Hypoxic-Ischemic Encephalopathy in Adults

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Introduction

Sudden cardiac arrest (CA)—the complete cessation of cardiac mechanical activity in a pulseless, apneic (or with agonal breathing) and unresponsive individual—continues to claim millions of lives across the world and is a major cause of long-term disability.1,2 The precise estimation of the epidemiologic impact of CA worldwide is difficult, as incidences and survival vary widely according to factors pertaining to details of arrest (location, etiology, and non-perfusing rhythm); whether the event was assisted by Emergency Medical Services (EMS); and in what region of the world it occurred. Table 1 shows a brief comparison of reported incidences across different world areas. In the US, over half million CA occur every year, with approximately 2/3 taking place outside medical facilities (out-of-hospital cardiac arrest – OHCA); less than half of these receive bystander cardiopulmonary resuscitation (CPR).3 In the hospital, CPR is performed in 2.73 and 2.37 per 1,000 in elderly and non-elderly adult admissions, respectively.4 5 Approximately 10% of OHCA and 1 in 4 adults who experience an in-hospital cardiac arrest (IHCA) survive to hospital discharge in the US.3 The presence of comorbidities seems to have little overall influence on short-term survival following OHCA,6 including malignancy,7 but comorbidities do influence outcomes in non-shockable rhythms in both OHCA8 and IHCA.< a href="#_ENREF_9">9,10 Survival rates are uniformly higher in shockable rhythms across all patient populations, and conflicting evidence supports lower survival in women, older, and non-white patients; however, these findings may be substantially influenced by several other factors acting as confounders, such as CA rhythm, hospital site, timing of urgent coronary reperfusion, use of targeted temperature management (TTM), duration of resuscitation efforts, and many more. There is an independent and inverse relationship between duration of resuscitation and favorable survival—in particular, for total downtimes greater than 35 minutes regardless of underlying CA rhythm.11,12 Nonetheless, a significant proportion of patients with prolonged arrest times may survive and achieve a good neurologic outcome should prompt aggressive care be sustained.13 Similarly to patients who received standard cardiopulmonary resuscitation (CPR), having shorter downtime, shockable rhythms, higher arterial pH value, and lower serum lactic acid concentrations at admission are also associated with better outcomes in patients undergoing extracorporeal CPR.14

HIE Chapter_Table 1 - Distribution of Cardiac Arrest Incidences

In addition to overall survival, outcomes in CA studies also take into consideration functional status, and the Glasgow-Pittsburgh Cerebral Performance Category (CPC) scale is the most commonly used tool (Table 2). Death, regardless of its main determinant (recurrent and/or refractory CA, multisystem organ failure, brain death, or death related to withdrawal of life-sustaining therapies) is classified as CPC 5. A CPC score of 1 – 3 represents a conscious state (awakening); however, as CPC 3 reflects severe disability with complete dependence on others for daily living activities, it is often considered a poor outcome. Traditionally, good outcome is reserved for CPC scores of 1 – 2 in the CA literature. Families and individuals may consider regaining of consciousness an acceptable outcome in specific scenarios; thus, it is important to ascertain what is considered meaningful neurologic recovery for each individual before sharing neuroprognostic impressions. Besides, all these outcome categories include substantial heterogeneity of deficits, and a more granular analysis of functional outcomes is indispensable. The extended version of CPC (CPC-E) was developed to address this gap and potentially guide further interventions or the need for services following hospital discharge of CA survivors. This comprehensive evaluation comprises 10 domains: alertness, logical thinking, attention, short-term memory, motor function, basic and complex activities of daily living, mood, fatigue, and return to work. The end score is obtained in staged evaluations (at discharge and on follow up) and has demonstrated good to excellent inter-rater reliability,22 which makes it a promising comprehensive tool for outcome assessment in this population.

The war against death fought by a CA patient includes 5 major battles that occur from resuscitation to the rehabilitation period. These steps are demonstrated in Figure 1 and constitute promising targets for interventions to improve outcomes in this deadly disease.


HIE Chapter_Table 2- Glasgow-Pittsburgh Cerebral Performance Category (CPC) Scale

Figure 1 – Saving the Survivors of Cardiac Arrest in Five Steps
HIE Chapter_Figure 1 – Saving the Survivors of Cardiac Arrest in Five Steps

Pathophisiology

The mechanisms involved in the development of systemic and neurologic hypoxic injury result from the global ischemia during circulation cessation and from the pathologic state of reperfusion with restoration of forward flow. The “two-hit” model24 includes complex cascades involving widespread molecular, cellular, and organ-specific responses in addition to the ongoing pathophysiologic process that led to the cardiac arrest; the interplay of these factors is summarized in Figure 2. The new systemic state following restoration of spontaneous circulation, first recognized in the early 1970s, is now called Post-Cardiac Arrest Syndrome (PCAS), and includes brain injury, myocardial dysfunction, and diffuse endotheliopathy with systemic ischemia/reperfusion response.25 Early extra-cerebral organ dysfunction is common in non-survivors, and is directly related to the extent of global hypoxic-ischemic injury; this relationship with survival does not seem to occur when organ dysfunction happens late during the intensive care unit stay.26 Severe renal dysfunction is an independent predictor of early mortality,26 and may be present in over 50% of resuscitated patients,27 more often in prolonged shock, in older individuals, and in those with prior chronic renal disease.

No-flow Period and Primary Injury

Lacking energy stores, the brain relies heavily on sustained circulation to maintain its function. In fact, 20 – 25% of the cardiac output is used by the brain; thus, within minutes of CA, depletion of adenosine triphosphate (ATP) occurs, triggering neural ischemia and cell death due to massive ionic dysregulation and anoxic depolarization.24,28 Intracellular acidosis subsequently ensues, following the rise in cerebral lactic acid concentrations from the metabolism shift towards anaerobic pathways as energy substrates decrease.24 This culminates in an influx of Na+ and consequent cytotoxic edema, and the rise in intracellular Ca+2 activates lytic enzymes, promotes release of excitatory neurotransmitters, and activates apoptosis. Aquaporin-4 channels are disrupted, contributing further to cerebral edema formation.29

The effects of these events impact all organ systems, the brain in particular. Areas of increased aerobic metabolism are more vulnerable, such as the cerebellum, striatum, thalamus, hippocampus, and primary sensory cortex.30 On the other hand, hypothalamic and brainstem neurons display increased resilience to ischemia due to their intrinsic ability to resist anoxic depolarization; hence, the preservation of basic vital functions and reflexes in severe HIE survivors in persistent vegetative state.31 Several studies have demonstrated that consciousness disruption along with diffuse slowing followed by attenuation of cerebral rhythms on electroencephalogram (EEG) occur within 10 – 30 seconds of circulation cessation, regardless of the underlying CA rhythm.24,32,33 To some extent, the clinical manifestations of hypoperfusion during no-flow state are reversible, particularly in the setting of immediate high-quality CPR.

Figure 2 – Pathophysiology of Post-Cardiac Arrest Syndrome
HIE Chapter_Figure 2 – Pathophysiology of Post-Cardiac Arrest SyndromeQuite unnervingly, a recent survey of CA survivors demonstrated that approximately 2% of respondents described awareness with explicit recall of events related to their CPR.34 In fact, signs of regaining of consciousness during CPR such as spontaneous eye opening, random body movements, and even spontaneous speech may occur in up to 1% of resuscitated patients. Their clinical significance is still being elucidated, but evidence points towards an increased likelihood of survival to hospital discharge if these occur in unwitnessed/bystander-witnessed CA events compared to EMS-witnessed CA, as the former are less likely to receive sedating medications should these signs occur.35

Re-flow, Failure of Microcirculation and “No Re-flow,” Excitotoxicity, and Secondary Injury

The pathologic state that ensues upon resumption of forward circulation following whole body ischemia is probably the main determinant of injury burden and outcomes. The reperfusion injury is complex and involves a cascade of dysregulated inflammatory and prothrombotic events, as well as ongoing bioenergetic failure from the imbalance between metabolic demand and availability of energy substrates. The microcirculation was thought to be initially preserved in the early phase following return of spontaneous circulation (ROSC),36 but a recent pre-cliniccal study demonstrated theoccurrence of red blood cell flow arrest, or “no re-flow” phenomenon, as early as 5 minutes following ROSC.37 The subsequent ischemia, likely due to a combination of impaired autoregulation and factors related to the endotheliopathy that arises following reperfusion. This is the hallmark of secondary brain injury.24,38 Despite clear evidence of fibrinogenesis,39,40 microthrombi formation, and the benefits of systemic thrombolysis on the cerebral vasculature and overall perfusion in preclinical studies,41 the TROICA study (Thrombolysis during Resuscitation for OHCA) was interrupted early after enrolling 1050 patients demonstrating no differences in survival, ROSC rates, or neurologic outcomes between tenecteplase and placebo groups.42 Studies targeting endotheliopathy in PCAS are underway and may change the course of multisystem organ failure in this setting.43 In addition to endothelial damage and disruption of interstitial media, accumulation of intracellular Ca+2 coupled with decreased clearance of free radicals result in further neuronal dysfunction and cell death, thus constituting the final pathway in secondary brain injury.

Resuscitation

The field of resuscitation continues to develop at an astonishing pace, changing paradigms and increasing ROSC rates, adding promise toward improving neurologic outcomes. Updated recommendations by the American Heart Association quickly assimilate novel findings debunking old resuscitation standards and focusing on optimizing cardio-cerebral perfusion.44 Intriguing emerging evidence challenges most current resuscitation standards and includes: different optimal chest compression rates and adjustment of compression in real time,45-47 incorporating point-of-care focused ultrasound for the identification of reversible causes48 and of fine ventricular fibrillation that may go unrecognized or mistaken for asystole, deferring epinephrine administration in shockable rhythms, 49 delaying a definitive airway50 or using supraglotic devices in selected settings,51 and more. The PARAMEDIC-2 trial revisited the role of epinephrine in OHCA and failed to demonstrate benefit over placebo on neurologically favorable survival, despite higher ROSC rates and 30-day survival.52 Real time optimization of resuscitation efforts is also being targeted based on various physiologic monitoring strategies such as end-tidal CO253 and arterial diastolic blood pressure54—interventions that are likely cost-effective and widely available. Further, simple original interventions focused on optimizing cerebral perfusion pressure by enhancing brain venous return during resuscitation, such as elevating the head of the bed during CPR—the so called “heads-up CPR”— have promising supportive preclinical data.55,56 Novel devices that optimize compression and decompression phases during resuscitation are being developed, such as the impedance threshold device (ITR),57,58 the intrathoracic pressure regulator (ITPR), and the active compression decompression (ACD),59 which can be used alone or in combination60,61 to mimic physiologic negative intrathoracic pressure, thereby enhancing cerebral venous return and optimizing coronary perfusion; however, further randomized studies are needed prior to their widespread use.62-65 Nonetheless, these interventions cannot substitute for high-quality CPR, as demonstrated in subsequent analysis of the PRIMED trial showing negligible benefits of the routine use of ITR if CPR that met AHA standards for compression rate and depth occurred.66,67

Recognition of the etiology of CA is key to a successful resuscitation. Several case features commonly associated with unfavorable outcomes have been identified; however, these parameters alone should never be used to guide decisions on termination of resuscitation efforts or withdrawal of life sustaining therapies down the road. Interestingly, the presence of gasping during out-of-hospital arrest was showing to be associated with higher rates of 1-year survival, regardless of the first recorded rhythm. 68 Reports of cases of unexpected satisfactory recovery with continued extraordinary efforts despite unfavorable odds for survival with recurrent prolonged arrests69-71 stir the debate on when it is acceptable to allow natural death to occur during resuscitation. Duration of resuscitation has been traditionally used to guide decisions regarding whether or not to proceed with novel invasive methods (such as extracorporeal membrane oxygenation—ECMO) or termination of resuscitation efforts in OHCA and IHCA, as shorter resuscitation duration is associated with an increased likelihood of favorable outcomes; however, specific factors justifying longer or shorter durations remain poorly defined.72,73

Management of Post-Cardiac Arrest Syndrome

Achieving ROSC is only the first step in surviving CA. Subsequently, avoiding recurrent arrests by promptly addressing the CA etiology and focusing on limiting secondary brain injury are the mainstays of PCAS management. Challenges to a successful implementation of state-of-art PCAS management include significant inter- and intra-institutional practice variation and fragmentation of care by having multiple subspecialties involved who may be focused only on one or few aspects of post-CA care. The development and consistent execution of protocols with a multidisciplinary approach for comprehensive care has been shown to improve outcomes.74-76 Moreover, centers more experienced in the intensive care management of PCAS may exert a positive impact on the outcome of CA survivors,77-80 although this association does not seem to be uniform.81 A recent multistate study demonstrated that the direct transport to a cardiac arrest receiving center from the scene and early inter-facility transfer of OHCA patients to a specialized cardiac arrest center were independently associated with reduced mortality.82

Approximately 10% of those successfully resuscitated with conventional CPR and over one quarter of patients who undergo extracorporeal CPR have severe hypoxic-ischemic brain injury that ultimately evolves to brain death; this progression usually occurs in the initial 96 hours following ROSC.83,84 Patients at increased risk for malignant anoxic cerebral edema display abrupt hemodynamic changes, have a sudden dramatic increase in urinary output due to ensuing diabetes insipidus, and often have suffered a CA due to a catastrophic neurologic cause.84 Early head imaging with computed tomography in patients sharing these characteristics, or in those whose etiology of arrest is indeterminate, may be helpful; diffuse loss of gray-white differentiation and crowding of the basilar cisterns in the absence of hypercarbia should be considered alarming radiologic signs. The prompt recognition of this subset of patients is of the utmost importance to provide closure for families, avoid the cost of futile interventions and delays in brain death determination, and to honor the last wishes of potential organ donors.

Cardiac-Specific Targeted Care

In OHCA, the main precipitating factor is cardiac, accounting for 50-91% of cases in published studies.85 Early coronary reperfusion is a key time-sensitive intervention in improving survival in CA patients with shockable rhythms from underlying acute coronary syndrome.86 Not surprisingly, direct transport of resuscitated OHCA patients to a percutaneous coronary intervention center (regardless of transport time and need to bypass the nearest hospital) is associated with better outcomes.87 Despite this, a significant proportion of patients with shockable OHCA do not receive cardiac-specific targeted care, particularly those without obvious ischemic changes on electrocardiography (ECG).88 Patient selection processes vary, and may be based on ECG alone or in combined algorithmic approaches using serum biochemical markers and echocardiography.89 This is important, as up to 1 in 4 OHCA survivors with nonspecific electrocardiogram findings following ROSC may have coronaropathy.90 Patients with inconclusive coronary angiography pose a diagnostic and management dilemma, and may potentially benefit from advanced imaging with cardiovascular magnetic resonance in selected cases.91 The CREST score, which was developed to assist in the identification of individuals with a circulatory etiology of cardiac arrest (with possible downstream cardiac-specific management implications), holds promise in improving the triage of survivors of cardiac arrest without ST-segment-elevation myocardial infarction.92 Importantly, the timely implementation of TTM should not conflict with coronary angiography and cardiac specific interventions, and recent evidence suggest that the order of such interventions carries no impact on survival.93 These interventions should be carried on concurrently with TTM.

Targeted Temperature Management

Despite decades of research investigating the performance of neuroprotection strategies, no intervention has been as successful as TTM with mild hypothermia (32 – 36 °C), an intervention with an impressive number needed to treat of 6 to achieve one additional good outcome.94 In part, this success can be attributed to the effect of temperature modulation in multiple steps in the pathophysiologic cascade of hypoxic-ischemic injury.

Ultra-Early Cooling

Data remain largely limited to preclinical studies regarding intra-arrest cooling with a few small human studies; however, benefits including improved ROSC rates, overall survival and neurologic outcomes, and reduced myocardial infarct size resulting in better cardiac function were seen.95 Pre-hospital cooling successfully achieves lower temperatures at hospital admission; however, conflicting data exist regarding its effect on survival, favorable neurologic outcome, and re-arrest rates—all likely due to considerable methodological heterogeneity.96,97 It is possible that some of the negative results from hypothermia in the pre-hospital setting come from the chosen method of cooling, namely intravenous cold saline, which has been linked to an increased incidence of re-arrests.98

Landmark Trials and Systemic Effects of Hypothermia

The use of hypothermia targeting 32 – 34 °C for 12 – 24 hours in unresponsive resuscitated patients became the standard of care following the publication of the European and Australian seminal studies published in 2002, demonstrating increased survival and a positive effect in neurologic recovery in OHCA from shockable rhythms.99,100 Subsequently in 2013, the TTM trial demonstrated non-inferiority of targeting 36 °C vs. 33 °C for 24 hours by recruiting over 900 patients across several countries in OHCA including all rhythms with the exception of unwitnessed asystole. 101

Contraindications for TTM are largely relative and arise from the exclusion criteria used in prior studies; of these, the only absolute ones remaining are pre-morbid unresponsive state and spontaneous hypothermia. Pre-existing coagulation disorders and active bleeding must be pondered against possible benefits, since a recent meta-analysis failed to demonstrate a higher risk of bleeding during TTM.102 Nonetheless, evidence of impaired thrombin generation when cooling targeting 32 – 34 °C is maintained for 48 hours was recently demonstrated by thromboelastometry.103 Hemodynamic instability requiring vasopressor support is commonly misinterpreted as an absolute contraindication for TTM in clinical practice. Evidence supports the safety of cooling induction in patients with vasopressor-dependency after cardiac arrest;104 however, particular attention to titration is necessary during rewarming, as vasodilation and potential transient increased need for support may occur. The deeper the hypothermic level targeted, the higher the chance of impactful electrolyte derangements (commonly involving potassium) due to shifting between the intra- and extracellular space as well as increased elimination through cold diuresis.101

The negative impact of hypothermia in the immune system is often cited as a relative contra-indication for this treatment modality. A post-hoc analysis of the TTM trial demonstrated no significant differences between the two targeted temperature approaches in the incidence of severe infectious complications.105 Nonetheless, a pooled analysis of randomized and quasi-randomized hypothermia trials demonstrated a higher incidence of pneumonia in hypothermic patients, with a number needed to harm of 15.106 Aspiration events are common in CA survivors; however, the routine use of prophylactic antimicrobials is not indicated.107 Despite being commonly used in the critical care setting to aid in the identification of infectious complications, serial procalcitonin and C-reactive protein levels have been shown to be of limited value in this specific patient population.105 Having a high index of suspicion and initiating an infectious work up whenever fever is signaled based on episodic increased demand from the selected cooling device (e.g., lower water bath temperatures in feedback-loop surface cooling devices) is prudent. Additionally, lower temperature targets have increased detrimental effects on the cardiovascular system, with higher risk for arrhythmias and hypotension, increased lactate, and need for vasopressor support;108 each of these factors have been independently associated with worse outcomes. Abnormalities in heart rate and rhythms commonly occur in hypothermia, but are often transient and may not require any intervention. In fact, bradycardia during TTM has been associated with good neurologic outcome at hospital discharge.109 Cooling can also mitigate myocardial injury (particularly if maintained for 48 hours)110 and may temper the systemic inflammatory state following reperfusion, although this systemic inflammatory response does not seem to exhibit a dose dependent effect according to target temperature.111,112 Hypothermia affects multiple organ systems as summarized in table 3 and illustrated in figure 3. The treating clinician must be well versed in recognizing the systemic effects of cooling so that appropriate contraindications for this therapy are promptly recognized and transient abnormal findings during hypothermia are not over treated.

HIE Chapter_Table 3 – Systemic Effects of Hypothermia HIE Chapter_Table 3 – Systemic Effects of Hypothermia

Effects of Hypothermia on Pharmacodynamics and Pharmacokinetics

Therapeutic hypothermia vastly alters drug pharmacokinetics and pharmacodynamics due to the temperature dependent processes affecting enzymatic activity. Consequently, many of the commonly used agents (e.g., antiplatelet agents, sedatives, anesthetics, anticonvulsants, antiarrhythmics, neuromuscular blockers, and vasopressors) require close monitoring for relevant dose adjustments to avoid concentration dependent toxicities and to maintain desired therapeutic benefits. One of the main mechanisms accounting for alterations in drug activity is reduced metabolism mediated by modifications in the cytochrome (CYP) P450 enzyme system, which plays a significant role in both drug activation and detoxification of numerous medications. The reduction in drug metabolism is followed by a reduced elimination of medications. These modifications demand attention to the potential for both drug accumulation and toxicity, often warranting reduced doses of medications during cooling. Reductions of approximately 7 – 22% in the clearance of CYP450-reliant medications when temperatures drop below 37 °C have been noted.114 This reduced clearance of medications is further exacerbated by an impairment in hepatic blood flow, which ultimately translates to lower required doses to achieve similar therapeutic effects. Furthermore, clearance becomes less dependent on steady state concentrations.

Table 3 – Systemic Effects of HypothermiaHIE Chapter_Table 3 - Systemic Effects of Hypothermia

Adapted from106,108


The bioactivation of some drugs, particularly clopidogrel, may also be hindered due to impaired enzymatic activity during hypothermia. Opposite effects may be observed during the rewarming phase due to resumption of enzyme metabolism and increased clearance, likely warranting dose adjustments. Table 4 lists commonly utilized medications in the critical care setting that may have their clearance affected by hypothermia, and their respective elimination pathways involving CYP450 enzymes. Expectations in drug effects are also at stake. An example is blunting of catecholamine effects during the cooling process necessitating reduced vasopressor concentrations to achieve the same therapeutic effects.116 In most instances, both pharmacokinetic and pharmacodynamic responses may be isolated and more clear, depending on the degree of hypothermia, binding site of the medication, mechanism of action, and specific metabolic pathways. It is difficult to predict the ultimate result of such a complex interplay of factors, and both toxicity or therapy failure are possible. More recent evidence suggests that altered metabolism of drugs may persist well beyond rewarming, as the return to the basal activity may be delayed in the setting of metabolic derangements.117


HIE Chapter - Table 4_Respective Elimination Pathways for Commonly Used Medications in the ICU Setting

Pharmacokinetics and drug responses have also been found to be impacted by the actual hypoxic insult that may have caused direct damage to the liver and kidneys. Decreased rates of absorption have been observed depending on the acid-base status of the medication along with dysmotility that is present during the hypothermic state itself, thus contributing to an overall delay in medication availability. Hypothermia induces vasoconstriction, diverting blood away from various organs to coronary and cerebral territories. Additionally, there is a direct relationship between higher acid dissociation constants (more basic states) and a medication’s ability to cross the blood brain barrier, which may contribute to an increased drug effect during hypothermia. Moreover, plasma protein binding capacity may increase, decrease, or simply remain unaltered. The volume of distribution is regulated by both blood perfusion and pH, but the effects from cooling are variable and less predictable. Agents that rely on hepatic enzymatic processes for elimination may have increased drug half-lives as a result of reduced clearance, with high-clearance compounds requiring more attention than low clearance compounds. Overall, the effects of hypothermia and its contributions to alterations in plasma concentrations as well as the drug response are complex requiring vigilant monitoring of each medication due to high risk for both drug toxicity and for significant reduction or even omission of therapeutic effects. In particular, close attention should be given to home medications with long half-lives that patients were receiving prior to cardiac arrest. Agents with narrow therapeutic indexes, active metabolites, and those exhibiting high first pass metabolism should also be cautiously monitored. Table 5 lists alternative considerations and practical management strategies for some commonly used agents.

HIE Chapter_Table 5-Alternative Agent Considerations During Therapeutic Hypothermia

Device Considerations

Technology and devices for TTM therapy continue to evolve at a rapid pace. Table 6 summarizes a few commercially available devices and their mechanism of action. Several device characteristics should be considered when evaluating new or existing device technology for use within a TTM program. These include the feedback control mechanism and degree of drift when the target temperature is set, ability to control rewarming and at what rate, the ease of device application, and patient safety considerations.118 Patients should be monitored closely for skin integrity and signs of skin breakdown when using surface cooling devices, particularly when circulating water temperatures are low for extended periods of time. Patients cooled with endovascular devices should be monitored for catheter-related complications, including infection and deep vein thrombosis.118 Workflow analysis is also key to determining the best device for an individual TTM program, considering the ease of application and which practitioners are required at the bedside to initiate cooling therapy. The methods used to achieve and maintain target temperature vary and can be external or internal (core cooling methods). External methods can be based on convection, such as air circulating cooling blankets; conduction, such as ice packs and water-circulating cooling blankets; or evaporation, which is much less commonly used in this scenario, such as alcohol sprays and sponge baths.94 Intravascular cooling methods are based on conduction, and include chilled saline administration and endovascular cooling devices, the latter requiring central access. The endovascular approach is associated with faster induction and less fluctuation of temperatures during maintenance phases of TTM; however, only a trend toward benefit was seen with no statistically significant improved outcomes.119 Additional devices using techniques such as cranial, nasal and esophageal cooling are also available.

Practice Considerations

Significant variability is still seen in the practice of TTM in the post-CA period regarding target temperature, method, duration, patient selection, and prognostication methods in the setting of cooling.120 Practices are often extrapolated from landmark studies, and extended to IHCA, non-cardiac etiology of CA, and all cardiac rhythms. The SPAME study surveyed European large teaching and University hospitals, and demonstrated that 2/3 of ICUs continue to target 32 – 34 °C.120 Since the publication of the TTM trial, institutions are slowly shifting practices,121 as both temperature targets are acceptable according to guidelines.122,123 There is criticism to the methodology and questions regarding reliability of conclusions in both higher and lower temperature targets. Regarding the lower temperature target, the following concerns have been raised: a) the European landmark trial targeting 32 – 34 °C had no strict temperature management in the control arm; b) no guidelines for neuroprognostication and criteria for withdrawal of life sustaining therapy were provided (in the Australian trial the majority of subjects that remained comatose at 72 hours had life support withdrawn); c) lack of prior power calculation and low rate of enrollment; d) the Australian trial was pseudorandomized according to day of the week; e) rewarming was passive or active without a rate limit; f) heterogeneous outcome selection (type of disposition versus standard outcome scales). On the other hand, the TTM study had an unusually high enrollment rate at 66% of screened patients, and the 33 °C arm had a relatively faster rate of rewarming (although the average rate was acceptable), greater prevalence of spontaneous hypothermia prior to induction phase of cooling, more patients who met the criteria for withdrawal of life support, and higher rates of seizures—all factors that have been associated with poor outcomes, thus representing a “sicker patient population.”124 It has been hypothesized that different temperature targets and durations of cooling may benefit specific subsets of patients. However, lower temperature targets failed to provide increased benefit for patients with longer no-flow times, as previously suggested,125 and prolonged cooling may increase complications.126 For now, until further studies address such questions, these remain speculative. There seems to be no difference in the feasibility of implementing a TTM protocol according to target temperature; however, lower temperatures may require more sedation and may be associated with increased shivering,127 although some feel that more shivering may actually occur when trying to keep the patient at a temperature of 36 °C. The promotion of interdisciplinary collaboration by the means of educational activities and the use of loop feedback temperature modulation equipment have been identified as facilitators for the implementation of institutional guidelines of TTM care.128

HIE Chapter_Table 6- Commercially Available Devices for Targeted Temperature Management (TTM)HIE Chapter_Table 6 – Commercially Available Devices for Targeted Temperature Management (TTM)

HIE Chapter_Table 7 – Cooling and Management of Post-Cardiac Arrest Syndrome Checklist HIE Chapter_Table 7 – Cooling and Management of Post-Cardiac Arrest Syndrome Checklist HIE Chapter_Table 7 – Cooling and Management of Post-Cardiac Arrest Syndrome Checklist

There are three distinct phases of cooling: induction, maintenance, and rewarming. A brief summary of cooling in 8 steps is demonstrated in table 7. Ideally, goal temperature should be reached as soon as possible following ROSC.129 Interestingly, shorter induction times and steeper induction curves have been associated with worse outcomes130—a finding that supports that patients with more severe neurologic injury have impaired thermoregulation and are less capable of “resisting” temperature modulation.131 These thermoregulatory responses include both vasoconstriction and shivering, and are primarily regulated by the hypothalamus. The temperature threshold for vasoconstriction is approximately 36.5 °C, and shivering responses are usually triggered around 35.5 °C; however, significant variations in temperature thresholds depending on drug effects, gender, and overall health state may occur.132,133 Spontaneous hypothermia has been associated with worse outcomes in conventionally resuscitated patients and in those who undergo extracorporeal CPR.131 This likely shares the same pathophysiologic mechanisms that substantiate the fact that CA survivors who undergo TTM and shiver have better prospects of neurologic recovery than those who do not, as the ability to generate heat is associated with better baseline health and reduced ischemic injury burden.134,135 Overall, high variability in body temperature is common in CA survivors undergoing TTM.136 Hyperthermia may occur in nearly half of TTM-treated CA survivors, and may be associated with worse outcomes.137-140 Importantly, brain temperature does not correlate often with core temperature: it usually runs higher by approximately 0.3 – 1° C and display slower changes lagging behind of core temperature changes by approximately 30 – 40 minutes.141 Following rewarming, maintenance of normothermia is strongly encouraged, but there is insufficient evidence to guide the clinician in the selection of the approach (pharmacologic or surface cooling devices) and for how long this should be maintained.

Shivering: Pathophysiology, Detection, and Management

Shivering is commonly seen in TTM, regardless of target temperature, and should be promptly recognized and treated as it can mitigate the benefits of cooling by causing heat generation (up to a 600% increase) and ultimately increasing oxygen consumption (up to 3 fold).142-145 The bedside shivering assessment scale (BSAS) (Table 8) is one of the most widely used tools for shivering identification. The BSAS should be used to frequently assess for shivering, generally hourly in patients undergoing TTM, or more frequently if actively treating shivering. Shivering preventative measures should be part of all treatment protocols for temperature modulation and include skin surface counter-warming, buspirone, and optimized serum magnesium levels. Skin counter warming is not completely effective in obliterating the shivering effect; therefore, medications become essential leading to central inhibition of the shivering response.146 Sedatives, analgesics, and neuromuscular blockade are commonly employed to treat shivering. In the setting of neuromuscular blockade usage, short-acting agents used intermittently at minimal doses to achieve desired effects may be preferred. This minimizes the potential to overdose during the cooling period that result from decreased metabolism and elimination.147 Emerging evidence favors shivering management with neuromuscular blockade in conjunction with adjunctive sedation over sedation alone.148 Further, when compared to intermittent bolus dosing, continuous neuromuscular blockade during the first day after ROSC reduced shivering, midazolam and fentanyl requirements, time to awakening and time to discharge from the intensive care unit.149 Table 9 summarizes available pharmacologic treatment options for shivering management.

Neuromuscular blockers and meperidine have been considered the most effective agents to reduce the vasoconstrictive shivering response. Meperidine’s advantage to other opioids at equianalgesic doses is likely due to its strong effect on various receptors, particularly kappa (ĸ), and its central anticholinergic activity. Limitations that prevent the routine use of meperidine is its association with seizures in the setting of the accumulation of an active metabolite, normeperidine. Usually, a combination of agents is used to mitigate large doses of single agents. By default, first-line agents are sedatives and anesthetics since they are routinely employed in patients undergoing hypothermia. Adequate sedation is paramount in patients requiring paralytics and should remain a vital component of treatment during the cooling process. Irrespective of the agents used, the effects of hypothermia on drug metabolism and anticipations of altered drug response should always be considered.


HIE Chapter_Table 8- Bedside Shivering Assessment Scale

Program Management

As TTM effects every body system and can place the patient at risk for complications, the therapy should be administered through a planned approach. Programs should monitor their outcomes and safety events to identify trends and adjust accordingly. A number of publications detail how individual organizations and regional systems monitored their program processes, outcomes and complications, and instituted process changes to improve outcomes.150-152 A regional Canadian analysis of the impact of patient volume on TTM demonstrated patients were more likely to receive TTM and achieve target temperature if they received care at a high-volume center.153 Interventions and tools studied to improve processes for TTM include an organized postcardiac arrest team, protocols, pathways and checklists. Applying rapid quality improvement methodology to the TTM process is useful to monitor and improve aggregate patient outcomes.
Table_9_1_Pharmacologic_Options_for_Shivering_Management
Table_9_2_Pharmacologic_Options_for_Shivering_Management
Table_9_3_Pharmacologic_Options_for_Shivering_Management

Brain-Targeted Critical Care Management

The extent of brain injury is the main determinant of survival regardless of the etiology or underlying rhythm of cardiac arrest. Over 2/3 of deaths in OHCA and approximately 1/4 of IHCA deaths are attributed to hypoxic-ischemic brain injury.154 Avoiding further bioenergetic failure by tailoring critical care management to meet brain-targeted goals is the backbone of management in the acute and subacute post-CA periods. These goals are summarized in Figure 4. There are no data available to guide the treatment of diffuse cerebral edema in hypoxic-ischemic brain injury, particularly regarding osmotic therapy. In fact, it is likely that the presence of this ominous radiologic finding in the absence of hypercarbia may be one of the very few scenarios where it is appropriate to claim futility early and not pursue further aggressive care.

Figure 4 –Brain-Targeted Post-Cardiac Arrest Management
HIE Chapter_Figure 4 –Brain-Targeted Post-Cardiac Arrest ManagementHIE Chapter_Figure 4 –Brain-Targeted Post-Cardiac Arrest Management

Seizures

Seizures are common in the early post-CA period. Seizures and periodic discharges are associated with increased metabolic demand, and may be associated with neuronal dysfunction and confound the clinical exam of unresponsive CA survivors. The incidence of clinical seizures may reach approximately 30% and does not seem to be affected by treatment with TTM, as demonstrated in a post-hoc analysis of the largest trial of temperature modulation in CA survivors.155 Electrographic (nonconvulsive) post-anoxic status epilepticus is also common, may occur early in the initial 24 hours post-CA, and has a reported prevalence of 12-32%;156-162 this difference is likely due to variations in duration and timing of EEG monitoring and discrepant electrographic definitions with broader criteria than the definition of unequivocal electrographic seizures by the American Clinical Neurophysiology Society. There are no reliable means to predict which patients are at higher risk for seizure development, nor the timing of its occurrence; thus, continuous EEG monitoring is preferred. Despite its growing availability across institutions, continuous EEG monitoring may not be feasible everywhere. Repeated 60-minute studies at prespecified time points capturing at least the induction of hypothermia (as early as possible following ROSC), the transition from maintenance phase to rewarming (during which some patients may have increased susceptibility to developing epileptiform activity), and normothermia, are recommended. EEG should be obtained also when patients display any jerking involving any body parts (head, limbs, trunk, abdomen, face) or stereotypic behavior (such as eye opening followed by a single jerk or posturing), even if these are subtle as may represent clinical correlate of nonconvulsive seizures. Post-anoxic status epilepticus has been pragmatically associated with absolute mortality;160,163 however, similar to any single parameter used for neuroprognostication, reports contradicting this association have emerged over the years, and suggest a beneficial role for aggressive seizure suppression.161,164-172 The concurrent findings of a continuous background, preserved reactivity, and intact brainstem reflexes may help identifying which subset of patients with status epilepticus may survive with an acceptable outcome, thus justifying further aggressive care.157,158,171,173 Benzodiazepines are considered first-line agents for emergent control of seizures, regardless of their etiology. Thus, in the absence of studies comparing efficacy and safety of different strategies in post-anoxic seizures, similar antiseizure regimens for the treatment of seizures and status epilepticus used in other etiologies may be considered after cardiac arrest.123 Table 9 summarizes medications commonly utilized in the management of seizures. Detailed guidance for the treatment of seizures and status epilepticus can be found in the guidelines for the management of status epilepticus by the Neurocritical Care Society and the American Epilepsy Society.174,175

Ventilation

Abnormal arterial oxygen and carbon dioxide concentrations are present in the vast majority of CA survivors and carry an independent U-shaped relationship with hospital mortality.176 Gas exchange dynamics are variable in PCAS and depend on the presence of specific co-existing chronic and acute lung and heart morbidities; thus, the “one size fits all” approach to ventilation will invariably fail in this patient population. This is of major importance, as arterial concentrations of carbon dioxide and oxygen play a significant and independent role in the potential development of secondary brain injury. 176-178 Notably, the initial prescribed minute ventilation (tidal volume / ideal body weight X respiratory rate) correlates weakly with subsequent PaCO2 levels during PCAS.179 Thus, close monitoring of arterial blood gas (ABG) and using end-tidal CO2 is imperative. There are no data to support definitive recommendations on how frequently PaCO2 and PaO2 should be sampled; institutional protocols vary and commonly include every 4 – 8 hours assessments (or more frequently if any ventilator adjustments are made). Cerebral microdialysis is able to demonstrate evidence of impaired cerebral perfusion associated with relative hypocapnia during hypothermia in CA survivors.180 Further, decreasing arterial carbon dioxide from ~40 to ~30mmHg leads to a significant reduction in cerebral tissue oxygenation, as demonstrated with near-infrared spectroscopy during TTM.181 Consequently, adjusting the ventilatory parameters and paying close attention to PaCO2 is absolutely necessary; this is particularly important in TTM-treated patients, as hypothermia induces a lower metabolic state and consequently decreases the production of CO2, rendering these patients more susceptible to the deleterious effects of hypocarbia. A post hoc analysis of the TTM trial demonstrated that targeting 33°C results in lower end-tidal CO2 and higher alveolar dead space fraction when compared to targeting 36°C.182 Blood gas sampling is typically performed every 4 – 6 hours during TTM. Analysis of blood gases are temperature dependent, and if the sample is warmed to ~37 °C, an overestimation of the partial concentration of carbon dioxide and oxygen is to be expected.116 A quick formula to correct for these overestimations is to subtract the following for each 1 °C below 37 °C: for PaCO2, deduct 2 mmHg; for PaO2, deduct 5 mmHg. There are no definitive data guiding the ideal tidal volume in PCAS. However, there is evidence that lung protective ventilation with lower tidal volumes is independently associated with favorable neurocognitive outcome, more ventilator-free days, and more shock-free days in OHCA. 183,184 These benefits may be attributed to factors beyond hypocarbia-cerebral hypoperfusion mechanisms, as lung protective ventilation reduces the likelihood of further proinflammatory cytokine release, which commonly occurs with lung parenchyma stretching, as sepsis shares many pathophysiologic aspects with PCAS.175 However, similar benefits were not demonstrated in IHCA.185 Hyperoxia (PaO2 ≥ 300mmHg) is also detrimental in PCAS, as arterial accumulation of dissolved oxygen facilitates further injury via reactive oxygen species and pulmonary toxicity.187 In fact, a single exposure to hyperoxia was independently associated with an increased risk of death in two retrospective studies.188,189

Table_10__1__Medications_for_Seizure_Management.jpgHIE Chapter_Table 10 – Medications for Seizure ManagementHIE Chapter_Table 10 – Medications for Seizure ManagementHIE Chapter_Table 10 – Medications for Seizure Management

Hemodynamics

Approximately 2/3 of CA survivors experience hypotensive episodes (systolic blood pressure < 90 mmHg) in the initial 6 hours of PCAS due to a combination of myocardial stunning and systemic inflammatory state; exposure to systolic blood pressures < 100mmHg has been independently associated with death, with an OR of 3.5 (95%CI 1.3 – 9.6).190 Hypotension has been associated with worse outcomes in observational studies;109,191 this association held true even with single episodic hypotension.192 On the other hand, higher mean arterial pressures (regardless of method used to achieve target values) is associated with better neurologic outcomes and overall survival.193 Beyond avoiding hypotension, the fine tuning of systemic hemodynamics is a potential target for reducing the burden of ischemic brain injury, as cerebral blood flow becomes even more dependent on systemic blood pressure after ROSC due to impaired autoregulation, particularly in the early phase. Additionally, soon after CA, there is increased cerebrovascular resistance with evidence of low mean flow velocities in large intracranial arteries.194 Nevertheless, optimal blood pressure targets are yet to be defined in the light of the association of higher blood pressure values and improved neurologic outcomes.193,195,196 Further studies are needed to identify the ideal method for accomplishing hemodynamic goals and the ideal time window for such interventions. Intravenous fluid therapy should be used judiciously and hypotonic solutions should be avoided, as it is quite challenging to ascertain where a patient falls on the Starling Curve; the high incidence of myocardial dysfunction (nearly half of OHCA)197 in this patient population adds another level of complexity in hemodynamic management. Early resuscitation to maintain mean arterial pressure (MAP) ≥ 65 mmHg at a minimum is imperative, and intravascular volume expansion may be a suitable alternative to high vasopressor doses.198 While the optimum MAP targets remain unclear, there are ongoing scientific efforts to refine hemodynamic goals following ROSC to mitigate the burden of brain injury. The Neuroprotect post-CA trial will investigate whether a more aggressive hemodynamic strategy targeting a MAP 85-100 mm Hg and central venous oxygen saturations of 65-75% is more effective in decreasing brain ischemic injury and improving outcome compared to standard treatment (MAP 65 mm Hg) in comatose post-CA survivors.199 The COMACARE pilot study combines different hemodynamic targets (MAP 65-75mmHg versus 80-100mmHg) with low-normal or high-normal arterial carbon dioxide tension, and normal or moderately elevated arterial oxygen tension during the initial 36 hours following ROSC;200 however, interim results demonstrate no significant differences in NSE levels which is a surrogate of neuronal damage, although NIRS values, albeit a secondary outcome, were improved. Further, the duration of exposure to blood pressure <75mmHg in OHCA with shockable rhythms in the initial 96 hours following ROSC was demonstrated to have a direct correlation with neurologic outcomes, illustrating the complex relationship between hemodynamic targets and overall burden of neuronal injury, challenging the design of future studies.201 The selection of appropriate medications to manage hypotension and/or decreased cardiac output should be based on the delicate balance of desired effects.202-204 Tables 10 and 11 list vasopressors and inotropes according to their mechanisms of action and expected effects. Phenylephrine and vasopressin are considered vasopressors and dobutamine and milrinone are inotropes. Epinephrine, norepinephrine, and dopamine have both overlapping vasopressor and inotropic properties.

HIE Chapter_Table 11_Receptor and Messenger Activity for Vasopressors and Inotropes

Serial lactic acid measurements are indicated in the setting of hemodynamic instability during PCAS and may be helpful in guiding resuscitation efforts, also adding prognostic value to multimodal models.205

As in any critically ill patient, anemia is relatively common in PCAS and the suggestion of a minimum hemoglobin target of 8.6-9.0 g/dL based on the AHA recommendations for oxygen carrying capacity has been made.206 The ideal hemoglobin concentration range in the post-CA period remains to be unveiled by future prospective studies, but maintaining a minimum of 7g/dL is recommended while further studies explore the effects of higher targets.

Electrolytes & Metabolism

During the early post-CA period, additional factors may tilt the delicate bioenergetic state towards metabolic crisis and potentiate secondary brain injury. Dysregulated glucose metabolism is common following CA,30 and glycemic extremes must be avoided.207,208 Patients treated with TTM are particularly susceptible to glycemic fluctuations due to the variation of insulin sensitivity that occurs in various stages of cooling and rewarming. Soon after ROSC, sympathetic overdrive as a stress response leads to hyperglycemia, which is potentiated by cooling due to an increase in insulin resistance and decreased insulin production in the pancreas.209 Any intensive insulin therapy significantly increases the risk of hypoglycemia in neurocritically ill patients210 and CA survivors are particularly vulnerable as high insulin requirements early on need to be constantly adjusted as insulin sensitivity improves during rewarming. Patients may require higher doses of continuous insulin to maintain glucose control due to potentiated insulin resistance during TTM, and should be closely monitored for hypoglycemia. Shifting of potassium intracellularly during induction of hypothermia may be exacerbated by rapid increases in insulin infusion doses, and should be monitored closely in patients on an insulin infusion during TTM induction. While the insulin dosage may stabilize during the maintenance phase of hypothermia, glucose may shift quickly during and shortly after rewarming. Therefore, serum glucose and electrolytes should be closely monitored throughout all phases of TTM. Long-acting insulin formulations should also be avoided, not only to account for these changes in requirements, but also due to their potentially erratic absorption during different cooling phases, as there is variation on perfusion of subcutaneous tissue depending on distinct phases of TTM. Hyperglycemic thresholds for insulin therapy may differ between diabetics and nondiabetics, as recent evidence suggests a potential benefit of slightly higher glucose levels in diabetic patients.211


HIE Chapter_Table 12 –  Vasopressors and InotropesHIE Chapter_Table 12 –  Vasopressors and Inotropes

Neuroprognostication After Cardiac Arrest

The art of neuroprognostication in the modern era is a complicated and dynamic process. Despite this, significant headway has been made, with a trend toward using a multi-modality approach (rather than the results of a single test) incorporating complementary data achieved via different means to give a more cohesive picture. Also, more attention has been gained for the concept of the self-fulfilling prophecy of premature termination of life-sustaining therapy, as many important reports have surfaced that have drawn into question the pre-existing dogmas and fatalistic approaches. It is clear that the coming years will bring a calibration of our approach to neuroprognostication in this population, one that will likely be more comprehensive and appropriately patient. It seems prudent to account for comorbidities when neuroprognosticating;212 however, comorbidities have not been associatetd with short-term6 or 1-year survival rates.213

Prior to the widespread use of therapeutic hypothermia post-CA, there was some agreement as to the most useful clinical examination findings and ancillary test results, as well as the best time frames in which to utilize them for prognostication. However, the use of TTM has muddied the waters, as the impact on both the clinical examination and ancillary testing can be significant.214 There are conflicting reports on the impact of the exposure to TTM on awakening, and reports of delayed regaining of consciousness in patients exposed to deeper hypothermia (32-33°C) compared with those with higher temperature targets (>34°C) suggest that careful delayed prognostic assessments may be warranted in this setting.215,216 This is for two reasons: 1) neurons that are hypothermic may take longer to recover; and 2) medications used during TTM to keep the patient comfortable, such as sedatives, are likely to remain in the system longer than usual in the setting of hypothermia. Furthermore, sedatives will also take longer to clear in the setting of hepatic and/or renal dysfunction, both of which are not uncommon in this population, either pre-morbidly or post-CA. Finally, the target temperature for post-CA patients is now a moving target, as many centers are now using 36°C based on the TTM trial,101 while some are still using 33°C. The amount of sedative medications may vary quite a bit between these temperatures, as patients cooled to 33°C may not require paralysis to keep them from shivering, thus minimizing the amount type of sedative medications necessary. Finally, the upcoming TTM2 study will provide further data, as it will be studying 33°C vs. 37°C, although patients in this range will likely still need some medications to keep them comfortable, depending on the temperature control method. Caregivers concerned with prognosis will need to take all of these factors into account when prognosticating, and likely many more factors as well. Unfortunately, a significant proportion of ICUs still does not use a standard operating procedure for neurologic assessment and prognostication when using TTM.120 Several risk scores have been proposed for the early prediction of poor outcome in OHCA over the years and, most recently, the TTM score has showed promise with an area under the receiver operating curve of 0.842 (0.818 corrected for optimism), whereas the CAHP and OHCA risk scores were similarly inferior to TTM at 0.746.217 The factors most reliably predicting poor prognosis were older age, CA occurring at home, non-shockable initial rhythm, longer duration of no-flow and low-flow times, early administration of epinephrine in shockable rhythms, pupillary and corneal areflexia, no motor response to noxious stimulation, lower pH, delayed lactate clearance and hypocarbia.217

Recent studies have looked at outcome prediction scores, including attempting to predict good outcome rather than poor outcome, such as the GO-FAR score, although these lack external validation.218

Clinical Examination

The clinical examination remains central to assessing prognosis; in fact, its importance should not be overlooked or underemphasized. Of all of the findings that have been assessed for accuracy of prediction of prognosis, none have rivaled the clinical examination, which has stood the test of time. However, like all testing, staying true to proper technique of examination and correct interpretation of examination findings are integral to the process. Furthermore, the timing of the clinical examination is crucial, and, in the setting of therapeutic hypothermia, this should be delayed until at least 5 days post-arrest, if not longer.219

The first steps in the evaluation of an unresponsive patient after cardiac arrest are observation and stimulation. Observation should include an evaluation of the ventilator settings, such as whether the patient is over-breathing the set rate on the ventilator. The breathing pattern of the patient should be assessed, as this can give an indication of the degree of brain injury and possible brainstem dysfunction. The patient’s limbs should be uncovered during the examination (always maintaining decency) so that responsiveness to stimulation at one location (e.g., pressure on the supra-orbital notch) can be observed in a remote location (e.g., foot movement). The patient should be observed closely for any spontaneous movements, such as myoclonic or seizure-like movements, or spontaneous eye opening. Next, the patient should be stimulated, and this should include auditory, visual, and tactile stimulation. We recommend working from mild to more noxious stimulation in order to assess what degree of stimulation is necessary to establish consciousness. A common mistake of junior clinicians is to not be loud or noxious enough. Auditory stimulation should reach the point of yelling the patient’s name and clapping loudly. Visual stimulation is accomplished by opening the eyes of the patient (assuming they are not already open spontaneously) and testing for a blink to visual threat by approaching the patient with the edge of the hand or tips of fingers (so as to not create an air current and thus test a corneal reflex inadvertently), first coming from the lateral fields, then down the center of vision. Tactile stimulation should reach the point of deep noxious stimulation, both on the extremities and head (the head must be stimulated, as the patient may have an unknown spinal cord injury or severe peripheral neuropathy that could preclude responsiveness to noxious peripheral stimulation). Cranial stimulation should take place first with a “nasal tickle” using a Q-tip inserted into the nares, followed by deep pressure on the supra-orbital notch as well as the temporo-mandibular joint. Pressure on the extremities should be on the nail bed first, and then at more proximal locations to determine if a given response is stereotyped or not. The goal of this stimulation is to try to establish whether the patient is comatose or not. The strict definition of coma is that the patient shows no evidence of responsiveness to any stimulation; the only responses that are seen are reflexive, including brainstem and spinal.

Next, brainstem testing is performed, with particular attention to pupillary and corneal reflexes, which have shown the highest reliability in prognostication. Again, technique is paramount. Pupils should be tested for reactivity in a dimly lit room, and optimally, a pupillometer should be used, especially in cases of questionable reactivity. In the absence of a pupillometer, a magnifying glass should be used. The reliability of the “swinging flashlight” test is likely quite poor in this setting, as the halo from conventional flashlights likely initiates pupillary constriction prior to the pupil coming into focus, reducing the likelihood that the clinician will be able to appreciate reactivity in subtle cases. The light, which should be LED to maximize power and focus, should be shined off and on repeatedly, looking for pupillary constriction as well as the speed of constriction, if present. The pupillary light reflex may be affected by drug overdose, states of low cardiac output, and/or resuscitation drugs; thus, early non-reactivity may still reverse following the acute period of resuscitation.220 Additionally, despite taking every measure to improve sensitivity of testing, it still remains a subjective test with moderate inter-rater reliability based on the skill of the examiner.221 The use of automated pupillometry shows promise in increasing the reliability of this finding by means of an objective assessment.222,223 The corneal reflex should be tested by touching the cornea where it has significant innervation (which is over the iris and aperture of the pupil, and not on the conjunctiva, where innervation is less robust); we recommend testing at the border of the iris with the conjunctiva. Intensivists surprisingly often miss the target when testing the corneal, per a recent large international survey (Figure 5). Furthermore, to say that a corneal reflex is absent requires sufficient stimulation; squirting the eye with sterile saline/water or lightly touching the eye with a wisp of cotton is not sufficient to determine that a corneal reflex is absent. In the setting of neuroprognostication, the cornea should be pressed with a sterile Q-tip. Other brainstem reflexes should also be tested, including oculocephalic, oculovestibular, cough, and gag reflexes, although their current impact on neuroprognostication is uncertain and needs to be studied.

Figure 5_Heat map of locations

Traditionally, the motor examination findings were felt to carry prognostic weight, specifically extensor or no motor response to noxious stimulation. However, especially in the era of therapeutic hypothermia, poor motor response has been associated with unacceptably high false positive rates in prediction of poor outcome, up to 24%, making it a suspect prognostic finding at best. Again, attention to technique is likely important, as outlined above.

Finally, the presence of myoclonic jerking should be noted, as the presence of myoclonic status epilepticus (MSE) has been associated with poor outcome in prior studies.224,225 However, recent pool analyses demonstrate that approximately 10% of patients with MSE may, in fact, achieve a good neurologic outcome.226 Additionally, the definition of MSE varies from study to study, and may or may not require an EEG. The most common definition is the presence of non-rhythmic but repetitive and unrelenting jerking of the face, eyes, eyelids, limbs, and axial musculature. We would caution that it is impossible to know whether or not a patient with overt clinical MSE is having electrographic seizures, and when MSE is seen, an EEG should be performed (and if seizures are seen, they should be treated with antiseizure drugs). The EEG itself may be difficult to interpret in the setting of MSE, as much EMG artifact is generated; in this case, a dose of short-acting paralytics may be administered. Emerging evidence from the use of continuous EEG in patients with cortical myoclonus points towards two distinct clinic-encephalographic phenotypes: high voltage polyspikes time-locked with myoclonus in a burst suppressed background with an ominous prognosis, versus midline spike-wave discharges time-locked with myoclonus in a continuous background, which are associated with delayed but potentially good neurologic recovery in some patients.164,173,227 MSE is often treated with antiseizure drugs and muscle relaxants, with marginal effect. However, the use of these medications likely leads to a significant sedative effect, thereby hindering awakening in these patients. There is likely a strong self-fulfilling prophecy bias, as MSE is difficult for families and ancillary staff to observe, and often leads to over-treatment with pharmacologic agents and early withdrawal of life-sustaining therapies (WLST). We would caution that MSE does not necessarily indicate a poor prognosis, and continued prudent care may often lead to good patient outcomes.

Electrophysiology

Electrophysiological evaluations in post-CA patients are crucial, lending keen insights to patterns of injury and recovery. The two techniques that are commonly used are evoked potentials (specifically, somatosensory evoked potentials SSEP) and EEG.

The data in support of neuroprognostication using SSEP typically has evaluated median nerve stimulation with measurement of the contralateral cortical (N20) responses. Bilaterally absent N20 potentials within the first several days after arrest has been associated with poor outcome in multiple studies. The N20 peak represents the thalamo-cortical pathway, and it is important to note that the integrity of the pathway from the median nerve through the brachial plexus and brainstem must be intact, and structural lesions (e.g., prior stroke or subdural hematoma) can influence the findings as well. N70 potentials, representing the cortico-cortical pathways, have also been evaluated in cardiac arrest, but are technically more challenging and not used in many centers. The largest study to evaluate SSEP in a prospective fashion was the PROPAC study,228 which served as the basis for the 2006 guidelines for prognostication from the American Academy of Neurology.229 PROPAC evaluated 407 post-CA patients from 32 Dutch ICUs, and found that no patients with absent N20 peaks bilaterally survived to a good outcome. However, this study has been criticized for a lack of blinding, as well as a clear self-fulfilling prophecy bias: 23% of patients has WLST at 24 hours post-arrest, an alarmingly early time for decision-making regarding neuroprognosis. Furthermore, false positives have been reported in patients with absent N20 potentials shortly after undergoing TH, who later recovered function (and N20 potentials). Environmental noise, commonly seen in ICU due to equipment in the room, and shivering artifacts frequently limit interpretation of SSEP studies in this patient population.230 Technical aspects of adequacy of SSEP studies for interpretation are important and basic requirements of testing are summarized in Table 12. Despite these limitations, SSEPs are felt to be a valuable ancillary test in the assessment of prognosis post-CA, when put into the proper context and employed at the right time points. (Figure 6) A recent small study investigated the use of brainstem auditory evoked potentials (BAEPs), but found them to be of limited use.231

Figure 6_41 year old man who suffered an witnessed PEA arrest


HIE Chapter_Table 13 – Technical Standards for SSEP Testing in Unresponsive States

EEG gives complementary electrical information, and is an emerging, useful tool in the evaluation of prognosis and in the diagnosis and treatment of post-anoxic seizures. EEG can be very helpful in the early setting, when a patient is displaying signs of myoclonus, to ascertain if these are cortical or subcortical in nature. Non-convulsive status epilepticus (NCSE) cannot be detected without EEG, especially in the setting of sedation (and paralysis) when undergoing TTM. As a neuroprognostic tool, several EEG findings have been reported as useful, but none have maintained 100% positive predictive value for poor outcome, including burst-suppression, diffuse attenuation, and lack of variability with identical bursts.236-239 Reactivity has also emerged as important finding;158 patients who lack EEG reactivity to external graduated stimulation appear to be destined for a poor outcome. Nonetheless, subjectivity of reactivity assessment and lack of standardization of stimulation continue to challenge the prognostic yield of this EEG feature. It should be noted, however, that the presence of reactivity on EEG does not ensure a good outcome. The use of quantitative EEG analysis holds promise by offering increased objectivity.240 Seizures and epileptiform findings have been associated with poor outcomes with modest specificity in retrospective analysis, likely due to factors linked to how aggressive treatment was pursued and consequent self-fulfilling prophecy bias. Conversely, lack of epileptiform activity may be an optimistic sign in the absence of other ominous signs.241,242 Surprisingly, patients with epileptiform patterns may not demonstrate imaging evidence of hypoxic brain injury, according to a recent retrospective review of clinical, magnetic resonance imaging, and electroencephalography data of TTM treated CA survivors.243 (Figure 7)

Figure 7_External StimulusFigure 7_External StimulusFigure 7_External StimulusFigure 7_External Stimulus

Figure 8_1_Abnormal Variability_Identical BurstsFigure 8_1_Abnormal Variability_Identical BurstsFigure 8_1_Abnormal Variability_Identical Bursts
Continuous EEG is preferable in the first several days after arrest, but is not feasible or available at all centers, and sequential EEGs may be a reasonable alternative.244 The EEG typically evolves during the course of monitoring,245 and may be significantly affected by temperature, sedating and non-sedating antiseizure drugs246 and anesthetics, renal/hepatic impairment and hypoperfused states; thus, it is important to not use a single snapshot of a patient’s EEG to make prognostic judgments. EEGs with initially poor or malignant appearing patterns may improve and the recording may display positive trends over time; hence, the need for repeated testing comprising different stages in the post-CA course. In fact, approximately one in 6 patients with initially non-reactive backgrounds to external stimuli during TTM regain reactivity during normothermia. Promising emerging neurophysiologic strategies in outcome prediction include longitudinal analysis of continuous quantitative EEG variables247 and progression of auditory discrimination based on EEG responses during unresponsiveness.248 It is prudent to note that, although widely used,249 neuroprognostic assessments based on EEG continue to be challenged by the lack of high levels of evidence, vulnerability of findings to the effect of confounders, lack of uniform classification in traditional studies based on standardized nomenclature,241 inconstant inter-rater variability,250 and the impact of self-fulfilling prophecy bias on existing evidence. Nonetheless, when used in a multimodal approach, EEG findings provide valuable data enriching prognostic models.156,251-254

Chemical Biomarkers

Multiple chemical biomarkers have been evaluated as a method of detecting the degree of neuronal injury and breakdown, but all have their limitations in terms of accuracy and testing. The biomarker with the most data in this setting is neuron specific enolase (NSE), but it is subject to variations for multiple reasons: 1) multiple assays are available for testing, and laboratory variations can be significant;255 2) it is often a send-out lab, and delays on results can be lengthy; and 3) NSE is also found in red blood cells and platelets, and its release from these can result in elevated levels that are due to hemolysis or systemic factors and not necessarily reflective of neuronal injury. Thus, NSE can be a “dirty” biomarker, and relying on single values is likely a fallacy. It is probably more prudent to evaluate NSE on a serial basis over the first 1-5 days post-arrest, as this is a time when the patient is often improving from a medical/systematic standpoint, and thus NSE levels that are trending up during this time are likely indicative of ongoing neuronal injury and poor prognosis. This approach needs to be studied prospectively and in an unbiased population.

It should be noted that hypothermia attenuates NSE levels, but despite this, recent studies have found false positives for elevated NSE levels predicting prognosis. The primary data for NSE also came from the PROPAC study228 (see above in SSEP section), in which a cutoff value of >33 mcg/L was uniformly associated with a poor outcome. However, since that time there have been multiple patients with good outcome despite having NSE levels well above that. NSE has also been studied in patients on ECMO, and may be a useful marker of cerebral injury in this subset of patients.256

Post hoc analyses of the TTM trial demonstrated a promising role of light chain neurofilament, Tau and admission lactate (although not lactate clearance).257-259 The neutrophil-to-lymphocyte ratio (NLR) has also been the subject of limited studies, with some suggesting an NLR >6 at 72 hours post-ROSC is associated with worse outcomes.260

A quick word on what would make the optimal chemical biomarker: one of the challenges with the biomarkers studied to date is that they have primarily been studied in the blood, which is a contaminated environment. The optimal chemical biomarker would be most reflective of neuronal damage, or at least procured from a non-contaminated environment. The CSF is an obvious such environment, but studies of biomarkers obtained from the CSF are sparse. Clinicians may have pause in the concept of performing lumbar puncture in patients post-CA due to concerns of causing herniation. However, in a patient with radiographic signs of severe cerebral edema, a CSF examination is not necessary, as the prognosis is not in question (it is poor!). Lumbar puncture could be reserved for patients without these radiographic findings, which are the vast majority.

Neuroimaging

Neuroimaging has the distinct advantage of providing structural information about the brain, and both CT and MRI are valuable in the acute and subacute setting. Advanced MRI techniques are also able to tell us about brain perfusion and the integrity of white matter pathways and connectivity, which will all be important concepts moving forward. But even conventional CT imaging remains highly useful from a practical standpoint, and MRIs may not be able to be performed in all patients due to safety or compatibility issues. It should be noted that neither CTs nor MRIs have been validated for use in prognostication,261 but from a practical standpoint, both provide important information, and can and should be used in the context of the overall information gathered about the patient and their prognosis.

CT imaging is commonly performed on cardiac arrest patients at the time of admission, but this is not often a time point that is useful from a neuroprognostication standpoint. However, it is useful to rule out a cerebral cause for the arrest (such as in a younger patient or one without evidence of cardiac ischemia on ECG or enzyme analysis), or to evaluate for traumatic brain/spine injury in patients who are found down or have a witnessed fall with head/neck impact. From a prognostication standpoint, a CT scan performed on day 2-3 post-arrest is an appropriate time point, as ischemic changes that may have been delayed initially should have appeared by then, and it can give useful information to corroborate the clinical exam and other ancillary testing. Widespread hypodensities and/or diffuse cerebral edema with loss of grey-white differentiation likely portend a poor outcome, and specific brain regions, such as the Hounsfield unit ratio between the putamen (grey matter) and internal capsule (white matter) have correlated with outcome in several studies. Global Hounsfield unit reduction, especially in combination with the clinical examination findings on day 3, appears to strongly correlate with poor outcome with high specificity.262


Figure 9 – CT in cardiac arrest – A 20-year-old male suffered a 20-minute cardiac arrest. His CT is shown on day 4 post-arrest, with the pseudosubarachnoid hemorrhage sign caused by engorgement of the veins at the base of the brain.

Figure 9_CT in cardiac arrest

However, the CT is commonly normal post-cardiac arrest, and MRI may be necessary, as it is more sensitive to demonstrating the degree of ischemic injury.263 Again, the time point for testing is important, as premature testing may give falsely optimistic (e.g., minimal changes) results.264 The optimal time point for procuring the MRI post-arrest is likely 3-5 days post-arrest, as that is when the changes on diffusion-weighted imaging (DWI) are most likely to be maximal. If imaging is performed at other time points, it is important to keep in mind where to expect the changes, and with what sequence (DWI vs. FLAIR/T2); early changes typically involve the cerebellum and basal ganglia, which then migrate to the cerebral cortices, and then finally to the subcortical white matter.265 Some specific imaging findings have shown promise in predicting poor outcome, such as the “bright hippocampus sign,”266 but these need to be validated in prospective and unbiased studies.

Figure 10 – 42-year-old woman with cardiac arrest. MRI on day 4 post-arrest shows diffuse cortical restricted diffusion on (a) diffusion-weighted imaging and (b) apparent diffusion coefficient maps.

A:

Figure 10_A
B:
Figure 10_B

Guidelines

We will now discuss three guidelines for neuroprognostication post-CA, including their notable differences: the American Academy of Neurology Practice Parameters (AANPP) from 2006,229 the European Society of Intensive Care Medicine (ESICM) guidelines from 2015,269 and the American Heart Association (AHA) guidelines from 2015.123

The AANPP, the first of its kind, were primarily based on data prior to the widespread use of TH, and thus quickly became of questionable value in the modern era. They touted strong evidence for aspects of the clinical examination in predicting poor outcome, all measured at 72 hours post-CA, including absent pupillary and corneal reflexes, as well as motor exam findings of extensor posturing or no response, which has since fallen out of favor (although pupillary and corneal reflexes are still felt to be valid). The presence of myoclonic status epilepticus was also felt to indicate a poor prognosis, but with a lower level recommendation. Absent N20 responses on SSEP performed 1-3 days post-CA correlated with poor prognosis, but a burst-suppression pattern or generalized epileptiform discharges were felt to have insufficient evidence to achieve a strong recommendation. Serum NSE levels >33 mcg/L measured 1-3 days post-arrest were given a fairly strong recommendation (level B), but again, this was based on somewhat biased data and has since been debunked. There was felt to be insufficient evidence to support or refute the use of neuroimaging at that time.

The ESICM guidelines prudently took into account the impact of hypothermia on prognostication, and advocated for providing more time in situations of uncertainty. There is an up-front emphasis on excluding confounders, particularly residual effects of sedation. The motor examination at ≥72 hours post-arrest with findings of extension or no response is used as a sensitive sign for potential poor prognosis (in the setting of an unconscious patient), followed by one or both of the following at 3-5 days post-arrest: absent pupillary AND corneal reflexes, or bilaterally absent N20 peaks on SSEP. If these were not present, they suggested an additional waiting period of at least 24 hours, and then two or more of the following to indicate a high likelihood of poor outcome: status myoclonus ≤48 hours after ROSC, “high” NSE levels (not defined), unreactive burst-suppression or status epilepticus on EEG, or “diffuse” anoxic brain injury on brain CT/MRI (not defined). In the absence of these, the outcome should be considered indeterminate, and continued observation and re-evaluation is encouraged. The authors advocated the “use [of] multimodal prognostication whenever possible,” which is laudable.

The AHA guidelines also take into account the effect of TH/TTM, and advocate that the earliest time for prognostication using the clinical examination in this setting should be 72 hours after the return to normothermia, and longer if the residual effects of sedation or paralysis might potentially confound the examination. Absent pupillary and corneal reflexes again carried a strong recommendation for poor prognosis, but the motor exam findings of extensor or no movement were felt to have an unacceptably high false positive rate of 10% (95% CI, 7-15%). Any myoclonus was felt to predict a poor outcome, but with a 5% false positive rate (95% CI, 3-8%). Absence of EEG reactivity, persistent burst-suppression pattern, or status epilepticus were felt to correlate with poor outcome, but with a lower level of evidence. Absent N20 responses on SSEP again were felt to indicate a poor outcome, but the authors cautioned that technique and expertise were paramount in ensuring their validity. Both CT and MRI were felt to be reasonable to consider, and “marked reduction” in the grey-white ratio, or “extensive restriction” of diffusion on MRI were felt to be reasonable indicators of poor prognosis, in combination with other established predictors. Noting the high false positive rates, the AHA stated blood biomarkers (NSE and S-100B) should not be used alone to predict poor neurological outcome, but it would be reasonable to consider “high” serum values of NSE 48-72 hours post-arrest to support a possible poor prognosis, especially if repeated testing revealed persistently high levels.

Practical Advice

Neuroprognostication after cardiac arrest remains challenging, and several principles should help guide the clinician. First, the presence of confounding should always be taken into account, including the effects of age, temperature, systemic disease, metabolic abnormalities and medications. When in doubt, err on the side of caution, correcting these abnormalities as much as possible, and giving the patient more time to recover, particularly younger patients and/or in the setting of limited indicators of poor outcome. A multi-modality approach should always be used; the clinician should take into consideration the findings in the context of ancillary data, and if the data is not internally consistent (e.g., the patient is not awakening, yet the neuroimaging shows little or no damage), this must be explained and the patient given more time to recover. Recent studies have explored the utility of multimodal approaches using different aspects of the investigative work up.270-272 We would advocate, in the proper clinical setting, that the finding of electrographic seizures or status epilepticus could be treated aggressively, as it is one of the few treatable conditions in the subacute setting. Finally, the effect of hypothermia should always be considered,273 not only for the clinical examination but also for ancillary testing. When in doubt, give more time.

The following table gives an algorithmic approach to specific testing and the time points at which they should be utilized.

Table 14

Hypoxic-Ischemic Encephalopathy Recovery

The true natural history of hypoxic-ischemic encephalopathy unshaped by the commonly practiced WLST remains unknown. The pace of recovery and the distribution of outcomes according to the varying degrees of hypoxic brain injury severity remain to be explored by further studies in settings where optimal brain-oriented acute and subacute care can be delivered, but WLST is uncommon. Even when good neurologic outcome is achieved, impactful cognitive and motor deficits are common: memory loss, variable motor impairment, and executive and processing impacts.274,275 These patients are commonly discharged home without appropriate referral to rehabilitation or services despite significant deficits. Families are often overwhelmed and unprepared for the subsequent challenges that ensue during the arduous journey towards recovery in the post-hospitalization phase. Importantly, CA survivors may have unique rehabilitation requirements of care that are not only targeted at neurologic deficits, but are also tailored to overall functional needs according to coexisting multisystem comorbidities. A family-centered approach to the post-hospital care of these patients should be explored in a structured program,276 focusing on identifying the need for support personnel, focused rehabilitation based on overall functional needs, and in accordance with underlying comorbidities, mental health services, and so forth. A recent single center study attempted to elucidate the factors that may lead to persistently poor outcome at 1 year post-arrest, and identified older age, Hispanic ethnicity and discharge disposition of home with outpatient services.277

Future Directions

This is an exciting time in post-cardiac arrest research, with multiple prospective studies underway. It will be important to keep in mind in these studies the nearly ubiquitous effects of the self-fulfilling prophecy of early withdrawal of life-sustaining therapies, and caution should be exercised when the same prognostic tests that are being tested are also used for clinical decision making, the so-called behavior confirmation effect. A 2016 Canadian multicenter study utilized a multifaceted quality intervention consisting of education, pathways, local champions and audit-feedback, resulting in improved rates of appropriate neurologic prognostication, but without an increase in survival with good neurologic outcome.278 Improving neuroprognostication is a major cornerstone in increasing survival with good neurologic outcome in HIE, and studies with different approaches are promising in developing more accurate neuroprognostic algorithms. The ongoing MOCHA study (Multimodal Outcome Characterization in Cardiac Arrest) is a broad international observational study that will enroll >2000 patients from countries with various WLST practices, and will investigate the impact of WLST on the prediction ability of commonly used prognostic tools by using propensity score matching. Another promising observational study aiming to improve neuroprognostication by mitigating the self-fulfilling prophecy bias, Project HOPE will actively educate families and providers about the existing conflicting data on prognostic accuracy and will employ a multimodal approach.279 Prospective studies are also taking place to better assess the validity of EEG reactivity, using more objective criteria with quantitative analysis and accounting for the evolution of the recording over time during PCAS as prognosis indicators. Some groups are beginning to tease out the granularities of abnormal but present N20 responses on SSEP and their prognostic implications.280 Advanced MRI techniques, including functional MRI, diffusion tensor and diffusion kurtosis imaging are showing great promise to inform us about patterns of injury and potential recovery. Neuroprotective strategies targeting reduced cerebrovascular resistance and enhanced blood flow, and post-conditioning strategies limiting reperfusion cardio-cerebral injury with halogenated anesthetics, noble gases, membrane stabilizing agents, and even ischemic post-conditioning techniques are being developed and tested at an astonishing pace.281 Refining temperature modulation practices is also a target of future studies. The TTM2 trial, comparing 33° C vs. 37° C, will provide useful information regarding the effect of therapeutic hypothermia, testing the hypothesis that hypothermia may not be as important as simply keeping the patient normothermic post-arrest. Moreover, more insights regarding time-differentiated approaches to TTM—exploring potential benefits of maintaining 33° C for 24- or 48 hours—are underway with the TTH48 trial.282 HYPERION is investigating whether different hypothermia (32.5 - 33.5° C) and/or controlled normothermia (36.5 - 37.5° C) is beneficial in CA due to non-shockable rhythms.283 Tailoring critical care to brain-directed goals is also a target of future studies in post-CA syndrome. After encouraging results from the CCC phase II trial,284 targeted therapeutic hypercapnia (50 – 55 mmHg) following ROSC will be prospectively compared to normocapnia (35 – 45 mmHg) in the TAME Cardiac Arrest trial.285 By using a PROBE design, TELSTAR is investigating whether aggressive suppression of post-anoxic electroencephalographic status epilepticus has an impact in outcomes.286 Cardio-neuroprotective therapies, such as hydrogen gas and Xenon, are currently being investigated with promising translational pilot data.287-290 The adoption of an intensive coronary strategy immediately following ROSC in patients with non-ST elevation myocardial infarction is being compared to deferring coronary interventions until neurologic recovery is achieved in the COAT trial.291 Finally, invasive brain monitoring is being explored in this field—employing such techniques as cerebral blood flow monitoring, cerebral oxygenation, intracranial EEG and microdialysis—and this disease, with global anoxic brain injury, is likely the perfect disease to study with this technique. We can expect that the next decade will bring major advances in the diagnosis and care of patients with hypoxic-ischemic brain injury from CA.

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