Advances and Future Trends in the Diagnosis and Management of Intracerebral Hemorrhage.

Spontaneous intracerebral hemorrhage accounts for approximately 10% to 15% of all strokes in the United States and remains one of the deadliest. Of concern is the increasing prevalence, especially in younger populations. This article reviews the following: epidemiology, risk factors, outcomes, imaging findings, medical management, and updates to surgical management.

Systolic blood pressure measurements are unreliable for the management of acute spontaneous intracerebral hemorrhage.

PURPOSE: Whether systolic blood pressure (SBP) is reliable in acute spontaneous intracerebral (sICH) by assessing agreement between simultaneous BP measurements obtained from cuff non-invasive blood pressure (NIBP) and radial arterial invasive blood pressure (AIBP) devices. MATERIAL AND METHODS: Among 766 prospectively screened sICH subjects, 303 (39.5%) had NIBP and AIBP measurements. During the first 24 h, 2157 simultaneous paired measurement readings were abstracted. Paired NIBP/AIBP measurements were included in a Bland-Altman technique with 95% agreement limits and coefficients from regression analysis derived from a bootstrap procedure. RESULTS: Variance for SBP was 66.1 mmHg, which was larger than the 44.3 mg Hg for diastolic blood pressure (DBP) or the 46.1 mmHg for mean arterial pressure (MAP). Pairwise comparison of mean biases showed a significant difference between SBP when compared to DBP (p < 0.0001) or MAP (p < 0.0001). The mean bias between DBP and MAP was not different (p = 0.68). Regression-based Bland Altman analysis found significant bias (slope -0.16, 95% CI -0.23, -0.09, p < 0.05) over the range of mean SBP. Bias over the range of mean DBP or MAP was not significant. CONCLUSIONS: We concluded that SBP is an unreliable blood pressure measurement in patients with sICH.

Inattentional blindness to DWI lesions in spontaneous intracerebral hemorrhage.

PURPOSE: Inattentional blindness refers to when an individual fails to recognize an event or object due to their awareness being engaged in a different task and has been described in radiology. The purpose of this study is to determine whether the sensitivity of detecting diffusion-weighted imaging (DWI) lesions in spontaneous intracerebral hemorrhage (sICH) is reduced due to inattentional blindness. METHODS: Using a prospective observational cohort, select sICH patients received an MRI scan within 72 h of admission. The scans were subject to an "official read" that occurred as part of the routine workflow. Separately, each scan underwent two "preliminary research reads" with task-specific instructions to detect DWI lesions. A "final research read" via three-party adjudication was used to calculate sensitivity and specificity for detecting these lesions. Board-certified neuroradiologists blinded to the clinical history of the patients reviewed all imaging. RESULTS: Amongst 121 sICH participants with research MRI scans, 49.6% (n = 60) scans were noted to have DWI lesion on their "final research read." The "official read" detected these DWI lesions with a sensitivity of 65% (95% CI, 52-77%). In contrast, the "preliminary research read" sensitivity for readers 1 and 2 was 98% (CI 95%, 91 to 100%) and 87% (CI 95%, 75 to 94%), respectively. Both were significantly different (p < 0.05) from the sensitivity of the "official read." CONCLUSIONS: Given the increased sensitivity with task-specific instructions, our results suggest that inattentional blindness may be leading to the decreased detection of DWI lesions in patients with concomitant sICH.

Timing of diffusion weighted imaging lesions in spontaneous intracerebral hemorrhage.

INTRODUCTION: Diffusion weighted imaging (DWI) lesions are common after spontaneous intracerebral hemorrhage (sICH). However, their timing relative to a patient's admission to the hospital is unknown. The purpose of this study is to estimate the timing of new DWI lesions after admission for acute sICH. MATERIAL AND METHODS: Select patients enrolled in a single center prospective study examining the prevalence DWI lesions in acute primary sICH received two MRI scans of the brain after admission. The presence of a new DWI lesion between MRI scans was defined as a new DWI event. A lognormal parametric model was used to estimate the median time (50% percentile) to develop a new DWI lesion. RESULTS: Among the 121 participants enrolled in the study, 63 (52%) had two brain MRIs. The median time from admission to 1st MRI was 1 day (IQR 1.2, range 0.1-8.4). The median time between the 2 MRI scans was 2.1 (IQR 2.9, range 0.02-17.4) days. 30.2% (n = 19) of participants developed a new DWI lesion between MRI scans. The estimated median time from 1st MRI to new DWI event was 6.3 days (95% CI, 4.1 to 9.6). DISCUSSION AND CONCLUSION: Accounting for time from admission to 1st MRI, we found that 50% of new DWI lesions occurred by 7.3 days after sICH admission. Pathophysiologic changes in sICH during this time frame need to be studied in order to elucidate a mechanism for DWI lesions.

Systemic Oxygen Utilization in Severe COVID-19 Respiratory Failure: A Case Series.

BACKGROUND: Management of hypoxemia in patients with severe COVID-19 respiratory failure is based on the guideline recommendations for specific SpO2 targets. However, limited data exist on systemic O2 utilization. The objective of this study was to examine systemic O2 utilization in a case series of patients with this disease. PATIENTS AND METHODS: Between March 24, and April 9, 2020, 8 patients intubated for severe COVID-19 respiratory failure had near-simultaneous drawing of arterial blood gas (ABG), central venous blood gas (cVBG), and central venous oxygen saturation (ScvO2) at a mean of 6.1 days into hospitalization. Three patients were managed with indirect cardiac output (CO) monitoring by FloTrac sensor and Vigileo monitor (Edwards Lifesciences, Irvine, CA). The oxygen extraction index (OEI; SaO2-ScvO2/SaO2) and oxygen extraction fraction (OEF; CaO2-CvO2/CaO2 ≥ 100) were calculated. Values for hyperoxia (ScvO2 ≥ 90%), normoxia (ScvO2 71-89%), and hypoxia (ScvO2 ≤ 70%) were based on the literature. Mean values were calculated. RESULTS: The mean partial pressure of oxygen (PaO2) was 102 with a mean fraction of inspired O2 (FiO2) of 44%. One patient was hyperoxic with a reduced OEI (17%). Five patients were normoxic, but 2 had a reduced OEF (mean 15.9%). Two patients were hypoxic but had increased systemic O2 utilization based on OEF or OEI. CONCLUSION: In select patients with severe COVID-19 respiratory failure, O2 delivery (DO2) was found to exceed O2 utilization. SpO2 targets based on systemic O2 utilization may help in reducing oxygen toxicity, especially in the absence of anaerobic metabolism. Further data are needed on the prevalence of systemic O2 utilization in COVID-19. HOW TO CITE THIS ARTICLE: Garg RK, Kimbrough T, Lodhi W, DaSilva I. Systemic Oxygen Utilization in Severe COVID-19 Respiratory Failure: A Case Series. Indian J Crit Care Med 2021;25(2):215-218.

Association of Longitudinal Glycemia with Diffusion Weighted Imaging Lesions in Spontaneous Intracerebral Hemorrhage.

OBJECTIVES: Higher glycemia on admission has been associated with diffusion weighted imaging (DWI) lesions in patients with spontaneous intracerebral hemorrhage (sICH). However, the influence of longitudinal glycemia after admission and during a patient's hospitalization on DWI lesions in sICH has not been studied. Our aim was to compare longitudinal glycemia in sICH patients with and without DWI lesions. MATERIAL AND METHODS: Glycemia measurements were abstracted on participants enrolled in a prospective observational study examining predictors for DWI lesions in sICH. Univariate analysis was used to compare mean longitudinal glycemia in sICH patients with and without DWI lesions. Logistical regression was used to determine whether mean longitudinal glycemia was predictive of DWI lesions. RESULTS: DWI lesions were found in 60 of the 121 (49.6%) participants. Mean time-to-MRI was 99.6 h (SD ± 89). During this time interval, 2,101 glucose measurements were analyzed with a median number of 7 (IQR 12, 1-261) measurements per patient. Mean longitudinal glycemia was higher in the DWI positive group compared to the DWI negative group until time-to-MRI (132 mg/dL vs 122 mg/dL, p = 0.03). Mean longitudinal glycemia was found to be predictive of DWI lesions (OR 1.02, 95% CI 1.005 to 1.035, p = 0.011). CONCLUSIONS: Mean longitudinal glycemia was higher in sICH patients with DWI lesions compared to those without DWI lesions. Future research into the association between higher glycemia and DWI lesions in sICH may provide insight into a pathophysiologic mechanism.

The Influence of Diffusion Weighted Imaging Lesions on Outcomes in Patients with Acute Spontaneous Intracerebral Hemorrhage.

BACKGROUND/OBJECTIVE: Diffusion weighted imaging (DWI) lesions have been well described in patients with acute spontaneous intracerebral hemorrhage (sICH). However, there are limited data on the influence of these lesions on sICH functional outcomes. We conducted a prospective observational cohort study with blinded imaging and outcomes assessment to determine the influence of DWI lesions on long-term outcomes in patients with acute sICH. We hypothesized that DWI lesions are associated with worse modified Rankin Scale (mRS) at 3 months after hospital discharge. METHODS: Consecutive sICH patients meeting study criteria were consented for an magnetic resonance imaging (MRI) scan of the brain and evaluated for remote DWI lesions by neuroradiologists blinded to the patients' hospital course. Blinded mRS outcomes were obtained at 3 months. Logistic regression was used to determine significant factors (p < 0.05) associated with worse functional outcomes defined as an mRS of 4-6. The generalized estimating equation (GEE) approach was used to investigate the effect of DWI lesions on dichotomized mRS (0-3 vs 4-6) longitudinally. RESULTS: DWI lesions were found in 60 of 121 patients (49.6%). The presence of a DWI lesion was associated with increased odds for an mRS of 4-6 at 3 months (OR 5.987, 95% CI 1.409-25.435, p = 0.015) in logistic regression. Using the GEE model, patients with a DWI lesion were less likely to recover over time between 14 days/discharge and 3 months (p = 0.005). CONCLUSIONS: DWI lesions are common in primary sICH, occurring in almost half of our cohort. Our data suggest that DWI lesions are associated with worse mRS at 3 months in good grade sICH and are predictive of impaired recovery after hospital discharge. Further research into the pathophysiologic mechanisms underlying DWI lesions may lead to novel treatment options that may improve outcomes associated with this devastating disease.

Analysis and Temporal Evolution of Extubation Parameters for Patients Undergoing Single-Stage Circumferential Cervical Spine Surgery.

OBJECTIVE: Airway obstruction after postoperative extubation is a dreaded but uncommon complication in patients undergoing circumferential cervical spine surgery (CCSS). The cuff leak test (CLT) has been utilized to assess air leak around the endotracheal tube which may reflect airway swelling. In this prospective observational study, we analyze the temporal evolution of CLT and perioperative factors that may influence it. METHODS: Twenty patients undergoing single-stage CCSS were managed according to our extubation protocol. Patients were maintained intubated overnight following surgery. They were extubated if a CLT > 200 mL and both intensive care unit (ICU) and Neurosurgery teams agreed that it was safe. Patients extubated in the first postoperative day (8 of 20) comprised the early group, and the remaining patients (12 of 20) the delayed group. Patient and operative data were analyzed as a single group and comparing both groups. RESULTS: The main indication for surgery was cervical deformity. Median number of levels fused was 5 anteriorly (range, 1-6) and 6 (range, 1-13) posteriorly. Patients were kept intubated for an average of 73.6 hours (range, 26-222 hours) and stayed in the ICU for 119.1 hours (range, 36-360 hours). There were 4 failed extubations and 3 patients (15%) required a tracheostomy. Patient profiles between both groups were very similar across most patient variables but differed significantly regarding infraglottic luminal area (p < 0.05). Patients with larger preoperative cuff leak values tended to have a shorter intubation period (p = 0.053). CONCLUSION: This study objectively demonstrates the difficulties in airway management following CCSS and provides useful insight for preoperative planning and counseling. Local anatomic factors influence airway outcome more than operative factors. The study format does not allow for testing of interventions but we suggest that patients with favorable anatomy (larger infraglottic luminal area) may benefit from a less strict airway management protocol.

Primary extra-nodal non-Hodgkin's lymphoma of gingiva: A diagnostic dilemma.

Primary non-Hodgkin's lymphoma (NHL) is a rare entity. When it does occur, mandibular NHL typically manifests similar to an odontogenic pathology. This results in delayed diagnosis and treatment. We present a 50-year-old female who was erroneously treated for a pyogenic granuloma several months before the correct diagnosis of extranodal primary NHL of the oral cavity was made. Fortunately, the solitary bony lymphoma had not disseminated and management by chemo-radiation allowed for disease eradication and new post-treatment bone formation. The purpose of this report is to describe a rare case of primary NHL of the mandible, explore the diagnosis and work-up and discuss treatment strategies. This case illustrates the need for co-operative diagnostic referrals between physicians and dentists.

Cardiac abnormalities in patients with acute subdural hemorrhage.

BACKGROUND: Although cardiac abnormalities are well described among patients with acute brain injury, they have not been investigated systematically for acute subdural hemorrhage (SDH). We sought to investigate the prevalence and characteristics of cardiac abnormalities in patients with SDH. METHODS: Consecutive adult patients admitted to Rush University Neurosciences Intensive Care Unit with a diagnosis of SDH were analyzed. Electrocardiograms (ECGs), obtained within 48 h of admission were reviewed. Myocardial injury, defined as troponin I elevation (>0.09 ng/ml) on admission was identified. RESULTS: One hundred and fourteen patients admitted with SDH between 1 January 2010 and 31 December 2011 were included. Mean age was 67.9 years (SD 16.6 years), 60% were male. Comorbidities included hypertension (74%), diabetes mellitus (31%), cardiovascular disease (35%), and cerebrovascular disease (25%). The SDH was right-sided in 47%, and the most common location was frontoparietal (43%). SDH size was 14.4 ± 7.9 mm, with 4.6 ± 5.5 mm midline shift. One or more ECG abnormalities were found in 75% of patients. Troponin was elevated in nine patients. Cardiac abnormalities were not associated with SDH characteristics. Classic neurogenic ECG findings were not encountered. CONCLUSIONS: Although we found ECG abnormalities to be common in patients with SDH, they were not associated with SDH characteristics, and classic neurogenic findings were not observed. Myocardial injury was infrequent and not associated with SDH characteristics. While cardiac abnormalities in acute intracerebral injury often are attributed to neurocardiogenic causes, these are unlikely prominent mechanisms in SDH. Other medical causes need to be considered, as this will have important implications for management.

Heart failure with a normal left ventricular ejection fraction: epidemiology, pathophysiology, diagnosis and management.

Heart failure (HF) with a normal left ventricular (LV) ejection fraction (HFNEF) occurs in 40-71% of patients with HF and carries a prognosis similar to that of HF with a reduced LV ejection fraction (LVEF). The pathophysiology of HFNEF is distinct from that of HF with a reduced LVEF and is characterized by impaired relaxation of myocardium, LV stiffness and, in many cases, increased arterial stiffness. Systemic hypertension accounts for most cases of HFNEF in the United States. Those with HFNEF tend to be older and obese. Diabetes mellitus and atrial fibrillation occur with disproportionately high frequency in HFNEF. The diagnosis of HFNEF requires the presence of symptoms or signs of HF, a normal or near-normal LVEF and evidence of LV diastolic dysfunction based on cardiac catheterization or Doppler echocardiographic techniques and/or elevation of plasma natriuretic peptide levels. Current guidelines for management of HFNEF include control of systolic and diastolic hypertension, control of the ventricular rate in patients with atrial fibrillation and judicious use of diuretics. In selected cases, coronary revascularization or restoration of sinus rhythm in those with atrial fibrillation may be indicated. To date, no drug or drug group has consistently improved survival in HFNEF. For this reason and because of the poor long-term prognosis, preventative measures and effective treatment of underlying causes and precipitating factors are particularly important in avoiding HF exacerbations in patients with HFNEF.

Warfarin-associated intracerebral hemorrhage is inadequately treated at community emergency departments.

BACKGROUND AND PURPOSE: The purpose of this study was to investigate time delays, adherence to guidelines, and their impact on outcomes in patients with warfarin-associated intracerebral hemorrhage transferred from community emergency departments to a comprehensive stroke center. METHODS: We collected demographic, clinical, transfer time, treatment, and outcome data for patients transferred to our institution with warfarin-associated intracerebral hemorrhage from community emergency departments. RESULTS: Among 928 patients with intracerebral hemorrhage, 56 (6%) with warfarin-associated intracerebral hemorrhage (median international normalized ratio, 2.55) were transferred to the comprehensive stroke center. Twenty patients received no acute reversal therapy before transfer, only 4 of whom had international normalized ratios ≤1.4 in the community emergency department. Median time of emergency department stay was 3.66 hours and median time to initiation of acute reversal therapy was 4.48 hours. Those who received ≥3 U of fresh-frozen plasma or recombinant activated Factor VIIa (11 patients) before transfer had lower repeat international normalized ratios and better discharge dispositions than those treated less aggressively. CONCLUSIONS: Treatment of warfarin-associated intracerebral hemorrhage in community emergency departments is often suboptimal and does not adhere to published guidelines. Treating coagulopathy aggressively before interhospital transfer may improve outcomes and warrants further investigation.

Blood pressure reduction, decreased diffusion on MRI, and outcomes after intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Decreased diffusion (DD) consistent with acute ischemia may be detected on MRI after acute intracerebral hemorrhage (ICH), but its risk factors and impact on functional outcomes are not well-defined. We tested the hypotheses that DD after ICH is related to acute blood pressure (BP) reduction and lower hemoglobin and presages worse functional outcomes. METHODS: Patients who underwent MRI were prospectively evaluated for DD by certified neuroradiologists blinded to outcomes. Hemoglobin and BP data were obtained via electronic queries. Outcomes were obtained at 14 days and 3 months with the modified Rankin Scale, a functional scale scored from 0 (no symptoms) to 6 (dead). We used logistic regression for dependence or death (modified Rankin Scale score 4-6). RESULTS: DD distinct from the hematoma was found on MRI in 39 of 95 patients (41%). DD was associated with greater BP reductions from baseline and a higher risk of dependence or death at 3 months (odds ratio, 4.8; 95% confidence interval, 1.7-13.9; P=0.004) after correction for ICH score (1.8 per point; 95% confidence interval, 1.2-3.1; P=0.01). Lower hemoglobin was associated with worse ICH score, larger hematoma volume, and worse outcomes, but not DD. CONCLUSIONS: DD is common after ICH, associated with greater acute BP reductions, and associated with disability and death at 3 months in multivariate analysis. The potential benefits of acute BP reduction to reduce hematoma growth may be limited by DD. The prevention and treatment of cerebral ischemia manifested as DD are potential methods to improve outcomes.

Therapeutic Hypothermia After Cardiac Arrest is Underutilized in the United States.

Little is known about the frequency of therapeutic hypothermia use after cardiac arrest in the United States. We, therefore, analyzed the Nationwide Inpatient Sample (NIS) to determine the prevalence of hypothermia use after cardiac arrest and patient and hospital factors associated with its use. Using 2007 NIS data, we identified adult patients with cardiac arrest using the ICD-9 diagnosis code, 427.5, while the use of therapeutic hypothermia was based on the ICD-9 procedure code, 99.81. Among 26,519 adult patients with cardiac arrest, only 92 (0.35%) were coded as having received therapeutic hypothermia. In a multivariable logistic regression model, independent factors associated with the use of therapeutic hypothermia included age as a continuous variable ([odds ratios] OR 0.97, 95% CI 0.963-0.989, p<0.001), comorbidity adjusted mortality score (OR 1.06, 95% CI 1.04-1.08, p<0.001), admission from the emergency room (OR 2.17, 95% CI 1.191-3.949, p=0.011), teaching hospital status (OR 2.68, 95% CI 1.36-5.29, p=0.005), acute myocardial infarction (OR 1.96, 95% CI 1.14-3.36, p=0.015), hospital location in the western United States (OR 2.21, 95% CI 1.16-3.14, p=0.011), and >97% registered nurse hospital staffing (OR 2.64, 95% CI 1.62-4.30, p<0.001). Therapeutic hypothermia may be utilized in <1% of cardiac arrest patients in U.S. hospitals. We identified important patient and hospital factors associated with therapeutic hypothermia utilization. Efforts to increase generalized utilization of this effective resuscitation strategy are warranted.

Prospective, randomized trial of higher goal hemoglobin after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: In patients with subarachnoid hemorrhage (SAH), higher hemoglobin (HGB) has been associated with better outcomes, but packed red blood cell (PRBC) transfusions with worse outcomes. We performed a prospective pilot trial of goal HGB after SAH. METHODS: Forty-four patients with SAH and high risk for vasospasm were randomized to goal HGB concentration of at least 10 or 11.5 g/dl. We obtained blinded clinical outcomes at 14 days (NIH Stroke Scale and modified Rankin Scale, mRS), 28 days (mRS), and 3 months (mRS), and blinded interpretation of brain MRI for cerebral infarction at 14 days. This trial is registered at www.stroketrials.org. RESULTS: Forty-four patients were randomized. Patients with goal HGB 11.5 g/dl received more PRBC units per transfusion [1 (1-2) vs. 1 (1-1), P < 0.001] and more total PRBC units [3 (2-4) vs. 2 (1-3), P = 0.045]. Prospectively defined safety endpoints were not different between groups. HGB concentration was different between study groups from day 4 onwards. The number of cerebral infarctions on MRI (6 of 20 vs. 9 of 22), NIH Stroke Scale scores at 14 days [1 (0-9.75) vs. 2 (0-16)], and rates of independence on the mRS at 14 days (65% vs. 44%) and 28 days (80% vs. 67%) were similar, but favored higher goal HGB (P > 0.1 for all). CONCLUSIONS: Higher goal hemoglobin in patients with SAH seems to be safe and feasible. A phase III trial of goal HGB after SAH is warranted.

Moderate Hypoglycemia is associated with vasospasm, cerebral infarction, and 3-month disability after subarachnoid hemorrhage.

BACKGROUND: Many ICUs have implemented protocols for tight glucose control, but there are few data on hypoglycemia and neurologic outcomes in patients with subarachnoid hemorrhage (SAH). METHODS: We prospectively ascertained 172 patients with SAH, who were treated according to a standard protocol for target glucose 80-110 mg/dl. Outcomes were assessed with the modified Rankin scale (mRS) at 14 days, 28 days, and 3 months. RESULTS: Worse neurologic injury at admission (P < 0.001) and a history of diabetes (P = 0.002) were associated with increased glucose variance. There was lower nadir glucose in patients with radiographic cerebral infarction (81 +/- 15 vs. 87 +/- 16 mg/dl, P = 0.02), symptomatic vasospasm (78 +/- 12 vs. 84 +/- 16 mg/dl, P = 0.04) and angiographic vasospasm (79 +/- 14 vs. 86 +/- 16 mg/dl, P = 0.01), but maximum and mean glucose values were not different. Glucose < 80 mg/dl was earlier and more frequent in patients with worse functional outcome at 3 months (P < 0.001). Progressive reductions in nadir glucose were associated with increasing functional disability at 3 months (P = 0.001) after accounting for neurologic grade and mean glucose. Severe hypoglycemia (<40 mg/dl) occurred in one patient. CONCLUSIONS: In patients with SAH, nadir glucose < 80 mg/dl is associated with cerebral infarction, vasospasm, and worse functional outcomes in multivariate models. Protocols for target glucose 80-110 mg/dl effectively control hyperglycemia, but may place patients with SAH at risk for vasospasm, cerebral infarction, and poor outcome even when severe hypoglycemia does not occur.

Dronedarone--a new alternative for management of atrial fibrillation.

The maintenance of sinus rhythm in patients with Atrial Fibrillation (AF) is difficult and is complicated by adverse drug reactions of antiarrhythmic drugs or the adverse events related with ablation procedures. Amiodarone can be used for preventing AF recurrence; but it has the risk of serious toxicities secondary to its iodinated nature. Dronedarone, an amiodarone analogue without iodine, has been shown to decrease the frequency of AF recurrence and to provide heart rate control during AF recurrence. Dronedarone is a benzofuran derivative; specifically N-[2-Butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5-benzofuranyl]methane-sulfonamide and its production process has been patented. In the ATHENA trial, dronedarone therapy was associated with a significant reduction in the combined primary endpoint of death from any cause or hospitalization due to cardiovascular causes. However, dronedarone has been noted to increase cardiovascular mortality among patients with advanced congestive heart failure (NYHA class III and IV). On March 18, 2009, the Cardiovascular and Renal Drugs Advisory Committee of the Food and Drug Administration (FDA) approved dronedarone for an indication of atrial fibrillation suppression, with a warning against its use in patients with NYHA class III and IV heart failure or recently decompensated heart failure.