High-Sensitivity Troponin I and the Risk of Flow Limiting Coronary Artery Disease in Non-ST Elevation Acute Coronary Syndrome (NSTE-ACS)

Ali Abdul Jabbar, MD ^1,3,4

Omar Mufti, MD¹

Sayf Altabaqchali, MD RPVI⁴

Chowdhury Ahsan, MD PhD²

Mohanad Hasan, MD²

Ronald Markert, PhD¹

Bryan White, MD¹

George Broderick, MD¹

¹Cardiology Division, Department of Internal Medicine, Wright State University Boonshoft School of Medicine, Dayton, Ohio.

²Cardiology Division, Department of Internal Medicine, University of Nevada School of Medicine, Las Vegas, Nevada.

³Department of Cardiovascular Medicine, University of Toledo Health Science Campus, Toledo, Ohio.

⁴Department of Cardiology, Ochnser Heart and Vascular Institute, New Orleans, Louisiana.

Abstract

Background: In acute coronary syndrome, elevated troponins are associated with worse clinical outcomes. We examined the relationship between the level of troponin elevation and the presence of a flow-limiting lesion for patients with no history of coronary disease admitted with NSTE-ACS.

Methods: From January of 2010 until April of 2013, 561 patients received coronary angiography for new-onset NSTE-ACS. The Mann-Whitney Test, chi-square test, and Spearman correlation were used to examine relationships. Inferences were made at the 0.05 level of significance. The independent samples t test and the chi square test were used to identify predictors of LV systolic dysfunction- LVSD.

Results: The 430 patients with a flow-limiting coronary lesions had a higher troponin I level than the 131 patients without obstructive coronary disease (5.69 ng/ml vs. 2.85 ng/ml, p=0.002). Further, within troponin categories, those in the greater than 5.0 ng/ml group were more likely to have angiographically significant CAD than those in the less than 0.5 ng/ml group (p=0.012). Elevated troponins were also associated with increased thrombus burden, worse systolic function, higher complexity of the lesions, and worse post intervention TIMI flow. Cardiac troponin >5ng/ml [odds ratio=2.13 (95%CI=1.22 to 3.70) p=0.008] and DM [odds ratio=1.74 (95%CI=1.02 to 2.97) p=0.042] were independent predictors of LVSD. Advanced LM disease and age were marginally significant.

Conclusion: The degree of cardiac troponin I elevation should be incorporated into the risk stratification models of NSTE-ACS to promptly triage high-risk patients to early invasive strategies and tailored anticoagulant therapy to reduce troponin elevation and improve myocardial perfusion.

Background

Cardiac troponin is the main biomarker of myocardial ischemia. In acute coronary syndrome, elevated troponin levels are associated with complex obstructive coronary anatomy and impaired myocardial tissue perfusion. Elevated troponins can identify high-risk patients with non-ST elevation acute coronary syndrome (NSTE-ACS), who may benefit from early invasive management. However, the degree of troponin elevation has not been incorporated in risk stratification models for NSTE-ACS. To triage patients for conservative versus invasive management strategies, we need to define the significance of the magnitude of troponin elevation following NSTE-ACS (1).

NSTE-ACS is the most common form of acute coronary syndrome. Troponin elevation signifies a delayed presentation in ST elevation MI not so for NSTE-ACS. The determination of ischemic injury timing becomes more challenging when NSTE-ACS patient present with variable levels of troponin elevation.

Thus, we examined the relationship between troponin levels and the extent of coronary disease and myocardial dysfunction, as assessed by coronary angiography, in a subset of patients with no history of coronary disease admitted with NSTE-ACS.

Methods

Study design

This is a retrospective study of a cohort admitted to a university-affiliated teaching hospital with highly specialized cardiovascular care over a period of 40 months. The data for this study were obtained from the National Cardiovascular Data Registry (NCDR) database and electronic chart review of study participants.

Serum cardiac troponin levels were measured using a high-sensitivity enzyme-linked immune-absorbent assay kit (VITROS® Troponin I ES Assay, © Ortho Clinical Diagnostics, Johnson & Johnson -Hong Kong- Ltd. 2003-2014). A level greater than 0.033 ng/ml is considered above the reference range and represents a positive test value. The highest troponin I level prior to coronary angiography was used in the analyses.

Selection of study participants

The study investigated the association of cardiac troponin I levels and the presence of a flow-limiting coronary arterial lesion; a flow-limiting lesion was defined as an angiographically significant coronary lesion warranting percutaneous and/or surgical revascularization. The study only included patients with new-onset (de novo) NSTE-ACS. Patients with a history of coronary artery disease, heart failure, and cardiac bypass were excluded.

Study Objectives and Data Analysis

In addition to determining the association between cardiac troponin I levels and the presence of flow-limiting coronary artery disease, the study also examined the relationship between cardiac troponin I levels and various other factors, including vascular anatomy, lesion complexity, success of percutaneous intervention (based on the post-intervention Thrombolysis In Myocardial Infarction - TIMI - study grading system of the coronary blood flow), and incidence of Left Ventricular Systolic Dysfunction (LVSD), defined by an ejection fraction of less than 40% on left ventriculogram, in de-novo NSTE-ACS patients.

Means and standard deviations are reported for continuous variables, and counts and percents for categorical variables. The independent samples Mann-Whitney Test (two groups), Kruskal-Wallis Test (three groups), one-way analysis of variance (ANOVA) with Least Significance Difference post hoc test, chi square test, and Spearman correlation were used to examine relationships. Inferences were made at the 0.05 level of significance with no corrections for multiple comparisons. Multivariable logistic regression was used to determine if troponin is an independent risk factor for LVSD. Analyses were conducted using IBM SPSS Statistics 22.0 (IBM, Armonk, NY).

Results

Baseline characteristics

From January 2010 through April 2013, 561 patients received coronary angiography for new onset NSTE-ACS. Of this total, 485 (86.5%) had left ventricular functional assessment at the time of cardiac catheterization. All patients were managed invasively.

Patients were divided into three groups according to the degree of troponin I elevation (mild <0.5 ng/ml [n = 167], moderate 0.5-5 ng/ml [n = 263], and high >5 ng/ml [n = 131]).  Table 1 shows that age differed among the three groups (p = 0.008): the moderate group was older than the mild group (mean age = 66.3±13.9 vs. 62.2±12.5) but not the high groups (64.1±13.3).  

Table 1. Characteristics of troponin groups.

Abbreviations - GFR: glomerular filtration rate; PCI: percutaneous coronary artery intervention; IABP: intra-aortic balloon pump; UH: unfractionated heparin; LMWH: low molecular weight heparin

^a The moderate group was older than the mild group (mean age = 66.3±13.9 vs. 62.2±12.5) but not the high group (64.1±13.3).

^bPatients were more likely to be Caucasian as troponin categories increased (66.5% for the <0.5 ng/ml group, 78.2% for the 0.5-5 ng/ml group, 81.5% for the >5.0 ng/ml group) and less likely to be African American as troponin categories increased (32.3% for the <0.5 ng/ml group, 21.0% for the 0.5-5 ng/ml group, 17.7% for the >5.0 ng/ml group); p value for chi square test excludes Asians and Hispanics due to low counts.

^cThe moderate and high groups had a higher euroscore than the mild group (mean euroscore = 5.44±3.3 and 5.98±6.1 vs. 4.38±2.8).

^dPatients were more likely to receive unfractionated heparin as troponin categories increased (63.4% for the <0.5 ng/ml group, 69.7% for the 0.5-5 ng/ml group, 84.2% for the >5.0 ng/ml group).

Patients were more likely to be Caucasian as troponin categories increased (66.5% for the <0.5 ng/ml group, 78.2% for the 0.5-5 ng/ml group, 81.5% for the >5.0 ng/ml group) and less likely to be African American as troponin categories increased (32.3% for the <0.5 ng/ml group, 21.0% for the 0.5-5 ng/ml group, 17.7% for the >5.0 ng/ml group).

The moderate and high groups had a higher euro-score than the mild group (mean euro-score = 5.44±3.3 and 5.98±6.1 vs. 4.38±2.8 p = 0.003). Patients were more likely to have been treated with unfractionated heparin as troponin levels increased (63.4% for the <0.5 ng/ml group, 69.7% for the 0.5-5 ng/ml group, 84.2% for the >5.0 ng/ml group (p = 0.01).

Primary outcomes

Patients with flow-limiting coronary lesions (n = 430) had higher mean troponin I levels than patients without obstructive coronary disease (n = 131) [5.69±12.57 ng/ml vs. 2.85±5.76 ng/ml, p = 0.002]. More importantly, the proportion of patients with angiographically significant CAD increased as troponin levels increased (70.7% for the <0.5 ng/ml group, 77.2% for the 0.5-5 ng/ml group, 83.2% for the >5.0 ng/ml group (p = 0.038) (Figure 1).

Figure 1. Troponin groups and the presence of flow-limiting CAD.

Secondary outcomes

Elevated troponin levels were associated with increased thrombus burden (8.34±15.44 ng/ml for patients with intracoronary thrombus vs 5.29±13.11 ng/dl for those without thrombotic lesions, p = 0.001), worse systolic function (6.62+9.77 ng/dl for those with LVEF <40% compared to 4.42+8.70 ng/dl for those with preserved LV function, p=0.003), higher complexity of the lesions (patients with high - type C – lesions, per AHA/ACC classification, had mean troponin level of 8.38±17.71 ng/ml vs 3.44±7.7 ng/ml for those with non-high - type C - lesions, p < 0.001), and worse TIMI flow (patients with TIMI grade 0 flow post-intervention had mean troponin of 49.1±71.99 ng/ml vs 5.16±10.41 ng/ml for those with TIMI grade 3 flow, p = 0.017) post intervention.

Patients with LVSD were more likely to be older, have diabetes (DM), have more advanced left main coronary disease, and have cardiac troponin levels greater than 5 ng/ml. When the statistically significant predictors for LVSD (p<0.05) from the univariate analysis were entered into a multivariable logistic regression model of analysis, cardiac troponin levels > 5ng/ml [odds ratio = 2.13 (95%CI = 1.22 to 3.70) p = .008] and DM [odds ratio = 1.74 (95%CI = 1.02 to 2.97) p = .042] were found to be independent predictors for LVSD (Table 2). Age and left main coronary disease almost reached statistical significance.

Table 2. Independent predictors of LVSD.

Discussion

The classic definition of myocardial infarction (MI) by the World Health Organization (WHO) is based on symptoms, electrocardiographic abnormalities, and elevated cardiac enzymes. However, over the past decade the Global MI Task Force has integrated new elements to the definition of MI based on the mechanisms of myocardial injury. Obstructive coronary lesion is the most clinically relevant form of injury and results in troponin release (2,3).

Routine detection of troponin levels using high sensitivity assays that yield a continuous gradient in apparently normal subjects makes it difficult to differentiate myocardial necrosis related to plaque rupture in ACS patients from necrosis in non-ACS patients. Newby et al. discussed the impact of improved test sensitivity on the interpretation of cardiac troponin and emphasized the value of pretest probability when interpreting troponin elevation (3).

The major findings of the present study were: 1) obstructive coronary lesions (flow-limiting) related myocardial injury resulted in greater troponin elevation when compared to other etiologies of myocardial injury, 2) in the context of a flow-limiting coronary artery disease, the degree of troponin elevation implies high-risk features for invasively managed NSTE-ACS patients related to their vascular anatomy, lesion complexity, and the eventual success of percutaneous intervention, and 3) regardless of the mechanism of troponin release, a high level of troponin I was an independent predictor of LVSD in de novo NSTE-ACS patient population.

Troponin I and the presence of hemodynamically significant (flow-limiting) coronary artery disease

Troponin I is independently associated with in-hospital mortality in NSTE-ACS patients. Antman et al. reported that short-term mortality increases with rising levels of cardiac troponin I, and the highest increment in mortality was observed when levels are > 5 ng/ml (4). Additionally, Kleiman et al. (5) demonstrated that invasive management could improve mortality risk in a NSTE-ACS subset of patients with positive cardiac biomarkers.

Interestingly, analyses from the ACTION Registry (NCDR published data) indicate that single vessel flow-limiting coronary artery disease was the most common finding identified by cardiac angiography, and that percutaneous coronary artery intervention was the most common mode of treatment in invasively managed NSTE-ACS patients (6,7). We previously reported that the likelihood of hemodynamically significant coronary artery disease in invasively managed NSTE-ACS patients when the troponin level is more than 5 ng/ml was significantly higher than that in individuals with a lower troponin level (8).

Concern about elevated troponin was reflected in the guidelines that recommend incorporating risk stratification models (TIMI risk score, Grace risk score, or PURSUIT risk model) to the management strategy for NSTE-ACS patients (9). However, none of these models has integrated the additive value of the degree of troponin elevation in their risk-score calculation (10-12).

Being closely associated with mortality and the presence of flow-limiting coronary artery disease, the degree of cardiac troponin elevation should be scored properly in risk stratification modules and contemplated in the timing for invasive management of those presenting with NSTE-ACS.

Troponin I and percutaneous coronary artery interventions in NSTE-ACS

In the setting of ACS, elevated troponin is associated with impaired myocardial tissue perfusion and lower rate of coronary recanalization after percutaneous coronary intervention (13-18). Troponin elevation also signifies adverse short and long-term prognosis in this patient population (19-22). Similarly, in our study, we observed that elevated troponin was associated with increased thrombus burden, worse systolic function, higher complexity of the lesions, and worse post intervention TIMI flow.

Subgroup analysis of ACS clinical trials showed that elevated troponin identified a subset of NSTE-ACS patients who would derive benefit from the addition of antithrombotic therapy and intravenous anti-platelet therapy to a conventional regimen. This is gained via reduction of thrombus formation at the culprit lesion and facilitation of distal micro-thrombi resolution (23-26).

The current guidelines identify the value of elevated troponin when choosing anti-thrombotic therapy, with or without invasive strategy. However, there is no consensus regarding a clinically relevant level of troponin that will provide the most benefit to invasively managed NSTE-ACS patients.

Predictors of left ventricular systolic dysfunction (LVSD) in NSTE-ACS:

Ischemic cardiomyopathy is the main etiology for LVSD in the United States and North America. The development of LVSD following ACS significantly worsens short- and long-term prognosis (17,27,28).  

We targeted patients with no prior history of coronary artery disease, heart failure or cardiac surgery who were referred for coronary angiograms for a new diagnosis of NSTE-ACS to assess the predictors of LVSD. Cardiac troponin I levels >5 ng/ml were the most important predictor of LVSD following a new onset NSTE-ACS in patients with no prior history of coronary artery disease (Table 2).

The previous ACC/AHA (2012-2013) guidelines recommended early invasive strategy in NSTE-ACS patients with a systolic ejection fraction of less than 40% (9). The timing of this recommendation was revised in the most recent guidelines (29).

Using clinical characteristics and risk factors at admission to identify risk of heart failure influences therapeutic decisions and permits an individualized approach to each patient. LVSD is a major concern among invasively managed ACS patients and imposes a large economic burden on the health care system. Troponin level could be used as a cost-effective tool to stratify patients who are at risk of LVSD, allowing appropriate early measures to improve their outcome.

Troponin I and Early versus Delayed Intervention in NSTE-ACS

The optimal timing of angiography has not been conclusively established in NTE-ACS (29). In earlier randomized trials, better outcomes were obtained with an early invasive strategy in patient with troponin I elevation when compared to those with normal troponin levels (30). In other reports, investigators found that early invasive intervention was not superior to a delayed invasive approach in NSTE-ACS patients for the prevention of death or myocardial infarction, even in those with positive cardiac biomarkers (31, 32).

The most notable beneficial effect of an invasive versus a conservative strategy in the management of NSTE-ACS patients was demonstrated in the reduction of recurrent MI, although the effect on mortality was seen in high-risk patients only (29,33).  Prospective trials to determine a clinically relevant troponin level that will determine the timing of an invasive strategy and its impact on patients’ outcomes are yet to be conducted (1).

Study Limitations

Our cohort study is subject to the standard bias associated with retrospective observations including selection bias, incomplete records, and loss of patients’ long-term follow-up.

The results of our study were derived from a single-center using a particular assay kit for serum troponin testing; thus, generalizability is a concern. Follow-up of cardiac events, recurrent hospitalizations, and long-term adverse events was beyond the scope of our study.

Conclusion

The degree of cardiac troponin I elevation should be incorporated into the risk stratification models of NSTE-ACS to promptly triage high-risk patients to early invasive strategies and tailored anticoagulant therapy to reduce troponin elevation and improve myocardial perfusion.

Acknowledgement

The authors of the study would like to thank Melissa Hodges (Cardiac Clinical Nurse Specialist) for her help with data abstraction.

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Cite as: Abdul Jabbar A, Mufti O, Altabaqchali S, Ahsan C, Hasan M, Markert R, White B, Broderick G. High-sensitivity troponin i and the risk of flow limiting coronary artery disease in non-ST elevation acute coronary syndrome (NSTE-ACS). Southwest J Pulm Crit Care. 2017;14(6):296-307. doi: https://doi.org/10.13175/swjpcc059-17 PDF 

June 2017 Critical Care Case of the Month

Stephanie Fountain, MD

Pulmonary and Critical Care Medicine

Banner University Medical Center Phoenix

Phoenix, AZ USA

History of Present Illness

The patient is a 60-year-old woman who presented with a month long history of of odynophagia with retrosternal pain and occasional nausea and vomiting.

Past Medical History, Social History and Family History

She has a past medical history of mixed connective tissue disease with anti-phosopholipid antibody. There is also a history of leukocytoclastic vasculitis, chronic leg ulcers, and poor dentition. She also has a history of chronic obstructive lung disease (COPD) and is a current smoker having accumulated about 50 pack-years of cigarette smoking.

Current Medications

• Prednisone 20 mg daily
• Azathioprine 75 mg daily
• Plaquenil 400 mg daily
• Salmeterol/fluticasone BID
• Albuterol prn

Electrocardiographic, Radiologic and Laboratory Evaluation

Her electrocardiogram and chest x-ray were unremarkable. Complete blood count showed a white blood cell count of 10,500 cells per microliter (mcL), hemoglobin 10.3 grams/deciliter (dL), hematocrit 31%, and platelet count of 48,000 cells per mcL. Electrolytes were unremarkable and creatinine was 0.6 mg/dL.

What should be done next? (Click on the correct answer to proceed to the second of six pages)

1. Bronchoscopy
2. Gastroenterology consult
3. Platelet and red blood cell (RBC) transfusion
4. 1 and 3
5. All of the above

Cite as: Fountain S. June 2017 critical care case of the month. Southwest J Pulm Crit Care. 2017;14(6):262-8. doi: https://doi.org/10.13175/swjpcc061-17 PDF

Clinical Performance of an Interactive Clinical Decision Support System for Assessment of Plasma Lactate in Hospitalized Patients with Organ Dysfunction

Robert A. Raschke, MD MS

Hargobind Khurana, MD 

Huw Owen-Reece, MBBS 

Robert H. Groves Jr, MD

Steven C. Curry, MD

Mary Martin, PharmD

Brenda Stoffer, RN BSN

Banner University Medical Center Phoenix

Phoenix, AZ USA

Abstract

Purpose: Elevated plasma lactate concentration can be a useful measure of tissue hypo-perfusion in acutely deteriorating patients, focusing attention on the need for urgent resuscitation. But lactate is not always assessed in a timely fashion in patients who have deteriorating vital signs. We hypothesized that an electronic medical record (EMR)-based decision support system could interact with clinicians to prompt assessment of plasma lactate in appropriate clinical situations in order to risk stratify a population of inpatients and identify those who are acutely deteriorating in real-time.

Methods: All adult patients admitted to our hospital over a three month period were monitored by an EMR-based lactate decision support system (lactate DSS) programmed to detect patients exhibiting acute organ dysfunction and engage the clinician in the decision to order a plasma lactate concentration. Inpatient mortality was determined for the five risk categories that this system generated, and chart review was performed on a high-risk subgroup to describe the spectrum of bedside events that triggered the system logic.

Results: The lactate DSS segregated inpatients into five strata with mortality rates of 0.8% (95%CI:0.6-1.0%); 2.7% (95%CI:1.0-4.4%); 7.9% (95%CI: 6.0-10.1%), 13.0% (95%CI: 9.0-17.8%) and 42.1% (95%CI: 32.0-52.4%), achieving a discriminant accuracy of 80% (95%CI:76-84%) by AUROC for predicting inpatient mortality. Classification into the two highest risk strata had a positive predictive value for detecting acute life-threatening clinical events of 54% (95%CI: 41.5-66.5%).

Conclusions: Our lactate decision support system is different than previously-described computerized “early warning systems”, because it engages the clinician in decision-making and incorporates clinical judgment in risk stratification. Our system has favorable operating characteristics for the prediction of inpatient mortality and real-time detection of acute life-threatening deterioration.

Introduction

Over 700,000 deaths occur annually in U.S. hospitals (1). Sepsis accounts directly for 37% and indirectly for 56% of these deaths (2). Other common causes of inpatient mortality such as acute hemorrhage and venous thromboembolism (3) share certain early clinical findings with sepsis, in that they may present with deterioration of vital signs and biochemical variables before life-threatening manifestations become obvious (4). Recognition of these findings provides an opportunity for early intervention, which has been shown to improve mortality (5,6). Studies have shown that failure to rapidly recognize acute clinical deterioration is one of the most common root causes of preventable inpatient mortality (4,8).

Early warning systems (EWSs) are a type of clinical decision support system (CDSS) utilized to provide surveillance of hospitalized patients in order to alert clinicians when a patient has findings associated with acute deterioration (19). These typically monitor for abnormal vital signs or laboratory evidence of organ dysfunction, but have included many other types of clinical and laboratory variables (20-23). Modern EWSs utilize logistic regression to weight up to 36 different independent variables and yield highly stratified risk scores (24-26).

We had previous experience developing a simple EWS that triggered when at least two systemic inflammatory response syndrome (SIRS) criteria plus at least one of 14 acute organ dysfunction (OD) parameters was detected. Although this system references SIRS it was found to be nonspecific for sepsis (27), and was subsequently employed in our healthcare system to identify patients deteriorating in real-time regardless of the cause. Subsequent research showed that our SIRS/OD alert system was triggered during the course of 19% of admissions, and that patients who triggered the alert had an odds ratio of 30.1 (95% CI: 26.1-34.5) for inpatient mortality (28). We hypothesized that this SIRS/OD alert system could be used to identify high risk patients who might be further risk-stratified by obtaining a plasma lactate concentration.

Elevated plasma lactate concentration is a particularly useful biochemical marker of acute decompensation. Hyperlactemia is pathophysiologically associated with acute tissue hypoperfusion, and clinically associated with organ dysfunction and mortality (7-11). Hyperlactemia is also associated with the need for urgent clinical interventions such as transfusion and urgent surgery in trauma patients (13,14), and resuscitation of medical patients with sepsis or other life-threatening illnesses (5,15). Lactate assessment is integral to the definition of sepsis (7,16), and an essential component of the Surviving Sepsis Campaign sepsis resuscitation bundle (6). Lactate assessment is integral to achieving sepsis bundle compliance as defined by the Centers for Medicare and Medicaid Services (CMS), which has mandated participating hospitals to report as a measure of quality of care. However, lactate is only ordered about half the time that it ought to be in patients with severe sepsis and septic shock (17,18). To our knowledge, only one previously reported EWS incorporates lactate assessment (29), but this system passively utilized lactate concentration results obtained on admission from the emergency room and was not used for surveillance during hospitalization.

We sought to use our SIRS/OD alert system to actively trigger lactate assessment to identify patients suffering from sepsis or any other life-threatening disease process requiring immediate intervention during hospitalization. We hypothesized that the resulting “lactate decision support system” (lactate DSS) would provide inpatient mortality risk stratification with high discriminant accuracy, and detect acute life-threatening events with high positive predictive value compared to contemporary EWSs.

A lactate DSS with these favorable characteristics could theoretically be used to guide emergent interventions in an effort to save lives, although it was not our aim at this time to perform an interventional trial. The specific aims of this study were to pilot an interactive lactate DSS in our healthcare system, and to calculate its discriminant accuracy for mortality risk stratification, and its positive predictive value as a real-time early warning system.

Methods

We prospectively studied a cohort of all adult inpatients admitted to Banner-University Medical Center - Phoenix, a 650-bed academic hospital in Phoenix Arizona, during the first quarter of 2014. Our research was part of an ongoing system-level patient safety project and was approved by our Institutional Review Board.

The decision support logic was developed at Banner Health using Discern Expert^® (Cerner Corporation, North Kansas City MO, USA). The lactate decision support system (lactate DSS) monitored each patient in our EMR for vital signs and laboratory results consistent with SIRS and organ dysfunction, using criteria derived from the standard definition of sepsis (5-7) (Table 1).

Table 1. Lactate DSS trigger logic

If criteria for SIRS and organ dysfunction overlapped in any eight-hour window, the lactate DSS was triggered to respond. An electronic notification was generated to the patient’s nurse and physician alerting them to the possibility of acute clinical deterioration suggested by SIRS and organ dysfunction, and recommending evaluation and resuscitation if appropriate. Decision support included automatic generation of an order for a STAT plasma lactate if one was not previously ordered by the clinician, interactively prompting the clinician to cancel it if they felt it was unnecessary.

Adult admissions during the three-month study period and subsequent inpatient mortality were enumerated using our hospital’s general financial database: MedSeries4^® (Siemens Corporation, Washington DC). Although some patients triggered the lactate DSS multiple times over the course of their hospital stay, only the first trigger event was included in our analysis.

Inpatient mortality rates with ninety-five percent confidence intervals were calculated for each of five subgroups: 1) patients who did not exhibit SIRS and organ dysfunction during their hospitalization and therefore did not trigger a lactate DSS response; 2) patients who triggered a lactate DSS response, for whom a DSS-generated lactate order was cancelled by their clinician; 3) patients who triggered the lactate DSS and had a lactate concentration <2.2 mmol/L (normal for our laboratory); 4) patients who triggered the lactate DSS and had an elevated lactate of 2.2-3.9 mmol/L; and 5) patients who triggered the lactate DSS and had a highly elevated lactate >4.0 mmol/L.

It was our hypothesis that mortality in patients who triggered the lactate DSS logic would be equivalent whether the clinician chose not to cancel a DSS-generated lactate order, or the clinician had already entered a lactate order themselves. Therefore, we classified patients into the subgroups above regardless of whether their lactate order was DSS-generated or entered independently by the clinician. In order to confirm the validity of this hypothesis, the mortality rate of all patients with any lactate concentration result (the sum of groups 3, 4 and 5 above), and mortality rates within each lactate concentration strata, were separately analyzed to determine if mortality depended on the method of lactate order entry.

Stratified likelihood ratios and the area under the receiver operating curve (AUROC) generated using the five subgroups described above were calculated to determine the discriminant accuracy of the lactate DSS for the outcome of inpatient mortality.

A subgroup analysis was performed of all study patients with an elevated lactate >2.2 mmol/L (above the upper limit of normal range at our laboratory) detected by a DSS-generated lactate order during the first six weeks of the study. These patients’ charts were reviewed in order to characterize the acute clinical events that triggered a lactate DSS response in this subgroup of patients. A physician researcher reviewed progress notes, laboratory and microbiology results at the time of system activation, and for 72 hours afterwards to make this determination. Patient were determined to be suffering an acute life-threatening clinical event if a new-onset or rapidly-progressive disease process was present at the time the lactate DSS was triggered that required emergent treatment with any one of the following: >1 L intravenous fluid resuscitation, vasopressor infusion, >2 units of packed red blood cell transfusion, endotracheal intubation, advanced cardiac life support, or emergent surgical intervention. Minor clinical events included any diagnosis that required initiation of treatment not included in the definition of acute life threatening clinical events above. False alerts were said to have occurred when no evidence was found that the patient was clinically deteriorating in temporal relationship to lactate DSS activation, or within 72 hours. The positive predictive value of the system was calculated for the real-time detection of acute life-threatening clinical events. Microsoft Research and VassarStats^® on-line statistical software were used for statistical calculations.

Results

8,867 adult patients were admitted during our three-month study period. One hundred and ninety-six of 8867 patients (2.2% 95%CI: 1.9-2.5%) died while in the hospital. Seventy percent (138/196) of these inpatient deaths occurred in the 16% (1400/8867) of patients who triggered a lactate DSS response.

Four hundred seventy-nine of 1400 patients who triggered the lactate DSS already had a clinician-ordered lactate. A DSS-generated order for plasma lactate was entered for the remaining 921 patients, but clinicians cancelled 337 of these. DSS-generated lactate orders were resulted for the remaining 584 patients. These patients were merged with 479 patients who had clinician –ordered lactates for the purposes of further analysis after confirmation that mortality did not depend on how the lactate was ordered (Figure 1).

Figure 1. Stratification of inpatients into five subgroups by the lactate DSS.

Patients who did not trigger the lactate DSS logic (n=7467) had a mortality rate of 0.78% (95%CI: 0.58-0.98). Patients who triggered the lactate DSS and for whom a DSS-generated lactate order was cancelled by the clinician (n=337) had mortality of 2.7% (95%CI: 1.0-4.4%). Patients who triggered the lactate DSS and had a lactate concentration in the normal range (< 2.2 mmol/L; n=721) had mortality of 7.9% (95%CI: 6.0-10.1%), and those with elevated lactates of 2.2-3.9 and >4.0 mmol/L (n=247 and n=95) had mortality rates of 13.0% (95%CI: 9.0-17.8%) and 42.1% (95%CI: 32.0-52.4%) respectively (Figure 2).

Figure 2. Inpatient mortality rates (Y-axis: Percent mortality) with 95% confidence intervals for five subgroups of patients stratified by lactate DSS.

The mortality of patients who triggered a lactate DSS response and for whom a lactate concentration was resulted did not depend on whether the order was DSS-generated or entered by the clinician (13.0% versus 12.1% (P=0.71)). Clinician-entered lactate orders were closely temporally related to the onset of organ dysfunction, preceding lactate DSS triggering by < six hours in 52%, <12 hours in 64%, and <24 hours in 75% of cases. Likelihood ratios for mortality in subgroups of patients with lactates <2.2, 2.2-3.9, and >4.0 mmol/L were 6.1 (95%CI: 5.4-6.9), 11.8 (95%CI: 9.5-14.7), and 32.4 (95%CI: 22.0-47.1) respectively.

Five-strata of mortality risk generated by the lactate DSS yielded an AUROC of 0.80 (95% CI: 0.76-0.84) (Figure 3).

Figure 3. Receiver-operating characteristic curve for mortality risk stratification by the lactate DSS.  

Focused chart review was performed on 61 patients who had elevated lactate (>2.2 mmol/L) detected by a DSS-generated lactate order. Thirty-three (54%) were experiencing acute life-threatening clinical events at the time the lactate DSS was triggered. These included 18 episodes of sepsis. Sepsis was due to pneumonia in nine patients, catheter-associated blood stream infection, bowel perforation, cellulitis, ascending cholangitis, endocarditis, liver abscess, cholecystitis, perianal abscess, or an unidentified source. Other acute life threatening clinical events included five cases of acute gastrointestinal hemorrhage, three of acute respiratory failure, and one each of post-operative bleeding, cardiogenic shock, acute liver failure, retroperitoneal bleeding, acute myocardial infarction, subdural hematoma, and cerebral dural sinus thrombosis. Twenty-one (64%) of these events occurred outside the intensive care unit. The positive predictive value of the detection of SIRS, organ dysfunction and elevated lactate by the lactate DSS for acute life-threatening clinical events was 54% (95%CI: 41.5-66.5%).

Ten minor clinical events included anemia, atrial fibrillation, post-op third spacing, transient mild hypotension associated with end stage liver disease, sedation related to narcotics, and dialysis disequilibrium. There were 18 false alerts among patients with SIRS, organ dysfunction and elevated lactate detected by the system. (18/61=29%).

Discussion

Our lactate DSS effectively segregated a population of adult inpatients into five subgroups with increasing inpatient mortality. Clinician engagement was critically important in achieving this result. About a quarter (337/1400) of patients who triggered the lactate DSS (simultaneously exhibited SIRS and organ dysfunction) were doing well enough in their clinician’s opinion that the DSS-generated lactate order was cancelled. Clinicians exercised good judgment in this regard, identifying a subgroup of patients with inpatient mortality rate not significantly higher than the overall mortality of all patients admitted during the study. This supports our decision to incorporate clinician judgment in our risk stratification method.

Approximately half of patients (721/1400) who triggered the lactate DSS turned out to have a normal lactate concentration, yet suffered inpatient mortality ten-times higher than patients who did not trigger the system. This likely represents the independent association between SIRS and organ dysfunction with the risk for mortality (27, 31,32).

One hundred twenty-nine patients over 3 months (14.5 per 1000 patient admissions) triggered the lactate DSS and were found to have an elevated lactate concentration because of a DSS-generated lactate order. These patients had >50% probability of experiencing an acute life-threatening clinical event at the time the lactate DSS was triggered, and subsequently suffered 50% inpatient mortality.

Our lactate DSS is consistent with the new definition of sepsis because it uses organ dysfunction in addition to SIRS criteria (7). As stated in the new definition of sepsis, “Nonspecific SIRS criteria such as pyrexia or neutrophilia will continue to aid in the general diagnosis of infection” (7). Although these criteria are nonspecific, they appear to be relatively sensitive for sepsis (7,27). Our lactate DSS has excellent discriminant accuracy for predicting inpatient mortality (AUROC=0.80). It is comparable to other criteria such SOFA (AUROC = 0.74) and the Logistic Organ Dysfunction System (AUROC=0.75).The five strata into which it segregates patients could further translate into a decision support-guided treatment protocol, directing appropriate real-time interventions such as those proposed in Table 2.

Table 2. Proposed stratified clinical response to lactate DSS.

* Our data indicate that RRT activation would occur about twice a week at our hospital.

Our lactate DSS is different than EWSs because it specifically prompts assessment of plasma lactate in patients exhibiting SIRS and organ dysfunction, rather than simply generating a warning. But a discussion of the operating characteristics of previously reported EWSs is useful for purposes of comparison. A review of 33 EWSs has reported AUROCs ranging from 0.66-0.78 (19). Several more recent EWSs reported AUROCs of 0.81-0.88 (23,24,26,33), but AUROC comparisons are confounded by lack of consensus regarding which clinical outcome to analyze. Authors have variously chosen 24-hour mortality, ICU transfer, and cardiac arrest, among other outcomes (20,23,24). Many EWSs yield highly stratified results, which may increase the AUROC by adding detail to the shape of the ROC curve, but this will not improve clinical discrimination unless each resulting strata has a distinct clinical response. If a EWS is simply used to activate a rapid response team (RRT), the clinically-achievable discriminant accuracy is best described by a polygonal AUROC derived from a single cutoff with two resulting strata (activate the RRT, or do not activate the RRT). This two-strata AUROC will invariably be lower than the highly stratified AUROC that many authors report (23,24,26,33). Our AUROC analysis is based on 5 strata, each of which could reasonably trigger a distinct clinical response (Table 2).

Our lactate decision support system has a positive predictive value (PPV) for acute life-threatening clinical events that is superior to that of our previous “sepsis alert” (27) and to those reported in several reviews of EWSs. One review of 39 EWSs reported PPVs ranging from 13.5-26.1% (34), and another review of 25 systems reported a median PPV of 36.7% with interquartile range 29.3-43.8% (34). PPV was not reported for several of the most elegant and well-studied EWSs (22,23,25,32). From the perspective of bedside clinicians and rapid response team members, the efficiency of an alert system is strongly influenced by the PPV, because a poor PPV translates to frequent false alerts. The PPV is of particularly concern when the pretest probability of the outcome of interest is low, as in the case of inpatient mortality (2% at our hospital). Bayes theory indicates that a test with relatively good AUROC will have a poor PPV if the pretest probability is low enough.

Our study has several limitations. Our sample size is small compared to many contemporary EWS studies. We did not have the resources to perform focused chart reviews on all study patients and therefore had to limit individual case analysis to a subgroup of study patients. Our simple treatment of vital sign abnormalities as markers of SIRS is not as elaborate as in many EWSs. Our study is only hypothesis-generating, whereas several EWSs are well validated (25,32). We cannot provide data on how our alert might change bedside interventions by clinicians. To our knowledge, no study to date has proven that using a computerized decision support system or EWS to trigger rapid clinical intervention actually improves patient outcomes.

Conclusions

We developed an automated decision-support system that prompts assessment of plasma lactate concentration in patients exhibiting SIRS and organ dysfunction. Our lactate decision support system is different than previously-described EWSs because it engages the clinician in decision-making and incorporates clinical judgment into risk stratification. This system has favorable operating characteristics for the prediction of inpatient mortality and for detecting acute life-threatening events in real time. We have proposed a stratified clinical response based on classification of patients into five subgroups by this system that requires further testing, but our current study was not designed to demonstrate a benefit on clinical outcomes. Our lactate DSS has the potential to improve sepsis bundle compliance by helping clinicians appropriately order lactate concentrations in patients deteriorating due to the onset of sepsis – a hypothesis we are currently investigating. It also has potential for easy generalizability, particularly to other healthcare systems that share the same EMR as ours, but requires further refinement and validation.

Author Contributions

All authors were involved in conceptualization, design and implementation of the decision support system described in this manuscript, and in preparation of the manuscript, and all approve of the content of the manuscript and vouch for the validity of the data. We list below additional contributions from several of the authors:

RAR: data analysis and interpretation, main author of initial draft of the manuscript.

HOW: data analysis and interpretation, contribution to discussion/conclusions

HK: directly in charge of design and pilot implementation team for the decision support system, data interpretation, contribution to discussion, conclusions

RHG: data interpretation, contribution to discussion, conclusions

SCC: data analysis and interpretation, contribution to discussion, conclusions. Manuscript editing.

MM: data collection and analysis

BS: data collection and analysis

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Cite as: Raschke RA, Khurana H, Owen-Reece H, Groves RH Jr, Curry SC, Martin M, Stoffer B. Clinical performance of an interactive clinical decision support system for assessment of plasma lactate in hospitalized patients with organ dysfunction. Southwest J Pulm Crit Care. 2017;14:241-52. doi: https://doi.org/10.13175/swjpcc058-17 PDF 

May 2017 Critical Care Case of the Month

Sapna Bhatia, MD

David Ling, DO

Michel Boivin, MD

Division of Pulmonary, Critical Care and Sleep Medicine

University of New Mexico School of Medicine

Albuquerque, NM USA

History of Present Illness

A 54-year-old Hispanic male who was incarcerated 3 days prior to hospital admission was brought into the emergency room from prison for alcohol related withdrawal seizures.

Physical Examination

Upon arrival to the ER, the patient was noted to be hypoxic with copious thick secretions in his mouth. He was intubated for airway protection, started on propofol and fentanyl drips as well as intravenous thiamine and folic acid.

Radiography

A chest radiograph was performed (Figure 1).

Figure 1. Portable anterior-posterior (AP) radiograph of the chest.

Which of the following are true regarding management of this patient?

1. Phenytoin should be administered for prevention of seizures
2. Prophylactic antibiotics for aspiration pneumonia should be administered
3. Thiamine and folic acid should be administered
4. 1 and 3
5. All of the above

Cite as: Bhatia S, Ling D, Boivin M. May 2017 critical care case of the month. Southwest J Pulm Crit Care. 2017;14(5):192-8. doi: https://doi.org/10.13175/swjpcc051-17 PDF

Management of Life Threatening Post-Partum Hemorrhage with HBOC-201 in a Jehovah’s Witness

Andrea Mytinger, DO¹

Elyce Sheehan, MD¹

Nathan Blue, MD²

Kendall P. Crookston, MD, PhD³

Ali I. Saeed, MD ⁴

¹Department of Internal Medicine, ²Department of Maternal and Fetal Medicine, ³Departments of Pathology of Transfusion Medicine, and ⁴Divisions of Pulmonary, Sleep and Critical Care Medicine

University of New Mexico School of Medicine

Albuquerque, NM USA

Abstract

Background: Post-partum hemorrhage remains the leading cause of maternal mortality worldwide. The obstetrician and critical care physician should be aware of local alternative treatment options for symptomatic anemia secondary to post-partum hemorrhage in patients who cannot receive red blood cell transfusion. Transfusion may not be an option due to strong personal belief, lack of compatible blood, or blood shortage.

Case: A 21-year-old woman, gravida 1 para 1001, was transferred to a tertiary care center for management of severe post-partum hemorrhage (hemoglobin 4.2 g/dL). She had undergone emergent dilation and curettage followed by Bakri tamponade balloon placement at an outside facility. As a member of the Jehovah’s Witness faith, she refused red blood cell transfusion. HBOC-201, a bovine hemoglobin based oxygen carrier, was successfully used to reverse symptomatic, life-threatening anemia.

Conclusion:  HBOC-201 can act as a means to reverse severe end-organ damage for patients with severe post-partum hemorrhage and should be considered when no other treatment options are available.

Teaching Points

1. HBOC-210 (Hemopure®) is a bovine hemoglobin-based oxygen carrier (HBOC), used as a means to reverse severe anemia in those patients who cannot receive RBC transfusion.
2. The current generation of HBOCs carry fewer side effects than their predecessors. Common side effects include transient hypertension, abdominal complaints, jaundice, elevated liver and pancreatic enzymes and decreased urine output.
3. The teratogenic effects of HBOC-201 remains unknown in humans.

Introduction

Worldwide, there are an estimated 14 million pregnancy-related hemorrhages each year and 25% of maternal mortality can be attributed to post-partum hemorrhage (1). While the majority of post-partum hemorrhage leading to acute blood loss anemia is treated with red blood cell (RBC) transfusion, there remains a significant subset of patients who are unable to receive this life-saving modality. In instances where RBC transfusion is not an option due to lack of compatible blood, blood shortage, or strong patient personal beliefs, there remain alternative options for management. We report the case of a young Jehovah’s Witness who presented with symptomatic anemia secondary to severe post-partum hemorrhage, treated successfully with an experimental protocol using HBOC-201 (Hemopure®).

Case

A 21-year-old female, gravida 1 para 1001, Jehovah’s Witness was transferred to a tertiary care hospital for management of post-partum hemorrhage after spontaneous vaginal delivery at 40 weeks of gestation. The patient received 3 boluses of intravenous oxytocin, 800mcg of misoprostol and 1 dose of intramuscular (IM) carboprost trimethamine. She then underwent a dilation and curettage for presumed retained products of conception. A Bakri tamponade balloon catheter (Figure 1) was placed vaginally and the patient was transferred for a higher level of care.

Figure 1.  An example illustration of the Bakri vaginal tamponade balloon, placed in the uterus in attempt to apply pressure to bleeding vessels.

Prior to delivery, the patient’s hemoglobin (Hb) and hematocrit (Hct) were initially 12.4 g/dL and 36.4 %, respectively, which decreased to 5.5 g/dL and 16.4%.

On arrival, the patient ‘s heart rate was 148 beats per minute while on 2L of oxygen. The blood pressure was 93/36 mmHg. She was pale and tired-appearing with conjunctival pallor.  Her abdomen exhibited generalized mild tenderness to palpation. The Bakri balloon was in place with 100 mL of drainage noted. Laboratory results revealed Hb of 4.2 g/dL, lactate of 1.2 mmol/L and troponin I of 1.820 ng/mL. The patient refused transfusion of RBC, and the other major blood products, citing her faith. After a prolonged discussion, the patient consented to the use of HBOC-201.

The patient received 2 units of HBOC-201 along with 1,000 mg of ascorbic acid. Her Hb increased from 4.2 g/dL to 4.8 g/dL, much less than the anticipated 1 g/dL increase with each unit of HBOC-201 raising concern for ongoing hemorrhage. An ultrasound was performed which revealed ongoing bleeding from the lower uterine segment behind the balloon. Methylergonovine 0.2mg IM every 6 hours was started and the patient received two additional units of HBOC-201 however, during infusion of the second unit her oxygen requirement increased from 2L by nasal cannula to 15L high flow mask at 80% FiO2. The transfusion was stopped and a chest radiograph revealed diffuse parenchymal opacities with prominent interstitial markings and small bilateral pleural effusions suggestive if fluid overload / pulmonary edema. The patient then underwent gel foam uterine artery embolization by Interventional Radiology for definitive management.

On hospital day 2 the patient’s heart rate was 114 beats per minute and Hb was 5.2 g/dL, prompting infusion of an additional 2 units of HBOC-201. Due to continued hypoxia and radiographic evidence of fluid overload, diuretic therapy was administered. Her oxygen requirement decreased to 5L by nasal cannula, however did not improve from there despite a negative fluid balance, so a CT scan of the chest was performed which revealed significant bilateral basal atelectasis. The patient’s oxygen requirement resolved with incentive spirometry. The Bakri vaginal balloon was removed and minimal bleeding was observed.

On hospital day 3 the patient’s blood pressure increased to 176/78 mmHg. This, in the setting of proteinuria, peripheral edema and elevated aspartate aminotransferase (AST) to 104 unit/L (6-58 Unit/L) raised a suspicion for post-partum preeclampsia with severe features. Intravenous magnesium sulfate was briefly initiated for seizure prophylaxis, however it was discontinued after her blood pressure stabilized and the hypertension was attributed to a possible side effect of HBOC-201.

The patient received a total of 7.5 units of HBOC-201 over the course of 4 days in the MICU. Her troponin peaked on hospital day 2 at 2.930 ng/mL, and continued to downtrend with multiple infusions of HBOC-201. The patient’s own hematocrit began rising on hospital day 5 (Figure 2).

Figure 2.  Illustration of the hemoglobin and hematocrit over the course of the patient’s hospitalization and at her first out-patient follow up visit. The arrows indicate when HBOC-201 was infused.  Troponin I is also depicted on this graph to illustrate the resolution of severe end-organ damage due to the severe anemia.

The patient was transferred to the obstetrics floor on hospital day 7. In accordance with recent post-partum hemorrhage recommendations, she received 1025 mg of IV iron dextran. She was discharged home in stable condition on hospital day 8 with a Hb of 6.7 g/dL and Hct of 21%. Outpatient follow-up revealed significant improvement in anemia with a Hb of 9.2 g/dL and Hct of 30% one week after discharge.

Discussion

Acute post-partum hemorrhage leading to severe anemia remains the leading cause of maternal death worldwide (2). While the majority of post-partum hemorrhage leading to acute blood loss anemia is treated with transfusion of packed RBC or other blood products, there are certain subsets of patients who are unable to accept these products. This case demonstrates the use of a bovine hemoglobin-based oxygen carrier in a Jehovah’s Witness patient with severe post-partum hemorrhage who refused blood products. There have been multiple case reports regarding the use of HBOC-201 in severely anemic Jehovah’s Witness patients; however, there is no published report to our knowledge on the use of HBOC-201 in patients with symptomatic post-partum hemorrhage.

Hemoglobin-based oxygen carriers were developed in response to the infectious issues associated with donor RBC and in an attempt to come up with an alternative treatment in those situations where RBC transfusion was not an option. The first generation of these products was known to cause renal toxicity and coagulopathy (3,4). HBOC-201 is a second generation HBOC that is a cell-free, stroma-free, polymerized version of bovine hemoglobin. Because it contains no cell membrane, it is compatible with all blood types (no cross matching is needed).  The shelf life is 36 months at room temperature (5) (no refrigeration or sophisticated supply network is needed). A number of randomized control trials have been done to evaluate HBOC-201 (and other similar products) as a potential RBC replacement.  However, after infusion the short 24-hour half-life and statistical increase in adverse events associated with administration made it apparent that these HBOCs were not interchangeable with RBC for routine transfusion. While they are not interchangeable, many clinicians feel that the risk-benefit profile is favorable in severely anemic patients who cannot receive RBC. HBOC-201 is not yet approved for use in the United States, and therefore cannot be used outside of clinical trials. Several compassionate use studies are available in the United States to treat patients with life-threatening anemia when no other treatment option is available. Worldwide only a few countries have approved the use of HBOC-201 (6).

The side effect profile of the second generation HBOC’s is much preferable to that of the first (4). Reported class effects of HBOC use include hypertension, esophageal dysmotility and increased risk for myocardial infarction, all of which are related to vasoconstriction secondary to increased nitric oxide scavenging in these products (5). HBOC-201 in particular, has not been reported to increase risk of myocardial infarction. Rather, it has been reported that HBOC-201 reduces cardiac hypoxia in the setting of severe anemia (7). Mongan et al. (8) found that, while HBOC-201 causes transient systemic and pulmonary hypertension in swine, blood flow to 8 major organs, including the heart, was unchanged compared to controls. Serruys et al. (9) found no significant change in coronary blood flow and no vasoconstriction in humans pre-oxygenated with HBOC-201 prior to Percutaneous Coronary Intervention for coronary artery disease. In this case, the patient presented with troponinemia, indicating type 2 demand ischemia in the setting of severe anemia. Troponin levels began to down-trend after HBOC-201 infusion.

Common side effects of HBOC-201 in particular include transient hypertension, abdominal complaints, jaundice, elevated liver and pancreatic enzymes (10) and bovine methemoglobinemia (11). To prevent the increased oxidation of infused HBOC-201 to methemoglobin, ascorbic acid is co-administered; methemoglobin levels should be monitored and treated with methylene blue should they become significantly elevated (5).

This patient did experience increased hypoxia while receiving a unit of HBOC-201 which resulted in concern for transfusion reaction and transient discontinuation of the HBOC-201 infusion. It must be noted that HBOC-201 contains no cellular or plasma components, thus many transfusion reactions such as Transfusion Related Acute Lung Injury (TRALI) are an impossibility. HBOC-201 has been associated with volume overload; as it is a colloid this is a known complication (12). Volume overload was suspected, however, the patient did not improve with diuresis, and a chest CT revealed profound atelectasis. Given that her hypoxia greatly improved with incentive spirometry and ambulation, this was deemed unlikely to be a reaction associated with HBOC-201, but rather related to being bed-bound and critically ill.

One unit of HBOC-201 will raise serum Hb from 0.5g/dL to 2g/dL (12). One to two units of HBOC-201 are typically given for Hb levels <6 g/Dl, with additional units provided to maintain a goal Hemoglobin greater than 6g/dL (11, 12). With a half-life of 19-24 hours (5, 13), HBOC-201 must be infused regularly until the patient’s bone marrow production of RBC is sufficient, as evidenced by increases in hematocrit. It should be noted that HBOC-201 will only increase serum hemoglobin and not hematocrit; an initial decrease in hematocrit may be seen after infusion secondary to hemodilution (12).

The patient presented above experienced both transient hypertension and an increase in her serum AST, raising concern for post-partum preeclampsia. She was started on treatment for severe preeclampsia, however these affects were later attributed to the HBOC-201.

HBOC-201 is currently not recommended during pregnancy. One animal study in rats indicated that HBOC-201 infusion during organogenesis resulted in decreased litter size and increased incidence of external fetal malformations. This was thought to be related to decreased function of an inverted yolk sac, the primary nutritive organ for rat pups in utero (14). Holson et al. (15) performed a similar study on dogs which did not reveal a statistically significant difference in fetal malformations or other study end-points when compared to control. Canines and humans do not have an inverted yolk sac. Thus, it has been hypothesized that teratogenic effects of HBOC-201 do not apply to humans, however, more studies are needed. At least one US expanded access study allows pregnant women with the potential of massive blood loss (e.g. those with placenta accreta, placenta percreta) to consent to the study while still pregnant. However, HBOC-201 cannot be given until after delivery.

HBOC-201 in this case was utilized as a means to reverse severe end-organ damage due to anemia. This Jehovah’s Witness patient refused blood products, citing religious beliefs. Jehovah’s Witnesses in general will not receive “primary” blood components which include red blood cells, platelets and plasma. Other components, including albumin, clotting factors and HBOCs are considered “conscience items” through the church, where-in the individual can decide for themselves if they wish to receive them (5). With an estimated 1.2 million Jehovah’s Witnesses in the United States alone, alternative treatment options for this patient population are imperative (5).

While transfusion of allogeneic blood products remains the standard of care for treatment of severe post-partum hemorrhage, there are certain situations where this is not available. These might include lack of resources in a rural setting, blood product shortages, and inability to cross-match blood products given patient antibodies or patient denial of blood products due to personal or religious beliefs. HBOC’s are currently not approved for use in the United States, however they can be used on a limited compassionate use basis with FDA IND and local IRB approval, either as part of a planned expanded use study or on an emergency approval basis. Referral to a center with an expanded use protocol should be considered for a woman with the potential for massive bleeding who cannot receive RBC.

References

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Cite as: Mytinger A, Sheehan E, Blue N, Crookston KP, Saeed AI. Management of life threatening post-partum hemorrhage with HBOC-201 in a Jehovah’s witness. Southwest J Pulm Crit Care. 2017;14(4):177-84. doi: https://doi.org/10.13175/swjpcc031-17 PDF