Twite, Mark, MA, MB, BChir, FRCP
CRASH 2015: Pulmonary Hypertensive Crisis
Disclosures
CRASH 2015
Pulmonary Hypertensive Crisis
• No financial disclosures
• Some drugs discussed are an off-label application
Mark Twite
MA MB BChir FRCP
Children’s Hospital Colorado & University of Colorado
Anschutz Medical Campus
[email protected]
2
Objectives
Case Scenario
After 30 minutes, understand:
1. Pathophysiology of pulmonary hypertension (PH)
2. Anesthetic management of PH
3. Strategies to prevent and treat a PH crisis
• 18yr old, 70kg female with PH
• Requires Broviac® catheter placement and lung biopsy
• Last Echocardiogram report
– Tricuspid regurgitant (TR) jet 5m/sec (BP 110/70)
– No PFO
• Patient’s medications
–
–
–
–
–
Epoprostenol sodium (Flolan®)
Sildenafil (Revatio®)
Bosentan (Tracleer®)
Aspirin
Nifedipine
3
4
Definition: Pulmonary Hypertension
Question
What is the degree of this patient’s PH?
• mPAP ≥ 25 mmHg at rest
• Normal mean pulmonary artery pressure (mPAP)≈15mmHg
– independent of age, gender, ethnicity
1. Supra-systemic
2. Systemic
3. Sub-systemic
• During exercise mPAP increases slightly
– dependent on age and level of exertion
• PVRI ≥ 3 Wood units m2
• In association with variable degrees of:
• Pulmonary vascular remodeling
• Vasoconstriction
• In-situ thrombosis
5
Nef Heart 2010;96:552-559
6
Twite, Mark, MA, MB, BChir, FRCP
CRASH 2015: Pulmonary Hypertensive Crisis
Case Scenario
ECHO: Systolic TR Velocity
• 18yr old, 70kg female with PH
• Requires Broviac® catheter placement and lung
biopsy
Bernoulli Equation
sPAP = 4v2 + RAP
= 4(52) + 10
= 110 mmHg
• Last Echocardiogram report
– TR jet 5m/sec (BP 110/45)
– No PFO
Limitations:
• Need TR
• Assumes perfect alignment
between Doppler and TR jet
• Patient’s medications
–
–
–
–
–
Epoprostenol sodium (Flolan®)
Sildenafil (Revatio®)
Bosentan (Tracleer®)
Aspirin
Nifedipine
7
8
Definition: Pulmonary Hypertension
Relationship between sPAP and mPAP
• mPAP ≥ 25 mmHg at rest
mPAP = (0.61 x sPAP) + 2 mmHg
• Normal mean pulmonary artery pressure (mPAP)≈15mmHg
sPAP > 40 mmHg highly suggestive PH
Chemla Chest 2009;135:760-768
Rich Chest 2011;139:988-993
• PVRI ≥ 3 Wood units m2
9
Pulmonary Vascular Resistance
Nef Heart 2010;96:552-559
10
Cardiac Cath: Gold standard
1. Hemodynamics
PVR
ΔP
PVR = mPAP – LAP / CO
Normal PVR 1-1.4 Wood units m2 (90 – 120 dynes/s/cm5)
PH PVR > 3 Wood units m2 (240 dynes/s/cm5)
Wood units x 80 = dynes/s/cm5
= ΔP/flow
(TPG) = mPAP – LAP
2. Vasoreactivity testing
Short acting pulmonary vasodilator
PVR
• iNO, IV adenosine
= mPAP – LAP/CO
Drop in mPAP > 10 mmHg
Responders (<10%) may benefit from calcium channel
blockers
3. Rule out associated disease states
Pulmonary vein disease
11
12
Twite, Mark, MA, MB, BChir, FRCP
CRASH 2015: Pulmonary Hypertensive Crisis
Non-invasively monitor patients with PH?
Non-invasively monitor patients with PH?
Increase of 0.1 in S:D ratio
associated with 13% increase in
yearly risk for lung transplant
or death.
• Right ventricle (RV) function
– Ability of the RV to cope with progressive increase
in PA pressure
– Determines patient’s functional capacity and survival
S:D ratio > 1.4 associated with
worse:
• RV function
• hemodynamics
• exercise capability
• clinical status
• Other ECHO parameters (observer angle dependent):
– TAPSE (Tricuspid Annular Plane Systolic Excursion)
– Tei index
13
Non-invasively monitor patients with PH?
Alkon Am J Cardiol 2010;106:430-436
14
PH Classification: What increases mPAP?
PVR = mPAP – LAP/CO
mPAP = LAP + (CO x PVR)
4D-Cardiac MRI
• 3D + time
RV function
indices correlate
with PA pressures
from right heart
cath
1. LAP
– LV systolic / diastolic dysfunction
– Mitral valve stenosis / regurgitation
2. CO
– Congenital heart disease with L to R shunt
WHO I – V
Classification
3. PVR
– Pulmonary parenchymal disease
– Thromboembolic disease
Menon Clin Med Insights: Cardiology 2014:8
15
WHO Classification Conferences
1973 Geneva
1988 Evian
2003 Venice
2008 Dana Point
2011 Panama
– Pulmonary Vascular Research Institute
– Classification specific to children
• 2013 Nice, France
Ivy Curr Opin Cardiol 2012;27:1-12
16
WHO Classification
Evolving research & improved
understanding
•
•
•
•
•
Strumpher JCVA 2011;25:687
17
 Group I
PAH
 Group II
Left sided heart disease
 Group III
Lung disease and/or hypoxia
 Group IV
Chronic embolic/thrombotic
 Group V
Miscellaneous
18
Twite, Mark, MA, MB, BChir, FRCP
CRASH 2015: Pulmonary Hypertensive Crisis
WHO Classification
 Group II
Left heart disease
• Mitral valve disease
 Group I
•
•
•
•
•
PAH
 Group III Lung disease and/or hypoxia
Idiopathic
Heritable: TGF-β Family (BMPR2, ALK-1, Endoglin)
Drugs: Fenfluramine, methamphetamine
Herbal supplements: St. John’s Wort
Associated with:
–
–
–
–
–
–
Congenital heart disease
Connective tissue disease (SLE)
HIV
Chronic hemolytic anemias (Sickle cell disease)
Schistosomiasis
Pulmonary veno-occlusive disease (PVOD)
•
•
•
•
•
COPD
BPD
Interstitial lung disease
Sleep-disordered breathing
High altitude
 Group IV Chronic embolic/thrombotic
 Group V Miscellaneous
• Myeloproliferative disorders
• Metabolic disorders
19
20
PH: Congenital Heart Disease
Pediatric Pulmonary Hypertension
Biventricular Circulation
– mPAP > 25mmHg & PVRI > 3 Wood units m2
– Positive vasodilator response is a fall in mPAP and
PVRI by 20% with no change in CO
Chromosomal or
Genetic
syndrome
Pathological
insults on a
growing lung
Univentricular Circulation
Lung
development
abnormalities
– following cavopulmonary anastomosis
– PVRI > 3 Wood units m2 or TPG > 6 mmHg
EVEN IF mPAP < 25mmHg
21
Adult: Epidemiology & Survival
22
Pediatric: Epidemiology & Survival
• Rare disease 5-15 cases / million
• REVEAL
TOPP1
– Age of presentation increased from 35yrs in 1980s
to 53yrs
– Male:Female 1:4
– 1yr survival 80-90%
– 3yr survival 60%
Benza Chest 2012; 142
Del Cerro Pulm Circ 2011;1:286-98
23
• Global registry
• At diagnosis:
REVEAL2
• USA registry
• At diagnosis:
– Median age 7yrs
– Dyspnea & fatigue
– 43% other disorders
–
–
–
–
–
• 85% CHD, 12% BPD
– Chromosome anomalies
13% (Trisomy 21)
1Berger
Lancet 2012; 379:537-46
2Barst
Median age 7yrs
Dyspnea
mPAP 56mmHg
PVRI 17 Wood units m2
5yr survival 75%
Circulation 2012;125:113-122
24
Twite, Mark, MA, MB, BChir, FRCP
CRASH 2015: Pulmonary Hypertensive Crisis
Case Scenario
Question
With no PFO on ECHO, what may happen during an
acute increase in PVR?
• 18yr old, 70kg female with PH
• Requires Broviac® catheter placement and lung biopsy
• Last Echocardiogram report
– TR jet 5m/sec (BP 110/45)
– No PFO
Option
1
2
3
4
• Patient’s medications
Epoprostenol sodium (Flolan®)
Sildenafil (Revatio®)
Bosentan (Tracleer®)
Aspirin
Nifedipne
–
–
–
–
–
BP
SpO2
25
26
Pathophysiology of Pulmonary Circulation
Physiology of Pulmonary Circulation
Poiseuille’s Law R = π r4 p / 8nl
• Pulmonary vascular bed is a high-flow low-pressure
circulation system
•
•
•
•
Large cross sectional area
High compliance arterioles with thin walls (less smooth muscle cells)
Pressure and resistance are 10% of systemic circulation
Sympathetic nervous system innervation
8mm ≈ 1 x R
4mm ≈ 16 x R
2mm ≈ 256 x R
• Pulmonary arteries
• Constrict with hypoxia (Euler-Liljestrand reflex) and relax with
hyperoxia
• Respond to changes in cardiac output and airway pressure
FIXED
Structural changes decrease X-sectional area
REACTIVE
Vascular smooth muscle contraction
27
28
PH: Pathology
PH: Pathology
Plexiform lesion
1. Endothelial
Intimal hyperplasia
2. Smooth muscle cell (SMC)
Medial hypertrophy
3. Adventitial
Proliferation
Less distensible vessel
Fixed vs. Reactive
A. Vasculopathy of the pulmonary arteriole cells
B. Vasoconstriction
C. Thrombosis
Normal
29
Cool Chest 2005;128:656-571
30
Twite, Mark, MA, MB, BChir, FRCP
CRASH 2015: Pulmonary Hypertensive Crisis
PVR changes with pH and PaO2
PH: Ventilation
Ventilation strategy for PH:
• Oxygen
• Tidal volume 6ml/kg
• Rate – mild hypocarbia
• Optimum PEEP
• Recruitment maneuvers
• Drain pleural
effusions/pneumothorax
Adapted from West’s Essential Physiology 10th Ed.
Rudolph J Clin Invest 1966;45:399-411
31
Discussion
32
Case Scenario
• 18yr old, 70kg female with PH
• Requires Broviac® catheter placement and lung biopsy
• Last Echocardiogram report
What will be your airway and ventilation
strategy to facilitate the lung biopsy?
– TR jet 5m/sec (BP 100/45)
– No PFO
Concerns?
• Patient’s medications
Does anyone want a type & screen or cross
match?
–
–
–
–
–
Epoprostenol sodium (Flolan®)
Sildenafil (Revatio®)
Bosentan (Tracleer®)
Aspirin
Nifedipine
33
34
Case Scenario
Endothelin Pathway
Bosentan (Tracleer®)
ETA & ETB antagonist
Ambrisentan (Letairis®)
ETA selective antagonist
Prostacyclin Pathway
(Flolan®)
Epoprostenol
Treprostinil (Remodulin®)
Iloprost (Ventavis®)
• 18yr old, 70kg female with PH
• Requires Broviac® catheter placement and
lung biopsy
• Flolan® running via PIV
• NPO status good
Nitric Oxide Pathway
iNO
Sildenafil (Revatio®)
Tadalafil (Adcirca®)
35
36
Twite, Mark, MA, MB, BChir, FRCP
CRASH 2015: Pulmonary Hypertensive Crisis
PH: Peri-operative risk
Question
What is this patient’s risk of cardiac arrest under
general anesthesia?
1.
2.
3.
4.
10 times LESS
SAME
10 times GREATER
40 times GREATER
37
Population
Procedures (n)
Cardiac
arrest (%)
Death
(%)
Reference
All children
All (1,089,200)
0.027
0.004
Morray et al.
Anesthesiology
2000;93:6-14
All children
All except cardiac surgery
(88,639)
0.029
0.016
Flick et al.
Anesthesiology
2007;106:226-237
Children with
heart disease
Cardiac cath (4,454)
0.49
0.08
Bennett et al.
Pediatr Anesth
2005;15:1083-88
Children with
PAH
All except cardiac surgery
(256)
1.17
0.78
Carmosino et al
Anesth Analg
2007;104:521-527
Children with
PAH
Cardiac cath (141)
2.13
1.42
Carmosino et al
Anesth Analg
2007;104:521-527
Children with
PAH
Cardiac cath (70)
5.71
1.43
Taylor et al
Br J Anaesth
2007;98:657-661
Children with
PAH
Cardiac cath (128)
0.8
0
Williams et al
Pediatr Anesth
2010;20:28-37
Adapted from Friesen Pediatr Anesthesia 2008;18:208-216
PH: Peri-operative risk
Discussion
Population
Procedures (n)
Cardiac
arrest (%)
Death
(%)
Reference
All children
All (1,089,200)
0.027
0.004
Morray et al.
Anesthesiology
2000;93:6-14
All children
All except cardiac surgery
(88,639)
0.029
0.016
Flick et al.
Anesthesiology
2007;106:226-237
Children with
heart disease
Cardiac cath (4,454)
x409
0.08
Bennett et al.
Pediatr Anesth
2005;15:1083-88
Children with
PAH
All except cardiac surgery
(256)
1.17
0.78
Carmosino et al
Anesth Analg
2007;104:521-527
Children with
PAH
Cardiac cath (141)
2.13
1.42
Carmosino et al
Anesth Analg
2007;104:521-527
Children with
PAH
Cardiac cath (70)
5.71
1.43
Taylor et al
Br J Anaesth
2007;98:657-661
Children with
PAH
Cardiac cath (128)
0.8
0
Williams et al
Pediatr Anesth
2010;20:28-37
Adapted from Friesen Pediatr Anesthesia 2008;18:208-216
38
What is your plan for induction of anesthesia?
Use the existing PIV?
Drugs?
39
40
Hemodynamic effects of anesthetic drugs
PH: Goals of anesthetic management
1. Avoid increases in pulmonary vascular
resistance (PVR)
• Hypoxia, Hypercarbia, Metabolic acidosis
• Sympathetic stimulation secondary to noxious stimuli
(endotracheal intubation, surgery, tracheal suctioning)
2. Avoid systemic hypotension
•
•
Decreases coronary artery blood flow leading to
myocardial ischemia and ventricular dysfunction
A rapid increase in PVR to a point where PAP > SBP
leads to RV failure especially if there is no PFO (or
atrial septostomy)
41
42
Twite, Mark, MA, MB, BChir, FRCP
CRASH 2015: Pulmonary Hypertensive Crisis
Preparation
Pulmonary Hypertensive Crisis
• iNO in the room
– Set-up and working, weaning plan to avoid rebound PH
•
•
•
•
• Anesthesia drugs
– 4% topical lidocaine spray for vocal cords
– Balanced technique
– Resuscitation drugs ready
• Communicate with surgeon
Pulse-oximetry desaturation
Hypotensive
Tachycardia
Bradycardia
ECG ST segment changes
Sats 70%
BP 60/30
HR 30
– High risk patient
– Local anesthetic
• Post-op plan
• Communicate with PH team
43
PH: Pathophysiology of RV Failure
44
Pulmonary Hypertensive Crisis
Treatment
Rationale / Therapy
Administer 100% O2
↑PAO2 and PaO2 will ↓PVR
Hyperventilate
PVR is directly related to PaCO2
Exclude pneumothorax
Optimize ventilation
Mean Airway Pressure
Correct metabolic acidosis
Avoid Palv > Part
PVR is directly related to H+ level
Administer pulmonary vasodilators iNO
Price Crit Care 2010;14:R169
45
Disposition and Follow-up
Analgesia
Decrease sympathetic mediated PVR
Support cardiac output
Adequate preload, epinephrine, vasopressin
ECMO
Support cardiac output and oxygenation
46
Summary
• Extubated and returned to the ICU
• Knowledge & therapy of PH is an evolving field
• Returned emergently to the OR 3 hours later
• Patients with systemic PH are HIGH risk
– Bleeding via Chest Tube
– Hypoxic and hypotensive
• Goals for anesthesia in PH
– Preparation
– Good airway management
– Balanced anesthetic drug technique
47
48
Twite, Mark, MA, MB, BChir, FRCP
CRASH 2015: Pulmonary Hypertensive Crisis
Bibliography
Thankyou!
1. Alkon J, Humpl T, Manlhiot C, McCrindle BW, Reyes JT, Friedberg MK. Usefulness of the right ventricular systolic to diastolic duration ratio to predict functional capacity and survival in children with pulmonary arterial hypertension. The American journal of cardiology. Aug 1 2010;106(3):430‐436.
2. Alswang M, Friesen RH, Bangert P. Effect of preanesthetic medication on carbon dioxide tension in children with congenital heart disease. Journal of cardiothoracic and vascular anesthesia. Aug 1994;8(4):415‐419.
3. Archer SL, Weir EK, Wilkins MR. Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation. May 11 2010;121(18):2045‐2066.
4. Barst RJ, McGoon MD, Elliott CG, Foreman AJ, Miller DP, Ivy DD. Survival in childhood pulmonary arterial hypertension: insights from the registry to evaluate early and long‐term pulmonary arterial hypertension disease management. Circulation. Jan 3 2012;125(1):113‐122.
5. Bennett D, Marcus R, Stokes M. Incidents and complications during pediatric cardiac catheterization. Paediatric anaesthesia. Dec 2005;15(12):1083‐1088.
6. Berger RM, Beghetti M, Humpl T, et al. Clinical features of paediatric pulmonary hypertension: a registry study. Lancet. Feb 11 2012;379(9815):537‐546.
7. Berger S, Konduri GG. Pulmonary hypertension in children: the twenty‐first century. Pediatric clinics of North America. Oct 2006;53(5):961‐987, x.
8. Blaise G, Langleben D, Hubert B. Pulmonary arterial hypertension: pathophysiology and anesthetic approach. Anesthesiology. Dec 2003;99(6):1415‐1432.
9. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation. Jan 20 2004;109(2):159‐165.
10. Carmosino MJ, Friesen RH, Doran A, Ivy DD. Perioperative complications in children with pulmonary hypertension undergoing noncardiac surgery or cardiac catheterization. Anesthesia and analgesia. Mar 2007;104(3):521‐527.
11. Cerro MJ, Abman S, Diaz G, et al. A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: Report from the PVRI Pediatric Taskforce, Panama 2011. Pulmonary circulation. 2011;1(2):286‐298.
12. Chemla D, Castelain V, Provencher S, Humbert M, Simonneau G, Herve P. Evaluation of various empirical formulas for estimating mean pulmonary artery pressure by using systolic pulmonary artery pressure in adults. Chest. Mar 2009;135(3):760‐768.
[email protected]
49
13. Cool CD, Groshong SD, Oakey J, Voelkel NF. Pulmonary hypertension: cellular and molecular mechanisms. Chest. Dec 2005;128(6 Suppl):565S‐571S.
14. Farber HW, Loscalzo J. Pulmonary arterial hypertension. The New England journal of medicine. Oct 14 2004;351(16):1655‐1665.
15. Fischer LG, Van Aken H, Burkle H. Management of pulmonary hypertension: physiological and pharmacological considerations for anesthesiologists. Anesthesia and analgesia. Jun 2003;96(6):1603‐1616.
16. Flick RP, Sprung J, Harrison TE, et al. Perioperative cardiac arrests in children between 1988 and 2005 at a tertiary referral center: a study of 92,881 patients. Anesthesiology. Feb 2007;106(2):226‐237; quiz 413‐224.
17. Friesen RH, Williams GD. Anesthetic management of children with pulmonary arterial hypertension. Paediatric anaesthesia. Mar 2008;18(3):208‐216.
18. Haworth SG. The management of pulmonary hypertension in children. Archives of disease in childhood. Jul 2008;93(7):620‐625.
19. Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease; a description of six grades of structural changes in
the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation. Oct 1958;18(4 Part 1):533‐547.
20. Hickey PR, Hansen DD, Cramolini GM, Vincent RN, Lang P. Pulmonary and systemic hemodynamic responses to ketamine in infants with normal and elevated pulmonary vascular resistance. Anesthesiology. Mar 1985;62(3):287‐293.
21. Hickey PR, Hansen DD, Strafford M, Thompson JE, Jonas RE, Mayer JE. Pulmonary and systemic hemodynamic effects of nitrous oxide in infants with normal and elevated pulmonary vascular resistance. Anesthesiology. Oct 1986;65(4):374‐378.
22. Hickey PR, Hansen DD, Wessel DL, Lang P, Jonas RA. Pulmonary and systemic hemodynamic responses to fentanyl in infants. Anesthesia and analgesia. May 1985;64(5):483‐486.
23. Hickey PR, Hansen DD, Wessel DL, Lang P, Jonas RA, Elixson EM. Blunting of stress responses in the pulmonary circulation of infants by fentanyl. Anesthesia and analgesia. Dec 1985;64(12):1137‐1142.
24. Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. Journal of the American College of Cardiology. Jun 16 2004;43(12 Suppl S):13S‐24S.
25. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. The New England journal of medicine. Sep 30 2004;351(14):1425‐1436.
26. Ivy D. Advances in pediatric pulmonary arterial hypertension. Current opinion in cardiology. Mar 2012;27(2):70‐81.
27. MacKnight B, Martinez EA, Simon BA. Anesthetic management of patients with pulmonary hypertension. Seminars in cardiothoracic and vascular anesthesia. Jun 2008;12(2):91‐96.
28. MacNee W. Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease. Part two. American journal of respiratory and critical care medicine. Oct 1994;150(4):1158‐1168.
29. MacNee W. Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease. Part One. American journal of respiratory and critical care medicine. Sep 1994;150(3):833‐852.
51
50
30. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. Sep 26 2006;114(13):1417‐1431.
31. Morray JP, Geiduschek JM, Ramamoorthy C, et al. Anesthesia‐related cardiac arrest in children: initial findings of the Pediatric Perioperative Cardiac Arrest (POCA) Registry. Anesthesiology. Jul 2000;93(1):6‐14.
32. Nef HM, Mollmann H, Hamm C, Grimminger F, Ghofrani HA. Pulmonary hypertension: updated classification and management of pulmonary hypertension. Heart. Apr 2010;96(7):552‐559.
33. Penaloza D, Arias‐Stella J. The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness. Circulation. Mar 6 2007;115(9):1132‐1146.
34. Price LC, Wort SJ, Finney SJ, Marino PS, Brett SJ. Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review. Crit Care. 2010;14(5):R169.
35. Rashid A, Ivy D. Severe paediatric pulmonary hypertension: new management strategies. Archives of disease in childhood. Jan 2005;90(1):92‐98.
36. Rich JD, Shah SJ, Swamy RS, Kamp A, Rich S. Inaccuracy of Doppler echocardiographic estimates of pulmonary artery pressures in patients with pulmonary hypertension: implications for clinical practice. Chest. May 2011;139(5):988‐993.
37. Rudolph AM, Yuan S. Response of the pulmonary vasculature to hypoxia and H+ ion concentration changes. The Journal of clinical investigation. Mar 1966;45(3):399‐411.
38. Shukla AC, Almodovar MC. Anesthesia considerations for children with pulmonary hypertension. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. Mar 2010;11(2 Suppl):S70‐73.
39. Strumpher J, Jacobsohn E. Pulmonary hypertension and right ventricular dysfunction: physiology and perioperative management. Journal of cardiothoracic and vascular anesthesia. Aug 2011;25(4):687‐704.
40. Taylor CJ, Derrick G, McEwan A, Haworth SG, Sury MR. Risk of cardiac catheterization under anaesthesia in children with pulmonary hypertension. British journal of anaesthesia. May 2007;98(5):657‐661.
41. Williams GD, Jones TK, Hanson KA, Morray JP. The hemodynamic effects of propofol in children with congenital heart disease. Anesthesia and analgesia. Dec 1999;89(6):1411‐1416.
42. Williams GD, Maan H, Ramamoorthy C, et al. Perioperative complications in children with pulmonary hypertension undergoing general anesthesia with ketamine. Paediatric anaesthesia. Jan 2010;20(1):28‐37.
43. Williams GD, Philip BM, Chu LF, et al. Ketamine does not increase pulmonary vascular resistance in children with pulmonary hypertension undergoing sevoflurane anesthesia and spontaneous ventilation. Anesthesia and analgesia. Dec 2007;105(6):1578‐
1584, table of contents.
44. Wolfe RR, Loehr JP, Schaffer MS, Wiggins JW, Jr. Hemodynamic effects of ketamine, hypoxia and hyperoxia in children with surgically treated congenital heart disease residing greater than or equal to 1,200 meters above sea level. The American journal of cardiology. Jan 1 1991;67(1):84‐87.
52