HEPATOPULMONARY SYNDROME IN PEDIATRIC PATIENTS WITH PORTAL HYPERTENSION - AN INTEGRATIVE REVIEW

ALBERTO, Letícia Drumond; FAGUNDES, Eleonora Druve Tavares; RODRIGUES, Adriana Teixeira; QUEIROZ, Thaís Costa Nascentes; CASTRO, Gustavo Valverde de; FERREIRA, Alexandre Rodrigues

doi:10.1590/S0004-2803.24612024-040

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ORIGINAL ARTICLE/HEPATOLOGY • Arq. Gastroenterol. 61 • 2024 • https://doi.org/10.1590/S0004-2803.24612024-040 copy

HEPATOPULMONARY SYNDROME IN PEDIATRIC PATIENTS WITH PORTAL HYPERTENSION - AN INTEGRATIVE REVIEW

Síndrome hepatopulmonar em pacientes pediátricos com hipertensão portal - uma revisão integrativa

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Background:

Hepatopulmonary syndrome (HPS) is characterized by the triad of abnormal arterial oxygenation caused by intrapulmonary vascular dilatations (IPVD) in the setting of advanced liver disease or portal hypertension, impacting the patient’s quality of life and survival. There are still many gaps in the literature on this topic, especially in pediatrics, with practices frequently based on extrapolation of data obtained from adults.

Objective:

Provide a synthesis of the current knowledge about HPS in children.

Methods:

The research was carried out through narrative review. The databases used for the search include Medline, Embase, Elsevier, Lilacs and Scielo. The keywords used were “hepatopulmonary syndrome” AND child, children, infant, preschool, pediatric.

Results:

In cirrhotic children, the prevalence of HPS can reach up to 42.5%, and it is even more common in those whose underlying condition is biliary atresia, reaching up to 63%. Screening with pulse oximetry (O₂ saturation <96%), unlike in adults, has low sensitivity in the pediatric age group. Management involves supportive care with oxygen therapy; liver transplantation is the only definitive treatment to reverse the condition and HPS is considered an exceptional criterion for waitlist. The waitlist mortality is similar among children listed by HPS as a special criterion when compared to those listed for other reasons. The reported rates of complete resolution of hypoxemia after liver transplantation are close to 100% in children. The post-liver transplantation survival is similar or slightly lower in children with HPS when compared to those without HPS. Contrary to findings from adults, no differences were found in post- liver transplantation mortality between children of different hypoxemia ranges, although longer mechanical ventilation time and hospital stay were observed in children with PaO₂ <50 mmHg.

Conclusion:

HPS is not an uncommon complication of cirrhosis in children and adolescents, particularly when biliary atresia is the underlying condition. There are still many gaps to be filled regarding the condition, and this article demonstrates that not all data obtained in studies with adults reflects the disease’s behavior in pediatrics, especially concerning prognosis.

Keywords:
Hepatopulmonary syndrome; portal hypertension; liver cirrhosis; hypoxemia; liver transplantation; pediatrics

HIGHLIGHTS

•Hepatopulmonary syndrome (HPS) is not an uncommon complication of cirrhosis in children and adolescents, particularly when biliary atresia is the underlying condition.

•Screening with pulse oximetry (O2 saturation <96%), unlike in adults, has low sensitivity in the pediatric age group.

•No differences were found in post-liver transplantation mortality between children of different hypoxemia ranges, contrary to findings from adults.

•There are still many gaps to be filled regarding the condition and not all data obtained in studies with adults reflects the disease’s behavior in pediatrics, especially concerning prognosis.

All of the criteria below must be present:
1 - Liver disease, portal hypertension or congenital portosystemic shunts.
2 - Abnormal arterial oxygenation defined as alveolar-arterial oxygen gradient (A-aO₂) ≥15 mmHg (or ≥20 mmHg if age >64 years) in arterial blood gas analysis collected in room air with the patient seated at rest at sea level.
3 - Intrapulmonary vascular dilations (IPVD) diagnosed using contrast enhanced transthoracic echocardiography (CE-TTE) or ^99mtechnetium-macroaggregated albumin perfusion lung scan (^99mTc-MAA).

Study	Population	Diagnostic criteria	Prevalence
Noli et al. 2008⁴⁹49. Noli K, Solomon M, Golding F, Charron M, Ling SC. Prevalence of hepatopulmonary syndrome in children. Pediatrics. 2008;121:e522-7.	301 children with liver disease screened by pulse oximetry ≤97% or cirrhosis or severe PH (n=26)	PaO₂ <70 mmHg or A-aO₂ ≥15 mmHg and	Overall: 0.66%
		IPVD (CE-TTE or ^99mTc-MAA)	Cohort selected in screening: 8%
Gupta et al. 2007²¹21. Gupta NA, Abramowsky C, Pillen T, Redd D, Fasola C, Heffron T, et al. Pediatric hepatopulmonary syndrome is seen with polysplenia/interrupted inferior vena cava and without cirrhosis. Liver Transpl. 2007;13:680-6.	211 children referred to LT	PaO₂ <70 mmHg and	3.3%
		IPVD (CE-TTE or ^99mTc-MAA)
Raza et al. 2023²³23. Raza MH, Kwon Y, Kobierski P, Misra AC, Lim A, Goldbeck C, et al. Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease exception policy and outcomes in pediatric patients with hepatopulmonary syndrome requiring liver transplantation. Liver Transpl. 2023;29:134-44.	3082 children listed for LT	Patients accepted by SRTR for extra PELD/MELD HPS points	4%
Mushtaq et al. 2021²⁸28. Mushtaq I, Cheema HA, Malik HS, Waheed N. Indicators Of Hepatopulmonary Syndrome In Patients With Portal Hypertension. Its Various Aetiologies, Clinical Presentations And Outcome. J Ayub Med Coll Abbottabad. 2021;33:14-9.	203 children with PH (48 with EHPVO)	Pulse oximetry <96% or PaO₂ <70 mmHg and	7%
		IPVD (CE-TTE or ^99mTc-MAA)
Sari et al. 2012²⁶26. Sari S, Oguz D, Sucak T, Dalgic B, Atasever T. Hepatopulmonary syndrome in children with cirrhotic and non-cirrhotic portal hypertension: a single-center experience. Dig Dis Sci. 2012;57:175-81.	40 children with PH (60% cirrhotic)	ERS/ILTS	Overall: 10%
			Cirrhotic: 16%
			Non-cirrhotic: 0%
Awad et al. 2014²⁵25. Awad Ml-D, El-Arabi HA, El-Sharnouby KA, Abo Dewan KA. Diagnostic evaluation of hepatopulmonary syndrome in Egyptian children with chronic liver disease. J Egypt Soc Parasitol. 2014;44:97-112.	120 children with CLD (65% cirrhotic)	ERS/ILTS	Overall: 11.7%
			Cirrhotic: 12.8%
			Non-cirrhotic: 9.5%
Tumgor et al. 2008²⁴24. Tumgor G, Arikan C, Yuksekkaya HA, Cakir M, Levent E, Yagci RV, et al. Childhood cirrhosis, hepatopulmonary syndrome and liver transplantation. Pediatr Transplant. 2008;12:353-7.	172 cirrhotic children (22% with BA)	ERS/ILTS	19%
Borkar et al. 2015²⁷27. Borkar VV, Poddar U, Kapoor A, Ns S, Srivastava A, Yachha SK. Hepatopulmonary Syndrome in children: a comparative study of non-cirrhotic vs. cirrhotic portal hypertension. Liver Int. 2015;35:1665-72.	135 children with PH (25% cirrhotic /75% EHPVO)	ERS/ILTS	Overall: 20%
			Cirrhotic: 40%
			EHPVO: 13%
Hoerning et al. 2014¹⁵15. Hoerning A, Raub S, Neudorf U, Müntjes C, Kathemann S, Lainka E, et al. Pulse oximetry is insufficient for timely diagnosis of hepatopulmonary syndrome in children with liver cirrhosis. J Pediatr. 2014;164:546-52.e1-2.	45 cirrhotic children referred for LT (64% with BA)	ERS/ILTS	40%
Pandey et al. 2020¹³13. Pandey S, Sood V, Khanna R, Lal BB, Sood AK, Kabra SK, et al. Natural history, risk factors, and outcome of hepatopulmonary syndrome in pediatric liver diseases. Indian J Gastroenterol. 2020;39:66-74.	104 children with CLD (40% with BA)	ERS/ILTS	Overall: 42.3%
			BA: 57%
			Successful-Kasai: 42%
			Unsuccessful-Kasai: 81%
			Other CLD: 32%
Ceza et al. 2018¹⁴14. Ceza MR, Garcia E, Anselmi CE, Epifanio M, Melere MU, Ferreira CT, et al. Prevalence and characteristics of hepatopulmonary syndrome in children with cirrhosis in southern Brazil. Eur J Gastroenterol Hepatol. 2019;31:10-5.	40 cirrhotic children (48% with BA)	ERS/ILTS	Cirrhotics: 42.5%
			BA: 63%

Study		El- Shabrawi et al.³⁷37. El-Shabrawi MH, Omran S, Wageeh S, Isa M, Okasha S, Mohsen NA, et al. (99m)Technetium-macroaggregated albumin perfusion lung scan versus contrast enhanced echocardiography in the diagnosis of the hepatopulmonary syndrome in children with chronic liver disease. Eur J Gastroenterol Hepatol. 2010;22:1006-12.	Sari et al.²⁶26. Sari S, Oguz D, Sucak T, Dalgic B, Atasever T. Hepatopulmonary syndrome in children with cirrhotic and non-cirrhotic portal hypertension: a single-center experience. Dig Dis Sci. 2012;57:175-81.	Awad et al.²⁵25. Awad Ml-D, El-Arabi HA, El-Sharnouby KA, Abo Dewan KA. Diagnostic evaluation of hepatopulmonary syndrome in Egyptian children with chronic liver disease. J Egypt Soc Parasitol. 2014;44:97-112.	Ceza et al.¹⁴14. Ceza MR, Garcia E, Anselmi CE, Epifanio M, Melere MU, Ferreira CT, et al. Prevalence and characteristics of hepatopulmonary syndrome in children with cirrhosis in southern Brazil. Eur J Gastroenterol Hepatol. 2019;31:10-5.
HPS prevalence		17.5%	10%	11.7%	42.5%
		7/40	4/40	14/120	17/40
CE-TTE	Sensitivity	42.8%	100%	71.4%	94.1%
	Specificity	100%	91.6%	98.1%	4.3%
	Accuracy	90%	92.5%	95%	42.5%
^99mTc-MAA	Sensitivity	100%	25%	100%	35%
	Specificity	100%	100%	94.3%	87%
	Accuracy	100%	92.5%	95%	65%

Study	N	MV time	O₂ time	ICU stay	Hospital stay	Improvement of hypoxemia	Survival	Follow-up
Obbergh et al.³⁵35. Van Obbergh LJ, Carlier M, De Kock M, Otte JB, Moulin D, Veyckemans F. Hepatopulmonary syndrome and liver transplantation: a review of the peroperative management of seven paediatric cases. Paediatr Anaesth. 1998;8:59-64.	7	58h	-	8.7 days	-	100%	-	-
		(13-145)		(3-24)		Average time:
						6 months (0.5-16)
Al- Hussaini et al.¹⁷17. Al-Hussaini A, Taylor RM, Samyn M, Bansal S, Heaton N, Rela M, et al. Long-term outcome and management of hepatopulmonary syndrome in children. Pediatr Transplant. 2010;14:276-82.	14	1 day	9 days	3 days	19 days	100%	85.7%	2-12.5 years
		(1-12)	(1-75)	(2-13)	(9-71)	Average time:
						14 days (3-80)
Willis et al.³⁴34. Willis AD, Miloh TA, Arnon R, Iyer KR, Suchy FJ, Kerkar N. Hepatopulmonary syndrome in children - is conventional liver transplantation always needed? Clin Transplant. 2011;25:849-55.	6	-	-	-	-	100% in 2 months	100%	2.9-10.6 years
Warner et al.¹⁸18. Warner S, McKiernan PJ, Hartley J, Ong E, van Mourik ID, Gupte G, et al. Hepatopulmonary Syndrome in Children: A 20-Year Review of Presenting Symptoms, Clinical Progression, and Transplant Outcome. Liver Transpl. 2018;24:1271-9.	16	1 day	12 days	3 days	20 days	100%	87.5%	5-20
		(1-23)	(2-139)	(2-25)	(11-168)			years
Turine Neto et al.³³33. Turine Neto P, Seda Neto J, da Fonseca EA, Porta G, Pugliese R, Benavides MAR, et al. Impact of hypoxemia on pediatric liver transplantation for hepatopulmonary syndrome. Pediatr Transplant. 2021;25:e13968.	21	1 day	21 days	PaO₂	PaO₂	100%	81%	90 months
		(1-23)	(1-437)	≥50	≥50
				7 days	16 days
				(4-10)	(12-21)
				PaO₂	PaO₂
				<50	<50
				24.5 days	31.5 days
				(14.7-37)	(26.2--80.2)
Hoerning et al.¹⁵15. Hoerning A, Raub S, Neudorf U, Müntjes C, Kathemann S, Lainka E, et al. Pulse oximetry is insufficient for timely diagnosis of hepatopulmonary syndrome in children with liver cirrhosis. J Pediatr. 2014;164:546-52.e1-2.	15	4.9 days	-	-	-	100%	80%	1 year
						Average time:
						14 months (6-18)

FACTORS RELATED TO THE INCREASED OCCURRENCE OF HPS
• More common in cirrhotic than in non-cirrhotic portal hypertension.
• More common in Biliary Atresia than in other chronic liver diseases.
• More common in patients with polysplenia/interrupted inferior vena cava.
• There is no established relationship between the severity of liver disease measured by Child-Pugh, MELD or PELD scores and the occurrence of HPS.
	SCREENING AND DIAGNOSIS
	What do we know?	New perspectives
Screening	SpO₂ <96% has low sensitivity in the pediatric age group.	CBG collected from the ear lobe may be a less invasive screening method than arterial blood gas analysis (but has low specificity, especially in children under 2 years of age).
		The saturation differential between the supine and standing positions ≥ 4% may be promising as a screening method.
Diagnosis of gas exchange failure	Arterial blood gas analysis is the recommended method, but it is invasive and painful.	Other methods such as transcutaneous oxygen tension and the oxyhemoglobin dissociation curve have not yet been validated.
	Cutoff point in pediatrics: A-aO₂ ≥15 mmHg	A- aO₂ above that expected by age group may be more sensitive.
Diagnosis of IPVD	CE-TTE has good accuracy
	^99mTc-MAA has good specificity.	The relationship of lung uptake to whole body uptake may be more sensitive than the percentage of brain uptake.
	PROGNOSIS
Mortality list	Similar among children listed by HPS as a special criteria when compared to those listed for other reasons.
Post-LT survival	Similar or slightly lower in children with HPS when compared to those without HPS.
Influence of pre-LT PaO₂ on post-LT evolution	No difference was observed in post-LT survival between children with HPS of different PaO₂ ranges.
	Longer MV time, ICU stay and hospital stay were observed in children with PaO₂ <50 mmHg.
	A longer time was observed for the resolution of hypoxemia and O₂ weaning in patients with lower PaO₂ and higher shunt fractions.
	Greater survival was observed in children with PaO₂ above 300 mmHg when collected using an inspired fraction of O₂ equal to 100% (type 1 HPS).

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[1] Corresponding author: Eleonora Druve Tavares Fagundes. E-mail: eleonoradruve@medicina.ufmg.br