Anatomy, Article, Emergency Medicine

Passive leg raising during cardiopulmonary resuscitation results in improved neurological outcome in a swine model of prolonged ventricular fibrillation

Unlabelled imagepassive leg raising during cardiopulmona”>American Journal of Emergency Medicine (2012) 30, 1935-1942

Original Contribution

Passive leg raising during cardiopulmonary resuscitation results in improved neurological outcome in a swine model of Prolonged ventricular fibrillation?,??

Vasileios Dragoumanos MSc a, Nicoletta Iacovidou PhD b, Athanasios Chalkias PhD a,?, Pavlos Lelovas MSc c, Anastasios Koutsovasilis MSc d, Apostolos Papalois PhD e,

Theodoros Xanthos PhD a

aDepartment of Anatomy, National and Kapodistrian University of Athens, Medical School, Athens, Greece

b2nd Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Medical School,

Aretaieion Hospital, Athens, Greece

cNational and Kapodistrian University of Athens, Medical School, Laboratory for Musculoskeletal Research, KAT Hospital,

Athens, Greece

dDepartment of Internal Medicine, General Hospital of Ierapetra, Crete, Greece

eExperimental-Research Center ELPENPharmaceutical Co, Athens, Greece

Received 6 January 2012; revised 21 March 2012; accepted 11 April 2012

Abstract

Objective: The objective was to evaluate whether passive leg raising during cardiopulmonary resuscitation in a porcine model of prolonged ventricular fibrillation improves hemodynamics, return of spontaneous circulation, 24-hour survival, and neurological outcome.

Methods: Ventricular fibrillation was induced in 20 healthy Landrace/Large White piglets, which were subsequently left untreated for 8 minutes. Ten animals were randomly assigned into the control group and were resuscitated according to the 2005 European Resuscitation Council guidelines, and 10 piglets were assigned into the passive leg raising group and were resuscitated with the legs passively raised at 45? with the aid of a special purpose-made metallic device. End points were either return of spontaneous circulation or asystole.

Results: Return of spontaneous circulation was observed in 6 and 9 animals from the control and the passive leg raising group, respectively (P = .121; odds ratio = 0.16; 95% confidence interval, 0.01-1.87). Just prior to the first defibrillation attempt, coronary perfusion pressure was significantly higher in the passive leg raising group (22.8 +- 9.5 vs 10.6 +- 6.5 mm Hg, P b .004); but no subsequent significant differences were observed. Although all animals that Restored spontaneous circulation survived for 24 hours, neurologic alertness score was significantly better in the animals treated with passive leg raising (90 +- 10 vs 76.6 +- 12.1, P = .037).

Conclusions: Passive leg raising during cardiopulmonary resuscitation significantly increased coronary perfusion pressure in the minute prior to the first shock. Return of spontaneous circulation and 24-hour

? Funding sources: Experimental-Research Center “ELPEN” Pharmaceutical Co, Athens, Greece.

?? Conftict of interests: none.

* Corresponding author. Tel.: +30 2104133992; fax: + 30 2107462305.

E-mail address: [email protected] (A. Chalkias).

0735-6757/$ – see front matter (C) 2012 http://dx.doi.org/10.1016/j.ajem.2012.04.014

survival rate were comparable between groups. However, the animals in the passive leg raising group exhibited significantly higher neurological scores.

(C) 2012

Introduction

Cardiac arrest is a major health issue affecting about 700000 individuals in Europe every year and a leading cause of death in both Europe and United States, as approximately 1000000 people die annually [1,2]. Initial Rhythm analysis indicates a declining frequency of ventricular fibrillation (VF) over the last 20 years, but it remains the commonest rhythm soon after collapse [3,4]. The recommended treatment of VF cardiac arrest is immediate chest compres- sions, rescue breathing, and early electrical defibrillation.

Optimization of resuscitation interventions aims mainly at the rapid and effective rise of coronary perfusion pressure [5]. However, despite the fact that long- term survival rates tend to increase over the last decades [6], prognosis of cardiac arrest victims remains dismal and more than half of the survivors have various degrees of permanent brain injury [7-9].

Passive leg raising (PLR) is a mechanical maneuver involving the elevation of lower limbs from the horizontal plane without the patient’s active participation. It is used to evaluate the need for further ftuid resuscitation in critically ill patients and as an empiric Rescue therapy for acute hypotension [10]. In addition, this simple maneuver has been used to assess baroreceptor function, to detect subclinical left ventricular dysfunction, and to unmask pulmonary hypertension [11]. A similar position–the Trendelenburg position–was initially used to improve surgical exposure of the pelvic organs and later was also used for the management of patients in shock [12-14]. During PLR, gravity causes redirection of venous blood from the lower extremities to the thorax and this, in turn, causes an increase not only in systemic venous return and right ventricular preload but also in left ventricular end-diastolic volume and carotid blood ftow [15-17].

Based on these data, we hypothesized that, during

cardiopulmonary resuscitation (CPR), the increased systemic venous return after PLR may affect CPP and eventually the outcome of patients. Therefore, the aim of our study was to evaluate the effect of PLR on hemodynamics, return of spontaneous circulation, 24-hour survival, and neurological outcome in a swine model of prolonged VF.

Methods

The experimental protocol was approved by the General Directorate of Veterinary Services (permit no. 3338/23-9-09) according to Greek legislation regarding ethical and experimental procedures. The experiment was carried out

in ELPEN Experimental-Research Center, Athens, Greece. Twenty healthy male Landrace/Large White piglets, all supplied by the same breeder (Validakis, Athens, Greece), aged 10 to 15 weeks, with an average weight of 19 +- 2 kg comprised the study population. The animals were fasted overnight but had free access to water.

Animals were premedicated with Intramuscular injection of 10 mg/kg ketamine hydrochloride, 0.5 mg/kg midazolam, and 0.05 mg/kg atropine sulfate (Fig. 1) [18]. The marginal auricular vein was catheterized, and anesthesia was induced with an Intravenous bolus dose of 2 mg/kg propofol. They were then intubated with a 4.5-mm endotracheal tube (Portex, 4.5 mm ID; Mallinckrodt Medical, Athlone, Ireland). Animals were immobilized in the supine position on a surgical table. Additional 1 mg/kg propofol, 0.15 mg/kg cis-atracurium, and 4 ug/kg fentanyl were administered immediately prior to connecting the animals to a ventilator (Alpha Delta lung ventilator, Siare, Bologna, Italy) in 21% oxygen. Propofol infusion of 0.1 mg/(kg min) and additional doses of cis-atracurium at 20 ug/(kg min) and fentanyl at

0.6 ug/(kg min) were administered to maintain adequate anesthetic depth.

All animals were volume-controlled ventilated with a total tidal volume of 15 mL/kg. End-tidal CO2 pressure (ETCO2) was monitored (Tonocap-TC200; Datex Engstrom, Helsinki, Finland), and the respiratory rate was adjusted to maintain an ETCO2 of 35 to 40 mm Hg. noninvasive monitoring (Datascope Expert DS-5300 W ECG; Fukuda Denshi, Tokyo, Japan) also included electrocardiogram and pulse oximetry. For measurement of aortic pressures, a ftuid- filled (model 6523, USCI CR; Bart Inc, Papapostolou, Athens, Greece) arterial catheter was inserted into the aorta via the right Common carotid artery.

Mean arterial pressure (MAP) was determined by the electronic integration of the aortic blood pressure waveform and was calculated electronically. The internal jugular vein was surgically prepared, and a Swan-Ganz catheter (Opticath 5.5F, 75 cm; Abbott, Ladakis, Athens, Greece) was inserted into the right atrium for continuous measure- ment of right atrial pressure. Coronary perfusion pressure was electronically calculated as the difference between minimal aortic diastolic pressure (DAP) and the simulta- neously measured right atrial diastolic pressure. The second internal jugular vein was also surgically prepared, and a 5F ftow-directed pacing catheter (Pacel, 100 cm; St Jude Medical, Ladakis, Athens, Greece) was advanced into the apex of the right ventricle.

The animals were randomly assigned into 2 groups. The control group consisted of 10 animals to be resuscitated in the ftat position, and the PLR group consisted of the remaining 10 to be resuscitated in the relevant position [19].

Fig. 1 Timeline ftowchart of experimental protocol. NAS = Neurological Alertness Score.

The investigators involved in data recording, data entry, and data analysis were blinded to each animal’s allocation.

In our study, PLR was achieved with the aid of a special purpose-made metallic device in the shape of a triangular prism with an angle of 45? [20]. The metallic device facilitated animal’s raising of hip, knee, and ankle. A lateral interrupted line passing above the hind limbs ventrally and the Iliac crest dorsally was drawn in all animals. The metallic device was placed caudally under that mark to ensure exactly the same degree of anatomic elevation in all animals. The animals’ lower extremities were appropriately secured on the metallic device, which was immobilized on the surgical table to remain firm during the entire procedure.

Ventricular fibrillation was induced with a 9-V ordinary

cadmium battery. Arrhythmia was recognized electrocardio- graphically and confirmed by a sudden drop in MAP. After

VF induction, mechanical ventilation was discontinued; and the animals were left untreated for 8 minutes. At the end of the eighth minute of VF, the animals were positioned to their allocation. Resuscitation was immediately initiated accord- ing to the 2005 European Resuscitation guidelines for Resuscitation with ventilation in 100% oxygen and chest compressions at a rate of 100/min (LUCAS, Jolife, Lund, Sweden) [21,22]. Adrenaline was given after the second shock and then every 3 to 5 minutes (during alternate cycles of CPR) at a dose of 1 mg followed by a 20-mL ftush of isotonic sodium chloride solution, whereas amiodarone 300 mg was given after the third shock. Defibrillation was attempted with a 4-J/kg monophasic waveform shock delivered between the right infraclavicular area and the cardiac apex (Primedic Defi-B Defibrillator; Metrax GmbH, Rottweil, Germany).

End points of the experiment were defined as either asystole or successful resuscitation. Successful resuscitation was defined as restoration of spontaneous circulation (ROSC) with a MAP of at least 60 mm Hg for a minimum of 5 minutes. The metallic device was removed when ROSC was achieved, and the animals were monitored for 60 more minutes. Subsequently, anesthesia was discontinued, all catheters were removed as previously described, and manual ventilation was initiated [23]. Atropine 0.2 mg/kg followed by neostigmine 0.05 mg/kg was administered when spontaneous swallowing reftex was detected, whereas extubation was performed after adequate inspiration depth was confirmed. Each animal was then transferred to the animal house for observation for 24 hours.

A quantitative neurological alertness score was used for the evaluation of neurological recovery 24 hours later [24]. The alertness score was based on objective grading of level of consciousness, respiration, posture, and food and water intake. Alertness was scored from 0 (coma) to 100 (fully alert). The investigator who assessed the pigs neurologi- cally was blinded as to the allocation of each animal. Finally, all animals that survived were humanely eutha- nized by an intravenous overdose of pentobarbital 3 g and underwent necropsy [25]. Thoracic and abdominal organs were examined for gross evidence of traumatic injuries or other pathology.

Statistical analysis

Power analysis was performed to determine the sample size that would be adequate to detect significant differences in the neurological outcome. Ten animals in each group assured a power of 0.82. Data are expressed as mean +- standard deviation for continuous variables and as percent- ages for categorical data. Kolmogorov-Smirnov test was utilized for normality analysis of the parameters. Compar- isons of continuous variables were analyzed using Student t test and Mann-Whitney nonparametric test, as appropriate.

Table 1 Hemodynamic parameters of the 2 groups

Hemodynamic parameters

Baseline

Control group

After 8 minutes of untreated VF

PLR group

P value

Control group

PLR group

P value

Comparisons of categorical variables were analyzed using Fisher exact test. Pearson correlation coefficient and Spearman ? were calculated to examine linear relationships between variables. Statistically significant values were considered for P b .05. Statistical analyses were performed with the SPSS statistical software (version 17; SPSS Inc., Chicago, Illinois).

Results

No significant difference was observed in ROSC between the 2 groups, as 6 animals (60%) from the control group and 9 animals (90%) from the PLR group achieved ROSC (P =

.121; odds ratio [OR] = 0.16; 95% confidence interval [CI], 0.01-1.87). More specifically, after the first shock, 3 animals (30%) from the control group and 7 animals (70%) from the PLR group had restored ROSC (P = .074; OR = 0.18; 95% CI, 0.03-1.24). After the second shock, 5 animals (50%) from the control group and 9 animals (90%) from the PLR group had restored ROSC (P = .051; OR = 0.11; 95% CI, 0.01-1.23). After the third shock, 6 animals (60%) from the control group and 9 animals (90%) from the PLR group had restored ROSC (P = .121; OR = 0.16; 95% CI, 0.01-1.87).

No more animals achieved ROSC during the subsequent 2 defibrillation attempts.

No statistically significant differences were observed in baseline and 8-minute untreated VF hemodynamic param- eters between the 2 groups (Table 1). Furthermore, no significant differences were observed between groups in CPP (12.2 +- 10.3 vs 8.5 +- 5.9 mm Hg, P = .339) after 1 minute of CPR. However, after 2 minutes of CPR, CPP was significantly higher in the PLR group vs the control group; but no significant differences were observed in ETCO2 (Table 2). At that instance, a marked but still insignificant difference in aortic systolic pressure (SAP), DAP, and MAP was observed. Coronary perfusion pressure values in the PLR group were significantly higher compared to those in

HR (beat/min)

99.5

+- 16.4

108.2 +- 16.2

.25

NA

NA

NA

SAP (mm Hg)

97.1

+- 8.8

101.7 +- 14.5

.405

19.4 +- 2.7

20.7 +- 2.9

.322

DAP (mm Hg)

67.8

+- 10.8

74.8 +- 11.1

.157

17.2 +- 2.5

18 +- 1.7

.417

MAP (mm Hg)

81.2

+- 8.3

86 +- 12.5

.325

18.1 +- 2.8

19.1 +- 2.1

.381

RASP (mm Hg)

15

+- 2.9

13 +- 2.7

.131

16.8 +- 2.3

17.9 +- 2

.282

RADP (mm Hg)

6.6

+- 3.9

6.6 +- 2.3

1

14.2 +- 3.8

15.8 +- 2.1

.261

RMAP (mm Hg)

9.7

+- 3.4

8.9 +- 2.7

.571

14.9 +- 3.8

17 +- 1.7

.143

CPP (mm Hg)

58.1

+- 8.9

65.9 +- 11.7

.112

2.2 +- 1

1.6 +- 0.7

.146

SpO2 (%)

93.7

+- 4.4

94.9 +- 4

.536

76.7 +- 2.5

77.6 +- 3.8

.544

ETCO2 (mm Hg)

37.8

+- 3.7

40.1 +- 3.3

.175

7.3 +- 2.5

7.9 +- 2.1

.563

HR = heart rate, RASP = right atrial systolic pressure, RADP = right atrial diastolic pressure, RMAP = right atrial mean pressure, SpO2 = saturation of peripheral oxygenation, NA = nonapplicable.

Discussion

Table 2 Hemodynamic parameters of the 2 groups before attempting the first defibrillation

Variables

Control group

PLR group

P value

SAP (mm Hg)

128 +- 32.4

153

+- 25.6

.074

DAP (mm Hg)

58 +- 12.9

68.9

+- 13.4

.082

MAP (mm Hg)

81.3 +- 21.1

96.7

+- 16.8

.088

RASP (mm Hg)

164.2 +- 44.3

148.6

+- 29.4

.368

RADP (mm Hg)

47.4 +- 14.1

46.1

+- 6.9

.799

RMAP (mm Hg)

86.3 +- 23.7

80.2

+- 12.8

.49

CPP (mm Hg)

10.6 +- 6.5

22.8

+- 9.5

.004

SpO2 (%)

83.5 +- 7.8

85.6

+- 8.3

.568

ETCO2 (mm Hg)

15.1 +- 2.1

17.2

+- 2.6

.064

the control group only after the second minute of CPR (Fig. 2), whereas the ETCO2 values were not significantly different any time throughout the experiment (Fig. 3).

All animals that were successfully resuscitated were monitored for 1 hour. No difference was observed in hemodynamic values between the 2 groups in CPP or ETCO2 during this time period (Table 3). Twenty minutes after ROSC, 3 animals from the control group and 4 animals from the PLR group restored sinus rhythm (P = .833; OR = 0.8; 95% CI, 0.1-6.34). However, 20 minutes after ROSC, 3 animals from the control group and 5 animals from the PLR still had supraventricular tachycardia. All animals that achieved ROSC survived after 24 hours (P = .121; relative risk = 0.16; 95% CI, 0.01-1.87). Although there was no significant difference between the 2 groups regarding the 24-hour survival rate, Neurological examination was significantly better in the animals of the PLR group (90 +- 10 vs 76.6 +- 12.1, P = .037).

Until now, the use of PLR maneuver in the treatment of acute hypotensive patients has been confticting. Although it is mainly used as a supportive and temporal measure until ftuid or drug administration occurs, studies have shown that it does not exhibit any beneficial hemodynamic effects because it causes small and ineffective changes only [12]. Reuter et al [13] studied 12 mechanically ventilated hypovolemic patients after cardiac surgery. Apart from a small increase in the preload, they reported that Trendelen- burg position at 30? did not significantly improve MAP or cardiac index. Furthermore, Sibbald et al [26] reported nonconsistent hemodynamic beneficial effects in MAP by Trendelenburg position at 15? to 20? in hypotensive critically ill patients. In another study, however, the Trendelenburg position resulted in a marked increase in MAP and cardiac output, although it led to impaired respiration [14]. Similarly, Gentili et al [27] found that the Trendelenburg position improves MAP, cardiac output, and central venous pressure, but only for 15 minutes.

In our study, we found significant differences in CPP between the 2 groups before the first defibrillation attempt, although, subsequently, the hemodynamic effects of this maneuver seemed to diminish. Moreover, we found that the main factor involved in elevating CPP in the PLR group was an increase in DAP. The most possible explanation for the increase in CPP is the retrograde volume loading of the aorta from PLR. The increase in intraabdominal pressure hinders antegrade aortic blood ftow and DAP increases during CPR. This is very interesting because PLR in a low-ftow state where compliance is low in both arterial and venous beds is

Fig. 2 Coronary perfusion pressure ftuctuation during the experimental procedure. Numbers above mean values indicate animals with ROSC at next rhythm check, and numbers in parenthesis indicate the total number of animals with ROSC at next rhythm check. BL = baseline.

Fig. 3 End-tidal CO2 ftuctuations during the experimental procedure. No significant differences were observed during CPR. Numbers above mean values indicate animals with ROSC at next rhythm check, and numbers in parenthesis indicate the total number of animals that achieved ROSC at next rhythm check.

much different from that in an intact circulation where venous resistance is an order of magnitude lower than arterial resistance. In addition to intraabdominal pressure, however, PLR also increases intrathoracic pressure; and thus, the net effect of these opposing forces with regard to DAP and CPP remains unknown. Based on the aforementioned, it would be of great interest to test the addition of an impedance threshold device during PLR-CPR, as it impedes air entry into the chest cavity during the decompression phase of CPR and improves venous return to the heart [28].

If we take into account the size of the animals and that chest compression began seconds after the PLR maneuver, right atrial pressure was expected to remain increased for only a while after the onset of CPR [16,29]. Accordingly, we did not find a significant increase in ETCO2 in the PLR group before the first defibrillation. It is important to remember, however, that although capnography is a useful tool to optimize and individualize CPR, several confound-

Table 3 Hemodynamic parameters of both groups 60 minutes after ROSC

Variables

Control group

PLR group

P value

HR (beat/min)

139.3 +- 20.6

151.1 +- 24.4

.862

SAP (mm Hg)

89.1 +- 25.5

99.7 +- 19.5

.29

DAP (mm Hg)

48.6 +- 17.1

65 +- 20.2

.515

MAP (mm Hg)

60.1 +- 15.5

74.3 +- 17.5

.439

RASP (mm Hg)

13.5 +- 1.8

15.3 +- 3.7

.053

RADP (mm Hg)

9.3 +- 2.5

8.2 +- 2.2

.914

RMAP (mm Hg)

10.8 +- 2.4

10.7 +- 2.9

.441

CPP (mm Hg)

42.8 +- 15.7

49.3 +- 13.9

.415

SpO2 (%)

94.5 +- 2.9

94.1 +- 3.6

.715

ETCO2 (mm Hg)

37 +- 3.7

39.1 +- 2.5

.21

ing factors have an impact on its values and inftuence its interpretation, especially in case of increased intrathoracic pressure [14,30-32]. In general, autotransfusion of the aorta by PLR seems to be a cheap and effective method to enhance CPP. Nevertheless, given the anatomical differ- ences between humans and swine, it might be possible that PLR may increase right atrial pressure in humans and decrease CPP.

In our study, all animals resuscitated with PLR had better neurological status and 100% 24-hour survival rate than controls, as the increased carotid blood ftow and cerebral oxygen delivery during CPR contributed to the minimization of cerebral ischemia and post-cardiac arrest brain injury [17]. The increased cerebral perfusion pressure after PLR- CPR may ameliorate the severity of total body ischemia/ reperfusion injury and, thus, the amount of Reactive oxygen species that intensify endothelial injury, contribute to blood- brain barrier disruption, and increase the exchange vessel’s permeability and microvascular filtration [10,12,16,29]. Zadini et al [17] reported that the use of Trendelenburg position at 30? in a porcine model improved carotid ftow during open-chest heart CPR. However, a possible decrease in the jugular blood venous return caused by the increase in intrathoracic pressure after PLR could lead to increased intracranial pressure, edema, and decreased cerebral perfu- sion pressure [21]. It has been suggested that CPR in Trendelenburg position with simultaneous cervical ftexion may result in greater benefit to cerebral perfusion because it may diminish arteriolar blood ftow and inverse the theory of increased intracranial pressure [12]. After cervical ftexion, however, the decrease of carotid blood ftow may exacerbate post-cardiac arrest brain injury; and thus, this maneuver requires further research. In general, animals in the PLR

group had better neurologic outcomes because they achieved ROSC earlier because of the enhanced CPP.

We recognize several difficulties regarding PLR applica- tion during laboratory experiments. Careful coordination was essential to ensure correct placement of the metallic device under the animal’s legs. In addition, animal stabilization over the surgical table was time consuming and required further attention to ensure firmness during chest compressions. However, PLR implementation during CPR in real-life circumstances is simple, requires minimum training, and can be applied quickly to cardiac arrest victims.

Limitations

The authors recognize several limitations in this exper- imental study. Firstly, the sample size was small to recognize accurately significant differences in ROSC, survival, or hemodynamics. However, the Power of the study was high and safe conclusions can be extracted. Secondly, humans have substantially bigger lower extremities and consequently larger lower extremity venous blood network capacity compared to piglets and this may result in more extreme hemodynamic differences. Moreover, the animals’ hips and legs were maintained at 45o and, thus, the effects of PLR at different angles have to be elucidated. Another limitation is that PLR’s hemoconcentration benefits during CPR might be demonstrated better in a hypovolemic cardiac arrest model. Furthermore, our experiment was conducted on apparently healthy pigs with no underlying disease. This is not common to human cardiac arrest victims who, most of the time, have various comorbidities. Finally, the dose of adrenaline provided is not physiologic and corresponds to 3 times the dose in a 70-kg human. Nevertheless, all animals received it following Guideline recommendations, as the exact dose of adrenaline in swine remains unknown.

Conclusions

Passive leg raising during CPR exhibits comparable results to standard positioning in ROSC and 24-hour survival rates in a porcine model of VF. However, better neurological outcome is observed among surviving animals in the PLR group. Passive leg raising is a cheap and effective method that rapidly increases CPP the minute before the first defibrillation attempt and with no significant effect after- wards. This maneuver requires additional research to be established as an optimal resuscitation position.

Acknowledgments

Nothing to acknowledge.

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