Current and Future Therapies of Pediatric Cardiopulmonary Arrest

Abstract

Objective

To review contemporary guidelines and therapies for pediatric cardiac arrest and discuss potential novel therapies.

Methods

Key articles and guidelines in the field were reviewed along with recent publications in the fields of neurointensive care and neuroscience germane to cerebral resuscitation.

Results

A total of 45 articles were reviewed. The majority of arrests in the pediatric population are asphyxial in origin—which differs importantly from the adult population. The International Consensus on CPR guidelines are discussed, including good quality CPR, chest compressions without interruptions, resuscitation with 100% oxygen and subsequent titration of oxygen to normal oxygen saturations, correct dose of epinephrine, and use of hypothermia in the first 12-24 hours. Novel therapies that showed success in animal studies, such as hypertensive reperfusion, thrombolytics, hemodilution and extracorporeal CPR are also discussed.

Conclusion

With only 30% return of spontaneous circulation, 12% survival to hospital discharge and 4% intact neurologic survival, pediatric cardiac arrest remains an area of intense research for therapies to improve its outcomes. In addition to the rapid implementation of basic and advanced life support interventions, new therapies that may have value include mild hypothermia, extracorporeal support, promotion of cerebral blood flow and other more novel therapies targeting oxidative stress, excitotoxicity, neuronal death, and rehabilitation.

Cardiac arrest (CA) is defined by the task force of the American Academy of Pediatrics, American Heart Association and the European Resuscitation Council as “cessation of cardiac mechanical activity, determined by the inability to palpate a central pulse, unresponsiveness and apnea”.¹ CA is a clinical entity, and exists even in the presence of cardiac electrical activity, as long as pulses cannot be palpated in an unresponsive child (pulseless electrical activity). In this review we will focus on therapy for CA in infants and children. Neonatal CA, with its unique etiology and pathophysiology, represents a separate topic that is outside of the scope of this review.

EPIDEMIOLOGY AND PHYSIOLOGY

In the United States, it is estimated that approximately 16,000 patients die annually of unexpected CA. Worldwide, the scope of the problem is staggering. In a comprehensive review of literature (45 articles, 5363 patients), the incidence of out of hospital CA ranged from 2.6 to 19.7 annual cases per 100,000 pediatric population.² Children younger than one year of age comprise the majority of cases of pediatric CA (56%) and CA is slightly more prevalent in boys (62%).³

Respiratory compromise is the most common cause of non-traumatic pediatric CA.⁴ Respiratory compromise in children can be secondary to 1) upper or lower airway obstruction as a result of secretions, aspiration, suffocation, infection, and trauma and/or 2) depressed respiratory drive secondary to neurological conditions. The succession of events in an asphyxial pediatric CA is: hypoxemia, hypercarbia, acidosis, hypotension, ultimately resulting in CA. Although respiratory compromise and the resultant asphyxial CA occur in a majority of pediatric patients, ventricular fibrillation can occur and represents the etiology of the arrest in 10-15% of pediatric cases.^{2, 4} The period of hypoxemic perfusion of tissues preceding CA is specific to asphyxial CA and is implicated in causing greater neuronal damage than the immediate cessation of flow resulting from ventricular fibrillation. The ECG rhythm during CA in children is most often asystole, bradyarrhythmia or pulseless electrical activity.

CA in children generally results in a dismal outcome. Return of spontaneous circulation is achieved in approximately 30% of children who suffer out-of-hospital CA, but only 12% of these children survive to hospital discharge.^{2, 3} Moreover, only 4% of children who sustain out-of-hospital CA have intact long-term neurological outcome.² Pediatric patients who suffer in-hospital CA have a slightly better prognosis: 52% have return of spontaneous circulation, 27% survive to hospital discharge, and 15% have intact neurological survival, as reported in the series described by Nadkarni et al.⁵ Thus, pediatric CA is a significant public health issue, which combines poor survival, considerable physical debilitation of children who survive, emotional burden to the family and significant monetary⁶ and psychosocial burden. Moreover, these problems generally produce a life-long problem.

CARDIOPULMONARY RESUSCITATION (CPR)

The International Liaison Committee on Resuscitation (ILCOR) recently published new guidelines for pediatric basic and advanced life support. The main goal of the new guidelines is to emphasize good quality CPR without interruptions for both pre-hospital and in-hospital CPR “push hard, push fast, minimize interruptions; allow full chest recoil, and don’t hyperventilate”.⁷

Basic Life Support, field interventions

The interventions of basic life support recommended by ILCOR in 2005 are based on the knowledge that most cases of the pediatric CA are secondary to asphyxia, and rapid initiation of good quality CPR will impact survival.^8-10 Thus, the sequence of events for a lone rescuer arriving at the scene of an unwitnessed arrest or non-sudden collapse should be immediate initiation of CPR with subsequent activation of emergency medical services (EMS). However, if a lone rescuer presents to the scene of a witnessed sudden collapse (unresponsive victim) he/she should activate EMS immediately and if available should get an Automated External Defibrillator (AED), due to the higher probability that the victim has a shockable rhythm disturbance (VF, pulseless ventricular tachycardia). For a summary of the BLS ILCOR recommendations, please refer to table 1.

Table 1.

Succession of Events in the Scenario of Alone Rescuer Responding to the Scene of a CA. If More Than One Rescuer Responds to the Scene, CPR Can be Started Immediately by One of the Rescuers While the Other Rescuer Activates EMS and Brings the AED.

	Unwitnessed Non-sudden collapse	Sudden collapse
First intervention	CPR	Activate EMS/get AED
Subsequent intervention	Activate EMS	CPR
	Call fast	Call first

Advanced Life Support

Airway and breathing

Maintaining a patent airway is the first important step in resuscitation. Patent airway can be maintained by the jaw thrust maneuver, chin lift/head tilt maneuver (if trauma is not suspected), or by airway adjuncts, for example nasopharyngeal airways, oropharyngeal airways, laryngeal mask airways and endotracheal tubes (ETT). The choice of the airway adjunct depends on the level of expertise and on the transport time. Given the high incidence of asphyxiation as the etiology of pediatric CA, the situation where a victim of an evolving insult has only a respiratory arrest should be considered and, in that setting, addressed with immediate control of airway and ventilation.

It has been shown that bag valve mask ventilation (BVM) is an effective way of ventilating a pediatric patient after CA. In a prospective study that included pediatric patients with CA the groups receiving ventilation via either BVM or ETT had equal survival to hospital discharge.¹¹ Thus, for a short transport time in the hands health care providers with less experience in pediatric intubation, BVM is the method of choice in patients who require ventilatory support.⁷ For long transport times, the choice of ETT vs BVM is made taking into consideration the experience of the healthcare provider with endotracheal intubation of infants or children and the means of monitoring via end-tidal CO2 (ETCO2).⁷ Use of cuffed ETT is safe in any pediatric patient, including infants.¹² When an ETT is used, its placement should be confirmed with an ET CO2 detector.⁷ While presence of exhaled CO2 confirms correct tube placement, ETCO2 can be absent in CA due to prolonged time of non-perfusing rhythm. In this instance, ETT placement can be confirmed using direct laryngoscopy.

The laryngeal mask airway (LMA) is an alternative airway adjunct during CA; however, there are no studies to date examining use of LMA in CA in children. The complication rate of LMA use in small children is greater than in adults, and this complication rate decreases with experience.¹³

Circulation- CPR compression and ventilation rates

The emphasis for both the prehospital and in hospital CPR is on effectiveness of compression “push hard, push fast, minimize interruptions; allow full chest recoil”.⁷ For lone rescuers the recommended compression for ventilation ratio is 30:2 for all age groups.

For two rescuers, the recommended compression for ventilation ratio in children is 15:2. After an advanced airway is placed, ventilation and chest compressions can be given independently. Chest compressions are given at a rate of 100/minute without pauses for ventilation. Ventilation will be delivered at 8 to 10 breaths per minute (1 breath approximately every 6-8 seconds). The health care provider doing chest compressions should be replaced every 2 minutes during CPR, if possible, to prevent decreased performance secondary to fatigue. Of note, the recommended compression for ventilation ratio for adults is 30:2 regardless of the numbers of rescuers.

MEDICATIONS USED DURING AND AFTER CPR

Medications during CPR should be given by the intravenous or intraosseous route if possible. Intratracheal route results in poor absorption of drug.¹⁴ Epinephrine remains the principle medication during CA. Other medications (magnesium, vasopressin) have not proven to improve outcome and their use is recommended if there is a suspicion of particular pathology (i.e., magnesium for torsades de pointes). The concentration of oxygen used during resuscitation remains a controversial topic, and will be addressed in this section.

Epinephrine

The recommended dose of epinephrine during CA is 0.01 mg/Kg, 1:10 000 concentration, given during CA every 3-5 minutes. High dose epinephrine does not improve survival and worsens outcome after asphyxial CA,¹⁵ thus it is no longer recommended.

Oxygen

Traditionally resuscitation with 100% oxygen has been employed. Oxidative stress is increased by resuscitation with high concentrations of oxygen; reactive oxygen and nitrogen species have the potential to worsen neurological damage in experimental animal models of CA.¹⁶ Therefore, resuscitation with room air rather than 100% oxygen emerged as a potential therapy to improve neurological outcome after CA. Animal studies demonstrated either improved outcome with room air resuscitation.^17-19 Or no advantage in resuscitation or outcome from high concentration oxygen versus room air administration during CPR.²⁰ Human studies of newborns resuscitated from perinatal asphyxia demonstrate equal survival and outcomes in infants resuscitated with room air.^21-25 Given insufficient evidence, ILCOR recommends resuscitation with 100% oxygen until return of spontaneous circulation, followed by titration of therapy to maintain normal oxygen saturation values. This is an important area for future research and approaches such as the combination of 100% oxygen and antioxidant therapies have not been evaluated.

Other medications and interventions

Minimizing secondary injury to the brain after restoration of spontaneous circulation is important; factors precipitating secondary injury include: hypotension, hypercarbia, hypoxemia, hypoglycemia and hyperthermia.²⁶ These factors need to be vigilantly addressed after resuscitation. After CA hypotension occurs secondary to myocardial dysfunction and potentially secondary to reactive oxygen and nitrogen species generated during asphyxia and reperfusion, along with other mechanisms. Vasoactive drugs are indicated after restoration of spontaneous circulation and should be titrated to improve arterial blood pressure in the pediatric patient after CA. Both hypoglycemia and hyperglycemia should be avoided or, depending on the degree of derangement, treated after CA.^{27, 28}

NOVEL AND EXPERIMENTAL THERAPIES IN PEDIATRIC CARDIOPULMONARY ARREST

Therapies aimed to restoring adequate cerebral blood flow

Neurological outcome after CA is correlated with duration of cerebral ischemia. Cerebral blood flow (CBF) in the first hours after resuscitation is an important factor influencing neurological outcome and can be a target for improving neurological survival. CBF in infants and children immediately after resuscitation from CA is not well characterized.

Normal CBF in children is 50-70 ml/100g/min, and is age dependent, being lower in infancy. Due to the unstable clinical condition of children immediately after CA, CBF after CA in children has been reported only at several hours or days after resuscitation. One study shows that low CBF after CA (less than 10 ml/100 g/min at 24 hours) is associated with poor outcome.²⁹

Experimental models in adult animals show that CBF during CA is cyclic in nature. During the arrest, global ischemia is produced with no flow to the brain. This is followed by low flow during CPR. Immediately after reperfusion a period of global hyperemia for 15-30 min is followed by delayed hypoperfusion from 30 min after ROSC to 3-6 hours. During the reperfusion phase a phenomenon of multifocal no-reflow is reported to occur, where areas of no flow are interspersed with areas of low and normal perfusion. This is believed to occur as a result of microcirculatory changes in the brain during no flow such as stasis, slugging and vasoparalysis. Hypertensive reperfusion, hemodilution and thrombolysis are strategies that can potentially decrease the no-reflow areas of the brain. CBF promotion strategies employing hypertensive reperfusion, hemodilution (hematocrit 30%) and hypothermia proved beneficial in animal models.³⁰ The first and only study trying to explore the benefit of hypertensive reperfusion in humans is a retrospective review of adult CA survivors; this study found that the level of arterial blood pressure during the first 2 hours after resuscitation was directly correlated with good functional neurological recovery, whereas arterial hypertension in the first 5 minutes after ROSC did not influence outcome.³¹ Another blood flow promoting strategy, thrombolytics administered during CPR, improved outcomes in animal models³² and in small series of patients.^{33, 34} This approach could have theoretical merit in two ways—treating pulmonary embolism, if it happened to be the cause of the CA (although uncommon as a cause of pediatric CA), and potentially attenuating microcirculatory thrombosis in the setting of prolonged stasis. Larger studies in adults are underway to establish if this therapy is beneficial after CA.³⁵ Other promising, albeit more speculative potential CBF promoting strategies tested only in the laboratory include endothelin A antagonists, remifentanil, adenosine A2a-receptor agonists, nitrous oxide and nitric oxide donors.

Hypothermia

Mild hypothermia (32-34°C) is a safe and effective therapy after CA, as shown in adult studies of CA due to ventricular fibrillation. Hypothermia has multiple effects such as decreasing cerebral metabolic rate and energy consumption and reduces the oxidative stress, the excitotoxic cascade, and apoptotic and necrotic cell death. However, it is not certain, even in experimental model, what mechanism or mechanisms are producing beneficial effects when therapeutic hypothermia is used after CA. This is particularly true in the setting of mild hypothermia where effects on energy failure may not be a key mechanism. Although no studies to date have documented outcomes after mild hypothermia in children resuscitated from CA, data from multiple studies 1) in experimental animal model, 2) neonates with birth asphyxia and 3) ventricular fibrillation CA in adults support the safety and efficacy of hypothermia in improving neurologic outcome after CA.^36-38 Hypothermia between 32 and 34°C applied for between 12 and 24 hours is currently recommended as an option in children who remain comatose after CA.⁷ There are some potential theoretical disadvantages that might make therapeutic mild hypothermia less efficacious in the pediatric setting than in adult VF. First, it may be that the neurological injury from asphyxial CA could be highly refractory to all therapeutic approaches—given the fact that the CA is preceded by a period of anoxic or hypoxemic perfusion. Second, exacerbation of infectious complications from hypothermia such as pneumonia could also be more likely in the setting of asphyxial insults such as drowning compared to ventricular fibrillation. Nevertheless, studies in experimental models of pediatric CA suggest benefit from therapeutic hypothermia³⁸ and infections can be minimized by minimizing the duration and depth of cooling, and/or treatment with appropriate antibiotics. Additional clinical use and investigation of mild therapeutic hypothermia in the setting of pediatric CA is needed to further explore this potentially important therapy. Finally, some adjunctive therapies may augment the benefit of mild hypothermia. One of the most interesting in this regard with potential clinical applicability is the use of inhaled xenon gas—which is an anti-excitotoxic agent.³⁹ This strategy has shown some potential promise in laboratory studies and is one of several approaches that deserve additional investigation. Further investigation and evaluation of mild therapeutic hypothermia in the setting of pediatric CA should represent a high research priority in our field.⁴⁰

Extracorporeal Membrane Oxygenation for Resuscitation

Extracorporeal CPR (ECPR) is a method of resuscitating patients from CA by means of ECMO. Its use represents a reasonable therapeutic approach in a child who has a reversible disease process and where ECMO can be initiated before central nervous system damage occurs. This is the case for in-hospital arrests or witnessed CA with short transport time to the hospital. The largest series of ECMO-CPR in pediatric patients was published in 2004 and reports the outcome of 66 patients cannulated for ECMO during active CPR compressions. In this series, 33% of patients survived to hospital discharge. Median time of CPR before ECMO cannulation was 50 minutes; 3 of 6 patients with CPR time greater than 60 min before ECMO resuscitation had grossly intact neurologic function.⁴¹ Initial reports on the use of ECPR in children are promising. In the setting of a witnessed arrest, such as a child with evolving and refractory myocarditis or from post-operative refractory cardiogenic shock, the use of ECMO, where available, can represent a lifesaving bridge to myocardial recovery. Moreover, ECPR also represents a convenient means of rapidly delivering mild hypothermia during the first 12-24 hours. Fig. 1 illustrates novel therapies for optimizing prognosis in children resuscitated from CA.

Fig. 1.

Novel and experimental therapies for pediatric cardiac arrest that may improve outcome. Currently, therapeutic hypothermia and extracorporeal cardiopulmonary resuscitation (ECPR) have the Greatest amount of literature support for clinical efficacy, although additional investigation is desired. Please see text for additional details. CBF = cerebral blood flow.

Other futuristic therapies for pediatric CA include anti-excitotoxic therapies, drugs targeting energy failure (such as pyruvate, ketone, or lactate infusion), and anti-apoptotic strategies. Excitotoxicity has a pivotal role in the evolution of hypoxic ischemic injury.⁴² Antiexcitotoxic therapies have proven to be beneficial in animal models after cerebral ischemia, but have failed to show benefit in human studies of cerebral ischemia. These therapies include conventional agents such as Pentobarbital or Thiopental, and therapies targeting N-methyl- D-aspartate (NMDA) and Alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, or more novel transient receptor potential (TRP) channels.⁴³ Therapies preventing energy failure are logical to target, given that cerebral metabolism is altered during brain ischemia and the cells switch to anaerobic respiration during ischemia to preserve energy stores. Ketone administration proved benefic in juvenile mice after ischemia; ketogenic diets have also been tested in animal models. A theoretical schematic time-line for sequential implementation of these potential futuristic therapies is presented in fig. 2.

Fig. 2.

Schematic of the theoretical time course for application of current or future therapeutic strategies for pediatric CA. The temporal sequence proposed is based on the best available literature in experimental models or human trials. Mild hypothermia has the most support for implementation immediately after restoration of spontaneous circulation (ROSC), but may be even more efficacious when initiated during CPR.⁴⁵ Please see text for details on the other more futuristic therapeutic approaches.

In conclusion, the unique form of CA in the pediatric population, namely asphyxial arrest appears to represent a particularly deleterious insult, which leads to poor outcomes. In addition to aggressive conventional resuscitation, we have discussed several adjunctive approaches, namely CBF promotion, hypothermia and extracorporeal support that may improve outcome in selected patients and deserve addition application and investigation. Rehabilitation should also not be dismissed in the setting of pediatric CA—although additional investigation is needed to optimize this important therapy. Studies in animal models of brain injury suggest a powerful effect of rehabilitation-related strategies that even includes enhanced synaptogenesis and cortical thickening.⁴⁴ Finally, the search for additional neuroprotective therapies is ongoing and combined therapies–particularly with mild hypothermia⁴⁵ should be pursued.