blood flow. Yorimitsu et al. [24] reported that a blood flow of over 1.5 mL/min in AV circuits was not feasible for rats. Peng et al. [26] showed that venovenous circuits had fewer complications than AV circuits. In our model, a 14-gauge catheter placed into jugular vein allowed us to obtain sufficiently high blood flow from rats.
Our study had several limitations. First, anemia was observed in animals because of large priming volume of two extracorporeal circuits. Liam et al. [27] suggested that a hematocrit of 25% was sufficient to match whole body oxygen consumption; however, a hematocrit of less than 18% might lead to oxygen deficit. Therefore, we considered that a hematocrit of 26%–28% was sufficient to supply oxygen to the whole body. Second, we did not examine FCL of middle size of molecules, such as inflammatory mediators [28-31]. Our objective of this study was to develop a novel rodent model with dual extracorporeal circuits and to examine its function. Therefore, we investigated small molecules in this study. We intend to examine the effects of CVVHF on removing inflammatory mediators in the near future.
5. Conclusions
In conclusion, we developed a practical method to study dual extracorporeal circulation using CVVHF with ECPB for rodents and demonstrated that it was feasible to apply HV CVVHF to rodents. Stability of TMP and FCL for small molecules was maintained throughout CVVHF. This method may be used for studies that aim to assess the usefulness of extracorporeal therapies in research fields beyond resuscitation science.
Acknowledgment
The authors thank Sarah Lampe and Ameena Al-Amin for their assistance with editing language, writing assistance, and providing figures of extracorporeal circuits. They thank GAMBRO Industries, Meyzieu, France, for providing hemofilters that were used in this study. Research reported in this publication was supported by the NHLBI of the National Institutes of Health under award number RO1HL67630 (L.B.B.). K.S. has grant/research support from Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad and is supported by internal institutional funding from Chiba University.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Appendix
Pressure sensors were placed at prefilter (PBi), post-filter (PBo), and two side holes. The sensor at the side hole was placed between effluent pump and side hole of the filter column. Another sensor for filter-inflow (PFi) was placed between stopcock and the other side of the side hole of filter, which was locked by stopcock.
TMP was calculated as
whereas sTMP was calculated as
Values are expressed as mean ± standard deviation. Pressure data during ECPB were obtained as 10 s averages at every 3 min during 30 min of ECPB operation and those after ECPB was every 15 min after the end of the ECPB operation.
BUN indicates blood uremia nitrogen.
Sieving coefficient (SC) was calculated as
where Cf is the concentration of the effluent sample, Ci is the blood levels of sample collected at PBi, and Co is those at PBo. Four samplings (artery, PBi, PBo, and effluent) were completed within 5 min at each time point.
Intraclass correlation of single measure between three point samples (artery, PBi, and PBo) is 0.978 (P < 0.01).
Sieving coefficient (SC) was calculated as
where Cf is the concentration of the effluent sample, Ci is the blood levels of sample collected at PBi, and Co is those at PBo. Four samplings (artery, PBi, PBo, and effluent) were completed within 5 min at each time point.
Intraclass correlation of single measure between three point samples (artery, PBi, and PBo) is 0.995 (P < 0.01).
Appendix A –
Four point pressure measurements of hemofilter during and after ECPB.
| Measurements | During ECPB | After ECPB |
|---|---|---|
| Rat1 | ||
| Prefilter (PBi) | 470 ± 151 | 69 ± 38 |
| Post-filter (PBo) | 461 ± 148 | 58 ± 38 |
| TMP | 17.1 ± 11.9 | 23.6 ± 4.5 |
| sTMP | 20.1 ± 14.3 | 29.5 ± 4.8 |
| Subtractions | ||
| PBi – PBo, mm Hg | 8.5 ± 5.7 | 10.6 ± 1.1 |
| TMP – sTMP, mm Hg | −3.0 ± 3.7 | −5.9 ± 0.6 |
| Rat2 | ||
| Prefilter (PBi) | 207 ± 84 | 66 ± 4 |
| Post-filter (PBo) | 192 ± 84 | 53 ± 2 |
| TMP | 29.2 ± 1.8 | 29.8 ± 2.5 |
| sTMP | 37.4 ± 1.6 | 37.3 ± 3.1 |
| Subtractions | ||
| PBi – PBo, mm Hg | 14.7 ± 1.7 | 13.1 ± 1.7 |
| TMP – sTMP, mm Hg | −8.2 ± 0.8 | −7.5 ± 0.6 |
Appendix B –
Blood and effluent levels of BUN and SC of hemofilter at different time point.
| Levels | Artery | PBi | PBo | Effluent | SC |
|---|---|---|---|---|---|
| Rat1 | |||||
| T1, mg/dL | 27 | 28 | 29 | 28 | 0.98 |
| T2, mg/dL | 32 | 32 | 34 | 33 | 1.00 |
| T3, mg/dL | 36 | 39 | 36 | 37 | 0.99 |
| T4, mg/dL | 40 | 42 | 41 | 42 | 1.01 |
| Rat2 | |||||
| T1, mg/dL | 26 | 25 | 25 | 26 | 1.04 |
| T2, mg/dL | 31 | 30 | 31 | 30 | 0.98 |
| T3, mg/dL | 40 | 42 | 40 | 36 | 0.89 |
| T4, mg/dL | 49 | 53 | 52 | 48 | 0.91 |
Appendix C –
Blood and effluent levels of potassium and SC of hemofilter at different time point.
| Levels | Artery | PBi | PBo | Effluent | SC |
|---|---|---|---|---|---|
| Rat1 | |||||
| T1, mg/dL | 4.6 | 4.7 | 4.5 | 5.0 | 1.09 |
| T2, mg/dL | 6.5 | 6.2 | 6.4 | 6.3 | 1.00 |
| T3, mg/dL | 6.2 | 6.4 | 6.3 | 6.4 | 1.01 |
| T4, mg/dL | 9.4 | 9.6 | 9.4 | 9.3 | 0.98 |
| Rat2 | |||||
| T1, mg/dL | 4.0 | 4.2 | 4.0 | 4.0 | 0.98 |
| T2, mg/dL | 5.4 | 5.5 | 5.4 | 5.6 | 1.03 |
| T3, mg/dL | 4.8 | 5.1 | 5.1 | 5.1 | 1.00 |
| T4, mg/dL | 5.8 | 6.0 | 5.8 | 5.8 | 0.98 |
Footnotes
Disclosure
J.W.L., C.-H.W., T.Y., S.O., J.K., and H.H. have no known conflicts of interest associated with this study and there has been no significant financial support for this work that could have influenced its outcome.
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