Abstract
Per the American Academy of Neurology Practice Parameter published in 2006 regarding prognostication after cardiac arrest, there is insufficient evidence to use brain swelling or an inversed gray and white matter ratio measured in Hounsfield units on CT to predict poor outcomes in survivors of cardiac arrest (Wijdicks, Hijdra et al. 2006). This recommendation was based on a study published by Torbey et al. in 2000 which looked at inversed gray and white matter ratios on CT in 25 patients with return of spontaneous circulation (ROSC) after cardiac arrest. A ratio of less than 1.18 at the level of the basal ganglia was 100% predictive of death (Torbey, Selim et al. 2000). A similar study was published in Korea in 2008 that found that a ratio of less than 1.22 was predictive of death and vegetative state with a specificity and positive predictive value of 100% but only a sensitivity of 63% and negative predictive value of 56% (Choi, Park et al. 2008). Both of these studies were retrospective in nature, done with CT images obtained 24–48 hours after ROSC and collected patient data from the early 2000s before the wide adoption of therapeutic hypothermia.
One of the first studies assessing early CT changes immediately after ROSC showed that early hypoattenuation in the basal ganglia had a specificity of 92% and sensitivity of 81% for death or severe disability (Inamasu, Miyatake et al. 2010). Similar findings were found in a retrospective analysis of early CT changes in patients who received therapeutic hypothermia after ROSC (Yamamura, Kaga et al. 2013). Despite all of these studies, caution must be used in making decisions about prognosis based on early CT changes. All of these studies were retrospective with small patient samples and the findings have not been validated prospectively. Myoclonic status epilepticus (MSE) was once thought to be a universal marker of death or severe disability with a very high specificity and positive predictive value but in very recent study 9% of patients with MSE treated with therapeutic hypothermia had a good outcome (Seder, Sunde et al. 2015). Early CT changes are one data point that can be used to counsel families regarding prognosis, but it should not be used alone to guide the initiation or discontinuation of therapeutic hypothermia. As with all studies of neurologic prognosis after cardiac arrest, there are probably good outcomes in patients with early CT changes but we are unable to detect them given the self-fulfilling prophecy of withdrawal of care.
Authored by:
Stephen A. Figueroa, MD
Assistant Professor
Division of Neurocritical Care
The University of Texas Southwestern Medical Center
Dallas, Texas
References
Choi, S. P., H. K. Park, K. N. Park, Y. M. Kim, K. J. Ahn, K. H. Choi, W. J. Lee and S. K. Jeong (2008). “The density ratio of grey to white matter on computed tomography as an early predictor of vegetative state or death after cardiac arrest.” Emerg Med J
Inamasu, J., S. Miyatake, M. Suzuki, M. Nakatsukasa, H. Tomioka, M. Honda, K. Kase and K. Kobayashi (2010). “Early CT signs in out-of-hospital cardiac arrest survivors: Temporal profile and prognostic significance.” Resuscitation
Seder, D. B., K. Sunde, S. Rubertsson, M. Mooney, P. Stammet, R. R. Riker, K. B. Kern, B. Unger, T. Cronberg, J. Dziodzio and N. Nielsen (2015). “Neurologic outcomes and postresuscitation care of patients with myoclonus following cardiac arrest.” Crit Care Med
Torbey, M. T., M. Selim, J. Knorr, C. Bigelow and L. Recht (2000). “Quantitative analysis of the loss of distinction between gray and white matter in comatose patients after cardiac arrest.” Stroke
Wijdicks, E. F., A. Hijdra, G. B. Young, C. L. Bassetti and S. Wiebe (2006). “Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.” Neurology
Yamamura, H., S. Kaga, K. Kaneda, T. Yamamoto and Y. Mizobata (2013). “Head Computed Tomographic measurement as an early predictor of outcome in hypoxic-ischemic brain damage patients treated with hypothermia therapy.” Scand J Trauma Resusc Emerg Med
There are several hemodynamic effects of therapeutic hypothermia (TH) including decrease in heart rate, cardiac output and vasoconstriction of peripheral arteries or arteriole which leads to an increase systemic vascular resistance (Saigal S. et al. 2015). Currently in post cardiac arrest patients the use of inotropic are used to increase myocardial contractility and vasopressor therapy increases vascular tone (Bangashm MN., et al. 2012). Inotropes are potentially hazardous in ischemic heart failure due to the increased myocardial oxygen demand, and vasopressors can worsen peripheral tissue perfusion and microcirculation (Bangashm MN., et al. 2012). The CVad Registry indicates there is increased mortality with the increased numbers of inotropes and vasopressor (Basir M, et al.,2016).
Mechanical circulatory support (MCS) is considered the standard of care in the treatment of refractory cardiogenic shock. The Intra-aortic balloon pump (IABP) has been used for many years in critical care as a mechanical circulatory support to increase coronary perfusion pressure and reduce the end-diastolic pressure. More recently a single-arm, multicenter study in Detroit using the Impella for mechanical circulatory support showed a significant improvement in mortality (Basir M, et al.,2016; O'Neil et al. 2014). The Impella is placed percutaneously or surgically and produces continuous flow from the left ventricle into the aorta which directly increases cardiac output and reduces cardiac workload. Based on this study and the recent FDA approval for Impella use in cardiogenic shock, there has been an increase use of the Impella devices used in patient undergoing therapeutic hypothermia post cardiac arrest.
There is an absence of randomized clinical trials and little known about the combined use of therapeutic hypothermia and mechanical circulatory support for patients in cardiogenic shock. Currently the literature is only includes case reports or data from a national inpatient database suggesting concomitant use of therapeutic hypothermia and mechanical circulatory system are both safe and feasible (Silverman MG, et al. 2018, Hernandez GA, et al 2017).
Although there is an absence of randomized clinical trials it is important to aim for the desired therapeutic effect at the lowest possible dose of vasopressor and inotropes in use of either the IABP or the Impella. Both devices will work more effectively with reduced afterload so it is important to titrate off the vasopressor as soon as possible since we cannot impact the effect of cooling until we rewarm the patient.
Authored by:
Teresa Wavra, RN, MSN, CCRN
Cardiovascular CNS
Mission Hospital
Mission Viejo, California
References
Bangash, MN Kong, ML, and Pearse RM., Use of inotropes and vasopressor agents in critically ill patients. BR J Pharmacol 2012;165(7): 2015–2033. doi: 10.1111/j.1476-5381.2011.01588.
Basir MB, Schreiber TL, Grines CL, Dixon SR, Moses JW, Maini BS, Khandelwal AK, Ohman EM, O'Neill WW. Effect of early initiation of mechanical circulatory support on survival in cardiogenic shock. Am. J. of Cardiology 2017;119(6):845–851. doi: 0.1016/j.amjcard.2016.11.037.
FDA U.S Food and Drug Administration, Impella Ventriucalr Support systems-P14003/@018. Available at: https://www.fda.gov/medicaldevices/productsandmedicalprocedures/deviceapprovalsandclearances/recently-approveddevices/ucm598801.htm
Hernandez GA, Lemor A, Blumer V, Patel N, Patel N, Chapparro SV, Alfonso C, Abstract 21137: Nationwide trends and outcomes of mechanical circulatory support with and without therapeutic hypothermia for in-hospital cardiac arrest. Circulation 2017;136:Suppl_1.
O'Neill WW, Schreiber T, Wohns DHW, et al. The current use of Impella 2.5 in acute myocardial infarction complicated by cardiogenic shock: results from the USpella Registry. J Intervent Cardiol. 2013;27:1–11. https://doi.org/10.1111/joic.12080.
Pieri M, Contri R, Winterton D, Montorfano M, Colombo A, Zangrillo A, De Bonis A, Pappalard F. The contemporary role of Impella in comprehensive mechanical circulatory support program: a single institutional experience. BMC Cardiovasc Disord 2015;15:126.
Saigal S. Sharma JP Dhurwe R. Targeted temperature management: Current evidence and practices in critical care. IndianJ Crit Care Med 2015;19(9):537–546.
Silverman MG, O'Brien MH, Avery KR, Pierce CD, Griswold K, Henderson GV, Hirning BA, Kyller M, Massaro AF. Abstract 240: Concomitant use of therapeutic hypothermia with mechanic circulatory support in patient post cardiac arrest in cardiogenic shock: A single center. Circulation 2018;130:A240.
This question highlights one of the challenges of working on protocols and pathways for organizations; all protocols and pathways must be built to meet the needs of the individual organization, and it is easier to react to a draft than it is to create a protocol from a blank page. For space purposes, I will share the general structure and approach to targeted temperature management (TTM) after cardiac arrest at Rush University Medical Center (RUMC), and then share a few final thoughts on building protocols. As with most organizations, we are happy to share our paper drafts with anyone who contacts us.
At RUMC, all patients who have an in-hospital cardiac arrest are screened for TTM. The pharmacist involved in the code pages the neurocritical care fellow who evaluates the patient for eligibility. This is a more recent process developed by the physician optimizing the TTM program and several doctoral students who've worked to improve TTM processes at RUMC. Patients who arrest out-of-hospital are managed in the emergency department and screened for TTM. Once the decision is made to start TTM, the ordering practitioner chooses the target temperature and the patient receives a series of interventions to initiate TTM. Induction includes the application of a cooling device, administration of cooled saline, magnesium and sedating medication. Patients are maintained at the goal temperature for 24 hours, rewarmed slowly and in a controlled manner for 24 hours and then fever prevention (or normothermia) using the device is continued for an additional 72 hours. Nursing staff assesses for shivering using the Bedside Shiver Assessment Score and provides shiver management using a step-wise approach based on the assessed score to minimize the use of paralytic medication. Outcomes are monitored through the RUMC Emergency Resuscitation Committee.
When developing a protocol, pathway or order set, I find it useful to refer to the Avedis Donabedian quality model (1). The model includes 3 distinct categories to consider when assessing healthcare quality: structure, process and outcome. Any good protocol should include an assessment of structural elements required to provide care, the process steps necessary to deliver care and the process for assessing the outcome of care. Structural elements related to TTM may include the cooling device, expert practitioners who are willing to provide care for eligible patients and the development of a protocol to guide care. Process elements may include how patients are screened for TTM, the process for rapidly administering TTM including roles and responsibilities of each team member throughout the 72-hour process. Outcome elements may include monitoring the process, such as how long does it take on average to reach target temperature, and what percentage of patients who have a cardiac arrest are screened for or receive TTM. Outcome elements may also include patient outcomes after TTM such as discharge disposition and neurologic outcomes. Each of these elements must be considered in the context of the individual organization.
Acknowledgments
I acknowledge Dr. George Lopez, Dr. Carissa Waters, and Ms. Heather Wilson for their work to improve post-cardiac arrest resuscitation at RUMC as referenced in this answer.
Authored by:
Sarah L. Livesay, DNP, APRN, ACNP-BC, ACNS-BC
Associate Professor
Department of Adult and Gerontological Nursing
College of Nursing
Rush University
Chicago, Illinois
References
Donabedian A. The quality of care: How can it be addressed? JAMA. 1988;260(12):1743–8.
Trials of mild therapeutic hypothermia after cardiac arrest by Bernard et al. (2002) and the Hypothermia after Cardiac Arrest Study Group (2002) utilized surface cooling techniques (ice packs or cooling blanket) to achieve a target temperature of 32 to 34°C. Target temperature was attained in a median of 4 to 8 hours after cardiac arrest (Hammer et al., 2009). Animal models, however, demonstrated that even a brief delay in cooling may attenuate functional outcome (Kuboyama et al., 1993; Nozari et al., 2006). This information led to the hypothesis that development of cooling techniques to achieve target temperature more promptly would further improve patient outcomes (Bernard et al., 2003). One such technique was the out-of-hospital administration of a large volume of ice-cold (4°C) crystalloid solution.
Bernard et al. (2003) reported results of a preliminary clinical study in which patients resuscitated from out-of-hospital cardiac arrest were administered large volume (30 ml/kg) of ice cold (4°C) lactated Ringers intravenous (IV) over 30 minutes in the Emergency Department. At the end of the 30 minute infusion core temperature was reduced by 1.6°C, significantly faster than the 0.9°C per hour temperature reduction achieved with ice packs in the landmark Bernard et al. study (2002). Importantly, no patient developed clinical or radiographic evidence of pulmonary edema. It should be noted that this preliminary study only enrolled 22 patients. Kim et al. (2005) completed a similar pilot study in which hospitalized survivors of out-of-hospital cardiac arrest were administered 2L of 4°C cold, normal saline over 20–30 minutes followed by either passive or active cooling. Patients in the active cooling group had a temperature reduction of 1.7°C within the first 30 minutes. Despite a moderately reduced baseline ejection fraction (EF) of 34%, pulmonary artery and central venous pressures did not change significantly after fluid administration. Similar to Bernard et al. (2003), this pilot study was limited by a small sample size (17 patients) and the lack of a control group. These studies, along with other preliminary investigations of pre-hospital administration of cooled saline, demonstrated the efficacy of cold saline in rapidly reducing core temperature and provided promising safety data.
Subsequent randomized, controlled trials sought to further validate the safety and efficacy of cold saline administered following return of spontaneous circulation (ROSC). Kim et al. (2014) randomized 1359 patients to either standard care alone (control) or to standard care plus early prehospital cooling with 2L of 4°C normal saline (intervention). While the intervention group achieved target temperature 1.3 hours sooner than the control group (4.2 v 5.5 hours, p < 0.001), prehospital cooling was not associated with improved neurological status or survival to hospital discharge. Of concern, the cold saline (intervention) group experienced greater re-arrest in the field (26% vs 21%, p = 0.008), diuretic use (18% vs. 13%, p = 0.009), and pulmonary edema on first chest x-ray (41% vs. 30%, p < 0.001). Bernard et al. (2016) conducted a multicenter, randomized controlled trial of induction of hypothermia with cold saline during CPR (intra-arrest). Patients with out-of-hospital cardiac arrest undergoing CPR (N = 1198) were randomized to either rapid IV infusion of up to 2L of cold saline or standard of care. Patients with an initial shockable rhythm randomized to intra-arrest cold saline had a decreased rate of ROSC (41.2% vs. 50.6%, p = 0.03). Further, patients with intra-arrest cooling required longer duration of CPR (22.6 vs. 20.0 minutes, p = 0.01), received more epinephrine (6.5 mg vs. 5.9 mg, P = 0.006), and had increased rates of pulmonary edema (10% vs. 4.5%, p < 0.001). A recent single-center trial (N = 132) of in-hospital administration of IV cold saline found a shorter time to target temperature (280 vs 345 minutes, p = 0.05), but an increased incidence of pulmonary edema (51.5% vs. 31.8%, p = 0.006) and increased diuretic use (63.6% vs. 42.4%, p = 0.014) (Suppogu et al., 2018).
The 2015 American Heart Association (AHA) Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care (2015) recommend against the routine prehospital cooling of patients after ROSC with rapid administration of cold IV fluids. While administration of cold saline appears to reduce time to target temperature, its use has not improved survival or neurological recovery and is associated with greater rates of pulmonary edema.
Authored by:
William D. Cahoon, Jr., PharmD,
BCPS (AQ-Cardiology), BCCCP
Clinical Pharmacist
Coronary and Cardiothoracic Intensive Care
VCU Health System
Richmond, Virginia
References
Bernard S, Buist M, Monteiro O, Smith K. Induced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of out-of-hospital cardiac arrest: a preliminary report. Resuscitation 2003;56(1):9–13.
Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–63.
Bernard SA, Smith K, Finn J, et al. Induction of therapeutic hypothermia during out-of-hospital cardiac arrest using a rapid infusion of cold saline. Circulation 2016;134:797–805.
Callaway CW, Donnino MW, Fink EL, et al. Part 8: Post-Cardiac Arrest Care: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015;132:S465–482.
Hammer L, Vitrat F, Savary D, et al. Immediate prehospital hypothermia protocol in comatose survivors of out-of-hospital cardiac arrest.
Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549–56.
Kim F, Nichol G, Maynard C, et al. Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest. JAMA 2014:311(1):45–52.
Kim F, Olsufka M, Carlbom D, et al. Pilot study of rapid infusion of 2L of 4°C normal saline for induction of mild hypothermia in hospitalized, comatose survivors of out-of-hospital cardiac arrest. Circulation 2005;112:715–19.
Kuboyama K, Safar P, Radovsky A, et al. Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study. Crit Care Med 1993;21(9):1348–58.
Nozari A, Safar P, Stezoski SW, et al. Critical time window for intra-arrest cooling with cold saline flush in a dog model of cardiopulmonary resuscitation. Circulation 2006;113:2690–96.
Suppogu N, Panza GA, Kilic S, et al. The effects of in-hospital intravenous cold saline in postcardiac arrest patients treated with targeted temperature management. Ther Hypothermia Temp Manag 2018;8(1):18–23.
As a patient is cooled for therapeutic hypothermia, sedation and analgesia are started to often achieve a deep level of sedation. Depending on each institution's protocol and characteristics of individual patients, neuromuscular blockade may be initiated for shivering. Shivering should be avoided as it causes increases in body temperature and can cause delays in reaching goal temperatures. Deep levels of sedation also assist in suppressing shivering (Callaway et al., 2015).
While many institutions use deep sedation, one study investigated the use of more moderate-dose sedation in patients undergoing therapeutic hypothermia (May et al., 2015). Deep levels of sedation can be problematic after a patient is rewarmed as clearance of medications may be delayed, which further delays neurologic prognostication. In this study, 166 patients received more moderate-dose sedation and analgesia and were excluded if they received continuous infusions of neuromuscular blockade. Fentanyl and propofol were the most common agents used, with median doses of 25 mcg/hour and 20 mcg/kg/minute respectively (May et al., 2015). The authors conclude that a moderate-dose strategy for analgesia and sedation is well-tolerated and effective.
Because patients are receiving continuous analgesia, sedation, and often neuromuscular blockade, it is not appropriate to initiate a sedation vacation during active cooling and during the rewarming phase. Cooling also prolongs the duration of these agents when compared to the duration in normothermic patients. Once a patient reaches a goal temperature after rewarming, the neuromuscular blocking agent should be discontinued, following by tapering and discontinuation of the sedatives and analgesics as tolerated. Based on the research published by May and colleagues, further research is needed as to the optimal dose of sedative and analgesic agents and more moderate sedation may be a useful tool in allowing faster clearance of medications once a patient is rewarmed. Overall, sedation vacations should not be attempted until neuromuscular blockade is discontinued and a patient is rewarmed.
Authored by:
Leslie A. Hamilton, PharmD, FCCP, FCCM, BCPS, BCCCP
Associate Professor
Clinical Pharmacy and Translational Science
University of Tennessee Health Science Center
College of Pharmacy
Knoxville, Tennessee
References
Callaway CW, Donnino MW, Fink EL, et al. 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132: S465–82.
May TL, Seder DB, Fraser GL, et al. Moderate-Dose Sedation and Analgesia During Targeted Temperature Management After Cardiac Arrest. Neurocrit Care 2015; 22: 105–11.
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