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Adrenaline, Terlipressin, and Corticoids Versus Adrenaline in the Treatment of Experimental Pediatric Asphyxial Cardiac Arrest* Rafael González, MD1,2,3; Javier Urbano, MD1,2,3; Marta Botrán, MD1,2,3; Jorge López, MD1,2,3; Maria J. Solana, MD1,2,3; Ana García, MD1,2,3; Sarah Fernández, MD1,2,3; Jesús López-Herce, PhD, MD1,2,3
Objective: To analyze if treatment with adrenaline (epinephrine) plus terlipressin plus corticoids achieves higher return of spontaneous circulation than adrenaline in an experimental infant animal model of asphyxial cardiac arrest. Design: Prospective randomized animal study. Setting: Experimental department in a University Hospital. Subjects: Forty-nine piglets were studied. Interventions: Cardiac arrest was induced by at least 10 minutes of removal of mechanical ventilation and was followed by manual external chest compressions and mechanical ventilation. After 3 minutes of resuscitation, piglets that did not achieve return of spontaneous circulation were randomized to two groups: adrenaline 0.02 mg kg–1 every 3 minutes (20 animals) and adrenaline 0.02 mg kg–1 every 3 minutes plus terlipressin 20 μg kg–1 every 6 minutes plus hydrocortisone 30 mg kg–1 one dose (22 animals). Resuscitation was discontinued when return of spontaneous circulation was achieved or after 24 minutes. Measurement and Main Results: Return of spontaneous circulation was achieved in 14 piglets (28.5%), 14.2% with only cardiac massage and ventilation. Return of spontaneous circulation was achieved in 25% of piglets treated with adrenaline and in 9.1% of those treated with adrenaline plus terlipressin plus hydrocortisone (p = 0.167). Return of spontaneous circulation was achieved in 45.4% of animals with pulseless electric activity, 20% with asystole, and 0% with ventricular fibrillation (p = 0.037). Shorter dura*See also p. 573. 1 Paediatric Intensive Care Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain. 2 Instituto de Investigación del Hospital General Universitario Gregorio Marañón, Madrid, Spain. 3 Spanish Health Institute Carlos III. Maternal, Child Health and Development Network, Madrid, Spain. All authors received support for article research: PI09/0545 from Carlos III Institute of Health, Spain. Address requests for reprints to: Jesús López-Herce, PhD, MD, Pediatric Intensive Care Service, Hospital General Universitario Gregorio Marañón, Dr Castelo 47, 28009 Madrid, Spain. E-mail: [email protected] Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000127
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tion of cardiac arrest, higher mean blood pressure and Etco2 and lower Paco2 before resuscitation, and higher mean blood pressure during resuscitation were associated with higher return of spontaneous circulation. Conclusions: Treatment with adrenaline plus terlipressin plus corticoids does not achieve higher return of spontaneous circulation than that with adrenaline in an infant animal model of asphyxial cardiac arrest. (Pediatr Crit Care Med 2014; 15:e280–e287) Key Words: adrenaline; cardiac arrest; cardiopulmonary resuscitation; children; corticoids; resuscitation; terlipressin
C
urrent cardiopulmonary resuscitation (CPR) guidelines for cardiopulmonary arrest in children recommend the use of adrenaline given its inotropic and vasopressive effects (1, 2). Nevertheless, studies in adults have not proven that adrenaline achieves better survival to hospital discharge or neurologic outcome than placebo (3). Terlipressin is a synthetic analog of vasopressin with a longer half-life. Some studies have demonstrated its usefulness in the treatment of cardiopulmonary arrest as it increases blood flow to vital organs and increases oxygen delivery to the brain when administered alone or combined with adrenaline (4–7). Several clinical and experimental studies have analyzed the efficacy of other drugs such as vasopressin or terlipressin in the treatment of cardiac arrest (4–17), but there is not enough evidence to prove that they are superior to adrenaline (1, 2). CA in children has some unique characteristics, since there is a higher percentage of respiratory causes and asphyxia is the main mechanism of the arrest, with a higher prevalence of asystole and pulseless electric activity (PEA) (18). For this reason, vasopressin and terlipressin may be more useful in pediatric patients than in adult patients (4–8, 15–20). Furthermore, several studies have highlighted the importance of the activation of the adrenal axis in CA. Low baseline cortisol levels may be associated with an increased risk of fatal early refractory shock after CA, suggesting adrenal dysfunction in these patients. On the other hand, higher cortisol levels have been associated with July 2014 • Volume 15 • Number 6
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increased return of spontaneous circulation (ROSC) rates and better outcomes in resuscitated patients (21–24). This is why it has been proposed to include corticoids in the treatment of CA given its favorable hemodynamic effect and its ability to modulate inflammatory response. Some studies in adults show a higher probability of ROSC when using corticoids (9, 15, 25), but there are no such published studies in children or infant animal models. Our hypothesis was that treatment with adrenaline, terlipressin, and corticoids is more effective than adrenaline alone to achieve ROSC in a pediatric animal model with asphyxial CA.
MATERIAL AND METHODS A prospective randomized animal study was performed. The experimental protocol was approved by the local Institutional Review Board for Animal Research. The experiments were performed in the Department of Experimental Medicine and Surgery of the Gregorio Marañón University Hospital in Madrid, Spain. Animal care was performed by qualified technicians supervised by veterinarians according to the Spanish laws on animal research. International guidelines for ethical conduct in the care and use of experimental animals were applied throughout the study. Table 1.
Forty-nine healthy 2- to 3-month-old Maryland pigs with a mean weight of 9.1 ± 1.6 kg were used. Initial anesthesia was performed with intramuscular ketamine (15 mg kg–1) and atropine (0.02 mg kg–1). After canalization of a peripheral vein, boluses of propofol (5 mg kg–1), fentanyl (5 μg kg–1), and atracurium (0.5 mg kg–1) were administered for oral endotracheal intubation. The animals were ventilated using a mechanical ventilator (Dräger Babylog N, Lübeck, Germany) with a respiratory rate of 20 breaths/min, tidal volume of 10 mL kg–1, Fio2 of 50%, and positive end-expiratory pressure of 3 cm H2O. Ventilation was adjusted to achieve an expired Co2 (Etco2) between 33 and 35 mm Hg and a Paco2 between 35 and 45 mm Hg. Sedation and muscle relaxation (propofol, 10 mg kg–1 hr–1; fentanyl, 10 μg kg–1 hr–1; and atracurium, 2 mg kg–1 hr–1, by continuous infusion) were maintained throughout the procedure, inhibiting the presence of spontaneous respiration. Monitoring included electrocardiogram, peripheral oxygen saturation (Visconnet monitor; KGB, Madrid, Spain), and cerebral and abdominal tissue oxygenation index (TOI) in the liver area by near infrared spectroscopy (INVOS Cerebral Oxymeter monitor; Somanetics, Troy, MI) with sensors placed on the skin of forehead and abdomen in the liver area. Respiratory volumes and pressures, Fio2, and Etco2
Basal and Before Resuscitation Data Basal Adrenaline (n = 20)
Variable
Mean
sd
Before Resuscitation Adrenaline (n = 20)
ATC (n = 22) Mean
sd
ATC (n = 22)
p
Mean
sd
Mean
sd
p
—
—
—
—
Weight (kg)
9.9
1.8
8.7
1.3
0.024
—
Time to cardiac arrest (min)
—
—
—
—
—
6.8
1.4
6.6
1.1
0.545
Heart rate (beats/min)
121
31.1
119
21.7
0.85
63
35.3
55
28.8
0.694
Systolic BP (mm Hg)
114
21.1
118
22.4
0.252
23
18.1
16
8.1
0.265
Diastolic BP (mm Hg)
65
17.8
66
17.3
0.597
9
4.1
8
4.2
0.413
Mean BP (mm Hg)
85
18.1
86
18.2
0.571
12
4.9
11
5.3
0.346
5
2.4
4
2.4
0.099
10
1.8
9
2.2
0.108
End-tidal Co2 (mm Hg)
38
4.8
37
6
0.827
—
—
—
—
—
Oxygen saturation (%)
99
1.6
100
0.9
0.924
28
38.9
68
23.2
0.165
Cerebral TOI (%)
59
38.9
53
23.2
0.06
37
24
24
17.1
0.102
Abdominal TOI (%)
59
9.2
54
14
0.377
27
8.5
27
9.6
1
4.4
12.3
0.687
—
—
—
—
—
Central venous pressure (mm Hg)
Cardiac index (L min–1 m–2)
4.7
Arterial pH
7.45
8.5
7.46
9.6
0.565
7.11
0.1
7.1
0.1
0.553
42
6.8
42
5.1
0.84
91
11.9
95
17.3
0.614
164
10.1
169
4.3
0.791
8
3.8
9
4.3
0.8
Lactate (mmol L )
1.6
1.3
0.9
0.8
0.077
6
1.3
6
1.4
0.86
Central venous saturation (%)
69
41.3
67
44.5
0.48
5
3.3
6
5.1
0.417
Paco2 (mm Hg) Pao2 (mm Hg) –1
14
ATC = adrenaline, terlipressin, and corticoids, BP = blood pressure, TOI = tissue oxygenation index. Significant p values are in bold. Dashes indicate values are not applicable.
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catheter was inserted through the femoral vein to measure the central venous pressure (CVP) and to administrate drugs. Blood gases were analyzed using the GEM Premier 3000 blood gas analyzer (Instrumentation Laboratory, Lexington, KY). After collection of baseline data, asphyxial CA was induced by disconnection from the respirator. Resuscitation was started 10 minutes after disconnection, after confirmation of CA (defined as a heart rate < 60 beats/min and systolic arterial pressure < 30 mm Hg). Initial resuscitation was performed by means of manual external chest compressions (100 compressions/min) and mechanical ventilation (20 breaths/min with 100% oxygen). Vital data were collected after 3 minutes and ROSC was checked. The animals without ROSC were then randomly distributed into two study groups: adrenaline standard dose of 0.02 mg kg–1 every 3 minutes or adrenaline 0.02 mg kg–1 every 3 minutes plus terlipressin 20 μg Figure 1. Arrest rhythms and results of resuscitation by rhythm in each treatment group. PEA = pulseless kg–1 every 9 minutes plus hidroelectric activity, VF = ventricular fibrillation, ROSC = return of spontaneous circulation, ATC = adrenaline, terlipressin, and corticoids. cortisone 30 mg kg–1 one dose at 3 minutes of resuscitation. In all were measured by means of a spirometer connected to the endo- cases, bicarbonate (1 mEq kg–1) was administered after 9 and 18 tracheal tube and an S5 monitor (Datex Ohmeda, Madison, WI). minutes of resuscitation. Pigs in ventricular fibrillation (VF) or A 4F PiCCO catheter PiCCO catheter (PiCCO; Pulsion Medical with pulseless ventricular tachycardia were defibrillated during resuscitation using a defibrillation dose of 4 J kg–1. Systems, Munich, Germany) was inserted into the femoral artery Resuscitation was stopped when ROSC was achieved or after to measure the blood pressure (BP) and cardiac output by means of a femoral arterial thermodilution system (PiCCO), and a 5F 24 minutes. After ROSC, mechanical ventilation was maintained
Table 2.
Evolution of Parameters During Cardiac Arrest and Resuscitation Basal Variable
Before Resuscitation p
ATC
p
1
5
0.158
0.565
7.11
7.10
0.9
0.077
6.0
69
67
0.48
164
169
0.791
Adrenaline
ATC
End-tidal Co2 (mm Hg)
38
37
0.827
Arterial pH
7.45
7.46
Lactate (mmol L )
1.6
Central venous saturation (%)
–1
Pao2 (mm Hg)
6 Min ATC
p
15
14
0.895
0.553
7.19
7.26
0.171
6.0
0.86
7.8
7.4
0.43
5
6
0.417
24
28
0.542
8
9
0.8
81
101
0.811
Adrenaline
Adrenaline
ATC = adrenaline, terlipressin, and corticoids. Mean values are provided.
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Figure 2. Evolution of blood pressure during cardiac arrest (CA) and resuscitation. Mean blood pressure (MBP) at 3 min: adrenaline (A), MBP 31 mm Hg versus adrenaline plus terlipressin plus corticoids (ATC), MBP 22 mm Hg (p = 0.034). Systolic blood pressure (SBP) at 6 min: adrenaline, SBP 98 mm Hg versus ATC, SBP 58 mm Hg (p = 0.011). CPR = cardiopulmonary resuscitation.
RESULTS
with 50% oxygen and adjusted to obtain an arterial Pco2 between 35 and 45 mm Hg. The following variables were recorded at baseline and every 3 minutes during resuscitation: inspiratory tidal volume; Etco2; systolic, diastolic, and mean arterial pressure; CVP; peripheral hemoglobin O2 saturation; and cerebral and abdominal TOI.
12 Min Adrenaline
ATC
Cardiac index was measured by initial calibration by femoral thermodilution and then measured by pulse contour continuous analysis. Arterial and venous blood gases and serum lactate were also determined every 6 minutes during resuscitation. In those animals achieving ROSC, hemodynamic and laboratory data were collected at 5, 15, and 30 minutes after ROSC. On completion of the experiment, all successfully resuscitated animals were killed by the administration of sedative overdose and the IV injection of potassium chloride. The statistical analysis was performed using the SPSS (version 20.0) statistical package (IBM Corp, Armonk, NY). Quantitative values are expressed in mean and sd. Pearson chi-square test was used for qualitative variables analysis and Fisher exact test when n was less than 20 or when any value was less than 5. Mann-Whitney U test was used to compare quantitative variables between independent groups. A p value of less than 0.05 was considered significant.
Forty-nine animals were included in the study, and seven piglets reached ROSC in the first 3 minutes of resuscitation (with only chest compressions and ventilation), so 42 piglets were finally randomized: 20 treated with adrenaline (group A) and 22 with adrenaline, terlipressin, and corticoids (group ATC).
18 Min p
Adrenaline
ATC
24 Min p
Adrenaline
ATC
p
10
9
0.686
8
7
0.607
7
5
0.375
7.36
7.33
0.949
7.25
7.25
0.942
7.27
7.26
0.738
8.7
8.0
0.319
9.5
9.0
0.788
10.9
10.2
0.257
19
27
0.053
24
23
0.464
16
27
0.093
76
83
0.949
48
80
0.272
58
65
0.959
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Table 1 compares basal and pre-resuscitation characteristics of animals in both groups. There was a significant difference between groups only in weight, which was slightly higher in group A. Figure 1 shows the arrest rhythms and the results of resuscitation by rhythm in each treatment group. At the moment resuscitation started, 44.8% of animals had PEA, 40.8% had asystole, and 14.2% had VF. A higher percentage of animals with PEA at the beginning of the resuscitation reached ROSC (45.4%) than those with asystole (20%) or VF (0%) (p = 0.037). None of the animals with asystole that reached ROSC were treated with ATC; 25% of pigs treated with adrenaline reached ROSC versus 9.1% of those treated with ATC (p = 0.167). Figure 2 shows the evolution of BP. There were only significant differences between both groups in the mean BP at 3 minutes of resuscitation and in the systolic BP at 6 minutes. In both cases, BP was higher in the adrenaline group. There were no significant differences between treatment groups in any other variables (Table 2). Table 3 shows the comparison between pigs that reached ROSC and the rest of animals. Those reaching ROSC had a significantly longer time until CA and therefore shorter CA time, lower Paco2, and higher Etco2 and mean and systolic BP at the beginning of resuscitation. During resuscitation, ROSC animals had significantly higher mean BP, cerebral and abdominal TOI and Etco2 at 3 minutes, and higher mean and systolic BP and Etco2 at 6 minutes. No differences were seen between both treatment groups in any of the variables measured during the 60 minutes following ROSC (Table 4).
DISCUSSION Several studies have analyzed the effect of isolated vasopressin and terlipressin or in association with adrenaline in the treatment of CA in adults and children, with discordant results (8–10, 12, 15, 26). The global analysis of vasopressin in a recent meta-analysis that included six randomized clinical trials with 4,475 adult patients showed that its use was not associated with any overall benefit or harm (11). However, in the subgroup of 3,210 patients with asystole, vasopressin may improve long-term survival, especially when the average time to drug administration is less than 20 minutes. So the efficacy of vasopressin in CPR may be related to the underlying electrocardiographic rhythm (11, 14). Methylprednisolone may enhance the vasopressor effects of vasopressin and epinephrine. The effectiveness of the association of vasopressin, adrenaline, and corticoids in adult patients has been studied in two trials (9, 15). Both studies showed that, in adult patients with CA, combined vasopressin-epinephrine and methylprednisolone during CPR and stress-dose hydrocortisone in postresuscitation shock, compared with epinephrine/saline placebo, resulted in improved survival to hospital discharge with favorable neurologic status. e284
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The first one, a single-center, prospective, randomized, ouble-blind, placebo-controlled, parallel-group trial, included d 100 in-hospital patients with CA requiring adrenaline. Patients receiving vasopressin plus epinephrine plus methylprednisolone had more frequent ROSC (81% vs 52%, p = 0.003) and improved survival to hospital discharge (19% vs 4%, p = 0.02) than those who received only adrenaline. Study group patients with postresuscitation shock had improved survival to hospital discharge, hemodynamics and central venous oxygen saturation, and more organ failure-free days (9). The second one, a recent multicenter randomized, double-blind, placebo-controlled, parallel-group trial, included 268 consecutive patients with CA requiring adrenaline. Patients receiving vasopressin plus epinephrine plus methylprednisolone had higher probability for ROSC (83.9% vs 65.9%; p = 0.005) and survival to hospital discharge with favorable neurologic status (13.9% vs 5.1%; p = 0.020), than patients who received only adrenaline (15). Our results in an animal pediatric model with asphyctic CA differ from those of these two clinical studies, as the association of adrenaline, terlipressin, and corticoids did not achieve better results than adrenalin alone in survival or in hemodynamic, oxygenation, and tissue perfusion variables. Several differences exist between these clinical studies and our experimental study that could partly explain the difference in results: adult patients had better prognostic factors such as primary VF (16.8%), a shorter time to CPR initiation (2 min), and the fact that less than 40% had respiratory failure as a cause of CA. Thus, hypoxia and ischemia, which are both important prognostic factors, were probably less important in those adult patients than in our study group (at least 10 min of hypoxia). Another difference is that terlipressin was used instead of vasopressin, which has a slower but longer lasting effect than vasopressin. Nevertheless, our study confirms the importance of some factors as prognostic indicators in CA. Piglets presenting with PEA at the onset of CPR had greater rates of ROSC than those with asystole or VF. Our study also shows that VF is not a good prognosis rhythm in CA due to asphyxia, which is consistent with what has been seen in other pediatric studies (27). These results highlight the importance of hemodynamics during CPR. Piglets that achieved ROSC had better BP during the first minute of CPR, which is consistent with previous studies showing that maintaining an adequate coronary perfusion pressure (mainly depending on diastolic BP) has been associated with a greater rate of ROSC (28, 29). This fact supports the use of vasopressors such as terlipressin during CPR. Nevertheless, our study did not show higher BP levels in the terlipressin group than in the adrenaline group. Varvarousi et al compared the effect of vasopressin and epinephrine (16) and vasopressin, epinephrine, and nitroglycerin (17) with epinephrine alone in two recent experimental studies in a porcine model of asphyxial CA. In both studies, pigs treated with epinephrine alone achieved the same ROSC and survival rate than the combination of epinephrine and vasopressin or epinephrine, vasopressin, and July 2014 • Volume 15 • Number 6
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Table 3. Comparison Between Return of Spontaneous Circulation and Non–Return of Spontaneous Circulation Animals No ROSC Variable
Mean
ROSC sd
Mean
sd
p
Weight (kg)
9.3
1.7
8.9
1.4
0.504
Time to cardiac arrest (min)
6.6
1.1
7.9
1.8
0.005
Basal HR (beats/min)
125
25.8
100
17.8
0.002
Before resuscitation HR (beats/min)
58
34.7
60
15.6
0.499
Before resuscitation SBP (mm Hg)
15
5.9
46
20.2
0.001
SBP 3 min of resuscitation (mm Hg)
75
36.2
61
10.4
0.239
SBP 6 min of resuscitation (mm Hg)
74
41.8
100
31.0
0.142
Before resuscitation DBP (mm Hg)
8
3.9
11
4.7
0.068
DBP 3 min of resuscitation (mm Hg)
8
18.0
10
3.6
0.154
DBP 6 min of resuscitation (mm Hg)
5
10.8
37
22.5
0.015
Before resuscitation MBP (mm Hg)
10
4.5
18
5.6
0.003
MBP 3 min of resuscitation (mm Hg)
25
18.7
36
19.3
0.018
MBP 6 min of resuscitation (mm Hg)
18
8.5
47
34.7
0.002
Before resuscitation CVP (mm Hg)
10
2.1
9
1.9
0.313
CVP 3 min of resuscitation (mm Hg)
19
8.4
16
7.2
0.179
CVP 6 min of resuscitation (mm Hg)
16
11.5
21
9.7
0.155
Before resuscitation cerebral TOI (%)
25
16.4
44
28.6
0.065
Cerebral TOI 3 min of resuscitation (%)
29
20.4
60
15.5
0.001
Cerebral TOI 6 min of resuscitation (%)
33
23.6
46
21.8
0.236
Before resuscitation abdominal TOI (%)
27
8.7
32
12.3
0.289
Abdominal TOI 3 min of resuscitation (%)
33
8.2
45
17.2
0.041
Abdominal TOI 6 min of resuscitation (%)
31
12.0
36
16.6
0.53
3
6.0
10
11.2
0.039
Etco2 3 min of resuscitation (mm Hg)
14
9.7
28
10.8
0.001
Etco2 6 min of resuscitation (mm Hg)
10
6.4
42
21.5
0.003
Paco2 3 min of resuscitation (mm Hg)
94
15.1
83
11.0
0.012
Paco2 6 min of resuscitation (mm Hg)
53
24.1
60
16.6
0.276
Before resuscitation lactate (mmol L )
6.1
1.4
5.7
1.1
0.728
Lactate 6 min of resuscitation (mmol L )
7.6
1.3
7.7
1.1
0.8
Before resuscitation Etco2
–1
–1
ROSC = return of spontaneous circulation, HR = heart rate, SBP = systolic blood pressure, DBP = diastolic blood pressure, MBP = mean blood pressure, CVP = central venous pressure, TOI = tissue oxygenation index, Etco2 = end-tidal Co2. Significant p values are in bold.
nitroglycerin, although coronary perfusion pressure and mean arterial pressure were significantly increased with the combination of drugs (16, 17). On the other hand, in survival pigs both combination of drugs resulted in better clinical and cerebral histopathological outcome (16, 17). Authors suggest that the combination of epinephrine and vasopressin achieved higher coronary perfusion pressure and mean arterial pressure than epinephrine alone Pediatric Critical Care Medicine
and the addition of nitroglycerin could counterbalance the harmful effects of excessive vasoconstriction and optimizing benefits from vasopressor therapy (17). On the other hand, our study does show that patients with lower Paco2, higher Etco2, and systolic and diastolic BP at the beginning of CPR have better outcomes. Thus, the fact of having some residual perfusion and ventilation when CPR is started is a very important prognostic factor, which supports www.pccmjournal.org
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Table 4.
Comparison Between Treatment Groups After Return of Spontaneous Circulation Adrenaline
ATC
Mean
sd
Mean
sd
p
HR at ROSC (beats/min)
185
15.6
151
53.0
0.434
HR at 60 min (beats/min)
167
24.4
136
24.7
0.171
SBP at ROSC (mm Hg)
175
32.3
188
98.3
1
SBP at 60 min (mm Hg)
133
27.6
115
28.3
0.439
DBP at ROSC (mm Hg)
103
40.5
76
48.1
0.643
DBP at 60 min (mm Hg)
69
21.3
67
25.5
0.699
MBP at ROSC (mm Hg)
104
54.0
108
54.4
0.845
MBP at 60 min (mm Hg)
90
22.0
82
31.8
0.699
CVP at ROSC (mm Hg)
7
5.7
7
5.0
1
CVP at 60 min (mm Hg)
5
3.4
6
1.4
0.845
Etco2 at ROSC
32
19.1
48
19.8
0.554
Etco2 at 60 min
32
4.2
36
0.0
0.554
Cerebral TOI at ROSC (%)
43
22.6
53
0.7
1
Cerebral TOI at 60 min (%)
65
1.5
70
240
1
Arterial pH at ROSC
7.14
0.1
7.12
0.1
0.558
Arterial pH at 60 min
7.36
0.1
7.35
0.0
1
Lactate at ROSC (mmol/L)
6.6
1.2
7.2
1.9
0.845
Lactate at 60 min (mmol/L)
4.0
1.5
4.5
1.8
0.699
Satvo2 at ROSC (%)
81
6.1
77
1.4
0.439
Satvo2 at 60 min (%)
77
10.5
51
14.8
0.051
Glycemia (mg dL ) at ROSC
87
67.2
132
60.8
0.241
Glycemia (mg dL ) at 60 min
126
35.6
118
CI at ROSC (L min m )
5.79
1.9
4.56
—
0.48
4.82
1.2
3.84
—
0.655
SVRI at ROSC (dynes seg cm m )
1,700
1,037.8
2,557
—
0.48
SVRI at 60 min (dynes seg cm m )
1,711
858.8
1,179
—
0.655
Variable
–1
–1
–1
–2
CI at 60 min (L min m ) –1
–2
–5
–2
–5
–2
2.12
0.699
ATC = adrenaline, terlipressin, and corticoids, HR = heart rate, ROSC = return of spontaneous circulation, SBP = systolic blood pressure, DBP = diastolic blood pressure, MBP = mean blood pressure, CVP = central venous pressure, Etco2 = end-tidal Co2, TOI = tissue oxygenation index, CI = cardiac index, SVRI = systemic vascular resistance index. Dashes indicate values are not applicable.
the findings of previous studies that consider gasping a positive prognostic factor (30, 31). Finally, our results also show that animals with ROSC had higher Etco2 levels than those who never did. Thus, Etco2 monitoring during CPR can be a reliable indicator of the effectiveness of CPR (32, 33). Our study has several limitations. The animal model only analyzes a specific kind of CA. The sample size was not large. Nevertheless, it seems that an increase in the number of individuals included in the study probably did not lead to significant changes in the results.
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Another important limitation of our study was that the observation time after ROSC was short and we could not evaluate long-term survival and the effect of the drugs on the neurologic outcome. This fact could explain in part the different results with other experimental and clinical studies in adults. It is possible that less severe hypoxic CA could exist differences in survival and neurologic outcome between drugs. However, our study tried to reproduce hypoxic CA in children, and 10 minutes of hypoxia is a frequent period of time and the rate of ROSC in clinical studies of out-of-hospital CA is similar to our study.
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CONCLUSIONS We conclude that treatment with adrenaline plus terlipressin plus corticoids does not achieve higher ROSC than that with adrenaline alone in an infant animal model of asphyxial CA. Experimental and clinical studies in children are needed to assess the effectiveness of associating vasopressors and steroids in the treatment of CA and its effect on survival and neurologic outcome.
ACKNOWLEDGMENTS We thank Mercedes Adrados, Natalia Sánchez, and personnel of the Department of Experimental Medicine of the Gregorio Marañón University Hospital for their collaboration with the experiments. We thank Jose María Bellón for the statistical analysis.
REFERENCES
1. Kleinman ME, de Caen AR, Chameides L, et al; Pediatric Basic and Advanced Life Support Chapter Collaborators: Part 10: Pediatric basic and advanced life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation 2010; 122:S466–S515 2. Biarent D, Bingham R, Eich C, et al: European Resuscitation Council Guidelines for Resuscitation 2010 Section 6. Paediatric life support. Resuscitation 2010; 81:1364–1388 3. Olasveengen TM, Wik L, Sunde K, et al: Outcome when adrenaline (epinephrine) was actually given vs. not given—post hoc analysis of a randomized clinical trial. Resuscitation 2012; 83:327–332 4. Cheung DC, Gill RS, Liu JQ, et al: Vasopressin improves systemic hemodynamics without compromising mesenteric perfusion in the resuscitation of asphyxiated newborn piglets: A dose-response study. Intensive Care Med 2012; 38:491–498 5. Prengel AW, Linstedt U, Zenz M, et al: Effects of combined administration of vasopressin, epinephrine, and norepinephrine during cardiopulmonary resuscitation in pigs. Crit Care Med 2005; 33:2587–2591 6. Wenzel V, Lindner KH, Krismer AC, et al: Survival with full neurologic recovery and no cerebral pathology after prolonged cardiopulmonary resuscitation with vasopressin in pigs. J Am Coll Cardiol 2000; 35:527–533 7. Wenzel V, Lindner KH, Krismer AC, et al: Repeated administration of vasopressin but not epinephrine maintains coronary perfusion pressure after early and late administration during prolonged cardiopulmonary resuscitation in pigs. Circulation 1999; 99:1379–1384 8. Stiell IG, Hébert PC, Wells GA, et al: Vasopressin versus epinephrine for inhospital cardiac arrest: A randomised controlled trial. Lancet 2001; 358:105–109 9. Mentzelopoulos SD, Zakynthinos SG, Tzoufi M, et al: Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest. Arch Intern Med 2009; 169:15–24 10. Grmec S, Strnad M, Cander D, et al: A treatment protocol including vasopressin and hydroxyethyl starch solution is associated with increased rate of return of spontaneous circulation in blunt trauma patients with pulseless electrical activity. Int J Emerg Med 2008; 1:311–316 11. Mentzelopoulos SD, Zakynthinos SG, Siempos I, et al: Vasopressin for cardiac arrest: Meta-analysis of randomized controlled trials. Resuscitation 2012; 83:32–39 12. Sillberg VA, Perry JJ, Stiell IG, et al: Is the combination of vasopressin and epinephrine superior to repeated doses of epinephrine alone in the treatment of cardiac arrest-a systematic review. Resuscitation 2008; 79:380–386
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13. Meybohm P, Cavus E, Dörges V, et al: Revised resuscitation guidelines: Adrenaline versus adrenaline/vasopressin in a pig model of cardiopulmonary resuscitation—A randomised, controlled trial. Resuscitation 2007; 75:380–388 14. Wenzel V, Krismer AC, Arntz HR, et al; European Resuscitation Council Vasopressor during Cardiopulmonary Resuscitation Study Group: A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med 2004; 350:105–113 15. Mentzelopoulos SD, Malachias S, Chamos C, et al: Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: A randomized clinical trial. JAMA 2013; 310:270–279 16. Varvarousi G, Johnson EO, Goulas S, et al: Combination pharmacotherapy improves neurological outcome after asphyxial cardiac arrest. Resuscitation 2012; 83:527–532 17. Varvarousi G, Goulas S, Agrogiannis G, et al: Epinephrine, vasopressin, and nitroglycerin improve neurologic outcome in porcine asphyxial cardiac arrest. Am J Emerg Med 2012; 30:1549–1554 18. López-Herce J, García C, Domínguez P, et al; Spanish Study Group of Cardiopulmonary Arrest in Children: Characteristics and outcome of cardiorespiratory arrest in children. Resuscitation 2004; 63:311–320 19. López-Herce J, Fernández B, Urbano J, et al: Terlipressin versus adrenaline in an infant animal model of asphyxial cardiac arrest. Intensive Care Med 2010; 36:1248–1255 20. Gil-Antón J, López-Herce J, Morteruel E, et al: Pediatric cardiac arrest refractory to advanced life support: Is there a role for terlipressin? Pediatr Crit Care Med 2010; 11:139–141 21. Kim JJ, Hyun SY, Hwang SY, et al: Hormonal responses upon return of spontaneous circulation after cardiac arrest: A retrospective cohort study. Crit Care 2011; 15:R53 22. de Jong MF, Beishuizen A, de Jong MJ, et al: The pituitary-adrenal axis is activated more in non-survivors than in survivors of cardiac arrest, irrespective of therapeutic hypothermia. Resuscitation 2008; 78:281–288 23. Ito T, Saitoh D, Takasu A, et al: Serum cortisol as a predictive marker of the outcome in patients resuscitated after cardiopulmonary arrest. Resuscitation 2004; 62:55–60 24. Lindner KH, Haak T, Keller A, et al: Release of endogenous vasopressors during and after cardiopulmonary resuscitation. Heart 1996; 75:145–150 25. Tsai MS, Huang CH, Chang WT, et al: The effect of hydrocortisone on the outcome of out-of-hospital cardiac arrest patients: A pilot study. Am J Emerg Med 2007; 25:318–325 26. Callaway CW, Hostler D, Doshi AA, et al: Usefulness of vasopressin administered with epinephrine during out-of-hospital cardiac arrest. Am J Cardiol 2006; 98:1316–1321 27. Rodríguez-Núñez A, López-Herce J, García C, et al; Spanish Study Group of Cardiopulmonary Arrest in Children: Pediatric defibrillation after cardiac arrest: Initial response and outcome. Crit Care 2006; 10:R113 28. Friess SH, Sutton RM, Bhalala U, et al: Hemodynamic directed cardiopulmonary resuscitation improves short-term survival from ventricular fibrillation cardiac arrest. Crit Care Med 2013; 41:2698–2704 29. Sutton RM, Friess SH, Bhalala U, et al: Hemodynamic directed CPR improves short-term survival from asphyxia-associated cardiac arrest. Resuscitation 2013; 84:696–701 30. Zuercher M, Ewy GA: Gasping during cardiac arrest. Curr Opin Crit Care 2009; 15:185–188 31. Bobrow BJ, Zuercher M, Ewy GA, et al: Gasping during cardiac arrest in humans is frequent and associated with improved survival. Circulation 2008; 118:2550–2554 32. Eckstein M, Hatch L, Malleck J, et al: End-tidal CO2 as a predictor of survival in out-of-hospital cardiac arrest. Prehosp Disaster Med 2011; 26:148–150 33. Touma O, Davies M: The prognostic value of end tidal carbon dioxide during cardiac arrest: A systematic review. Resuscitation 2013; 84:1470–1479
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Adrenaline, Terlipressin, and Corticoids Versus Adrenaline in the Treatment of Experimental Pediatric Asphyxial Cardiac Arrest* Rafael González, MD1,2,3; Javier Urbano, MD1,2,3; Marta Botrán, MD1,2,3; Jorge López, MD1,2,3; Maria J. Solana, MD1,2,3; Ana García, MD1,2,3; Sarah Fernández, MD1,2,3; Jesús López-Herce, PhD, MD1,2,3
Objective: To analyze if treatment with adrenaline (epinephrine) plus terlipressin plus corticoids achieves higher return of spontaneous circulation than adrenaline in an experimental infant animal model of asphyxial cardiac arrest. Design: Prospective randomized animal study. Setting: Experimental department in a University Hospital. Subjects: Forty-nine piglets were studied. Interventions: Cardiac arrest was induced by at least 10 minutes of removal of mechanical ventilation and was followed by manual external chest compressions and mechanical ventilation. After 3 minutes of resuscitation, piglets that did not achieve return of spontaneous circulation were randomized to two groups: adrenaline 0.02 mg kg–1 every 3 minutes (20 animals) and adrenaline 0.02 mg kg–1 every 3 minutes plus terlipressin 20 μg kg–1 every 6 minutes plus hydrocortisone 30 mg kg–1 one dose (22 animals). Resuscitation was discontinued when return of spontaneous circulation was achieved or after 24 minutes. Measurement and Main Results: Return of spontaneous circulation was achieved in 14 piglets (28.5%), 14.2% with only cardiac massage and ventilation. Return of spontaneous circulation was achieved in 25% of piglets treated with adrenaline and in 9.1% of those treated with adrenaline plus terlipressin plus hydrocortisone (p = 0.167). Return of spontaneous circulation was achieved in 45.4% of animals with pulseless electric activity, 20% with asystole, and 0% with ventricular fibrillation (p = 0.037). Shorter dura*See also p. 573. 1 Paediatric Intensive Care Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain. 2 Instituto de Investigación del Hospital General Universitario Gregorio Marañón, Madrid, Spain. 3 Spanish Health Institute Carlos III. Maternal, Child Health and Development Network, Madrid, Spain. All authors received support for article research: PI09/0545 from Carlos III Institute of Health, Spain. Address requests for reprints to: Jesús López-Herce, PhD, MD, Pediatric Intensive Care Service, Hospital General Universitario Gregorio Marañón, Dr Castelo 47, 28009 Madrid, Spain. E-mail: [email protected] Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000127
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tion of cardiac arrest, higher mean blood pressure and Etco2 and lower Paco2 before resuscitation, and higher mean blood pressure during resuscitation were associated with higher return of spontaneous circulation. Conclusions: Treatment with adrenaline plus terlipressin plus corticoids does not achieve higher return of spontaneous circulation than that with adrenaline in an infant animal model of asphyxial cardiac arrest. (Pediatr Crit Care Med 2014; 15:e280–e287) Key Words: adrenaline; cardiac arrest; cardiopulmonary resuscitation; children; corticoids; resuscitation; terlipressin
C
urrent cardiopulmonary resuscitation (CPR) guidelines for cardiopulmonary arrest in children recommend the use of adrenaline given its inotropic and vasopressive effects (1, 2). Nevertheless, studies in adults have not proven that adrenaline achieves better survival to hospital discharge or neurologic outcome than placebo (3). Terlipressin is a synthetic analog of vasopressin with a longer half-life. Some studies have demonstrated its usefulness in the treatment of cardiopulmonary arrest as it increases blood flow to vital organs and increases oxygen delivery to the brain when administered alone or combined with adrenaline (4–7). Several clinical and experimental studies have analyzed the efficacy of other drugs such as vasopressin or terlipressin in the treatment of cardiac arrest (4–17), but there is not enough evidence to prove that they are superior to adrenaline (1, 2). CA in children has some unique characteristics, since there is a higher percentage of respiratory causes and asphyxia is the main mechanism of the arrest, with a higher prevalence of asystole and pulseless electric activity (PEA) (18). For this reason, vasopressin and terlipressin may be more useful in pediatric patients than in adult patients (4–8, 15–20). Furthermore, several studies have highlighted the importance of the activation of the adrenal axis in CA. Low baseline cortisol levels may be associated with an increased risk of fatal early refractory shock after CA, suggesting adrenal dysfunction in these patients. On the other hand, higher cortisol levels have been associated with July 2014 • Volume 15 • Number 6
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increased return of spontaneous circulation (ROSC) rates and better outcomes in resuscitated patients (21–24). This is why it has been proposed to include corticoids in the treatment of CA given its favorable hemodynamic effect and its ability to modulate inflammatory response. Some studies in adults show a higher probability of ROSC when using corticoids (9, 15, 25), but there are no such published studies in children or infant animal models. Our hypothesis was that treatment with adrenaline, terlipressin, and corticoids is more effective than adrenaline alone to achieve ROSC in a pediatric animal model with asphyxial CA.
MATERIAL AND METHODS A prospective randomized animal study was performed. The experimental protocol was approved by the local Institutional Review Board for Animal Research. The experiments were performed in the Department of Experimental Medicine and Surgery of the Gregorio Marañón University Hospital in Madrid, Spain. Animal care was performed by qualified technicians supervised by veterinarians according to the Spanish laws on animal research. International guidelines for ethical conduct in the care and use of experimental animals were applied throughout the study. Table 1.
Forty-nine healthy 2- to 3-month-old Maryland pigs with a mean weight of 9.1 ± 1.6 kg were used. Initial anesthesia was performed with intramuscular ketamine (15 mg kg–1) and atropine (0.02 mg kg–1). After canalization of a peripheral vein, boluses of propofol (5 mg kg–1), fentanyl (5 μg kg–1), and atracurium (0.5 mg kg–1) were administered for oral endotracheal intubation. The animals were ventilated using a mechanical ventilator (Dräger Babylog N, Lübeck, Germany) with a respiratory rate of 20 breaths/min, tidal volume of 10 mL kg–1, Fio2 of 50%, and positive end-expiratory pressure of 3 cm H2O. Ventilation was adjusted to achieve an expired Co2 (Etco2) between 33 and 35 mm Hg and a Paco2 between 35 and 45 mm Hg. Sedation and muscle relaxation (propofol, 10 mg kg–1 hr–1; fentanyl, 10 μg kg–1 hr–1; and atracurium, 2 mg kg–1 hr–1, by continuous infusion) were maintained throughout the procedure, inhibiting the presence of spontaneous respiration. Monitoring included electrocardiogram, peripheral oxygen saturation (Visconnet monitor; KGB, Madrid, Spain), and cerebral and abdominal tissue oxygenation index (TOI) in the liver area by near infrared spectroscopy (INVOS Cerebral Oxymeter monitor; Somanetics, Troy, MI) with sensors placed on the skin of forehead and abdomen in the liver area. Respiratory volumes and pressures, Fio2, and Etco2
Basal and Before Resuscitation Data Basal Adrenaline (n = 20)
Variable
Mean
sd
Before Resuscitation Adrenaline (n = 20)
ATC (n = 22) Mean
sd
ATC (n = 22)
p
Mean
sd
Mean
sd
p
—
—
—
—
Weight (kg)
9.9
1.8
8.7
1.3
0.024
—
Time to cardiac arrest (min)
—
—
—
—
—
6.8
1.4
6.6
1.1
0.545
Heart rate (beats/min)
121
31.1
119
21.7
0.85
63
35.3
55
28.8
0.694
Systolic BP (mm Hg)
114
21.1
118
22.4
0.252
23
18.1
16
8.1
0.265
Diastolic BP (mm Hg)
65
17.8
66
17.3
0.597
9
4.1
8
4.2
0.413
Mean BP (mm Hg)
85
18.1
86
18.2
0.571
12
4.9
11
5.3
0.346
5
2.4
4
2.4
0.099
10
1.8
9
2.2
0.108
End-tidal Co2 (mm Hg)
38
4.8
37
6
0.827
—
—
—
—
—
Oxygen saturation (%)
99
1.6
100
0.9
0.924
28
38.9
68
23.2
0.165
Cerebral TOI (%)
59
38.9
53
23.2
0.06
37
24
24
17.1
0.102
Abdominal TOI (%)
59
9.2
54
14
0.377
27
8.5
27
9.6
1
4.4
12.3
0.687
—
—
—
—
—
Central venous pressure (mm Hg)
Cardiac index (L min–1 m–2)
4.7
Arterial pH
7.45
8.5
7.46
9.6
0.565
7.11
0.1
7.1
0.1
0.553
42
6.8
42
5.1
0.84
91
11.9
95
17.3
0.614
164
10.1
169
4.3
0.791
8
3.8
9
4.3
0.8
Lactate (mmol L )
1.6
1.3
0.9
0.8
0.077
6
1.3
6
1.4
0.86
Central venous saturation (%)
69
41.3
67
44.5
0.48
5
3.3
6
5.1
0.417
Paco2 (mm Hg) Pao2 (mm Hg) –1
14
ATC = adrenaline, terlipressin, and corticoids, BP = blood pressure, TOI = tissue oxygenation index. Significant p values are in bold. Dashes indicate values are not applicable.
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catheter was inserted through the femoral vein to measure the central venous pressure (CVP) and to administrate drugs. Blood gases were analyzed using the GEM Premier 3000 blood gas analyzer (Instrumentation Laboratory, Lexington, KY). After collection of baseline data, asphyxial CA was induced by disconnection from the respirator. Resuscitation was started 10 minutes after disconnection, after confirmation of CA (defined as a heart rate < 60 beats/min and systolic arterial pressure < 30 mm Hg). Initial resuscitation was performed by means of manual external chest compressions (100 compressions/min) and mechanical ventilation (20 breaths/min with 100% oxygen). Vital data were collected after 3 minutes and ROSC was checked. The animals without ROSC were then randomly distributed into two study groups: adrenaline standard dose of 0.02 mg kg–1 every 3 minutes or adrenaline 0.02 mg kg–1 every 3 minutes plus terlipressin 20 μg Figure 1. Arrest rhythms and results of resuscitation by rhythm in each treatment group. PEA = pulseless kg–1 every 9 minutes plus hidroelectric activity, VF = ventricular fibrillation, ROSC = return of spontaneous circulation, ATC = adrenaline, terlipressin, and corticoids. cortisone 30 mg kg–1 one dose at 3 minutes of resuscitation. In all were measured by means of a spirometer connected to the endo- cases, bicarbonate (1 mEq kg–1) was administered after 9 and 18 tracheal tube and an S5 monitor (Datex Ohmeda, Madison, WI). minutes of resuscitation. Pigs in ventricular fibrillation (VF) or A 4F PiCCO catheter PiCCO catheter (PiCCO; Pulsion Medical with pulseless ventricular tachycardia were defibrillated during resuscitation using a defibrillation dose of 4 J kg–1. Systems, Munich, Germany) was inserted into the femoral artery Resuscitation was stopped when ROSC was achieved or after to measure the blood pressure (BP) and cardiac output by means of a femoral arterial thermodilution system (PiCCO), and a 5F 24 minutes. After ROSC, mechanical ventilation was maintained
Table 2.
Evolution of Parameters During Cardiac Arrest and Resuscitation Basal Variable
Before Resuscitation p
ATC
p
1
5
0.158
0.565
7.11
7.10
0.9
0.077
6.0
69
67
0.48
164
169
0.791
Adrenaline
ATC
End-tidal Co2 (mm Hg)
38
37
0.827
Arterial pH
7.45
7.46
Lactate (mmol L )
1.6
Central venous saturation (%)
–1
Pao2 (mm Hg)
6 Min ATC
p
15
14
0.895
0.553
7.19
7.26
0.171
6.0
0.86
7.8
7.4
0.43
5
6
0.417
24
28
0.542
8
9
0.8
81
101
0.811
Adrenaline
Adrenaline
ATC = adrenaline, terlipressin, and corticoids. Mean values are provided.
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Figure 2. Evolution of blood pressure during cardiac arrest (CA) and resuscitation. Mean blood pressure (MBP) at 3 min: adrenaline (A), MBP 31 mm Hg versus adrenaline plus terlipressin plus corticoids (ATC), MBP 22 mm Hg (p = 0.034). Systolic blood pressure (SBP) at 6 min: adrenaline, SBP 98 mm Hg versus ATC, SBP 58 mm Hg (p = 0.011). CPR = cardiopulmonary resuscitation.
RESULTS
with 50% oxygen and adjusted to obtain an arterial Pco2 between 35 and 45 mm Hg. The following variables were recorded at baseline and every 3 minutes during resuscitation: inspiratory tidal volume; Etco2; systolic, diastolic, and mean arterial pressure; CVP; peripheral hemoglobin O2 saturation; and cerebral and abdominal TOI.
12 Min Adrenaline
ATC
Cardiac index was measured by initial calibration by femoral thermodilution and then measured by pulse contour continuous analysis. Arterial and venous blood gases and serum lactate were also determined every 6 minutes during resuscitation. In those animals achieving ROSC, hemodynamic and laboratory data were collected at 5, 15, and 30 minutes after ROSC. On completion of the experiment, all successfully resuscitated animals were killed by the administration of sedative overdose and the IV injection of potassium chloride. The statistical analysis was performed using the SPSS (version 20.0) statistical package (IBM Corp, Armonk, NY). Quantitative values are expressed in mean and sd. Pearson chi-square test was used for qualitative variables analysis and Fisher exact test when n was less than 20 or when any value was less than 5. Mann-Whitney U test was used to compare quantitative variables between independent groups. A p value of less than 0.05 was considered significant.
Forty-nine animals were included in the study, and seven piglets reached ROSC in the first 3 minutes of resuscitation (with only chest compressions and ventilation), so 42 piglets were finally randomized: 20 treated with adrenaline (group A) and 22 with adrenaline, terlipressin, and corticoids (group ATC).
18 Min p
Adrenaline
ATC
24 Min p
Adrenaline
ATC
p
10
9
0.686
8
7
0.607
7
5
0.375
7.36
7.33
0.949
7.25
7.25
0.942
7.27
7.26
0.738
8.7
8.0
0.319
9.5
9.0
0.788
10.9
10.2
0.257
19
27
0.053
24
23
0.464
16
27
0.093
76
83
0.949
48
80
0.272
58
65
0.959
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Table 1 compares basal and pre-resuscitation characteristics of animals in both groups. There was a significant difference between groups only in weight, which was slightly higher in group A. Figure 1 shows the arrest rhythms and the results of resuscitation by rhythm in each treatment group. At the moment resuscitation started, 44.8% of animals had PEA, 40.8% had asystole, and 14.2% had VF. A higher percentage of animals with PEA at the beginning of the resuscitation reached ROSC (45.4%) than those with asystole (20%) or VF (0%) (p = 0.037). None of the animals with asystole that reached ROSC were treated with ATC; 25% of pigs treated with adrenaline reached ROSC versus 9.1% of those treated with ATC (p = 0.167). Figure 2 shows the evolution of BP. There were only significant differences between both groups in the mean BP at 3 minutes of resuscitation and in the systolic BP at 6 minutes. In both cases, BP was higher in the adrenaline group. There were no significant differences between treatment groups in any other variables (Table 2). Table 3 shows the comparison between pigs that reached ROSC and the rest of animals. Those reaching ROSC had a significantly longer time until CA and therefore shorter CA time, lower Paco2, and higher Etco2 and mean and systolic BP at the beginning of resuscitation. During resuscitation, ROSC animals had significantly higher mean BP, cerebral and abdominal TOI and Etco2 at 3 minutes, and higher mean and systolic BP and Etco2 at 6 minutes. No differences were seen between both treatment groups in any of the variables measured during the 60 minutes following ROSC (Table 4).
DISCUSSION Several studies have analyzed the effect of isolated vasopressin and terlipressin or in association with adrenaline in the treatment of CA in adults and children, with discordant results (8–10, 12, 15, 26). The global analysis of vasopressin in a recent meta-analysis that included six randomized clinical trials with 4,475 adult patients showed that its use was not associated with any overall benefit or harm (11). However, in the subgroup of 3,210 patients with asystole, vasopressin may improve long-term survival, especially when the average time to drug administration is less than 20 minutes. So the efficacy of vasopressin in CPR may be related to the underlying electrocardiographic rhythm (11, 14). Methylprednisolone may enhance the vasopressor effects of vasopressin and epinephrine. The effectiveness of the association of vasopressin, adrenaline, and corticoids in adult patients has been studied in two trials (9, 15). Both studies showed that, in adult patients with CA, combined vasopressin-epinephrine and methylprednisolone during CPR and stress-dose hydrocortisone in postresuscitation shock, compared with epinephrine/saline placebo, resulted in improved survival to hospital discharge with favorable neurologic status. e284
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The first one, a single-center, prospective, randomized, ouble-blind, placebo-controlled, parallel-group trial, included d 100 in-hospital patients with CA requiring adrenaline. Patients receiving vasopressin plus epinephrine plus methylprednisolone had more frequent ROSC (81% vs 52%, p = 0.003) and improved survival to hospital discharge (19% vs 4%, p = 0.02) than those who received only adrenaline. Study group patients with postresuscitation shock had improved survival to hospital discharge, hemodynamics and central venous oxygen saturation, and more organ failure-free days (9). The second one, a recent multicenter randomized, double-blind, placebo-controlled, parallel-group trial, included 268 consecutive patients with CA requiring adrenaline. Patients receiving vasopressin plus epinephrine plus methylprednisolone had higher probability for ROSC (83.9% vs 65.9%; p = 0.005) and survival to hospital discharge with favorable neurologic status (13.9% vs 5.1%; p = 0.020), than patients who received only adrenaline (15). Our results in an animal pediatric model with asphyctic CA differ from those of these two clinical studies, as the association of adrenaline, terlipressin, and corticoids did not achieve better results than adrenalin alone in survival or in hemodynamic, oxygenation, and tissue perfusion variables. Several differences exist between these clinical studies and our experimental study that could partly explain the difference in results: adult patients had better prognostic factors such as primary VF (16.8%), a shorter time to CPR initiation (2 min), and the fact that less than 40% had respiratory failure as a cause of CA. Thus, hypoxia and ischemia, which are both important prognostic factors, were probably less important in those adult patients than in our study group (at least 10 min of hypoxia). Another difference is that terlipressin was used instead of vasopressin, which has a slower but longer lasting effect than vasopressin. Nevertheless, our study confirms the importance of some factors as prognostic indicators in CA. Piglets presenting with PEA at the onset of CPR had greater rates of ROSC than those with asystole or VF. Our study also shows that VF is not a good prognosis rhythm in CA due to asphyxia, which is consistent with what has been seen in other pediatric studies (27). These results highlight the importance of hemodynamics during CPR. Piglets that achieved ROSC had better BP during the first minute of CPR, which is consistent with previous studies showing that maintaining an adequate coronary perfusion pressure (mainly depending on diastolic BP) has been associated with a greater rate of ROSC (28, 29). This fact supports the use of vasopressors such as terlipressin during CPR. Nevertheless, our study did not show higher BP levels in the terlipressin group than in the adrenaline group. Varvarousi et al compared the effect of vasopressin and epinephrine (16) and vasopressin, epinephrine, and nitroglycerin (17) with epinephrine alone in two recent experimental studies in a porcine model of asphyxial CA. In both studies, pigs treated with epinephrine alone achieved the same ROSC and survival rate than the combination of epinephrine and vasopressin or epinephrine, vasopressin, and July 2014 • Volume 15 • Number 6
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Table 3. Comparison Between Return of Spontaneous Circulation and Non–Return of Spontaneous Circulation Animals No ROSC Variable
Mean
ROSC sd
Mean
sd
p
Weight (kg)
9.3
1.7
8.9
1.4
0.504
Time to cardiac arrest (min)
6.6
1.1
7.9
1.8
0.005
Basal HR (beats/min)
125
25.8
100
17.8
0.002
Before resuscitation HR (beats/min)
58
34.7
60
15.6
0.499
Before resuscitation SBP (mm Hg)
15
5.9
46
20.2
0.001
SBP 3 min of resuscitation (mm Hg)
75
36.2
61
10.4
0.239
SBP 6 min of resuscitation (mm Hg)
74
41.8
100
31.0
0.142
Before resuscitation DBP (mm Hg)
8
3.9
11
4.7
0.068
DBP 3 min of resuscitation (mm Hg)
8
18.0
10
3.6
0.154
DBP 6 min of resuscitation (mm Hg)
5
10.8
37
22.5
0.015
Before resuscitation MBP (mm Hg)
10
4.5
18
5.6
0.003
MBP 3 min of resuscitation (mm Hg)
25
18.7
36
19.3
0.018
MBP 6 min of resuscitation (mm Hg)
18
8.5
47
34.7
0.002
Before resuscitation CVP (mm Hg)
10
2.1
9
1.9
0.313
CVP 3 min of resuscitation (mm Hg)
19
8.4
16
7.2
0.179
CVP 6 min of resuscitation (mm Hg)
16
11.5
21
9.7
0.155
Before resuscitation cerebral TOI (%)
25
16.4
44
28.6
0.065
Cerebral TOI 3 min of resuscitation (%)
29
20.4
60
15.5
0.001
Cerebral TOI 6 min of resuscitation (%)
33
23.6
46
21.8
0.236
Before resuscitation abdominal TOI (%)
27
8.7
32
12.3
0.289
Abdominal TOI 3 min of resuscitation (%)
33
8.2
45
17.2
0.041
Abdominal TOI 6 min of resuscitation (%)
31
12.0
36
16.6
0.53
3
6.0
10
11.2
0.039
Etco2 3 min of resuscitation (mm Hg)
14
9.7
28
10.8
0.001
Etco2 6 min of resuscitation (mm Hg)
10
6.4
42
21.5
0.003
Paco2 3 min of resuscitation (mm Hg)
94
15.1
83
11.0
0.012
Paco2 6 min of resuscitation (mm Hg)
53
24.1
60
16.6
0.276
Before resuscitation lactate (mmol L )
6.1
1.4
5.7
1.1
0.728
Lactate 6 min of resuscitation (mmol L )
7.6
1.3
7.7
1.1
0.8
Before resuscitation Etco2
–1
–1
ROSC = return of spontaneous circulation, HR = heart rate, SBP = systolic blood pressure, DBP = diastolic blood pressure, MBP = mean blood pressure, CVP = central venous pressure, TOI = tissue oxygenation index, Etco2 = end-tidal Co2. Significant p values are in bold.
nitroglycerin, although coronary perfusion pressure and mean arterial pressure were significantly increased with the combination of drugs (16, 17). On the other hand, in survival pigs both combination of drugs resulted in better clinical and cerebral histopathological outcome (16, 17). Authors suggest that the combination of epinephrine and vasopressin achieved higher coronary perfusion pressure and mean arterial pressure than epinephrine alone Pediatric Critical Care Medicine
and the addition of nitroglycerin could counterbalance the harmful effects of excessive vasoconstriction and optimizing benefits from vasopressor therapy (17). On the other hand, our study does show that patients with lower Paco2, higher Etco2, and systolic and diastolic BP at the beginning of CPR have better outcomes. Thus, the fact of having some residual perfusion and ventilation when CPR is started is a very important prognostic factor, which supports www.pccmjournal.org
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Table 4.
Comparison Between Treatment Groups After Return of Spontaneous Circulation Adrenaline
ATC
Mean
sd
Mean
sd
p
HR at ROSC (beats/min)
185
15.6
151
53.0
0.434
HR at 60 min (beats/min)
167
24.4
136
24.7
0.171
SBP at ROSC (mm Hg)
175
32.3
188
98.3
1
SBP at 60 min (mm Hg)
133
27.6
115
28.3
0.439
DBP at ROSC (mm Hg)
103
40.5
76
48.1
0.643
DBP at 60 min (mm Hg)
69
21.3
67
25.5
0.699
MBP at ROSC (mm Hg)
104
54.0
108
54.4
0.845
MBP at 60 min (mm Hg)
90
22.0
82
31.8
0.699
CVP at ROSC (mm Hg)
7
5.7
7
5.0
1
CVP at 60 min (mm Hg)
5
3.4
6
1.4
0.845
Etco2 at ROSC
32
19.1
48
19.8
0.554
Etco2 at 60 min
32
4.2
36
0.0
0.554
Cerebral TOI at ROSC (%)
43
22.6
53
0.7
1
Cerebral TOI at 60 min (%)
65
1.5
70
240
1
Arterial pH at ROSC
7.14
0.1
7.12
0.1
0.558
Arterial pH at 60 min
7.36
0.1
7.35
0.0
1
Lactate at ROSC (mmol/L)
6.6
1.2
7.2
1.9
0.845
Lactate at 60 min (mmol/L)
4.0
1.5
4.5
1.8
0.699
Satvo2 at ROSC (%)
81
6.1
77
1.4
0.439
Satvo2 at 60 min (%)
77
10.5
51
14.8
0.051
Glycemia (mg dL ) at ROSC
87
67.2
132
60.8
0.241
Glycemia (mg dL ) at 60 min
126
35.6
118
CI at ROSC (L min m )
5.79
1.9
4.56
—
0.48
4.82
1.2
3.84
—
0.655
SVRI at ROSC (dynes seg cm m )
1,700
1,037.8
2,557
—
0.48
SVRI at 60 min (dynes seg cm m )
1,711
858.8
1,179
—
0.655
Variable
–1
–1
–1
–2
CI at 60 min (L min m ) –1
–2
–5
–2
–5
–2
2.12
0.699
ATC = adrenaline, terlipressin, and corticoids, HR = heart rate, ROSC = return of spontaneous circulation, SBP = systolic blood pressure, DBP = diastolic blood pressure, MBP = mean blood pressure, CVP = central venous pressure, Etco2 = end-tidal Co2, TOI = tissue oxygenation index, CI = cardiac index, SVRI = systemic vascular resistance index. Dashes indicate values are not applicable.
the findings of previous studies that consider gasping a positive prognostic factor (30, 31). Finally, our results also show that animals with ROSC had higher Etco2 levels than those who never did. Thus, Etco2 monitoring during CPR can be a reliable indicator of the effectiveness of CPR (32, 33). Our study has several limitations. The animal model only analyzes a specific kind of CA. The sample size was not large. Nevertheless, it seems that an increase in the number of individuals included in the study probably did not lead to significant changes in the results.
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Another important limitation of our study was that the observation time after ROSC was short and we could not evaluate long-term survival and the effect of the drugs on the neurologic outcome. This fact could explain in part the different results with other experimental and clinical studies in adults. It is possible that less severe hypoxic CA could exist differences in survival and neurologic outcome between drugs. However, our study tried to reproduce hypoxic CA in children, and 10 minutes of hypoxia is a frequent period of time and the rate of ROSC in clinical studies of out-of-hospital CA is similar to our study.
July 2014 • Volume 15 • Number 6
Online Laboratory Investigation
CONCLUSIONS We conclude that treatment with adrenaline plus terlipressin plus corticoids does not achieve higher ROSC than that with adrenaline alone in an infant animal model of asphyxial CA. Experimental and clinical studies in children are needed to assess the effectiveness of associating vasopressors and steroids in the treatment of CA and its effect on survival and neurologic outcome.
ACKNOWLEDGMENTS We thank Mercedes Adrados, Natalia Sánchez, and personnel of the Department of Experimental Medicine of the Gregorio Marañón University Hospital for their collaboration with the experiments. We thank Jose María Bellón for the statistical analysis.
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