**Focused Sonography in Cardiac Arrest**

**Focused Sonography in Cardiac Arrest**

Marc Delaney, Bjorn Flora and Sahar Ahmad Marc Delaney, Bjorn Flora and Sahar Ahmad Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70585

### **Abstract**

[22] Aramendi E, Ayala U, Irusta U, Alonso E, Eftestøl T, Kramer- Johansen J. Suppression of the cardiopulmonary resuscitation artefacts using the instantaneous chest compression

[23] González-Otero DM, Ruiz de Gauna S, Ruiz JM, Ayala U, Alonso E. Automatic detection of chest compression pauses using the transthoracic impedance signal. Computing in

[24] González-Otero DM, Ruiz de Gauna S, Ruiz J, Daya M, Wik L, Russell JK, et al. Chest compression rate feedback based on transthoracic impedance. Resuscitation. 2015;93:

[25] Brody D, Di Maio R, Crawford P, Navarro C, Anderson J. The impedance cardiogram amplitude as an indicator of cardiopulmonary resuscitation efficacy in a porcine model of

[26] Howe AJ, Di Maio R, Crawford P, Brody D, Navarro C, McEneaney D, et al. The impedance cardiogram as an indicator of chest compression efficacy during cardiopulmonary resuscitation in a porcine model: correlation with physiological parameters and comparison with compression depth and thrust. Circulation. 2011;124(21 Supplement):A54 [27] Di Maio RC, Navarro C, Cromie N, Anderson J, Adgey A. The impedance cardiogram is an indicator of CPR effectiveness for out-of-hospital cardiac arrest victims. European

[28] Navarro C, Cromie N, Maio RD, Anderson J. Use of the impedance cardiogram in public access defibrillators as an indicator of cardiopulmonary resuscitation effectiveness. Com-

[29] Di Maio R, Howe A, McCanny P, Crispino-O'Connell G, McIntyre A, Patton M, et al. Is the impedance cardiograma potential indicator of effective external cardiac massage in a human model? A study to establish if there is a linear correlation between the impedance cardiogram and depth in a cardiac arrest setting. Circulation. 2012;126(21 Supplement):

[30] Aramendi E, Ayala U, Irusta U, Alonso E. Use of the transthoracic impedance to deter-

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82-88

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A94

Cardiac arrest (CA) is a high mortality event where the ability for clinicians to diagnose etiology and assess for intervention has a direct impact on patient outcomes. Bedside ultrasound (US) has emerged in current literature as a clinical tool to aid clinicians in CA resuscitation, though it remains underutilized. Reversible etiologies that can be efficiently diagnosed with US include tension pneumothorax, hypovolemia, pulmonary embolus with acute cor pulmonale, and cardiac tamponade. Other US findings may provide evidence in regard to prognosis. In this review, we present major applications of US in CA, compare existing protocols, and propose future research needs.

DOI: 10.5772/intechopen.70585

**Keywords:** cardiac arrest, resuscitation, ultrasonography, echocardiography

### **1. Introduction**

Successful resuscitation in cardiac arrest (CA) requires discrete decision-making regarding circulation, airway, and breathing. It is crucial to identify and treat reversible causes of cardiac arrest during resuscitation in order to make decisions that reverse them and more efficiently achieve return of spontaneous circulation (ROSC) [1]. Bedside ultrasound (US) has emerged as an invaluable tool in the diagnosis and management of critically ill patients, including CA [2, 3]. US may aid to diagnose reversible causes of CA, such as pericardial tamponade, tension pneumothorax, or hypovolemia; guide procedures and other management strategies for quality resuscitation; and reveal signs that can serve in clinical context as prognosticators for the ability to achieve ROSC and longer term recovery. In critical care medicine, bedside US has been found to be faster and have greater sensitivity and specificity than conventional imaging, which is unavailable during resuscitation efforts [4].

Bedside US remains underutilized in resuscitation medicine as there is controversy as to how efficiently and reliably it can be implemented by clinicians, especially in a high-stakes and

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

time-sensitive setting such as CA. This review will present literature that evaluates implementation of US in CA resuscitation and demonstrates the potential of US to improve patient outcomes.

### **2. Intra-arrest: US to identify reversible causes of cardiac arrest**

The standard of care for advanced cardiac life support (ACLS) during pulseless electrical activity (PEA) or asystolic CA dictates that providers actively work to diagnose and treat the reversible causes of CA. The following is a summary of the role of US in detecting such reversible causes:

### **2.1. Tension pneumothorax**

Tension pneumothorax (PTX) is a well-known etiology of CA, especially in chest trauma, and can be rapidly reversed with emergent evacuation of air by needle or tube thoracotomy. Approximately 1% of non-traumatic in-hospital CA events are caused by PTX [5]. A metaanalysis showed US to be more sensitive and specific than chest roentgenography (CXR) for detecting PTX, with a sensitivity and specificity of 91 and 98% as compared to 50 and 99% for CXR [6]. Another meta-analysis showed that consultant performed and clinician performed US examinations had similar sensitivity and specificity for PTX [7].

US can also investigate how an identified PTX is altering patient physiology, as clinicians can obtain sub-xiphoid cardiac windows to see inferior vena cava (IVC) engorgement with impaired right heart filling as obstructive physiology. Further research is looking into how the location of a specific lung US finding, called lung point, can be used to quantify PTX size, with initial data showing that lung points found in the mid axillary line of supine patients predicting a greater than 15% lung collapse size as measured by CT with a sensitivity of 83% and specificity of 82% [8]. The convenience and repeatability of bedside US for PTX makes it clinically useful in CA [7, 9].

### **2.2. Pericardial effusion with cardiac tamponade**

Cardiac tamponade is a significant contributor to in-hospital CA, with reported incidence as high as 6% of in-hospital CA [5]. Performing cardiac ultrasound, or echocardiography, during chest compression holds, allows for rapid detection of pericardial effusion. Several studies have validated the diagnostic power of US in this setting, including in the hands of non-cardiologist physicians, with reported sensitivities ranging from 96 to 100% and specificities ranging from 87 to 98% [10, 11]. In the medical literature, outside of the case of CA, use of bedside US to detect tamponade physiology is widely supported. Internal medicine (IM) physicians with handheld US devices identified moderate to large pericardial effusions with moderate agreement (kappa of 0.51) compared to cardiologist-read formal echocardiography [12]. Detecting increased central venous congestion in this setting using the presence of IVC plethora on US has shown a sensitivity of 97% for predicting tamponade, with an understandably small specificity of 40% given the many causes of IVC plethora [13, 14]. Other US predictors of tamponade physiology relate to the enhanced ventricular interdependence seen in tamponade include right atrial collapse (sensitivity of 50–100%, specificity of 33–100%) [15, 16], left atrial collapse (sensitivity of 13%, specificity of 98%), and right ventricular collapse (sensitivity of 48–100%, specificity of 72–100%) [13, 17].

### **2.3. Pulmonary embolus with acute cor pulmonale**

time-sensitive setting such as CA. This review will present literature that evaluates implementation of US in CA resuscitation and demonstrates the potential of US to improve patient

The standard of care for advanced cardiac life support (ACLS) during pulseless electrical activity (PEA) or asystolic CA dictates that providers actively work to diagnose and treat the reversible causes of CA. The following is a summary of the role of US in detecting such

Tension pneumothorax (PTX) is a well-known etiology of CA, especially in chest trauma, and can be rapidly reversed with emergent evacuation of air by needle or tube thoracotomy. Approximately 1% of non-traumatic in-hospital CA events are caused by PTX [5]. A metaanalysis showed US to be more sensitive and specific than chest roentgenography (CXR) for detecting PTX, with a sensitivity and specificity of 91 and 98% as compared to 50 and 99% for CXR [6]. Another meta-analysis showed that consultant performed and clinician performed

US can also investigate how an identified PTX is altering patient physiology, as clinicians can obtain sub-xiphoid cardiac windows to see inferior vena cava (IVC) engorgement with impaired right heart filling as obstructive physiology. Further research is looking into how the location of a specific lung US finding, called lung point, can be used to quantify PTX size, with initial data showing that lung points found in the mid axillary line of supine patients predicting a greater than 15% lung collapse size as measured by CT with a sensitivity of 83% and specificity of 82% [8]. The convenience and repeatability of bedside US for PTX makes it

Cardiac tamponade is a significant contributor to in-hospital CA, with reported incidence as high as 6% of in-hospital CA [5]. Performing cardiac ultrasound, or echocardiography, during chest compression holds, allows for rapid detection of pericardial effusion. Several studies have validated the diagnostic power of US in this setting, including in the hands of non-cardiologist physicians, with reported sensitivities ranging from 96 to 100% and specificities ranging from 87 to 98% [10, 11]. In the medical literature, outside of the case of CA, use of bedside US to detect tamponade physiology is widely supported. Internal medicine (IM) physicians with handheld US devices identified moderate to large pericardial effusions with moderate agreement (kappa of 0.51) compared to cardiologist-read formal echocardiography [12]. Detecting increased central venous congestion in this setting using the presence of IVC plethora on US has shown a sensitivity of 97% for predicting tamponade, with

**2. Intra-arrest: US to identify reversible causes of cardiac arrest**

US examinations had similar sensitivity and specificity for PTX [7].

outcomes.

98 Resuscitation Aspects

reversible causes:

**2.1. Tension pneumothorax**

clinically useful in CA [7, 9].

**2.2. Pericardial effusion with cardiac tamponade**

US diagnosis of acute cor pulmonale due to pulmonary embolism (PE) relies on identification of right ventricle (RV) enlargement as an important finding during targeted echocardiography. Outside of the case of CA, other findings of acute cor pulmonale in include septal flattening or leftward bowing and RV systolic dysfunction [18, 19] . The RV:LV end diastolic diameter ratio, D-sign, and McConnel's sign are validated echocardiography patterns of acute cor pulmonale in PE [20]. Of course, these signs are a product of a large flow-obstructing PE altering hemodynamic physiology in the presence of spontaneous circulation, a factor that is not present at CA. However, several case reports and observational studies have reported that, even during CA, PE can still be identified using the same signs of disproportionate RV size and direct embolism visualization in the pulmonary artery, right atrium, or IVC as a homogenously echogenic structure independent of underlying anatomy (suggestive of thrombus presence [21–25]. Such findings may lead to change in management including use of thrombolysis, an intervention that could largely benefit mortality in these patients [26, 27]. Administration of thrombolytic agents during cardiopulmonary resuscitation (CPR) is a controversial and high-risk procedure that can produce serious complications, including fatal hemorrhage, leading to controversy in recommendations and guidelines [27]. Interestingly, studies have added contrast to early case reports of hemorrhage including a recent single-center retrospective analysis of 42 patients that found thrombolysis during CA yielded no significant difference in major and minor bleeding events [28]. In regards to resuscitation, one study on 42 CA patients with PE found higher rates of ROSC in patients who received emergent thrombolysis than those who did not (81% vs. 43%, p = 0.03) [29]. While prospective data in this setting is sparse, the largest randomized trial was performed by Böttiger et al. in 2008 with 1050 out-of-hospital CA patients. The trial was terminated early due to futility when no significant differences were detected between tenecteplase and placebo groups in 30-day survival, hospital admission rates, ROSC, 24-hour survival, survival to discharge, or neurologic outcomes [30].

Ultrasound can be used to view the lower extremity vessels for a rapid deep venous thrombosis (DVT) study without interfering with compressions or other resuscitation measures. Studies have shown that bedside US DVT exams performed by clinician-sonographers have similar speed and diagnostic accuracy as compared to a formal US study with a radiologist [31, 32]. One meta-analysis of 15 studies and nearly 7000 patients by Rodrigues et al. in 2016 showed that an abbreviated proximal-focused DVT study, had a pooled sensitivity of 41%, and specificity of 96% for DVT detection compared to 79 and 84% of a relatively time-intensive wholeextremity exam [33]. In this study, the positive likelihood ratio of the limited DVT studies was pooled at 11.9, suggesting a utility of this abbreviated study in settings such as cardiac arrest.

While there is a clear need for further research in this area, many sources are advocating for more widespread use of thrombolysis during CPR in CA patients, especially in those where intra-arrest US helps to diagnose PE early and identify those at the highest risk of mortality [34].

### **2.4. Hypovolemia**

Perhaps one of the most commonly used applications of bedside US is the evaluation of intravascular volume status and prediction of fluid tolerance or responsiveness [11, 35]. During management of CA, imaging of the IVC can help a code-leader rapidly diagnose hypovolemic shock, a tool whose sensitivity and specificity can be enhanced by adding US images of the lung fields and basic cardiac windows in conjunction with US of the IVC [36].

Early studies involved viewing the IVC in dialysis patients and blood donors, showing differences in IVC diameters pre and post infusions with associated changes in vessel caliber with respiratory cycle thoracic pressure changes [37, 38]. The largest meta-analysis in support of IVC US showed a pooled sensitivity of 76% and specificity of 86% for the detection of fluid responsiveness, defined as improved cardiac output (CO) on cardiac catheterization [39]. In both spontaneously breathing and mechanically ventilated patients, IVC US has high sensitivity and specificity for assessing fluid volume and responsiveness, suggesting applicability in the setting of CA, where hypovolemia may be a reversible etiology of arrest [39, 40]. However, US interrogation of fluid responsiveness during CA requires the clinician to be aware of the altered hemodynamic physiology of CA, where there is significant venous congestion and an elevated central venous pressure associated with decreased cardiac output (CO) [41]. In addition, sonographers need to be aware of the comorbidities that decrease IVC imaging sensitivity for hypovolemia, such as an obstructive physiology such as cor pulmonale, cardiac tamponade, or a myocardial infarction with markedly decreased CO [41].

With this hemodynamic physiology of CA in mind, US evaluation of hypovolemia as a cause of CA can still be useful as IVC imaging can be coupled with rapid and sensitive interrogation of the thoracic, abdominal, and pelvic cavities. In these spaces, such a large volume of fluid can accumulate to where this could cause significant hypovolemia if blood loss into these spaces has decreased effective circulating volume [41, 42]. US evaluation for significant intra-abdominal and pelvic fluid accumulation is a widely accepted modality, with sensitivities ranging from 60 to 100% [43–46]. In the setting of CA, this technique can take place without interruption of compressions and has the potential to alter CA management [47].

### **3. Peri-arrest and post-arrest care: US to guide ACLS**

Outside of its use in diagnosing reversible etiologies of CA, US has also been supported by the literature for guidance of interventions in the intra and peri-arrest period.

### **3.1. US to interrogate cardiac rhythm**

While there is a clear need for further research in this area, many sources are advocating for more widespread use of thrombolysis during CPR in CA patients, especially in those where intra-arrest US helps to diagnose PE early and identify those at the highest risk of

Perhaps one of the most commonly used applications of bedside US is the evaluation of intravascular volume status and prediction of fluid tolerance or responsiveness [11, 35]. During management of CA, imaging of the IVC can help a code-leader rapidly diagnose hypovolemic shock, a tool whose sensitivity and specificity can be enhanced by adding US images of the

Early studies involved viewing the IVC in dialysis patients and blood donors, showing differences in IVC diameters pre and post infusions with associated changes in vessel caliber with respiratory cycle thoracic pressure changes [37, 38]. The largest meta-analysis in support of IVC US showed a pooled sensitivity of 76% and specificity of 86% for the detection of fluid responsiveness, defined as improved cardiac output (CO) on cardiac catheterization [39]. In both spontaneously breathing and mechanically ventilated patients, IVC US has high sensitivity and specificity for assessing fluid volume and responsiveness, suggesting applicability in the setting of CA, where hypovolemia may be a reversible etiology of arrest [39, 40]. However, US interrogation of fluid responsiveness during CA requires the clinician to be aware of the altered hemodynamic physiology of CA, where there is significant venous congestion and an elevated central venous pressure associated with decreased cardiac output (CO) [41]. In addition, sonographers need to be aware of the comorbidities that decrease IVC imaging sensitivity for hypovolemia, such as an obstructive physiology such as cor pulmonale, cardiac tamponade, or a myocardial infarction with markedly

With this hemodynamic physiology of CA in mind, US evaluation of hypovolemia as a cause of CA can still be useful as IVC imaging can be coupled with rapid and sensitive interrogation of the thoracic, abdominal, and pelvic cavities. In these spaces, such a large volume of fluid can accumulate to where this could cause significant hypovolemia if blood loss into these spaces has decreased effective circulating volume [41, 42]. US evaluation for significant intra-abdominal and pelvic fluid accumulation is a widely accepted modality, with sensitivities ranging from 60 to 100% [43–46]. In the setting of CA, this technique can take place without interruption of compressions and has the potential to

Outside of its use in diagnosing reversible etiologies of CA, US has also been supported by the

lung fields and basic cardiac windows in conjunction with US of the IVC [36].

mortality [34].

100 Resuscitation Aspects

**2.4. Hypovolemia**

decreased CO [41].

alter CA management [47].

**3. Peri-arrest and post-arrest care: US to guide ACLS**

literature for guidance of interventions in the intra and peri-arrest period.

During CA resuscitation, one can directly visualize the heart both during compressions and at pulse checks. This has allowed clinicians more insight into the physiology of each patient in addition to data provided by pulse palpation and electrical monitors. US has bolstered the clinical utility of categorizing electromechanical dissociation (EMD) into "true-EMD" vs. "pseudo-EMD." Pseudo-EMD is defined as the sonographic evidence of intrinsic and coordinated myocardial and valvular movement in the absence of a palpable pulse [11, 48, 49]. Several authors have noted that this observation of pseudo-EMD is associated with a better prognosis for ROSC as compared to true-EMD, which shows no contractile movement of the heart. One such prospective observational study involving 49 intensive care unit (ICU) CA events showed pseudo-EMD to occur on US in 55% of PEA patients [48]. This study showed the rates of ROSC were 70% for those in pseudo-EMD compared to 20% for those in true EMD [48, 50]. This US distinction could aid clinicians in their prognostication and decisions to continue or halt resuscitative efforts, with implications to resource utilization. Alternatively, the finding of pseudo-EMD may support a clinical strategy of using vasopressors/inotropes to support this coordinated cardiac activity and better optimize cerebral and coronary perfusion pressures for achieving ROSC. While there is currently no data to support this practice in CA resuscitation, this approach has been utilized with success in shock patients [51, 52].

Similarly, authors have described resuscitative events where "pseudo-asystole" is identified as asystole on electrical cardiac monitor with asynchronous fibrillatory activity of the ventricles on echo, suggesting ventricular fibrillation (VF). In the existing case reports describing this finding, this immediately changed ACLS algorithm as unsynchronized defibrillation was indicated [53–55].

### **3.2. US to guide chest compressions**

US has been suggested as a means to optimize the effectiveness of chest compressions and to increase accuracy and efficiency of pulse check intervals [56]. While there remains a paucity of data to support these uses, the potential demonstrated by early case reports warrants discussion. Effective chest compressions allow for adequate coronary and cerebral perfusion pressure during CA [57]. While ACLS guidelines state the optimal site of compressions is on the lower half of the sternum along the nipple line, some studies suggest significant anatomical variation among structures at this site [58]. One study of 30 out-of-hospital CA patients tested this site compared to three caudal alternatives and found that maximal end-tidal carbon dioxide was achieved at the AHA recommended site in only 1/3rd of their sample [59]. Another study using transesophageal echocardiography (TEE) observed 34 non-traumatic CA patients and identified the anatomic area of maximal compression (AMC) to be over the aorta or left ventricular outflow tract in all cases with a statistically significant linear association between LV stroke volume and AMC distance from the aortic valve [60]. In a swine model of cardiac arrest, animals randomized to have compressions centered over their LV, as identified by transesophageal echocardiography (TEE), had a greater proportion of ROSC and survival to 60 minutes compared to those that had compressions centered over their aortic root [61]. While more research in this area is needed, it is reasonable to predict a role for bedside ultrasound and echocardiography to be identifying appropriate positioning for chest compression efforts, either by trans-thoracic echocardiography (TTE) and/or TEE by viewing the anatomic landmarks directly.

### **3.3. US to guide pulse checks**

Current ACLS guidelines state that pulse-checks during CA resuscitation should last no longer than 10 seconds. Some authors have called the accuracy of pulse palpation into question [62]. One study involving pulse palpation during cardiac bypass surgery (spontaneous vs. non-pulsatile blood flow) showed that, while health care providers with advanced levels of training had decreased decision delay, only 16.5% of the participants (34 of 206) were able to reach a confident decision about their patients' pulse status within 10 seconds [63]. A similar earlier study in basic life support-trained personnel found that although sensitivity of all participants for central pulselessness approached 90%, specificity was only 55% [64]. While these studies have their limitations, they call attention to a potential role for ancillary devices to augment the accuracy of pulse palpation. Case reports have shown handheld Doppler US devices can allow for faster pulse checks in patients during in-hospital CA [62]. Other authors have already reported the utility of US performed concomitantly with pulse palpation to be effective in identifying perfusing heart rhythms [21]. While US in this exact context is not yet well studied, it seems of little risk but some benefit to use US to eliminate some of this intrinsic inaccuracy in pulse palpation during CA resuscitation.

### **3.4. US for endotracheal tube (ETT) placement confirmation**

Verification of endotracheal intubation during ACLS can be accomplished with US of the neck. The usual methods of ETT placement verification have limitations when applied during cardiac arrest. Direct visualization is often not reliable especially if the intubation takes place during chest compressions due to the movements of the patient. Colorimetry methods can be misleading in the setting of a previously insufflated stomach, which is the case with the bag valve mask technique ongoing prior to intubation attempts or prior esophageal intubation with insufflation. Continuous waveform capnography remains as a reliable confirmatory method if this equipment is readily available. It can require time to set up and to evaluate the waveform over several breaths, which can be considered a limitation. US can distinguish an intubated trachea from and an intubated esophagus as each has distinct sonographic findings that can be rapidly attained.

Cadaver studies have shown that neck US findings of "double lumen sign" and "tube sliding" artifact can predict endotracheal or esophageal intubation with 100% sensitivity and 100% specificity [65]. The largest meta-analysis of studies with both adult patient and cadaveric models determined that bedside physicians and house staff had a pooled sensitivity and specificity of 93 and 97% [66]. US for ETT placement is especially useful when waveform capnography is not readily available [67] or if a conventional method is misleading, such as colorimetry-verified placement with continued hypoxia. Several authors have shown that US is quicker than conventional methodologies of ETT placement confirmation, demonstrating an average time to confirmation of 5.8 seconds, significantly faster than capnography at 11.8 seconds [68]. We advocate for enhancing testing characteristics by combining visualization of neck airway structures with lung field pleural sliding and respiratory diaphragmatic motion, which can be performed during pulse check.

### **3.5. US to guide post-ROSC hemodynamic management**

While more research in this area is needed, it is reasonable to predict a role for bedside ultrasound and echocardiography to be identifying appropriate positioning for chest compression efforts, either by trans-thoracic echocardiography (TTE) and/or TEE by viewing the anatomic

Current ACLS guidelines state that pulse-checks during CA resuscitation should last no longer than 10 seconds. Some authors have called the accuracy of pulse palpation into question [62]. One study involving pulse palpation during cardiac bypass surgery (spontaneous vs. non-pulsatile blood flow) showed that, while health care providers with advanced levels of training had decreased decision delay, only 16.5% of the participants (34 of 206) were able to reach a confident decision about their patients' pulse status within 10 seconds [63]. A similar earlier study in basic life support-trained personnel found that although sensitivity of all participants for central pulselessness approached 90%, specificity was only 55% [64]. While these studies have their limitations, they call attention to a potential role for ancillary devices to augment the accuracy of pulse palpation. Case reports have shown handheld Doppler US devices can allow for faster pulse checks in patients during in-hospital CA [62]. Other authors have already reported the utility of US performed concomitantly with pulse palpation to be effective in identifying perfusing heart rhythms [21]. While US in this exact context is not yet well studied, it seems of little risk but some benefit to use US to eliminate some of this intrinsic

Verification of endotracheal intubation during ACLS can be accomplished with US of the neck. The usual methods of ETT placement verification have limitations when applied during cardiac arrest. Direct visualization is often not reliable especially if the intubation takes place during chest compressions due to the movements of the patient. Colorimetry methods can be misleading in the setting of a previously insufflated stomach, which is the case with the bag valve mask technique ongoing prior to intubation attempts or prior esophageal intubation with insufflation. Continuous waveform capnography remains as a reliable confirmatory method if this equipment is readily available. It can require time to set up and to evaluate the waveform over several breaths, which can be considered a limitation. US can distinguish an intubated trachea from and an intubated esophagus as each has distinct sonographic findings

Cadaver studies have shown that neck US findings of "double lumen sign" and "tube sliding" artifact can predict endotracheal or esophageal intubation with 100% sensitivity and 100% specificity [65]. The largest meta-analysis of studies with both adult patient and cadaveric models determined that bedside physicians and house staff had a pooled sensitivity and specificity of 93 and 97% [66]. US for ETT placement is especially useful when waveform capnography is not readily available [67] or if a conventional method is misleading, such as colorimetry-verified placement with continued hypoxia. Several authors have shown that US is quicker than conventional methodologies of ETT placement confirmation, demonstrating

landmarks directly.

102 Resuscitation Aspects

**3.3. US to guide pulse checks**

that can be rapidly attained.

inaccuracy in pulse palpation during CA resuscitation.

**3.4. US for endotracheal tube (ETT) placement confirmation**

Post-ROSC management includes the immediate initiation of hemodynamic support measures such as fluids, vasopressors, and inotropes. The ability to quickly utilize bedside US to evaluate fluid responsiveness and overall cardiac function can be clinically useful to guide this hemodynamic support.

Goal-directed echocardiography (GDE) is a concept that uses high-fidelity qualitative analysis, without Doppler technology or valvular measurements, to assess targeted cardiac windows in real-time with high sensitivity of identifying marked abnormalities and gross pathophysiology. GDE emphasizes grading LV function as normal, decreased, or very decreased, allowing bedside clinicians to make real-time evaluations upon which to guide management of CA [69]. Current literature supports agreement of GDE interpretations between formal consultant cardiologists and clinician-sonographers at the bedside. One such study demonstrated that, after a brief training course, novice sonographers with hand-held US at the bedside demonstrated 75% agreement with cardiologist in their formal-US study interpretations of LV dysfunction, compared to 83% intra-cardiologist agreement [12]. Thereby, in a CA resuscitation event, when a cardiologist is not always available, a relatively novice-level sonographer is sufficient for diagnostic capability.

Using this concept of GDE, clinician-sonographers can use US to better inform their post-ROSC hemodynamic management including the use of inotropes, pressors, and/or fluid support with the treating clinician acquiring selected TTE views to characterize pre-load and cardiac contractility in the immediately post-arrest period.

### **4. US for prognostication in CA**

An important emerging area of current study in CA US involves using US data in prognostication for survival and neurological outcomes in CA. Despite best efforts during resuscitation, there is continued poor survivorship. The ability to prognosticate the patient's likelihood of achieving ROSC can improve the practitioner's ability to allocate resources and manage expectations of the treating team and patient's caretakers.

The strongest literature supporting prognostic value of US in CA relates to the presence or absence of coordinated cardiac activity as noted by US [11, 48, 70]. Pooled data from over 500 patients showed that the presence of any cardiac kinetics by intra-arrest US had a positive likelihood ratio of 4.26 and negative likelihood ratio of 0.18 to predict ROSC [71]. Another observational study observed the survivorship of nearly 800 non-traumatic CA patients who received US examination as part of their resuscitative efforts upon presentation to the emergency room and showed presence of any cardiac activity on US was associated with ROSC, survival to admission, and survival to discharge [72].

Further areas of research into US in CA prognostication are looking outside the heart, including measuring optic nerve sheath diameter (ONSD) to predict a positive neurological outcome. ONSD was measured in CA patients 12–72 hours after ROSC and at 28 days after ROSC or discharge from the hospital before 28 days [73]. ONSD of less than or equal to 5.4 mm predicted a favorable neuro-functional prognosis as measures by Glasgow Outcomes Scale with a sensitivity of 83%, specificity of 73%, positive likelihood ratio of 3.1 and negative likelihood ratio of 0.23 [73].

### **5. Bedside CA US is feasible to be implemented today**

The viability of using US during a cardiac arrest depends on the premise that non-radiologist and non- cardiologist physicians can obtain and rapidly interpret imaging data about patient anatomy and physiology with high diagnostic accuracy. Among the significant barriers to its implementation and widespread use are lack of confidence in usage of new technologies and inertia against supplementing traditional methods with new tools for guiding CA management.

In response to the issue of implementation, there is much known about the learning curve for non-radiologist and non-cardiologist practitioners to operate, interpret, and apply this bedside imaging technology. Authors from many different fields including emergency medicine, IM, and anesthesiology have conducted research to address this question of feasibility [74]. Multiple studies have shown that, after short-term (hours-days) educational sessions, novice and expert sonographers can perform without significant differences in sensitivity or specificity in challenging US applications such as ventricular function, volume status or cardiac tamponade [75].

Even at the trainee level, it has been shown that US is a technology which physicians can consistently learn. The Accreditation Council of Graduate Medical Education (ACGME) now requires that critical care ultrasonography be a mandatory component of critical care medicine fellowship training, surgical critical care fellowship training, and emergency medicine residencies [75, 76]. It is well established that this can be done successfully with a mixture of didactics, simulation, and hands on training [75]. In a 3 day critical care US course, 300 novice physicians were shown to proficiently acquire and interpret content from thoracic, vascular, and abdominal ultrasonography [77].

Integrating US techniques into CA management is simply a matter of targeted educational sessions focused on image acquisition, interpretation, and immediate application. After a 1-day training course in CA echocardiography given to novice clinicians of all training levels, the rate of US usage in CA management increased from 4.3 to 19.8% and that echocardiography during the CA event altered management in 70% of cases [78]. Another study found that novice sonographers as a part of an ACLS response team were able to integrate US into their management of cardiac arrest with images obtained and interpreted within an average of 8 min from CA alert activation and demonstrated strong image interpretation agreement with expert sonographers upon retrospective repeat interpretation [42]. In an analysis of CA events in the ICU where US was used in the setting of PEA or asystole, images of adequate quality were obtained during compressions in 100% of there were changes in management and diagnosis due to US findings in 51% of cases [48]. These data together suggest that US has significant potential to aid in CA resuscitation management and potentially improve patient mortality, morbidity, and outcomes [42, 72, 79, 80].

### **6. Overview of selected current CA US protocols**

to the emergency room and showed presence of any cardiac activity on US was associated

Further areas of research into US in CA prognostication are looking outside the heart, including measuring optic nerve sheath diameter (ONSD) to predict a positive neurological outcome. ONSD was measured in CA patients 12–72 hours after ROSC and at 28 days after ROSC or discharge from the hospital before 28 days [73]. ONSD of less than or equal to 5.4 mm predicted a favorable neuro-functional prognosis as measures by Glasgow Outcomes Scale with a sensitivity of 83%, specificity of 73%, positive likelihood ratio of 3.1 and negative likelihood

The viability of using US during a cardiac arrest depends on the premise that non-radiologist and non- cardiologist physicians can obtain and rapidly interpret imaging data about patient anatomy and physiology with high diagnostic accuracy. Among the significant barriers to its implementation and widespread use are lack of confidence in usage of new technologies and inertia against supplementing traditional methods with new tools for guiding CA

In response to the issue of implementation, there is much known about the learning curve for non-radiologist and non-cardiologist practitioners to operate, interpret, and apply this bedside imaging technology. Authors from many different fields including emergency medicine, IM, and anesthesiology have conducted research to address this question of feasibility [74]. Multiple studies have shown that, after short-term (hours-days) educational sessions, novice and expert sonographers can perform without significant differences in sensitivity or specificity in challenging US applications such as ventricular function, volume status or cardiac

Even at the trainee level, it has been shown that US is a technology which physicians can consistently learn. The Accreditation Council of Graduate Medical Education (ACGME) now requires that critical care ultrasonography be a mandatory component of critical care medicine fellowship training, surgical critical care fellowship training, and emergency medicine residencies [75, 76]. It is well established that this can be done successfully with a mixture of didactics, simulation, and hands on training [75]. In a 3 day critical care US course, 300 novice physicians were shown to proficiently acquire and interpret content from thoracic, vascular,

Integrating US techniques into CA management is simply a matter of targeted educational sessions focused on image acquisition, interpretation, and immediate application. After a 1-day training course in CA echocardiography given to novice clinicians of all training levels, the rate of US usage in CA management increased from 4.3 to 19.8% and that echocardiography during the CA event altered management in 70% of cases [78]. Another study found that novice sonographers as a part of an ACLS response team were able to integrate US into their management of cardiac arrest with images obtained and interpreted within an average

with ROSC, survival to admission, and survival to discharge [72].

**5. Bedside CA US is feasible to be implemented today**

ratio of 0.23 [73].

104 Resuscitation Aspects

management.

tamponade [75].

and abdominal ultrasonography [77].

Implementation of US for CA will be most organized if a standardized approach can be systematically integrated into CA management. There are several example US for CA protocols noted to date, including our institutional protocol (**Table 1**). These protocols focus on rapidly identifying causes of PEA/asystole such as cardiac tamponade, PE, PTX, and hypovolemia. Each protocol is designed to minimally interfere with ACLS. Our institutional protocol


Abd, abdomen; IVC, inferior vena cava; ETT, endotracheal tube; CPR, cardiopulmonary resuscitation.

**Table 1.** Comparison of currently proposed organized protocols for cardiac arrest ultrasound.

includes the use of neck tracheal US for confirming placement of the ETT. Most protocols were estimated to take less than 1 min to complete and none endorse interruption of chest compressions beyond the standard time limit of a pulse check. One protocol advocates for saving a video loop of a subcostal view of the heart during a 10 s pulse check, allowing for repeat image analysis [42]. Most protocols emphasize knowledge of diagnostic limitations and careful image interpretation. The complexity of the protocols ranges from 1 view (echocardiography only) to 6 views (**Table 1**).

### **6.1. Reflections on institutional experience**

Our institution is a tertiary care center in New York State, where all inpatient medicine CA resuscitative events are led by senior IM residents, variably with attending. Since early 2014, our institution has incorporated US training into CA management training for these team leaders. In addition, the pulmonary and critical care medicine (PCCM) fellowship program incorporates extensive educational experience in using bedside US in many aspects of critical care, including that for CA. Since the advent of use of this US protocol (**Table 1** and **Figure 1**) for CA, our institution has conducted over 280 CA events and we have implemented use of handheld US devices when a trained clinician can participate. So far, we have received positive feedback from residents regarding the incorporation of ultrasound in CA. Finding a reversible cause has so far been rare. The largest impact has been that the use of US at CA allows code leaders to feel more comfortable stopping resuscitation by ruling out reversible etiologies of CA or findings that represent poor prognosis.

**Figure 1.** CA US protocol at Stony Brook University medical center critical care ultrasound (SBUS) program.

### **7. Summary and conclusions**

includes the use of neck tracheal US for confirming placement of the ETT. Most protocols were estimated to take less than 1 min to complete and none endorse interruption of chest compressions beyond the standard time limit of a pulse check. One protocol advocates for saving a video loop of a subcostal view of the heart during a 10 s pulse check, allowing for repeat image analysis [42]. Most protocols emphasize knowledge of diagnostic limitations and careful image interpretation. The complexity of the protocols ranges from 1 view (echocardiogra-

Our institution is a tertiary care center in New York State, where all inpatient medicine CA resuscitative events are led by senior IM residents, variably with attending. Since early 2014, our institution has incorporated US training into CA management training for these team leaders. In addition, the pulmonary and critical care medicine (PCCM) fellowship program incorporates extensive educational experience in using bedside US in many aspects of critical care, including that for CA. Since the advent of use of this US protocol (**Table 1** and **Figure 1**) for CA, our institution has conducted over 280 CA events and we have implemented use of handheld US devices when a trained clinician can participate. So far, we have received positive feedback from residents regarding the incorporation of ultrasound in CA. Finding a reversible cause has so far been rare. The largest impact has been that the use of US at CA allows code leaders to feel more comfortable stopping resuscitation by ruling out reversible

**Figure 1.** CA US protocol at Stony Brook University medical center critical care ultrasound (SBUS) program.

phy only) to 6 views (**Table 1**).

106 Resuscitation Aspects

**6.1. Reflections on institutional experience**

etiologies of CA or findings that represent poor prognosis.

Bedside US has significant implications in the setting of guiding cardiac arrest management. In CA resuscitation, clinicians must make rapid, yet informed decisions about patient care in a fast-paced and high pressure environment. In the case of CA characterized by PEA/ asystole, US can quickly assess for reversible causes. US can help physicians better interrogate cardiac rhythm or intrinsic cardiac activity, perform more effective chest compressions, reduce error in pulse checks, more rapidly rule out esophageal intubation, provide more tailored post-ROSC hemodynamic support, and provide assistance in prognostication. CA US allows clinicians to offer a higher level of care quality in concordance with, yet beyond, basic ACLS.

Incorporation of US at all CA may improve cost effectiveness and efficiency of hospital resource distribution. Rapid TTE improved the use of health care resources in patients with CA secondary to trauma, where patients who did not received US had a significantly higher mean cost of care, with an average of approximately \$1100 less spent on the US examined group [81]. The prognostic value of US in CA carries an additional resource utilization benefit when considering effects such as ending futile resuscitative efforts earlier and redirecting valuable physician time, hospital personnel resources, as well as medication and equipment costs.

US has become a required part training and accreditation for several medical specialties and it has been consistently shown that physicians can learn US through targeted cumulative educational exposures, even starting at the residency and fellowship levels. It follows that emerging clinicians can be expected to gradually learn to apply these skills to the challenging clinical setting of CA. Most authors advocate for the adoption of a protocolized approach to US in CA as such an approach allows physicians to implement high-yield bedside US in conjunction with ACLS and with minimal interference. Protocolized approaches should include views of the heart to assess cardiac function and for pericardial fluid, IVC for volume status, lung fields to rule out PTX and fluid dependent spaces in the abdomen and pelvis for hemorrhage. Additionally, DVT study and airway confirmation by US may be employed.

Several authors agree that there is a paucity of research to evaluate differences in patient outcomes from US use in CA, therefore true benefits are difficult to assess [82]. Recent survey data identified that there is an existing perception that training in hemodynamic relevant US imaging takes too long, and that only specialized individuals can perform these examinations [83]. However, the literature reviewed here advocate against this criticism. Several authors have shown that time constraints do not prohibit a limited US study and that bedside clinicians can demonstrate success in learning US applications after simple educational interventions. Another barrier is the perception that US devices and sonographers will not be able to join an already crowded space. At our institution, we have found that an US provider, with either a portable or handheld US unit, can easily navigate a resuscitation event without interrupting ACLS. A dedicated sonographer is easily able to adopt to the needs of the resuscitation, change positions and deliver diagnostics to code leaders without interfering with team communications, medication administration, or procedural interventions.

We strongly support the role of US in guiding CA resuscitation management. In light of our and others' experiences reporting US changes management in a majority of CA cases and we suggest that there needs to be support of ongoing research to investigate correlations of US to patient outcomes. US should be part of the standard of care in cardiac resuscitation events as it is currently one of the only means of real time diagnosis of several reversible causes of CA [84].

### **Author details**

Marc Delaney, Bjorn Flora and Sahar Ahmad\*

\*Address all correspondence to: sahar.ahmad@stonybrookmedicine.edu

Division of Pulmonary and Critical Care Medicine, Stony Brook University Medical Center, Stony Brook, New York, USA

### **References**


[9] Azad A, Al Juma S, Bhatti JA, Dankoff J. Validity of ultrasonography to diagnosing pneumothorax: A critical appraisal of two meta-analyses. CJEM. 2015;**17**:199-201

We strongly support the role of US in guiding CA resuscitation management. In light of our and others' experiences reporting US changes management in a majority of CA cases and we suggest that there needs to be support of ongoing research to investigate correlations of US to patient outcomes. US should be part of the standard of care in cardiac resuscitation events as it is currently one of the only means of real time diagnosis of several reversible causes of CA [84].

Division of Pulmonary and Critical Care Medicine, Stony Brook University Medical Center,

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**Provisional chapter**

### **Extraterrestrial CPR and Its Applications in Terrestrial Medicine Medicine**

**Extraterrestrial CPR and Its Applications in Terrestrial** 

DOI: 10.5772/intechopen.70221

Thais Russomano and Lucas Rehnberg

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Thais Russomano and Lucas Rehnberg Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70221

### **Abstract**

Cardiopulmonary resuscitation (CPR) is a well-established part of basic life support (BLS), saving countless lives since its first development in the 1960s. Recently, work has been undertaken to develop methods of basic and advanced life support (ALS) in microgravity and hypogravity. Although the likelihood of a dangerous cardiac event occurring during space mission is rare, the possibility exists. The selection process for space missions nowadays considers individuals at ages and with health standards that would have precluded their selection in the past. The advent of space tourism may even enhance this possibility. This chapter presents a synthesis of the results obtained in studies conducted at the MicroG-PUCRS, Brazil, examining extraterrestrial CPR during ground-based microgravity and hypogravity simulations and during parabolic flights and sustained microgravity. It outlines the extraterrestrial BLS guidelines for both low-orbit and deepspace missions. The former are based on a combination of factors, unique for the environment of space. In a setting like this, increased physiological stress due to gravitational adaptation and the isolated nature of the environmental demands can affect the outcome of resuscitation procedure.

**Keywords:** extraterrestrial CPR, microgravity, hypogravity, medical emergencies, cardiac arrest, BLS, space tourism, space missions, space medicine, space physiology

### **1. Introduction**

Cardiopulmonary resuscitation (CPR) is a well-established part of basic life support (BLS) and has saved tens of thousands of lives [1] since its development by Peter Safar in the 1960s [2]. Terrestrial BLS guidelines are developed by national organisations, such as the American Heart Association (AHA), the European Resuscitation Council (ERC) and the International Liaison Committee on Resuscitation (ILCOR). The terrestrial method of performing CPR has

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

not changed significantly since it was first implemented, the locked straight-arm method with the rescuer accelerating their chest to generate the force needed to compress the victim's chest. Other aspects of the BLS guidelines often change and evolve as new evidence emerges, one example being the Chain of Survival, which has recently been updated [3]: (1) immediate recognition of cardiac arrest and activation of the emergency response system, (2) early CPR with an emphasis on chest compressions, (3) rapid defibrillation, (4) effective advanced life support and (5) integrated post-cardiac arrest care [4–6].

Changes in gravitational fields, such as those found in the microgravity of space and hypogravity of Mars or the Moon, pose several practical and logistical problems that will impact on the effectiveness of the CPR administered and affect the outcome for any patient who experiences a cardiac arrest in a space mission. In recent years, several studies have been undertaken to develop methods of basic and advanced life support (ALS) in microgravity and hypogravity, using ground-based simulations, parabolic flights or training for medical emergencies in actual space missions.

It is important firstly to understand some of the physics behind space life sciences. The gravitational force of the Earth, which produces an acceleration of approximately 9.81 m/s<sup>2</sup> at mean sea level and is indicated by the symbol 'g' (small letter), has shaped the anatomy and physiology of human beings over millions of years. The concept of human body G vectors uses an axial nomenclature system that has been the basis for studies related to acceleration physiology since its introduction [7]. The three major axes are longitudinal (Z), lateral (Y) and horizontal (X). The direction of acceleration forces along the axes is called (+) or (−), but in general the positive sign is omitted. The inertial forces are opposite to the acceleration forces, as indicated in **Figure 1**. Therefore, when considering the effects of the G force on human physiology, it is important to indicate the axis and the direction of the acceleration force along it. For example, when a volunteer is performing terrestrial CPR manoeuvres, it is said that they are under the influence of 1 Gz.

It is a common misconception that gravity does not exist in space, either aboard space ships or space stations in lower earth orbit (LEO). Typical LEO ranges from between 120 and 360 miles above the Earth, and the gravitational field at this distance is still quite strong, roughly 88% of that felt at the Earth's surface. Therefore, what is often referred to as 'zero gravity' is in fact microgravity, an important difference to note, and the objects or astronauts seen to be 'floating' in space are in reality in a constant state of free fall. This means they are actually falling around the Earth at the same rate as the orbital speed of their spacecraft, which is approximately 17,500 miles/h (28,000 km/h), providing the same effect that would be given by real microgravity [9].

The prefix micro (μ) derives from the original Greek mikros (μικρός), meaning small. A microgravity environment is one that imparts to an object a net acceleration that is extremely small compared with that produced by Earth at its surface, which can be achieved using various methods, including Earth-based drop towers, parabolic aircraft flights and Earth-orbiting laboratories. Exposure to microgravity has been shown to affect every single body system, and the resultant physiological changes can lead to undesirable health consequences [9, 10].

not changed significantly since it was first implemented, the locked straight-arm method with the rescuer accelerating their chest to generate the force needed to compress the victim's chest. Other aspects of the BLS guidelines often change and evolve as new evidence emerges, one example being the Chain of Survival, which has recently been updated [3]: (1) immediate recognition of cardiac arrest and activation of the emergency response system, (2) early CPR with an emphasis on chest compressions, (3) rapid defibrillation, (4) effective advanced life

Changes in gravitational fields, such as those found in the microgravity of space and hypogravity of Mars or the Moon, pose several practical and logistical problems that will impact on the effectiveness of the CPR administered and affect the outcome for any patient who experiences a cardiac arrest in a space mission. In recent years, several studies have been undertaken to develop methods of basic and advanced life support (ALS) in microgravity and hypogravity, using ground-based simulations, parabolic flights or training for medical emergencies in

It is important firstly to understand some of the physics behind space life sciences. The gravitational force of the Earth, which produces an acceleration of approximately 9.81 m/s<sup>2</sup>

mean sea level and is indicated by the symbol 'g' (small letter), has shaped the anatomy and physiology of human beings over millions of years. The concept of human body G vectors uses an axial nomenclature system that has been the basis for studies related to acceleration physiology since its introduction [7]. The three major axes are longitudinal (Z), lateral (Y) and horizontal (X). The direction of acceleration forces along the axes is called (+) or (−), but in general the positive sign is omitted. The inertial forces are opposite to the acceleration forces, as indicated in **Figure 1**. Therefore, when considering the effects of the G force on human physiology, it is important to indicate the axis and the direction of the acceleration force along it. For example, when a volunteer is performing terrestrial CPR manoeuvres, it is said that

It is a common misconception that gravity does not exist in space, either aboard space ships or space stations in lower earth orbit (LEO). Typical LEO ranges from between 120 and 360 miles above the Earth, and the gravitational field at this distance is still quite strong, roughly 88% of that felt at the Earth's surface. Therefore, what is often referred to as 'zero gravity' is in fact microgravity, an important difference to note, and the objects or astronauts seen to be 'floating' in space are in reality in a constant state of free fall. This means they are actually falling around the Earth at the same rate as the orbital speed of their spacecraft, which is approximately 17,500 miles/h (28,000 km/h), providing the same effect that would be given

The prefix micro (μ) derives from the original Greek mikros (μικρός), meaning small. A microgravity environment is one that imparts to an object a net acceleration that is extremely small compared with that produced by Earth at its surface, which can be achieved using various methods, including Earth-based drop towers, parabolic aircraft flights and Earth-orbiting laboratories. Exposure to microgravity has been shown to affect every single body system, and the resultant physiological changes can lead to undesirable health conse-

at

support and (5) integrated post-cardiac arrest care [4–6].

actual space missions.

116 Resuscitation Aspects

they are under the influence of 1 Gz.

by real microgravity [9].

quences [9, 10].

**Figure 1.** Standard acceleration nomenclature. Note that the arrows indicate the direction of the inertial reaction to an equal and opposite acceleration [7, 8].

The acceleration due to gravity at the surface of a planet varies directly as the mass and inversely as the square of the radius. The Moon is 384,403 km distant from the Earth, and it has a diameter of 3476 km. The acceleration due to gravity is 1.62 m/s<sup>2</sup> (1/6 of the Earth) because the Moon has less mass than the Earth. Mars and Earth have diameters of 6775 km and 12,775 km, respectively. The mass of Mars is 0.107 times that of the Earth. This makes the gravitational acceleration on Mars 3.73 m/s<sup>2</sup> , as expressed in Eq. (1):

$$\text{gm} = \ 9.8 \times 0.107 \times (12775/6775) \text{2} = \ 3.73 \text{m/s}^2 \tag{1}$$

Therefore, if a body weighs 200 N on Earth, it is possible to calculate how much it would weigh on Mars. Knowing that the weight of an object is its mass (m) times the acceleration of gravity, we can have W = m × g, 200 = 9.8 × m and m = 20.41 kg. This mass is the same on Mars, so the weight on Mars is WMars = 3.73 × 20.41 = 76.1 N and mMars = 7.61 kg.

Some of the physical principles of microgravity and hypogravity have been explained above to clarify some of the common terminology and misconceptions. Throughout this chapter, we will use the terms microgravity and hypogravity. When discussing microgravity, commonly referred to as 'weightlessness' by laypersons, we are referring to being in space either aboard a space craft or aboard a space station and not on the surface of any extraterrestrial body. When talking about hypogravity, this relates to being on the surface of another extraterrestrial body (i.e. Mars, Moon) as these surfaces do have a gravitational field; however, they are weaker than that of Earth's.

This chapter will first present the effects of a space mission on human physiology, considering in particular cardiovascular and pulmonary function and their adaptation to the hostile environment of space. It will then discuss more than a decade of research involving a series of studies examining extraterrestrial CPR during ground-based microgravity and hypogravity simulations and during parabolic flights. It will also outline the essential CPR steps, in the form of extraterrestrial CPR guidelines, to be applied for both low-orbit and deep-space missions, such as a trip to Mars. The rationale behind the creation of specific guidelines for microgravity and hypogravity BLS and CPR is based on a combination of factors that render current traditional methods inappropriate for use in the unique environment of space, a setting in which the human body must adapt to altered gravitational conditions that lead to increased physiological stress, and where the isolated nature of the environment demands greater self-reliance, all of which may hinder a successful outcome when resuscitating a patient.

### **2. The effects of microgravity on human physiology and its impact on the cardiopulmonary system**

Physiological alterations suffered by astronauts during space missions have been observed, reported and studied from the beginning of manned space flight. The microgravity of space appears to affect every single organ and body system of the astronauts, in different intensities and manner, both during short- and long-term missions. The first men to remain in space longer than 24 h were Soviet cosmonauts Titov and Nikolayev in the 1960s. Postflight data collection revealed that the cardiovascular systems of the cosmonauts presented problems in readapting to the gravity of the Earth, with both exhibiting difficulties in maintaining arterial blood pressure levels when standing [9].

During the initial phases of the American space programme, NASA astronauts from the Gemini, Apollo and Skylab missions also showed deleterious signs and symptoms related to exposure to microgravity. Although these early ventures into the space environment were shorter than the missions nowadays, with the longest being a 3-month Skylab flight, it was already evident that the effects of microgravity on the human body would be very challenging. For example, astronauts presented decreases in plasma volume (around 10–20%); red blood cells (space anaemia); bone calcium levels (bone demineralisation); skeletal muscle size and strength (muscle atrophy), especially those that support posture (anti-gravitational muscles and bones); intestinal mobility; immune responses; and sleeping hours [10–13]. Most astronauts also suffered from space motion sickness, which is a common condition, affecting around 70% of astronauts during the first 72 h of a space mission, causing nausea, vomiting, dizziness and light-headedness and consequently decreasing physical and mental performance and overall well-being [14].

Moreover, very early in the manned space flight era, it became clear that the harmful effects on human physiology and anatomy would not be restricted solely to the time spent in microgravity. Important postflight alterations were also apparent after the return of astronauts to Earth's gravity, such as neurovestibular disturbances, orthostatic intolerance and reduced aerobic capacity [15].

### **2.1. Space cardiovascular physiology**

a space craft or aboard a space station and not on the surface of any extraterrestrial body. When talking about hypogravity, this relates to being on the surface of another extraterrestrial body (i.e. Mars, Moon) as these surfaces do have a gravitational field; however, they are

This chapter will first present the effects of a space mission on human physiology, considering in particular cardiovascular and pulmonary function and their adaptation to the hostile environment of space. It will then discuss more than a decade of research involving a series of studies examining extraterrestrial CPR during ground-based microgravity and hypogravity simulations and during parabolic flights. It will also outline the essential CPR steps, in the form of extraterrestrial CPR guidelines, to be applied for both low-orbit and deep-space missions, such as a trip to Mars. The rationale behind the creation of specific guidelines for microgravity and hypogravity BLS and CPR is based on a combination of factors that render current traditional methods inappropriate for use in the unique environment of space, a setting in which the human body must adapt to altered gravitational conditions that lead to increased physiological stress, and where the isolated nature of the environment demands greater self-reliance, all of which may hinder a successful outcome

**2. The effects of microgravity on human physiology and its impact on** 

Physiological alterations suffered by astronauts during space missions have been observed, reported and studied from the beginning of manned space flight. The microgravity of space appears to affect every single organ and body system of the astronauts, in different intensities and manner, both during short- and long-term missions. The first men to remain in space longer than 24 h were Soviet cosmonauts Titov and Nikolayev in the 1960s. Postflight data collection revealed that the cardiovascular systems of the cosmonauts presented problems in readapting to the gravity of the Earth, with both exhibiting difficulties in maintaining arterial

During the initial phases of the American space programme, NASA astronauts from the Gemini, Apollo and Skylab missions also showed deleterious signs and symptoms related to exposure to microgravity. Although these early ventures into the space environment were shorter than the missions nowadays, with the longest being a 3-month Skylab flight, it was already evident that the effects of microgravity on the human body would be very challenging. For example, astronauts presented decreases in plasma volume (around 10–20%); red blood cells (space anaemia); bone calcium levels (bone demineralisation); skeletal muscle size and strength (muscle atrophy), especially those that support posture (anti-gravitational muscles and bones); intestinal mobility; immune responses; and sleeping hours [10–13]. Most astronauts also suffered from space motion sickness, which is a common condition, affecting around 70% of astronauts during the first 72 h of a space mission, causing nausea, vomiting, dizziness and light-headedness and consequently decreasing physical and mental perfor-

weaker than that of Earth's.

118 Resuscitation Aspects

when resuscitating a patient.

**the cardiopulmonary system**

blood pressure levels when standing [9].

mance and overall well-being [14].

A progressive shift of body fluids and blood from the lower extremities to the upper body occurs in the absence of Earth's gravitational force [16, 17]. Initially, this upward shift increases the central fluid volume, cardiac size (around 20%) and cardiac output. It then leads to a negative fluid balance and reduction of 12–20% in the circulating blood volume [17], which causes a decreased resting stroke volume of 10–20% and a reduced cardiac output with an average of 1.5 L min−1 lower than preflight values [18, 19]. These changes are secondary to the reduction in circulating blood volume [20].

This condition has been nicknamed the 'puffy-face and bird-legs syndrome', as the face of the astronaut becomes rounded, redder and more swollen, while the legs become thinner, due to the redistribution of fluids and blood from the lower to upper body. The situation is reversed when the astronaut is once more subject to the gravitational force of the Earth, which distributes the fluid and blood back to its original position [16, 21]. These stages of cardiovascular adaption to microgravity and subsequent readaptation upon return to Earth are represented in **Figure 2**.

Arterial blood pressure and heart rate are more difficult to evaluate during a space mission. While some studies have demonstrated that microgravity can decrease both arterial blood pressure and heart rate [20, 22], others have shown that heart rate, for example, remains unchanged in microgravity [23]. Research is reporting average decrease of 15 bpmin flight resting heart rate and an average decrease of 6 mmHg in mean arterial pressure. These cardiovascular changes were observed when compared with preflight standing values and not supine [22]. In addition, the arterial blood pressure reduction occurred in diastolic values, while systolic blood pressure remained unchanged from that of preflight.

More recently, visual impairment intracranial pressure (VIIP) syndrome has been identified as a health issue occurring in astronauts who have stayed in microgravity for at least 6 months. This syndrome was first reported in 2005, when a refractive change in visual acuity (mainly hyperopia) was detected after a long-term space mission. This finding was further confirmed through evaluations conducted by means of a series of questionnaires applied to astronauts who took part in long space flight missions on the ISS [24]. Very little is known regarding the risk factors and pathophysiological mechanisms involved in space VIIP syndrome. The current consensus within the space flight community is that visual changes and eye alterations (papilloedema, posterior globe flattening, hyperopic shift, choroidal folds) are a consequence of raised intracranial pressures resulting in optic nerve sheath distension. This increase in optic nerve sheath diameter can readily be measured using a simple, non-invasive and low-cost ophthalmic procedure, resulting in an easy way to diagnose this medical condition [25]. However, other factors, such as increased levels of carbon dioxide in the spacecraft, genetic predisposition and ocular and/or brain structural changes secondary to microgravity could also be involved in the aetiology of this syndrome.

**Figure 2.** Schematic view of the blood and fluid distribution on Earth (1), after insertion into microgravity (2), during space adaptation (3) and upon return to Earth (4). Note that the puffy-face and bird-legs syndrome occurs in numbers 2 and 3 [16, 21].

Although no serious cardiac events in space have required resuscitation to date, the overall risk of potential cardiac deconditioning developing into a life-threatening illness is approximately 1% per year [26, 27]. Despite this low figure, some documented cases of astronauts presenting disturbances in cardiac rhythm have been observed, such as ventricular tachycardia and prolonged QTc interval after short- and long-duration flights. However, there is little compelling evidence from flight data that space causes cardiac dysfunction or life-threatening dysrhythmias [28, 29]. Ventricular arrhythmias were also reported during the second month aboard the MIR space station [30], and a loss of left ventricular mass was seen during the exposure to microgravity [31]. These factors combined could pose extra stress to the cardiovascular system and, in a worst-case scenario, lead to cardiac arrest [32].

### **2.2. Space respiratory physiology**

Although no serious cardiac events in space have required resuscitation to date, the overall risk of potential cardiac deconditioning developing into a life-threatening illness is approximately 1% per year [26, 27]. Despite this low figure, some documented cases of astronauts presenting disturbances in cardiac rhythm have been observed, such as ventricular tachycardia and prolonged QTc interval after short- and long-duration flights. However, there is little compelling evidence from flight data that space causes cardiac dysfunction or life-threatening dysrhythmias [28, 29]. Ventricular arrhythmias were also reported during the second month aboard the MIR space station [30], and a loss of left ventricular mass was seen during the exposure to microgravity [31]. These factors combined could pose extra stress to the cardiovascular system and, in a worst-case scenario, lead to

**Figure 2.** Schematic view of the blood and fluid distribution on Earth (1), after insertion into microgravity (2), during space adaptation (3) and upon return to Earth (4). Note that the puffy-face and bird-legs syndrome occurs in numbers

cardiac arrest [32].

2 and 3 [16, 21].

120 Resuscitation Aspects

Short- and long-term exposure to microgravity produces several effects on lung volumes, capacities and function, which have been assessed during space missions and parabolic flights, as well as in ground-based studies.

Evidence has shown that there is a 4 mm increase in the anteroposterior (AP) dimension of the chest wall at the level of the fifth intercostal space during microgravity exposure. This expansion can be explained by a decrease in weight of the abdominal wall, which allows the sternum to move in a cranial direction. As well as expanding the ribcage, this induces subsequent relaxation of parasternal intercostal muscles, further increasing the AP distance [33]. The effect of microgravity on chest anatomy was also observed during parabolic flights, whereby a displacement of the sternum in the cranial direction was found in microgravity, accompanied by an increase in diameter of the lower rib cage. This change in position of the chest wall was predicted to cause the volume-pressure curve to lie between the standingupright and the supine-position curves, with the net result of a reduction in lung volumes. In five subjects studied in a KC-135 aircraft during parabolic flight, functional residual capacity decreased by 432 ml during exposure to the acute microgravity phase. Vital capacity also reduced from a mean value of 4.72 L at 1 G to 4.35 L at 0 G. Forced vital capacity and forced expiratory volume in 1 s were also decreased by an average of 2.5% in the 20 s of microgravity per parabola in a parabolic flight [34].

During the 9-day-long Space Life Sciences-1 space mission, forced vital capacity and forced expiratory volume in 1s were significantly reduced on flight day 2 due to the effect of sustained microgravity but were greater than preflight values at day 9. In comparison with standing preflight values, tidal volume was decreased by 15% (110 ml) in microgravity, and this reduction remained during the entire space flight. Functional residual capacity and expiratory reserve volume decreased significantly in-flight by 520 and 370 ml, respectively, when compared with preflight standing values. Residual volume was less during flight by 350 ml, when compared with standing control values. This 20% reduction in the residual volume was unexpected as it is normally fairly resistant to change. It is believed that lung volumes are affected by the changes in intrathoracic blood volume that occurs throughout a mission and by the alterations in respiratory mechanics and cranial displacement of the diaphragm and abdominal content that happens in the absence of gravity [35].

The gravitational gradient affects the distribution of ventilation and perfusion in the upright human lung. This uneven distribution of ventilation and blood flow within the lungs leads to variations in ventilation-perfusion ratios. Cardiogenic oscillations of CO<sup>2</sup> decreased to approximately 60% in amplitude in microgravity [36], and there was also a significant reduction in cardiogenic oscillations of nitrogen (to 44%) and argon (to 24%) in comparison to preflight standing values [37]. Possible causes of the residual inhomogeneity of ventilation include regional differences in lung compliance, airway resistance and the motion of the chest wall and diaphragm. Microgravity was expected to completely abolish apicobasal differences in perfusion, and its persistence is possibly related to other mechanisms not affected by gravity, such as central-peripheral differences in blood flow and interregional differences in conductance.

The diffusion capacity of the lung has been shown to increase by 62% in a parabolic flight study and by 28% in sustained microgravity when values were compared with preflight standing values [36, 38]. The standing-to-supine transition pre- and postflight caused a significant elevation in blood volume in pulmonary capillaries. Diffusing capacity of the membrane was unchanged preflight in the standing-to-supine transition and significantly elevated in-flight in comparison to standing (27%) and supine (21%). In microgravity, the capillary filling is uniform, which is associated with a large increase in the surface area of the blood-gas barrier. Consequently, the membrane-diffusing capacity is substantially raised. This suggests an absence of subclinical interstitial pulmonary oedema in microgravity, as had been previously speculated [38, 39].

The overall effect of acute and sustained exposure to microgravity, although affecting the respiratory system, does not cause any deleterious effects to gas exchange in the lungs. However, there is no current suitable method of accessing arterial blood in space. Consequently, at present, values for blood-gas tensions are usually derived from measurements of respiratory gas partial pressures. To this end, the earlobe arterialised blood technique for collecting blood-gas tensions has been considered for use in space [40]. Access to arterial blood analysis would allow better physiological evaluations and the management of clinical emergencies during space missions, resulting in increased safety for crewmembers.

### **3. Current cardiopulmonary resuscitation (CPR) practice in microgravity and hypogravity and its simulations on Earth**

Although the likelihood of a dangerous cardiac event occurring in a space mission at present is rare, the possibility exists. The selection process for space missions nowadays considers individuals at ages and with health standards that would have precluded their selection in the past. With increased age, less stringent health requirements, longer duration missions and increased physical labour, due to a rise in orbital extravehicular activity, the risk of an acute life-threatening condition occurring in space has become of greater concern. The advent of space tourism may even enhance this possibility, with its popularity set to rise over the coming years as private companies test their new technology. Therefore, space scientists and physicians will have a greater responsibility to ensure space travellers, whether professional astronauts or space tourists, are adequately trained and familiarised with extraterrestrial BLS and CPR methods.

It is currently estimated that the time between the occurrence of cardiac arrest and the performance of ALS on a secured patient during a space mission ranges between 2 and 4 min [41]. However, BLS guidelines highlight that failure of the circulation for 3 min will lead to cerebral damage and that delay, even within this time frame, will lessen the chances of a successful outcome. Therefore, the rate of decline of a patient who has suffered cardiac arrest is dependent, amongst other things, upon the immediate initiation of CPR and the provision and adequacy of such prior to the return of spontaneous circulation, should this be achieved [3].

### **3.1. Extraterrestrial CPR simulations**

The diffusion capacity of the lung has been shown to increase by 62% in a parabolic flight study and by 28% in sustained microgravity when values were compared with preflight standing values [36, 38]. The standing-to-supine transition pre- and postflight caused a significant elevation in blood volume in pulmonary capillaries. Diffusing capacity of the membrane was unchanged preflight in the standing-to-supine transition and significantly elevated in-flight in comparison to standing (27%) and supine (21%). In microgravity, the capillary filling is uniform, which is associated with a large increase in the surface area of the blood-gas barrier. Consequently, the membrane-diffusing capacity is substantially raised. This suggests an absence of subclinical interstitial pulmonary oedema in microgravity, as had been previ-

The overall effect of acute and sustained exposure to microgravity, although affecting the respiratory system, does not cause any deleterious effects to gas exchange in the lungs. However, there is no current suitable method of accessing arterial blood in space. Consequently, at present, values for blood-gas tensions are usually derived from measurements of respiratory gas partial pressures. To this end, the earlobe arterialised blood technique for collecting blood-gas tensions has been considered for use in space [40]. Access to arterial blood analysis would allow better physiological evaluations and the management of clinical emergencies during

**3. Current cardiopulmonary resuscitation (CPR) practice in microgravity** 

Although the likelihood of a dangerous cardiac event occurring in a space mission at present is rare, the possibility exists. The selection process for space missions nowadays considers individuals at ages and with health standards that would have precluded their selection in the past. With increased age, less stringent health requirements, longer duration missions and increased physical labour, due to a rise in orbital extravehicular activity, the risk of an acute life-threatening condition occurring in space has become of greater concern. The advent of space tourism may even enhance this possibility, with its popularity set to rise over the coming years as private companies test their new technology. Therefore, space scientists and physicians will have a greater responsibility to ensure space travellers, whether professional astronauts or space tourists, are adequately trained and familiarised with extraterrestrial BLS

It is currently estimated that the time between the occurrence of cardiac arrest and the performance of ALS on a secured patient during a space mission ranges between 2 and 4 min [41]. However, BLS guidelines highlight that failure of the circulation for 3 min will lead to cerebral damage and that delay, even within this time frame, will lessen the chances of a successful outcome. Therefore, the rate of decline of a patient who has suffered cardiac arrest is dependent, amongst other things, upon the immediate initiation of CPR and the provision and adequacy of such prior to the return of spontaneous circulation, should this

space missions, resulting in increased safety for crewmembers.

**and hypogravity and its simulations on Earth**

ously speculated [38, 39].

122 Resuscitation Aspects

and CPR methods.

be achieved [3].

The main difference in CPR in hypogravity and microgravity compared to terrestrial CPR is the strength of the gravitational field. In microgravity, patient and rescuer are both essentially weightless. When thinking about the technique of terrestrial CPR, with the rescuer accelerating their chest and upper body to generate a force to compress the patient's chest, it is obvious that this cannot work in microgravity without significant aids. To this end, several microgravity CPR techniques have been developed and tested in parabolic flights [4, 42, 43] and during ground simulations, such as when using a body suspension device system, to test their efficacy [5, 44, 45].

### *3.1.1. Body suspension device system*

Many partial-gravity suspension systems have been designed and used since the Apollo program. The cable suspension method typically uses vertical cables to suspend the major segments of the body and relieve some of the weight exerted by the subject on the ground, thus simulating partial gravity. A body suspension device (BSD) system used to simulate both hypogravity and microgravity was developed by the Aerospace Engineering Laboratory, MicroG Centre, PUCRS, Porto Alegre, Brazil. It consists of carbon steel bars, 0.6 mm × 0.3 mm in thickness, which are shaped into a prism frame. It has a height of 2000 mm, with a base of 3000 mm × 2260 mm [46].

This BSD has been used to simulate microgravity by fully suspending a volunteer and CPR mannequin. A steel cross bar (1205 mm × 27.5 mm) was hung using reinforced steel wiring that gave it the ability to withstand up to 600 kg. A static nylon rope was attached to the steel wiring of the cross bar, with carabineers fastened at each end, which were clipped to the corresponding hip attachments of the body harness worn by the volunteer. A safety carabineer was also attached to the volunteer's back. **Figure 3(A)** and **(B)** illustrates how CPR methods can be studied during microgravity simulations on Earth [5].

**Figure 3.** (a) The body suspension device system of the MicroG Centre, with the volunteer perpendicular and the CPR mannequin parallel to the floor, both being fully suspended, simulating microgravity. (b) The body suspension device system of the MicroG Centre, with both the fully suspended volunteer and CPR mannequin parallel to the floor, simulating microgravity.

Another way to simulate microgravity for the performance of CPR is placing the mannequin in the vertical position supported by a wall, which avoids the use of the rescuer body weight during the external chest compressions, as represented in **Figure 4**.

The BSD comprises of a body harness and counterweight system made of 20 bars of 5 kg each. Counterweights were used to simulate hypogravity by partially offsetting the effects of the +1 Gz environment in order to simulate Mars (0.35 Gz) or the Moon (0.16 Gz) gravities. Reinforced steel wire was used in a pulley system that connects the weights at the end of the body suspension device to the volunteer. A carabineer connects the steel wire to the attachment point on the back of the body harness (Fesp P100PGP). The manikin was positioned on the floor during the hypogravity simulation and +1 Gz [6, 46, 47]. **Figure 5** presents a schematic view of CPR being performed during ground-based hypogravity simulation.

The amount of counterweight used to simulate the hypogravity conditions, such as Mars or the Moon, was calculated for each volunteer based on their body weight, as presented in Eqs. (2) and (3) [46].

$$\text{RM} = \langle 0.6 \text{BM} \times \text{SCF} \rangle / 1 \text{G} \tag{2}$$

$$\text{CW} = \text{0.6BM} - \text{RM} \tag{3}$$

Using Eq. (2), the relative mass of a subject in a simulated gravitational field can be calculated, where RM = relative mass (kg), BM = body mass on Earth (kg), SGF = simulated gravitational force (m/s<sup>2</sup> ) and 1G = 9.81 m/s<sup>2</sup> . Eq. (3) gives the counterweight (CW, in kg) necessary to simulate body mass at a preset hypogravity level. The 0.6 refers to the 60% of the weight of the upper body, as the legs are supported on the floor.

**Figure 4.** Microgravity simulation for CPR performance with the mannequin supported by a wall, in the vertical position, perpendicular to the floor. The volunteer is performing external chest compressions by flexing and extending his legs and therefore moving his body back and forth on top of a wheeled trolley.

**Figure 5.** The body suspension device system of the MicroG Centre, with the CPR mannequin on the floor and volunteer assuming the terrestrial CPR position, being partially suspended through the counterweight system, simulating hypogravity.

For these ground-based hypogravity simulation studies, a standard CPR manikin (Resusci Anne Skill Reporter, Laerdal Medical Ltd., Orpington, UK) was modified to include a linear displacement transducer capable of measuring external chest compression (ECC) depth and rate. The steel spring located in the mannequin's chest depressed 1 mm with every 1 kg of weight applied to it. A real-time feedback of each ECC was provided to the volunteers via a modified electronic guiding system with an LED display. The LED display consisted of a series of coloured lights that indicated depth in mm of ECCs (red and yellow, too shallow; green, ideal). An ECC rate of 100–110 compressions/min−1 was established using an audio metronome. A 6 s interval between each ECC set represented the time taken for two mouthto-mouth ventilations. Although not true to real life, by adding in these aids, it allowed standardisation of the volunteers as their experience and training in CPR varied.

### *3.1.2. Parabolic flights*

Another way to simulate microgravity for the performance of CPR is placing the mannequin in the vertical position supported by a wall, which avoids the use of the rescuer body weight

The BSD comprises of a body harness and counterweight system made of 20 bars of 5 kg each. Counterweights were used to simulate hypogravity by partially offsetting the effects of the +1 Gz environment in order to simulate Mars (0.35 Gz) or the Moon (0.16 Gz) gravities. Reinforced steel wire was used in a pulley system that connects the weights at the end of the body suspension device to the volunteer. A carabineer connects the steel wire to the attachment point on the back of the body harness (Fesp P100PGP). The manikin was positioned on the floor during the hypogravity simulation and +1 Gz [6, 46, 47]. **Figure 5** presents a sche-

The amount of counterweight used to simulate the hypogravity conditions, such as Mars or the Moon, was calculated for each volunteer based on their body weight, as presented in Eqs.

RM = (0.6BM × SGF) / 1G (2)

CW = 0.6BM − RM (3)

Using Eq. (2), the relative mass of a subject in a simulated gravitational field can be calculated, where RM = relative mass (kg), BM = body mass on Earth (kg), SGF = simulated gravitational

late body mass at a preset hypogravity level. The 0.6 refers to the 60% of the weight of the

**Figure 4.** Microgravity simulation for CPR performance with the mannequin supported by a wall, in the vertical position, perpendicular to the floor. The volunteer is performing external chest compressions by flexing and extending his legs

. Eq. (3) gives the counterweight (CW, in kg) necessary to simu-

matic view of CPR being performed during ground-based hypogravity simulation.

during the external chest compressions, as represented in **Figure 4**.

(2) and (3) [46].

124 Resuscitation Aspects

force (m/s<sup>2</sup>

) and 1G = 9.81 m/s<sup>2</sup>

upper body, as the legs are supported on the floor.

and therefore moving his body back and forth on top of a wheeled trolley.

Reduced gravity can be achieved with a number of technologies, each depending upon the act of free fall, such as drop towers, small rockets and parabolic flights. The latter is the only way to allow human subjects to be studied under conditions of microgravity or hypogravity. Therefore, many physiological and operational studies have been conducted by space agencies around the world in parabolic flights.

In parabolic flights, adapted airplanes execute a series of manoeuvres (parabolas), each providing around 20 s of reduced gravity (hypogravity) or weightlessness (microgravity), during which experiments can be performed and data collected. A typical NASA parabolic flight lasts 3 h and carries experiments and crewmembers. It climbs from an altitude of 7 km above sea level at a 45° (pull up) angle, traces a parabola (pushover) and then descends at 45° (pull out). Microgravity by means of free fall is experienced during the pushover phase. In the pull-up and pull-out segments, crew and experiments are subjected to hypergravity that ranges between 2 and 2.5 Gz [9].

**Figure 6.** ESA parabolic flight profile, in which each parabola provides 20 s of microgravity that is preceded and succeeded by 20 s of hypergravity.

During a European Space Agency (ESA) campaign, there are typically 3 days of flights with 31 parabolas per flight. For each parabola, there are also two periods of increased gravity (approximately 1.8 Gz), which last for 20 s immediately before and after the 20 s of reduced gravity, as shown in **Figure 6**.

### **4. Extraterrestrial CPR methods**

Some of the challenges faced in this unique environment have already been presented, including the practical, logistical and physical. The physiological changes and increased physical demands that occur in an extraterrestrial environment make the performance of CPR already difficult, but add to this, the limited storage and parameters found on any spacecraft or orbiting station, such as the ISS, and the task become all the more daunting, especially if ill prepared. To this end, several methods of CPR have been developed to bridge the gap between the time of occurrence of a cardiac arrest and the time when further resuscitation equipment can be available. These methods focus in particular on the ability of a single person to apply CPR, in particular the Evetts-Russomano (ER), reverse bear hug (RBH) and handstand (HS) CPR methods.

The rationale for the development of these single-person methods is that in microgravity, whether in a spacecraft or space station, all equipment is stored away as cabin space is limited and equipment floating freely is hazardous. Thus, the time to elapse between a fellow crewmember recognising the need for retrieval and deployment of life support equipment could range anywhere from 2 to 4 min [41]. This time period is obviously a critical window that will affect patient survival, and therefore, to maximise the chances of a successful outcome, a single-person method of microgravity CPR is needed so chest compressions can begin while advanced life support equipment is retrieved.

Evidence regarding the applicability and suitability of the three single-person rescuer methods discussed in the next section is scarce and varies for several reasons. Parabolic flights have been used to research these methods [4, 42, 43], and although these flights provide an excellent microgravity analogue, the short periods of actual microgravity provided mean the data collected and the conclusions drawn from the results have limitations. The majority of the scientific data comes from ground-based analogues, wherein these unique CPR methods can be studied over longer periods of time. Nonetheless, it is difficult with these analogues to fully reproduce the microgravity environment and physiological changes usually seen in microgravity. As with all analogues, they are good but never a perfect replication of the actual environment.

### **4.1. Evetts-Russomano CPR method**

During a European Space Agency (ESA) campaign, there are typically 3 days of flights with 31 parabolas per flight. For each parabola, there are also two periods of increased gravity (approximately 1.8 Gz), which last for 20 s immediately before and after the 20 s of reduced

**Figure 6.** ESA parabolic flight profile, in which each parabola provides 20 s of microgravity that is preceded and

Some of the challenges faced in this unique environment have already been presented, including the practical, logistical and physical. The physiological changes and increased physical demands that occur in an extraterrestrial environment make the performance of CPR already difficult, but add to this, the limited storage and parameters found on any spacecraft or orbiting station, such as the ISS, and the task become all the more daunting, especially if ill prepared. To this end, several methods of CPR have been developed to bridge the gap between the time of occurrence of a cardiac arrest and the time when further resuscitation equipment can be available. These methods focus in particular on the ability of a single person to apply CPR, in particular the Evetts-Russomano (ER), reverse bear hug (RBH) and handstand (HS) CPR methods. The rationale for the development of these single-person methods is that in microgravity, whether in a spacecraft or space station, all equipment is stored away as cabin space is limited and equipment floating freely is hazardous. Thus, the time to elapse between a fellow crewmember recognising the need for retrieval and deployment of life support equipment could range anywhere from 2 to 4 min [41]. This time period is obviously a critical window that will affect patient survival, and therefore, to maximise the chances of a successful outcome, a single-person method of microgravity CPR is needed so chest compressions can begin while

gravity, as shown in **Figure 6**.

succeeded by 20 s of hypergravity.

126 Resuscitation Aspects

**4. Extraterrestrial CPR methods**

advanced life support equipment is retrieved.

The ER technique is the newest of the three methods to be discussed and perhaps the most technically difficult, potentially requiring more training of the individual than other methods to ensure its proficient application. The rescuer places their left leg over the right shoulder of the patient and their right leg around the patient's torso, allowing their ankles to be crossed approximately in the centre of the patient's back; this is to provide stability and a solid platform against which to deliver force, without the patient being pushed away (**Figure 7(A)**). From this position, chest compressions can be performed while still retaining easy access to perform ventilation. When adopting the ER method, the rescuer must be situated in a manner that also allows sufficient space on the patient's chest for the correct positioning of their hands to deliver the chest compressions.

It is important to note that the rescuer simply wrapping their legs around the patient's waist is not an adequate position; this will not provide a firm enough base, and the chest compressions applied will extend the patient's back and reduce the actual depth of the compressions.

The advantage of the ER position over other methods is that by being face-to-face with the patient, single-person ventilation is easier. Initial parabolic flight and ground-based simulation data showed the ER method as delivering an adequate rate and depth of chest compressions, although this was according to the 2005 resuscitation guidelines [5, 42]. More recent data from ground-based simulations, using the updated 2010 guidelines, demonstrated that rescuers using the ER method fell slightly below par in terms of depth of compression but were able to maintain an adequate rate [45, 47].

A disadvantage of the ER method lies in its being technically more difficult and potentially requiring the most amount of training in order to be effective. In addition, the ER method is fatiguing after 2 min of chest compressions following the current guidelines, being considered more tiring than the HS method, although less so than the RBH technique. It has been found that rescuer fatigue leads to a failure to decompress the chest completely. This is a common problem across all three methods as fatigue takes effect, but it is more pronounced with the ER method, and this may be in part due to the positioning of the rescuer [48].

Although there is no statistical data to support the idea, it has been observed and surmised by researchers that height and anthropometric measurements may not be a predetermining factor for successful chest compressions using the ER method. This signifies that a rescuer

**Figure 7.** Three single-person microgravity CPR methods in ground-based microgravity simulations at the MicroG Centre and in parabolic flights: (A) Evetts-Russomano, (B) reverse bear hug and (C) handstand.

with short legs who may not be able to cross their ankles behind the patient's back may still be capable of performing CPR to an adequate standard using the ER method [5].

### **4.2. Reverse bear hug CPR method**

The RBH method is possibly the simplest of the three single-person methods presented and is essentially similar to the Heimlich manoeuvre. The rescuer needs no additional equipment or to be wary of their surroundings as the RBH method is independent of capsule parameters.

The rescuer takes up position behind the patient to easily wrap their arms around the patient and lock their hands across the patient's chest. Arm flexion is primarily used to produce the force needed for chest compressions. The rescuer can use their legs to stabilise both themselves and the patient (**Figure 7(B)**).

The advantage of the RBH method lies in its simplicity to learn and apply. The rescuer can easily assume a position behind the patient, find the correct spot on the patient's chest and begin chest compressions. Parabolic flight data has shown the RBH method to be an effective method of CPR in simulated microgravity [4]. However, when assessed during a groundbased analogue over a prolonged period of time, such as 2 min, the RBH fell dramatically short of the current resuscitation guidelines [45]. Despite the relative simplicity of the method, ground-based studies suggest that it is an ineffective and inefficient method when performed over time. CPR using the RBH was seen to initially provide an adequate depth and rate of chest compression, in accordance with the most recent guidelines. Nonetheless, as early as the second cycle of chest compressions, rescuers rapidly tired—resulting in a decline in the depth of chest compressions and overall drop in the quality of CPR [44, 45]. Logistically, this method also presents a problem in ventilating as the rescuer is positioned to the rear of the patient. Assuming the rescuer is alone, they would need to rotate the patient so they are face to face in order to provide ventilations, before rotating the patient back again in order to continue compressions. This manoeuvring would delay the resumption of chest compressions and ultimately affect the quality of the CPR applied.

### **4.3. The handstand CPR method**

with short legs who may not be able to cross their ankles behind the patient's back may still

**Figure 7.** Three single-person microgravity CPR methods in ground-based microgravity simulations at the MicroG

The RBH method is possibly the simplest of the three single-person methods presented and is essentially similar to the Heimlich manoeuvre. The rescuer needs no additional equipment or to be wary of their surroundings as the RBH method is independent of capsule parameters.

be capable of performing CPR to an adequate standard using the ER method [5].

Centre and in parabolic flights: (A) Evetts-Russomano, (B) reverse bear hug and (C) handstand.

**4.2. Reverse bear hug CPR method**

128 Resuscitation Aspects

Performance of the HS method also requires no equipment, but the patient does need to be placed against the inner side of the capsule or spacecraft in which they are located. Importantly, this must be a solid surface that is capable of withstanding the force and vibration generated by the application of the CPR. Once a suitable site to position the patient has been identified, the rescuer must then place their feet on the surface opposite to the patient, having their arms stretched out above their head, as demonstrated in **Figure 7(C)**.

From this position, the rescuer can flex/extend their hips while keeping their arms straight and locked on the patient's chest in the traditional spot, to generate the force needed for chest compressions. Parabolic flights [4] and ground-based simulations [45] have found the HS method to be the least fatiguing of the three single-person CPR methods, with rescuers able to provide an adequate depth and rate of chest compressions, in accordance with the latest guidelines [4, 44, 45].

The major limiting factor of this technique is its reliance on the physical parameters of the vessel itself. The HS method is dependent on a capsule that is between a range of diameters in order to have sufficient space for the patient and rescuer, as well as enough distance between the two to allow sufficient hip and knee movement in order to generate enough force for chest compressions. Furthermore, the height of the rescuer is crucial with this method; a shorter rescuer may not be able to achieve good placement of the feet on the surface opposite to the patient, thereby being unable to generate enough force and resulting in inadequate chest compressions.

### **4.4. Restrained CPR method: standard position**

The restrained CPR method using the standard position is identical to that of terrestrial CPR but requires the use of equipment to restrain both the rescuer and the patient to prevent both from floating away from each other after the delivery of force. The restraint system currently used aboard the ISS is known as the crew medical restraint system (CMRS). The patient rests on the CMRS, which is used to strap the patient into a supine position. The standard technique, as the name suggests, is the same conventional CPR technique used on Earth. The difference lies in the rescuer having straps around their waist and a restraint cord across their lower legs (**Figure 8**). Researchers conducted in parabolic flights have shown this method to require a great deal of effort on the part of the rescuer, as they must counteract the force of the chest compressions. Thus, this method was seen to fatigue the rescuer quickly, even more so than the single-person HS method [4, 43].

### **4.5. Restrained CPR method: straddling position**

In the straddling manoeuvre, the rescuer performs chest compressions by kneeling across the patient's waist but uses the same retraining equipment as with the standard technique. The delivery of the chest compressions is the same as that of terrestrial CPR, in that arms are kept straight and placed on the chest. The advantage of this position over the standard technique is that it requires less space. The standard position requires an area large enough for both the CMRS and rescuer to fit side by side, whereas the rescuer is positioned above the patient in the straddling technique, thereby reducing the total space in use. This could be an important factor to consider, given the limited dimensions of a spacecraft or the ISS. Despite the familiarity and

**Figure 8.** Crew medical restraint system (CMRS) being tested in a parabolic flight (A) and at the international space station (B) [43].

relative ease of use of these techniques, parabolic flight data has indicated that CPR performed using both restraint methods fall below current AHA guidelines, suggesting they may not be the most appropriate method to use in the event of a cardiac arrest scenario on board [43].

### **4.6. Hypogravity CPR methods**

**4.4. Restrained CPR method: standard position**

130 Resuscitation Aspects

**4.5. Restrained CPR method: straddling position**

station (B) [43].

The restrained CPR method using the standard position is identical to that of terrestrial CPR but requires the use of equipment to restrain both the rescuer and the patient to prevent both from floating away from each other after the delivery of force. The restraint system currently used aboard the ISS is known as the crew medical restraint system (CMRS). The patient rests on the CMRS, which is used to strap the patient into a supine position. The standard technique, as the name suggests, is the same conventional CPR technique used on Earth. The difference lies in the rescuer having straps around their waist and a restraint cord across their lower legs (**Figure 8**). Researchers conducted in parabolic flights have shown this method to require a great deal of effort on the part of the rescuer, as they must counteract the force of the chest compressions. Thus, this method was

seen to fatigue the rescuer quickly, even more so than the single-person HS method [4, 43].

In the straddling manoeuvre, the rescuer performs chest compressions by kneeling across the patient's waist but uses the same retraining equipment as with the standard technique. The delivery of the chest compressions is the same as that of terrestrial CPR, in that arms are kept straight and placed on the chest. The advantage of this position over the standard technique is that it requires less space. The standard position requires an area large enough for both the CMRS and rescuer to fit side by side, whereas the rescuer is positioned above the patient in the straddling technique, thereby reducing the total space in use. This could be an important factor to consider, given the limited dimensions of a spacecraft or the ISS. Despite the familiarity and

**Figure 8.** Crew medical restraint system (CMRS) being tested in a parabolic flight (A) and at the international space

### *4.6.1. Terrestrial-style hypogravity CPR*

In hypogravity, sufficient gravitational field is present on most celestial bodies that humans could encounter (Moon or Mars), meaning that CPR could begin without any adjuncts or equipment. Unlike the conditions for administering CPR in microgravity, the presence of at least some gravity in these environments makes CPR feasible with traditional terrestrial CPR. However, the technique of CPR may need adjustment to counter the negative impact of the reduced gravitational field. Traditional CPR instruction advises the use of straight, rigid arms placed on the patient's chest to perform compressions. However, a reduction in the upper body weight of the rescuer due to a reduced gravitational field will lead to a decreased ability to generate force through acceleration of the upper body and the subsequent transfer of that force through the straight arms. Research has shown that a natural tendency to adapt takes place, seeking to generate more force by flexing/extending the upper limbs in order to augment acceleration of the upper body [46]. In instances where traditional CPR in hypogravity is not sufficient to generate enough force to achieve the necessary depth of chest compressions, rescuers are encouraged to have a combined technique of accelerating their upper body and extending their upper limbs to generate enough force to compress the chest to 50–60 mm [45, 47].

### *4.6.2. The seated arm-lock (SeAL) method*

The seated arm-lock (SeAL) method is a new concept but has many similarities to the traditional CPR technique used for hypogravity [49]. It was devised as a means of combatting the potential negative issues caused by performing CPR in hypogravity. The SeAL method involves the rescuer straddling the patient, with the patient's arms being locked in behind the rescuers' knees. The rescuers knees should be positioned in the shoulder area of the patient and their toes by the patient's hips (**Figure 9**). When used in a low-gravitational-field environment, the position prevents the rescuer from being pushed away from the patient by using the arms as a secure and comfortable pivot point. No residual tone is required in the patient's arms.

A small preliminary study found that rescuers were able to produce adequate depth of chest compression across a range of gravity conditions, Earth (1 Gz), Moon (0.38 Gz) and Mars (0.16 Gz). Additionally, the authors suggest that the SeAL method will allow the rescuer to be better secured to the patient and therefore prevent the two from being pushed apart from each other [49]. A preliminary study has recently been conducted at the MicroG-PUCRS, Brazil, testing a variation of this technique, called the Mackaill-Russomano hypoG CPR method. This adaptation of the SeAL technique sees the rescuer straddling the mannequin (CPR victim) and using their legs to embrace the legs of the dummy to act as an anchor. The weight of the mannequin legs were calculated and adapted to be in accordance with the gravitational force of the hypoG environment being simulated.

**Figure 9.** The seat arm-lock method in simulated hypogravity at the European Astronaut Centre.

### **5. Summary of ground-based space analogue studies**

### **5.1. Microgravity CPR studies**

Research into extraterrestrial CPR, particularly CPR in microgravity, has been ongoing for more than a decade. Several parabolic flight campaigns [4, 42, 43] have investigated the feasibility of the main CPR methods. As previously mentioned, although parabolic flights provide an excellent analogue of microgravity, their short duration (about 20 s per parabola) limits the amount of data that can be collected and interpreted. Accordingly, most of the available evidence investigating the different CPR methods has come from ground-based simulation studies, using such devices as the BSD. Although still with limitations, ground-based simulation studies do provide additional insight into the effectiveness and feasibility of microgravity CPR methods, particularly over prolonged time periods. Resuscitation guidelines are in general updated every 5 years, with adaptations made based on current evidence. This requires that CPR research in simulated extraterrestrial environments be periodically re-evaluated to determine if the various methods continue to meet current guidelines.

Earlier studies examining the ER method showed it could be administered and comply with the 2010 CPR guidelines while also correlating with parabolic flight data, indicating its use could provide effective CPR in microgravity. In addition, the research aimed to evaluate the physiological impact of performing the ER method, using subjective (Borg scale) and objective measurements (heart rate). Although found to be very tiring in comparison to terrestrial CPR, the ER method could be sustained effectively for up to 2 min [5]. Building on this work, comparative studies were conducted of the three main single-person CPR techniques, the ER, RBH and HS methods. A preliminary study comparing these methods proved the suitability of the BSD for conducting this type of research, which then led to a larger study. Results from the larger comparative study, carried out using the 2010 guidelines, found the HS method to be the most effective in terms of depth (also called 'true depth' to account for adequate decompression of the chest during ECC) and rate of administered ECCs, closely followed by the ER method, while the RBH gave the worst clinical results, as well as being extremely fatiguing (**Figures 10** and **11**). These studies also assessed the physiological cost of performing these methods, compared to terrestrial CPR. Using more objective measures, such as oxygen uptake (VO<sup>2</sup> ), these studies demonstrated that all three methods had a greater VO<sup>2</sup> than terrestrial CPR, with the HS being the least aerobically demanding and the RBH the most demanding [44, 48].

The physiological challenge of these methods is potentially a very important issue, as a welldocumented decline in VO2max occurs when in microgravity for a prolonged period, even when using countermeasures. These ground-based studies, which aim for 50–60 mm compression depth in accordance with both the 2010 and 2015 resuscitation guidelines, highlight the significant increase in VO<sup>2</sup> that takes place, when compared to the 2005 guidelines. These findings emphasise the importance of maintaining aerobic capacity in case the need to perform CPR in microgravity should arise [47, 50].

A series of studies have considered muscle activation, via superficial electromyography (EMG), while performing CPR in micro- and hypogravity, in order to understand the muscle groups used in comparison to terrestrial CPR. The rationale behind this was to potentially identify the responsible muscle groups so as to tailor exercise programs to ensure these muscle groups are maintained [6, 51, 52]. EMG data showed the triceps, pectoralis major and rectus abdominis muscles to be more active when conducting microgravity CPR, particularly for the ER method, when compared to 1 Gz and hypogravity CPR. This data adds to the evidence found in other studies indicating that astronauts need to maintain their muscle endurance in these particular muscle groups, as well as preserve their cardiorespiratory capacity to be able to adequately perform CPR should they need to in an emergency [52].

### **5.2. Hypogravity CPR studies**

**5. Summary of ground-based space analogue studies**

**Figure 9.** The seat arm-lock method in simulated hypogravity at the European Astronaut Centre.

determine if the various methods continue to meet current guidelines.

Research into extraterrestrial CPR, particularly CPR in microgravity, has been ongoing for more than a decade. Several parabolic flight campaigns [4, 42, 43] have investigated the feasibility of the main CPR methods. As previously mentioned, although parabolic flights provide an excellent analogue of microgravity, their short duration (about 20 s per parabola) limits the amount of data that can be collected and interpreted. Accordingly, most of the available evidence investigating the different CPR methods has come from ground-based simulation studies, using such devices as the BSD. Although still with limitations, ground-based simulation studies do provide additional insight into the effectiveness and feasibility of microgravity CPR methods, particularly over prolonged time periods. Resuscitation guidelines are in general updated every 5 years, with adaptations made based on current evidence. This requires that CPR research in simulated extraterrestrial environments be periodically re-evaluated to

Earlier studies examining the ER method showed it could be administered and comply with the 2010 CPR guidelines while also correlating with parabolic flight data, indicating its use could provide effective CPR in microgravity. In addition, the research aimed to evaluate the physiological impact of performing the ER method, using subjective (Borg scale) and objective measurements (heart rate). Although found to be very tiring in comparison to terrestrial CPR, the ER method could be sustained effectively for up to 2 min [5]. Building on this work, comparative studies were conducted of the three main single-person CPR techniques, the ER, RBH and HS methods. A preliminary study comparing these methods proved the suitability of the BSD for conducting this type of research, which then led to a larger study. Results from

**5.1. Microgravity CPR studies**

132 Resuscitation Aspects

The BSD has also been successfully used in a series of studies evaluating CPR in simulated hypogravity. These studies have focused on the feasibility of performing CPR using the terrestrial method in hypogravity, as well as assessing the alterations in technique in hypogravity, physiological impact and weight as a pivotal factor in performing CPR in these environments. Initial hypogravity studies showed that CPR in hypogravity, particularly Lunar and Martian environments, was feasible using traditional terrestrial CPR. Furthermore, they highlighted the occurrence of an increase in the arm flexion angle of the rescuer [46]. Traditional teaching of BLS and CPR advocates that arms should be kept rigid in order to transfer the force of acceleration of the rescuers' upper body to the chest of the patient. These studies show that for CPR to be effective, and achieve guideline recommendations, the rescuer needs to flex and extend their arms, up to 14° (±8.1°), and use their upper limb musculature to generate force to compress the chest to a sufficient depth. This was even greater in microgravity using the ER method, up to 16.5° (±10.1°); however, as the technique used is markedly different to terrestrial CPR, a direct comparison between the two is difficult [46, 47, 50] (**Figure 12**).

**Figure 10.** Mean true depth of ECC over 1.5 min for terrestrial and microgravity CPR using the three methods. Dashed line represents greater than 50 mm of depth set by the ILCOR 2010 guidelines; n = 23. Adapted from Ref. [48].

**Figure 11.** Mean rate of external chest compression (6 SEM) over 1.5 min for terrestrial and microgravity CPR using the three methods. Dashed line represents the lower limit of 100 compressions/min set by the ILCOR 2010 guidelines; n = 23. \* Significantly different from +1 Gz, ER and RBH. Adapted from Ref. [48].

Similar to the microgravity studies, the physiological cost was measured subjectively and objectively, using the Borg scale and VO<sup>2</sup> , respectively. Compared to terrestrial CPR, hypogravity CPR is more tiring and requires a greater VO<sup>2</sup> , but not to the same extent as the microgravity CPR methods [47] (**Figure 13**). EMG hypogravity CPR studies have shown the occurrence of more muscle activation in the rectus abdominis compared to +1 Gz CPR, as the rescuer needs to accelerate their upper body faster to generate the same force as would be found at +1 Gz. Considering Newton's second law of motion, F = m × a, a reduction in mass will require an increase in acceleration to maintain the same force.

**Figure 12.** Mean (±SD) range of elbow flexion in the dominant arm at +1 Gz, 0.38 Gz and microgravity. Adapted from Ref. [47].

**Figure 13.** Peak oxygen consumption (VO<sup>2</sup> peak) at +1 Gz, +0.38 Gz and microgravity.

Similar to the microgravity studies, the physiological cost was measured subjectively and objec-

**Figure 11.** Mean rate of external chest compression (6 SEM) over 1.5 min for terrestrial and microgravity CPR using the three methods. Dashed line represents the lower limit of 100 compressions/min set by the ILCOR 2010 guidelines; n = 23.

**Figure 10.** Mean true depth of ECC over 1.5 min for terrestrial and microgravity CPR using the three methods. Dashed line represents greater than 50 mm of depth set by the ILCOR 2010 guidelines; n = 23. Adapted from Ref. [48].

CPR methods [47] (**Figure 13**). EMG hypogravity CPR studies have shown the occurrence of more muscle activation in the rectus abdominis compared to +1 Gz CPR, as the rescuer needs to accelerate their upper body faster to generate the same force as would be found at +1 Gz. Considering Newton's second law of motion, F = m × a, a reduction in mass will require an

, respectively. Compared to terrestrial CPR, hypogravity

, but not to the same extent as the microgravity

tively, using the Borg scale and VO<sup>2</sup>

134 Resuscitation Aspects

CPR is more tiring and requires a greater VO<sup>2</sup>

\* Significantly different from +1 Gz, ER and RBH. Adapted from Ref. [48].

increase in acceleration to maintain the same force.

Hypogravity studies have considered weight and gender and their importance in performing CPR in these reduced gravitational fields. As the data shows, the more you effectively reduce the rescuers' body weight or possibly muscle mass, the harder it is to generate force for ECC, and therefore the more tiring it becomes. As greater numbers of females join the astronaut corp, it is important to address the differences in weight and muscle mass to determine how pivotal they are in performing CPR in hypogravity. These studies demonstrated the possible existence of a gender difference in the effectiveness of BLS when delivering ECCs, according to the 2010 guidelines.

Female subjects were more likely to perform inadequate ECCs, as they tended to be shorter, weigh less and possibly have a smaller muscle mass than the males. Moreover, they were shown to have a higher physiological demand when performing ECCs. This was compared to males when performing CPR in hypogravity. Even when males had an effective reduction in their weight, they were still able to generate enough force to produce adequate depth and rate of ECC. This indicates that weight is not the only factor in effective ECC and that muscle mass may play an important role that counterbalances low-weight situations. Therefore, female rescuers may require additional strength training and alternative CPR techniques to overcome their lower bodyweight and muscle mass to ensure they can perform adequate ECCs in accordance with the current CPR guidelines [47, 50].

### **6. Extraterrestrial CPR guidelines**

The extraterrestrial CPR guidelines presented in this chapter are based on the experience of the authors who conducted several studies at the MicroG-PUCRS, Brazil, and an extensive revision of the literature related to this topic. Therefore, the rationale behind specific guidelines for microgravity and hypogravity BLS and CPR is a combination of the novelty of the environment, increased physiological stress and isolated nature of these environments, all of which can affect the success of resuscitating a patient. However, familiarity and training of the appropriate BLS protocols and novel CPR methods for these environments will be a great benefit for both rescuer and patient. Furthermore, with the popularity of space tourism set to increase over the coming years, as private companies test new technology, there is a responsibility of space scientists and physicians to make sure that participants are familiar with and adequately trained in these novel BLS and CPR methods. Laypersons on Earth, such as schoolteachers and civil servants, learn BLS and CPR for a variety of reasons, and this custom should also apply to space tourists, who should be encouraged to become familiar with extraterrestrial resuscitation techniques. Therefore, extraterrestrial CPR guidelines have been developed and designed for all adults who will, for example, experience microgravity or hypogravity as part of their professional careers when participating in parabolic flights and space missions or who are involved in the training of astronauts.

Once cardiac arrest has been recognised, external chest compressions and ventilations need to be started immediately to maximise chances of survival. The best evidence for depth and rate of chest compressions come from international guidelines that are updated every 5 years by the International Liaison Committee on Resuscitation (ILCOR), who suggest changes to the European Resuscitation Council (ERC) and American Heart Association (AHA) based on the best possible evidence. Despite the well-documented altered physiology of astronauts in microgravity, there is insufficient evidence to suggest altering any of the parameters set by these international guidelines.

Summary of terrestrial ERC Guidelines for resuscitation (2015):


The specific guidelines for chest compressions in microgravity and hypogravity remain the same on Earth:

**1.** Compress the chest at a rate of 100–120 min−1.

shown to have a higher physiological demand when performing ECCs. This was compared to males when performing CPR in hypogravity. Even when males had an effective reduction in their weight, they were still able to generate enough force to produce adequate depth and rate of ECC. This indicates that weight is not the only factor in effective ECC and that muscle mass may play an important role that counterbalances low-weight situations. Therefore, female rescuers may require additional strength training and alternative CPR techniques to overcome their lower bodyweight and muscle mass to ensure they can perform adequate ECCs in

The extraterrestrial CPR guidelines presented in this chapter are based on the experience of the authors who conducted several studies at the MicroG-PUCRS, Brazil, and an extensive revision of the literature related to this topic. Therefore, the rationale behind specific guidelines for microgravity and hypogravity BLS and CPR is a combination of the novelty of the environment, increased physiological stress and isolated nature of these environments, all of which can affect the success of resuscitating a patient. However, familiarity and training of the appropriate BLS protocols and novel CPR methods for these environments will be a great benefit for both rescuer and patient. Furthermore, with the popularity of space tourism set to increase over the coming years, as private companies test new technology, there is a responsibility of space scientists and physicians to make sure that participants are familiar with and adequately trained in these novel BLS and CPR methods. Laypersons on Earth, such as schoolteachers and civil servants, learn BLS and CPR for a variety of reasons, and this custom should also apply to space tourists, who should be encouraged to become familiar with extraterrestrial resuscitation techniques. Therefore, extraterrestrial CPR guidelines have been developed and designed for all adults who will, for example, experience microgravity or hypogravity as part of their professional careers when participating in parabolic flights and

Once cardiac arrest has been recognised, external chest compressions and ventilations need to be started immediately to maximise chances of survival. The best evidence for depth and rate of chest compressions come from international guidelines that are updated every 5 years by the International Liaison Committee on Resuscitation (ILCOR), who suggest changes to the European Resuscitation Council (ERC) and American Heart Association (AHA) based on the best possible evidence. Despite the well-documented altered physiology of astronauts in microgravity, there is insufficient evidence to suggest altering any of the parameters set by

accordance with the current CPR guidelines [47, 50].

space missions or who are involved in the training of astronauts.

Summary of terrestrial ERC Guidelines for resuscitation (2015):

• Rate of chest compression of 100 min−1 (but not exceeding 120 min−1).

these international guidelines.

• Ratio of 30:2 (compression/ventilation).

• Depth of chest compression between 5 and 6 cm.

**6. Extraterrestrial CPR guidelines**

136 Resuscitation Aspects


Chest compression-only CPR is important during resuscitation as it will benefit those who are not fully trained or are unwilling to perform mouth-to-mouth rescue breaths; this applies more to those who are entering hypogravity or microgravity as space tourists because all astronauts receive suitable BLS training. Under no circumstances should chest compressions be sacrificed for ventilations. Evidence suggests that compressions are more essential than ventilations during CPR and thus should be favoured during resuscitation [53]. There is no evidence to suggest that a change in ratio would be of benefit in hypogravity or microgravity. Therefore, rescuers should still aim for a ratio of 30:2 with a rate of compressions at 100 compressions min−1 and a depth of 5–6 cm, as stated above.

With regard to the depth of chest compression, it can be affected by the expansion of the chest in microgravity. There is no specific evidence to support changes to the terrestrial guidelines; however, it is theorised that a change in the chest wall dimensions of a patient in microgravity may alter the requirements for effective delivery of CPR, meaning that 5–6 cm may not be a sufficient depth of compression and a depth of >6 cm may need to be considered. However, more evidence is needed before contemplating any important change in these guidelines.

Currently, there is little supporting evidence for the best practice of ventilation in either hypogravity or microgravity. There is no reason to suppose that this would be different in a hypogravity environment, compared to terrestrial CPR. As the technique of CPR is essentially the same for both conditions, the rescuer should be equally capable of providing ventilations to the patient. The only caveat to this is if the patient and rescuer are in spacesuits, either while performing an extravehicular activity or walking on the surface of a planetary body, as the suit will obviously prevent them from giving mouth-to-mouth ventilation or administering CPR. However, future research into hypogravity BLS should evaluate the practicality of providing ventilations. With respect to microgravity, some research involving parabolic flight studies [4, 42] has evaluated ventilation, as well as chest compression depth and rate of these CPR methods. Findings have shown that rescuers using the Evetts-Russomano method were able to provide adequate ventilations of 491 ± 50.4 ml, in accordance to the 1998 ERC guidelines that applied at the time [42]. Other research focusing on the use of ventilation adjuncts, which required the mannequin to be intubated with a Kendall CardioVent device, showed that a lone rescuer could provide adequate chest compressions with the ventilation adjunct. However, setting up this equipment as a lone rescuer would delay the beginning of chest compressions and would go against the new guidelines, C-A-B, where compressions take priority [4].

Throughout these guidelines the patient refers to the individual who has a suspected cardiac arrest, and the rescuer refers to the person who is immediately responsible for their resuscitation. The initial sequence in determining if the patient is responsive remains very similar to the ERC 2015 CPR guidelines but takes into account the communication and resource limitations whenwnments (**Figure 14**):

	- Find a suitable place to secure the patient to avoid risk of floating and suffering further trauma or leave them in their present position if no alternative is available.
	- Seek help from crewmembers, and attempt to determine what is wrong with the patient.
	- Reassess regularly until help arrives or communication is established with mission control/flight surgeon.
	- Shout for help immediately; when help arrives instruct them to find resuscitation equipment and more help. However, do not wait until they return; you must immediately begin chest compressions.
	- Follow the C-A-B sequence (compressions, airway, breathing).
	- Start chest compressions, selecting the appropriate CPR method depending on the environment you are in.
	- Place in a safe position.

same for both conditions, the rescuer should be equally capable of providing ventilations to the patient. The only caveat to this is if the patient and rescuer are in spacesuits, either while performing an extravehicular activity or walking on the surface of a planetary body, as the suit will obviously prevent them from giving mouth-to-mouth ventilation or administering CPR. However, future research into hypogravity BLS should evaluate the practicality of providing ventilations. With respect to microgravity, some research involving parabolic flight studies [4, 42] has evaluated ventilation, as well as chest compression depth and rate of these CPR methods. Findings have shown that rescuers using the Evetts-Russomano method were able to provide adequate ventilations of 491 ± 50.4 ml, in accordance to the 1998 ERC guidelines that applied at the time [42]. Other research focusing on the use of ventilation adjuncts, which required the mannequin to be intubated with a Kendall CardioVent device, showed that a lone rescuer could provide adequate chest compressions with the ventilation adjunct. However, setting up this equipment as a lone rescuer would delay the beginning of chest compressions and would go against the new guidelines, C-A-B, where compressions take priority [4].

Throughout these guidelines the patient refers to the individual who has a suspected cardiac arrest, and the rescuer refers to the person who is immediately responsible for their resuscitation. The initial sequence in determining if the patient is responsive remains very similar to the ERC 2015 CPR guidelines but takes into account the communication and resource limita-

• Check if you and other crewmembers are safe. If environmental factors are likely to be the precipitating factor (failure of life support systems, toxin build-up, trauma from projectile), make sure these are no longer a threat to you and other crewmembers before attempting

• Check for response—gently shake shoulders, and ask loudly in each ear, 'Can you hear

• Find a suitable place to secure the patient to avoid risk of floating and suffering further

• Seek help from crewmembers, and attempt to determine what is wrong with the patient.

• Reassess regularly until help arrives or communication is established with mission con-

• Shout for help immediately; when help arrives instruct them to find resuscitation equipment and more help. However, do not wait until they return; you must immediately

• Start chest compressions, selecting the appropriate CPR method depending on the en-

trauma or leave them in their present position if no alternative is available.

• Follow the C-A-B sequence (compressions, airway, breathing).

tions whenwnments (**Figure 14**):

to rescue the patient.

138 Resuscitation Aspects

• If patient does respond:

trol/flight surgeon.

• If patient does not respond:

begin chest compressions.

vironment you are in.

me?' or 'Are you all right?'

	- Seek someone for further help, and establish communication with mission control. Further resuscitation and AED are required.

**Figure 14.** Microgravity and hypogravity adult basic life support algorithm, adapted from ERC 2010 guidelines. Reflect on the updated sequence of steps from airway, breathing and compressions (ABC) to compressions, airway and breathing (CAB).

• Start chest compressions, selecting the appropriate method depending on the environment you are in.

There is insufficient evidence, especially for the SeAL technique, to say which method is superior in hypogravity. However, it is recommended that the traditional terrestrial CPR method should be implemented first, as it produces adequate depth of compression with low levels of fatigue, suggesting that traditional CPR with an increased elbow flexion is an effective method of CPR [47]. **Figure 15** presents the algorithm for CPR to be applied in hypogravity environments.

### **6.1. Risks to rescuers**

Altered physiology in microgravity and greater susceptibility to fatigue due to deconditioning could potentially affect the quality of CPR. The main factors that need to be considered are:


Research examining CPR performance in simulated microgravity has shown all methods to be more fatiguing compared to terrestrial CPR [48]. CPR in hypogravity is also found to be more tiring than CPR on Earth, however, not to the same degree as in microgravity [47].

Current ERC guidelines recommend rotating rescuers every 2 min to prevent a drop in quality of chest compressions. A similar or possibly shorter window, such as 90 s, would be recommended for CPR in hypogravity. For microgravity, if enough crewmembers are present, an even shorter window for rotating is recommended, such as 60 s, to preserve the quality of chest compressions.

It is also important to consider that microgravity is a novel environment in itself and can be disorientating, which could be a potential hazard in an emergency scenario. The internal environment of a spacecraft or the ISS is also small, with confined spaces that can limit the ability of the rescuer and patient to manoeuvre and transfer during CPR or any emergency. Specifically for the HS method, particular consideration must be given to placement of the patient and positioning of the rescuer's feet, as lots of equipment are found within the capsule and there is the potential for damage to be caused to walls or partitions if they are not strong enough to withstand the force applied for performance of the CPR chest compressions. For the RBH and ER methods, there is always the danger of floating and hitting the sides of the internal environment of the capsule/spacecraft when performing CPR.

The use of an AED also imposes risks. Its use must be controlled and applied only by those trained to handle the equipment. Evidence shows that there have been few injuries due to poor AED use; however, the isolated and unique environment of microgravity in particular

**Figure 15.** Algorithm for CPR in hypogravity.

• Start chest compressions, selecting the appropriate method depending on the environment

There is insufficient evidence, especially for the SeAL technique, to say which method is superior in hypogravity. However, it is recommended that the traditional terrestrial CPR method should be implemented first, as it produces adequate depth of compression with low levels of fatigue, suggesting that traditional CPR with an increased elbow flexion is an effective method of CPR [47]. **Figure 15** presents the algorithm for CPR to be applied in hypogravity

Altered physiology in microgravity and greater susceptibility to fatigue due to deconditioning could potentially affect the quality of CPR. The main factors that need to be con-

• Reduced gravitational field requires greater amount of force to be generated by the rescuer, resulting in increased muscle strain and shortness of breath in comparison to Earth.

• Deconditioning due to prolonged exposure to microgravity and/or hypogravity can place rescuers in a suboptimal physiological state when attempting to perform CPR. This could

Research examining CPR performance in simulated microgravity has shown all methods to be more fatiguing compared to terrestrial CPR [48]. CPR in hypogravity is also found to be more tiring than CPR on Earth, however, not to the same degree as in microgravity [47].

Current ERC guidelines recommend rotating rescuers every 2 min to prevent a drop in quality of chest compressions. A similar or possibly shorter window, such as 90 s, would be recommended for CPR in hypogravity. For microgravity, if enough crewmembers are present, an even shorter window for rotating is recommended, such as 60 s, to preserve the quality of

It is also important to consider that microgravity is a novel environment in itself and can be disorientating, which could be a potential hazard in an emergency scenario. The internal environment of a spacecraft or the ISS is also small, with confined spaces that can limit the ability of the rescuer and patient to manoeuvre and transfer during CPR or any emergency. Specifically for the HS method, particular consideration must be given to placement of the patient and positioning of the rescuer's feet, as lots of equipment are found within the capsule and there is the potential for damage to be caused to walls or partitions if they are not strong enough to withstand the force applied for performance of the CPR chest compressions. For the RBH and ER methods, there is always the danger of floating and hitting the sides of the

The use of an AED also imposes risks. Its use must be controlled and applied only by those trained to handle the equipment. Evidence shows that there have been few injuries due to poor AED use; however, the isolated and unique environment of microgravity in particular

internal environment of the capsule/spacecraft when performing CPR.

result in both a poor CPR performance and significant and rapid onset of fatigue.

you are in.

140 Resuscitation Aspects

environments.

sidered are:

**6.1. Risks to rescuers**

chest compressions.

can provide additional challenges in terms of making sure that rescuers are safe and clear when an AED is discharged.

### **7. Conclusion: extraterrestrial CPR—applications in space and on earth**

As the space tourism industry commences and looks to expand over the following years, greater numbers of individuals will undertake suborbital flights and enter the microgravity environment. Before space tourism becomes a viable industry with regular flights, its technology will be tried and tested to the highest standards. The rapid rise in numbers of people who enter microgravity will pose a potentially significant increase in health problems, many of which participants will be unaware. Growing numbers of individuals will enter the space environment who will not have been subject to a strict preselection screening, such as that undergone by people preparing to join the astronaut corp [54]. This scenario could lead to potential difficulties: individuals will be at greater risk of a life-threatening cardiac event if they have not been screened for such health issues beforehand, and/or the physiological stress of launching and remaining in microgravity could exacerbate any underlying cardiovascular condition. This scenario could be further compounded by a shortage of individuals who have undertaken emergency training. This is a similar problem to that faced on Earth, with a varying uptake of BLS/CPR training across countries. However, the novelty factor of the microgravity environment combined with a serious medical emergency could create a highly stressful situation in which these bystanders are likely to be ill prepared and lacking the appropriate training necessary to carry out CPR techniques for the performance of adequate BLS. To this end, it is recommended that such individuals undergo appropriate training prior to a flight that would take them into an altered gravity environment. Healthcare professionals, schoolteachers and other civil servants who work with the public are currently given first aid and CPR training, and this exposure to basic BLS and CPR methods should be extended to all travellers into space. It is unrealistic to expect these individuals to be fully trained in all methods prior to launch, but familiarity with all methods, in accordance with ERC/AHA guidelines for CPR depth and rate of chest compressions, could better prepare them for the possibility of a serious cardiac event occurring that requires CPR.

Individuals who do find themselves in a situation of needing to administer BLS/CPR should initially follow the steps in **Figure 14**, making sure that a crewmember or ground control is aware that there is a medical emergency in progress. When commencing CPR, laypersons familiar with all three methods should be encouraged to perform the technique with which they feel the most comfortable and are consequently better able to deliver effective external chest compressions. As with the ERC/AHA guidelines, effective chest compressions should be favoured over ventilations.

Training and familiarisation with the novel CPR methods used in microgravity can enable laypersons to provide chest compressions and therefore maintain cardiac output and organ perfusion, until either a more qualified crewmember can takeover the procedure or until the craft ends its suborbital trajectory and returns to a normal gravitational environment where terrestrial CPR can commence. These steps will improve the chances of the patient having a favourable outcome.

Research into terrestrial CPR has shown that height and weight of the rescuer are correlated to effectiveness of chest compressions, and therefore, extraterrestrial CPR research could be used to improve terrestrial CPR, especially when physical disparities are encountered, such as when a rescuer is of smaller stature or lacks sufficient upper body weight. Examples of these scenarios include a child attempting to resuscitate an adult outside of a hospital situation or a small nurse resuscitating a large adult in hospital, who may also be obese or have significant lung pathology, such as pulmonary fibrosis or chronic obstructive pulmonary diseases, thus restricting further compliance of the chest.

Using the traditional straight-arm CPR technique, there reaches a point of critical mass when a rescuer is unable to overcome the resistance of the patient's chest to achieve the required 50–60 mm depth of chest compression. Without sufficient depth, not enough of a pressure gradient is created to circulate blood and perfuse organs. In these scenarios, the authors suggest a footnote to the CPR guidelines, concluding that extension of the upper limbs (triceps extension) can help augment the traditional straight-arm method with a synergistic acceleration of the body and extension of upper body to generate the force required to compress the chest.

### **Author details**

can provide additional challenges in terms of making sure that rescuers are safe and clear

**7. Conclusion: extraterrestrial CPR—applications in space and on earth**

possibility of a serious cardiac event occurring that requires CPR.

be favoured over ventilations.

favourable outcome.

Individuals who do find themselves in a situation of needing to administer BLS/CPR should initially follow the steps in **Figure 14**, making sure that a crewmember or ground control is aware that there is a medical emergency in progress. When commencing CPR, laypersons familiar with all three methods should be encouraged to perform the technique with which they feel the most comfortable and are consequently better able to deliver effective external chest compressions. As with the ERC/AHA guidelines, effective chest compressions should

Training and familiarisation with the novel CPR methods used in microgravity can enable laypersons to provide chest compressions and therefore maintain cardiac output and organ perfusion, until either a more qualified crewmember can takeover the procedure or until the craft ends its suborbital trajectory and returns to a normal gravitational environment where terrestrial CPR can commence. These steps will improve the chances of the patient having a

As the space tourism industry commences and looks to expand over the following years, greater numbers of individuals will undertake suborbital flights and enter the microgravity environment. Before space tourism becomes a viable industry with regular flights, its technology will be tried and tested to the highest standards. The rapid rise in numbers of people who enter microgravity will pose a potentially significant increase in health problems, many of which participants will be unaware. Growing numbers of individuals will enter the space environment who will not have been subject to a strict preselection screening, such as that undergone by people preparing to join the astronaut corp [54]. This scenario could lead to potential difficulties: individuals will be at greater risk of a life-threatening cardiac event if they have not been screened for such health issues beforehand, and/or the physiological stress of launching and remaining in microgravity could exacerbate any underlying cardiovascular condition. This scenario could be further compounded by a shortage of individuals who have undertaken emergency training. This is a similar problem to that faced on Earth, with a varying uptake of BLS/CPR training across countries. However, the novelty factor of the microgravity environment combined with a serious medical emergency could create a highly stressful situation in which these bystanders are likely to be ill prepared and lacking the appropriate training necessary to carry out CPR techniques for the performance of adequate BLS. To this end, it is recommended that such individuals undergo appropriate training prior to a flight that would take them into an altered gravity environment. Healthcare professionals, schoolteachers and other civil servants who work with the public are currently given first aid and CPR training, and this exposure to basic BLS and CPR methods should be extended to all travellers into space. It is unrealistic to expect these individuals to be fully trained in all methods prior to launch, but familiarity with all methods, in accordance with ERC/AHA guidelines for CPR depth and rate of chest compressions, could better prepare them for the

when an AED is discharged.

142 Resuscitation Aspects

Thais Russomano1,2,3,4\* and Lucas Rehnberg1,5

\*Address all correspondence to: thais.russomano@innovaspace.org

1 Centre of Human and Aerospace Physiological Sciences, Faculty of Life Sciences & Medicine, King's College, London, UK


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**Provisional chapter**

### **Resuscitation of Overcooled Mammals without Rewarming Rewarming**

**Resuscitation of Overcooled Mammals without** 

DOI: 10.5772/intechopen.68422

### Kirill P. Ivanov Kirill P. Ivanov Additional information is available at the end of the chapter

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148 Resuscitation Aspects

Medicine. 2002;**73**(11):1132-1134

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68422

### **Abstract**

Cold is a deadly danger for man. If the temperature of the surrounding air is +1°C, it is death for a naked man, owing to the arrest of respiration at the body temperature 25–28°C. After the heart is arrested, the death occurs at 23–24°C. Our aim was to prolong life at an absolutely deadly body temperature. This problem is important nowadays owing to a lot of sea catastrophes, the investigations in Arctic and Antarctic areas, and so on.

**Keywords:** rewarming, potassium ions, calcium ions, artificial ventilation

### **1. Introduction**

Temperature is the most important criterion of life. As it increases, the limit is achieved quickly. For homoeothermic organisms, the body temperature between 42 and 45°C is practically incompatible with life. The cold diapason is substantially wider. Humans and mammals can decrease their body temperature to 32–33°C and then restore it without any pathological after effect. At lower temperature, rewarming becomes dangerous. A too intensive external rewarming results in increased oxygen consumption by various, almost indifferent, tissues, so that the brain and heart are subjected to a deficit in the energy material. In such a case, a deterioration of their functions occurs, which can result in the death of an organism. Generally speaking, the resistance to cold in living organisms is essentially higher than the resistance to heat. This is associated with the fact that a high temperature disrupts the tissues, whereas low temperature, to the contrary, favors the conservation of the tissue structure. According to the old data of Andjus [1], a rat frozen at 0 to −1°C revived for a short time if its heart was rewarmed by a special thermode, and thus its circulation was partially restored. However, rewarming a man at a very deep cooling is very dangerous since the distribution of temperature fields may appear

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

unfavorable for the most important organs of a living organism: brain and heart. This can result in the death of deeply cooled organisms. But, let us consider the possibilities of resuscitation of overcooled organism by rewarming.

Rewarming is a conventional method of resuscitation of a frozen man or animal. However, this seemingly irreproachable procedure appears to require compliance with certain rules. First of all, the effect of rewarming the whole organism depends on the state of respiration and circulation. If these functions still operate at the temperature in the rectum 26–28°C, the rescue team has a hope to restore the organism's life. If a man's respiration is arrested upon deep cooling, but a weak circulation is still preserved, there is a hope for recovery of life, but it is very weak, since after arrest of respiration the heart operates briefly, by common opinion only for 15–30 min. Unfortunately, this period of time has not been adequately explored, and it is impossible to say something strictly definite about it. Burton and Edholm [2] described a case when a victim of cold lied in a cold morgue for several hours without respiration. He was supposed to have an extremely weak heart activity and eventually survived. It is supposed that only separate heart impulses remained in him, which resulted in a very weak circulation. It is conceivable that such cases are of frequent occurrences. In this instance, the absence of visual respiration is not the reason for sending a victim of overcooling to a morgue.

There is one more rule. During rewarming, if the brain is warmed more quickly than the heart, the supply of the blood to the brain may appear to be insufficient for the brain life and consequently for the life of the whole organism. At any rate, from the practical point of view, upon the arrest of respiration, the main emphasis must be placed on rewarming the heart. The attention must be focused on the problem that upon rewarming the whole organism, the brain was not rewarmed well before the heart [2–6].

Now we shall consider other methods, which can be used upon resuscitation of overcooled organism without general rewarming.

### **2. Materials and methods**

The studies on the influence of the decrease in the content of potassium ions in the blood were performed on the isolated rat hearts. They were perfused by Krebs-Ginzelite solution with various concentrations of potassium, and the heart activity was studied at normal and decreased temperatures.

The experiments on the influence of calcium ion concentration in the blood on thermoregulation were carried out on white male Wistar rats 280–310 g in mass. After narcotization (125 mg of urethane per 100 g of weight intraperitoneally), the animals were fixed in a special stand. Polyethylene catheters were inserted into the femoral vein and artery for injections and for measuring the blood pressure. The temperature in the rectum (at a depth of 4.5 cm) and in the region of medulla oblongata was measured with the help of copper-constantan thermocouples. One hour after the beginning of narcotization and inserting catheters and thermocouples, the rat on a special stand was immersed into water with the temperature ~+8°C. In this case, the head and nostrils of the animal were located above the water level. The temperature of the animal body decreased gradually at a rate of about 0.35–0.40°C per minute. During the experiments, we periodically recorded the pneumogram (a carbon sensor on the animal breast) and electrocardiogram (ECG), and also measured the blood pressure in the femoral artery and the body temperature in the rectum and brain. The control animals were observed after the respiration arrest and immediately after injection of 1 ml of physiological solution as a placebo up to the moment of the heart arrest and the decrease in the arterial blood flow to zero. Another group of animals was injected with 1 ml of 0.5% solution of ethylenediaminetetraacetate (EDTA) into the femoral vein 8–10 min after the arrest of respiration.

Calcium ion concentration in the whole blood was determined by the method of direct potentiometry with film calcium selective electrodes. The method of determining Ca2+ concentration in the blood is described in detail in our previous work [5]. The blood samples for the determination of Ca2+ content had the volume not more than 0.3 ml.

We carried out the statistical treatment of the results with the help of Statistica program. We calculated the average values (M) and the error (m); the reliability of the differences was determined by Wilcoxson criteria (pw).

Artificial ventilation was carried out with the help of special small self-made apparatus for the rats. The maximal power of the apparatus was 13–15 inhales per min. Each inhale contained 1.5 ml of air.

### **3. Results and discussion**

unfavorable for the most important organs of a living organism: brain and heart. This can result in the death of deeply cooled organisms. But, let us consider the possibilities of resuscita-

Rewarming is a conventional method of resuscitation of a frozen man or animal. However, this seemingly irreproachable procedure appears to require compliance with certain rules. First of all, the effect of rewarming the whole organism depends on the state of respiration and circulation. If these functions still operate at the temperature in the rectum 26–28°C, the rescue team has a hope to restore the organism's life. If a man's respiration is arrested upon deep cooling, but a weak circulation is still preserved, there is a hope for recovery of life, but it is very weak, since after arrest of respiration the heart operates briefly, by common opinion only for 15–30 min. Unfortunately, this period of time has not been adequately explored, and it is impossible to say something strictly definite about it. Burton and Edholm [2] described a case when a victim of cold lied in a cold morgue for several hours without respiration. He was supposed to have an extremely weak heart activity and eventually survived. It is supposed that only separate heart impulses remained in him, which resulted in a very weak circulation. It is conceivable that such cases are of frequent occurrences. In this instance, the absence of visual respiration is not the reason for sending a victim of overcool-

There is one more rule. During rewarming, if the brain is warmed more quickly than the heart, the supply of the blood to the brain may appear to be insufficient for the brain life and consequently for the life of the whole organism. At any rate, from the practical point of view, upon the arrest of respiration, the main emphasis must be placed on rewarming the heart. The attention must be focused on the problem that upon rewarming the whole organism, the brain

Now we shall consider other methods, which can be used upon resuscitation of overcooled

The studies on the influence of the decrease in the content of potassium ions in the blood were performed on the isolated rat hearts. They were perfused by Krebs-Ginzelite solution with various concentrations of potassium, and the heart activity was studied at normal and

The experiments on the influence of calcium ion concentration in the blood on thermoregulation were carried out on white male Wistar rats 280–310 g in mass. After narcotization (125 mg of urethane per 100 g of weight intraperitoneally), the animals were fixed in a special stand. Polyethylene catheters were inserted into the femoral vein and artery for injections and for measuring the blood pressure. The temperature in the rectum (at a depth of 4.5 cm) and in the region of medulla oblongata was measured with the help of copper-constantan thermocouples. One hour after the beginning of narcotization and inserting catheters and

tion of overcooled organism by rewarming.

was not rewarmed well before the heart [2–6].

organism without general rewarming.

**2. Materials and methods**

decreased temperatures.

ing to a morgue.

150 Resuscitation Aspects

### **3.1. Decrease in potassium ion concentration in the blood**

A comparatively small increase in potassium ion concentration in the rat blood has no distinct effect on the thermal reactions of the animals. However, a decrease in the concentration of these ions in the blood upon its dilution results in a pronounced increase in the resistance to cold.

When an isolated heart of a rat is perfused with the blood with normal concentration of potassium ions (K+ 5.9 mM), it terminates contractions as the temperature of the heart tissues decreases to 14–12°C. But if the content of K+ in the blood with which the heart is perfused is 3.6 mM, the heart is arrested at lower temperature of about 10–8°C. If the K+ content is reduced to 2.5 mM, a complete arrest of the heart will occur at 6–5°C (**Figure 1A**–**C**; **Table 1**) [7].

Therefore, a decrease in the concentration of potassium ions distinctly increases the heart's resistance to cold and, consequently, decreases the danger of disrupting the circulation. True enough, it is hardly possible to save the victim of overcooling at such low body temperatures with the help of decreasing potassium concentration in the blood. However, a dilution of the blood with the aim of decreasing K+ concentration along with other procedures may be useful.

**Figure 1.** Mechanograms of the heart cooled and perfused with physiologic salt solution with K+ content: (A) 5.9 mM; (B) 3.6 mM; (C) 2.48 mM.


**Table 1.** Restoration of the contractions of cold paralyzed isolated hearts [6].

It appears difficult to find the data on the effect of ionic composition of the blood on their resistance to cold in the current literature. We were able to find a very interesting paper in Federation Proceedings [8], which supports our data about the role of potassium in this process. Furthermore, the effect of a decrease in potassium concentration on the increase in the heart tissues resistance to cold is very interesting and important from theoretical point of view. We emphasize that this fact opens the way to the studies of a number of other ions with the same purpose. The mechanisms of such action of ions are very interesting; however, such investigations seem to be scarce in the current literature.

#### **3.2. Decrease in calcium ion concentration in the blood**

**Figure 1.** Mechanograms of the heart cooled and perfused with physiologic salt solution with K+

(B) 3.6 mM; (C) 2.48 mM.

152 Resuscitation Aspects

content: (A) 5.9 mM;

As far back as in 1986, Hochachka [9] reported that in an overcooled organism, the cells die owing to the excess of calcium ions resulting from disrupting metabolism. These extra calcium ions must be removed from the intercellular fluids, but this process requires energy. The matter is that the concentration of calcium ions in the cells is about 10−8 M and in the intercellular fluids it is 10−3 M, thus we have the diffusion against a great concentration gradient, and the energy deficit in an overcooled organism prevents it.

We decided to examine the effect of calcium ion concentration in the blood on resuscitation of the functions of an overcooled organism.

We did not find any essential changes in the thermoregulation upon a small increase in the Ca2+ concentration in the blood. However, when the most important thermoregulation reaction—the cold shivering—is completely oppressed upon deep cooling of an organism, a comparatively small decrease in calcium ion concentration restores this most important muscle reaction in a short period of time (**Figure 2**) [5]. At a low body temperature of an animal, it is recommenced if a solution of ethylenediaminetetraacetate (EDTA) is introduced into the blood. EDTA decreases the calcium ion concentration since it reacts with them to give a complex compound, thus practically removing them from the blood. The introduction of 1 ml of 0.5% solution of EDTA into the blood of a rat 210–240 g in mass results in a decrease in calcium ion concentration by 15–25%. We emphasize that EDTA is a pharmacological preparation which is in wide use in medicine, and we inserted it in the relationships never exceeding those recommended for animals and humans.

**Figure 2.** Arrest of cold shivering and thermoregulation tone in rats during cooling of the body and restoration of these physiological functions without rewarming the body after inserting 0.016 mmol of EDTA into the blood. (1) Brain temperature (Tb)—28°C; rectum temperature (Tr)—25°C; maximal intensity of the cold shivering and of the thermoregulation muscle tone. (2) Tb—20°C; Tr—17.2°C; retardation of the functions of thermoregulation center and an almost complete oppression of shivering. (3) Five min after inserting 0.016 mmol of EDTA into the blood: Tb—18.9°C, Tr—17.2°C. (4) Ten min after a repeated insertion of the same dose of EDTA (0.016 mmol): Tb—18.7°C, Tr—17.2°C.

If a decrease in calcium ion concentration exhibits such a distinct positive effect on the most important thermoregulation reaction, the question arises inevitably about how such an action will influence respiration, heart activity, and blood pressure at a low body temperature.

**Tables 2** and **3** [10] answer this question. According to these data, EDTA excites the cold paralyzed respiration center and makes it work at a temperature, which under normal conditions results in its cold paralysis. Moreover, a partial restoration of the work of respiration center after EDTA insertion not only restores the cold shivering but also increases the frequency of the heart contractions and the blood pressure. Even though all these functions appear in an abruptly slowed down rhythm, this effect may continue for 1–1.5 h. Only gradually, it tapers down to nothing. If the cooling is stopped, and the animals are removed from water, dried, and left at room temperature, in this case the animal is warmed up on its own during 2.5–3 h


**Table 2.** Physiological parameters of the rats in 15 min after the arrest of respiration.


**Table 3.** Physiological parameters of these very animals after the arrest of respiration and immediate insertion of 1 ml of 0.5% EDTA solution into the blood.

and later does not differ from other control rats by its behavior. In this case, the insertion of EDTA saves the animal from death.

If a decrease in calcium ion concentration exhibits such a distinct positive effect on the most important thermoregulation reaction, the question arises inevitably about how such an action will influence respiration, heart activity, and blood pressure at a low body temperature.

**Figure 2.** Arrest of cold shivering and thermoregulation tone in rats during cooling of the body and restoration of these physiological functions without rewarming the body after inserting 0.016 mmol of EDTA into the blood. (1) Brain temperature (Tb)—28°C; rectum temperature (Tr)—25°C; maximal intensity of the cold shivering and of the thermoregulation muscle tone. (2) Tb—20°C; Tr—17.2°C; retardation of the functions of thermoregulation center and an almost complete oppression of shivering. (3) Five min after inserting 0.016 mmol of EDTA into the blood: Tb—18.9°C, Tr—17.2°C. (4) Ten min after a repeated insertion of the same dose of EDTA (0.016 mmol): Tb—18.7°C, Tr—17.2°C.

**Tables 2** and **3** [10] answer this question. According to these data, EDTA excites the cold paralyzed respiration center and makes it work at a temperature, which under normal conditions results in its cold paralysis. Moreover, a partial restoration of the work of respiration center after EDTA insertion not only restores the cold shivering but also increases the frequency of the heart contractions and the blood pressure. Even though all these functions appear in an abruptly slowed down rhythm, this effect may continue for 1–1.5 h. Only gradually, it tapers down to nothing. If the cooling is stopped, and the animals are removed from water, dried, and left at room temperature, in this case the animal is warmed up on its own during 2.5–3 h

> **Arterial blood pressure, mm Hg**

13.5 13.9 20 0 25 11.4 13.4 10 0 10 12.8 14.0 18 0 25 14.0 15.0 10 0 10 13.2 15.7 18 0 20 14.3 16.1 10 0 19 14.8 15.8 24 0 16 **13.4 ± 0.6 14.8 ± 0.2 16 ± 6.1 0 21 ± 5.0**

**Table 2.** Physiological parameters of the rats in 15 min after the arrest of respiration.

**Respiration frequency,** 

**Frequency of the heart contractions, imp/min**

**cycles/min**

**Temperature in the rectum, °C**

154 Resuscitation Aspects

**Temperature in the** 

**brain, °C**

If a comparatively small decrease in calcium ion concentration exerts such an effect on an animal, it is necessary to reveal the action of this factor on the whole thermoregulation system, that is, on peripheral and central thermosensors. First, we tried to reveal the effect of a decrease in calcium ion concentration by 15–20–25% on the skin thermoreceptors. These experiments were carried out on the skin thermoreceptors of the nose and back skin of a rabbit. They were rather complicated since we have not always met with success trying to keep the even pulsation of the cold thermoreceptors for 1–2 h in the starting state before cooling and then for a sufficiently long time after cooling and EDTA insertion. In **Table 4**, we demonstrate five experiments which distinctly show the restoration of receptor pulsation after their cold paralysis in several minutes after insertion of EDTA solution into the blood [10]. The restored pulsation after its complete or partial oppression with cold continues variously from 20 to 30 min and even more. The secondary paralysis may result from restoration of calcium ion concentration in the blood to the norm.


**Table 4.** Pulsing frequency of thermoreceptors in 5–10 min after EDTA insertion at the skin temperature at the site of their location from 0 to +5°C.

Of course, it was of great interest and importance from theoretical and practical point of view to learn how a decrease in calcium ion concentration affects the center of thermoregulation apparatus immediately. The neurons taking part in thermoregulation are known to be located in various parts of the central nervous system, in the hypothalamus among them. Hence, in order to put the central nervous thermoregulation as a whole to a test, we decided to insert EDTA immediately into the brain ventricles of the animals. We selected a minimal dose of 10–15 mmoles for the whole rate 210–240 g in mass. This dose is many times less than the dose that had been inserted into the blood of these animals. As has been found earlier, respiration is completely paralyzed at the rat body temperature 17–18°C. The insertion of this dose of EDTA into the brain ventricles restored the respiration in its frequency and amplitude in 10–15 min, though still far from the norm, that is, the respiration center acquired a certain resistance to cold. Later, we carried out many experiments and confirmed all the results [6]. That means an inhibiting effect of cold on thermoregulation, respiration, and circulation and removal of the cold paralysis from these functions at the expense of activation of peripheral and central thermosensors.

### **3.3. Artificial ventilation**

This is another method of saving a man from death during hypothermia.

Usually, artificial ventilation is considered as a help for the lungs in supplying an organism with oxygen. This is so indeed. A conventional artificial ventilation by manual operation without a special device may appear low efficient and give no expected result for 1 or even 2 h of its use even if there is a weak circulation.

It is seen from **Tables 5** and **6** that the lung respiration disappeared in the animals at the temperatures in the rectum 15.4°C, in the esophagus 16.6°C, in the brain 17.9°C (**Table 5**). In 12–15 min, when the temperature decreased by 1.5–2.0°C more, we switched on the artificial


**Table 5.** Arrest of respiration and an abrupt decrease in the arterial blood pressure and in the frequency of the heart contractions after the animals stay in water with the temperature 8–9°C.


**Table 6.** Test rats 2 min after starting artificial respiration of 12–13 inhales per min.

Of course, it was of great interest and importance from theoretical and practical point of view to learn how a decrease in calcium ion concentration affects the center of thermoregulation apparatus immediately. The neurons taking part in thermoregulation are known to be located in various parts of the central nervous system, in the hypothalamus among them. Hence, in order to put the central nervous thermoregulation as a whole to a test, we decided to insert EDTA immediately into the brain ventricles of the animals. We selected a minimal dose of 10–15 mmoles for the whole rate 210–240 g in mass. This dose is many times less than the dose that had been inserted into the blood of these animals. As has been found earlier, respiration is completely paralyzed at the rat body temperature 17–18°C. The insertion of this dose of EDTA into the brain ventricles restored the respiration in its frequency and amplitude in 10–15 min, though still far from the norm, that is, the respiration center acquired a certain resistance to cold. Later, we carried out many experiments and confirmed all the results [6]. That means an inhibiting effect of cold on thermoregulation, respiration, and circulation and removal of the cold paralysis from these functions at the expense of activation of peripheral

This is another method of saving a man from death during hypothermia.

**Temperature in the brain, °C**

15 16 17.6 0 17 25 17.2 18.4 19.7 0 21 20 14 15 16.3 0 17 30 14.5 15.3 16.6 0 23 10 15.5 17.4 18.7 0 24 24 14.5 15.8 17.1 0 28 18 17 18.4 19.3 0 19 14 **15.4 ± 0.5 16.6 ± 0.5 17.9 ± 0.5 0 21.3 ± 1.5 20.4 ± 2.6**

Usually, artificial ventilation is considered as a help for the lungs in supplying an organism with oxygen. This is so indeed. A conventional artificial ventilation by manual operation without a special device may appear low efficient and give no expected result for 1 or even 2

It is seen from **Tables 5** and **6** that the lung respiration disappeared in the animals at the temperatures in the rectum 15.4°C, in the esophagus 16.6°C, in the brain 17.9°C (**Table 5**). In 12–15 min, when the temperature decreased by 1.5–2.0°C more, we switched on the artificial

> **Respiration frequency, cycles/**

**Frequency of the heart contractions, imp/min**

**Arterial blood pressure, mm Hg**

**min**

**Table 5.** Arrest of respiration and an abrupt decrease in the arterial blood pressure and in the frequency of the heart

and central thermosensors.

156 Resuscitation Aspects

**3.3. Artificial ventilation**

**Temperature in the rectum, °C**

h of its use even if there is a weak circulation.

**Temperature in the esophagus, °C**

contractions after the animals stay in water with the temperature 8–9°C.

ventilation. Two min after switching on the artificial ventilation, as is seen from **Table 6**, a distinct increase in the frequency of the heart contractions and in the blood pressure occurred, which is necessary for increasing the muscle heat production. If at this point we stopped cooling the animal, that is, removed it from cold water, artificial ventilation resulted in further increase in the frequency of the heart contractions and in the blood pressure, and in 2.5–3.5 h the animal restored completely the normal frequency of the heart contractions and the normal frequency of respiration and arterial blood pressure. But if the artificial ventilation was absent, at this low body temperature, the heart work gradually slowed down, oxygen consumption decreased, and the blood pressure decreased to zero. The animal died.

### **3.4. The last reserve for saving a homoeothermic organism from cold**

Up to 0°C cold does not destroy the construction of the tissues. Consequently, no mechanical destructions of the tissues occur in the death from cold. In a complete physiological rest, the organism tissues consume a physiological minimum of energy. In a man of average weight and age, the energy consumption on the level of normal metabolism is about 1860 kcal per day. This is the required level of energy for maintaining all the living processes in various organs and tissues of a man at a relative rest. If a man is cooled and his average body temperature decreases, the energy consumption also decreases naturally. If a decrease in the energy supply of the tissues appears to be lower than the required quantity, under specific conditions, the tissues die. The last reserve for maintaining the living ability of the tissue is the limit of its temperature decrease (up to 0°C) and the limit of the decrease in the oxygen consumption. With the aim of preventing the animal brain from being devoid of the blood influx and of the minimum of oxygen, we slightly warmed up the heart to 19–20°C. Under these conditions, the heart retained its living ability and provided the brain with a minimum of oxygen and energy at its temperature of about 0°C. This means that under a sufficiently slow and careful rewarming, the heart, the brain, and the organism as a whole can still return to life. **Figure 3** shows one of the experiments of this series. As can be seen from the figure, the brain, after the

**Figure 3.** Cooling the rat brain to 1°C under artificial respiration, and local warming the heart retaining the arterial blood pressure at the level 40–45 mm Hg. *X*-axis—the time, h. *Y*-axis to the left—the temperature in the brain and in the rectum; to the right—arterial blood pressure, mm Hg. (1) Arterial blood pressure; (2) to of the heart; (3) to in the rectum; (4) to in the brain; (5) the beginning of cooling the animal; (6) the beginning of warming up; (7) switching on the artificial respiration; (8) switching off the artificial respiration.

beginning of cooling, retained the temperature close to 0°C for a period of about 1.5 h. After the beginning of a careful rewarming, the brain temperature started to increase rapidly, and so did the arterial blood pressure. This experiment showed that the brain retained its living ability and still could exert control over the circulation being at a temperature close to 0°C for about an hour and a half. These animals after a complete resuscitation did not differ in anything from the control rats. This is a very important fact both for the theory of living activity of various animals and from the point of view of practical medicine. This supports the old observations of Andjus on overcooled rats [1]. Now we know that a severe minimum of metabolism is retained up to the lowest temperatures of about −100 or −130°C [11]. At such temperatures, the tissues acquire a complete independence from further decreases in temperature, since they have no need in energy anymore and pass into "eternal" existence without energy.

### **4. Conclusions**

In this short chapter, we gave several sufficiently impressive remarks about the physiological mechanisms of the death and physiological mechanisms of resuscitation of mammals and humans during deathly hypothermia. As has been noted, cold does not destroy the construction of tissues. Ultimately, it only denudes the tissues of oxygen. According to a known axiom, only oxygen releases energy necessary for the living activity of all the organs and tissues as the result of oxidation reactions with carbohydrates, fats, and proteins. There is no alternative to oxygen. Therefore, hypoxia and cold are almost to the same extent responsible for the result and for resuscitation during hypothermia. This is an important reasoning. We hope that medicine will estimate it highly enough and will use it.

In practical medicine, the arrest of respiration and an abrupt decrease in the body temperature are the reasons for sending the "corps" to a morgue. Our experiments show that there are many prerequisites for resuscitation of the victim of overcooling. We suggest that this property of a living material to retain the living ability during a complete loss of the main life symptoms will make possible for the future science the creation of a living creature, which would lose life for centuries and recover after this great period of time. Broadly speaking, the conservation of life with cold is a large and badly developed problem. Of course, for the complete success of this act, a hard and long work is necessary, in the first place the study of the mechanisms of heat production in mammals and the reasons for its decrease up to a complete arrest. The latter is the main trend of our studies.

### **Author details**

Kirill P. Ivanov

Address all correspondence to: kpivanov@nc2490.spb.edu

Laboratory for Physiology of Thermoregulation and Bioenergetics, I.P. Pavlov Institute of Physiology, Russian Academy of Sciences, St. Petersburg, Russia

### **References**

beginning of cooling, retained the temperature close to 0°C for a period of about 1.5 h. After the beginning of a careful rewarming, the brain temperature started to increase rapidly, and so did the arterial blood pressure. This experiment showed that the brain retained its living ability and still could exert control over the circulation being at a temperature close to 0°C for about an hour and a half. These animals after a complete resuscitation did not differ in anything from the control rats. This is a very important fact both for the theory of living activity of various animals and from the point of view of practical medicine. This supports the old observations of Andjus on overcooled rats [1]. Now we know that a severe minimum of metabolism is retained up to the lowest temperatures of about −100 or −130°C [11]. At such temperatures, the tissues acquire a complete independence from further decreases in temperature, since they have no need in energy anymore and pass into "eternal" existence without energy.

**Figure 3.** Cooling the rat brain to 1°C under artificial respiration, and local warming the heart retaining the arterial blood pressure at the level 40–45 mm Hg. *X*-axis—the time, h. *Y*-axis to the left—the temperature in the brain and in the

in the brain; (5) the beginning of cooling the animal; (6) the beginning of warming up; (7) switching on the artificial

of the heart; (3) to

in the rectum;

rectum; to the right—arterial blood pressure, mm Hg. (1) Arterial blood pressure; (2) to

respiration; (8) switching off the artificial respiration.

In this short chapter, we gave several sufficiently impressive remarks about the physiological mechanisms of the death and physiological mechanisms of resuscitation of mammals and humans during deathly hypothermia. As has been noted, cold does not destroy the construction of tissues. Ultimately, it only denudes the tissues of oxygen. According to a known axiom, only oxygen releases energy necessary for the living activity of all the organs and tissues as the result of oxidation reactions with carbohydrates, fats, and proteins. There is no alternative to oxygen. Therefore, hypoxia and cold are almost to the same extent responsible for the result and for resuscitation during hypothermia. This is an important reasoning. We

hope that medicine will estimate it highly enough and will use it.

**4. Conclusions**

(4) to

158 Resuscitation Aspects


**Provisional chapter**

### **Strategies of Neuroprotection after Successful Resuscitation Resuscitation**

**Strategies of Neuroprotection after Successful** 

DOI: 10.5772/intechopen.70593

Enikő Kovács and Endre Zima Enikő Kovács and Endre Zima Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70593

### **Abstract**

[9] Hochachka PW. Different strategies against hypoxia and hypothermia. Science.

[10] Ivanov KP. Resuscitation of vital activity after cold arrest of respiration by physiological methods without rewarming the body. Vestnik Rossiiskoi Akademii Meditsinskikh

[11] Lozino-Lozinskii LK. Essay About Criobiology. Leningrad: Nauka; 1972. p. 280 [In

Nauk – Annals of Russian Academy of Medical Sciences. 2014;**7**-**8**:5-9

1986;**231**:234-241

Russian]

160 Resuscitation Aspects

Post-cardiac arrest syndrome (PCAS) incorporates post-cardiac arrest brain injury, postcardiac arrest myocardial dysfunction, systemic ischemia/reperfusion syndrome and the precipitating pathology. Brain injury remains the leading cause of death in the postcardiac arrest period. One of our main goals during post-resuscitation care is to guide a proper neuroprotective strategy. We are going to summarize the tools of neuroprotection in post-cardiac arrest therapy. The role of normoxia/normocapnia, normoglycemia, seizure control, sedation and pharmacologic strategies will be discussed in brief. The handling of temperature management and the management of hemodynamic variables to secure satisfactory cerebral perfusion will be worked out in details. Targeted temperature management is the main tool of neuroprotection in post-cardiac arrest therapy. We are going to conclude the principles of temperature control after successful resuscitation pointing out its beneficial effects. This method has also several complications that are going to be discussed highlighting its hemodynamic impacts. There is no evidence about target hemodynamic parameters during post-cardiac arrest syndrome to maintain cerebral perfusion neither about the most effective hemodynamic monitoring system. We are presenting preliminary data of our study where we investigate the effect of PiCCO™ (Pulse index Continous Cardiac Output) monitoring on the outcome in this patient group.

**Keywords:** post-cardiac arrest syndrome, post-cardiac arrest brain injury, post-resuscitation therapy, targeted temperature management, hemodynamic parameters

### **1. Introduction**

Sudden cardiac arrest is one of the leading causes of death in Europe [1]. The outcome is still very poor: the hospital discharge varies between 7 and 10% after out-of-hospital cardiac arrest (OHCA) and it is approximately 25% after in-hospital cardiac arrest (IHCA) [1]. The chain of

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

survival describes links that lead to a successful resuscitation [2]. The fourth element covers proper post-resuscitation care to restore quality of life. It is well known that the management of post-resuscitation cardiac arrest syndrome affects outcome and it is an important part of the resuscitation process. Pointing out the growing importance of post-resuscitation therapy, the European Resuscitation Council (ERC) introduced a separate chapter about post-resuscitation care in the 2015 guidelines [3]. One of the key elements to improve survival rate after sudden cardiac arrest may be the enhancement of post-resuscitation therapy.

The post-cardiac arrest brain injury remains the main cause of mortality in the post-cardiac arrest period, being as high as 68% after OHCA and 25% after IHCA [4]. These data show that one of our leading goals during post-resuscitation therapy is to prevent secondary brain damage and guide a proper neuroprotective therapy.

We are going to point out the importance and process of recent neuroprotective strategies in this chapter. The role of normoxia, normocapnia, normoglycemia, seizure control, sedation and pharmacotherapy will be discussed in brief and we will work out in more details the place of control of hemodynamic parameters and targeted temperature management (TTM) in post-cardiac arrest condition.

### **2. Post-cardiac arrest syndrome**

The post-resuscitation disease, later called post-cardiac arrest syndrome (PCAS) was first described in 1972 by Vladimir Negovsky as the unnatural pathophysiological state created by successful cardiopulmonary resuscitation (CPR) once resumption of spontaneous circulation has been achieved after whole body ischemia [5].

Post-cardiac arrest syndrome is the unique and complex combination of pathophysiological processes, including post-cardiac arrest brain injury, post-cardiac arrest myocardial dysfunction, systemic ischemia-reperfusion response and the unresolved pathological process causing cardiac arrest [6]. The contribution of each of these components in an individual patient depends on several factors including comorbidities, duration of the ischemic insult and the cause of cardiac arrest itself.

### **2.1. Systemic ischemia-reperfusion response**

The pathophysiology of PCAS is very complex and contains processes that are still not completely understood. It is dominated by ischemia and reperfusion followed by systemic inflammatory response syndrome (SIRS). The reduced oxygen supply during ischemia or the so-called "no-flow phase" brings a decrease in adenosine-triphosphate synthesis and leads to cell membrane depolarization and opens the voltage-dependent calcium channels. Intracytoplasmic calcium level increases as a consequence that is responsible for cell damage. During reperfusion or the "low-flow phase", blood flow restores but oxygen radical species are formed. The hydroxyl radical is cytotoxic and causes cell death [7]. The plasma of patients after OHCA was analyzed and an acute pro-oxidant state within the cells was showed [8]. Cytokine production, activation of complements and expression of leukocyte adhesion molecules stimulate the activation of polymorphonuclear neutrophils and lead to systemic inflammation and multiorgan failure. Inflammatory response syndrome is associated with changes of hemostasis effecting secondary damage in endothelium that is followed by thrombus formation and increased capillary permeability [9]. It is important to point out that the worsening of visceral lesions occurs during reperfusion and is extended over the first hours, explaining the potential efficacy of delayed TTM. The clinical manifestation of PCASinduced inflammatory response reaction shows a lot of similarities with sepsis [9]. The clinical picture is dominated by hemodynamic instability in the first hours and days. It leads to organ hypoperfusion if untreated and a consecutive multiorgan failure. The hypoperfusion of brain, caused by these hemodynamic changes, may lead to secondary brain damage and worse neurological outcome in this patient group.

### **2.2. Post-cardiac arrest brain injury**

survival describes links that lead to a successful resuscitation [2]. The fourth element covers proper post-resuscitation care to restore quality of life. It is well known that the management of post-resuscitation cardiac arrest syndrome affects outcome and it is an important part of the resuscitation process. Pointing out the growing importance of post-resuscitation therapy, the European Resuscitation Council (ERC) introduced a separate chapter about post-resuscitation care in the 2015 guidelines [3]. One of the key elements to improve survival rate after

The post-cardiac arrest brain injury remains the main cause of mortality in the post-cardiac arrest period, being as high as 68% after OHCA and 25% after IHCA [4]. These data show that one of our leading goals during post-resuscitation therapy is to prevent secondary brain dam-

We are going to point out the importance and process of recent neuroprotective strategies in this chapter. The role of normoxia, normocapnia, normoglycemia, seizure control, sedation and pharmacotherapy will be discussed in brief and we will work out in more details the place of control of hemodynamic parameters and targeted temperature management (TTM)

The post-resuscitation disease, later called post-cardiac arrest syndrome (PCAS) was first described in 1972 by Vladimir Negovsky as the unnatural pathophysiological state created by successful cardiopulmonary resuscitation (CPR) once resumption of spontaneous circulation

Post-cardiac arrest syndrome is the unique and complex combination of pathophysiological processes, including post-cardiac arrest brain injury, post-cardiac arrest myocardial dysfunction, systemic ischemia-reperfusion response and the unresolved pathological process causing cardiac arrest [6]. The contribution of each of these components in an individual patient depends on several factors including comorbidities, duration of the ischemic insult and the

The pathophysiology of PCAS is very complex and contains processes that are still not completely understood. It is dominated by ischemia and reperfusion followed by systemic inflammatory response syndrome (SIRS). The reduced oxygen supply during ischemia or the so-called "no-flow phase" brings a decrease in adenosine-triphosphate synthesis and leads to cell membrane depolarization and opens the voltage-dependent calcium channels. Intracytoplasmic calcium level increases as a consequence that is responsible for cell damage. During reperfusion or the "low-flow phase", blood flow restores but oxygen radical species are formed. The hydroxyl radical is cytotoxic and causes cell death [7]. The plasma of patients after OHCA was analyzed and an acute pro-oxidant state within the cells was

sudden cardiac arrest may be the enhancement of post-resuscitation therapy.

age and guide a proper neuroprotective therapy.

in post-cardiac arrest condition.

162 Resuscitation Aspects

cause of cardiac arrest itself.

**2. Post-cardiac arrest syndrome**

has been achieved after whole body ischemia [5].

**2.1. Systemic ischemia-reperfusion response**

The anoxic-ischemic neurological damages remain the leading cause of death occurring in patients resuscitated from cardiac arrest [4]. Its clinical manifestation is very widespread: coma, seizures, myoclonus, varying degrees of neurocognitive dysfunction and brain death may occur [10].

The neurological damage is initiated during "no-flow phase", but is accelerated during the "low-flow period". The triggers of brain injury after cardiac arrest and a successful resuscitation are: excitotoxicity, disrupted calcium homeostasis, formation of free radicals, activation of protease cascades and apoptosis signaling pathways [11, 12]. Most of these pathways activate over hours to days after the return of spontaneous circulation (ROSC). If cardiac arrest is prolonged, failure of microcirculatory reperfusion may appear despite adequate cerebral perfusion pressure (CPP) leading to micro-infarctions. On the other hand, in the first minutes immediately after ROSC, a macroscopic hyperemia may occur that is caused by elevated CPP and impaired autoregulation [13]. As a consequence brain edema and reperfusion injury will exacerbate. Mullner et al. showed that a higher mean arterial pressure (MAP) did not improve the neurological outcome in the first 5 minutes after ROSC but if they were kept at a higher MAP in the first 2 hours after ROSC, the neurological outcome improved [14]. There are growing data to show that overload of oxygen during the initial phase after ROSC may be also harmful and can exacerbate cerebral damage through mitochondrial injury and free radical production [15].

Secondary brain injury may be evoked by a number of insults caused mainly by inappropriate post-cardiac arrest treatment in the first hours and days after cardiac arrest: hypo/hyperoxia, hypo/hypercapnia, hypotension, hypo/hyperglycemia, pyrexia, impaired cerebral autoregulation and brain edema.

One of the consequences of the primary brain damage is the impairment in cerebral autoregulation, however human data are limited [13]. It results that the cerebral perfusion varies with CPP in the acute and subacute phase of the disease. Experimental and clinical studies show that cerebral blood flow (CBF) and metabolic rate of cerebral oxygen consumption is decreased in the first 24–48 hours after ROSC due to increased cerebral vascular resistance [16].

Specific brain regions appear to be most commonly affected with events causing poor systemic circulation [17]. These regions are insulted because they lie in watershed vascular areas or their neurons are located at areas with a higher metabolic rate and oxygen/glucose demand more vulnerable to ischemia.

The neurological syndromes that occur in cardiac arrest survivors can be partially explained by the focal areas of brain injury [17]. The CA1 pyramidal neurons of the hippocampus are commonly damaged with prolonged ischemia, resulting impairment in memory functioning. Cerebellar Purkinje cell injury may result in ataxia, commonly manifesting as a gait disturbance from axial instability. Other commonly affected neurons include thalamic reticular neurons, the medium-sized striatal neurons and the pyramidal neurons in the layers 3, 5 and 6 of neocortex. With more prolonged periods of ischemia, arterial border zone regions can be appreciated macroscopically on neuroimaging. Patients with prolonged period of hypoxia followed by a global ischemic event appears to be susceptible to preferential injury to the subcortical white matter, in what appears to be a primary myelinolytic process. It is postulated that injury occurs preferentially in the subcortical matter in situations in which there is a significant period of alveolar hypoventilation, progressive acidosis and severe metabolic disturbances in the peri-arrest period.

### **2.3. Post-cardiac arrest myocardial dysfunction**

Post-cardiac arrest myocardial dysfunction also contributes to the low survival rate after OHCA and IHCA [4]. However, this phenomenon is responsive to therapy and is reversible. Heart rate and blood pressure may be extremely variable immediately after ROSC caused by the transient increase in serum catecholamine concentration of endogenous and exogenous origin. When post-cardiac arrest myocardial dysfunction occurs, it can be detected within minutes of ROSC by appropriate monitoring. During the period with significant dysfunction, coronary blood flow is not reduced, indicating a true stunning phenomenon rather than permanent injury or infarction. This global dysfunction is transient and full recovery can occur, usually between 24 and 48 hours after the cardiac arrest. The responsiveness of post-cardiac arrest global myocardial dysfunction to inotropic drugs is well documented in animal studies [18]. In swines, dobutamine infusions dramatically improve systolic (left ventricular ejection fraction) and diastolic (isovolumetric relaxation of left ventricle) dysfunction after cardiac arrest [19].

### **2.4. Persistent precipitating pathology**

The pathophysiology of post-cardiac arrest syndrome is commonly complicated by persisting acute pathology that caused or contributed to the cardiac arrest itself. On the other hand differential diagnosis and management of the precipitating pathology can be made more difficult by the symptoms and pathophysiologic changes caused by post-cardiac arrest syndrome. Some of the most frequent conditions leading to cardiac arrest are the followings: acute coronary syndrome, acute aortic syndromes, pulmonary embolism, pulmonary diseases (COPD, asthma bronchiale, pneumothorax), hypovolemia due to hemorrhage or dehydration, sepsis, central nervous system diseases and various toxidromes. The potential treatments are interventions specific for each disease guided by the patient's condition.

### **3. Tools of neuroprotection in post-resuscitation care**

### **3.1. Normoxia and normocapnia**

Specific brain regions appear to be most commonly affected with events causing poor systemic circulation [17]. These regions are insulted because they lie in watershed vascular areas or their neurons are located at areas with a higher metabolic rate and oxygen/glucose demand

The neurological syndromes that occur in cardiac arrest survivors can be partially explained by the focal areas of brain injury [17]. The CA1 pyramidal neurons of the hippocampus are commonly damaged with prolonged ischemia, resulting impairment in memory functioning. Cerebellar Purkinje cell injury may result in ataxia, commonly manifesting as a gait disturbance from axial instability. Other commonly affected neurons include thalamic reticular neurons, the medium-sized striatal neurons and the pyramidal neurons in the layers 3, 5 and 6 of neocortex. With more prolonged periods of ischemia, arterial border zone regions can be appreciated macroscopically on neuroimaging. Patients with prolonged period of hypoxia followed by a global ischemic event appears to be susceptible to preferential injury to the subcortical white matter, in what appears to be a primary myelinolytic process. It is postulated that injury occurs preferentially in the subcortical matter in situations in which there is a significant period of alveolar hypoventilation, progressive acidosis and severe metabolic

Post-cardiac arrest myocardial dysfunction also contributes to the low survival rate after OHCA and IHCA [4]. However, this phenomenon is responsive to therapy and is reversible. Heart rate and blood pressure may be extremely variable immediately after ROSC caused by the transient increase in serum catecholamine concentration of endogenous and exogenous origin. When post-cardiac arrest myocardial dysfunction occurs, it can be detected within minutes of ROSC by appropriate monitoring. During the period with significant dysfunction, coronary blood flow is not reduced, indicating a true stunning phenomenon rather than permanent injury or infarction. This global dysfunction is transient and full recovery can occur, usually between 24 and 48 hours after the cardiac arrest. The responsiveness of post-cardiac arrest global myocardial dysfunction to inotropic drugs is well documented in animal studies [18]. In swines, dobutamine infusions dramatically improve systolic (left ventricular ejection fraction) and diastolic (isovolumetric relaxation of left ventricle) dysfunction after cardiac arrest [19].

The pathophysiology of post-cardiac arrest syndrome is commonly complicated by persisting acute pathology that caused or contributed to the cardiac arrest itself. On the other hand differential diagnosis and management of the precipitating pathology can be made more difficult by the symptoms and pathophysiologic changes caused by post-cardiac arrest syndrome. Some of the most frequent conditions leading to cardiac arrest are the followings: acute coronary syndrome, acute aortic syndromes, pulmonary embolism, pulmonary diseases (COPD, asthma bronchiale, pneumothorax), hypovolemia due to hemorrhage or dehydration, sepsis, central nervous system diseases and various toxidromes. The potential treatments are inter-

ventions specific for each disease guided by the patient's condition.

more vulnerable to ischemia.

164 Resuscitation Aspects

disturbances in the peri-arrest period.

**2.4. Persistent precipitating pathology**

**2.3. Post-cardiac arrest myocardial dysfunction**

Arterial oxygen could be a modifiable component of patient care after cardiac arrest in order to deliver better neurological outcomes.

In the search for modifiable ROSC factors, the role of supplemental oxygen, which is often administered in high concentrations to patients after cardiac arrest, has come into controversy. Early oxygen administration can influence oxidative metabolism, respiratory markers, vasoconstrictive status and blood flow, and may thus be an important predictor of outcome [20]. Although it is intuitive that insufficient oxygen delivery can exacerbate cerebral anoxia, excessive oxygen delivery can also be harmful by increasing the amount of oxygen free radicals and subsequent reperfusion injury. Pure oxygen therapy after cardiac arrest has previously been shown to worsen neurological outcome in animal models and exposure to hypocapnia and hypercapnia after ROSC has been associated with poor neurological function at hospital discharge [20].

Oxygen creates a paradox when delivered to the damaged brain. If there is too little oxygen then potential anoxic injury may occur, while too much oxygen may increase the production of oxygen free radicals, leading to cellular injury and apoptosis [21].

In clinically relevant experimental models of cardiac arrest, hyperoxia has been shown to worsen the severity of oxidative stress, causing a greater loss of pyruvate dehydrogenase complex, impairment of oxidative energy metabolism and higher oxidation of brain lipids, culminating in more severe brain histopathologic changes and worse neurological deficits [21].

Kilgannon et al. reported data from adult intensive care units (ICU) of 120 US hospitals incorporated in a large administrative database named "Project IMPACT" and it included 6326 patients divided into three groups (hyperoxia, normoxia and hypoxia) according to the first partial pressure of oxygen in arterial blood (PaO2 ) obtained within 24 hours following ICU arrival [22]. Arterial hyperoxia and hypoxia were defined as a PaO<sup>2</sup> higher than 300 mmHg and a PaO2 lower than 60 mmHg, respectively. The authors found that in-hospital mortality was significantly higher in the hyperoxia group as compared with both the normoxia and the hypoxia group (63 vs. 45 and 57%, respectively).

In addition, among hospital survivors, patients with hyperoxia had a significantly lower likelihood of independent functional status at hospital discharge as compared with patients with normoxia (29 vs. 38%, respectively).

A secondary analysis showed a dose-dependent association between supranormal PaO2 and risk of in-hospital death [23]. In particular, 25 mmHg increase in PaO2 was associated with 6% increase in relative risk of death. Given that the median post-resuscitation PaO2 in this sample was 231 mmHg, it appears that a high proportion of adult patients resuscitated from cardiac arrest have exposure to supranormal oxygen tension. Considering the linear increase in risk of death associated with PaO2 , these results suggest a need for clinical trials of a controlled oxygen therapy after resuscitation from cardiac arrest.

The ERC guidelines for post-resuscitation care recommend the avoidance of unnecessary arterial hyperoxia and a controlled reoxygenation strategy targeting an arterial oxygen saturation of 94–96% [3].

Carbon-dioxide (CO2 ) may have neuroprotective properties, as it is thought that mild increase in its level improves cerebral perfusion and it has anticonvulsant, anti-inflammatory and antioxidants properties [24]. On the other hand, its decrease has been associated with neuronal injury in animal models and after traumatic brain injury.

Schneider et al. published an observational cohort study to observe the relationship between arterial CO2 partial pressure (PaCO2 ) and outcome in 16,542 patients admitted to the ICU after cardiac arrest [24]. This study was the first to report the relationship between PaCO<sup>2</sup> and mortality and an alternative marker of likely neurological outcome.

Within 24 hours of admission, about one in five patients had at least one episode of hypercapnia. Such abnormal values most often occurred within the first 2 hours of ICU admission and that hypercapnia may have been associated with non-ventricular fibrillation (VF) cardiac arrest and underlying respiratory disease. Compared with normocapnia, hypocapnia was associated with a greater risk of death and a lower likelihood of being discharged home among survivors.

On the other hand, hypercapnia was associated with similar mortality or outcome rates to normocapnia but with a higher chance of being discharged home among survivors.

Cerebral autoregulation is impaired after ROSC, but cerebrovascular reactivity to CO2 is preserved. A decrease in PaCO2 determines cerebral vasoconstriction with a consequent reduction of cerebral blood flow (CBF) whereas the opposite occurs when PaCO<sup>2</sup> is increased. There is evidence that CBF could be decreased in the post-resuscitation phase due to an imbalance between local vasodilators and vasoconstrictors but CO2 -mediated vasodilatation might reverse these abnormalities.

The ERC guidelines suggest adjusting ventilation to achieve normocapnia and monitoring the ETCO2 (end tidal carbon dioxide level) and arterial blood gas values during post-resuscitation therapy [3].

### **3.2. Glucose control**

Any stressful systemic injury, such as cardiac arrest, evokes a complex response involving glucoregulatory hormones such as catecholamines, glucagon and glucocorticoids. The increase of these hormones may result in glucose intolerance and hyperglycemia, as they can mobilize glucose and other energy substrates from storage pools. Glucose metabolism via anaerobic glycolysis is the only brain energy pathway that can sustain energy metabolism for any significant period of time (minutes) during an ischemic episode.

Unfortunately, it is common following CPR that the transport of glucose to brain tissues may become inadequate to satisfy cerebral metabolism [25]. Consequently, when cerebral perfusion is compromised, moderate hyperglycemia may facilitate glucose transport through the elevated blood glucose diffusion gradient that maximizes cellular glucose uptake.

On one hand, there are various studies that have shown that high blood glucose levels after ROSC are associated with increased mortality and poor neurological outcome for patients who experience OHCA. For IHCA patients, Beiser et al. reported that for patients without diabetes mellitus, both hypoglycemia and hyperglycemia were associated with decreased survival odds. However, for patients with diabetes mellitus, there was little association between blood glucose level and survival, except with extreme hyperglycemia [26].

On the other hand, there are several studies that have found out that normalization of blood glucose levels in critically ill patients with brain injury may be associated with greater risk of critical reductions in brain glucose levels and energy crises [27]. Therefore, acute stress hyperglycemia noted during the early post-ROSC phase might be a physiologic, rather than a pathologic response and attempts at interfering with this complex adaptive response may be harmful rather than protective.

It is proven that hypoglycemia needs to be avoided in critically ill patients. In a study by Arabi et al., mortality in patients with hypoglycemia was multipled compared to patients with conventional therapy [28]. Unrecognized episodes of hypoglycaemia are more harmful than the benefit of strict normoglycemia, especially in patients with brain damage [29].

The American Heart Association (AHA) guidelines do not recommend a target blood glucose range for post-ROSC patients [30]. The ERC guidelines suggest that blood glucose level should be maintained below 180 mg/dl (10 mmol/L) in these patients and that hypoglycemia should be strictly avoided [3].

### **3.3. Seizures control**

The ERC guidelines for post-resuscitation care recommend the avoidance of unnecessary arterial hyperoxia and a controlled reoxygenation strategy targeting an arterial oxygen satu-

in its level improves cerebral perfusion and it has anticonvulsant, anti-inflammatory and antioxidants properties [24]. On the other hand, its decrease has been associated with neuronal

Schneider et al. published an observational cohort study to observe the relationship between

Within 24 hours of admission, about one in five patients had at least one episode of hypercapnia. Such abnormal values most often occurred within the first 2 hours of ICU admission and that hypercapnia may have been associated with non-ventricular fibrillation (VF) cardiac arrest and underlying respiratory disease. Compared with normocapnia, hypocapnia was associated with a greater risk of death and a lower likelihood of being discharged home

On the other hand, hypercapnia was associated with similar mortality or outcome rates to

is evidence that CBF could be decreased in the post-resuscitation phase due to an imbal-

The ERC guidelines suggest adjusting ventilation to achieve normocapnia and monitoring the

Any stressful systemic injury, such as cardiac arrest, evokes a complex response involving glucoregulatory hormones such as catecholamines, glucagon and glucocorticoids. The increase of these hormones may result in glucose intolerance and hyperglycemia, as they can mobilize glucose and other energy substrates from storage pools. Glucose metabolism via anaerobic glycolysis is the only brain energy pathway that can sustain energy metabolism for

Unfortunately, it is common following CPR that the transport of glucose to brain tissues may become inadequate to satisfy cerebral metabolism [25]. Consequently, when cerebral perfusion is compromised, moderate hyperglycemia may facilitate glucose transport through the

elevated blood glucose diffusion gradient that maximizes cellular glucose uptake.

(end tidal carbon dioxide level) and arterial blood gas values during post-resuscitation

normocapnia but with a higher chance of being discharged home among survivors.

tion of cerebral blood flow (CBF) whereas the opposite occurs when PaCO<sup>2</sup>

ance between local vasodilators and vasoconstrictors but CO2

any significant period of time (minutes) during an ischemic episode.

Cerebral autoregulation is impaired after ROSC, but cerebrovascular reactivity to CO2

after cardiac arrest [24]. This study was the first to report the relationship between PaCO<sup>2</sup>

injury in animal models and after traumatic brain injury.

mortality and an alternative marker of likely neurological outcome.

partial pressure (PaCO2

) may have neuroprotective properties, as it is thought that mild increase

) and outcome in 16,542 patients admitted to the ICU

determines cerebral vasoconstriction with a consequent reduc-

and

is pre-

is increased. There


ration of 94–96% [3].

166 Resuscitation Aspects

Carbon-dioxide (CO2

arterial CO2

among survivors.

served. A decrease in PaCO2

reverse these abnormalities.

ETCO2

therapy [3].

**3.2. Glucose control**

Many of patients who remain comatose after successful resuscitation, will suffer from seizures. The appearance of seizures may be variable, from single focal onset through myoclonus to generalized tonic-clonic fit.

Acute post-hypoxic myoclonus (PHM) occurs in about 18–25% of these patients, typically within the first 24 hours after CPR [31]. Commonly, the myoclonus appears days or weeks after the hypoxic episode when consciousness is regained. Myoclonus is a hyperkinetic movement disorder characterized as a sudden, jerky, shock-like movement. It can involve different body parts individually (focal), contiguously (segmental) or asynchronously (multifocal). When repetitive, the jerks may be regular or irregular, sometimes mimicking tremor.

There are several EEG findings in acute PHM: burst suppression (56%), spike-wave activity (37%), myoclonic status epilepticus (31%), diffuse slow background and waves (21%) and alpha coma (7%). These severe diffuse EEG abnormalities are consistent with marked diffuse cerebral dysfunction.

The exact neuronal damage and pathophysiology that gives origin to acute PHM is not clear. [32] Treatment is indeed challenging and no published guidelines exist as the hypoxic injury may lead to mixed and varying clinical findings of this myoclonus. Moreover, a drug treatment for one type may not work well in another or may even induce worsening [33].

### **3.4. Sedation**

Sedative agents play a vital role in the management of patients with an acute brain damage. However, there is no evidence to support the defined duration of sedation neither the agent that should be used after cardiac arrest. Sedation acts to protect the brain against the extension of primary acute brain injury and secondary cerebral insults [34]. It has always been used in association with cooling methods, since the first non-randomized trials investigating targeted temperature management or therapeutic hypothermia (TH) effects on outcome. In this setting sedatives were often co-administered with muscle relaxants.

The main goals to use sedation during targeted temperature management are the reduction of oxygen consumption, control of shivering, the reduction of agitation and ventilator dyssynchrony, which may be detrimental for neurological recovery [34]. Clinically detectable shivering can increase systemic metabolic rate with 24–160% above baseline resting energy expenditure and increase inflammatory markers. The use of neuromuscular blocking agents to avoid shivering is controversial and we think it should be the agent of an ultimate case because it may mask seizures and its prolonged use (more than 1 day) may lead to muscle weakness, prolonged ventilation and ICU stay.

There are no data about the influence of outcome of sedatives used after cardiac arrest. A combination of hypnotics and opioids is used in the most of cases [35]. Short-acting drugs are preferred, for example, remifentanil, alfentanil and propofol.

### **3.5. Pharmacologic strategies**

There is still lack of proved pharmacological interventions providing neuroprotection for patients after successful resuscitation. However, there are some promising drugs that may have some beneficial effect on neurological recovery in this patient group. Most of these agents have been studied in experimental research and only a few clinical data are achievable.

Xenon is one of the most commonly investigated pharmacologic treatments in post-resuscitation therapy. Pre-clinical studies have shown that it can prevent the development of ischemic-reperfusion brain injury [36]. A randomized single blind trial investigated the cerebroprotective effect of xenon in 110 comatose patients after OHCA [37]. One half of patients received xenon combined with therapeutic hypothermia and the other half was treated only with hypothermic therapy. They did not find any difference in survival and neurologic outcome after 6 months but there was less white matter damage controlled with magnetic resonance imaging (MRI) in the xenon-treated group. On the basis of these findings the efficacy of xenon must be investigated in further clinical trials at this patient group. Also we need to point out its disadvantages: it is still quite expensive and its storage needs special circumstances.

The impact of early high-dose erythropoietin was also investigated in patients after OHCA in a single blind randomized trial but neither mortality, neither Cerebral Performance Category (CPC) scale improved after this treatment, only rate of thrombotic complications increased [38].

Rosuvastatin was shown to improve survival, myocardial function and neurologic recovery in a rat model after successful resuscitation [39]. A combination of three drugs (lovastatin, minocycline and lamotrigine) was also studied in a mouse model after brain ischemia provoked by artery carotid occlusion [40]. As a result a decreased neurological deficit was reached suggesting a potential beneficial effect of this treatment in post-cardiac arrest therapy.

One of the promising, easily achievable and affordable drugs that may have potential benefit in neuroprotection after cardiac arrest is thiamine. It is a type of B vitamins that is essential for the proper functioning of nervous system. It modulates the activity of pyruvate dehydrogenase that is a main enzyme in Krebs cycle. It has been shown that mitochondrial dysfunction and impaired aerobic metabolism may be a cause of cerebral damage after cardiac arrest [41]. This led to the idea to investigate the effect of thiamine in mice after successful resuscitation [42]. Mice treated with thiamine after cardiac arrest had a better 10-day survival and improved neurological outcome than control individuals. The histology also showed an ameliorated brain injury after thiamine treatment. The investigators also checked the activity of pyruvate dehydrogenase in human blood in patients after successful resuscitation and found that it was significantly lowered compared to control healthy volunteers. We think thiamine may be a pharmacological pathway in treating post-cardiac arrest brain injury but its clinical effect and proper dosage need to be investigated in clinical trials.

### **3.6. Targeted temperature management**

### *3.6.1. Principles and guidelines*

**3.4. Sedation**

168 Resuscitation Aspects

Sedative agents play a vital role in the management of patients with an acute brain damage. However, there is no evidence to support the defined duration of sedation neither the agent that should be used after cardiac arrest. Sedation acts to protect the brain against the extension of primary acute brain injury and secondary cerebral insults [34]. It has always been used in association with cooling methods, since the first non-randomized trials investigating targeted temperature management or therapeutic hypothermia (TH) effects on outcome. In

The main goals to use sedation during targeted temperature management are the reduction of oxygen consumption, control of shivering, the reduction of agitation and ventilator dyssynchrony, which may be detrimental for neurological recovery [34]. Clinically detectable shivering can increase systemic metabolic rate with 24–160% above baseline resting energy expenditure and increase inflammatory markers. The use of neuromuscular blocking agents to avoid shivering is controversial and we think it should be the agent of an ultimate case because it may mask seizures and its prolonged use (more than 1 day) may lead to muscle

There are no data about the influence of outcome of sedatives used after cardiac arrest. A combination of hypnotics and opioids is used in the most of cases [35]. Short-acting drugs are

There is still lack of proved pharmacological interventions providing neuroprotection for patients after successful resuscitation. However, there are some promising drugs that may have some beneficial effect on neurological recovery in this patient group. Most of these agents have been studied in experimental research and only a few clinical data are achievable. Xenon is one of the most commonly investigated pharmacologic treatments in post-resuscitation therapy. Pre-clinical studies have shown that it can prevent the development of ischemic-reperfusion brain injury [36]. A randomized single blind trial investigated the cerebroprotective effect of xenon in 110 comatose patients after OHCA [37]. One half of patients received xenon combined with therapeutic hypothermia and the other half was treated only with hypothermic therapy. They did not find any difference in survival and neurologic outcome after 6 months but there was less white matter damage controlled with magnetic resonance imaging (MRI) in the xenon-treated group. On the basis of these findings the efficacy of xenon must be investigated in further clinical trials at this patient group. Also we need to point out its disadvantages: it is still quite expensive and its storage needs special circumstances.

The impact of early high-dose erythropoietin was also investigated in patients after OHCA in a single blind randomized trial but neither mortality, neither Cerebral Performance Category (CPC) scale improved after this treatment, only rate of thrombotic complications increased [38]. Rosuvastatin was shown to improve survival, myocardial function and neurologic recovery in a rat model after successful resuscitation [39]. A combination of three drugs (lovastatin, minocycline and lamotrigine) was also studied in a mouse model after brain ischemia provoked by

this setting sedatives were often co-administered with muscle relaxants.

weakness, prolonged ventilation and ICU stay.

**3.5. Pharmacologic strategies**

preferred, for example, remifentanil, alfentanil and propofol.

Two trials published by the New England Journal of Medicine in 2002, involving patients who remained unconscious after resuscitation from cardiac arrest, compared therapeutic hypothermia (32–34°C for 12–24 hours) with standard treatment [43, 44]. These trials showed a significant improvement in neurologic function and survival with therapeutic hypothermia. This treatment method was incorporated into the resuscitation guidelines in 2005. For more than a decade, mild-induced hypothermia (32–34°C) was the standard of care for patients remaining comatose after resuscitation from OHCA with an initial shockable rhythm, and this has been extrapolated to survivors with initially non-shockable rhythms and to patients with IHCA.

Traditionally, therapeutic hypothermia (TH) refers to deliberate reduction of the core body temperature to a range of 32–34°C in patients who do not regain consciousness after ROSC.

Since the 2015 ERC guidelines, term targeted temperature management (TTM) is suggested to use instead of therapeutic hypothermia and the new recommendation is to keep patients' core temperature between 32 and 36°C [3]. However, this expression is not always unique and many use phrase therapeutic hypothermia for goal temperature 32–34°C and term TTM for goal temperature 36°C.

There are still several unanswered questions regarding targeted temperature management after cardiac arrest. We still do not exactly know which patients benefit from lower and which from a higher level of temperature. Only the detrimental effect of fever is proven of the effects of temperature in post-cardiac arrest syndrome. Further questions are when exactly to start cooling and how long to keep cooling, which still need more clinical trials to be answered.

The 2016 guidelines of American Academy of Neurology (AAN) on reducing brain injury following cardiac arrest try to give a more precise direction how to handle temperature management in this patient group [45].

Because patients with initial rhythm of ventricular fibrillation/ventricular tachycardia (VF/ VT) or pulseless electrical activity (PEA)/asystole differ in causes of cardiac arrest and outcome, the guideline deals separately with these patient groups. It recommends the use of therapeutic hypothermia (32–34°C for 24 hours) if the initial rhythm was VF/VT and patients remain comatose after successful resuscitation. It also says that for patients with an initial rhythm of VF/VT or PEA/asystole TTM (36°C for 24 hours followed by 8 hours of rewarming to 37°C and temperature maintenance below 37.5°C until 72 hours) is likely as effective as TH and may be a good alternative. If the initial rhythm is PEA/asystole, than the use of TH possibly improves outcome over non-hypothermia treatment.

In 2013 a trial to investigate the benefits and harms of two targeted temperature regimens was conducted, called the Targeted Temperature Management (TTM) trial [46].

In the TTM trial, 950 all-rhythm OHCA patients from 36 ICUs in Europe and Australia were randomized for 36 hours of temperature control (comprising 28 hours at the target temperature followed by slow rewarm) at either 33°C or 36°C. Temperature was managed with intravascular or surface cooling devices for 36 hours, while the patients were sedated and mechanically ventilated. TTM at 33°C was associated with decreased heart rate, elevated serum lactate level, the need for increased vasopressor support and a higher extended cardiovascular SOFA score compared with TTM at 36°C. However, it is important to point out the higher proportion of bystander witnessed cardiac arrest (90%) and of bystander CPR (73%). Moreover, the time to start basic life support (BLS) was shorter in both groups, among 1 minute. These facts by themselves would provide an improvement in the outcome of patients regardless the hypothermia. Nevertheless, the median time of ROSC was 25 minutes in both groups.

The TTM trial has also been criticized because the temperature was tightly controlled and it took a short time to reach 33°C, but also because the whole trial cohort was less ill than in previous trials. It should be taken into account that the previous studies were performed several years ago, and that during the last decade the intensive care therapy has improved a lot itself [47].

It is also a very important fact that in TTM trial there was no fever during the therapy. When comparing the TTM trial and the previous trial temperature results, we can appreciate that the temperature after re-warming was lower in the TTM trial [43, 44, 46].

Kaneko et al. conducted an observational study between January 2005 and March 2013 called the J-Pulse-Hypo Japanese prospective cohort. The objective of the study was to identify subgroups of patients who might be suitable candidates for lower targeted temperature during TTM after ROSC [48].

Participants were divided into lower (32–33.5°C) or moderate (34–35°C) temperature groups. In this study a favorable primary outcome was defined as CPC (Cerebral Performance Category) 1–2 on day 30. The subgroups of patients were divided and analyzed in the following way: age ≤60 vs. >60 years and resuscitation interval of ≤30 vs. >30 minutes.

The results demonstrated that the lower temperature group significantly improved the proportion of patients with favorable neurological outcomes in the subgroup of patients with a resuscitation interval of ≤30 minutes. There were some differences between this study and the TTM Trial, including shorter time to reach the targeted temperature (180 minutes), longer time at the targeted temperature (34 hours), and longer re-warming period (3 days).

When to start cooling is also an interesting and still unanswered question regarding TTM. It was shown in preclinical studies that initiating cooling as soon as possible after resuscitation improves neurologic outcome [49]. Clinical studies investigating the beneficial effects of cooling initiated in pre-hospital setting did not show positive outcome. A Cochrane review studied 7 trials (2369 patients) investigating the effect of pre-hospital cooling on survival, cerebral injury, side effects, quality of life and length of hospital stay [50]. There was no difference in survival between pre-hospital and intra-hospital cooling groups, neither in neurologic outcome. The rate of re-arrests was higher among patients who received pre-hospital cooling in four of the investigated trials.

The guidelines of AAN do not suggest the use of pre-hospital cooling while it is ineffective in improving neurological outcome and survival [45]. One of the explanations for this phenomenon may be the fact, which has been already mentioned, that there are some complex mechanisms leading to post-cardiac arrest brain injury appearing some hours after ROSC. On the other hand high volumes of cold infusions are used to initiate TTM during pre-hospital cooling leading to pulmonary edema and complications causing more harm than benefit. We also need to mention the heterogeneity of studied cooling methods in pre-hospital setting. To prove its efficacy or inefficiency further studies are needed.

### *3.6.2. Beneficial effects in post-cardiac arrest syndrome*

Because patients with initial rhythm of ventricular fibrillation/ventricular tachycardia (VF/ VT) or pulseless electrical activity (PEA)/asystole differ in causes of cardiac arrest and outcome, the guideline deals separately with these patient groups. It recommends the use of therapeutic hypothermia (32–34°C for 24 hours) if the initial rhythm was VF/VT and patients remain comatose after successful resuscitation. It also says that for patients with an initial rhythm of VF/VT or PEA/asystole TTM (36°C for 24 hours followed by 8 hours of rewarming to 37°C and temperature maintenance below 37.5°C until 72 hours) is likely as effective as TH and may be a good alternative. If the initial rhythm is PEA/asystole, than the use of TH pos-

In 2013 a trial to investigate the benefits and harms of two targeted temperature regimens was

In the TTM trial, 950 all-rhythm OHCA patients from 36 ICUs in Europe and Australia were randomized for 36 hours of temperature control (comprising 28 hours at the target temperature followed by slow rewarm) at either 33°C or 36°C. Temperature was managed with intravascular or surface cooling devices for 36 hours, while the patients were sedated and mechanically ventilated. TTM at 33°C was associated with decreased heart rate, elevated serum lactate level, the need for increased vasopressor support and a higher extended cardiovascular SOFA score compared with TTM at 36°C. However, it is important to point out the higher proportion of bystander witnessed cardiac arrest (90%) and of bystander CPR (73%). Moreover, the time to start basic life support (BLS) was shorter in both groups, among 1 minute. These facts by themselves would provide an improvement in the outcome of patients regardless the hypothermia. Nevertheless, the median time of ROSC was 25 minutes in both

The TTM trial has also been criticized because the temperature was tightly controlled and it took a short time to reach 33°C, but also because the whole trial cohort was less ill than in previous trials. It should be taken into account that the previous studies were performed several years ago, and that during the last decade the intensive care therapy has improved a

It is also a very important fact that in TTM trial there was no fever during the therapy. When comparing the TTM trial and the previous trial temperature results, we can appreciate that

Kaneko et al. conducted an observational study between January 2005 and March 2013 called the J-Pulse-Hypo Japanese prospective cohort. The objective of the study was to identify subgroups of patients who might be suitable candidates for lower targeted temperature during

Participants were divided into lower (32–33.5°C) or moderate (34–35°C) temperature groups. In this study a favorable primary outcome was defined as CPC (Cerebral Performance Category) 1–2 on day 30. The subgroups of patients were divided and analyzed in the follow-

The results demonstrated that the lower temperature group significantly improved the proportion of patients with favorable neurological outcomes in the subgroup of patients with a

the temperature after re-warming was lower in the TTM trial [43, 44, 46].

ing way: age ≤60 vs. >60 years and resuscitation interval of ≤30 vs. >30 minutes.

sibly improves outcome over non-hypothermia treatment.

groups.

170 Resuscitation Aspects

lot itself [47].

TTM after ROSC [48].

conducted, called the Targeted Temperature Management (TTM) trial [46].

Hypothermia provides significant cardiac and neurological protective effects through different pathways. Hypothermic mechanisms providing myocardial protection include improved energy production during ischemia, increased calcium sensitivity of myocytes, regulation of mitochondrial oxidative phosphorylation and preserved myocardial vascular autoregulation. All of these protective mechanisms would result in increased myocardial contractility.

After a post-anoxic injury, hypothermia may also protect cerebral function through decreasing apoptosis, reducing the release of excitatory (glutamate and dopamine) neurotransmitters, attenuating the reactive oxygen species production, preserving the blood-brain barrier, providing protection of cerebral microcirculation and decreasing intracranial pressure. Hypothermia decreases the cerebral metabolic rate of oxygen by about 6% for each 1°C reduction in core temperature and this may reduce the release of excitatory amino acids and free radicals.

Shivering will increase metabolic and heat production, thus reducing cooling rates. The occurrence of shivering in cardiac arrest survivors who undergo mild induced hypothermia is associated with a good neurological outcome. Occurrence of shivering was similar at a target temperature of 33 and 36°C.

Mild induced hypothermia increases systemic vascular resistance and causes arrhythmias (usually bradycardia). However, the bradycardia caused by mild induced hypothermia may be beneficial: it reduces diastolic dysfunction and its occurrence has been associated with good neurological outcome.

### *3.6.3. Side effects*

Therapeutic hypothermia is an effective tool in neuroprotection after cardiac arrest, however it may cause several side effects that need to be monitored and declined during its use. Polyuria and electrolyte abnormalities such as hypophosphatemia, hypokalemia, hypomagnesemia and hypocalcemia may appear.

Insulin sensitivity and insulin secretion are decreased, that lead to hyperglycemia. Moreover, coagulation system can get impaired and bleeding risk is increased.

Hypothermia can impair immune system and extend infection rates. It is associated with an increased incidence of pneumonia, although the use of prophylactic antibiotics may prevent it to emerge.

The clearance of sedative drugs and neuromuscular blockers is reduced by up to 30% at a core temperature of 34°C. Clearance of sedative and other drugs will be closer to normal at a temperature of 37°C.

### *3.6.4. Practice of cooling*

Whenever the indication is established the hypothermic treatment should be started as soon as possible. The trial performed in 2002 had the induction within 6–26 hours, with a median of 8 hours [43].

Hypothermic treatment and TTM has three phases such as induction of cooling, maintenance and rewarming.

Cooling may be delivered via external, internal and combined cooling methods. External cooling is carried out by traditional icepacks placed on the groin, axilla and sides of neck; surface temperature changer devices with thermo-feedback function such as blankets or selfadhesive plastic fluid-containers or cooling helmets over the head of the patient.

Internal cooling means intrabody cooling as intravascular, intrabladder or intragastrical method. It may be delivered via infusion of 30 ml/kg of 4°C saline, which decreases core temperature by 1.5°C. Intravascular cooling enables more precise control than external methods. The most precise temperature control with the fastest induction, reaction to temperature changes and rewarming is achievable via endovascular heat-exchange catheter. This latter is the most expensive method on the field.

### *3.6.5. Practice of TTM and post-cardiac arrest therapy in Semmelweis University Heart and Vascular Center*


and four intraaortic balloon pumps are available. For patients who need mechanical circulatory support extracorporeal membrane oxygenator (ECMO)/ventricular assist device (VAD) background is available by the cardiac surgeons and cardiac surgical ICU.


### **3.7. Cerebral perfusion**

*3.6.3. Side effects*

172 Resuscitation Aspects

it to emerge.

temperature of 37°C.

*3.6.4. Practice of cooling*

of 8 hours [43].

and rewarming.

*Vascular Center*

nesemia and hypocalcemia may appear.

the most expensive method on the field.

survival with potentially good neurological outcome.

Therapeutic hypothermia is an effective tool in neuroprotection after cardiac arrest, however it may cause several side effects that need to be monitored and declined during its use. Polyuria and electrolyte abnormalities such as hypophosphatemia, hypokalemia, hypomag-

Insulin sensitivity and insulin secretion are decreased, that lead to hyperglycemia. Moreover,

Hypothermia can impair immune system and extend infection rates. It is associated with an increased incidence of pneumonia, although the use of prophylactic antibiotics may prevent

The clearance of sedative drugs and neuromuscular blockers is reduced by up to 30% at a core temperature of 34°C. Clearance of sedative and other drugs will be closer to normal at a

Whenever the indication is established the hypothermic treatment should be started as soon as possible. The trial performed in 2002 had the induction within 6–26 hours, with a median

Hypothermic treatment and TTM has three phases such as induction of cooling, maintenance

Cooling may be delivered via external, internal and combined cooling methods. External cooling is carried out by traditional icepacks placed on the groin, axilla and sides of neck; surface temperature changer devices with thermo-feedback function such as blankets or self-

Internal cooling means intrabody cooling as intravascular, intrabladder or intragastrical method. It may be delivered via infusion of 30 ml/kg of 4°C saline, which decreases core temperature by 1.5°C. Intravascular cooling enables more precise control than external methods. The most precise temperature control with the fastest induction, reaction to temperature changes and rewarming is achievable via endovascular heat-exchange catheter. This latter is

• Protocolisation: our cardiac ICU has a prospective protocol of care to anticipate, monitor, and treat each of the impaired organ functions by optimizing systemic perfusion, restoring metabolic homeostasis and support organ system function to increase the likelihood of

• Technical background: our cardiac ICU has 11 monitored beds, with central monitoring system as well. Seven invasive mechanical ventilators, two non-invasive mechanical ventilators

adhesive plastic fluid-containers or cooling helmets over the head of the patient.

*3.6.5. Practice of TTM and post-cardiac arrest therapy in Semmelweis University Heart and* 

coagulation system can get impaired and bleeding risk is increased.

Patients with post-cardiac arrest syndrome experience on-going oxidant damage, profound systemic inflammation with vasodilation, myocardial stunning and adrenal axis suppression, which commonly result in major hemodynamic instability. Targeted temperature management with a lower core body temperature affects circulatory variables also negatively. As we previously mentioned the injured brain commonly has a dysfunctional autoregulation. This leads to the fact that blood pressure alterations in the post-cardiac arrest period may influence on-going cerebral injury and eventual neurologic outcome [51]. With disruption of normal cerebrovascular autoregulation, CBF may become directly related to cerebral perfusion pressure, which is dependent on MAP.

Hypotension may lead to persistent tissue hypoperfusion after ROSC, which may produce secondary cellular injury after the initial insult.

Kilgannon et al. studied the time-weighted average mean arterial pressure (TWA-MAP) for the first 6 hours after ROSC [51]. It was found that arterial hypotension was common while relatively fewer patients had an intrinsic hypertensive surge. It was determined that TWA-MAP was associated with neurologic outcome. This association appears to be driven by the strong association between hypotension and poor neurologic outcome, as opposed to an association

**Figure 1.** Thermo-feedback device used for external cooling in our practice.

between intrinsic hypertension and better neurologic outcome. In the analysis, there was a threshold effect with a TWA-MAP greater than 70 mmHg having the greatest association with good neurologic function, and they did not find higher MAP thresholds to be associated with favorable outcome.

The frequency and significance of post-ROSC arterial hypotension among cardiac arrest victims was measured at the time of ICU admission in a large, multicenter cohort study performed by Trzeciak et al. [52]. It was found that 47% of patients who survive cardiac arrest have post-ROSC hypotension, and two-thirds of these patients do not survive to hospital discharge. The presence of post-ROSC hypotension at the time of ICU admission is associated with an approximate twofold risk of in-hospital mortality. It was identified that the post-ROSC condition is characterized by patchy microcirculatory cerebral hypoperfusion, and arterial pressure in the post-cardiac arrest period is a major determinant of the degree of cerebral perfusion impairment.

In spite of the studies that have tried to determine the appropriate blood pressure target after ROSC for a better neurological outcome, the results have not been conclusive. A recent study showed inverse effect between arterial pressure and survival [53]. In the absence of definitive data, the ERC guidelines recommend a target blood pressure that secures a satisfactory urine output (1 ml/kg/h) and a decreasing/normalizing lactate level taking into consideration the patient's normal blood pressure [3].

As a conclusion we can state that there are no clear data about the target blood pressure in post-cardiac arrest patients neither in shock patients [54]. There is lack of studies investigating the optimal target blood pressure in cardiogenic shock. However, it is showed that a target MAP of 65 mmHg may be satisfactory in septic shock patients, we need to point out that it is associated with a higher risk of acute kidney injury if the patient has a history of hypertension [55]. The main message of these findings is that the target blood pressure should be individualized to secure a proper perfusion of organs and an adequate perfusion of brain to prevent further secondary cerebral damage.

### **3.8. Hemodynamic monitoring during post-cardiac arrest syndrome and the hemodynamic effects of therapeutic hypothermia: a case control study (preliminary data)**

We think that an expanded hemodynamic monitoring may be a more precise and useful tool to guide the hemodynamic management of post-cardiac arrest patients than observing only blood pressure. As we mentioned previously, there are several components leading to hemodynamic instability in this patient group and we need to mention also the complexity of the precipitating pathology causing cardiac arrest. To monitor cardiac output and its components (preload, afterload and contractility) gives a more synthetic picture about the condition of the patient's circulation and consecutive organ perfusion.

The most ideal method should be the least invasive providing the most information about the patient's circulatory condition with a simple usability. Echocardiography is a method that helps in characterizing the hemodynamic disorders, selecting the most optimal therapeutic intervention and assessing the response to it [54]. On the other hand it should be mentioned as a limitation that it is not a continuous technique for hemodynamic monitoring and it needs a lot of time of practice to reach an adequate level of usage.

Pulmonary artery catheter (PAC) provides important information about hemodynamic variables and tissue perfusion but it is one of the most invasive tools and there is no evidence about its superiority over other monitoring methods [56]. It is not the most useful system in determining preload because it measures only static parameters (central venous pressure and pulmonary occlusion pressure) instead of dynamic variables. The 2015 European Society of Intensive Care Medicine (ESICM) consensus on hemodynamic monitoring does not recommend its routine use in shock only in refractory shock with right ventricular dysfunction [54].

between intrinsic hypertension and better neurologic outcome. In the analysis, there was a threshold effect with a TWA-MAP greater than 70 mmHg having the greatest association with good neurologic function, and they did not find higher MAP thresholds to be associated with

**Figure 1.** Thermo-feedback device used for external cooling in our practice.

The frequency and significance of post-ROSC arterial hypotension among cardiac arrest victims was measured at the time of ICU admission in a large, multicenter cohort study performed by Trzeciak et al. [52]. It was found that 47% of patients who survive cardiac arrest have post-ROSC hypotension, and two-thirds of these patients do not survive to hospital discharge. The presence of post-ROSC hypotension at the time of ICU admission is associated with an approximate twofold risk of in-hospital mortality. It was identified that the post-ROSC condition is characterized by patchy microcirculatory cerebral hypoperfusion, and arterial pressure in the post-cardiac

In spite of the studies that have tried to determine the appropriate blood pressure target after ROSC for a better neurological outcome, the results have not been conclusive. A recent study showed inverse effect between arterial pressure and survival [53]. In the absence of definitive data, the ERC guidelines recommend a target blood pressure that secures a satisfactory urine output (1 ml/kg/h) and a decreasing/normalizing lactate level taking into consideration the

arrest period is a major determinant of the degree of cerebral perfusion impairment.

favorable outcome.

174 Resuscitation Aspects

patient's normal blood pressure [3].

Transpulmonary thermodilution devices like PiCCO™ (Pulse index Contour Cardiac Output) are less invasive than PAC and they still provide enough precise information to be used in critically ill patients. Its additive advantage is the possibility to measure dynamic variables in fluid management. Tagami et al. validated this method in post-cardiac arrest patients even if therapeutic hypothermia (32–34°C) was used [57].

Recently developed non-invasive methods using pulse contour analysis and volume clamp technique to measure cardiac output should be limited to perioperative use because its value during shock, vasopressor therapy or targeted temperature management is questionable [54].

There is no evidence if the use of these methods affects patients' outcome in critical care not even in post-resuscitation therapy. Taking the above mentioned findings altogether we think PiCCO™ monitoring system may be a suitable tool in post-cardiac arrest patients hemodynamic monitoring. There is still lack of evidence which hemodynamic variables should be monitored and which parameters should be targeted.

The aim of our study was to investigate if the use of PiCCO™ monitoring and the PiCCO™ guided hemodynamic assessment of post-cardiac arrest patients affect the survival, length of ventilation, length of ICU stay and the application of catecholamines. We also investigated the changes of hemodynamic variables during therapeutic hypothermia and were interested in how the most important tool of neuroprotection in post-cardiac arrest syndrome affects hemodynamics.

### *3.8.1. Patients and methods*

We enrolled comatose patients after successful resuscitation who received therapeutic hypothermia and were treated in Semmelweis University Heart and Vascular Center between 2008 January and 2012 July. Inclusion and exclusion criteria are specified in **Figure 2**. We excluded patients who were given hypothermic therapy with physical cooling and ice packs, because the target temperature was not reached in most of the cases.

The post-resuscitation therapy and therapeutic hypothermia was initiated as soon as possible after the admission following the ERC guideline. The goal temperature was 32–34°C according to the even actual protocol (that is the reason we use term "therapeutic hypothermia" instead of "targeted temperature management"). The hypothermic treatment contained three phases: induction, maintenance and rewarming. The patients received 30 ml/kg cold (4°C) crystalloids in

**Figure 2.** Inclusion and exclusion criteria.

the induction phase and were further cooled with Blanketrol III™ (Cincinatti SubZero) thermofeedback device. The same device was used during the maintenance phase. The rewarming was a passive process where we tried to keep the 0.25°C/h rewarming speed. The patients' temperature was measured with an esophageal thermometer and they were sedated with benzodiazepine and opioids given intravenously. If it was indicated, we performed coronarography and percutanous coronary intervention before initiating hypothermia.

Patients were divided into two groups on the basis of what type of hemodynamic monitoring has been administered. We monitored by the members of nonPiCCO group oxygen saturation, ECG, invasive arterial blood pressure, central venous pressure, diuresis, blood gas parameters and serum lactate level. The patients' vasopressor, inotrope and fluid therapy was guided on the basis of these variables.

The previously mentioned monitoring and interventions were augmented with PiCCO™ (Pulsion Medical System) thermodilution device in PiCCO group. We accomplished a measurement at the initiation of hypothermia and performed it every 6 hours in the first 48 hours of treatment. The following variables were controlled: cardiac index (CI: l/min/m2 ), systemic vascular resistance index (SVRI: dyn sec/cm5 ), global end-diastolic volume index (GEDI: l/m2 ), extravascular lung water index (ELWI: ml/kg/m2 ).

The allocation of patients was directed by the access of the thermodilution device. Mortality, circumstances of CPR, length of ventilation and ICU stay and the usage of catecholamine therapy were recorded in both groups and compared. In PiCCO group, the hemodynamic variables (CI, SVRI, GEDI, ELWI) were controlled at the initiation of hypothermia, in the 12th, 24th and 48th hour of hypothermia and after rewarming. The statistical analysis was performed with two-tailed t-test and Mann-Whitney test when we compared the two groups. We used Wilcoxon test and Bonferroni correction in analyzing the PiCCO measurements. Significance of p value was set at <0.05. The Semmelweis University Regional and Institutional Committee of Science and Research Ethics accepted our study.

### *3.8.2. Results*

PiCCO™ monitoring system may be a suitable tool in post-cardiac arrest patients hemodynamic monitoring. There is still lack of evidence which hemodynamic variables should be

The aim of our study was to investigate if the use of PiCCO™ monitoring and the PiCCO™ guided hemodynamic assessment of post-cardiac arrest patients affect the survival, length of ventilation, length of ICU stay and the application of catecholamines. We also investigated the changes of hemodynamic variables during therapeutic hypothermia and were interested in how the most important tool of neuroprotection in post-cardiac arrest syndrome affects

We enrolled comatose patients after successful resuscitation who received therapeutic hypothermia and were treated in Semmelweis University Heart and Vascular Center between 2008 January and 2012 July. Inclusion and exclusion criteria are specified in **Figure 2**. We excluded patients who were given hypothermic therapy with physical cooling and ice packs, because

The post-resuscitation therapy and therapeutic hypothermia was initiated as soon as possible after the admission following the ERC guideline. The goal temperature was 32–34°C according to the even actual protocol (that is the reason we use term "therapeutic hypothermia" instead of "targeted temperature management"). The hypothermic treatment contained three phases: induction, maintenance and rewarming. The patients received 30 ml/kg cold (4°C) crystalloids in

monitored and which parameters should be targeted.

the target temperature was not reached in most of the cases.

hemodynamics.

176 Resuscitation Aspects

*3.8.1. Patients and methods*

**Figure 2.** Inclusion and exclusion criteria.

We treated 147 successfully resuscitated patients in Semmelweis University Heart and Vascular Center between 2008 January and 2012 July. On the basis of our inclusion and exclusion criteria 40 patients were enrolled into our study: 28 in PiCCO group and 12 in nonPiCCO group. There was no significant difference in demographic data and the circumstances of CPR between the two groups (**Table 1**).

The survival (**Figure 3**), length of ventilation and length of ICU stay were also similar in both groups (**Table 1**). Length of ventilation was 5 ± 3 days in PiCCO and 6 ± 5 days in nonPiCCO group, respectively (p = 0.57). The patients in PiCCO group spent 7 ± 4 days at ICU and the members of nonPiCCO group 8 ± 5 days (p = 1.00).

In the usage of catecholamines we found that patients in nonPiCCO group received less vasopressors and inotropes than patients in PiCCO group (PiCCO: 71% of patients vs. nonPiCCO: 58% of patients), however the difference was not significant **(Table 2)**.


OHCA: out-of-hospital cardiac arrest; IHCA: in-hospital cardiac arrest; ROSC: return of spontaneous circulation; VF: ventricular fibrillation; VT: ventricular tachycadria; PEA: pulseless electrical activity.

**Table 1.** The comparison of demographic data, circumstances of CPR, length of mechanical ventilation and length of ICU stay between PiCCO and nonPiCCO groups. Significance of p value was set at <0.05.

**Figure 3.** The comparison of survival between PiCCO and nonPiCCO group.


**Table 2.** The comparison of catecholamine administration between PiCCO and nonPiCCO group.

In the course of the measurement of hemodynamic variables during therapeutic hypothermia there was significant difference in cardiac index and systemic vascular resistance index between the values in the 12th hour of hypothermia and after rewarming (CI: 1.8 ± 0.5 l/min/m2 vs. 2.9 ± 0.9 l/min/m2 , p < 0.001; SVRI: 3686 ± 1264 dyn sec/cm5 vs. 1627 ± 414 dyn sec/cm5 , p < 0.001) (**Figure 4**). Cardiac index decreased in the first 12–24 hours and showed improvement after this period. Systemic vascular resistance index changed parallel with cardiac index but the opposite way. The changes in ELWI and GEDI did not show significant difference during the examined interval.

#### *3.8.3. Discussion*

**Figure 3.** The comparison of survival between PiCCO and nonPiCCO group.

**PiCCO (n = 28) nonPiCCO (n = 12) p**

Age (years) 62 ± 10 69 ± 8 **0.095** Male 82% 67% **0.25**

OHCA 64% 46% **0.22**

Time until ROSC (minutes) 13 ± 6 17 ± 4 **0.059**

VF/pnVT 63% 58% **0.4**

Performed 72% 90% **0.07**

**Length of mechanical ventilation (days)** 7 ± 4 8 ± 5 **0.57 Length of ICU stay (days)** 5 ± 3 6 ± 5 **1**

OHCA: out-of-hospital cardiac arrest; IHCA: in-hospital cardiac arrest; ROSC: return of spontaneous circulation; VF:

**Table 1.** The comparison of demographic data, circumstances of CPR, length of mechanical ventilation and length of ICU

Female 18% 33%

IHCA 36% 54%

PEA/Asy 37% 42%

Did not performed 18% 10%

ventricular fibrillation; VT: ventricular tachycadria; PEA: pulseless electrical activity.

stay between PiCCO and nonPiCCO groups. Significance of p value was set at <0.05.

**Initial rhythm**

178 Resuscitation Aspects

**Bystander CPR**

Post-resuscitation therapy as the fourth link of chain of survival is one of the mortality determining factors among post-cardiac arrest patients. One of the most important parts of

**Figure 4.** The changes of hemodynamic variables during therapeutic hypothermia (CI: cardiac index; SVRI: systemic vascular resistance index; GEDI: global end-diastolic volume index; ELWI: extravascular lung water index; H: hour).

post-resuscitation therapy is the proper attendance of cardiovascular disorders and an adequate guidance of hemodynamic management. The main goal is to secure a satisfactory organ perfusion and to prevent secondary brain damage by providing a sufficient cerebral blood flow despite the impaired cerebral autoregulation.

As we mentioned previously, there are several components leading to hemodynamic instability in patients after successful resuscitation [6]. There is pronounced vasodilatation due to systemic inflammatory response syndrome (SIRS) following an ischemia-reperfusion episode. The precipitating pathology itself resulted that cardiac arrest is a cardiovascular disease in most of cases. Cardiac stunning may develop after ROSC as a consequence of SIRS.

Targeted temperature management and therapeutic hypothermia may also affect hemodynamic variables of post-cardiac arrest patients in a negative manner: bradycardia, decrease in cardiac output and increase in systemic vascular resistance can evolve [58, 59]. As a consequence of lower temperature primarily during induction phase polyuria may occur resulting in hypovolemia [60]. Systolic and diastolic dysfunction was provoked in pigs while they were treated with hypothermia [61]. On the other hand these effects may be advantageous in this patient group because it has been shown that post-cardiac arrest patients with bradycardia had better outcome than patients whose heart rate was higher [62]. The increase of systemic vascular resistance is also a beneficial effect and may compensate the vasodilatory consequence of SIRS.

Bernard et al. used PAC as a hemodynamic monitoring in post-cardiac arrest patients and found that cardiac index was in tendency lower and systemic vascular resistance index was significantly higher in hypothermic group compared to normothermic patients [44]. It was also shown that cardiac index was in 66% of patients below 1.5 l/min/m2 in the first 12 hours after ROSC in OHCA patients who were treated with therapeutic hypothermia. [63] They also used PAC to monitor hemodynamic variables.

As we mentioned it previously, we chose PiCCO™ monitoring system because it is less invasive than PAC and it was earlier validated in PCAS and therapeutic hypothermia [57]. We found during our measurements that cardiac index had the lowest value in the 12th hour of hypothermic treatment and it was significantly higher after rewarming. Investigating peripheral vascular resistance we measured the highest value of SVRI in the 12th hour of therapeutic hypothermia and a significantly lower value after rewarming. Our findings are similar to the measurements that have been performed with PAC.

On the basis of our results we think that there is a deteriorating hemodynamic instability during the first 24 hours after ROSC as a part of post-resuscitation syndrome. We also need to point out that treatment with lower temperature may also affect hemodynamic parameters. Our opinion is that taking these facts into consideration it is important to use a higher level of hemodynamic monitoring in this patient group to guide our hemodynamic therapy mainly if the patients are treated with targeted temperature management.

It is a different question if hemodynamic monitoring affects patients' outcome and mortality. There is no evidence which non-invasive, semi-invasive or invasive tool for hemodynamic monitoring should be used in critically ill patients. We think the answer is not simple and depends on patient, disease, patient's condition and the staff's practical knowledge. There is no evidence neither which parameters should we monitor and target during our therapy. To get closer to the answer more studies and randomized controlled trials are needed.

We were investigating in our study weather PiCCO™-guided therapy affects outcome in patients after successful resuscitation. There was no significant difference in demographic data and the circumstances of CPR between the two groups, so they were comparable. There was no difference in mortality, neither in the length of ventilation nor ICU stay between the groups. We found the same what was previously published in international literature. We found that in tendency more vasopressors and inotropes were used during the PiCCO™ guided therapy. It is very important to use these agents for the shortest time and in the lowest dose as possible to avoid side effects. PiCCO™-guided therapy, as it is shown in our study, may be a helpful equipment to fulfill this role.

The limitation of our study is the low number of study participants. We are planning to expand the investigation and we hope that with the increased number of patients enrolled we are getting a clearer result.

### *3.8.4. Conclusion*

post-resuscitation therapy is the proper attendance of cardiovascular disorders and an adequate guidance of hemodynamic management. The main goal is to secure a satisfactory organ perfusion and to prevent secondary brain damage by providing a sufficient cerebral blood

As we mentioned previously, there are several components leading to hemodynamic instability in patients after successful resuscitation [6]. There is pronounced vasodilatation due to systemic inflammatory response syndrome (SIRS) following an ischemia-reperfusion episode. The precipitating pathology itself resulted that cardiac arrest is a cardiovascular disease

Targeted temperature management and therapeutic hypothermia may also affect hemodynamic variables of post-cardiac arrest patients in a negative manner: bradycardia, decrease in cardiac output and increase in systemic vascular resistance can evolve [58, 59]. As a consequence of lower temperature primarily during induction phase polyuria may occur resulting in hypovolemia [60]. Systolic and diastolic dysfunction was provoked in pigs while they were treated with hypothermia [61]. On the other hand these effects may be advantageous in this patient group because it has been shown that post-cardiac arrest patients with bradycardia had better outcome than patients whose heart rate was higher [62]. The increase of systemic vascular resistance is also a beneficial effect and may compensate the vasodilatory conse-

Bernard et al. used PAC as a hemodynamic monitoring in post-cardiac arrest patients and found that cardiac index was in tendency lower and systemic vascular resistance index was significantly higher in hypothermic group compared to normothermic patients [44]. It was

after ROSC in OHCA patients who were treated with therapeutic hypothermia. [63] They also

As we mentioned it previously, we chose PiCCO™ monitoring system because it is less invasive than PAC and it was earlier validated in PCAS and therapeutic hypothermia [57]. We found during our measurements that cardiac index had the lowest value in the 12th hour of hypothermic treatment and it was significantly higher after rewarming. Investigating peripheral vascular resistance we measured the highest value of SVRI in the 12th hour of therapeutic hypothermia and a significantly lower value after rewarming. Our findings are similar to the

On the basis of our results we think that there is a deteriorating hemodynamic instability during the first 24 hours after ROSC as a part of post-resuscitation syndrome. We also need to point out that treatment with lower temperature may also affect hemodynamic parameters. Our opinion is that taking these facts into consideration it is important to use a higher level of hemodynamic monitoring in this patient group to guide our hemodynamic therapy mainly if

It is a different question if hemodynamic monitoring affects patients' outcome and mortality. There is no evidence which non-invasive, semi-invasive or invasive tool for hemodynamic monitoring should be used in critically ill patients. We think the answer is not simple and

in the first 12 hours

also shown that cardiac index was in 66% of patients below 1.5 l/min/m2

used PAC to monitor hemodynamic variables.

measurements that have been performed with PAC.

the patients are treated with targeted temperature management.

in most of cases. Cardiac stunning may develop after ROSC as a consequence of SIRS.

flow despite the impaired cerebral autoregulation.

quence of SIRS.

180 Resuscitation Aspects

As a conclusion of our study, we can say that PiCCO™-guided therapy did not improve mortality, length of ventilation and ICU stay among our post-cardiac arrest patients. On the other hand we need to point out that it may play a role in conducting the vasoactive and inotrope therapy more adequately in this patient group. We proved that the decrease of cardiac index and increase of systemic vascular resistance index is observable also with PiCCO™ monitoring in the first 24 hours after successful resuscitation, during targeted temperature management.

### **4. Summary**

A strong chain of survival can increase the chances of survival and recovery for victims of cardiac arrest. We summarized our recent knowledge about neuroprotective strategies after successful resuscitation in this chapter, that is, one of the most important parts of post-resuscitation therapy.

Normoxia, normocapnia, normoglycemia and a proper level of sedation must be maintained in order to avoid secondary brain damage. The use of pharmacologic strategies is questionable but thiamine may be a promising agent in improving neurological outcome. Its efficiency needs further clinical investigations.

Targeted temperature management is the most effective tool in our hand today. It has positive effect in the neurological recovery by decreasing fever, providing myocardial protection, slowing the brain metabolism and decreasing the inflammatory response. However, there are still many questionable topics in its implementation, like the targeted temperature, method, timing, duration of the therapy and the rewarming rate.

The proper management of hemodynamics in this patient group is also essential to secure a satisfactory brain perfusion, but the way of hemodynamic monitoring and the targets of hemodynamic variables are also subjects of further investigations. We think that PiCCO™ guided therapy can be a good direction to tailor vasopressor, inotrope and fluid therapy after cardiac arrest and during TTM.

### **Author details**

Enikő Kovács1† and Endre Zima2†\*

\*Address all correspondence to: zima.endre@gmail.com

1 Department of Anesthesiology and Intensive Therapy, Semmelweis University, Budapest, Hungary

2 Heart and Vascular Center, Semmelweis University, Budapest, Hungary

†These authors are contributed equally.

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The proper management of hemodynamics in this patient group is also essential to secure a satisfactory brain perfusion, but the way of hemodynamic monitoring and the targets of hemodynamic variables are also subjects of further investigations. We think that PiCCO™ guided therapy can be a good direction to tailor vasopressor, inotrope and fluid therapy after

1 Department of Anesthesiology and Intensive Therapy, Semmelweis University, Budapest,

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\*Address all correspondence to: zima.endre@gmail.com

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