Methylene Blue Treatment of Pediatric Patients in the Cardiovascular Intensive Care Unit

Ashley L. Scheffer, MD^1,2

Frederick A. Willyerd, MD^1,2

Allison L. Mruk, PharmD, BCPPS³

Sarah Patel, BS²

Lucia Mirea, MSc, PhD⁴

Chasity Wellnitz, RN, BSN, MPH⁵

Daniel Velez MD^2,5

Brigham C. Willis, MD, MEd^2,6,7

¹Division of Critical Care Medicine, Phoenix Children's Hospital, Phoenix, AZ

²Department of Child Health, University of Arizona College of Medicine-Phoenix, Phoenix, AZ

³Department of Pharmacy Services, Phoenix Children's Hospital, Phoenix, AZ

⁴Department of Biostatistics, Phoenix Children’s Hospital, Phoenix, AZ

⁵Division of Cardiovascular Surgery, Phoenix Children’s Hospital, Phoenix, AZ

⁶Division of Cardiovascular Intensive Care, Phoenix Children’s Hospital, Phoenix, AZ

⁷Department of Pediatrics, University of California Riverside School of Medicine, Riverside, CA

Abstract

Background: In both adults and children, hypotension related to a vasoplegic state has multiple etiologies, including septic shock, burn injury or cardiopulmonary bypass-induced vasoplegic syndrome likely due to an increase in nitric oxide (NO) within the vasculature. Methylene blue is used at times to treat this condition, but its use in pediatric cardiac patients has not been described previously in the literature.

Objective: 1) Analyze the mean arterial blood pressures and vasoactive-inotropic scores of pediatric patients whose hypotension was treated with methylene blue compared to hypotensive controls; 2) Describe the dose administered and the pathologies of hypotension cited for methylene blue use; 3) Compare the morbidity and mortality of pediatric patients treated with methylene blue versus controls.

Design: A retrospective chart review.

Setting: Cardiac ICU in a quaternary care free-standing children’s hospital.

Patients: Thirty-two patients with congenital heart disease who received methylene blue as treatment for hypotension, fifty patients with congenital heart disease identified as controls.

Interventions: None.

Measurements and Main Results: Demographic and vital sign data was collected for all pediatric patients treated with methylene blue during a three-year study period. Mixed effects linear regression models analyzed mean arterial blood pressure trends for twelve hours post methylene blue treatment and vasoactive-inotropic scores for twenty-four hours post treatment. Methylene blue use correlated with an increase in mean arterial blood pressure of 10.8mm Hg over a twelve-hour period (p< 0.001). Mean arterial blood pressure trends of patients older than one year did not differ significantly from controls (p=1.00), but patients less than or equal to one year of age had increasing mean arterial blood pressures that were significantly different from controls (p=0.02). Mixed effects linear regression modeling found a statistically significant decrease in vasoactive-inotropic scores over a twenty-four-hour period in the group treated with methylene blue (p< 0.001). This difference remained significant comparted to controls (p=0.003). Survival estimates did not detect a difference between the two groups (p=0.39).

Conclusion: Methylene blue may be associated with a decreased need for vasoactive-inotropic support and may correlate with an increase in mean arterial blood pressure in patients who are less than or equal to one year of age.

Introduction

One well recognized risk associated with placing patients on cardiopulmonary bypass (CPB) during cardiac surgery is vasoplegic syndrome (VS). VS is a constellation of symptoms comprised of hypotension refractory to volume resuscitation and inotropic support, an adequate to high cardiac output state, and low systemic vascular resistance (SVR) (1-4). In adult patients placed on cardiopulmonary bypass the incidence of VS is as high as 4.8%- 8.8% (1,2). For at risk adult populations, such as those who have used heparin, angiotensin converting enzyme inhibitors, or calcium channel blockers pre-operatively, this incidence increases to 44.4%-55.6% (3). Additionally, adult patients who experience vasoplegia after cardiac surgery demonstrate an increased mortality of 10.7%-24% (1,3). Since this syndrome does not respond to conventional fluid resuscitation and vasoactive therapy, patients who experience vasoplegic syndrome often experience poor systemic perfusion that can progress to multisystem organ failure and ultimately death (2).

In both adults and children, hypotension related to a vasoplegic state has multiple etiologies, including septic shock, burn injury or cardiopulmonary bypass-induced vasoplegic syndrome. Various studies have demonstrated an increase in nitric oxide (NO) as the cause of this hypotension (4,6). Vascular endothelial and smooth muscle cells contain enzymes that actively produce NO. Vasoplegia is hypothesized to result from the disruption of blood vessel endothelial homeostasis through increased inflammation and dysregulation of the nitric oxide and cyclic guanosine 3’, 5’ monophosphate pathway (cGMP) (5). Published literature demonstrates decreased morbidity and mortality when NO synthesis is inhibited preventing microcirculation impairment (4). Pharmacologic treatments that inhibit NO synthase (NOS) have been developed in an attempt to decrease NO production in disease pathologies where the upregulation of NO causes hypotension. Initial animal and human studies testing nonspecific NOS inhibitors showed NOS inhibition did reduce hypotension and increase systemic vascular resistance (SVR) (8). However, nonspecific NOS inhibition was also associated with severe adverse side effects including myocardial depression with decreased cardiac output, decreased oxygen delivery, and increased mortality, thereby making it unsafe for clinical treatment of vasoplegic syndrome (8).

In order for a pharmacologic agent to successfully inhibit NO, while avoiding serious adverse events, it would theoretically need to inhibit the NO pathway through a different mechanism. In cases of NO upregulation, methylene blue appears to inhibit soluble guanylate cyclase (sGC), a downstream biochemical messenger of NO, and ultimately decreases cGMP. cGMP is the final molecular messenger in the NO pathway. Theoretically, decreasing cGMP might avoid the myocardial depression and other adverse side effects seen in nonspecific NO synthase inhibition. Methylene blue is currently approved by the United States Food and Drug Administration for the treatment of methemoglobinemia, but has been studied in the medical literature as an off-label treatment for vasoplegic syndrome in adults. Levin et. al. used methylene blue (MB) as a treatment of CPB-induced vasoplegia in adults and showed a reduction in mortality in those who received the treatment (1,6). In a study treating adults with norepinephrine refractory VS Leyh et.al. demonstrated a subsequently higher SVR and decreased need for catecholamine therapy in the methylene blue treatment group (2,6).

Whether methylene blue is an effective treatment for hypotension in pediatric patients in the cardiovascular intensive care unit remains unknown. There is very limited data published on the use of methylene blue in pediatrics. Methylene blue is used, however, in pediatric cardiovascular intensive care units to treat patients experiencing CPB-induced VS refractory to traditional clinical management based on the decreased mortality reported in the adult literature. Pediatric patients represent a subpopulation whose cardiac pathologies vary greatly from the adults examined in published studies. Due to the variability in cardiac pathology, we aim to describe the type of pathologies for which methylene blue was administered. We examine the association between methylene blue and vital sign trends of pediatric patients, specifically mean arterial blood pressures and vasoactive-inotropic scores. Finally, we compare morbidity and mortality of patients who received methylene blue treatment to controls. In this way, our study investigates if methylene blue is a safe and effective treatment, in conjunction with conventional vasopressor therapy, for hypotension in a pediatric population with congenital heart disease.

Materials and Methods

This retrospective chart review study was approved by the Institutional Review Board at Phoenix Children’s Hospital and the Institutional Review Board waived the need for subjects to provide informed consent. Electronic medical records were queried to identify patients who were treated with methylene blue in the cardiac intensive care unit of a single, quaternary care free-standing children’s hospital from February 1st, 2013 to June 30th, 2016. A clinically comparable control sample not treated with methylene blue from the same cardiac intensive care unit and time period was identified through a pharmacy database. Control patients received traditional medical therapy for vasoplegia, which included treatment with a combination of epinephrine, vasopressin, and stress dose steroids. Consistent with previous studies, methylene blue was dosed according to weight using a dose of 1-2mg/kg per institutional pharmacy recommendations. This study included any patient who received methylene blue as treatment for hypotension during the study period. Patients who received methylene blue for a diagnostic or radiographic procedure instead of treatment for hypotension were excluded.

For both treated and control patients, trained investigators manually extracted demographic data, vital sign data, and vasoactive-inotropic scores (VIS) during a designated collection period. VIS composite scores reflecting the amount of inotrope and vasopressor support required by infants postoperatively and include dopamine, dobutamine, epinephrine, milrinone, vasopressin, and norepinephrine. As methylene blue has a half-life of five hours, mean arterial blood pressure (MAP) values were collected at the time the medication was administered and at 2, 4, 6, 8, 10, and 12 hours post treatment, more than two half-lives of the drug. Similarly, VIS were collected at the time of treatment and at 6, 12, 18, and 24 hours post treatment, more than four half-lives of methylene blue. The control cohort had similar electronic medical record data collected for assessment. Morbidity and mortality data for both groups was obtained from the Society of Thoracic Surgeons Database. Time-to-death in days was computed from the date of surgery to the date of death from all causes.

The distributions of demographic data, baseline clinical factors, cardiac surgical repair, and post-operative conditions were summarized using descriptive statistics for both the methylene blue and control group. Comparison between groups was performed using parametric (Pearson Chi-square test, T-test) or non-parametric (Fisher exact, Wilcoxon rank sum) analyses as appropriate for the data distribution. Similar analysis compared the amount of fluid resuscitation and steroid treatment between patients in the methylene blue group and the control group. Univariate mixed effect models were used to estimate the change in MAP and VIS over time while controlling for extracorporeal membrane oxygenation (ECMO) support. Post-operative ventilator support, post-operative complications, length of stay, and mortality were described and compared between the two groups using appropriate statistical tests as listed above. Overall survival was displayed for each group using Kaplan-Meier curves and compared between the two groups using the Log-rank test. All statistical tests were 2-sided with significance evaluated at the 5% level. Analyses were performed using the statistical package SAS (SAS Institute 2011) and STATA (7).

Results

During the study period, methylene blue was administered on thirty-nine occasions to treat thirty-two unique patients. After excluding four patients treated with methylene blue for diagnostic procedures instead of hypotension, the final sample treated with methylene blue included twenty-eight unique patients, of which seven patients were treated twice, resulting in a total of thirty-five methylene blue treatments. Repeat treatments in the same patients were treated as independent events as they were during separate clinical encounters. Indications for using methylene blue included hypotension secondary to cardiogenic shock in seven patients (25%), post cardiopulmonary bypass vasoplegia in sixteen patients (57%), ECMO decannulation hemodynamic instability in two patients (7%), and septic shock in three patients (11%) (Supplemental Digital Content 1). Doses of methylene blue ranged from 0.3mg/kg- 2mg/kg with an average dose of 1.1mg/kg for the treatment cohort.

Among patients less than one year of age, those treated with methylene blue received surgery at a significantly younger age and had a lower mean weight at the time of surgery than did controls (Table 1).

Table 1. Baseline characteristics for patients treated with methylene blue and controls.

SD = standard deviation

¹P-value from Fisher exact test for categorical variables or Kruskal-Wallis test for continuous measures.

Congenital heart disease diagnosis was comparable between the two groups, except for tetralogy of Fallot with zero patients (0%) among the methylene blue group, but ten patients (21%) in the control group (Table 1). No significant differences were detected in disease severity as measured by the Society of Thoracic Surgeons (STAT) Category.

At baseline mean arterial blood pressures (mean ± SD) were significantly lower (T-test p-value = 0.004) in patients treated with methylene blue (45mmHg ± 10) compared to controls (52mmHg ± 10). The average increase in mean arterial blood pressure from baseline to twelve hours did not vary significantly (T-test p-value = 0.40) between methylene blue patients (8.5mmHg ± 13) and controls (5.6mmHg ± 16). However, when analyses were restricted to subjects less than one year of age, a larger increase in mean arterial blood pressure was suggested (T-test p-value = 0.08) for MB patients (8.5 ± 14) compared to controls (1.4 ± 16). Mixed effects linear models examining MAP measurements over time among patients ≤ 1 year with adjustment for ECMO, confirmed a significant increase in MAP over time for those who were treated with MB (slope coefficient = 0.57, p-value <0.001) whereas no trend in MAP values was detected for control patients ≤ 1 year (slope coefficient = 0.08, p-value 0.6). Among patients > 1 year, MAP increased over time for both MB and controls, with no detectable difference between the slopes estimates (Table 2).

Table 2. Mixed effects linear regression analyses examining time trends in mean arterial pressure (MAP) and vasoactive-inotropic score (VIS) of patients treated with methylene blue and controls by age.

MAP= mean arterial pressure; VIS= vasoactive-inotropic scores; SE = standard error

*All models included a random patient-level intercept, assumed unstructured correlation, and were adjusted for ECMO.

Figures 1A and 1B show the MAP measurements over time, and the estimated slopes for MB and control patients adjusted for clustering and ECMO.

Figure 1. Mean arterial blood pressure mixed effects linear regression models stratified by age.

The mean VIS at baseline was significantly higher in MB (27 ± 26) compared to control (12 ± 11) patients (T-test p-value = 0.002). From baseline to 24 hours, MB patients had a significantly larger mean decrease in VIS than controls overall (T-test p-value <0.006). Analyses stratified by age detected a significant negative trend in VIS for MB patients, especially among MB patients > 1 year (Table 2). Weak negative trends in VIS were detected among controls (Figures 2A and 2B).

Figure 2. Vasoactive inotropic score mixed effects linear regression models stratified by age.

Patients treated with methylene blue were extubated approximately twenty-four hours sooner than those in the control group (Table 3).

Table 3. Outcomes among patients treated with methylene blue and controls.

SD = standard deviation

¹P-value from Fisher exact test for categorical variables or Kruskal-Wallis test for continuous measures

However, methylene blue patients had higher incidence of ECMO support and multisystem organ failure, but a lower incidence of cardiac arrest compared to controls (Table 3). There were no reported adverse effects from methylene blue use. Mortality at thirty days post operatively did not vary significantly between groups (Table 3). At discharge, methylene blue patients had notably higher mortality compared to controls (31% vs. 14%), but statistical significance was not reached (Table 3). There was no difference in length of ICU stay or hospital length of stay between the two groups (Table 3). Furthermore, no significant differences in survival were detected between the methylene blue patients and control patients (Figure 3; Log-rank p-value= 0.39); however, our study was not powered adequately to show equivalence of a clinical outcome.

Figure 3. Kaplan-Meier survival estimates for patients treated with methylene blue versus controls.

Discussion

Overall, we found that methylene blue use was associated with a decreased need for vasoactive-inotropic support when compared to the control cohort and may correlate with an increase in mean arterial blood pressure over time, specifically in those patients who are less than or equal to one year of age. Vasoplegia results in increased mortality because it often remains resistant to standard clinical interventions such as administration of intravenous fluids and the use of multiple inotropic medications leading to refractory shock and poor oxygen delivery in patients who experience it (2). If a patient’s shock state is unable to be reversed, vasoplegic syndrome (VS) could lead to increased mortality in vulnerable populations such as pediatric patients undergoing cardiopulmonary bypass for cardiac surgery. In our study, we demonstrated that methylene blue use was associated with an increase in mean arterial blood pressure over a twelve-hour period and a decrease in vasoactive-inotropic scores over a twenty-four-hour period. When compared with controls, the decrease in vasoactive-inotropic score maintained statistical significance in all ages, but mean arterial blood pressure trends were only significant compared to controls in children less than or equal to one year of age.  These results support the theory that methylene blue could be an effective treatment for vasoplegia in the pediatric population, although more prospective studies would be needed to verify causation. However, as mentioned above, given the retrospective nature of our study, the difficulty in identifying a more completely matched control cohort (especially for the group of patients <1 year of age), and the limited numbers, such conclusions must be tempered until such trials are performed.

During our evaluation we noted that the increase in mean arterial blood pressure was only statistically significant when ages were stratified. In children older than a year, the increasing mean arterial blood pressure trends observed over time may have resulted from improvement of low cardiac output syndrome after cardiopulmonary bypass since both the control and treatment cohort mixed effects linear regression models had similarly increasing slopes that were not statistically different from each other. In ages less than or equal to one year, however, the control cohort mixed effects linear regression model did not show any trend toward increasing mean arterial blood pressures. Additionally, the methylene blue cohort had an initial lower average mean arterial blood pressure and a statistically significant trend up in mean arterial pressures over a twelve-hour period. Although this subgroup analysis was a smaller sample, the difference in the two regression models suggests that there may be a correlation between the use of methylene blue and increasing mean arterial blood pressures in children less than or equal to one year of age.

Both our treatment cohort and our control cohort were very heterogeneous in certain demographic characteristics, specifically in age and weight, but are very typical of the clinical patient population. Normal values for vital signs such as mean arterial blood pressure vary greatly between ages, which can make statistical interpretation of these vital sign trends difficult. In our study, heterogeneity of age resulted in variability of mean arterial blood pressure data that limited our interpretation of vital signs trends unless age groups were stratified. Ideally, we would have examined all vital sign trends stratified by age to improve the accuracy of our interpretation. However, our population was too small to appropriately power such a subgroup analysis.

Attempting to identify the control group without introducing bias may also have contributed to the difference seen in mean arterial blood pressure trends between the methylene blue cohort and the control cohort. There are multiple factors that control mean arterial blood pressure and vasoactive-inotropic scores. In an attempt to limit cofounding factors, a control group was selected using a pharmacy database that identified patients who received both vasoactive-inotropic treatment and stress dose steroids to treat refractory hypotension after cardiac surgery to find a clinically comparable cohort. The control cohort varied slightly in demographic characteristics, but did not appear statistically different in fluid resuscitation or steroid use (Supplemental Digital Content 2). However, this remains a significant limitation of the current study, given its small numbers, heterogeneous population, and difficulty identifying a better-matched control group. In the future, a prospective, randomized trial of methylene blue in this population could address this.

For adult patients who experienced vasoplegic syndrome, multiple studies have demonstrated an overall reduction in mortality in patients who were treated with methylene blue (1,2,6). However, unlike the adult studies, our study did not find any statistically significant survival difference between the methylene blue cohort and the control cohort. Our study did demonstrate, however, that methylene blue was not associated with increased mortality. Patients treated with methylene blue were also extubated sooner that patients in the control cohort. Speculatively, methylene blue treatment may have been associated with less cardiopulmonary liability, increasing the clinician’s confidence to wean toward extubation sooner than the control group. In addition, our study showed a higher incidence of extracorporeal membrane oxygenation support and multisystem organ failure in the methylene blue group as compared to controls. This is likely a result of the high incidence of refractory hypotension and severe shock that led to the use of methylene blue. There was no difference between the two groups in their number of intensive care days or hospital length of stay. No adverse side effects directly attributable to methylene blue were reported in any of our cases, indicating it is a potentially safe treatment for vasoplegic syndrome.

Our study was designed as a retrospective chart review and therefore had limitations inherent with this design. We examined blood pressure trends of any pediatric patient that was given methylene blue for hypotension, regardless of the pathophysiology. Accurately pinpointing the justification for methylene blue treatment retrospectively was difficult especially given the complex nature of the patients’ disease processes, resulting in multiple reasons for hypotension cited in the electronic medical record. We could not accurately limit our patient selection to patients with cardiopulmonary bypass-induced vasoplegia without introducing selection bias and therefore decided to look at all patients who were treated with methylene blue during the study period. Furthermore, limiting our sample size to only those patients who received methylene blue as treatment for post cardiopulmonary bypass vasoplegic syndrome would have resulted in a sample size too small to appropriately power our study.

The definition of vasoplegia requires patients to maintain a high cardiac output state. There were no objective measurements of cardiac output that could be identified retrospectively, thus our study relied on clinician estimation of high cardiac output. In nearly thirty percent of the methylene blue cohort, methylene blue was used as treatment for hypotension that was related to low cardiac output or cardiogenic shock, not vasoplegia. The adult studies that showed a difference in mean arterial blood pressures as well as mortality of patients were examining methylene blue treatment of hypotension secondary to vasoplegic syndrome specifically. Additional prospective studies in pediatric patients are needed to evaluate the effectiveness of methylene blue in treating vasoplegic syndrome.

Conclusion

Methylene blue may be a safe and effective treatment for vasoplegia in pediatric patients with congenital heart disease.  Methylene blue use was associated with a decreased need for vasoactive-inotropic support when compared to the control cohort and may correlate with an increase in mean arterial blood pressure over time, specifically in those patients who are less than or equal to one year of age. There was a statistically significant decrease in ventilator days between the methylene blue cohort and the control cohort. There was no difference in survival estimates between those patients who received methylene blue versus controls.

References

1. Levin RL, Degrange MA, Bruno GF, Del Mazo CD, Taborda DJ, Griotti JJ, Boullon FJ. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg. 2004 Feb;77(2):496-9. [CrossRef] [PubMed]
2. Leyh RG, Kofidis T, Strüber M, Fischer S, Knobloch K, Wachsmann B, Hagl C, Simon AR, Haverich A. Methylene blue: the drug of choice for catecholamine-refractory vasoplegia after cardiopulmonary bypass? J Thorac Cardiovasc Surg. 2003 Jun;125(6):1426-31. [CrossRef] [PubMed]
3. Ozal E, Kuralay E, Yildirim V, Kilic S, Bolcal C, Kücükarslan N, Günay C, Demirkilic U, Tatar H. Preoperative methylene blue administration in patients at high risk for vasoplegic syndrome during cardiac surgery. Ann Thorac Surg. 2005 May;79(5):1615-9. [CrossRef] [PubMed]
4. Evora PR, Alves Junior L, Ferreira CA, Menardi AC, Bassetto S, Rodrigues AJ, Scorzoni Filho A, Vicente WV. Twenty years of vasoplegic syndrome treatment in heart surgery. Methylene blue revised. Rev Bras Cir Cardiovasc. 2015 Jan-Mar;30(1):84-92. [CrossRef] [PubMed]
5. Werner I, Guo F, Bogert NV, Stock UA, Meybohm P, Moritz A, Beiras-Fernandez A. Methylene blue modulates transendothelial migration of peripheral blood cells. PLoS One. 2013 Dec 10;8(12):e82214. [CrossRef] [PubMed]
6. Omar S, Zedan A, Nugent K. Cardiac vasoplegia syndrome: pathophysiology, risk factors and treatment. Am J Med Sci. 2015 Jan;349(1):80-8. [CrossRef] [PubMed]
7. SAS Institute Inc. 2011. Base SAS® 9.3 Procedures Guide. Cary, NC: SAS Institute Inc.
8. Farina Junior JA, Celotto AC, da Silva MF, Evora PR. Guanylate cyclase inhibition by methylene blue as an option in the treatment of vasoplegia after a severe burn. A medical hypothesis. Med Sci Monit. 2012 May;18(5):HY13-7. [CrossRef] [PubMed]
9. Víteček J, Lojek A, Valacchi G, Kubala L. Arginine-based inhibitors of nitric oxide synthase: therapeutic potential and challenges. Mediators Inflamm. 2012;2012:318087. [CrossRef] [PubMed]
10. Rutledge C, Brown B, Benner K, Prabhakaran P, Hayes L. A Novel Use of Methylene Blue in the Pediatric ICU. Pediatrics. 2015 Oct;136(4):e1030-4. [CrossRef] [PubMed]
11. Corral-Velez V, Lopez-Delgado JC, Betancur-Zambrano NL, Lopez-Suñe N, Rojas-Lora M, Torrado H, Ballus J. The inflammatory response in cardiac surgery: an overview of the pathophysiology and clinical implications. Inflamm Allergy Drug Targets. 2015;13(6):367-70. [CrossRef] [PubMed]

Cite as: Scheffer AL, Willyerd FA, Mruk AL, Patel S, Mirea L, Wellnitz C, Velez D, Willis BC. Methylene blue treatment of pediatric patients in the cardiovascular intensive care unit. Southwest J Pulm Crit Care. 2021;23(1):8-17. doi: https://doi.org/10.13175/swjpcc022-21 PDF

Presented, in part, in abstract form at the 2018 Society of Critical Care Medicine Conference in February 25-28, 2018, San Antonio, TX.

The authors have disclosed that they do not have any potential conflicts of interest.   

July 2021 Critical Care Case of the Month: When a Chronic Disease Becomes Acute

Kara Calhoun MD, MPH

Division of Pulmonary Sciences & Critical Care Medicine

University of Colorado

Denver, CO USA

History of Present Illness

A 32-year-old woman with no known past medical history presented with progressive shortness of breath for the past 2 weeks. She denied having a cough, fever, or chills, but she did have a one-month history of fatigue, weakness, and painful rashes on her hands.

PMH, SH, and FH

• No known past medical history
• Former tobacco user (quit 2 years prior to admission)
• No drug use
• Worked as an office assistant
• Has two pet dogs and four pet macaws
• No family history of lung disease
• Not taking any prescription medications

Physical Exam

• BP: 116/65, Pulse: 105, T: 37°C, RR: 28, SpO2: 89% on HHFNC (60L; 100%)
• Pulmonary: Tachypneic, in respiratory distress, crackles throughout
• Cardiovascular: Tachycardic but regular, no murmurs
• Extremities: No edema
• Skin: Palms with purplish discoloration and erythematous papules

Radiography

Figure 1. Initial portable chest x-ray.

Which of the following should be done next?

1. CT Chest
2. COVID-19 testing
3. Sputum gram stain and culture
4. 1 and 3
5. All of the above

Cite as: Calhoun K. July 2021 Critical Care Case of the Month: When a Chronic Disease Becomes Acute. Southwest J Pulm Crit Care. 2021;23(1):1-4. doi: https://doi.org/10.13175/swjpcc023-21 PDF

Arizona Hospitals and Health Systems’ Statewide Collaboration Producing a Triage Protocol During the COVID-19 Pandemic

Patricia A. Mayer, MD

David H. Beyda, MD

C. Bree Johnston, MD

Department of Bioethics and Medical Humanism and Medicine, The University of Arizona College of Medicine-Phoenix, Phoenix, AZ USA

Abstract

We describe the process by which all hospitals and health systems in Arizona, normally competitors, rapidly cooperated to develop a statewide protocol delineating how to allocate scarce resources during the COVID-19 pandemic should triage be required anywhere in the state. Eight physician ethicists from seven different health systems created the Addendum* (see editor's note after Abstract), which was accepted by all hospitals and health systems, approved by the State Disaster Medical Advisory Committee (SDMAC), and then formally adopted by the Arizona Department of Health Services (ADHS). In addition, the entire state developed a plan to “stick together” such that no facility would be forced to triage unless all were overwhelmed. Because we are unaware of any other state’s hospitals and health systems producing and committing to a shared triage protocol and plan, we believe this experience can serve as a model for other locales during the absence of sufficient state or federal guidance.

Editor's Note

The Addendum initially posted on ADHS has been removed. It appears to have been altered including removal of the authors. To see the original Addendum click here.

Abbreviations

• ADHS: Arizona Department of Health Services
• CMO: Chief Medical Officer
• CSC: Arizona Crisisi Standards of Care Plan, 3rd edition 
• SDMAC: State Disaster Medical Advisory Committee

The Challenge

Potential shortages of ventilators and other scarce resources during COVID-19 compelled creation of plans to allocate resources fairly (1). Without protocols, resources would be allocated on a first come first serve basis, which is inefficient and ethically problematic (1-4). Without a cohesive state plan, public confusion combined with uneven resources could lead to “hospital shopping” with vastly different individual outcomes that would likely benefit patients with greater social or economic advantages and be determined by geography rather than medical criteria.  

The Goal  

Because the existing Arizona Crisis Standards of Care Plan, 3^rd edition (CSC, 2) was deemed too non-specific to apply usefully in the pandemic, representatives from hospitals and hospital systems across the state, including small rural hospitals, competing private hospital systems, and  federal agencies (Indian Health Service and the Veteran’s Administration) sought a common triage protocol to addend the CSC. The goal was to create  a protocol accepted by  all hospitals, health care systems and ADHS.

Background

The pandemic caused severe and previously unknown shortages of personal protective equipment and life-sustaining equipment and therapies (6).  Much has been written about the need to allocate scarce resources in a manner that is fair, consistent, and based on sound ethical principles. Multiple states, cities, and health systems have shared their processes and protocols for triage during the pandemic (7,8)  However, integration between disparate systems has proved challenging at both the local, state and federal levels. Arizona is the sixth largest state in the country and the fourteenth most populous, with five-sixths of the population concentrated in two main metropolitan areas:Phoenix and Tucson. In addition, Arizona is home to twenty-one Native American tribes/nations. Most of the state is rural, distances from populated areas to health care facilities can be great, and access to health care is unevenly distributed. In Arizona health insurance coverage of the population is 45.1% employer, 5.2% non-group, 21% AHCCCS (Arizona’s Medicaid equivalent), 21.6% Medicare, 1.5% Military, and 11.1% uninsured (9).

Triage ethics differ from “usual” clinical ethics in which the lens is the individual patient and all patients have access to life-sustaining treatments.  hen life-sustaining resources are insufficient (e.g., pandemics, war), the concentration of the lens shifts from the individual good to the greater community (10). This shift is not only challenging for health care workers but also for a society that is increasingly divided and distrustful of experts. Therefore, it was clear that any protocol had to be fair, transparent and uniform across the state in order to be  and acceptable. This necessitated cooperation between organizations traditional in competition with each other that lacked a solid framework for this kind of emergency cooperation.

Creation and Adoption

In the early months of 2020, New York City and Italy were epicenters of the pandemic, and the world watched as they were overwhelmed with cases causing a shortage of beds and personal protective equipment. In response, Arizona hospitals health systems rapidly   their existing triage protocols and the state CSC. Therefore, amid predictions for a major surge in Arizona by summer 2020, Phoenix area hospital chief medical officers (CMOs) created the Triage Collaborative.  The first meeting laid a foundation for seamless collaboration since all participants, CMOs or their physician designees, were empowered to make decisions during the meetings without delay . This framework, uniquely possible due to the acute time pressure of the pandemic, enabled broader, more streamlined collaboration than had previously been possible between organizations that were normally in competition.

At the second meeting a week later, with representatives from the entire state  ADHS proposed a “Surge Line”. This 24/7 state-run hotline accessible to all Arizona healthcare providers   rapid transfers of COVID-19 patients to needed levels of care possible due to its ability to monitor statewide resource availability. All agreed to take part in the Surge Line, and it was rapidly implemented (11) Notably, and critical to success of the Surge Line, participation  was mandated and insurers  required to cover transfers and COVID-19 treatment at in-network rates by the Governor’s Executive Order 2020-38 in late May (12).  

On April 9, the Governor issued Executive Order 2020-27 which called for immunity from civil liability “in the course of providing medical services in support of the State’s public health emergency for COVID-19… (including) triage decisions…based on…reliance of mandatory or voluntary state-approved protocols …” (13). This  the necessity of a state-approved protocol. ADHS agreed to consider any protocol presented to them by the medical community.  

Driven by that Order, the Collaborative immediately shifted from sharing individual protocols to developing the needed statewide protocol  In addition, the Collaborative committed to cooperation agreeing that no facility would have to triage unless the entire state was overwhelmed  (14). To create the protocol  writing group of eight  from seven different systems volunteered to begin work immediately.

The writing goup reviewed the existing CSC and individual system protocols for suitability and agreed a new protocol was required that would be transparent, ethically sound  and reflect current best practices. After reviewing protocols from other states and literature on triage ethics, the group agreed on  goal: maximize the number of lives saved while treating patients without discrimination.

ADHS convened the State Disaster Medical Advisory Committee (SDMAC) in mid-June where the Addendum was discussed and approved.  ADHS then accepted and published the final COVID-19 Addendum: Allocation of Scarce Resources for Acute Care Facilities (15). The SDMAC was reconvened again in late June and recommended activation of the CSC, including the Addendum. The formal activation of the CSC by the Governor and ADHS on June 29 was unprecedented and signaled the ability to proceed with triage per the Addendum if needed. Arizona experienced its first major surge shortly thereafter, in July 2020. (for Timeline see Table 1 below).

Ethical Considerations

After a great deal of discussion, the writing group agreed on several key concepts:

1. Goals of care should be assessed as the first step in triage so that patients who do not desire ventilators or ICU beds will not compete for scarce resources that are unwanted (10).
2. The best available acute assessment score (e.g., SOFA, PELOD) should be utilized as an initial triage tool but should not be used alone (6-8).
3. Limited life expectancy should be included as a triage factor.
4. The protocol should avoid categorical exclusions and instead be based on prioritization criteria.
5. Perceived quality of life should not be considered.
6. The value of all lives must be explicitly recognized with triage criteria never used to deny resources when they are not scarce.
7. Criteria is only to prioritize patients when resources are scarce.
8. Criteria must not include any ethically irrelevant discriminatory criteria including race, ethnicity, national origin, religion, sex, disability, age, or gender identity.
9. Patients should be re-assessed and re-prioritized periodically based on their clinical course and continued likelihood of benefit.
10. Where “ties” occur in priority scores, the group must agree on which other factors to consider.
11. An explicit statement rejecting reallocation of personal/home ventilators (or any other durable medical equipment) in order to further protect patients with chronic respiratory conditions or disabilities was essential.

The Process

Bringing together the various health systems was remarkably seamless . However, the group faced a tight timeline to complete the protocol to prepare for a potential emergency.

Although members of the writing group agreed on the primary goal (e.g., maximizing number of lives saved), reaching consensus on other principles (e.g., how to incorporate life expectancy, life cycle, and instrumental concerns) was more challenging. However, over a short but intense time, members were able to reach decisions that all “could live with”.

Previous articles have advocated considering not only the number of lives saved using an acute assessment tool but incorporating other considerations, such as maximizing the number of years of life saved and using life cycle considerations (19,20). While the writing group agreed, members expressed concern about possible unintended consequences with those criteria. First, groups that have faced institutional racism and lifelong health disparities were more likely to have a shorter life expectancy and could face “double jeopardy” in triage protocols, particularly if comorbidities more prevalent in communities of color were used (21-4). Likewise, older patients would often be disadvantaged with these criteria. Group members felt strongly that use of life-years saved should be tempered to address these concerns and so elected to include near term life expectancy and the Life Cycle principle. Other issues included whether and how to prioritize pediatric patients, pregnant women, and single caretakers (25,26).

The group did agree to prioritize healthcare and other frontline workers in case of equal scores, not because of greater estimation of “worth” but because of the instrumental value they serve in the community and as an acknowledgement of their increased risk.

While the writing group did resolve issues in a way all parties “could live with”, members recognized ongoing discussions and updates would be important. For instance, after our Addendum was created, a strong case was made that triage policies should also promote population health outcomes and mitigate health inequalities (23). We echo the need to grapple with how best to address these equity and justice concerns. And although no protocol can perfectly reconcile all tensions we hope the Addendum reflects our sincere attempt to balance competing considerations fairly, ethically, and in a way that could be widely implemented if needed.  

The Team 

Arizona demonstrated a collaboration between all its hospitals and health systems with a subgroup of physician-ethicist representatives writing, employees at ADHS formatting and supporting the work, the SDMAC endorsing it, and the ADHS then accepting and publishing the Addendum with the agreement of the Governor’s’ office.

The Follow-up 

Arizona survived both the July 2020 and the January 2021 surges without resorting to triage and all hospitals and health systems continue to cooperate. The state Surge Line continues to function and as of Feb 1 had transferred over 3700 patients across the state. We remain acutely aware of the ongoing challenges of public perception, news reports, and social media, particularly in a society as divided as the U.S. is today. Already, the Addendum has been mis-characterized on social media as allowing health care providers to refuse scarce resources to older people and those with disabilities. We particularly hope that further conversations occurring outside the acute impending emergency will allow time for public engagement, which will provide valuable input and may mitigate inaccurate perceptions of the criteria used. Meantime, we believe our statewide transparent approach, with the support of ADHS, provided a novel approach and contributed to the state avoiding triage during the worst of our surges.

Conclusion

We believe the cooperation of   in developing a shared triage Addendum  represents a unique contribution and may provide a model for other localities facing public health emergencies requiring rapid decisive action.

References

1. ADHS. COVID-19 Addendum: Allocation of Scarce Resources in Acute Care Facilities, Recommended for Approval by State Disaster Medical Advisory Committee (SDMAC) 6/12/2020.  Available at https://www.azdhs.gov/documents/preparedness/epidemiology-disease-control/infectious-disease-epidemiology/novel-coronavirus/sdmac/covid-19-addendum.pdf.
2. Ventilator allocation guidelines. Albany: New York State Task Force on Life and the Law, New York State Department of Health, November 2015 , available at https://www.health.ny.gov/regulations/task_force/reports_publications/#allocation
3. Ferraresi M. A coronavirus cautionary tale from Italy: don’t do what we did. Boston Globe. March 13, 2020.  Available at https://www.bostonglobe.com/2020/03/13/opinion/coronavirus-cautionary-tale-italy-dont-do-what-we-did/
4. Sprung CL, Danis M, Iapichino G, et al. Triage of intensive care patients: identifying agreement and controversy. Intensive Care Med. 2013 Nov;39(11):1916-24. [CrossRef] [PubMed]
5. ADHS. Arizona Crisis Standard of Care Plan, 3rd ED. 2020; Available at: https://www.azdhs.gov/documents/preparedness/emergency-preparedness/response-plans/azcsc-plan.pdf
6. Ranney ML, Griffeth V, Jha AK. Critical Supply Shortages - The Need for Ventilators and Personal Protective Equipment during the Covid-19 Pandemic. N Engl J Med. 2020 Apr 30;382(18):e41. [CrossRef] [PubMed]
7. Berger JT. Imagining the unthinkable, illuminating the present. J Clin Ethics. 2011 Spring;22(1):17-9. [PubMed]
8. White DB, Lo B. A Framework for Rationing Ventilators and Critical Care Beds During the COVID-19 Pandemic. JAMA. 2020 May 12;323(18):1773-1774. [CrossRef] [PubMed]
9. KFF Health Policy Analysis, State Health Facts, accessed March 15, 2020  at https://www.kff.org/other/state-indicator/total-population/?currentTimeframe=0&selectedRows=%7B%22states%22:%7B%22arizona%22:%7B%7D%7D%7D&sortModel=%7B%22colId%22:%22Location%22,%22sort%22:%22asc%22%7D
10. Berger JT. Imagining the unthinkable, illuminating the present. J Clin Ethics, 2011. 22(1): 17-9.
11. Villarroel L, Christ, CM, Smith L et al. Collaboration on the Arizona Surge Line:  How Covid-19 Became the Impetus for Public, Private, and Federal Hospitals to Function as One System. NEJM Catalyst, Jan 21, 2021, available at https://catalyst.nejm.org/doi/full/10.1056/CAT.20.0595
12. Office of Governor Doug Ducey. Executive Order: 2020-38: Ensuring Statewide Access to Care for COVID-19 Arizona Surge Line. AZ Governor. Published May 28, 2020.
13. Office of Governor Doug Ducey. Executive Order : 2020-27: The “Good Samaritan” Order Protecting Frontline Healthcare Workers Responding to the COVID-19 Outbreak”. AZ Governor. Published April 9, 2020.
14. Feldman SL, Mayer PA. Arizona Health Care Systems’ Coordinated Response to COVID-19-“In It Together”. JAMA Health Forum. Published online August 24, 2020. [CrossRef]
15. ADHS. COVID-19 Addendum: Allocation of Scarce Resources in Acute Care Facilities, Recommended for Approval by State Disaster Medical Advisory Committee (SDMAC) 6/12/2020.  Available at https://www.azdhs.gov/documents/preparedness/epidemiology-disease-control/infectious-disease-epidemiology/novel-coronavirus/sdmac/covid-19-addendum.pdf
16. Lambden S, Laterre PF, Levy MM, Francois B. The SOFA score-development, utility and challenges of accurate assessment in clinical trials. Crit Care. 2019 Nov 27;23(1):374. [CrossRef] [PubMed]
17. Leteurtre S, Duhamel A, Salleron J, Grandbastien B, Lacroix J, Leclerc F; Groupe Francophone de Réanimation et d’Urgences Pédiatriques (GFRUP). PELOD-2: an update of the PEdiatric logistic organ dysfunction score. Crit Care Med. 2013 Jul;41(7):1761-73. [CrossRef] [PubMed].
18. Straney L, Clements A, Parslow RC, Pearson G, Shann F, Alexander J, Slater A; ANZICS Paediatric Study Group and the Paediatric Intensive Care Audit Network. Paediatric index of mortality 3: an updated model for predicting mortality in pediatric intensive care*. Pediatr Crit Care Med. 2013 Sep;14(7):673-81. [CrossRef] [PubMed]
19. White DB, Lo B. A Framework for Rationing Ventilators and Critical Care Beds During the COVID-19 Pandemic. JAMA. 2020 May 12;323(18):1773-1774. [CrossRef] [PubMed]
20. Emanuel EJ, Persad G, Upshur R, Thome B, Parker M, Glickman A, Zhang C, Boyle C, Smith M, Phillips JP. Fair Allocation of Scarce Medical Resources in the Time of Covid-19. N Engl J Med. 2020 May 21;382(21):2049-2055. [CrossRef] [PubMed]
21. Cleveland Manchanda E, Couillard C, Sivashanker K. Inequity in Crisis Standards of Care. N Engl J Med. 2020 Jul 23;383(4):e16. [CrossRef] [PubMed]
22. Price-Haywood EG, Burton J, Fort D, Seoane L. Hospitalization and Mortality among Black Patients and White Patients with Covid-19. N Engl J Med. 2020 Jun 25;382(26):2534-2543. [CrossRef] [PubMed]
23. White DB, Lo B. Mitigating Inequities and Saving Lives with ICU Triage during the COVID-19 Pandemic. Am J Respir Crit Care Med. 2021 Feb 1;203(3):287-295. [CrossRef] [PubMed].
24. Yancy CW. COVID-19 and African Americans. JAMA, 2020. 323(19): 1891-1892. [CrossRef] [PubMed]
25. Antommaria AH, Powell T, Miller JE, Christian MD; Task Force for Pediatric Emergency Mass Critical Care. Ethical issues in pediatric emergency mass critical care. Pediatr Crit Care Med. 2011 Nov;12(6 Suppl):S163-8. [CrossRef] [PubMed]
26. Beyda DH. Limited Intensive Care Resources: Fair is What Fair Is Current Concepts in Pediatric Critical Care by the Society of Critical Care Medicine (2015 Edition): 55-59.
27. White DB, Lo B. Mitigating Inequities and Saving Lives with ICU Triage during the COVID-19 Pandemic. Am J Respir Crit Care Med, 2021. 203(3): 287-295.

Acknowledgments

The authors would like to acknowledge ADHS as well as all of their collaborators from the Arizona hospitals and health systems including Abrazo Healthcare and Carondelet Healthcare Phoenix, Tucson & Nogales; Banner Health System; Canyon Vista Medical Center; CommonSpirit Arizona Division Dignity Health; Havasu Regional Medical Center; Honor Health; Indian Health Service; Kingman Regional Medical Center; Northern Arizona HealthCare; Phoenix Children’s Hospital; Summit Healthcare; Tucson Regional Medical Center; University of Arizona College of Medicine; Veteran’s Administration; Valleywise Health; Yavapai Regional Medical Center; Yuma Regional Medical Center.

Cite as: Mayer PA, Beyda DH, Johnston CB. Arizona Hospitals and Health Systems’ Statewide Collaboration Producing a Triage Protocol During the COVID-19 Pandemic. Southwest J Pulm Crit Care. 2021;22(6):119-26. doi: https://doi.org/10.13175/swjpcc014-21 PDF

Ultrasound for Critical Care Physicians: Sometimes It’s Better to Be Lucky than Smart

Robert A. Raschke MD and Randy Weisman MD

Critical Care Medicine

HonorHealth Scottsdale Osborn Medical Center

Scottsdale, AZ USA

We recently responded to a code arrest alert in the rehabilitation ward of our hospital. The patient was a 47-year-old man who experienced nausea and diaphoresis during physical therapy. Shortly after the therapists helped him sit down in bed, he became unconsciousness and pulseless. The initial code rhythm was a narrow-complex pulseless electrical activity (PEA). He was intubated, received three rounds of epinephrine during approximately 10 minutes of ACLS/CPR before return of spontaneous circulation (ROSC), and was subsequently transferred to the ICU.

Shortly after arriving, a 12-lead EKG was performed (Figure 1), and PEA recurred.

Figure 1. EKG performed just prior to second cardiopulmonary arrest showing S1 Q3 T3 pattern (arrows).

Approximately ten-minutes into this second episode of ACLS, a cardiology consultant informed the code team of an S1,Q3,T3 pattern on the EKG. A point-of-care (POC) echocardiogram performed during rhythm checks was technically-limited, but showed a dilated hypokinetic right ventricle (see video 1).

Video 1. Echocardiogram performed during ACLS rhythm check: Four-chamber view is poor quality, but shows massive RV dilation and systolic dysfunction.

Approximately twenty-minutes into the arrest, 50mg tissue plasminogen activator (tPA) was administered, and return of spontaneous circulation (ROSC) achieved two minutes later. A tPA infusion was started. The patient’s chart was reviewed. He had received care in our ICU previously, but this wasn’t immediately recognized because he had subsequently changed his name of record to the pseudonym “John Doe” (not the real pseduonym), creating two separate and distinct EMR records for the single current hospital stay. Review of the first of these two records, identified by his legal name, revealed he had been admitted to our ICU one month previously for a 5.4 x 3.6 x 2.9 cm left basal ganglia hemorrhage. We stopped the tPA infusion.

On further review of his original EMR is was noted that two weeks after admission for intracranial hemorrhage, (and two weeks prior to cardiopulmonary arrest), he had experienced right leg swelling and an ultrasound demonstrated extensive DVT of the right superficial femoral, saphenous, popliteal and peroneal veins. An IVC filter had been due to anticoagulant contraindication. The patient’s subsequent rehabilitation had been progressing well over the subsequent two weeks and discharge was being discussed on the day cardiopulmonary arrest occurred.

On post-arrest neurological examination, the patient gave a left-sided, thumbs-up to verbal request. Ongoing hypotension was treated with a norepinephrine infusion and inhaled epoprostenol. An emergent head CT was performed and compared to a head CT from four weeks previously (Figure 2), showing normal evolution of the previous intracranial hemorrhage without any new bleeding. 

Figure 2. CT brain four weeks prior to (Panel A), and immediately after cardiopulmonary arrest and administration of tPA (Panel B), showing substantial resolution of the previous intracranial hemorrhage.

A therapeutic-dose heparin infusion was started. An official echo confirmed the findings of our POC echo performed during the code, with the additional finding of McConnell’s sign. McConnell’s sign is a distinct echocardiographic finding described in patients with acute pulmonary embolism with regional pattern of right ventricular dysfunction, with akinesia of the mid free wall but normal motion at the apex (1). A CT angiogram showed bilateral pulmonary emboli, and interventional radiology performed bilateral thrombectomies. Hypotension resolved immediately thereafter. The patient was transferred out of the ICU a few days later and resumed his rehabilitation.

A few points of interest:

• IVC filters do not absolutely prevent life-threatening pulmonary embolism (2,3).
• Sometimes, serendipity smiles, as when the cardiologist happened into the room during the code, and provided an essential bit of information.
• Emergent POC ultrasonography is an essential tool in the management of PEA arrest of uncertain etiology.
• Barriers to access of prior medical records can lead to poorly-informed decisions. But in this case, ignorance likely helped us make the right decision.
• Giving lytic therapy one month after an intracranial hemorrhage is not absolutely contra-indicated when in dire need.
• As the late great intensivist, Jay Blum MD used to say: “Sometimes it’s better to be lucky than smart.”

References

1. Ogbonnah U, Tawil I, Wray TC, Boivin M. Ultrasound for critical care physicians: Caught in the act. Southwest J Pulm Crit Care. 2018;17(1):36-8. [CrossRef]
2. Urban MK, Jules-Elysee K, MacKenzie CR. Pulmonary embolism after IVC filter. HSS J. 2008 Feb;4(1):74-5. [CrossRef] [PubMed]
3. PREPIC Study Group. Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d'Embolie Pulmonaire par Interruption Cave) randomized study. Circulation. 2005 Jul 19;112(3):416-22. doi: [CrossRef] [PubMed]

Cite as: Raschke RA, Weisman R. Ultrasound for Critical Care Physicians: Sometimes It’s Better to Be Lucky than Smart. Southwest J Pulm Crit Care. 2021;22(6):116-8. doi: https://doi.org/10.13175/swjpcc016-21 PDF 

High Volume Plasma Exchange in Acute Liver Failure: A Brief Review

Matthew D Rockstrom, MD¹

Jonathan D Rice, MD^1,2

Tomio Tran, MD³

Anna Neumeier, MD^1,4

¹Department of Medicine, University of Colorado School of Medicine, Aurora, CO USA

²Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO USA

³Department of Medicine, Division of Cardiology, University of Washington, Seattle, WA USA

⁴Department of Medicine, Division of Pulmonary Sciences and Critical Care, Denver Health and Hospital Authority, Denver, CO USA

Abstract

Acute liver failure (ALF) is characterized by acute liver injury, coagulopathy, and altered mental status. Acetaminophen overdose contributes to almost half the cases of ALF in the United States. In the era of liver transplantation, mortality associated with this condition has improved dramatically. However, many patients are not transplant candidates including many who present with overt suicide attempt from acetaminophen overdose. High volume plasma exchange (HVP) is a novel application of plasma exchange. Prior research has shown that HVP can correct the pathophysiologic derangements underlying ALF. A randomized control trial demonstrated improved transplant-free survival when HVP was added to standard medical therapy. In this case, we examine a patient who presented to the intensive care unit with ALF caused by intentional acetaminophen overdose. She was denied transplant due to overt suicide attempt, was treated with HVP, and made a rapid recovery, eventually discharged to inpatient psychiatry and then home.

Abbreviations: ALF: acute liver failure: CVVH: continuous veno-venous hemodialysis; DAMPs: damage associated molecular patterns; FFP: fresh frozen plasma; HVP: high volume plasma exchange; MODS: multisystem organ dysfunction; NAC: N-acetyl cysteine; NNT: Number needed to treat; SIRS: systemic inflammatory response syndrome; SMT: standard medical therapy; TNF-α: tumor necrosis factor alpha

Introduction

Acute liver failure (ALF) is a rare, life-threatening condition. Although survival has improved in the transplant era, mortality remains high without transplantation. Here we discuss a novel therapy for ALF patients which may provide improved transplant-free mortality.

Case Report

A 21-year-old woman arrived by ambulance, found to be obtunded and hypotensive in the field, with an empty bottle of acetaminophen and a suicide note. She had a history of depression, infrequent alcohol and marijuana use, and was otherwise healthy.

Upon presentation, she was afebrile (temperature 36.5°C), tachycardic (heart rate 155 beats-per-minute) and hypotensive requiring norepinephrine of 0.1 μg/kg/min to maintain mean arterial blood pressure above 65.  Due to grade IV encephalopathy, she was intubated.  Admission lab work is shown below (Table 1). Viral hepatitis and HIV serologies were negative and ultrasound demonstrated patent vasculature and normal liver parenchyma.

Table 1: Lab work on admission, hospital day 2, and following high-volume plasma exchange therapy.

BUN: blood urea nitrogen, AST: aspartate aminotransferase; ALT: alanine aminotransferase; INR: international normalized ratio; APAP: N-acetyl-para-aminophenol

N-acetyl cysteine (NAC) was administered and transplant evaluation was obtained. Despite meeting King’s College Criterion for transplantation, she was declined due to presentation for suicide attempt. She was managed supportively with vasopressors, continuous veno-venous hemodialysis (CVVH), and high-volume plasma exchange (HVP) at a rate of 8 liters of fresh frozen plasma (FFP) daily, receiving 24 liters total. After initiation of HVP, vasopressors were immediately weaned. The following day, her encephalopathy improved, and she followed simple commands. CVVH was discontinued on hospital day 4. She was extubated on hospital day 6 and was eventually discharged home.

Clinical Discussion

ALF is a life-threatening syndrome characterized by acute liver injury, encephalopathy, and coagulopathy. In the United States, the most common etiology is acetaminophen overdose, accounting for ~46% of cases (1). Standard medical therapy (SMT) is supportive, treating the underlying etiology and mitigating manifestations of multisystem organ dysfunction (MODS). The advent of transplantation dramatically improved the mortality associated with ALF but the benefit of transplant must be balanced with high-risk surgery, lifelong immunosuppression, and organ scarcity (2). Given these risks, patients undergo evaluation including psychologic evaluation which commonly excludes patients presenting with intentional acetaminophen overdose. Without transplantation, mortality for these patients remains high.

The pathophysiology of ALF is not entirely understood but is largely driven by hepatic necrosis leading to hepatic metabolic dysfunction and release of intracellular contents. Intracellular damage associated molecular pattern (DAMPs) and Kupffer cell activation trigger the release of pro-inflammatory cytokines like tumor necrosis factor alpha (TNF-α), which result in systemic inflammatory response syndrome (SIRS) and vasodilation (3,4). Subsequent hepatic metabolic dysfunction is manifested by hyperbilirubinemia, hyperammonemia, coagulopathy, and hypoglycemia.

High volume plasma exchange (HVP) has shown promise as a new modality of treatment for patients with ALF. A new implementation of plasma-exchange therapy, patient plasma is exchanged with donor FFP. In one prospective, randomized control trial by Larsen et al, 15% of ideal body weight of FFP was exchanged daily for three days in addition to SMT. HVP plus SMT improved survival to discharge when compared to SMT alone (58.7 % versus 47.8%, respectively; number needed to treat (NNT) 9.2) (5). HVP plus SMT has been shown to reverse clinical parameters associated with ALF including INR, bilirubin, vasopressor requirements, reliance on renal replacement, hepatic encephalopathy (5-7). HVP was also shown to significantly attenuate DAMPs, including IL-6 and TNF-α, indicating an ability to attenuate the biochemical nidus of MODS (6,7). A systematic review of HVP found evidence of mortality benefit in HVP for both ALF and acute on chronic liver failure, though Larsen et al remains the only randomized prospective trial. Subsequently, HVP has become a level I, grade 1 recommendation in European guidelines for ALF (6).

There are limitations associated with HVP including utilization of FFP, concerns for precipitation volume overload, and worsening cerebral edema. Additionally, there is no clear optimal regimen for dose and duration of HVP. In a recent randomized control trial by Maiwall et al, standard volume plasma exchange was shown to improve transplant free survival using only 1.5 to 2 times calculated patient plasma volume (4).

Conclusion

In this case, a 21-year-old patient presented with ALF following acetaminophen overdose. Despite qualifying for transplantation, she was denied due to presentation for suicide attempt. She was treated with standard medical therapy and HVP and had rapid improvement in hemodynamics and mentation. While it is impossible to quantify the degree to which HVP contributed to her recovery, her clinical improvement was dramatic despite presentation with severe disease. HVP has been shown to reverse the pathophysiologic hallmarks of ALF, improve transplant-free mortality, and is now a level I recommendation according to European guidelines. More trials are necessary to determine the optimal dose and duration of this life saving modality.

References

1. Lee WM. Etiologies of acute liver failure. Semin Liver Dis. 2008 May;28(2):142-52. [CrossRef] [PubMed]
2. Lee WM, Squires RH Jr, Nyberg SL, Doo E, Hoofnagle JH. Acute liver failure: Summary of a workshop. Hepatology. 2008 Apr;47(4):1401-15. [CrossRef] [PubMed]
3. Chung RT, Stravitz RT, Fontana RJ, Schiodt FV, Mehal WZ, Reddy KR, Lee WM. Pathogenesis of liver injury in acute liver failure. Gastroenterology. 2012 Sep;143(3):e1-e7. [CrossRef] [PubMed]
4. Maiwall R, Bajpai M, Singh A, Agarwal T, Kumar G, Bharadwaj A, Nautiyal N, Tevethia H, Jagdish RK, Vijayaraghavan R, Choudhury A, Mathur RP, Hidam A, Pati NT, Sharma MK, Kumar A, Sarin SK. Standard-Volume Plasma Exchange Improves Outcomes in Patients With Acute Liver Failure: A Randomized Controlled Trial. Clin Gastroenterol Hepatol. 2021 Jan 29:S1542-3565(21)00086-0. [CrossRef] [PubMed]
5. Larsen FS, Schmidt LE, Bernsmeier C, et al. High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial. J Hepatol. 2016 Jan;64(1):69-78. [CrossRef] [PubMed]
6. Tan EX, Wang MX, Pang J, Lee GH. Plasma exchange in patients with acute and acute-on-chronic liver failure: A systematic review. World J Gastroenterol. 2020 Jan 14;26(2):219-245. [CrossRef] [PubMed]
7. Larsen FS, Ejlersen E, Hansen BA, Mogensen T, Tygstrup N, Secher NH. Systemic vascular resistance during high-volume plasmapheresis in patients with fulminant hepatic failure: relationship with oxygen consumption. Eur J Gastroenterol Hepatol. 1995 Sep;7(9):887-92. [PubMed]

Cite as: Rockstrom MD, Rice JD, Tran T, Neumeier A. High Volume Plasma Exchange in Acute Liver Failure: A Brief Review. Southwest J Pulm Crit Care. 2021;22(5):102-5. doi: https://doi.org/10.13175/swjpcc009-21 PDF