Developing a Standard Method for Apnea Testing
in the Determination of Brain Death for Patients
on Venoarterial Extracorporeal Membrane
Oxygenation: A Pediatric Case Series
Rima J. Jarrah, MD1; Samuel J. Ajizian, MD1; Swati Agarwal, MD2; Scott C. Copus, RRT3;
Thomas A. Nakagawa, MD1
Objective: The revised guidelines for the determination of brain
death in infants and children stress that apnea testing is an integral
component in determining brain death based on clinical criteria.
Unfortunately, these guidelines provide no process for apnea testing during the determination of brain death in patients supported
on venoarterial extracorporeal membrane oxygenation. We review
three pediatric patients supported on venoarterial extracorporeal
membrane oxygenation who underwent apnea testing during their
brain death evaluation. This is the only published report to elucidate
a reliable, successful method for apnea testing in pediatric patients
supported on venoarterial extracorporeal membrane oxygenation.
Design: Retrospective case series.
Setting: Two tertiary care PICUs in university teaching hospitals.
Patients: Three pediatric patients supported by venoarterial extracorporeal membrane oxygenation after cardiopulmonary arrest.
Interventions: After neurologic examinations demonstrated cessation of brain function in accordance with current pediatric brain
death guidelines, apnea testing was performed on each child while
supported on venoarterial extracorporeal membrane oxygenation.
Measurements and Main Results: In two of the three cases, the
patients remained hemodynamically stable with normal oxygen
saturations as venoarterial extracorporeal membrane ­oxygenation
Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC.
2
Department of Pediatrics, Section of Pediatric Critical Care, Inova Fairfax
Hospital for Children, Falls Church, VA.
3
Department of Respiratory Care, Wake Forest Baptist Health, Brenner
Children’s Hospital, Winston-Salem, NC.
Supported by departmental funds.
Dr. Ajizian is a consultant for Covidien. Dr. Nakagawa is a consultant for
the U.S. Department of Health and Human Services, Health Resource
Service Administration, and The Organ Donation and Transplantation Alliance. The remaining authors have disclosed that they do not have any
potential conflicts of interest.
For information regarding this article, E-mail: [email protected]
Copyright © 2013 by the Society of Critical Care Medicine and the World
Federation of Pediatric Intensive and Critical Care Societies
DOI: 10.1097/PCC.0000000000000006
1
Pediatric Critical Care Medicine
sweep gas was weaned and apnea testing was undertaken.
Apnea testing demonstrating no respiratory effort was successfully completed in these two cases. The third patient became
hemodynamically unstable, invalidating the apnea test.
Conclusions: Apnea testing on venoarterial extracorporeal membrane oxygenation can be successfully undertaken in the evaluation of brain death. We provide a suggested protocol for apnea
testing while on venoarterial extracorporeal membrane oxygenation that is consistent with the updated pediatric brain death
guidelines. This is the only published report to elucidate a reliable, successful method for apnea testing in pediatric patients
supported on venoarterial extracorporeal membrane oxygenation.
(Pediatr Crit Care Med 2014; 15:00–00)
Key Words: apnea testing; brain death; end-of-life; extracorporeal
membrane oxygenation; pediatrics
T
he updated guidelines for the determination of brain
death for infants and children provide important direction for the intensivist tasked with determining death
(1). However, the consensus guidelines do not offer a process
for apnea testing when a patient is supported on venoarterial
(VA) extracorporeal membrane oxygenation (ECMO), as no
supporting literature exists for this clinical situation. In fact,
the pediatric and adult literature is bereft of reports regarding
apnea testing on VA-ECMO. A 1991 review of infants who died
on VA-ECMO cited “brain death” in 29% of their study group
(2). This article unfortunately did not specifically address how
apnea testing or clinical documentation of brain death was
determined. The authors note “[i]nfants were diagnosed as
having brain death after ultrasound evidence of brain injury
forced termination of ECMO” (2). This definition does not
meet current or past clinical guidelines for determining brain
death in infants and children. As early as 1987, the American
Academy of Pediatrics published guidelines for brain death
determination in children and infants (3). Those guidelines set
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Jarrah et al
forth specific criteria in the areas of history, physical examination, and ancillary testing needed to determine brain death
in children. Although intracranial bleeding may certainly lead
to brain death, neither ultrasound nor pathologic findings of
intracranial hemorrhage are sufficient to diagnose irreversible
cessation of brain function.
In a comprehensive review of 87 adult patients (15 yr
and older) over an 8-year period, patients who lost all brainstem reflexes were evaluated for apnea while supported on
VA-ECMO (4). Three patients met criteria. In two cases, apnea
testing was deemed “too difficult to perform,” no further
explanation is given. In the third case, support was withdrawn
before apnea testing could be performed (4).
The updated pediatric brain death guidelines for infants
and children address apnea testing for patients undergoing
clinical evaluation for brain death. The guidelines recommend
baseline and serial arterial blood gas (ABG) measurements to
determine Paco2 levels during apnea testing. The apnea test is
continued until Paco2 rises to greater than or equal to 60 mm
Hg and greater than or equal to 20 mm Hg above baseline. The
patient is continually monitored for respiratory activity during apnea testing. Any respiratory effort is inconsistent with
brain death, and the patient should be placed back on ventilatory support. Testing for brain death by clinical examination
and apnea testing may be repeated at a later time. Alternatively,
an ancillary study can be pursued to assist with the determination of neurologic death. The updated guidelines also stress
apnea testing must be performed safely and should be aborted
if the patient desaturates to less than 85%, develops hemodynamic instability, or if a Paco2 level of 60 mm Hg cannot
be safely achieved (1). Unlike patients on mechanical ventilation alone, gas exchange for patients supported on VA-ECMO
occurs mainly through the ECMO oxygenator. Carbon dioxide elimination is dependent on the sweep gas flow rate, which
must be reduced to allow Paco2 to rise to appropriate levels to
test for apnea.
Apnea testing for patients supported on VA-ECMO has
never been described in the pediatric literature. We review
three cases of children who met clinical examination criteria
for brain death and underwent apnea testing while supported
on VA-ECMO. Institutional review boards waived the need for
approval in our review of these cases.
CASE 1
A 2½-year-old, 13.6 kg, African American child with a history
of sickle cell anemia was admitted for suspected pain crisis
involving the abdomen. One day after admission, the patient
developed acute severe congestive heart failure. The patient
was treated with milrinone, furosemide, supplemental oxygen,
and transfused packed RBCs. Subsequently, the child developed leftward eye deviation with clenching of the jaw and
became bradycardic and then asystolic. Pediatric Advanced
Life Support (PALS) and cardiopulmonary resuscitation
(CPR) were initiated. The patient was cannulated for VAECMO (Medtronics, Woods Cross, UT; MAQUET Quadrox D
oxygenator, Wayne, NJ). The child had return of spontaneous
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circulation (ROSC) following 42 minutes of CPR. VA-ECMO
was initiated 44 minutes postarrest.
The child remained unresponsive and the neurologic examination deteriorated with bilateral fixed and dilated pupils. A
computed axial tomographic scan of the brain showed diffuse
hypoxic/ischemic insult in a watershed distribution, with herniation. After meeting all prerequisite criteria, brain death testing was initiated in accordance with the updated pediatric brain
death guidelines and was consistent with loss of all brainstem
reflexes (1). The patient was normothermic (36°C) and acceptable hemodynamics were maintained with VA-ECMO flows of
88 mL/kg/min (Table 1). Prior to initiation of apnea testing,
the patient was preoxygenated via the VA-ECMO circuit with
an Fio2 of 1.0. Sweep gas flow rate at the initiation of apnea
testing was 0.5 L/min. Following preoxygenation and normalization of Paco2, ABG analysis showed a pH of 7.48, Paco2 of
39 mm Hg, and Pao2 of 596 mm Hg (Table 2). The child was
placed on continuous positive airway pressure (CPAP) with
an Fio2 of 1.0 administered through a flow-inflating anesthesia
bag connected to the endotracheal tube. VA-ECMO flows were
maintained at 88 mL/kg/min and Fio2 at 1.0 while sweep gas
flow was titrated down. Continuous blood gas monitoring via
CDI blood parameter monitoring system (CDI 500, Terumo
Cardiovascular Systems, Ann Arbor, MI) was observed during
apnea testing. Blood gas information during the apnea test as
sweep gas flow rate was decreased is shown in Table 2.
The patient maintained adequate hemodynamics throughout the testing period with no hypotension (Table 1). No spontaneous respiratory effort during apnea testing was noted, with
documented Paco2 greater than 60 mm Hg and greater than or
equal to 20 mm Hg increase above the baseline Paco2.
CASE 2
A 14-year-old, 100 kg, African American child was admitted for open biopsy of a large retroperitoneal mass causing
compression of the inferior vena cava. The intraoperative
and immediate postoperative course was uncomplicated. On
postoperative day 1, the patient had syncope, progressing
to lethargy and cardiovascular collapse. The child became
bradycardic, followed by asystole. PALS and CPR were initiated, and the decision was made to cannulate for VA-ECMO
(Medtronics; MAQUET Quadrox D oxygenator) was made
after 60 minutes of resuscitation. The patient progressed to
complete unresponsiveness while on VA-ECMO. A head CT
revealed diffuse hypoxic ischemic insult with central herniation. After meeting all prerequisite criteria, brain death
testing was initiated in accordance with the updated pediatric brain death guidelines and was consistent with loss of
all brainstem reflexes (1). The patient was normothermic
(37.2°C) and acceptable hemodynamics were maintained
with VA-ECMO flows of 38 mL/kg/min. Prior to initiation
of apnea testing, the patient was preoxygenated via the VAECMO circuit with an Fio2 of 1.0. Sweep gas flow rate at the
initiation of apnea testing was 5.5 L/min. Following preoxygenation, ABG analysis showed a pH 7.5, Paco2 31.8 mm Hg,
and Pao2 207 mm Hg (Table 2). Oxygen saturation was 100%
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Table 1.
Summary of Patient Characteristics
Characteristics
Case 1
Case 2
Case 3
No
No
Yes. Examination was
undertaken 24 hr after
rewarming
24 hr 22 min
18 hr 45 min
> 48 hr
Time between last sedation/neuromuscular
blockade and examination
> 24 hr
8 hr
> 24 hr
Temperature at the time of examination
36.1°C
37.2°C
36.5°C
88 mL/kg/min
38 mL/kg/min
140 mL/kg/min
100% (calculated from arterial
blood gas)
100%
78%
Therapeutic hypothermia?
Time on ECMO when examination done
VA-ECMO flows during apnea test
Lowest recorded Spo2 during apnea test
Lowest recorded blood pressure/MAP
during apnea test
MAP = 44
Head CT
100/50
39/34
Diffuse hypoxic ischemic insult in Diffuse hypoxic ischemic
a watershed distribution, with
insult with central
herniation
herniation
None
Ancillary testing (i.e., EEG, cerebral blood
flow)
None
None
No evidence of electrical
activity on EEG
Time from arrest to return of spontaneous
circulation
42 min
76 min (when placed on
VA-ECMO)
Not available
Time from arrest to ECMO
44 min
76 min
~60 min
ECMO = extracorporeal membrane oxygenation, VA-ECMO = venoarterial extracorporeal membrane oxygenation, MAP = mean arterial pressure, EEG =
electroencephalogram.
on Fio2 of 1.0 via ECMO circuit. The patient was placed on
CPAP with an Fio2 of 1.0 administered through a flow-inflating anesthesia bag connected to the endotracheal tube. VAECMO flows were maintained at 38 mL/kg/min and Fio2 at 1.0
while sweep gas flow was weaned from 5.5 to 1.0 L/min over
60 minutes (Table 2). The child remained hemodynamically
stable and normothermic during apnea testing. Continuous
blood gas monitoring via CDI monitor was observed during apnea testing. After 60 minutes, an ABG was obtained,
with the following results: pH 7.21, Paco2 62 mm Hg, and
Table 2. Results of Weaning Sweep Flow on Arterial Blood Gases for Three Patients on
Venoarterial Extracorporeal Membrane Oxygenation
Apnea Test Time
(min)
ECMO Pump Flow
(mL/kg/min)
ECMO Sweep Flow (Fio2 1.0)
(L/min)
Arterial Blood Gas
(pH/Paco2/Pao2/Hco3)
Case 1
t0
88
0.5
7.48/39/596/29
t0 + 23
88
0.25
7.35/47/497/26
t0 + 35
88
0.1
7.31/57/532/29
t0 + 48
88
0.1
7.22/73/564/30
t0
38
5.5
7.50/32/207/25
t0 + 60
38
1
7.21/62/73/25
t0
140
0.22
7.41/40/135/25.4
t0 + 11
140
0.1
7.26/62.4/390/28
Case 2
Case 3
After t0, the patients were connected to a flow-inflating bag system providing continuous positive airway pressure and Fio2 of 1.0. Venoarterial extracorporeal
membrane oxygenation flows were not changed during apnea testing.
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Jarrah et al
Pao2 73 mm Hg (Table 2). Saturations remained 100% during apnea testing. The patient maintained adequate hemodynamics throughout the testing period with no hypotension
(Table 1). No spontaneous respiratory effort during apnea
testing was noted, with documented Paco2 greater than
60 mm Hg and greater than or equal to 20 mm Hg increase
above the baseline Paco2.
CASE 3
A 5-month-old infant with complex congenital heart disease developed bradycardia followed by cardiac arrest. PALS
and CPR were initiated, and after approximately 1 hour of
CPR without ROSC, the child was cannulated for VA-ECMO
(Medtronics; MAQUET Quadrox D oxygenator). The child
was maintained on full VA-ECMO support with flows of
140 mL/kg/min. The patient underwent 24 hours of hypothermia to 34°C postarrest, followed by gradual rewarming on
the second day of VA-ECMO. On ECMO day 3, the child was
unresponsive despite receiving no sedative or neuromuscular
blocking agents for more than 24 hours. After meeting all prerequisite criteria, brain death testing was initiated in accordance with the updated pediatric brain death guidelines and
was consistent with loss of all brainstem reflexes (1). Electroencephalogram showed no evidence of electrical activity. The
patient was normothermic (36.5°C) and acceptable hemodynamics were maintained with VA-ECMO flows of 140 mL/
kg/min. Prior to initiation of apnea testing, the patient was
preoxygenated via the VA-ECMO circuit with an Fio2 of 1.0.
Sweep gas flow rate at the initiation of apnea testing was
0.22 L/min. Following preoxygenation and normalization of
Paco2, ABG analysis showed a pH 7.41, Paco2 40 mm Hg, and
Pao2 135 mm Hg (Table 2). The infant was disconnected from
mechanical ventilatory support and placed on CPAP with
an Fio2 of 1.0 administered through a flow-inflating anesthesia bag connected to the endotracheal tube. VA-ECMO
flows were maintained at 140 mL/kg/min and Fio2 at 1.0. The
patient was continuously monitored and no respiratory effort
was noted over 11 minutes. Continuous blood gas monitoring via CDI parameter monitoring system demonstrated that
Paco2 increased to 65 during this time period. Temperature
remained unchanged during apnea testing. However, blood
pressure gradually decreased to 39/34 mm Hg with a heart rate
of 168. Oxygen saturations decreased to 78% although Pao2
on the CDI was greater than 100. After 11 minutes, an ABG
revealed a pH 7.26, Paco2 62.4 mm Hg, and Pao2 390 mm Hg,
and the apnea test was terminated.
DISCUSSION
Brain death is characterized by the absence of brainstem reflexes
and apnea in the presence of a known cause of irreversible
coma (5). Apnea testing is essential to demonstrate the failure
of the medullary respiratory centers to respond to hypercapnia and acidosis. Successful apnea testing for patients on VAECMO has not been documented in the literature. Apnea
testing in this patient population is challenging, as no defined
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or uniform standards exist. Additionally, apnea testing must be
done in a manner that does not compromise the safety of the
patient. Attention to pretest conditions can minimize potentially adverse circulatory effects during apnea testing (5, 6).
Various techniques have been described for performing
apnea testing in ventilated patients (1, 7). A flow-inflating bag
system with supplemental oxygen connected to the endotracheal
tube is a safe and commonly used method for apnea testing
(8). The updated pediatric brain death guidelines recommend
removing the patient from mechanical ventilation as newer ventilators will revert to a backup mode of ventilation once apnea
is sensed (1). Additionally, false triggering of the ventilator can
occur simulating respiration if sensitivity of the ventilator is not
adjusted appropriately (1, 5). Tracheal insufflation of oxygen has
been used, but caution is warranted to ensure adequate excursion of gases to prevent barotrauma and co2 washout preventing
adequate rise of Paco2 during apnea testing (1).
Oxygenation and ventilation in patients mechanically
supported on VA-ECMO relies on blood passing through an
oxygenator. Deoxygenated blood in the ECMO circuit passes
through the oxygenator and is circulated back to the patient.
Ventilation is accomplished by adjusting the flow of the sweep
gas, which directly influences co2 removal. In a patient who is
fully supported on VA-ECMO, nearly all ventilation is accomplished using the ECMO oxygenator. VA-ECMO presents
challenges to determine apnea for brain death testing because
oxygenators are highly efficient and may not allow the Paco2 to
rise to appropriate levels.
Our patients were placed on a CPAP circuit using a flowinflating anesthesia bag supplied with an Fio2 of 1.0. Once
ventilatory support was terminated and patients were connected to the flow-inflating circuit, the ECMO sweep gas was
decreased allowing the Paco2 to rise. In all cases, sweep gas Fio2
remained at 100% while supported on VA-ECMO. Paco2 was
continually monitored through the arterial limb of the ECMO
circuit using the CDI blood parameter monitoring system for
continuous blood gas measurement. An ABG sample was analyzed to confirm the Paco2 measurement and readings from the
CDI monitoring system.
In mechanically ventilated patients, Paco2 rises in a linear
fashion by approximately 3–5 mm Hg/min during apnea testing for brain death once a patient is removed from ventilatory
support (9–11). In cases of severe brain injury, this increase
may be variable because the injured or dead brain does not
contribute to co2 production. In two cases described, the rate
of Paco2 rise was much slower and attributable to weaning of
sweep gas flow (Table 2). The rate of Paco2 rise on ECMO is
a function of the co2 removal rate of the oxygenator, which,
in turn, is proportional to ECMO circuit flow, sweep gas flow,
and size of the oxygenator. We are not aware of any literature to
guide the clinician in the rate of Paco2 rise while on VA-ECMO.
A recent article proposed adding co2 to the oxygenator to elevate the Paco2 to the required levels to demonstrate apnea (4).
However, the researchers were unable to perform this maneuver as their patients were too unstable for apnea testing.
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Table 3. Proposed Process for Apnea Testing of Pediatric Patients Supported on
Venoarterial Extracorporeal Membrane Oxygenation
1. Normalize Paco2 by adjusting ECMO sweep gas and obtain a baseline ABG analysis
2. Preoxygenate the patient on VA-ECMO by increasing sweep gas Fio2 to 1.0
3. Remove the patient from mechanical ventilation and connect endotracheal tube to a flow-inflating bag system with adequate
continuous positive airway pressure and Fio2 1.0
4. Maintain the ECMO sweep gas Fio2 at 1.0. Decrease ECMO sweep gas flow to as low as possible, without precipitating
hypoxia. We find that a flow of 0.1 L/min for smaller children and 1 L/min for adult-sized children is well tolerated and allow
for successful apnea testing
5. A CDI monitor can assist with determination of Paco2, but must be confirmed with an ABG. If a CDI monitoring system is not
used, serial ABGs should be obtained at 5-min intervals throughout apnea testing until, 1) the Paco2 reaches the appropriate
threshold noted in the current guidelines; 2) the patient shows signs of spontaneous respiratory effort; or 3) the patient
becomes hemodynamically unstable
6. If the patient exhibits respiratory effort, desaturates to < 85%, or develops hemodynamic instability, the apnea test should
be terminated (1). Maintaining circulatory support in the event of hypotension may be accomplished in patients supported on
­VA-ECMO by increasing circuit flow or using additional inotropic agents
7. If the apnea test cannot be successfully completed, an ancillary study can be pursued to assist with the determination of brain
death or another attempt to test for apnea can be attempted at a later time
ECMO = extracorporeal membrane oxygenation, ABG = arterial blood gas, VA-ECMO = venoarterial extracorporeal membrane oxygenation.
Criteria for brain death testing rely on successful and safe
completion of apnea testing in conjunction with a clinical
examination that is consistent with brain death. Prerequisites
prior to brain death testing must be met to ensure variables
that could interfere with testing have been addressed and
treated (1). Brain death can be determined solely on clinical
criteria and apnea testing. Normalization and maintenance
of blood pressure and oxygenation are essential during apnea
testing. If the patient desaturates or becomes hemodynamically unstable during apnea testing, the apnea test should be
aborted. An ancillary study to assist with determination of
brain death or another attempt to perform apnea testing at a
later time can be pursued to see if apnea testing is better tolerated under different circumstances. Ancillary studies such as
cerebral blood flow or electroencephalogram can assist with
determination of brain death; however, maintaining normal
hemodynamic variables is essential when conducting brain
death testing.
We suggest the following processes when conducting apnea
testing for brain death on VA-ECMO (Table 3):
1.Normalize Paco2 by adjusting ECMO sweep gas and obtain
a baseline ABG analysis.
2.Preoxygenate the patient on VA-ECMO by increasing sweep
gas Fio2 to 1.0.
3.Remove the patient from mechanical ventilation and connect endotracheal tube to a flow-inflating bag system with
adequate CPAP and Fio2 1.0.
4.Maintain the ECMO sweep gas Fio2 at 1.0. Decrease ECMO
sweep gas flow to as low as possible, without precipitating
hypoxia. We find that a flow of 0.1 L/min for smaller children and 1 L/min for adult-sized children is well tolerated
and allows for successful apnea testing.
5.A CDI monitor for continuous blood gas assessment can
assist with determination of Paco2. Measurements must be
Pediatric Critical Care Medicine
confirmed with an ABG. If a CDI monitoring system is not
used, serial ABGs should be obtained at 5-minute intervals throughout apnea testing until 1) the Paco2 reaches
the appropriate threshold noted in the current guidelines; 2) the patient shows signs of spontaneous respiratory effort; or 3) the patient becomes hemo­dynamically
unstable.
6.If the patient exhibits respiratory effort, desaturates to less
than 85%, or develops hemodynamic instability, the apnea
test should be terminated (1). Maintaining circulatory support in the event of hypotension may be accomplished in
patients supported on VA-ECMO by increasing circuit flow
or using additional inotropic agents.
7.If the apnea test cannot be successfully completed, an ancillary study can be pursued to assist with the determination
of brain death or another attempt to test for apnea can be
tried at a later time.
To our knowledge, we report the only published cases of
apnea testing to determine brain death in children supported
on VA-ECMO. We describe a method for apnea testing to assist
clinicians declaring brain death by clinical criteria for patients
supported on VA-ECMO.
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