Left Ventricular Assist Devices: A Brief Overview

Bhargavi Gali MD

Department of Anesthesiology and Perioperative Medicine

Division of Critical Care Medicine

Mayo Clinic Minnesota

Rochester, MN, USA

Introduction

Second and third generation left ventricular assist devices (LVAD) have been increasingly utilized as both a bridge to transplantation and as destination therapy (in patients who are not considered transplant candidates) for advanced heart failure. Currently approximately 2500 LVADs are implanted yearly, with an estimated one year survival of >80% (1). Almost half of these patients undergo implantation as destination therapy. A recent systematic review and meta-analysis found no difference in one-year mortality between patients undergoing heart transplantation in comparison with patients undergoing LVAD placement (2).

Early LVADs were pulsatile pumps, but had multiple limitations including duration of device function, and requirement for a large external lead that increased risk of infection. Currently utilized second and third generation devices are continuous flow (first generation were pulsatile flow). Second generation devices have axial pumps (HeartMate II®). The third generation LVADs ((HeartMate III®), HVAD®) are also continuous flow, with centrifugal pumps, which are thought to decrease possibility of thrombus formation and increase pump duration in comparison to the second generation axial pumps. It is also felt that a lack of mechanical bearings contributes to this effect.

LVADs support circulation by either replacing or supplementing cardiac output. Blood is drained from the left ventricle with inflow cannula in the left ventricular apex to the pump, and blood is returned to the ascending aorta via the outflow cannula (3) (Figure 1).

Figure 1. Third generation Left Ventricular Assist Device. Heartware System ™. Continuous flow left ventricular assist device (LVAD) configuration. One of the third generation LVADs is the HeartWare System. With this device the inflow cannula is integrated into the pump. The pump is attached to the heart in the pericardial space, with the outflow cannula in the aorta. A driveline connects the device to the control unit. This control unit is attached to the two batteries. (Figure used with permission from Medtronic).

The device assists the left ventricle by the action of the axial (second generation) or centrifugal (third generation) pump that rotates at a very high speed and ejects the blood into the aorta via the outflow cannula. A tunneled driveline connects the pump to the external controller that operates the pump function. The controller connects to the power source via two cables, which can be battery or module-powered.

LVADs offload volume from the left ventricle, and decrease left ventricular work. Pulmonary pressures and the trans pulmonary gradients are also decreased by the reduced volume in the left ventricle (4). End organ perfusion is improved secondary to enhanced arterial blood pressure and micro perfusion.

There are four main parameters of pump function:

• Pump speed: the speed at which the LVAD rotors spin, and is programmed. Measured in RPM.
• Pump power: the wattage needed to maintain speed and flow, which is the energy needed to run the pump. Measured in Watts.
• Pump flow: estimate of the cardiac output, which is the blood returned to the ascending aorta, and is based on pump speed and power. Measure in L/min
• Pulsatility index (PI): a calculated value that indicates assistance the pump provides, in relation to intrinsic left ventricular A higher number indicates higher left ventricular contribution to pulsatile flow.

The cardiac output of currently utilized LVADs is directly related to pump speed and inversely related to the pressure gradient across the pump. As the pump speed is fixed, right ventricular failure can decrease the volume of blood transmitted to the pump and decrease LVAD flow (3, 4). With right ventricular failure, inotropic support may be needed to improve the LVAD pump flow. High afterload, such as may be seen with an increase in systemic vascular resistance can decrease pump flow.

Complications

Adverse events occur in more than 70% of LVAD patients in the first year (5). These complications include infections, bleeding, stroke, and LVAD thrombosis. More than 50% of patients are readmitted within the first 6 months after LVAD implantation (6).

Driveline infections are the most commonly reported LVAD infection, and are the most likely to respond to treatment (7). Pump pocket infections may require debridement plus/minus antibiotic bead placement. Bloodstream infections are less commonly reported, and more difficult to treat, and many patients are placed on chronic suppressive antibiotic therapy (7). There is a possible association between stroke and bloodstream infection, reported in some studies. Patients who were younger and had a higher body mass index were noted to have a higher incidence of LVAD infections.

Gastrointestinal bleeding is a major cause of nonsurgical bleeding, reported in almost 30% of patients after LVAD placement (1). Patients may develop acquired von Willebrand factor deficiency secondary to high shear forces in the LVAD that lead to breakdown of von Willebrand protein (6). Antithrombotic therapy is commonly instituted after LVAD implantation which also increases risk of bleeding. A high incidence of arteriovenous malformations is reported in these patients, although the etiology is not clear. Transfusion, holding antithrombotic therapy, and identifying possible sources are included in the standard approach to management.

There is a high risk of both ischemic and hemorrhagic strokes in the first year after LVAD placement (8). Surgical closure of the aortic valve and off-axis positioning of the cannulas have been suggested as altering shear forces, increasing thrombotic risk, and thus risk of stroke.  Post-surgical risks may include pump thrombosis, infections, supratherapeutic INR, and poorly controlled hypertension. Early diagnosis has led to consideration of interventions such as thrombectomy (8).

LVAD thrombosis can occur on either cannula (inflow or outflow) or the pump. Typically patients receive ongoing anticoagulation, commonly with warfarin, and antiplatelet agents, and often aspirin. Heartmate II® may have higher rate of thrombosis than HVAD or Heart Mate 3, although this is under debate (6). Thrombotic complications range in severity from asymptomatic increase in lactate dehydrogenase or plasma-free hemoglobin, to triggering of LVAD alarms, up to development of heart failure. The inflow and outflow cannulas and pump can be the site of thrombosis. Management typically involves revising the antithrombotic management. If there is no improvement or worsening, replacement of LVAD may be indicated. There is limited evidence to suggest that systemic thrombolysis may be of benefit in treating pump thrombosis, particularly in regards to the HVAD, though better data would be useful

Procedural Management

When a patient with an LVAD requires non cardiac surgery, optimal management includes having an on-site VAD technician, and close involvement of VAD cardiology and cardiac surgery in consultation. Anticoagulation will often be transitioned to heparin infusion prior to elective procedures (9). Suction events (LV wall is sucked into the inflow cannula) can occur secondary to under filled left heart, and this can become more apparent perioperatively. This can also decrease right heart contractility by moving the interventricular septum to the left, and thus decrease cardiac output. Management often involves fluid bolus. Suction events can lead to decreased flow, left ventricular damage, and ventricular arrhythmias. Hemodynamic management can be challenging with non-pulsatile flow, and placement of an arterial line can facilitate optimal management. Postoperative care in a monitored setting is beneficial in case of further volume related events and to watch for bleeding.

Emergent Complications

Arrhythmias occur in many patients after LVAD implantation. Atrial arrhythmias are reported in up to half of LVAD patients, and ventricular arrhythmias in 22-59% (10, 11).  Loss of AV synchrony can lead to decreased LV filling and subsequent RV failure. Rhythm or rate control with rapid atrial arrhythmias is necessary to decrease development of heart failure. Ventricular arrhythmias may be hemodynamically tolerated for some time secondary to the LVAD support (6).  If there is concern that the inflow cannula is touching the LV septum, as may occur with severe hypovolemia, echocardiography can help determine if volume resuscitation should be the initial step in treating ventricular arrhythmia.

If cardiac arrest occurs, the first step of cardiopulmonary resuscitation in patients with LVAD is assessment of appropriate perfusion via physical examination (12). If perfusion is poor or absent, assessment of LVAD function should take place. If the LVAD is not functioning appropriately, checking for connections and power is the next step. If unable to confirm function or restart LVAD, chest compressions are indicated by most recent guidelines from the American Heart Association. There is always concern of dislodgement of LVAD cannula or bleeding during these situations.

Conclusion

Currently implanted LVADS are continuous flow, and provide support via a parallel path from the left ventricle to the aorta. As the number of patients with LVADs increase all medical providers should have a basic understanding of the function and common complications associated with these devices. This will enhance the ability to initiate appropriate care.

References

1. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. J Heart Lung Transplant. 2017 Oct;36(10):1080-6. [CrossRef] [PubMed]
2. Theochari CA, Michalopoulos G, Oikonomou EK, et al. Heart transplantation versus left ventricular assist devices as destination therapy or bridge to transplantation for 1-year mortality: a systematic review and meta-analysis. Annals of Cardiothoracic Surgery. 2017;7(1):3-11. [CrossRef] [PubMed]
3. Lim HS, Howell N, Ranasinghe A. The physiology of continuous-flow left ventricular assist devices. J Card Fail. 2017;23(2):169-80. [CrossRef] [PubMed]
4. Roberts SM, Hovord DG, Kodavatiganti R, Sathishkumar S. Ventricular assist devices and non-cardiac surgery. BMC Anesthesiology. 2015;15(1):185. [CrossRef] [PubMed]
5. Miller LW, Rogers JG. Evolution of left ventricular assist device therapy for advanced heart failure: a review. JAMA Cardiol. 2018 Jul 1;3(7):650-8. [CrossRef] [PubMed]
6. DeVore AD, Patel PA, Patel CB. Medical management of patients with a left ventricular assist device for the non-left ventricular assist device specialist. JACC Heart Fail. 2017 Sep;5(9):621-31. [CrossRef] [PubMed]
7. O'Horo JC, Abu Saleh OM, Stulak JM, Wilhelm MP, Baddour LM, Rizwan Sohail M. Left ventricular assist device infections: a systematic review. ASAIO J. 2018 May/Jun;64(3):287-294. [CrossRef] [PubMed]
8. Goodwin K, Kluis A, Alexy T, John R, Voeller R. Neurological complications associated with left ventricular assist device therapy. pert Rev Cardiovasc Ther. 2018 Dec;16(12):909-17. [CrossRef] [PubMed]
9. Barbara DW, Wetzel DR, Pulido JN, et al. The perioperative management of patients with left ventricular assist devices undergoing noncardiac surgery. Mayo Clinic Proceedings. 2013;88(7):674-82. [CrossRef] [PubMed]
10. Enriquez AD, Calenda B, Gandhi PU, Nair AP, Anyanwu AC, Pinney SP. Clinical impact of atrial fibrillation in patients with the heartmate ii left ventricular assist device. J Am Coll Cardiol. 2014 Nov 4;64(18):1883-90. [CrossRef] [PubMed]
11. Nakahara S, Chien C, Gelow J, et al. Ventricular arrhythmias after left ventricular assist device. Circ Arrhythm Electrophysiol. 2013 Jun;6(3):648-54. [CrossRef] [PubMed]
12. Peberdy MA, Gluck JA, Ornato JP, et al. Cardiopulmonary resuscitation in adults and children with mechanical circulatory support: a scientific statement from the American Heart Association. Circulation. 2017;135(24):e1115-e34.`[CrossRef] [PubMed]

Cite as: Gali B. Left ventricular assist devices: a brief overview. Southwest J Pulm Crit Care. 2019;19(2):68-72. doi: https://doi.org/10.13175/swjpcc039-19 PDF 

July 2019 Critical Care Case of The Month: An 18-Year-Old with Presumed Sepsis and Progressive Multisystem Organ Failure

Robert A. Raschke, MD

The University of Arizona College of Medicine – Phoenix

Phoenix, AZ USA

History of Present Illness

An 18-year-old female student from Flagstaff was transferred to our hospital for refractory sepsis. She had presented with a 2 week history of fever, malaise, sore throat, myalgias, arthralgias and a rash.

PMH, SH and FH

She reported no significant past medical history or family history. She attended cosmetology school, denied smoking or drug abuse and was sexually monogamous. She had only traveled in-state, did not hike or camp and her only animal exposure was playing with her two pet Great Danes.

Physical Examination

The patient had a fever of 38.5°C. on original presentation. HEENT exam was reported as unrevealing. Lungs were clear. There were no heart murmurs and the abdominal exam was unremarkable. No joint effusions were apparent. A rash was mentioned, but not described and it apparently disappeared shortly after admission.

Initial laboratory testing was significant for WBCC of 12.1 K/mm3, creatinine of 1.5 mg/dL and AST of 45 IU/L. A rapid influenza screen, urinalysis and chest radiography were unrevealing. Blood cultures were drawn and intravenous fluids, piperacillin/tazobactam and azithromycin were administered. Over the next four days, the fever persisted and the blood cultures resulted in no growth. Serial laboratory values demonstrated progressive worsening in renal function and increasing hepatic enzymes. The patient became dyspneic and developed rales and progressive hypoxia prompting transfer.

On arrival in our ICU, the patient was alert, in mild respiratory distress and hypotensive to 78/43 mmHg, requiring immediate initiation of intravenous norepinephrine. She reported nausea and severe diffuse myalgia and arthralgia. On examination, she was ill-appearing with blood pressure 101/58 (on norepinephrine at 25 mcg/min), heart rate 104 beats/min, respiratory rate 33 breaths/min, temperature 38.8°C. She had mild oropharyngeal erythema, some shotty cervical lymph nodes, bilateral rales, mild epigastric and right upper quadrant tenderness, and a macular erythematous rash approximately 14 x 29 cm on her left forearm that disappeared within several hours.

Her ICU admission chest x-ray is shown in Figure 1.

Figure 1. Admission ICU portable chest X-ray showing bilateral areas of consolidation.

Her laboratory evaluation showed the following:

• WBCC: 2,500/mm³ 63% segs with toxic granulation/vacuolated segs
• Hemoglobin/Hematocrit: 7.9 g/dL/26.7%
• Platelets: 50,000/mm³
• BUN/creatinine: 23/1.25 mg/dL
• AST/ALT: 246/189 IU/L (normal 10-40 and 7-56)
• PT: 20.9 sec
• Lactate: 4.5 mmol/L
• Urinalysis: bland sediment, without bacteria or leukocytes
• ABG: 7.33, pCO2 34, pO2 78 (on 45% FiO2 by ventimask)
• Transthoracic echocardiogram showed normal LV and RV size and systolic function with no vegetations
• US abdomen showed hepatosplenomegaly, retroperitoneal lymphadenopathy, and normal kidneys and ureters.

What are diagnostic considerations at this time?  (Click on the correct answer to be directed to the second of six pages)

1. Rocky mountain spotted fever (RMSF)
2. Acute retroviral syndrome
3. Still’s disease
4. Systemic lupus erythematosus (SLE)
5. All of the above

Cite as: Raschke RA. July 2019 critical care case of the month: an 18-year-old with presumed sepsis and progressive multisystem organ failure. Southwest J Pulm Crit Care. 2019;19(1):1-9. doi: https://doi.org/10.13175/swjpcc043-19 PDF 

An Observational Study Demonstrating the Efficacy of Interleukin-1 Antagonist (Anakinra) in Critically-ill Patients with Hemophagocytic Lymphohistiocytosis

Kyle Henry MD, Banner University Medical Center

Robert Raschke MD, University of Arizona College of Medicine-Phoenix

Phoenix, AZ USA

Abstract

Secondary Hhmophagocytic lymphohistiocytosis (HLH) is an underrecognized cause of multisystem organ failure (MSOF) in critically ill adults, associated with high mortality even when recommended etoposide-based treatments are administered.  Anakinra, an interleukin-1 receptor antagonist, has shown promise in treating children with HLH. This retrospective case series describes seven adult patients who presented to our ICU with a unremitting syndrome consistent with sepsis / MSOF, who were subsequently diagnosed with secondary HLH and received anakinra.   Five of seven (71%) survived.  Two non-survivors died secondary to opportunistic fungal infections. Our study contributes to mounting observational evidence regarding anakinra’s possible efficacy in critically ill adults with HLH, and also raises awareness of possible infectious complications of its use. 

Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by immune dysregulation, hypercytokinemia and tissue infiltration by activated cytotoxic lymphocytes and macrophages (1-3). Primary HLH is a familial syndrome in which gene mutations causing abnormalities of cytotoxic T-lymphocyte and natural killer (NK) cell function result in a systemic hyperinflammatory state. Primary HLH typically presents in the first years of life, progressing to multisystem organ failure (MSOF) and death unless successfully treated with chemotherapy and bone marrow transplantation. Secondary HLH shares clinical features with primary HLH but typically occurs later in life after an underlying illness triggers a dysregulated inflammatory response (3, 4). The diagnosis of primary or secondary HLH is made when five of eight criteria proposed by the International Histiocyte Society are met (Table 1) (5). Heterogeneous groups of patients may satisfy HLH diagnostic criteria, including those in whom HLH is triggered by sepsis, malignancy, and rheumatologic disease (4). Macrophage Activation Syndrome (MAS) is a specific HLH subcategory describing those patients with secondary HLH due to underlying rheumatologic disease (2). The clinical course of secondary HLH is highly variable, progressing relatively slowly in some patients in whom a diagnosis may be made in an outpatient oncology or rheumatology clinic (2, 4, 6-9). Other patients deteriorate rapidly and may require ICU care before the diagnosis of HLH is suspected (3). It has been increasingly recognized that subgroups of patients with HLH have distinctive clinical features, and require special treatment considerations (1, 3-5, 10).

One distinct subgroup consists of adults who present to the intensive care unit (ICU) with sepsis syndrome and MSOF with progressive deterioration despite standard therapy for sepsis (3). Life threatening manifestations in such patients suspected of experiencing HLH may force consideration of presumptive immunotherapy before all HLH diagnostic tests have resulted. Infectious and/or rheumatologic triggers for secondary HLH are eventually found in many, but a clear distinction between sepsis and HLH cannot be made in some (3, 4, 10, 11). The standard treatment protocol for HLH incorporates etoposide – a myelosuppressive chemotherapy agent generally regarded as the standard of care, but has known serious side effects, especially in the setting of hepatic or renal dysfunction typical of sepsis (5, 12). Furthermore, etoposide-based HLH treatment may cause severe immunosuppression leading to opportunistic infections. The mortality of secondary HLH in the adult ICU exceeds 50% (13-16) regardless of the underlying catalyst for the hypercytokinemia. New therapeutic options are desperately needed.

Mounting observational evidence suggests that Anakinra, a recombinant interleukin-1 receptor antagonist (IL-1Ra), may have promise in the treatment of HLH (6,17). Naturally-occurring IL-1Ra is secreted by immune cells to inhibit the pro-inflammatory effects of interleukin 1β (IL-1β) – a key cytokine in the pathogenesis of sepsis and HLH (7, 18). Anakinra was originally developed as a potential therapy for sepsis (7), but is now FDA-approved for use in rheumatoid arthritis. A single case-series describes the successful use of anakinra in critically-ill children with secondary HLH and a few case reports describe its use in critically-ill adults (6, 8, 19, 20). More recently, Wohlfarth and colleagues showed that anakinra is a reasonable option for critically ill patients adults with HLH.  At the same time Wohlfarth et al were studying these effects in an Austrian population, we demonstrated similar results in a series of adult patients in the United States who presented to the ICU with sepsis syndrome and underwent treatment with anakinra for secondary HLH.

Methods

This retrospective study was approved by our institutional review board. The setting was the medical and surgical ICU at Banner-University Medical Center Phoenix – a 72-bed ICU in a 650-bed academic tertiary referral center. We identified consecutive adult patients at least 18 years old admitted with sepsis syndrome (known or suspected infection plus acute organ system dysfunction) (21) who subsequently met five or more HLH-2004 diagnostic criteria (Table 1) and received anakinra as part of their treatment regimen between May 2013 and May 2016.

Table 1. HLH-2004 Diagnostic Criteria for Secondary HLH: At least five of eight criteria needed for diagnosis.

Clinical management of patients was not strictly protocolized, but care was provided by an academic 24/7 on-site intensivist service with strong internal consensus regarding the management of HLH. All patients had at least daily complete blood counts and basic metabolic panels. In our practice, diagnostic workup for HLH generally commences upon recognition of unremitting sepsis syndrome with MSOF and bicytopenia. Such patients underwent workup for sepsis and potential causes of secondary HLH that included at minimum: blood cultures, ferritin, fibrinogen, triglycerides, bone marrow aspiration and biopsy, PCR and/or serological testing for systemic lupus erythematosus (SLE), Epstein-Barr virus (EBV), cytomegalovirus, herpes simplex virus, human immunodeficiency virus, hepatitis viruses and coccidioidomycosis (a mycosis endemic in the region). The decision to start HLH therapy was typically based on clinical suspicion plus consistent preliminary laboratory results such as hyperferritinemia, hypofibrinogenemia and/or hypertriglyceridemia, while awaiting the complete results of bone marrow aspiration/biopsy and send-out tests such as soluble interleukin-1 receptor and NK cell functional assays. Presumptive treatment of HLH began with corticosteroids - typically intravenous dexamethasone 10mg/m² daily. Additional therapies were added at the discretion of the intensivist with consideration of the rapidity of clinical deterioration and likely intolerance of some therapies due to kidney, liver, and/or bone marrow failure. Choice of HLH therapies was based on the HLH-1994 therapy protocol, and influenced by our prior unfavorable experience with etoposide (discussed in conclusions) and recognition of observational literature suggesting that anakinra might be efficacious in patients with secondary HLH. Anakinra was typically given in a dose of 100mg subcutaneously daily, except in patients with creatinine clearance <30ml/min who were dosed every other day.

We retrospectively performed chart reviews to abstract demographics and clinical features related to sepsis and MSOF including infections present on admission, mental status, acute respiratory failure requiring mechanical ventilation, acute renal failure requiring hemodialysis, shock requiring intravenous vasopressors, and liver injury (defined as total bilirubin >2 mg/dL and aminotransferase greater than two times upper limit of normal) (22). The sequential organ failure assessment (SOFA) score was calculated for each patient (21). HLH-2004 diagnostic criteria and the underlying disease process thought to have triggered HLH were abstracted. We documented all treatments including antibiotics and immunosuppressive therapy for HLH, including the dose and duration of anakinra. Outcomes included survival to hospital discharge, duration of fever, mechanical ventilation and renal replacement therapy and ICU length of stay indexed to the time anakinra commenced. Infectious complications occurring during admission after HLH therapy started were also documented. Simple descriptive statistics were performed.

The H Score for each patient was also calculated retrospectively. The H Score is a score used to estimate an individual's risk for having secondary HLH and was recently validated in a 147 patient cohort by Debaugnies et al. (23).

Results

Seven patients were treated with anakinra for a diagnosis of secondary HLH in our ICU between May 2013 and May 2016. Patient ages ranged from 22-59 years – three were female. All patients initially presented to our ICU with a febrile illness consistent with sepsis and received broad-spectrum intravenous antibiotics. Microbiological testing eventually documented infections in two patients – due to influenza A and EBV, respectively. All patients were encephalopathic, five required mechanical ventilation, four required hemodialysis due to acute renal failure, four had liver injury and three required vasopressors due to shock (Table 2).

Table 2. Patient characteristics and some clinical outcomes.

The median SOFA score was 13 (range: 3-17) predicted poor outcome for the group overall (13-16). H Scores for this cohort ranged from 122-263.  HLH diagnostic criteria and presumed etiologies are listed in Table 3.

Table 3. Suspected etiology and positive HLH-2004 diagnostic criteria for secondary HLH in patients treated with anakinra: Five of eight criteria required to diagnose HLH.

Two patients were known to have SLE prior to ICU admission and four others were subsequently diagnosed with underlying autoimmune diseases demonstrating a preponderance of MAS in this cohort.  

All patients initially received corticosteroids (dexamethasone 10mg/m² or methylprednisolone >500mg every 12 hours) followed by anakinra. Three patients also received cyclosporine, three underwent plasmapheresis and two received IVIG. Only one patient received etoposide and this was later transitioned to anakinra due to lack of response. Anakinra was started a median of seven days after ICU admission (range 2-58 days). All patients received anakinra 100mg daily, but Q48 hour dosing was used temporarily in five patients who transiently experienced creatinine clearances <30mL/min. Duration of anakinra therapy was 10-159 days - we were unable to determine duration of anakinra after discharge in one patient.

All patients appeared to clinically improve after initiation of anakinra. Of six patients experiencing fever at the time anakinra was started, five defervesced within 24 hours. In five patients that had follow-up ferritin levels within two weeks of starting anakinra, ferritin fell from a median of 7,371 ng/L (range 2,217->40,000) to 4,535 ng/L (range 2,137-26,634). Five of seven patients (71%) survived to hospital discharge with an ICU length of stay (LOS) ranging from 6-17 days and an overall LOS of 17-103 days. Once anakinra was started, liberation from the ventilator occurred within 1-3 days, transfer out of the ICU within 3-5 days, discharge from the hospital within 10-32 days and discontinuation of hemodialysis within 10-44 days.

Death in both non-survivors was due to opportunistic fungal infections - necrotizing pulmonary aspergillosis and disseminated mucormycosis (which occurred despite prophylaxis with amphotericin B).  Three other secondary infections all occurred in a single survivor: methicillin-sensitive S. aureus and E coli bacterial ventilator-associated pneumonias and C. difficile colitis all of which responded favorably to treatment while anakinra was continued.

Discussion

Secondary HLH may be more common in the ICU than previously recognized (3), overlapping with and at times indistinguishable from sepsis (3, 4, 10, 11). Rapid clinical deterioration in patients with suspected HLH may force treatment decisions to be made before full diagnostic test results are available. The risk of myelosuppression due to etoposide-based HLH treatment regimens may be intolerable in critically-ill, possibly septic patients with MSOF (4, 12). A therapeutic agent with a more HLH-specific mechanism of action and better safety profile is badly needed.

Anakinra is a recombinant IL-1Ra originally investigated as a potential immune-modulatory treatment for sepsis (7). Phase I and II studies established acceptable safety for further study in sepsis, but a phase III trial failed to demonstrate an overall survival benefit (7). A post-hoc analysis of data from this trial showed that septic patients with hepatobiliary dysfunction, hypofibrinogenemia and thrombocytopenia, such as often seen in secondary HLH, had significantly improved survival if they received anakinra vs placebo (65% vs. 35% 28-day survival, p=0.0007) (7). Anakinra was later approved for use in rheumatoid arthritis (18). Observational studies suggested efficacy in adult onset Still’s disease and systemic juvenile arthritis (9, 24, 25) and in non-critically-ill patients with secondary HLH triggered by these rheumatologic diseases (9, 25, 26). Case reports described the use of anakinra in critically-ill children with secondary HLH (25, 26, 27) and Rajasekaran and colleagues published a case series describing their experience using anakinra in eight critically-ill pediatric patients with secondary HLH/sepsis syndrome (6). All eight patients survived their initial illness, and no infectious complications were attributed to anakinra.

Fourteen cases describing the use of anakinra in adults with secondary HLH have previously been published (6, 8 ,17, 19, 20, 28).  Four were due to infections (EBV, CMV, MAC, histoplasmosis, four to autoimmune disease (two with AOSD, SLE antisynthetase syndrome), two post transplantation immunosuppression, one due to acute lymphocytic leukemia and three of unknown trigger.  Twelve of 15 (80%) required life support (mechanical ventilation, hemodialysis, vasopressors).  All but two received corticosteroids and just over half IVIg.  Overall survival was 67%, and no complications of immunosuppression were reported. 

The mechanism by which anakinra might ameliorate secondary HLH is not fully elucidated. Secondary HLH (and some forms of sepsis) are characterized by high levels of circulating cytokines including interleukin-6 (IL-6), tumor necrosis factor and interferon-gamma (IFN-γ) (2, 4, 7, 18, 29) - constituting what some have called a “cytokine storm”. Many investigators believe that hypercytokinemia is pathogenic in HLH. Renal failure, cytopenia, coagulopathy and cholestasis have been associated with elevated levels of IL-6 and IFN-γ (2, 18, 28). IL-1β activates lymphocytes responsible for production of these same cytokines (2, 7, 18, 28). IL-1Ra is a competitive inhibitor of IL-1β (7, 29). Therefore IL-1 receptor antagonism by anakinra might inhibit the maladaptive hypercytokinemia characteristic of secondary HLH. This brief explanation oversimplifies a complex and poorly-understood process that requires much further research.

The observed survival rate in our adult patients treated with anakinra (71%) appears favorable compared to that described in other comparable groups of patients (13-16) with survival rates ranging from 25-41%, although we cannot definitively attribute this to treatment effect. It is notable that the majority of our patients had MAS, which has a improved prognosis compared to other forms of HLH when it presents in the outpatient setting, but similar high mortality once the patient develops MSOF and requires intensive care (13-16). This finding supports the concept that secondary HLH of any cause is related to a cytokine storm universal to all underlying catalysts, and that after a critical point the inflammatory cascade becomes increasingly difficult to reverse.

We have previously diagnosed and treated a total of 29 cases of secondary HLH in our ICU. Survival among 22 patients who did not receive anakinra was 14%. This group included eight patients who received etoposide, all of whom died or developed severe neutropenia (WBC <0.5 X 10⁹/L) within a week of its initiation. The patient who survived etoposide did so after her regimen transitioned to anakinra. Statistical comparison of patients in our practice who did or did not receive anakinra was not undertaken due to potential bias and confounding. Controlled prospective trials are required to determine whether anakinra will improve survival of patients with secondary HLH. One such trial is currently under way (ClinicalTrials.gov Identifier: NCT02780583) specifically in regards to MAS.

Two of our patients died from opportunistic fungal infections. Fatal fungal infections have previously been reported to occur in patients receiving treatment for HLH who did not receive anakinra (28) and are likely a result of multiple risk factors including the underlying immune dysregulation associated with HLH, other immunosuppressive therapies and invasive procedures related to ICU care (30, 31), and therefore these infections cannot be specifically attributed to anakinra. We consider prophylactic posaconazole or amphotericin therapy in selected ICU patients at high risk for fungal infections given the evidence of invasive fungal infection prophylaxis including mucormycosis in similarly immunocompromised patients (30, 31). 

Conclusions

Our study contributes to mounting observational evidence supporting the hypothesis that anakinra may be efficacious in adult patients presenting to the ICU with life-threatening secondary HLH.  In our opinion, it can be considered as first line therapy, in combination with corticosteroids and IVIg, in selected patients for whom renal, hepatic and bone marrow dysfunction put them at higher risk of toxicity due to etoposide.  Vigilance is warranted in relation to opportunistic infections, particularly those due to fungi.  Prospective controlled trails are needed to definitively establish effective therapy of HLH. 

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17. Wohlfarth P, Agis H, Gualdoni GA, et al. Interleukin I receptor antagonist anakinra, intervenous immunoglobulin, and corticosteroids in the management of critically ill adult patients with hemophagocytic lymphohistiocytosis. J Intensive Care Med. 2017 Jan 1:885066617711386. [CrossRef] [PubMed]
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Cite as: Henry K, Raschke RA. An observational study demonstrating the efficacy of interleukin-1 antagonist (anakinra) in critically-ill patients with hemophagocytic lymphohistiocytosis. Southwest J Pulm Crit Care. 2019;18(6):177-86. doi: https://doi.org/10.13175/swjpcc034-19 PDF 

Editor's Note: The July 2019 Critical Care Case of the Month is a case presentation of HLH with 0.5 Hour CME credit. Click on the link to be directed to the case.

Which Half Are You? Almost Half of Pediatric Oncologists and Intensivists Are Burnt Out……

K. Sarah Hoehn, MD, MBe¹

Manjusha Abraham, MD²

John Gaughan, PhD³

Brigham C. Willis, MD⁴

¹Department of Pediatric Critical Care, University of Chicago Comer Children’s Hospital, Chicago IL

²Department of Pediatrics, Section of Critical Care, St. Mary’s Hospital, St Louis MO

³Biostatistics Consulting Center, Temple University School of Medicine, Philadelphia, PA

⁴Division of Cardiovascular Intensive Care, Department of Child Health, University of Arizona College of Medicine – Phoenix and Phoenix Children’s Hospital, Phoenix, AZ

Abstract

Objective: To study the prevalence of burnout, secondary traumatic stress, and wellbeing among pediatric critical care and pediatric hematology and oncology physicians 

Design: Observational cohort study

Setting: Online survey

Patients: Active American Academy of Pediatrics (AAP) members of the section of critical care and the section of hematology and oncology

Interventions: Surveys containing three validated instruments (the Maslach Burnout Inventory, the secondary traumatic stress scale and the Personal Wellbeing Index, as well as questions on demographics and lifestyle) were emailed out via the AAP.

Measurements and Main Results: We had 231 respondents with a response rate of 15.8% among PICU physicians and 26.1% among hematology-oncology physicians. 45.9% of our participants consisted of hematology-oncology physicians and 54.1% of pediatric critical care physicians. The population was a balanced gender mix but was predominantly Caucasian (82% Caucasian and 10% Asian). The overall rate of burnout was 46.6% (47.8% among hematology-oncology physicians and 45.8% among pediatric intensivists). We found significant rates of emotional exhaustion, with 43.0% of respondents scoring high on this subscale.

The prevalence of secondary traumatic stress was 46.8% (42.5% among hematology-oncology physicians and 50.9% among pediatric intensivists). Physicians in practice over 10 to 15 years had significantly higher rates of secondary traumatic stress (p < 0.05). No other demographic or lifestyle variable was significantly associated with an increased risk of burnout or secondary traumatic stress.

Conclusion: Our study reports concerning rates of burnout and secondary traumatic stress among pediatricians in the specialties of Hematology/Oncology and Pediatric Critical Care Medicine. The results raise concern for better screening and prevention for burnout in these high risk specialties. Promoting recognition of early symptoms is crucial, as well as creating a work environment that promotes mental health.

Background

For millennia, physicians have promised to take care of patients to the best of our abilities. In doing so, physicians make personal sacrifices and face challenging situations, including significant administrative burdens of the electronic medical record; all of which may contribute to burnout (1). This led to the AMA supporting a Charter of Physician Well Being, highlighting the importance of building resilience among physicians (2). The topic of physician burnout as one of the leading stories in 2017 (3). Physicians have a have a higher rate of burnout compared to US workers in other fields (4). Burnout has been defined as “a syndrome of emotional exhaustion and cynicism that occurs frequently among individuals who do ‘people-work’ of some kind” (5). Burnout syndrome has 3 key dimensions: emotional exhaustion, depersonalization and lack of personal accomplishment. These problems can affect not only physicians themselves but also patient care. Studies show that burnout is more common among physicians who are 11-20 years in practice (6). A German study suggests that female senior physicians having children are at the greatest risk for burnout (7).  

Along with burnout, physicians may face post-traumatic stress. It has become increasingly more evident that trauma does not only affect the individual(s) directly involved, but also others around them, including healthcare workers. Thus, the concept of secondary traumatic stress has been defined. Secondary traumatic stress (STS) is defined as “the natural, consequent behaviors and emotions resulting from knowledge about a traumatizing event experienced by a significant other. It is the stress resulting from helping or wanting to help a traumatized or suffering person” (8). STS has been studied in a variety of caregiving populations, including social workers, nurses, chaplains, and child life specialists, but there is only limited to no data on STS among pediatric physicians (9-12).

In studying the prevalence of burnout and secondary traumatic stress among physicians, we would be remiss not to also assess the overall wellbeing of these individuals. Wellbeing is defined as “a relative state where one maximizes his or her physical, mental, and social functioning in the context of supportive environments to live a full, satisfying, and productive life”.  The measurement of wellbeing in all Americans is a Healthy People 2020 objective (13).

We used standardized instruments to assess the prevalence of burnout, the prevalence of secondary post-traumatic stress, and the overall wellbeing of high-risk pediatric physicians. We hypothesized that pediatric critical care physicians and pediatric hematology/oncology physicians would have similarly high rates of burnout, STS and adverse effects on overall wellbeing.

Methods

The study was reviewed and approved by the Institutional Review Board of Kansas University Medical Center via expedited review. Four questionnaires (Maslach Burnout Scale, Secondary Traumatic Stress, Personal Wellbeing Index, demographic survey) were emailed to the section of critical care medicine and the section on pediatric hematology and oncology of the American Academy of Pediatrics. Reminders to complete the surveys were sent out at 4 and 6 weeks after the initial email. No identifiable data was recorded.

Maslach Burnout Inventory (MBI)

The Maslach Burnout Inventory (MBI) was developed to study burnout syndrome, and has 3 sub scales focusing on the areas of emotional exhaustion (EE), depersonalization (DP) and personal accomplishment (PA). It consists of 22 items on a questionnaire that uses a six point Likert scale (Appendix 1). A high degree of burnout is reflected by high scores on the emotional exhaustion and depersonalization scale in addition to low scores on the personal accomplishment scale. The MBI has been shown to have coefficient alpha between 0.70 to 0.80 in 84 different studies that used the MBI to assess burnout, indicating that the MBI has good internal consistency in low stakes testing (14). Since its initial publication in 1980, the MBI has been shown to adequately assess the presence or absence of burnout in a variety of physician groups (15-19). In our study we defined burnout as the presence of at least one of the following: EE ≥ 37 or DP ≥ 13 or PA < 31 (15).

Secondary Traumatic Stress Scale (STSS)

The Secondary Traumatic Stress Scale (STSS) was developed by Bride and colleagues (20) by using the seventeen symptoms of post traumatic stress disorder from the DSM-IV, and has seventeen items that are answered using a five point Likert type scale. It has been found to have an overall coefficient alpha of 0.94. There are three subscales and each subscale has a coefficient alpha as well: intrusion, 0.80; avoidance, 0.87; arousal 0.79.

Personal Wellbeing Index (PWI)

The Personal Wellbeing Index (PWI) scale contains 7 questions, each one addressing a quality of life domain: standard of living, achieving in life, health, relationships, safety, community-connectedness, and future security. In regards to reliability, the Cornbach alpha lies between 0.70 and 0.85 in Australia and overseas and the index has shown good test-retest reliability with an intra-class correlation coefficient of 0.84 (21).

Demographic Survey

The demographic questionnaire is a self-constructed survey with common factors (years in practice, hours of sleep at night, hours of exercise per week, healthy diet, marital status, number of children, religion) that can be associated as a risk versus protective factors for burnout, secondary traumatic stress and overall wellbeing. Each factor had a comment section for qualitative analysis.

Data Analysis

Variables measured on a continuous scale are presented as means with standard deviations. Groups were compared using the Wilcoxon rank sum test and ANOVA on ranks. Categorical measurements are presented as frequencies with percentages. Groups were compared using Fisher’s exact test and chi-square. A value of < 0.05 was considered statistically significant. All analyses were carried out using SAS V9.2 statistical software (SAS Institute, Cary, NC).

Results

Demographics

Our study population consisted of 231 participants, in which hematology/oncology physicians and pediatric critical care physicians were evenly distributed (45.89% vs 54.1%). Initially the study was sent out to 732 members of AAP section of pediatric critical care and 445 members of the AAP section of hematology and oncology. The response rate was 15.8% among PICU physicians and 26.1% among hematology and oncology physicians. We attribute our low response rate to the automated depersonalized email from a website, rather than individual requests to members. Surveys that were started but were determined to be incomplete were excluded.

The population was gender balanced (female 51.8%, male 48.2 %), but predominantly Caucasian. 82.5% identified themselves as Caucasian, 10.8% as Asian, 0.9% as African American and 5.8% as others. With regard to religion more than half identified themselves as Christians (56.1%) followed by 25.3% who chose not to specify their religion. 11.8% identified themselves as Jewish, 3.6% as Hindus and 3.2% as Muslims. Most of our participants (76.8%) were married. 35.1% had 2 children followed by 22.1% who had no children. This study group mostly consisted of physicians who were > 20 years in practice (40.6%). 75.5% sleep 5-7 hours per night and 58.4% exercise 2-3 times per week. Half of this group (53.1%) claimed to consume a healthy diet (Table 1-2).

Table 1. Demographic Characteristics (n=231)

Table 2. Habits (n=231)

Maslach Burnout Inventory

The overall burnout rate was 46.8% (45.8% among pediatric critical care physicians and 47.8% among hematology/oncology physicians) (Table 3).

Table 3: Comparison of burnout, secondary traumatic stress and wellbeing rates between pediatric critical care and hematology oncology physicians

Almost half of the participants scored high (42.9%) on the emotional exhaustion subscale and 20.2% scored high for depersonalization. 50.5% also scored high on the personal accomplishment scale. 52.4% of burned out physicians were female. One third of physicians at risk for burnout had 2 children, but the number of children did not correlate with an increased risk of burnout. No demographic factors were identified as a risk or a protective factor for the development of burnout.

Secondary Traumatic Stress Scale

STS was defined as a total score of > 38. The rate of STS was 46.7% (Table 3). A higher total STSS score was noted for physicians practicing for 10- 15 years compared to those practicing for 5-10 years (p=0.04) with a higher score on the arousal subscale (p=0.03). Physicians who followed a healthy diet had a lower total STS score (p=0.01) and a lower score on all three subscales. The same group also seems to have higher scores on the wellbeing scale (p=0.01).

Personal Wellbeing Index

A Personal Wellbeing Index score of >35 was defined as a positive score, which means that an individual was satisfied with his personal life. The overall rate of satisfaction was 95.3% (Table 3). There was no significant difference for PWI scores for critical care and hematology/oncology physicians. With regard to hours of sleep per night, there was no significant difference in burnout or STS rate. However, physicians who slept >7h had a higher score on the PWI scale compared to those who sleep 3-5h (p=0.008) and 5-7h (p=0.02). Married physicians scored higher on the wellbeing scale compared to single physicians (p=0.04). Neither the number of children nor any other lifestyle or demographic factors were associated with increased wellbeing.

Discussion

Our results demonstrate high rates of burnout and secondary traumatic stress in pediatric critical care and pediatric hematology/oncology physicians. This is consistent with recent studies showing that burn out starts during pediatrics residency (18). Fields et al studied burnout rates among PICU physicians 20 years ago and found a rate of 14%, which is significantly lower than our findings. Garcia et al reported a burnout rate of 50% among general pediatricians and pediatric intensivists (19), in line with our findings.  Burn out is not unique to Americans. Other studies have reported a rate of 41% at high risk for burnout among pediatric critical care physicians in Argentina (22).  Interestingly, this study also found the highest rates among academic pediatricians working in a university setting. Comparing with other specialties, surgeons had similar rates of burnout, ranging from 39-41% (4).

Interestingly our study shows that physicians that are in practice for >20 years had higher scores on the depersonalization subscale. This is in contrast to prior studies that showed that physicians in the middle of their career (11-20 years in practice) are at the greatest risk for burnout (4). Another study by Downey et al assessed burnout among anesthesiologists and came to the conclusion that doctors who are 5-15 years in practice are at the greatest risk for burnout. In our study, physicians who are 10-15 years into their careers had higher secondary traumatic stress scores. Unfortunately, there is not much literature to compare our rates of secondary traumatic stress to and available data is mainly focused on military physicians (22).

We did find that a number of factors can mitigate burnout and STS rates. A healthy diet, sleep and religion positively influenced wellbeing and secondary traumatic stress rates. A subjectively healthy diet was associated with decreased total secondary traumatic stress scores and increased scored on the personal wellbeing scale. Consuming fruits and vegetables is associated with lower incidents of depression and higher rates of happiness and higher life satisfaction (23-25). Along with a healthy diet, more than 7 hours of sleep is also associated with physician wellbeing. It is well known that sleep deprivation is associated with decreased cognitive function, memory and reaction time (26).

Burnout poses a risk for the physician and the patient. High scores on the depersonalization and emotional exhaustion subscale are associated with alcohol abuse or dependence (27). Oreskovich et al. (28) sampled 25,073 surgeons, out of which 15.4% were identified to have an alcohol abuse disorder. Participants who were burned out (odds ratio, 1.25; P = .01) and depressed (odds ratio, 1.48; P < .001) were more likely to have alcohol abuse or dependence. Other studies have identified a correlation between burnout rates (specifically emotional exhaustion) and patient safety risks. Clinicians who scored high on the emotional exhaustion subscale of the MBI had higher standardized mortality ratios (29). A Mayo Clinic study also clearly linked burnout with self-perceived medical errors in both internal medicine residents and surgeons (30). In contrast, a recent study conducted in the adult ICU setting established that there is an increased rate of medical errors by depressed physicians, but burn out did not seem to correlate with an increase rate of medical errors (31). Another prospective cohort study done in three children’s hospitals on pediatric residents have had similar results. (32). In our study we did not measure depression or assess for medical errors related with physician burnout. More studies are needed in the future to elicit if burnout leads to an increase rate of medical errors and the potential risks for the patients.

One important limitation of this study is that it was sent to members of the American Academy of Pediatrics, where 40.63% of the physicians are >20 years in practice. This could have skewed the outcomes. One limitation in our study may be that respondents to our survey could be those who are more likely to suffer from burnout and more likely to want to report their issues, or conversely, those most severely affected may have chosen not to participate. We also did not separately analyze burnout and STS against each other, and we presumed that the similar rates were in the same respondents, but that may not be accurate.

Conclusion

The rates of burnout and secondary traumatic stress are high in both pediatric critical care physicians and pediatric hematologist / oncologists. It may be that lifestyle factors, such as a healthy diet, sleep and exercise may serve as protective factors and increase overall wellbeing. Further studies need to be done to assess burnout, secondary traumatic stress rates among other pediatric subspecialties and to analyze proper coping mechanisms.

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 Cite as: Hoehn KS, Abraham M, Gaughan J, Willis BC. Which half are you? Almost half of pediatric oncologists and intensivists are burnt out…… Southwest J Pulm Crit Care. 2019;18(6):167-76. doi: https://doi.org/10.13175/swjpcc029-19 PDF 

Management of Refractory Hypoxemic Respiratory Failure secondary to Diffuse Alveolar Hemorrhage with Venovenous Extracorporeal Membrane Oxygenation

Evanpaul Gill²

Mohamed A. Fayed^1,2,

Elliot Ho^1,2

University of California San Francisco - Fresno Medical Education Program

¹Pulmonary and Critical Care Division

²Department of Internal Medicine

Fresno, CA USA

Abstract

Uncontrolled bleeding has been a relative contraindication for the use of venovenous extracorporeal membrane oxygenation (VV ECMO), but current practice is relatively institution dependent. With the recent advances in circuit technology and anticoagulation practices, the ability to manage patients with ongoing bleeding with ECMO support has increased. We report the case of a 66-year-old patient with refractory hypoxemic respiratory failure secondary to diffuse alveolar hemorrhage (DAH) from underlying anti neutrophil cytoplasmic antibody (ANCA) associated vasculitis who was successfully supported through his acute illness with VV ECMO. ECMO is often used to manage patients with refractory hypoxemic respiratory failure but the usage in the setting of DAH is less known given the risk of bleeding while receiving anticoagulation. Our patient was successfully managed without anticoagulation during his initial ECMO course and his respiratory failure rapidly improved after cannulation. Once managed through the acute phase of his illness and treatment started for his underlying disease process, anticoagulation was started. After being de-cannulated from ECMO and a 3 week stay in the acute rehabilitation unit, our patient was discharged home with complete recovery from his illness. We highlight that patients with refractory hypoxemic respiratory failure and suspicion of DAH as an etiology, ECMO without anticoagulation should be considered as supportive salvage therapy until the underlying process can be treated.

Case Presentation

A 66-year-old man presented with cough, fever, and dyspnea for 1 week. Upon presentation he was found to be in hypoxemic respiratory failure with bilateral pulmonary infiltrates on chest x ray (Figure 1) and positive testing for Influenza A.

Figure 1. Portable AP of chest on initial presentation showing bilateral infiltrates more prominent on the right.

He had an elevated creatinine of 8.1 mg/dl and an acute anemia with a hemoglobin of 7.4 g/dl during the initial work up. He was intubated on hospital day one and transferred to our center for a higher level of care early morning on hospital day two. He developed refractory hypoxemic respiratory failure despite maximum ventilator support as well as standard acute respiratory distress syndrome (ARDS) treatment including neuromuscular blockade. Prone positioning was not possible secondary to hemodynamic instability during the initial treatment plan. Infectious and autoimmune work up was sent. A thoracic CT scan showed extensive bilateral consolidation (Figure 2).

Figure 2. A representative image from the thoracic CT scan showing extensive bilateral consolidation.

At this point a decision was made to apply venovenous double lumen (VVDL) ECMO support as a supportive salvage therapy pending further evaluation into the etiology of his respiratory failure and ARDS. Etiologies at this point included severe influenza infection and DAH from an underlying vasculitis. Anticoagulation with heparin was not initiated given the significant anemia requiring multiple blood transfusions at that point. BUN was elevated, but no other signs of acute gastrointestinal bleeding were identified. Given the underlying renal failure, continuous renal replacement therapy (CRRT) was started on hospital day 2 with citrate used as the anticoagulant. After initiation of ECMO, he improved significantly in the next 72 hours, however, he developed bleeding from the endotracheal tube on day 4. Bronchoscopy was subsequently performed and showed bloody secretions throughout the respiratory bronchial tree, consistent with DAH. His ECMO course had been unremarkable with no thrombotic complications requiring changing of the circuit. Target flows were achieved with a Cardiohelp centrifugal pump and his Avalon 31F double lumen catheter was without complication. On day 5, his autoimmune panel showed a positive ANCA, with myeloperoxidase elevated at 82 AU/ml and serine protease elevated at 314 AU/ml. His anti-nuclear antibody (ANA) was also positive with his titer at 1:2,560. After rheumatology consultation, he was diagnosed with ANCA associated vasculitis with pulmonary hemorrhage and renal failure. His influenza infection was thought to be the trigger for the exacerbation of his underlying autoimmune disease. He was initiated on pulse dose steroids and plasmapheresis with significant clinical improvement and was de-cannulated from ECMO on day 8 with extubation following shortly afterward. He later had renal biopsy performed and it showed diffuse crescentic glomerulonephritis secondary to ANCA vasculitis. He was able to discontinue dialysis after requiring 8 days of CRRT and a further 3 weeks of intermittent hemodialysis. A chest x-ray showed complete clearing of the consolidation (Figure 3).

Figure 3. Chest x-ray just prior to discharge showing complete clearing of the consolidations.

He was eventually discharged home after a 3-week period in acute inpatient rehab.  

Discussion

VV ECMO is increasingly being used as a viable treatment option in patients with refractory acute respiratory failure, especially in patients with underlying ARDS. The ability to allow lung protective ventilation by use of an extracorporeal circuit is of significant value in the acute phase of severe respiratory failure. The general principle of VV ECMO involves removing deoxygenated blood from a venous catheter and passing it through a closed circuit which is comprised of a centrifugal pump and membrane oxygenator (1). This membrane oxygenator takes over the function of the diseased lungs and allows gas exchange to occur, mainly oxygenating the blood and removing carbon dioxide.¹ This blood is then returned into the venous circulation and eventually makes it to the systemic circulation to oxygenate the tissues.

Given that native blood is being passed through an artificial circuit, the risk for thromboembolism is thought to be relatively high. The pathophysiology behind this risk stems from contact of blood components with the artificial surface of the ECMO circuit (2). Proteins found in blood, mainly albumin and fibrinogen, will stick to the artificial surface (2). This results in other blood components congregating, which leads to the formation of a protein layer that servers as an anchor for platelet activation and the formation of insoluble fibrin clots (2). Given the risk of thromboembolism, Extracorporeal Life Support (ELSO) guidelines recommend routine anticoagulation for patients undergoing extracorporeal support (3).

The major complications regarding anticoagulation in the setting of ECMO is bleeding (4). The risk generally comes from acquired thrombocytopenia and anticoagulation (2). ELSO has guidelines regarding management of anticoagulation in VV ECMO but the current practice is relatively institution dependent. This was highlighted in a systematic review done by Sklar and colleagues (4) that investigated many different approaches to anticoagulation for patients on VV ECMO. The main anticoagulant used in those studies was unfractionated heparin and the means to measure its effect was activated clotting time (ACT) and partial thromboplastin time (PTT). They concluded that currently there is no high-quality data that can be employed in decision making regarding anticoagulation for patient’s on VV ECMO support for respiratory failure and that randomized controlled trials are needed for high quality evidence (4). Our own institution’s protocol uses unfractionated Heparin for anticoagulation with a PTT goal of 60-80.

The traditional risk of anticoagulation with ECMO has improved as the component technology of the ECMO circuit has progressed (2). Development of heparin coated inner tubing along with shorter circuit lengths are recent strategies that have been employed to help decrease the amount of thrombotic complications (2). ECLS guidelines state that patients can be managed without anticoagulation if bleeding cannot be controlled with other measures and that the use of high flow rates is recommended to help prevent thrombotic complications (3). The strategies mentioned above are non-chemical ways of preventing thrombosis and could potentially allow management of VV ECMO patients without anticoagulation for the initial period. This was demonstrated in a case report done by Muellenbach and colleagues (5). In their case series, they describe three cases of trauma patients with intracranial bleeding and severe ARDS refractory to conventional mechanical ventilation that were managed with VV ECMO without systemic anticoagulation for a prolonged time period. In their situation, anticoagulation could not be given secondary to severe traumatic brain injury (TBI) and intracranial bleeding (5). They stated that because newer circuits are completely coated by heparin and because circuit lengths have been shortened by specialized diagonal pumps and oxygenators, systemic anticoagulation can be reduced (5)

VV ECLS, as mentioned above, is commonly used in acute respiratory failure but use of VVECLS in DAH is a less known use due to the risk of anticoagulation in this clinical setting. Per ECLS guidelines, one of the relative contraindications for initiation of ECLS is risk of systemic bleeding from anticoagulation (3), and patients with DAH definitely fit this risk profile. But as mentioned above; with improving shortened ECMO circuits, use of heparin coated tubing, and high flow rates, the ability to initially manage patients without systemic anticoagulation until they are stabilized is very important in clinical settings such as our patient with DAH. Many case reports have been published that highlight the successful management of acute respiratory failure due to DAH with VV ECMO (6,7). Our patient was initially managed without systemic anticoagulation and required multiple blood transfusions given the significant bleeding appreciated from the endotracheal tube. Once the diagnosis of ANCA related DAH was made and the appropriate treatment initiated, bleeding significantly decreased and the patient was able to be started on anticoagulation. This highlights that patients with suspicion of DAH as an etiology of respiratory failure not be excluded from consideration VV ECMO as supportive salvage therapy given the potential for great clinical outcome if managed through the acute phase of bleeding.

References

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4. Sklar MC, Sy E, Lequier L, Fan E, Kanji HD. Anticoagulation practices during venovenous extracorporeal membrane oxygenation for respiratory failure. A systematic review. Ann Am Thorac Soc. 2016 Dec;13(12):2242-50. [CrossRef] [PubMed]
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7. Patel JJ, Lipchik RJ. Systemic lupus-induced diffuse alveolar hemorrhage treated with extracorporeal membrane oxygenation: a case report and review of the literature. J Intensive Care Med. 2014 Mar-Apr;29(2):104-9. [CrossRef] [PubMed]

Cite as: Gill E, Fayed MA, Ho E. Management of refractory hypoxemic respiratory failure secondary to diffuse alveolar hemorrhage with venovenous extracorporeal membrane oxygenation. Southwest J Pulm Crit Care. 2019;18(5):135-40. doi: https://doi.org/10.13175/swjpcc007-19 PDF