Edema Pulmonum

Noroyono Wibowo
Pulmonary Edema

• Pulmonary edema is the most common cardiopulmonary com-plication of preeclampsia, which

occurs in up to 3% of women, mainly in the peripartum or postpartum stage, and treatment is
similar to that used in the non obstetric patients.
• Pulmonary edema is a clinical diagnosis characterized by worsening dyspnea and orthopnea along
with signs of respiratory compromise (tachypnea, auditory crackles and rales, hypoxemia).
• Decreased colloid osmotic pressure and endothelial damage results in leakage of fluid in
pulmonary interstitial space which is accentuated by left ventricular dysfunction and increase in
peripheral vascular resistance.
• Lower platelet count, increased serum uric acid and use of magnesium sulfate in the delivery
process were the risk factors for pulmonary edema found by Gandhi in a 92 cohort of women.

Circulation. 1982;65:255–259. Eur Heart J. 2011;32:3147–3197.

Anaesthesia. 2012;67:646–659 Eur Heart J.2005;26:384–416.
J Obstet Gynecol Can. 2014;36; 1065 – 70 Obstet Gynecol. 2003; 101: 511–515.
 Anatomic and Physiologic Respiratory Adaptations to
Pregnancy
Upper airways • Mucosal edema and friability
• Capiary engorgement
(A smaller-sized endotracheal tube may be required for intubation
because of swelling of the arytenoid region of the vocal cords)
Chest walls • Increases in chest wall circumference (6 cm)
• Elevation of the diaphragm (5cm)
• Widening of the costal angels (from 70 to 104)
• Increase in diaphragmatic excursion (1.5 cm)
(All these changes occur before significant increases in uterine size,
maternal body weight, or intra-abdominal pressure)
Respiratory • Respiratory muscle function is unchanged
musculature • Diaphragm and intercostals accessory muscles contribute equally to
tidal volume during pregnancy
• Maximum inspiratory and expiratory pressures are unchanged
 Changes in Respiratory Variables During Pregnancy
Parameter Definiton
Respiratory rate Number of breaths per minute
Tidal volume Volume of air inspired and expired at
each breath
Minute ventilation (RR x Vt) Total amount of air (gas) inspired and
expired each minute
Sum of the volume of air (gas)
participating in gas exchange plus
the one filling the airway’s dead
space (ie, not participating in gas
exchange)
Vital capacity Maximum volume of air that can be
forcibily inspired after a maximum
expiration
Residual volume Volume of air remaining in the lungs
after a maximum expiration
Functional residual capacity (FRC) Volume of air in lungs at resting
expiratory level
Inspiratory capacity Maximum volume of air that can be
inspired from resting expiratory
level
RR, respiratory rate
Change in pregnancy
• No change
• Increase up to 40% since early pregnancy;
remans essentially constant for the
remainder of gestation (100-200 mL)
• Increase up to 40% since early pregnancy
and remains essentially constant for the
remainder of gestation (100-200 mL)
• Unchanged
• Decreases by -20% due to elevation of the
diaphragm
• Decreases by -20% due to elevation of the
diaphragm
• Increases 100-300 mL (5%-10%) as a result
of the reduction in FRC
 Hemodynamic changes in pregnancy
Change with Pregnancy
Measurement % Change (Absolute Change)
Cardiac output 30% - 50%  (2 L/min)
Heart rate 15% - 20%  (12 beats/min)
Stroke volume 20% - 30%  (18 mL)
Mean arterial pressure 0% - 5% 
Central venous pressure No change
Systemic vascular resistance 20% - 30%  (320 dyne – s/cm5)
Left ventricular stroke work index No change
Mean pulmonary artery pressure No change
Pulmonary capillary wedge pressure No change
Pulmonary vascular resistance 30%  (40 dyne – s/cm5)
Data from Refs. 48, 52, 81, 82
 Arterial blood gas (ABG) changes in pregnancy (sea level)
Pregnant State
ABG Measurement Nonpregnant State First Trimester Third Trimester
pH 7.40 7.42 – 7.46 7.43
PaO2 (mm Hg) 93 105 – 106 101 – 106
PaCO2 (mm Hg) 37 28 – 29 26 – 30
Serum HCO3 (mEg/L) 23 18 17
Data from Refs. 44, 57, 63
 Parameter Modification Magnitude Peak
Oxygen consumption (Vo2)  +20% Term
+40%-60% During labor
Oxygen delivery (Do2)  700-400 mL/min Term
Resistance of the pulmonary  -34% 34 wk
circulation
 Pathogenesis of Pulmonary Edema in Preeclampsia

• Decreased plasma colloid osmotic pressure

• Altered endothelial permeability
• High systemic vascular resistance
• Acute hypertensive crisis
• Impaired contractility and diastolic dysfunction

1. Dennis AT, Solnordal CB. Acute pulmonary oedema in pregnant women. Anaesthesia. 2012;67:646-59.
2. Smyth A, Ronco C,Garovic VD. Preeclampsia: a cardiorenal syndrome in pregnancy.Curr Hypertens ep. 2017;19:14-5.
N Engl J Med 2005;353:2788-96
 A Healthy non-pregnant adult B Pregnant woman with acute pulmonary oedema

lungs
lungs

Lym  Pt Lym  Pt

 Pmv increased  P mv
reduced
Pulmonary COP mv
Parterial Parterial
circulation
Pvenous Pvenous
RV VAS RV
VAS
VAS
VAS
LV LV
contractility contractility
utero-placental-
fetal circulation increased
lusitropy afterload reduced
afterload lusitropy
RA
LA increased
LA VAS
VAS preload
preload
VAS
VAS
LV / RV Left / Right ventricle
kidneys
Systemic LA / RA Left / Right atrium
brain circulation Local tissue factors
VAS Vaso-active substances
Lym Lymphatics
Nerves
Acute pulmonary oedema
P Pressure
COP Colloid osmotic pressure
Filtration forces in a healthy non-pregnant adult (a) and in a woman with pre-eclampsia and acute pulmonary oedema (b). There is t Tissue
increased afterload caused by hypertension and reduced lusitropy due to left ventricular structural changes such as left ventricular mv Microvascular
hypertrophy. This leads to increased microvascular forces and increased preload. Reduced colloid osmotic pressure combined with
alterations in capillary permeability further increases the chance of acute pulmonary oedema.

Anaesthesia 2012, 67, 646–659

 Risk Factor (1)
• Unrestricted intravenous fluid therapy (level 3 evidence)
• In a woman with normal renal function and stable serum creatinine levels,
unrestricted fluid administration is not recommended (level 1++ evidence)
• Volume expansion was not beneficial to improve maternal cardiovascular
parameters (level 1++ evidence)

1. Dennis AT, Solnordal CB. Acute pulmonary oedema in pregnant women. Anaesthesia. 2012;67:646-59.
2. Duley L, Williams J, Henderson-Smart DJ. Plasma volume expansion for treatment of pre-eclampsia. Cochrane Database of Systematic Reviews 1999; 4: CD001805.
 Risk Factor (2)
• Intravenous MgSO4 administration (level 1++ evidence)
• Negative inotropic effect, possible reduction in colloid osmotic pressure,
unrestricted parenteral fluid usage in extended MgSO4 administration
• Betamimetic tocolytic (terbutaline, salbutamol)
• B-adrenoceptor effects on capillary permeability, reduced myocardial
contractility
• Nifedipine are associated with less acute pulmonary oedema (level 1++
evidence)

1. Dennis AT, Solnordal CB. Acute pulmonary oedema in pregnant women. Anaesthesia. 2012;67:646-59.
2. Bain ES, Middleton PF, Crowther CA. Maternal adverse effects of different antenatal magnesium sulphate regimens for improving maternal and infant outcomes: a systematic review. BMC Pregnancy Childbirth
2013;13:195.
Risk Factors for the
Development of
Pulmonory Edema in
Pregnancy
Dennis AT, Solnordal CB. Acute pulmonary oedema in pregnant
women. Anaesthesia. 2012;67:646-59.
 Prediction (1)
• Lung ultrasound
• Easy tool to detect pulmonary edema and increased left ventricular end-
diastolic pressures (LVEDP)
• Detects lung edema early before severe deterioration of arterial oxygenation

1. Zieleskiewicz L, et al. Lung ultrasound predicts intertitial syndrome and hemodynamic profile in parturients with severe preeclampsia. Anesthesiology. 2014;120(4):906-14.
2. Castleman JS. Echocardiographic structure and function in hypertensive disorders of pregnancy: a systematic review. Circ Cardiovasc Imaging. 2016;9(9):1-11.
 Prediction (2)
• Echocardiography
• Categorize patients with gestational hypertension or preeclampsia into high-
and low-risk groups
• Echo  reveal cardiac impairment  changes antenatal management 
improve pregnancy outcomes and long-term cardiovascular health
• Important role in guiding fluid balance

1. Zieleskiewicz L, et al. Lung ultrasound predicts intertitial syndrome and hemodynamic profile in parturients with severe preeclampsia. Anesthesiology. 2014;120(4):906-14.
2. Castleman JS. Echocardiographic structure and function in hypertensive disorders of pregnancy: a systematic review. Circ Cardiovasc Imaging. 2016;9(9):1-11.
 Principles of Management of Pulmonary Edema
Diagnosis
• Progressive (not sudden) shortness of breath
• Desaturation
• Tachypnea
• Occasionally hypertension
• Bilateral crackles
• S3/Gallop (not always)
Predisposing factors
• Fluid overload
• Preeclampsia
• Tocolytic treatment
• Uncontrolled hypertension
Management
• Semi-Fowler position: Elevate head and chest to improve ventilation.
• Oxygen: Administer at 10 L/min via nonrebreather face mask or with CPAP (intubation may be required).
• Continuous pulse oximetry and cardiac monitoring.
• Establish IV access; limit intravenous fluid infusion (30-50 mL/h)
• Identify and control predisposing factor(s).
Pharmacologic therapy
• Morphine sulfate: 3-5 mg IV may be given; (avoid in the presence of altered consciousness, increased intracranial
pressure, or severe COPD)
• Furosemide: 20-40 mg IV; repeat as necessary (do not use more than 120 mg/h and give slowly to prevent
ototoxicity)
• Nitroglycerin: 2 in of paste to chest or 1 pill (1/150) until IV access is secured or no other therapy available
• Hydralazine: 5-10 mg IV may be considered if severe hypertension is mediating the pulmonary edema
Monitor
• Input and output
• Blood pressure and fetal heart rate monitoring if appropriate according to GA
 Hemodynamics Systolic function Diastolic function Cardiac structure

Appropriate
Cardiac output No change in Reduction in E/A
increase in left
increase by 30-40% ejection fraction with normal E/e’
ventricular mass*
Normal Pregnancy

Increased total No change in Exaggerated Increased left

vascular resistance ejection fraction reduction in E/A ventricular mass

Gestational Hypertension

Increased total Decreased stroke Decreased stroke Increased left

vascular resistance volume volume ventricular mass

Preeclampsia

Physiological or pathophysiological changes in pregnancy Changes associated with adverse maternal or fetal outcomes

Summary of results. Summary of major findings comparing normotensive pregnancy with gestational
hypertension/preeclampsia and association with adverse outcomes. *A progressive and slight increase in left ventricular
wall thickness and mass is seen during normal pregnancy that regresses postpartum.58,59
Circ Cardiovasc Imaging.2016;9:e004888
 Potential value of echocardiography in hypertensive disorders of pregnancy
Hypertension monitoring :
Severity Systolic BP Diastolic BP Recommended BP measurements
Mild 140-149 90-99 Weekly (twice weekly if < 32 weeks)
Risk assessment for GH/PET:
(history taken by health professional and blood pressure Moderate 150-159 100-109 Twice weekly
assessed at every visit)
Severe ≥ 160 ≥ 110 Every four hours as inpatient (minimum)
STANDARD CARE

Moderate risk High risk

First pregnancy Hypertension in previous If hypertensive, perform dipstick urinalysis at every visit until PET diagnosed. In severe cases, perform blood tests at
least weekly, combined with symptom-based assessment.
Age ≥ 40 years pregnancy
Pregnancy > 10 years ago Chronic kidney disease
Body mass index ≥ 35kg/m2 Autoimmune disease Scan for fetal Plan delivery or
Detailed Delivery before
Family history of PET Diabetes growth and prolong
anatomy scan of 34 weeks only if Plan for
Multiple pregnancy Chronic hypertension wellbeing at least pregnancy
fetus and uterine high risk of delivery with
every 2 weeks if depending on
artery Doppler in fetal/maternal senior input
If one high risk factor or 2 moderate risk factors, low-dose early onset or maternal/fetal
daily aspirin recommended from week 12 high-risk women morbidity
severe disease wellbeing

0 - 20 weeks 21 - 33 weeks 34+ weeks

ECHO-ASSISTED CARE

Echo: Low Risk Standard care

Chronic hypertension Wall thickness < 1.0 cm
See above
Normal systolic function
Lateral e’ ≥ 14 cm/s
GH
Echo: High Risk Intensive management
Wall thickness > 1.0 cm  Frequency of BP and proteinuria monitoring; Appropriate
PET LV ejection fraction <50% medical therapy; Timing of delivery; Echo-assisted fluid
Lateral e’ < 14 cm/s balance in severe cases

Circ Cardiovasc Imaging.2016;9:e004888

 Short-term management strategies in pregnant women with acute pulmonary oedema
Planning and communication
Close observation
Avoidance of precipitants
Early intervention
Prevention of further complications
Multidisciplinary team management [1] (level 3 evidence)
High dependency care and close monitoring with one-to-one nursing/midwifery staff
[1,2] (level 3 evidence)
Continuous monitoring of vital signs [1,2] (level 3 evidence)
Assessment of fetal wellbeing and multidisciplinary planning for safe birth if acute
pulmonary eodema occurs antenatally [1,2] (level 3 evidence)
Strict fluid balance and fluid restriction [8] (level 3 evidence)
Control of blood pressure [84] (level 1++ evidence)
Eclampsia prophylaxis with magnesium sulphate if woman has pre-eclampsia [85] (level
1++ evidence)
Prevention of deep vein thrombosis and pulmonary embolim
Prevention of stress ulceration of the gastrointestinal tract
Anaesthesia 2012, 67, 646–659
 Acute Pulmonary Oedema in a Pregnant Woman
Flow chart for management of pregnant
Active emergency response, call for help and skilled assistance woman with acute pulmonary oedema.
Airway Clear obstruction if present
SBP, systolic blood pressure;DBP,
Upright position
Administer oxygen
diastolic blood pressure.
Breathing • Assess respiratory rate
oxygen saturation
temperature
chest X-ray
arterial blood gases

• Auscultate chest
• Consider non-invasive/invasive ventilation

Circulation • Minimise aortocaval compression

• Maternal Assess
blood pressure
heart rate/rhythm/ecg
fluid balance
• Fetal Heart rate
Gestation
• Intravenous access
Full blood examination
Assess renal function
Assess liver function
Assess coagulation
Cardiac enzymes
• Transthoracic echocardiography
• Continuous monitoring
Hypertension ?
YES SBP > 140 mmHg NO
and/or DBP > 90 mmHg
Normotensive / hypotensive Normotensive / hypotensive
Consider cause - Administer drugs - Consider cause - Administer drugs -

Preeclampsia Nitroglycerin Cardiac disease Furosemide

Endocrine disorder Furosemide Sepsis ± vasodilator
Illicit drug intake Morphine Tocolysis ± inotropic support
Intravenous fluids ± MgSO 4 Amniotic fluid embolism ± mechanical support
Other ± Calcium channel Aspiration
antagonist Intravenous fluids
Other

Stabilise, plan safe birth, transfer to intensive care environment Anaesthesia 2012, 67, 646–659
Aust Prescr 2017;40:59–63
Aust Prescr 2017;40:59–63
Aust Prescr 2017;40:59–63
 Immediate Management
• Non-invasive ventilation
• increased inspired oxygen concentration, displaces fluid from the alveoli into
the pulmonary and subsequently systemic circulation, decreases the work of
breathing, and decreases the need for tracheal intubation
• Urgent reduction of critically high BP
• Nitroglycerin (glyceryl trinitrate) IV, sodium nitroprusside IV
• Target of reduction: 30 mmHg (over 3–5 min)  slower reductions to 140 ⁄ 90
mmHg
• Furosemide IV (bolus 20–40 mg)
• Venodilator and diuretic

Dennis AT, Solnordal CB. Acute pulmonary oedema in pregnant women. Anaesthesia. 2012;67:646-59.
 Immediate Management
• Calcium channel antagonist
• If hypertension persists despite the combination of nitroglycerin / sodium
nitroprusside and furosemide
• Intravenous morphine (2–3 mg)
• Venodilator and anxiolytic
• Prevention of further complication
• Eclampsia prophylaxis (MgSO4 ), prevention of deep vein thrombosis &
pulmonary embolism, prevention of stress ulceration

Dennis AT, Solnordal CB. Acute pulmonary oedema in pregnant women. Anaesthesia. 2012;67:646-59.
 Long-term Management
• Women who suffer from severe pre-eclampsia and
experience acute pulmonary oedema are at increased risk
of cardiovascular complications in later life
• Risk reduction strategies:
• Control of hypertension
• Weight reduction
• Smoking cessation programs
• Dietary modification
• Regular exercise

Dennis AT, Solnordal CB. Acute pulmonary oedema in pregnant women. Anaesthesia. 2012;67:646-59.
Strategies to reduce the
risk of pulmonary
edema in pregnant
women
Dennis AT, Solnordal CB. Acute pulmonary oedema in pregnant
women. Anaesthesia. 2012;67:646-59.
The Oxygenator in Venovenous ECMO.

N Engl J Med 2011;365:1905-14.

 Syncytial nuclear aggregates (SNA) and syncytiotrophoblast (STB) derived
extracellular vesicles (STBEV) isolated by ex vivo placental perfusion method.
Hypothesized targets of placental extracellular vesicles once they are shed from the placenta anddeported in the maternal blood. (A) Syncytial nuclear aggregates are trapped in the maternal lungs and
aremost likely cleared by endothelial cells. (B) In contrast, micro- and nanovesicles can freely pass through the lungs and enter the peripheral circulation where they could potentially have effects on
multiple organ systems in bothnormal and diseased pregnancies, like preeclampsia.
doi: 10.1111/imcb.12049 Cold Spring Harb Perspect Med2015;5:a023028
In severe acute lung injury (ALI) the alveolar epithelium is damaged to such an extent that epithelial repair is
needed before fluid clearance can be achieved. In contrast, in mild ALI the epithelium and its transport functions
are spared, and so pharmacologic stimulation of fluid clearance is possible. If epithelial cell proliferation occurs
after injury, either endogenously or due to the administration of mitogens such as keratinocyte growth factor, then
fluid clearance may be enhanced.
Critical Care2004,8:469-477 (DOI 10.1186/cc29
The Proliferative and Fibrotic Phases of
ARDS.
Molecular targets for new therapies that can lead to endothelial and epithelial barrier stabilization and reversal of increased permeability.
Mechanisms of ventilator-associated lung injury (VALI)

J Clin Invest.2012;122(8):2731-2740
 Prevention
Fulfill the nutritional requirements
• Vitamin A
Vitamin A deficiency results in alterations of lung structure and function. These
alterations could contribute to the impairment of lung function and predispose
to pulmonary disease.
• Vitamin D
Low levels of serum Vitamin D is associated with impaired pulmonary function,
increased incidence of inflammatory, infectious or neoplastic diseases.

1. Esteban-Pretel G, et al. Vitamin A deficiency alters rat lung alveolar basement membrane: reversibility by retinoic acid. J Nutr Biochem. 2010;1(3):27-36.
2. Herr C, et al. The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer. Respir Res. 2012; 12(1): 31.
Major Zn-proteins and their function on the immune system.
Protein Function Effector cells

Structural domains

PLZF (promyelocytic leukemia zinc finger)
NKT cell development NKT cells Savage AK, Constantinides MG, Han J,
Picard D, Martin E, Li B, et al. The
transcrip- tion factor PLZF directs the
effector program of the NKT cell lineage.
Immunity 2008;29:391–403.

Bcl-6 Proliferative expansion of germinal centers
of B cells
Gfi1 T-cells lymphogenesis and pre T-cell
development Differentiation of myeloid
precursors into granulocytes or monocytes
B lymphocyte maturation-induced protein- T-cell homeostasis and effector
1 (Blimp1) differentiation
Terminal differentiation of different
immune cells
B lymphocytes Phan RT, Saito M, Kitagawa Y, Means AR,
Dalla-Favera R. Genotoxic stress regulates
expression of the proto-oncogene Bcl6 in
germinal center B cells. Nat Immunol
2007;8:1132–9.
T-cell precursors Karsunky H, Zeng H, Schmidt T, Zevnik B,
Mature T-cells Kluge R, Schmid KW, et al. Inflammatory
Granulocytes reactions and severe neutropenia in mice
Monocytes lacking the transcriptional repressor Gfi1.
Nat Genet 2002;30:295–300.
T-cells Xin A, Nutt SL, Belz GT, Kallies A. Blimp1:
Short-lived CD8(+) cytotoxic T cells driving terminal differentiation to a T. Adv
Exp Med Biol 2011;780:85–100.

Thpok Necessary and partly redundant for T-cell T-cells Carpenter AC, Grainger JR, Xiong Y, Kanno
differentiation Y, Chu HH, Wang L, et al. The transcrip-
tion factors Thpok and LRF are necessary
and partly redundant for T helper cell dif-
ferentiation. Immunity 2012;37:622–33.
Major Zn-proteins and their function on the immune system.
Protein Function Effector cells

Catalytic and co-catalytic activity

The TNF-alpha Proteolytic release from cellular Macrophages, monocytes, and T- Menghini R, Fiorentino L, Casagrande V, Lauro R, Federici M. The role
converting enzyme membranes of some cytokines, cells for the production of pro- of ADAM17 in metabolic inflammation. Atherosclerosis 2013;228:12–
(TACE) chemokines, growth factors and their inflammatory molecules 7.
receptors, including TNF-α
Calprotectin (S100A8/A9) Heterodimer forms Myeloid cells in particular Nakatani Y, Yamazaki M, Chazin WJ, Yui S. Regulation of S100A8/A9
Zn binding protein expressed on immune neutrophils (calprotectin) binding to tumor cells by zinc ion and its implication for
cells apoptosis-inducing activ- ity. Mediators Inflamm 2005;2005:280–92.
MMPs (1 to 23) Promote chemotaxis by controlling Innate and adaptive immune Dollery CM, McEwan JR, Henney AM. Matrix metalloproteinases and
chemokines activity Remodeling and system cells cardiovascular disease. Circ Res 1995;77:863–8.
repairing tissues
Angio- and embryogenesis
MMP-2 Cleavage of CCL-7 creating chemokine Innate and adaptive immune McQuibban GA, Gong JH, Wong JP, Wallace JL, Clark-Lewis I, Overall
antagonist, Reduction of immune system cells CM. Matrix metalloproteinase processing of monocyte
response chemoattractant proteins generates CC chemokine receptor
antagonists with anti-inflammatory properties in vivo. Blood
2002;100:1160–7.
MMP 1-3-9-13-14 Cleavage of CCL1-2-3-9-13-14, and CXCL- Innate and adaptive immune Zhang K, McQuibban GA, Silva C, Butler GS, Johnston JB, Holden J, et
8 (by MMP-9) Reduction of immune cell system cells al. HIV-induced metalloproteinase processing of the chemokine
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SOD-1 Anti-inflammatory activity Macrophages Marikovsky M, Ziv V, Nevo N, Harris-Cerruti C, Mahler O. Cu/Zn
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Vitamin D deficiency causes deficits in lung function that are primarily explained by differences in lung volume.
Am J Respir Crit Care Med Vol 183. pp 1336–1343,
2011
Conclusion

Pulmonary edema is one of the severe complications of preeclampsia. It is important to

identify the at-risk patient. Risk reduction strategies should include restricted fluid
administration.
The goals of treatment are maternal stabilisation and prompt delivery. Close monitoring and
multdisciplinary team involmnet are needed. Appropriate long-term follow-up is necessary
to reduce the chance of further complications in later life.