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LLC “The Science Behind the Art” 
Volume 7 - No. 1 2019 

Anesthesia eJournal - Online 
ISSN 2333-2611

Page 1

Case Report of Acute Pulmonary Edema and Sudden Death After Heart Surgery
Joshua M. Thigpen, DNP, CRNA

Affiliation:
Dr Thigpen was a student at Texas Christian University at the time of writing this article.

Funding/Conflict of Interest Disclosure: 
None

KEYWORDS: Cardiac surgery, cardiopulmonary bypass, transfusion-related acute lung injury, protamine reaction, noncardiogenic 
pulmonary edema

INTRODUCTION
Aside from the inherent risks of heart surgery and individual morbidities, unforeseen risks are sometimes overlooked and 
can be devastating. These covert problems in the time period of coronary artery bypass graft surgery usually manifest after 
cardiopulmonary bypass (CPB), after hemodynamic stabilization, when complications are less likely. The post-CPB period is 
when protamine sulfate and blood products are commonly administered. Protamine sulfate reverses the effects of the heparin 
that was administered before and during CPB to prevent coagulation.
In this case, a 47-year-old man undergoing several procedures on his heart and requiring CPB experienced fulminant 
pulmonary edema after the administration of protamine and blood products. It is unclear whether the protamine or the 
blood products were responsible, because transfusion-related acute lung injury (TRALI) and severe reactions to protamine 
have similar presentations. Unfortunately, the severity of the resulting pulmonary edema led to this patient’s death. 
Anesthesia professionals should be familiar with the risk factors, presentation, and treatment for each.

Abstract
A 47-year-old man underwent aortic valve replacement surgery. After cessation of cardiopulmonary bypass, the patient 
exhibited refractory hypoxia, fulminant pulmonary edema, and hypotension and ultimately died less than 1 hour after his 
arrival to the intensive care unit. The patient may have experienced either a severe type III reaction to protamine sulfate 
or a transfusion-related acute lung injury. Both of these conditions can produce hypoxia, pulmonary edema, and hypoten-
sion. Anesthesia professionals must be able to identify patients at risk for both conditions, recognize their presentations, 
and respond quickly and appropriately when presented with these deadly reactions.

AEJ
Volume 7 - No. 1 2019



Anesthesia eJournal 
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         www.anesthesiaejournal.com 
Page 2

CASE SUMMARY
A 47-year-old man with a weight of 101 kg and height of 182.9 
cm was scheduled for a modified left atrial maze procedure, 
coronary bypass of the posterior descending artery, and aortic 
root replacement with a mechanical aortic valve conduit. The 
patient had a recently diagnosed history of hypertension, atrial 
fibrillation, coronary artery disease, nonruptured ascending aortic 
aneurysm, aortoannular ectasia with severe aortic insufficiency, 
and hyperlipidemia. The patient was taking metoprolol, 
furosemide, hydrochlorothiazide, lovastatin, and dabigatran 
(which had been discontinued for at least 3 days). The results 
of the patient’s chemistry panel and complete blood count were 
unremarkable, but hemoglobin and hematocrit values of 11.8 mg/
dL and 35%, respectively, were noted. Upon assessment in the 
preoperative holding area, the patient appeared alert with no signs 
of distress and a supportive family was present. The results of a 
physical examination were normal except for an obvious heart 
murmur and a continuous electrocardiogram displaying atrial 
fibrillation.
After the patient was administered fentanyl 100 mcg intravenous 
(IV) and midazolam 2 mg IV, a right radial arterial line was
placed in the preoperative holding area. The patient was then
transported to the operating room, standard monitors were
applied, and the arterial line was connected for blood pressure
(BP) monitoring. Induction of anesthesia was performed
with a combination of the inhalational agent sevoflurane and
additional administration of midazolam 5 mg, sufentanil 25
mcg, propofol 50 mg, and vecuronium 10 mg IV. The patient was
orally intubated with an 8.0-mm endotracheal tube via direct
laryngoscopy and the tube was secured at 22 cm at the teeth
following confirmation of placement. Anesthesia was maintained
with sevoflurane at variable end-tidal concentrations along with
sufentanil and propofol boluses to maintain a bispectral index
monitor reading of 40 to 60 while maintaining systolic BP
(SBP) at a desirable value of 90 to 110 mm Hg for the indicated
procedures. After induction, a right subclavian central line and
right internal jugular pulmonary artery catheter with a sheath
introducer were placed. The pulmonary artery catheter revealed
a pulmonary artery pressure of 32/22 mm Hg, central venous
pressure of 16 mm Hg, cardiac output of 5.5 L/min, cardiac
index of 2.5 L/min/m2, and a mixed venous oxygen saturation
(SvO2) of 68%. Cefuroxime 1.5 g IV was administered for
infection prophylaxis. Aminocaproic acid 10 g IV bolus was given
prior to incision and an additional 5 g was administered over
5 hours during the procedure. The other medication infusions
administered were dexmedetomidine 0.3 mcg/kg/h and milrinone
0.375 mcg/kg/min.
The procedure proceeded in the usual fashion for patients
undergoing coronary artery bypass with endoscopic vein harvest, 
save for the time taken to perform the maze procedure. The pre-
CPB period was uneventful. Minimal boluses of phenylephrine
100 mcg and ephedrine 5 mg IV were given to maintain SBP
at 90 to 110 mm Hg. CPB was initiated approximately 60
min after incision. Total CPB time was 4 hours. The aortic
valve and root were replaced along with the graft bypassing
the posterior descending coronary artery. The patient received
4 units of packed red blood cells while on CPB. As rewarming
began, norepinephrine was started at 0.04 mcg/kg/min. When

the primary aortic cross-clamp was removed, lidocaine 100 
mg IV was given along with calcium chloride (CaCl) 500 
mg IV. Albumin 5% 500 mL was given prior to cessation of 
CPB. After successful weaning from CPB and transesophageal 
echocardiography revealed satisfactory improvement of 
forward flow of blood through the mitral and aortic valves, 
protamine sulfate 500 mg IV was infused over 10 min with close 
hemodynamic monitoring. After the protamine had finished 
infusing, 2 units of fresh frozen plasma and 1 unit of platelets 
were infused. During the time of CPB weaning, crystalloids were 
given more liberally owing to inadequate filling of the heart. The 
total volume of crystalloid was approximately 2.3 L at 5 hours 
from the start of the case. The patient was hemodynamically 
stable after complete weaning from CPB and in sinus rhythm 
with a heart rate of 83, BP in the 90s/60s mm Hg, cardiac output 
of 5.1 L/min, cardiac index of 2.3 L/min/m2, pulmonary artery 
pressure of 48/34 mm Hg, central venous pressure of 30 mm Hg, 
and SvO2 of 63%.
Forty-five minutes after weaning from CPB and 30 minutes after 
infusion of the platelets and fresh frozen plasma, the patient’s 
oxygen saturation as measured by pulse oximetry (SpO2) was 
trending into the low 90s and upper 80s but responded to large 
manual breaths and was initially thought to be due to atelectasis. 
As time progressed, however, the patient’s SpO2 continued 
to decrease with a concomitant decrease in end-tidal CO2 
to approximately 20 mm Hg. The initial diagnosis included a 
possible pulmonary embolus or clot resulting in obstructed gas 
exchange. An arterial blood gas sample revealed a partial pressure 
of oxygen (PaO2) of 53 mm Hg (despite 100% FiO2 [fraction 
of inspired oxygen]), pH 7.24, and arterial oxygen saturation 
(SaO2) of 83%. It was almost accepted that an embolus was the 
precipitating factor owing to adequate tidal volumes, normal 
airway pressures, and transesophageal echocardiography (TEE) 
revealing significant improvement in cardiac function. A chest 
x-ray revealed pulmonary infiltrates versus effusion on the right
side. The sternum was reopened for inspection and a pleural
chest tube was placed. At 80 minutes post-CPB time, mucus
was present in the heat and moisture exchange filter where the
endotracheal tube (ETT) connects to the breathing circuit. 
In-line suctioning of the ETT produced copious amounts of
fluid that totaled a volume of 400 mL plus the large amount that
spilled onto the floor and onto towels. Fiberoptic bronchoscopy
revealed a lake of fluid. Suctioning with the bronchoscope was
performed and an additional 600 mL was removed. However, 
the lungs filled back up with fluid almost as fast as the fluid was
aspirated. Furosemide 20 mg IV was given but failed to improve
the situation.
The patient’s BP began to wane despite a high number of
phenylephrine boluses equalling 5 mg over about 1 hour, a
norepinephrine infusion at 0.5 mcg/kg/min, plus the addition
of epinephrine at 0.02 mcg/kg/min. Dexmedetomidine was
discontinued. The surgeon, anesthesia team, and intensivist all
agreed that all resuscitation measures had been taken; there was
nothing more to do. The patient was transported to the intensive
care unit 8 hours after the surgery began and was pronounced
dead 30 minutes after arrival. Postoperative laboratory values
were unremarkable aside from the arterial blood gas and slightly
elevated coagulation values, prothrombin time of 22.2, partial
thromboplastin time of 44, and international normalized ratio



Anesthesia eJournal 
Volume 7 - No. 1 2019 

         www.anesthesiaejournal.com 
Page 3

of 1.9. The patient received a total of 3500 mL of crystalloids, 4 
units of packed red blood cells, 2 units of fresh frozen plasma, 500 
mL of 5% albumin, and 1 unit of platelets. Urinary output was 
1400 mL and estimated blood loss was 795 mL.
DISCUSSION
The initial consideration was that the patient had developed a 
pulmonary embolus. The patient was in atrial fibrillation before 
the case and up to the time of the maze procedure. Dabigatran 
had been discontinued for at least 3 days before surgery, leading 
to the possibility of clot formation. The physician’s assistant noted 
the presence of clots during the endoscopic vein harvest of both 
legs. The low SpO2, low end-tidal carbon dioxide (ETCO2), and 
hemodynamics requiring vasopressor support lent credence to 
a diagnosis of a pulmonary embolus. However, no pulmonary 
embolus was detected by TEE. A pulmonary embolus was ruled 
out after manifestation of fulminant pulmonary edema. Other 
possibilities considered were TRALI or a severe reaction to 
protamine sulfate. Furosemide was administered, although it 
did little, if anything, to relieve the pulmonary edema. Despite 
almost continuous suctioning of the airway via the fiberoptic 
bronchoscope, fluid continued to fill the lungs. The only viable 
option at this point for resuscitation was extra-corporeal 
membrane oxygenation (ECMO). Unfortunately, ECMO was 
not available at the facility or in the local community. The exact 
cause of the devastating event was unknown. The presentation 
supported TRALI and a severe reaction to protamine as the 
culprit. Further investigation was required to identify the cause.
An acute lung injury occurring during or within 6 hours of the 
administration of blood products defines the rare and often 
deadly TRALI.1 Several signs may be observed as this process 
occurs, such as dyspnea, hypoxia, hypotension, pulmonary 
hypertension, pulmonary edema, pulmonary infiltrates on chest 
x-ray, and decreased lung compliance.2 The ALI is noncardiogenic
in nature and occurs without the presence of circulatory
overload.3 All of the aforementioned signs were part of the
clinical picture for the patient in this case except for the decrease
in lung compliance. However, it has been suggested that there is
a time gap between the development of pulmonary hypertension
and a decrease in lung compliance.2 The length of that time
gap may be patient-dependent. Because this patient died about
3 hours after the administration of the blood products, the
decreased compliance may not have manifested before transport
from the operating room. The complete pathophysiology of
TRALI is unknown but is likely precipitated by leukocyte
antibodies or the activation of inflammatory mediators that
can result in increased pulmonary capillary permeability and
ultimately poor pulmonary function.1 The treatment for TRALI
is primarily supportive with the primary goal of discontinuing
administration of the insulting blood products if possible. Some
evidence suggests that the use of steroids may be of benefit.1 In

the case of this patient, the devastating toll that the pulmonary 
edema caused could only be treated with ECMO. Unfortunately, 
ECMO was not available at this facility or within the local 
community. Some studies have presented evidence for increased 
risk factors linked to TRALI, such as higher interleukin-8 levels, 
elevated peak airway pressures during mechanical ventilation, 
smoking, and a positive fluid balance.3

A severe reaction to protamine sulfate is a second possible 
cause of the fulminant pulmonary edema and cardiovascular 
collapse. There are 3 types of reactions to protamine classified 
as type I, type II, and type III. The type III reaction is the most 
severe and exerts its profound effects by the formation of large 
heparin-protamine complexes that accumulate in the pulmonary 
circulation. This leads to the release of chemical mediators, a 
profound decrease in BP, and an elevation in pulmonary artery 
pressures that can ultimately lead to right ventricular failure.4 

Documented cases of noncardiogenic, fulminant pulmonary 
edema after the administration of protamine are published.5,6 

One case report describes a reduction in oxygen saturation and 
pink, frothy sputum suctioned from the ETT immediately after 
the administration of protamine.6 A second case report describes 
the same presentation but was unable to state with confidence 
whether the triggering agent was blood products or protamine.5 
The release of endothelial nitric oxide and histamine with mast 
cell degranulation due to rapid infusion of protamine has been 
suggested as the process for protamine reactions.4 Primary risk 
factors for protamine reactions include rapid infusion, prior 
exposure, history of vasectomy, impaired left ventricular function, 
and hemodynamic instability.7 During the slow administration 
of protamine to the patient in the present case, no hemodynamic 
instability was noted. The evidence suggests that slowing the 
infusion rate of protamine when hypotension is encountered is 
often enough to eliminate symptoms. However, in the case of 
severe type III reactions, it may be necessary to re-heparinize 
and resume CPB until stable by reducing the heparin-protamine 
complex size.4 Furthermore, if a patient has a known sensitivity to 
protamine or has had prior exposure, an alternative anticoagulant 
agent may be necessary.4

CONCLUSION
Noncardiogenic pulmonary edema after CPB can be deadly. 
Treatment to restore effective gas exchange and restore 
hemodynamic stability is difficult and multifaceted. In retrospect, 
prompt determination of differential diagnoses and treatment 
involving the surgical, anesthesia, and perfusion teams to resume 
CPB may have changed the outcome in the present case. There 
was no definitive diagnosis of TRALI vs type III protamine 
reaction for this patient. Anesthesia professionals must know the 
risk factors for TRALI and protamine reactions, identify onset 
promptly, and initiate treatment immediately.



Anesthesia eJournal 
Volume 7 - No. 1 2019 

         www.anesthesiaejournal.com 
Page 4

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1. Bitargil M, Arslan C, Basbug HS, et al. Transfusion-related acute lung injury following coronary artery bypass graft surgery. 

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2. Kojima T, Nishisako R, Sato H. A patient with possible TRALI who developed pulmonary hypertensive crisis and acute

pulmonary edema during cardiac surgery. J Anesth. 2012;26:460-463. PMID:22249282.
3. Miller RD. Patient blood management: transfusion therapy. In: Miller RD, ed. Miller’s Anesthesia. 8th ed. 

Philadelphia, PA: Elsevier; 2015:1830-1867.
4. Nussmeier NA, Sarwar MF, Searles BE, et al. Anesthesia for cardiac surgical procedures. In: Miller RD, ed. 

Miller’s Anesthesia. 8th ed. Philadelphia, PA: Elsevier; 2015:2007-2095.
5. Kindler C, Bircher A, Stulz P. Protamine-induced fulminating non-cardiogenic pulmonary edema following cardiopulmonary

bypass. Eur J Cardiothorac Surg. 1996;10(6):463-466. PMID:8817145.
6. Brooks JC. Noncardiogenic pulmonary edema immediately following rapid protamine administration. Ann Pharmacother. 

1999;33(9):927-930. PMID:10492491.
7. Kimmel SE, Sekeres MA, Berlin JA, et al. Risk factors for clinically important adverse events after protamine administration

following cardiopulmonary bypass. J Am Coll Cardiol. 1998;32(7):1916-1922. PMID:9857872.




