Biomarkers associated with postoperative cardiac surgery clinical outcomes in pediatric intensive care

Souza, Andressa Rodrigues de; Lima, Regina Aparecida Garcia de; Lopes Júnior, Luís Carlos

doi:10.37689/acta-ape/2021AR00171

Brasil

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Review Article • Acta Paul Enferm. 34 • 2021 • https://doi.org/10.37689/acta-ape/2021AR00171 linkcopy

Biomarkers associated with postoperative cardiac surgery clinical outcomes in pediatric intensive care

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Objective: To summarize and critically analyze the literature on potential biomarkers associated with clinical outcomes in the postoperative cardiac surgery period in infants and children under intensive care.

Methods: Integrative review, whose search was carried out in September and December 2019 in the databases MEDLINE, ISI Web of Knowledge, Cochrane Central Register of Controlled Trials, Embase, Cumulative Index to Nursing and Allied Health Literature, Science Direct, and Latin America and Caribbean Center on Health Sciences Information to answer the following guiding question: “What is the scientific evidence on potential biomarkers associated with clinical outcomes in the postoperative cardiac surgery period in infants and children under intensive care?”. Original articles published between 2000 and 2019 in English, Spanish, or Portuguese were included. Gray literature was excluded.

Results: Eight articles made up the final sample (six descriptive observational prospective studies and two prospective cohort studies). Most studies, pediatric patients were submitted to the intraoperative cardiopulmonary bypass technique during congenital heart disease surgeries. The potential biomarkers analyzed were molecules that participate in immune-inflammatory processes, mainly proinflammatory cytokines such as IL-1β, IL-6, IL-8, and tumor necrosis factor-alpha and its receptor, as well as anti-inflammatory cytokines such as IL-10.

Conclusion: The IL-6, IL-8, and IL-10 cytokines, cortisol, and lactate showed as promising molecules for elucidating mechanisms underlying clinical outcomes in the postoperative cardiac surgery period in infants and/or children under intensive care. These molecules can take on a preventive role by being used as a diagnostic and prognostic tool in the future in a protocol that allows to identify patients with high risk to develop clinical complications during the postoperative period.

Study/Design	Criteria														Level of evidence
Study/Design	1	2	3	4	5	6	7	8	9	10	11	12	Score	%	Level of evidence
Trotter et al.⁽⁴⁰⁾ (PDO)	Y	Y	Y	N	Y	Y	NR	Y	Y	Y	NR	Y	^a a Scale modified by Machotka et al. (2009).(39) This modified tool has 12 criteria that assess methodological elements of the studies. In this tool, each affirmative answer gets a score of 1 point, and the total score, which can reach 12 points, is converted into a percentage (0 to 100%). 9/12	75	VI
ElBarbary et al.⁽⁴¹⁾ (PDO)	Y	Y	Y	N	Y	Y	NR	Y	Y	Y	NR	Y	^a a Scale modified by Machotka et al. (2009).(39) This modified tool has 12 criteria that assess methodological elements of the studies. In this tool, each affirmative answer gets a score of 1 point, and the total score, which can reach 12 points, is converted into a percentage (0 to 100%). 9/12	75	VI
Madhok et al.⁽⁴²⁾ (PDO)	Y	Y	Y	N	Y	Y	NR	Y	Y	Y	NR	Y	^a a Scale modified by Machotka et al. (2009).(39) This modified tool has 12 criteria that assess methodological elements of the studies. In this tool, each affirmative answer gets a score of 1 point, and the total score, which can reach 12 points, is converted into a percentage (0 to 100%). 9/12	75	VI
Allen et al.⁽⁴³⁾ (PDO)	Y	Y	Y	N	Y	Y	NR	Y	Y	Y	NR	Y	^a a Scale modified by Machotka et al. (2009).(39) This modified tool has 12 criteria that assess methodological elements of the studies. In this tool, each affirmative answer gets a score of 1 point, and the total score, which can reach 12 points, is converted into a percentage (0 to 100%). 9/12	75	VI
Allan et al.⁽⁴⁴⁾ (PDO)	Y	Y	Y	N	Y	Y	NR	Y	Y	Y	NR	Y	^a a Scale modified by Machotka et al. (2009).(39) This modified tool has 12 criteria that assess methodological elements of the studies. In this tool, each affirmative answer gets a score of 1 point, and the total score, which can reach 12 points, is converted into a percentage (0 to 100%). 9/12	83	VI
Crow et al.⁽⁴⁵⁾ (PDO)	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	NR	Y	^a a Scale modified by Machotka et al. (2009).(39) This modified tool has 12 criteria that assess methodological elements of the studies. In this tool, each affirmative answer gets a score of 1 point, and the total score, which can reach 12 points, is converted into a percentage (0 to 100%). 10/12	75	VI

	Selection				Comparability	Outcomes			Score	Level of evidence
	Selection of the exposed cohort	Selection of the nonexposed cohort	Exposure	Result of interest was not present at the beginning	Comparability of cohorts based on the design or analysis	Outcome evaluation	Follow-up time	Follow-up adequacy	Score	Level of evidence
Correia et al.⁽⁴⁾ (PC)	*	*	*		*	*	*		^b b Newcastle-Ottawa Scale,(38) which is specific for study type. This scale evaluates three great domains: patient selection (0 to 4 stars); comparability of patients in the cohorts (0 to 2 stars); and outcomes (0 to 3 stars). The maximum possible score is 9 points. Scores for cohort studies and for prospective observational studies are not directly comparable. 6/9	IV
Wald et al.⁽⁷⁾ (PC)	*	*	*			*	*		^b b Newcastle-Ottawa Scale,(38) which is specific for study type. This scale evaluates three great domains: patient selection (0 to 4 stars); comparability of patients in the cohorts (0 to 2 stars); and outcomes (0 to 3 stars). The maximum possible score is 9 points. Scores for cohort studies and for prospective observational studies are not directly comparable. 5/9	IV

Reference/Country	Objectives	Sample/Average age	Evaluated biomarkers	Blood collection protocol	Analyzed clinical variables	Main results
Trotter et al.⁽⁴⁰⁾ (Germany)	To investigate the plasma levels of progesterone, IL-8, and IL-10 during and after CPB in infants/children according to gender and PO cardiac morbidities	n = 18 (10M;8F)/19 months (2 months to 15 years)	Progesterone, IL-8, and IL-10	Immediately before surgery; after anesthesia induction and heparin administration; ten minutes after the beginning of CPB; after disconnecting the protamine administration circuit; six hours, one day, three days, and seven days after surgery	CPB time; aortic clamp; mechanical ventilation; days in the PICU; and MOD^ DMO = multiple organ dysfunction (renal, respiratory, liver, heart, hematologic, and neurological).	After CPB, all the patients showed an increase in the levels of progesterone, IL-8, and IL-10, with the IL-10 level being considerably higher in girls (p < 0.05). Six out of ten boys and no girl showed MOD (p = 0.01)
ElBarbary et al.⁽⁴¹⁾ (Saudi Arabia)	To examine the behavior of the TNF-α p55 receptor before and after CPB and its relationship with the development of cytokinemia and clinical complications such as SIRS and MOD^ DMO = multiple organ dysfunction (renal, respiratory, liver, heart, hematologic, and neurological).	n = 20 (12M;8F)/ 4.4 years	IL-1β, TNF-α p55 and p75 receptors, TNF-α, IL-6, and IL-8	Immediately before CPB; two hours and one day after the beginning of CPB	Hypotension; coagulopathy; liver dysfunction; kidney dysfunction; respiratory dysfunction; and capillary leak	The levels of the TNF p55 receptor increased considerably two hours after CPB and remained stable up to one day after the procedure, showing a positive correlation with the presence of SIRS (r = 0.74, p = 0.0001) and MOD (r = 0.84, p = 0.0007). The preoperative levels of the TNF p55 receptor were predictors of hypotension, respiratory dysfunction, and coagulopathy in the patients (p < 0.005)
Madhok et al.⁽⁴²⁾ (United States)	To measure cytokine levels in the PO period of surgeries to treat congenital heart disease and correlate them with intraoperative variables and PO outcomes	n = 20 (11M;9F) 15 months (0.1 to 180)	TNF-α, IL-1β, IL-12, IL-6, IL-8, and IL-10	Preoperative (after anesthesia induction); one to three days in the PO period	Diagnosis; CPB time; aortic clamp; days in the PICU; mechanical ventilation; days in the hospital; inotropic score; venous oxygen saturation; and lactate	The levels of IL-6, IL-8, and IL-10 increased considerably in the first PO period (p < 0.01), and the IL-8 level showed a positive correlation with the need for inotropic support (r = 0.470, p = 0.057) and an inverse correlation with the IL-6 (r = -0.575; p = 0.016) and IL-8 (r = -0.614, p = 0.009) level and with the venous oxygen saturation
Allen et al.⁽⁴³⁾ (United Kingdom)	To determine the relationship between IL-10 observed levels, the genetic polymorphism that influences these levels, and the occurrence of severe hyperresponsiveness to endotoxin in children submitted to heart surgery with the use of CPB	n = 36 (21M;15F) 6.5 months (9 days to 24 months)	IL-10, IL-1 receptor antagonist, IL-6, IL-8, and TNF-α	After anesthesia induction and insertion of the arterial catheter; during the aortic clamp release; at the end of CPB; after ultrafiltration; when arriving at the PICU; and 2, 4, 8, 14,18, 24, and 48 hours after admission to the PICU	Duration of mechanical ventilation; days in the PICU; presence of sepsis; immunoparalysis; SIRS; and death	The response of blood IL-10 (p < 0.001), TNF-α (p < 0.001), and IL-6 (p < 0.05) to a lipopolysaccharide was reduced up to 50% in the first PO period in comparison with the response found in the preoperative period. Immunoparalysis was partially related to high circulating levels of IL-10 (p < 0.001), which exposed the patients to high risk of complications in the PO period. In addition, the IL-10 GCC genotype seemed to be a marker for risk of immunoparalysis (p < 0.01)
Allan et al.⁽²⁶⁾ (United States)	To evaluate the relationship between inflammatory status and clinical outcomes in infants submitted to CPB	n = 93 (61M;32F) 37 days (2 to 264)	CRP, IL-6, IL-8, IL-10, TNF-α, and IL-1β	Before CPB; immediately after CPB; and 6, 12, and 24 hours after CPB	Preoperative: use of inotropes and mechanical ventilation, for example; intraoperative: CPB, aortic clamp, administered hemoderivatives; PO: duration of intubation, days in the PICU and the hospital, and lactate concentration	The pre-CPB IL-6 and CRP levels were higher in young infants (p < 0.001). The levels of IL-6, IL-8, and IL-10 increased in the PO period, but only IL-6 (r = 0.29, p = 0.006) and IL-8 (r = 0.30, p = 0.004) showed a correlation with a longer PICU stay and the need for hemoderivatives administration. There was a positive correlation between IL-8 and lactate concentration 24 hours after surgery (r = 0.44, p < 0.001)
Wald et al.⁽⁷⁾ (United States)	To examine the effect of CPB on the HPA axis, specifically on the adrenal responsiveness, of infants/children with congenital heart disease submitted to surgeries to treat the problem	n = 52 (25M;27F) 1.6 years (0.4 to 6.5)	Total cortisol, globulin-bound cortisol, free serum cortisol, and albumin	Preoperative (immediately after the central catheter incision); PO: 30 minutes after surgery and 60 minutes after administration of cosyntropin	Inotropic score^* * Inotropic score = dopamine x 1 + dopamine x 1 + milrinone x 15 + epinephrine x 100 + norepinephrine x 100 + phenylephrine x 100. ; hemodynamic indexes and use of supplementary corticoids; heart surgery adjusted score risk; duration of mechanical ventilation; days in the PICU	Decreased levels of globulin-bound cortisol were associated with a considerable increase in free cortisol levels. After stimulation with CPB, they were associated with worse clinical outcomes, such as a longer PICU stay (p = 0.02), higher inotropic scores (p = 0.05), greater requirement for isotonic solutions (p = 0.007), and a longer period on mechanical ventilation (p = 0.013)
Crow et al.⁽⁴⁴⁾ (United States)	To evaluate whether there was variability in blood dexamethasone levels after the administration of a dosage of 1 mg/kg before CPB in infants	n = 32 (13M;19F) 199±114 days (group with a low dexa level) and 225±363 days (group with a high dexa level)	Dexamethasone, cortisol, ACTH, IL-6, IL-8, and IL-10	After anesthesia induction; after ultrafiltration; at the admission to the PICU; 4, 8, 12, and 24 hours after surgery	Congenital heart disease surgery adjusted score risk; time of CPB; aortic clamp; inotropic score; duration of mechanical ventilation; days in the PICU	The administration of 1 mg/kg of dexamethasone before CPB originated different levels of the drugs in the infants at the arrival at the PICU, which were highly correlated with the magnitude of the response to stress/cortisol in the PO period (p < 0.05). Patients with high dexamethasone levels had lower cortisol levels in the PO period in comparison with the baseline levels (pre-CPB) (p = 0.018)
Correia et al.⁽⁴⁾ (United Kingdom)	To evaluate the change in key metabolite levels after the surgery and examine the potential of a metabolic profile in the stratification of patients regarding expected clinical outcomes	n = 28 (15M;13F) 6.6 months (4.4 to 15.5)	IL-1 receptor antagonist, IL-6, IL-8, IL-10, and main metabolites	Preoperative (during anesthesia induction); PO: at the admission to the PICU (zero hour), 6, 24, and 28 hours after surgery	Congenital heart disease surgery adjusted score risk; pediatric organs dysfunction score at the admission to the PICU; inotropic score; lactate; arteriovenous oxygen saturation; days outside the PICU	A rigorous glycemic control did not change the response profile of the patients in the PO period considerably. Eight metabolites were associated with the disease severity and the surgery severity (3-d-hydroxibutirate, acetone, acetoacetate, citrate, lactate, creatine, creatinine, and alanine). The concentration of IL-6 (r = -0.73, p = 0.026) and IL-8 (r = -0.76, p = 0.017) showed an inverse correlation with the number of days outside the PICU, and the IL-6/IL-10 ratio showed a positive correlation with the plasma lactate level (p < 0.05)

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Escola Paulista de Enfermagem, Universidade Federal de São Paulo R. Napoleão de Barros, 754, 04024-002 São Paulo - SP/Brasil, Tel./Fax: (55 11) 5576 4430 - São Paulo - SP - Brazil
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[TFN7] PDO = prospective descriptive observational; PC = prospective cohort; N = no; NR = not reported; Y = yes. Criteria: 1 = reported study objective; 2 = relevant literature background; 3 = sample description; 4 = sample size justification; 5 = reliable and valid results measurements; 6 = intervention description; 7 = contamination and cointervention; 8 = statistical significance; 9 = appropriate analysis method(s); 10 = clinical significance; 11 = drop-outs; 12 = appropriate conclusions.

[TFN8] ^a
Scale modified by Machotka et al. (2009).⁽³⁹⁾ This modified tool has 12 criteria that assess methodological elements of the studies. In this tool, each affirmative answer gets a score of 1 point, and the total score, which can reach 12 points, is converted into a percentage (0 to 100%).

[TFN9] ^b
Newcastle-Ottawa Scale,⁽³⁸⁾ which is specific for study type. This scale evaluates three great domains: patient selection (0 to 4 stars); comparability of patients in the cohorts (0 to 2 stars); and outcomes (0 to 3 stars). The maximum possible score is 9 points. Scores for cohort studies and for prospective observational studies are not directly comparable.