Brian W. Roberts

Early arterial hypotension is common in the post-cardiac arrest syndrome and associated with increased in-hospital mortality

AIM After return of spontaneous circulation (ROSC) from cardiac arrest, profound myocardial stunning and systemic inflammation may cause hemodynamic alterations; however, the prevalence of post-ROSC hemodynamic instability and the strength of association with outcome have not been established. We tested the hypothesis that exposure to arterial hypotension after ROSC occurs commonly (>50%) and is an independent predictor of death. METHODS Single-center retrospective cohort study of all post-cardiac arrest patients over 1 year. INCLUSION CRITERIA (1) age >17; (2) non-trauma; (3) sustained ROSC after cardiac arrest. Using the Jones criteria, subjects were assigned to one of two groups based on the presence of hypotension within 6h after ROSC: (1) exposures-two or more systolic blood pressures (SBPs) <100mmHg or (2) non-exposures-less than two SBP <100mmHg. The primary outcome was in-hospital mortality. We compared mortality rates between groups and used multivariate logistic regression to determine if post-ROSC hypotension independently predicted death. RESULTS 102 subjects met inclusion criteria. In-hospital mortality was 75%. Exposure to hypotension occurred in 66/102 (65%) and was associated with significantly higher mortality (83%) compared to non-exposures (58%, p=0.01). In a model controlling for common confounding variables (age, pre-arrest functional status, arrest rhythm, and provision of therapeutic hypothermia (HT)), early exposure to hypotension was a strong independent predictor of death (OR 3.5 [95% CI 1.3-9.6]). CONCLUSIONS Early exposure to arterial hypotension after ROSC was common and an independent predictor of death. These data suggest that post-ROSC hypotension could potentially represent a therapeutic target in post-cardiac arrest care.

Multiple organ dysfunction after return of spontaneous circulation in postcardiac arrest syndrome.

Objectives:Recent guidelines for the treatment of postcardiac arrest syndrome recommend optimization of vital organ perfusion after return of spontaneous circulation to reduce the risk of postresuscitation multiple organ injury. However, the prevalence of extracerebral multiple organ dysfunction in postcardiac arrest patients and its association with in-hospital mortality remain unclear. Design:Single-center, prospective observational study. Setting:Urban academic medical center. Patients:Postcardiac arrest patients. Inclusion criteria were as follows: age older than 17 years, nontrauma cardiac arrest, and comatose after return of spontaneous circulation. Interventions:We prospectively captured all extracerebral components of the Sequential Organ Failure Assessment score over the first 72 hours after return of spontaneous circulation. The primary outcome measure was in-hospital mortality. We used multivariate logistic regression to determine if multiple organ dysfunction (defined as the highest extracerebral Sequential Organ Failure Assessment score) was an independent predictor of death, after adjustment for the presence of cerebral injury (defined as not following commands at any point over 0–72 hr). Measurements and Main Results:We enrolled 203 postcardiac arrest patients; 96% had some degree of extracerebral organ dysfunction and 66% had severe dysfunction in two or more extracerebral organ systems. The most common extracerebral organ failures were cardiovascular (i.e., vasopressor dependence) and respiratory (i.e., oxygenation impairment). The highest extracerebral Sequential Organ Failure Assessment score over 72 hours had an independent association with in-hospital mortality (odds ratio 1.95 [95% CI, 1.15–3.29]). Of the individual organ systems, only the cardiovascular and respiratory Sequential Organ Failure Assessment scores had an independent association with in-hospital mortality. Conclusions:The results of this study support the hypothesis that extracerebral organ dysfunction is common and associated with mortality in postcardiac arrest syndrome. This association appears to be driven by postresuscitation hemodynamic dysfunction and oxygenation impairment. Further research is needed to determine the value of hemodynamic and oxygenation optimization as a part of treatment strategies for patients with postcardiac arrest syndrome.

Arterial blood pressure and neurologic outcome after resuscitation from cardiac arrest

Objectives:Guidelines for post–cardiac arrest care recommend blood pressure optimization as one component of neuroprotection. Although some retrospective clinical studies suggest that postresuscitation hypotension may be harmful, and laboratory studies suggest that a postresuscitation hypertensive surge may be protective, empirical data are few. In this study, we prospectively measured blood pressure over time during the postresuscitation period and tested its association with neurologic outcome. Design:Single center, prospective observational study from 2009 to 2012. Patients:Inclusion criteria were age 18 years old or older, prearrest independent functional status, resuscitation from cardiac arrest, and comatose immediately after resuscitation. Measurements and Main Results:Our research protocol measured blood pressure noninvasively every 15 minutes for the first 6 hours after resuscitation. We calculated the 0- to 6-hour time-weighted average mean arterial pressure and used multivariable logistic regression to test the association between increasing time-weighted average mean arterial pressures and good neurologic outcome, defined as Cerebral Performance Category 1 or 2 at hospital discharge. Among 151 patients, 44 (29%) experienced good neurologic outcome. The association between blood pressure and outcome appears to have a threshold effect at time-weighted average mean arterial pressure value of 70 mm Hg. This threshold (mean arterial pressure > 70 mm Hg) had the strongest association with good neurologic outcome (odds ratio, 4.11; 95% CI, 1.34–12.66; p = 0.014). A sustained intrinsic hypertensive surge was relatively uncommon and was not associated with neurologic outcome. Conclusions:We found that time-weighted average mean arterial pressure was associated with good neurologic outcome at a threshold of mean arterial pressure greater than 70 mm Hg.

Nitric Oxide Donor Agents for the Treatment of Ischemia/reperfusion Injury in Human Subjects: A Systematic Review

ABSTRACT In animal models, administration of nitric oxide (NO) donor agents has been shown to reduce ischemia/reperfusion (I/R) injury. Our aim was to systematically analyze the biomedical literature to determine the effects of NO-donor agent administration on I/R injury in human subjects. We hypothesized that NO-donor agents reduce I/R injury. We performed a search of Cochrane Library, PubMed, CINAHL, conference proceedings, and other sources with no restriction to language using a comprehensive strategy. Study inclusion criteria were as follows: (a) human subjects, (b) documented periods of ischemia and reperfusion, (c) treatment arm composed of NO-donor agent administration, and (d) use of a control arm. We excluded secondary reports, reviews, correspondence, and editorials. We performed a qualitative analysis to collate and summarize treatment effects according to the recommended methodology from the Cochrane Handbook. Twenty-six studies involving multiple etiologies of I/R injury (10 cardiopulmonary bypass, six organ transplant, seven myocardial infarction, three limb tourniquet) met all inclusion and no exclusion criteria. Six (23%) of 26 were considered high-quality studies as per the Cochrane criteria for assessing risk of bias. In 20 (77%) of 26 studies and four (67%) of six high-quality studies, patients treated with NO-donor agents experienced reduced I/R injury compared with controls. Zero clinical studies to date have tested NO-donor agent administration in patients with cerebral I/R injury (e.g., cardiac arrest, stroke). Despite a paucity of high-quality clinical investigations, the preponderance of evidence to date suggests that administration of NO-donor agents may be an effective treatment for I/R injury in human subjects.

Randomized Controlled Trial of Inhaled Nitric Oxide for the Treatment of Microcirculatory Dysfunction in Patients With Sepsis

Objectives:Sepsis treatment guidelines recommend macrocirculatory hemodynamic optimization; however, microcirculatory dysfunction is integral to sepsis pathogenesis. We aimed to test the hypothesis that following macrocirculatory optimization, inhaled nitric oxide would improve microcirculation in patients with sepsis and that improved microcirculation would improve lactate clearance and multiple organ dysfunction. Design:Randomized, sham-controlled clinical trial. Setting:Single urban academic medical center. Patients:Adult patients with severe sepsis and systolic blood pressure less than 90 mm Hg despite intravascular volume expansion and/or serum lactate greater than or equal to 4.0 mmol/L. Interventions:After achievement of macrocirculatory resuscitation goals, we randomized patients to 6 hours of inhaled nitric oxide (40 ppm) or sham inhaled nitric oxide administration. We administered study drug via a specialized delivery device that concealed treatment allocation so that investigators and clinical staff remained blinded. Measurements and Main Results:We performed sidestream dark-field videomicroscopy of the sublingual microcirculation prior to and 2 hours after study drug initiation. The primary outcome measure was the change in microcirculatory flow index. Secondary outcomes were lactate clearance and change in Sequential Organ Failure Assessment score. We enrolled 50 patients (28 of 50 [56%] requiring vasopressor agents; 15 of 50 [30%] died). Although inhaled nitric oxide significantly raised plasma nitrite levels, it did not improve microcirculatory flow, lactate clearance, or organ dysfunction. In contrast to previous studies conducted during the earliest phase of resuscitation, we found no association between changes in microcirculatory flow and lactate clearance or organ dysfunction. Conclusions:Following macrocirculatory optimization, inhaled nitric oxide at 40 ppm did not augment microcirculatory perfusion in patients with sepsis. Further, we found no association between microcirculatory perfusion and multiple organ dysfunction after initial resuscitation.

Therapeutic hypothermia and vasopressor dependency after cardiac arrest

OBJECTIVE Clinical trials of therapeutic hypothermia (TH) after cardiac arrest excluded patients with persistent hemodynamic instability after return of spontaneous circulation (ROSC), and thus equipoise may exist regarding use of TH in these patients. Our objective was to determine if TH is associated with worsening hemodynamic instability among patients who are vasopressor-dependent after ROSC. METHODS We performed a prospective observational study in vasopressor-dependent post-cardiac arrest patients. Inclusion criteria were age >17, non-trauma cardiac arrest, comatose after ROSC, and persistent vasopressor dependence. The decision to initiate TH (33-34 ° C) was made by the treating physician. We measured cumulative vasopressor index (CVI) and mean arterial pressure (MAP) every 15 min during the first 6h after ROSC. The outcome measures were change in CVI (primary outcome) and MAP (secondary outcome) over time. We graphed median CVI and MAP over time for the treated and not treated cohorts, and used propensity adjusted repeated measures mixed models to test for an association between TH induction and change in CVI or MAP over time. RESULTS Seventy-five post-cardiac arrest patients were included (35 treated; 40 not treated). We observed no major differences in CVI or MAP over time between the treated and not treated cohorts. In the mixed models we found no statistically significant association between TH induction and changes in CVI or MAP. CONCLUSION In patients with vasopressor-dependency after cardiac arrest, the induction of hypothermia was not associated with a decrease in mean arterial pressure or increase in vasopressor requirement.

Emergency Department inter-hospital transfer for post-cardiac arrest care: Initial experience with implementation of a regional cardiac resuscitation center in the United States

OBJECTIVE The American Heart Association recently recommended regional cardiac resuscitation centers (CRCs) for post-resuscitation care following out-of-hospital cardiac arrest (OHCA). Our objective was to describe initial experience with CRC implementation. METHODS Prospective observational study of consecutive post-resuscitation patients transferred from community Emergency Departments (EDs) to a CRC over 9 months. Transfer criteria were: OHCA, return of spontaneous circulation (ROSC), and comatose after ROSC. Incoming patients were received and stabilized in the ED of the CRC where advanced therapeutic hypothermia (TH) modalities were applied. Standardized post-resuscitation care included: ED evaluation for cardiac catheterization, TH (33-34 °C) for 24h, 24h/day critical care physician support, and evidence-based neurological prognostication. Prospective data collection utilized the Utstein template. The primary outcome was survival to hospital discharge with good neurological function [Cerebral Performance Category 1 or 2]. RESULTS Twenty-seven patients transferred from 11 different hospitals were included. The majority (21/27 [78%]) had arrest characteristics suggesting poor prognosis for survival (i.e. asystole/pulseless electrical activity initial rhythm, absence of bystander cardiopulmonary resuscitation, or an unwitnessed cardiac arrest). The median (IQR) time from transfer initiation to reaching TH target temperature was 7(5-13)h. Ten (37%) patients survived to hospital discharge, and of these 9/10 (90% of survivors, 33% of all patients) had good neurological function. CONCLUSIONS Despite a high proportion of patients with cardiac arrest characteristics suggesting poor prognosis for survival, we found that one-third of CRC transfers survived with good neurological function. Further research to determine if regional CRCs improve outcomes after cardiac arrest is warranted.

Association Between Early Hyperoxia Exposure After Resuscitation From Cardiac Arrest and Neurological Disability: Prospective Multicenter Protocol-Directed Cohort Study

Background: Studies examining the association between hyperoxia exposure after resuscitation from cardiac arrest and clinical outcomes have reported conflicting results. Our objective was to test the hypothesis that early postresuscitation hyperoxia is associated with poor neurological outcome. Methods: This was a multicenter prospective cohort study. We included adult patients with cardiac arrest who were mechanically ventilated and received targeted temperature management after return of spontaneous circulation. We excluded patients with cardiac arrest caused by trauma or sepsis. Per protocol, partial pressure of arterial oxygen (PaO2) was measured at 1 and 6 hours after return of spontaneous circulation. Hyperoxia was defined as a PaO2 >300 mm Hg during the initial 6 hours after return of spontaneous circulation. The primary outcome was poor neurological function at hospital discharge, defined as a modified Rankin Scale score >3. Multivariable generalized linear regression with a log link was used to test the association between PaO2 and poor neurological outcome. To assess whether there was an association between other supranormal PaO2 levels and poor neurological outcome, we used other PaO2 cut points to define hyperoxia (ie, 100, 150, 200, 250, 350, 400 mm Hg). Results: Of the 280 patients included, 105 (38%) had exposure to hyperoxia. Poor neurological function at hospital discharge occurred in 70% of patients in the entire cohort and in 77% versus 65% among patients with versus without exposure to hyperoxia respectively (absolute risk difference, 12%; 95% confidence interval, 1–23). Hyperoxia was independently associated with poor neurological function (relative risk, 1.23; 95% confidence interval, 1.11–1.35). On multivariable analysis, a 1-hour-longer duration of hyperoxia exposure was associated with a 3% increase in risk of poor neurological outcome (relative risk, 1.03; 95% confidence interval, 1.02–1.05). We found that the association with poor neurological outcome began at ≥300 mm Hg. Conclusions: Early hyperoxia exposure after resuscitation from cardiac arrest was independently associated with poor neurological function at hospital discharge.

Partial pressure of arterial carbon dioxide and survival to hospital discharge among patients requiring acute mechanical ventilation: A cohort study.

Purpose: To describe the prevalence of hypocapnia and hypercapnia during the earliest period of mechanical ventilation, and determine the association between PaCO2 and mortality. Materials and Methods: A cohort study using an emergency department registry of mechanically ventilated patients. PaCO2 was categorized: hypocapnia (< 35 mm Hg), normocapnia (35–45 mm Hg), and hypercapnia (> 45 mm Hg). The primary outcome was survival to hospital discharge. Results: A total of 1,491 patients were included. Hypocapnia occurred in 375 (25%) patients and hypercapnia in 569 (38%). Hypercapnia (85%) had higher survival rate compared to normocapnia (74%) and hypocapnia (66%), P < 0.001. PaCO2 was an independent predictor of survival to hospital discharge [hypocapnia (aOR 0.65 (95% confidence interval [CI] 0.48–0.89), normocapnia (reference category), hypercapnia (aOR 1.83 (95% CI 1.32–2.54)]. Over ascending ranges of PaCO2, there was a linear trend of increasing survival up to a PaCO2 range of 66–75 mm Hg, which had the strongest survival association, aOR 3.18 (95% CI 1.35–7.50). Conclusions: Hypocapnia and hypercapnia occurred frequently after initiation of mechanical ventilation. Higher PaCO2 levels were associated with increased survival. These data provide rationale for a trial examining the optimal PaCO2 in the critically ill. HIGHLIGHTSHypocapnia and hypercapnia occur frequently after initiation of mechanical ventilation.Higher PaCO2 levels are associated with increased survival.Over ascending PaCO2, there is linear trend of increased survival up to PaCO2 of 66 ‐ 75 mmHg, which has highest survival.

Analgosedation Practices and the Impact of Sedation Depth on Clinical Outcomes Among Patients Requiring Mechanical Ventilation in the ED: A Cohort Study

BACKGROUND: Analgesia and sedation are cornerstone therapies for mechanically ventilated patients. Despite data showing that early deep sedation in the ICU influences outcome, this has not been investigated in the ED. Therefore, ED‐based sedation practices, and their influence on outcome, remain incompletely defined. This studys objectives were to describe ED sedation practices in mechanically ventilated patients and to test the hypothesis that ED sedation depth is associated with worse outcomes. METHODS: This was a cohort study of a prospectively compiled ED registry of adult mechanically ventilated patients at a single academic medical center. Hospital mortality was the primary outcome and hospital‐, ICU‐, and ventilator‐free days were secondary outcomes. A backward stepwise multivariable logistic regression model evaluated the primary outcome as a function of ED sedation depth. Sedation depth was assessed with the Richmond Agitation‐Sedation Scale (RASS). RESULTS: Four hundred fourteen patients were studied. In the ED, 354 patients (85.5%) received fentanyl, 254 (61.3%) received midazolam, and 194 (46.9%) received propofol. Deep sedation was observed in 244 patients (64.0%). After adjusting for confounders, a deeper ED RASS was associated with mortality (adjusted OR, 0.77; 95% CI, 0.63–0.94). CONCLUSIONS: Early deep sedation is common in mechanically ventilated ED patients and is associated with worse mortality. These data suggest that ED‐based sedation is a modifiable variable that could be targeted to improve outcome.