High-quality cardiopulmonary resuscitation (CPR) optimizes forward blood flow after cardiac arrest. However, the compression-related cardiac output is 15–30% of its prearrest values. As the kidney is very susceptible to hemodynamic perturbations, the intra-arrest and postcardiac ischemia and hypoxemia are main factors for acute kidney injury (AKI) [
Acute kidney injury is the sudden and sustained reduction in renal function, which causes a constant accumulation of nitrogenous and nonnitrogenous products and toxins, fluid disorders of rapid onset, and electrolyte and acid-base imbalance. During the last decade, various novel biochemical markers for the early detection of AKI have been identified. These are kidney-produced proteins, such as the neutrophil gelatinase-associated lipocalin (NGAL) and cytokine interleukin-18 (IL-18), as well as low molecular weight substances, such as the Liver-Type Fatty-Acid Binding Protein (L-FABP) [
Erythropoietin (EPO) is an endogenous glycoprotein and member of the family of type I cytokines. Although exogenous EPO is commonly used in daily clinical practice to treat anemia in patients with chronic kidney failure [
The objective of this observational animal study was to investigate the effect of EPO administration on renal function in an established model of cardiac arrest and resuscitation. The study was conducted according to the Utstein style guidelines for uniform reporting of laboratory CPR research. The experimental protocol was approved by the Directorate of Veterinary Services of Prefecture of Athens, Attica, Greece, according to Greek legislation regarding ethical and experimental procedures (protocol number 23/10-01-2012).
The study used 24 female Landrace/Large-White piglets aged 10–15 weeks with average weight of 18–20 kg, all supplied from the same breeder (Validakis, Athens, Greece). The animals were fasted overnight but had free access to water.
The protocol has been described in detail elsewhere [
The animals were mechanically ventilated with a volume-controlled ventilator with a tidal volume of 15 mL/kg and fraction of inspired oxygen (FiO2) of 0.21. The respiratory frequency was adjusted to maintain an arterial partial pressure of carbon dioxide between 35 and 40 mmHg. A bolus dose of cisatracurium (0.15 mg/kg) was administered to ascertain synchrony with the ventilator. Continuous infusion of propofol 150
Right carotid artery and right internal jugular vein were surgically prepared and catheterized under aseptic conditions. Aortic pressures were measured using a fluid-filled catheter (model 6523, USCI CR, Bart, Papapostolou, Athens, Greece) advanced via the right carotid artery into the thoracic aorta. Mean arterial pressure (MAoP) was determined by electronic integration of the aortic blood pressure waveform. A catheter was inserted into the right atrium via the right jugular vein for continuous measurement of right atrial pressures. Coronary perfusion pressure (CPP) was electronically calculated as the difference between minimal aortic diastolic pressure (DAoP) and the simultaneously measured right atrial diastolic pressure. The second internal jugular vein was also surgically prepared, and a 5 F flow-directed pacing catheter (Pacel, 100 cm; St. Jude Medical, Ladakis, Athens, Greece) was advanced into the apex of the right ventricle. All catheters were calibrated before use, and their correct position was verified by the presence of the typical pressure waveform.
After surgery, the animals were allowed a 30 min stabilization period before baseline data were collected. Before the experimental procedure, the piglets were randomly assigned to 2 different groups of 12 subjects each, according to the agents used, by means of a sealed envelope.
Ventricular fibrillation was induced with a 9 V ordinary cadmium battery via a pacing wire forwarded into the right ventricle through the exposed right jugular vein, as previously described [
After the end of the 8th minute, the control group (Group C) received saline as placebo (10-mL dilution, bolus), whereas the EPO group (Group E) received EPO 5000 U/kg. All drugs were injected via the marginal auricular vein, followed by a 10 mL saline flush to assist faster circulation of medications. The researchers were blinded to EPO or saline, respectively, until the experiment was completed and all hemodynamic and survival data were collected.
The animals were resuscitated according to the 2010 European Resuscitation Council Guidelines for Resuscitation immediately after EPO or saline administration [
Successful resuscitation was defined as return of spontaneous circulation (ROSC) with a MAoP of at least 60 mmHg for a minimum of 5 minutes. After ROSC, the animals were monitored closely and mechanically ventilated for 6 h under general anesthesia at the prearrest settings, while blood samples were collected at 2, 4, and 6 hours after ROSC for quantification of creatinine (creatinine, Abbott Diagnostics, Architect Analyzer, Germany) and NGAL (Pig NGAL 044 Elisa Kit, Bioporto Diagnostics, Denmark), as well as urine L-FABP (Human L-FABP HK404 Elisa Kit, cross-reactivity with swine, Hycult Biotech, The Netherlands) and IL-18 (Pig IL-18 Platinum Elisa Kit, eBioscience, Austria). No other interventions (drugs, cardioversion, or defibrillation attempts) were made after ROSC. Subsequently, anesthesia was discontinued, all catheters were removed as previously described, and manual ventilation was initiated [
Thoracic and abdominal organs were examined for gross evidence of traumatic injuries or other pathologies. A kidney sample, including the ureter, was collected in the hilar region along the lower kidney diameter in both kidneys, in all animals. Tissue samples were formalin-fixed, routinely processed, and paraffin-embedded. Five micron-thick sections were stained with H&E and PAS method for evidencing the brush border of the proximal tubules [
Statistical analysis of the data was performed using Statistical Package for the Social Sciences version 15.0 (SPSS Inc., Chicago, IL, USA) and Stata statistical software package version 9.2 (StataCorp LP, College Station, TX, USA). Fisher’s exact test was used to investigate associations between group and ROSC percentages. Due to small number of subjects, the nonparametric Wilcoxon-Mann–Whitney test for independent samples was utilized for comparisons of quantitative measurements between the two groups at each distinct time-point, either during CPR or after ROSC. Spearman’s rho nonparametric coefficient of correlation was utilized for investigating direct correlations between quantitative measurements. We further utilized clustered regression analysis for longitudinal data to examine overall effect of parameters on repeated measurements. A cut-off point of
Required sample size, with power of at least 80% at
A significant difference was observed in ROSC between the 2 groups, as 5 animals (41.67%) from Group C and 11 animals (91.67%) from Group E achieved ROSC (
Although no statistically significant differences were observed in baseline and 8-minute untreated VF hemodynamic parameters between the 2 groups, significant hemodynamic differences were observed between groups after the onset of CPR (Table
Hemodynamic variables presented as mean (±SD) values, between the two groups during cardiopulmonary resuscitation.
Variable | CPR 2′ min | CPR 4′ min | CPR 6′ min | CPR 8′ min | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Group C | Group E | | Group C | Group E | | Group C | Group E | | Group C | Group E | | |
| | | | | | | | |||||
SAoP (mmHg) | 58.3 (±7.98) | 73.6 (±5.26) | <0.001 | 59.4 (±9.31) | 69.0 (±4.84) | 0.045 | 60.3 (±11.50) | 66.5 (±9.19) | 0.373 | 50.5 (±6.36) | NA | NA |
DAoP (mmHg) | 27.8 (±9.65) | 46.2 (±13.53) | 0.010 | 31.5 (±8.52) | 40.8 (±9.09) | 0.020 | 32.5 (±7.64) | 40.5 (±17.67) | 0.381 | 26.0 (±2.82) | NA | NA |
MAoP (mmHg) | 37.9 (±8.73) | 55.3 (±10.60) | 0.001 | 40.7 (±8.49) | 50.0 (±7.51) | 0.023 | 41.8 (±8.31) | 49.5 (±14.84) | 0.322 | 34.0 (±4.24) | NA | NA |
CPP (mmHg) | 18.1 (±10.34) | 36.3 (±14.29) | 0.011 | 20.5 (±9.09) | 30.8 (±11.30) | 0.081 | 20.9 (±9.09) | 26.0 (±15.55) | 0.487 | 13.5 (±3.53) | NA | NA |
CPR = cardiopulmonary resuscitation, SAoP = systolic arterial pressure, DAoP = diastolic arterial pressure, MAoP = mean arterial pressure, CPP = coronary perfusion pressure, and NA = nonapplicable.
Hemodynamic variables presented as mean (±SD) values, between the two groups after return of spontaneous circulation.
Variable | ROSC 1 min | ROSC 2 h | ROSC 4 h | ROSC 6 h | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Group C | Group E | | Group C | Group E | | Group C | Group E | | Group C | Group E | | |
| | | | | | | | |||||
SAoP (mmHg) | 112.6 (±20.65) | 98.7 (±6.84) | 0.192 | 109.8 (±9.73) | 111.7 (±9.07) | 0.570 | 102.0 (±12.74) | 103.0 (±6.57) | 0.733 | 100.4 (±15.10) | 108.4 (±3.55) | 0.569 |
DAoP (mmHg) | 63.4 (±3.04) | 64.5 (±6.84) | 0.609 | 63.6 (±3.97) | 73.8 (±4.19) | 0.004 | 70.6 (±4.27) | 76.5 (±3.98) | 0.026 | 71.0 (±5.43) | 79.0 (±3.91) | 0.015 |
MAoP (mmHg) | 79.8 (±8.81) | 76.0 (±6.76) | 0.459 | 79.0 (±5.78) | 86.3 (±5.80) | 0.047 | 81.0 (±6.78) | 85.4 (±4.43) | 0.256 | 80.8 (±8.49) | 88.8 (±3.34) | 0.030 |
CPP (mmHg) | 56.2 (±5.58) | 56.5 (±7.63) | 0.776 | 56.2 (±6.22) | 66.5 (±4.01) | 0.005 | 63.0 (±5.33) | 69.0 (±3.72) | 0.031 | 63.6 (±5.77) | 72.3 (±3.82) | 0.017 |
HR (bpm) | 185.6 (±32.99) | 150.6 (±14.66) | 0.047 | 177.0 (±33.29) | 150.3 (±9.87) | 0.061 | 161.4 (±12.66) | 133.5 (±15.05) | 0.003 | 157.8 (±7.39) | 128.0 (±9.15) | 0.002 |
ROSC = return of spontaneous circulation, SAoP = systolic arterial pressure, DAoP = diastolic arterial pressure, MAoP = mean arterial pressure, CPP = coronary perfusion pressure, HR = heart rate.
At histology, multiple morphological changes were detected both in the control animals (Group C) and in animals treated with EPO (Group E). At low power, renal pathological changes appeared often subtle and complex. The most relevant pathological changes were detected in renal tubules, the most severe lesions being detected in proximal tubules. The spectrum of cell injury ranged from loss of cell adhesion, characterized at histology by a simple enlargement of the intercellular spaces, to severe coagulative necrosis involving large segments of affected nephrons. In less affected kidneys, pathological tubular changes were segmental, being difficult to detect at low power. Moreover, pathological changes in tubular epithelial cells might be seen as a continuum, ranging from subtle focal changes of the brush border to complete destruction of the cell structure. Many morphological changes were detected in animals of both groups, including loss of the brush border of proximal tubular cells, detachment of adjacent tubular cells, dilatation of the tubular lumen, vacuolization of the cytoplasm and of tubular cells, dedifferentiation of the proximal and distal tubular epithelium, necrosis of individual tubular cells, and tubular cell apoptosis. Decapitation, that is, the loss of the brush border in proximal tubular cells, was the most frequent pathological lesion detected in the kidney of both groups. Only two lesions were significantly more severe in the kidney of control group animals, as compared to the EPO-treated group animals: apoptosis of tubular epithelial cells, often appearing as small apoptotic globules that were highlighted by PAS staining method (Figures
Acute kidney injury: in the center, tubular cells undergoing apoptosis show multiple PAS-positive globules (Group C).
Acute kidney injury: apoptosis of tubular cells is better evidence at higher power (Group C).
Acute kidney injury: segmental glomerular necrosis associated with thrombosis of the afferent artery (Group C).
According to the tubular changes detected, we categorized AKI into two types, mild and severe. Mild AKI was diagnosed when the loss of the brush border was present alone, or in association with vacuolization. Severe AKI was diagnosed in all cases in which tubular cell death was observed, sometimes in association with tubular dilatation and/or cellular casts. Significant differences regarding kidney injury were noticed histologically between Group C and Group E subjects, regarding both all participating subjects and only ROSC-gaining subjects (Table
Number and frequency (%) of levels of biochemically and histologically confirmed renal injury among subjects and comparisons between control versus EPO and ROSC versus non-ROSC subjects.
Parameter | Total | Group C | Group E | |
---|---|---|---|---|
ROSC | 16 (66.67) | 5 (41.67) | 11 (91.67) | |
| ||||
Renal injury (ROSC subjects) | ||||
None | 3 (18.75) | 0 (0.00) | 3 (27.27) | |
Mild | 3 (18.75) | 0 (0.00) | 3 (27.27) | |
Moderate | 5 (31.25) | 0 (0.00) | 5 (45.45) | |
Severe | 0 (0.00) | 0 (0.00) | 0 (0.00) | |
AKI | 5 (31.25) | 5 (100.00) | 0 (0.00) | |
| ||||
AKI (ROSC subjects) | 5 (31.25) | 5 (100.00) | 0 (0.00) | |
| ||||
Severe injury or AKI (ROSC subjects) | 5 (31.25) | 5 (100.00) | 0 (0.00) | |
ROSC = return of spontaneous circulation; AKI = acute kidney injury.
Biochemical measurements and comparisons for ROSC subjects.
Parameter | All subjects | Group C | Group E | |
---|---|---|---|---|
( | ( | ( | ||
Mean (SD) | Mean (SD) | Mean (SD) | ||
Creatinine (mg/dL) | ||||
Baseline | 0.58 (0.088) | 0.58 (0.109) | 0.59 (0.083) | |
2 hours | 0.70 (0.081) | 0.76 (0.054) | 0.67 (0.078) | |
4 hours | 0.78 (0.065) | 0.84 (0.054) | 0.75 (0.052) | |
6 hours | 0.86 (0.051) | 0.86 (0.054) | 0.85 (0.052) | |
24 hours | 1.93 (0.614) | 2.76 (0.054) | 1.51 (0.087) | |
48 hours | 3.44 (1.053) | 5.27 (0.152) | 2.89 (0.166) | |
Mean | 1.43 (0.372) | 1.77 (0.462) | 1.28 (0.196) | |
| ||||
NGAL (ng/mL) | ||||
Baseline | 133.29 (15.893) | 129.01 (16.686) | 135.25 (15.941) | |
2 hours | 596.89 (104.449) | 743.47 (24.163) | 530.26 (22.464) | |
4 hours | 524.25 (92.649) | 653.77 (15.744) | 465.38 (24.026) | |
6 hours | 439.83 (130.717) | 624.03 (8.372) | 356.10 (30.400) | |
24 hours | 373.33 (160.136) | 591.57 (6.239) | 264.22 (13.568) | |
48 hours | 294.61 (160.889) | 576.43 (12.360) | 210.06 (7.952) | |
Mean | 457.53 (132.065) | 643.39 (11.222) | 373.06 (31.474) | |
| ||||
L-FABP (ng/mL) | ||||
Baseline | 1.40 (0.188) | 1.45 (0.222) | 1.38 (0.177) | |
2 hours | 1.91 (0.158) | 2.11 (0.008) | 1.82 (0.101) | |
4 hours | 2.52 (0.256) | 2.88 (0.033) | 2.35 (0.034) | |
6 hours | 2.73 (0.277) | 3.10 (0.003) | 2.56 (0.113) | |
24 hours | 2.41 (0.229) | 2.72 (0.064) | 2.26 (0.029) | |
48 hours | 2.22 (0.182) | 2.54 (0.035) | 2.12 (0.018) | |
Mean | 2.37 (0.223) | 2.68 (0.022) | 2.22 (0.047) | |
| ||||
IL-18 (ng/mL) | ||||
Baseline | 0.09 (0.006) | 0.09 (0.006) | 0.09 (0.006) | |
2 hours | 0.10 (0.005) | 0.10 (0.002) | 0.09 (0.002) | |
4 hours | 0.11 (0.003) | 0.11 (0.002) | 0.10 (0.001) | |
6 hours | 0.12 (0.014) | 0.14 (0.002) | 0.11 (0.002) | |
24 hours | 0.16 (0.039) | 0.21 (0.003) | 0.13 (0.002) | |
48 hours | 0.12 (0.018) | 0.15 (0.002) | 0.11 (0.002) | |
Mean | 0.12 (0.016) | 0.14 (0.003) | 0.11 (0.002) | |
ROSC = return of spontaneous circulation.
Correlations between creatinine and other biochemical markers for ROSC subjects (
Parameter | Spearman’s rho for correlation with creatinine | |
---|---|---|
NGAL | ||
Baseline | 0.906 | |
2 hours | 0.874 | |
4 hours | 0.844 | |
6 hours | 0.506 | |
24 hours | 0.979 | |
48 hours | 0.972 | |
Mean | 0.498 | |
| ||
L-FABP | ||
Baseline | 0.793 | |
2 hours | 0.789 | |
4 hours | 0.717 | |
6 hours | 0.478 | 0.061 |
24 hours | 0.966 | |
48 hours | 0.973 | |
Mean | 0.623 | |
| ||
IL-18 | ||
Baseline | 0.868 | |
2 hours | 0.750 | |
4 hours | 0.744 | |
6 hours | 0.509 | |
24 hours | 0.964 | |
48 hours | 0.905 | |
Mean | 0.773 | |
Biochemical markers and effect of hemodynamic measurements (per unit increase) for ROSC subjects (
Parameter | Effect of hemodynamic measurement on biochemical marker | |
---|---|---|
| ||
Creatinine (mg/dL) | ||
CPR: SAoP (per mmHg) | −0.004 (−0.030 to 0.023) | |
CPR: DAoP (per mmHg) | −0.016 (−0.032 to 0.001) | |
CPR: MAoP (per mmHg) | −0.015 (−0.035 to 0.004) | |
CPR: CPP (per mmHg) | −0.014 (−0.029 to 0.002) | |
ROSC: SAoP (per mmHg) | 0.029 (0.015 to 0.044) | |
ROSC: DAoP (per mmHg) | −0.018 (−0.060 to 0.023) | |
ROSC: MAoP (per mmHg) | 0.023 (−0.023 to 0.069) | |
ROSC: CPP (per mmHg) | −0.011 (−0.048 to 0.026) | |
| ||
NGAL (ng/mL) | ||
CPR: SAoP (per mmHg) | −12.730 (−19.455 to −6.006) | |
CPR: DAoP (per mmHg) | −8.317 (−14.341 to −2.293) | |
CPR: MAoP (per mmHg) | −10.293 (−17.009 to −3.577) | |
CPR: CPP (per mmHg) | −7.808 (−13.295 to −2.322) | |
ROSC: SAoP (per mmHg) | 6.789 (−1.845 to 15.424) | |
ROSC: DAoP (per mmHg) | −20.694 (−30.126 to −11.263) | |
ROSC: MAoP (per mmHg) | −3.240 (−23.362 to 16.883) | |
ROSC: CPP (per mmHg) | −13.899 (−22.804 to −4.994) | |
| ||
L-FABP (ng/mL) | ||
CPR: SAoP (per mmHg) | −0.021 (−0.033 to −0.009) | |
CPR: DAoP (per mmHg) | −0.014 (−0.024 to −0.004) | |
CPR: MAoP (per mmHg) | −0.017 (−0.029 to −0.006) | |
CPR: CPP (per mmHg) | −0.013 (−0.022 to −0.004) | |
ROSC: SAoP (per mmHg) | 0.011 (−0.004 to 0.026) | |
ROSC: DAoP (per mmHg) | −0.036 (−0.051 to −0.021) | |
ROSC: MAoP (per mmHg) | −0.006 (−0.041 to 0.028) | |
ROSC: CPP (per mmHg) | −0.025 (−0.039 to −0.010) | |
| ||
IL-18 (ng/mL) | ||
CPR: SAoP (per 10 mmHg)† | −0.013 (−0.021 to −0.005) | |
CPR: DAoP (per 10 mmHg)† | −0.010 (−0.017 to −0.003) | |
CPR: MAoP (per 10 mmHg)† | −0.012 (−0.020 to −0.004) | |
CPR: CPP (per 10 mmHg)† | −0.009 (−0.016 to −0.003) | |
ROSC: SAoP (per 10 mmHg)† | 0.010 (−0.001 to 0.020) | |
ROSC: DAoP (per 10 mmHg)† | −0.023 (−0.034 to −0.012) | |
ROSC: MAoP (per 10 mmHg)† | −0.001 (−0.026 to 0.023) | |
ROSC: CPP (per 10 mmHg)† | −0.015 (−0.026 to −0.005) | |
Biochemical measurements and concurrent effect of hemodynamic measurements (per unit increase) and histopathological group (presence of AKI) for ROSC subjects (
Parameter | Effect of hemodynamic measurement | | Effect of AKI presence | |
---|---|---|---|---|
| | |||
Creatinine (mg/dL) | ||||
CPR: SAoP (per mmHg) | 0.025 (−0.001 to 0.051) | | 0.675 (0.377 to 0.974) | |
CPR: DAoP (per mmHg) | −0.001 (−0.006 to 0.005) | | 0.513 (0.112 to 0.913) | |
CPR: MAP (per mmHg) | 0.005 (−0.006 to 0.015) | | 0.560 (0.177 to 0.944) | |
CPR: CPP (per mmHg) | 0.001 (−0.005 to 0.007) | | 0.526 (0.119 to 0.933) | |
ROSC: SAoP (per mmHg) | 0.020 (0.005 to 0.034) | | 0.381 (0.037 to 0.725) | |
ROSC: DAoP (per mmHg) | 0.027 (−0.019 to 0.072) | | 0.641 (0.293 to 0.989) | |
ROSC: MAP (per mmHg) | 0.027 (−0.003 to 0.058) | | 0.537 (0.234 to 0.840) | |
ROSC: CPP (per mmHg) | 0.018 (−0.015 to 0.050) | | 0.599 (0.260 to 0.939) | |
| ||||
NGAL (ng/mL) | ||||
CPR: SAoP (per mmHg) | −1.461 (−3.430 to 0.507) | | 264.050 (243.929 to 284.171) | |
CPR: DAoP (per mmHg) | −0.461 (−1.568 to 0.647) | | 268.321 (249.770 to 286.873) | |
CPR: MAP (per mmHg) | −0.739 (−2.115 to 0.637) | | 266.447 (246.608 to 286.285) | |
CPR: CPP (per mmHg) | −0.538 (−1.612 to 0.536) | | 267.324 (247.535 to 287.113) | |
ROSC: SAoP (per mmHg) | −0.231 (−1.077 to 0.616) | | 274.768 (253.272 to 296.265) | |
ROSC: DAoP (per mmHg) | −2.155 (−4.935 to 0.625) | | 263.286 (240.501 to 286.071) | |
ROSC: MAP (per mmHg) | −0.997 (−2.778 to 0.785) | | 272.461 (252.644 to 292.278) | |
ROSC: CPP (per mmHg) | −1.180 (−3.288 to 0.929) | | 267.717 (248.147 to 287.287) | |
| ||||
L-FABP (ng/mL) | ||||
CPR: SAoP (per mmHg) | −0.001 (−0.005 to 0.002) | | 0.449 (0.416 to 0.481) | |
CPR: DAoP (per mmHg) | −0.001 (−0.003 to 0.002) | | 0.450 (0.417 to 0.483) | |
CPR: MAP (per mmHg) | −0.001 (−0.004 to 0.002) | | 0.449 (0.417 to 0.480) | |
CPR: CPP (per mmHg) | −0.001 (−0.003 to 0.002) | | 0.452 (0.420 to 0.484) | |
ROSC: SAoP (per mmHg) | −0.001 (−0.003 to 0.001) | | 0.464 (0.418 to 0.511) | |
ROSC: DAoP (per mmHg) | −0.005 (−0.012 to 0.002) | | 0.434 (0.383 to 0.485) | |
ROSC: MAP (per mmHg) | −0.003 (−0.007 to 0.002) | | 0.456 (0.414 to 0.497) | |
ROSC: CPP (per mmHg) | −0.004 (−0.009 to 0.002) | | 0.441 (0.397 to 0.485) | |
| ||||
IL-18 (ng/mL) | ||||
CPR: SAoP (per 10 mmHg)† | 0.001 (−0.001 to 0.004) | | 0.034 (0.031 to 0.038) | |
CPR: DAoP (per 10 mmHg)† | −0.001 (−0.002 to 0.001) | | 0.033 (0.030 to 0.037) | |
CPR: MAP (per 10 mmHg)† | −0.001 (−0.002 to 0.001) | | 0.034 (0.030 to 0.037) | |
CPR: CPP (per 10 mmHg)† | −0.001 (−0.002 to 0.001) | | 0.034 (0.030 to 0.037) | |
ROSC: SAoP (per 10 mmHg)† | 0.001 (−0.001 to 0.003) | | 0.033 (0.030 to 0.036) | |
ROSC: DAoP (per 10 mmHg)† | 0.001 (−0.004 to 0.005) | | 0.034 (0.030 to 0.038) | |
ROSC: MAP (per 10 mmHg)† | 0.001 (−0.002 to 0.005) | | 0.034 (0.031 to 0.037) | |
ROSC: CPP (per 10 mmHg)† | 0.001 (−0.003 to 0.004) | | 0.034 (0.031 to 0.037) | |
AKI presence = Group C.
†Effects refer to per 10 mmHg change in mean hemodynamic measurements, due to very small
While research on postcardiac arrest syndrome focuses on myocardial dysfunction and brain injury, several studies indicate that AKI is common in cardiac arrest survivors, with rates of postcardiac arrest AKI ranging from 40 to 80% [
The pleiotropic actions of EPO are indicated by the identification of its receptor in nonhaematopoietic cells and tissues including neurons, astrocytes, microglia, and endothelial cells, as well as cells of myocardium and kidney, while the putative mechanisms involved in EPO-induced cardioprotection are related to its antiapoptotic, anti-inflammatory, and angiogenic effects [
In addition, EPO administration may increase systemic vasoconstriction and possess direct vasoconstrictive effects in isolated renal resistance vessels which may also preserve adequate renal perfusion after ROSC [
Although AKI is characterized by death of the tubular epithelium and activation and expansion of the tubulointerstitium with inflammatory cells, while extensive apoptosis and necrosis may exist, there is clear evidence that administration of EPO at or near the time of injury significantly improves recovery acutely via inhibition of apoptosis, stimulation of antioxidant and angiogenic action, and suppression of proinflammatory cytokine mediators [
Serum creatinine concentration does not change until around 50% of kidney function is lost, which increases the risk for missing a therapeutic opportunity and eventually mortality [
Of note, in our study there was positive correlation of creatinine with NGAL, L-FABP, and IL-18, all of which increased at 2 hours after ROSC. An increase in NGAL within a few hours of cardiac arrest has been suggested to indicate AKI, even in creatinine-negative patients [
Moreover, NGAL may increase its usefulness in the diagnosis of postresuscitation AKI when combined with IL-18 and L-FABP and if a curve of plasma values rather than a single plasma measurement is determined [
Considering that the time window between renal insult and development of AKI in postcardiac arrest patients with myocardial dysfunction and/or severe hemodynamic instability can be varied in different patients and AKI often is diagnosed too late, NGAL, L-FABP, and IL-18 seem promising biomarkers for early detection of AKI. Of note, the correlation between biochemical markers and histologically confirmed renal injury was stronger than the correlation between the hemodynamic parameters and the biochemical markers. However, before full adoption in clinical practice can be accomplished, adequately powered clinical trials are strongly warranted.
In our study, administration of EPO protected swine from postresuscitation AKI. Taking into account its pleiotropic effects, use of EPO during the periarrest period merits further research.
Drs. Charalampos Pantazopoulos and Nicoletta Iacovidou shared authorship.
The authors declare that there are no competing interests regarding this paper.
Charalampos Pantazopoulos, Nicoletta Iacovidou, Paraskevi Pliatsika, Apostolos Papalois, Dimitrios Barouxis, Panagiotis Vasileiou, Pavlos Lelovas, Olympia Kotsilianou, Ioannis Pantazopoulos, Clara Garosa, Gavino Faa, and Theodoros Xanthos performed the experiments. Paraskevi Pliatsika, Georgios Kaparos, and Clara Garosa were responsible for statistical analysis. Clara Garosa and Gavino Faa were responsible for histological analysis. Charalampos Pantazopoulos, Nicoletta Iacovidou, Evangelia Kouskouni, Georgios Kaparos, Panagiotis Vasileiou, and Georgios Gkiokas drafted the manuscript. Paraskevi Pliatsika, Gavino Faa, and Theodoros Xanthos critically revised the manuscript. Charalampos Pantazopoulos and Theodoros Xanthos were responsible for study design. Evangelia Kouskouni, Gavino Faa, and Theodoros Xanthos were responsible for supervising.
The authors would like to thank A. Zacharioudaki, E. Karampela, K. Tsarea, M. Karamperi, N. Psychalakis, A. Karaiskos, S. Gerakis, and E. Gerakis, staff members of the Experimental-Research Center ELPEN, for their invaluable assistance during the experiments. The study was supported by the Experimental-Research Center ELPEN, Athens, Greece, which provided the research facilities.