Adrenergic pathway targeting agents

Epinephrine, norepinephrine, and dopamine are alpha (α) and beta-(β) receptor agonists that promote inotropy and peripheral vasoconstriction in a dose-dependent manner.^{Reference Loomba and Flores6,Reference Pekkarinen and Hortling48–Reference Mueller52} These drugs are commonly used in the post-operative cardiac care of children,^{Reference Loomba and Flores6,Reference Roeleveld and de Klerk7} but only 1 study to date investigated the efficacy of epinephrine¹² and no studies were found on the efficacy of norepinephrine or dopamine. In a study of 39 children, epinephrine dosages of 0.01–0.23 µg/kg/minute was not shown to prevent post-operative low cardiac output syndrome.^{Reference Oualha, Urien and Spreux-Varoquaux12} Docarpamine, an oral dopamine precursor which degrades to stable dopamine levels in the serum,^{Reference Watarida, Shiraishi and Sugita13} was found to be safe in 11 post-operative children, but there was no control arm to evaluate efficacy and the drug is only available in Japan.^{Reference Watarida, Shiraishi and Sugita13}

Dobutamine is a synthetic β agonist, which promotes inotropy and chronotropy.^{Reference Ferrer-Barba, Gonzalez-Rivera and Bautista-Hernandez10,Reference Steen, Tinker, Pluth, Barnhhorst and Tarhan51,Reference Nakazawa, Takahashi, Aiba, Okuda, Ohta and Takao53,Reference Mills, Costello and Almodovar54} A total of 3 prospectives, including 2 with randomisation between arms, clinical trials of dobutamine enrolled a combined total of 110 children 0–18 years of age.^{Reference de Souza, de Carvalho, Maluf and Carvalho14–Reference Ebade, Khalil and Mohamed16} None of these studies demonstrated a clinical benefit of dobutamine using dosages of 6–10 µg/kg/minute. Dobutamine was not superior to milrinone in preventing low cardiac output syndrome in 50 children undergoing elective cardiac repair,^{Reference Cavigelli-Brunner, Hug and Dave15} and was inferior to levosimendan in increasing cardiac index in 50 children with elevated pulmonary arterial pressures undergoing atrial septal defect or ventricular septal defect repair.^{Reference Ebade, Khalil and Mohamed16} Furthermore, dobutamine showed no significant increase in splanchnic perfusion as measured by gastric tonometry in 10 post-operative children.^{Reference de Souza, de Carvalho, Maluf and Carvalho14}

Phenoxybenzamine and phentolamine, irreversible and reversible α blockers, respectively, were used for afterload reduction after the Norwood operation.^{Reference Fowler, Holmes, Gaffney, Privitera and Grupp55–Reference Collier, Nachev and Robinson58} In a single trial of 105 infants undergoing stage 1 surgical palliation for single-ventricle CHD, patients were consecutively recruited to receive phenoxybenzamine or not. There was a decrease in the sudden circulatory collapse in the group of infants who received phenoxybenzamine compared to the negative control.^{Reference De Oliveira, Ashburn and Khalid17} Phentolamine was studied against nitroprusside in 146 post-operative Norwood infants and showed lower mean arterial blood pressure and coronary perfusion pressure; however, deep hypothermia was used in the nitroprusside group only and may have confounded the results.^{Reference Furck, Hansen, Uebing, Scheewe, Jung and Kramer18}

One study looked at the association of tachyarrhythmias and adrenergic agent use in 65 Norwood patients. The prolonged use of epinephrine in the post-operative period was associated with an increased risk of tachyarrhythmias.^{Reference McFerson, McCanta and Pan11} Dopamine, norepinephrine, and vasopressin were included as covariates in the study analysis, but the overall association was only reported for epinephrine.

Vasopressin

Vasopressin activates V1 receptors in vascular smooth muscle to activate protein kinase C, increasing intracellular calcium, and producing smooth muscle contraction.^{Reference Silva and Rosenberg59,Reference Kaplan-Albuquerque and Di Salvo60} Vasopressin may have fewer proarrhythmic effects compared to catecholamines and may be more efficacious in catecholamine-refractory shock.^{Reference Barrett, Singer and Clapp61} Seven studies of vasopressin met our inclusion criteria, of which 1 was a prospective trial. The dosing of vasopressin ranged from 0.05 to 3 mU/kg/minute. Vasopressin reproducibly increased blood pressure in 127 post-operative cardiac infants and children with refractory shock.^{Reference Lechner, Hofer, Mair, Moosbauer, Sames-Dolzer and Tulzer19–Reference Burton, Kaufman, Goot and da Cruz21,Reference Lu, Wang, Yang, Li and Yan23} In four out of the five studies, other inotropes were able to be weaned without any adverse effects.^{Reference Lechner, Hofer, Mair, Moosbauer, Sames-Dolzer and Tulzer19–Reference Burton, Kaufman, Goot and da Cruz21,Reference Lu, Wang, Yang, Li and Yan23,Reference Mastropietro, Davalos, Seshadri, Walters and Delius24} Administration of vasopressin was also correlated with signs of improved systemic perfusion including decreased lactate, increased pH, and decreased fluid requirement.^{Reference Burton, Kaufman, Goot and da Cruz21,Reference Lu, Wang, Yang, Li and Yan23} In a retrospective study of 37 consecutive infants undergoing the Norwood or arterial switch operation, vasopressin was started de facto rather than as rescue therapy, and was likewise associated with improvements in systemic perfusion including lower lactates, higher cerebral oxygen levels, and decreased fluid requirements compared to historical controls.^{Reference Alten, Borasino, Toms, Law, Moellinger and Dabal22} No study reported clinically significant hyponatremia with the administration of vasopressin.^{Reference Lechner, Hofer, Mair, Moosbauer, Sames-Dolzer and Tulzer19–Reference Burton, Kaufman, Goot and da Cruz21,Reference Davalos, Barrett and Seshadri25}

Calcium, calcium sensitisers, and cAMP pathway targeting agents

A total of 22 studies investigated calcium or modulators of the calcium cyclic adenosine monophosphate pathway. Calcium infusion, directly and indirectly, increases blood pressure, by way of increasing serum calcium and by cyclic adenosine monophosphate excretion.^{Reference Murray, Alford and Haney26,Reference Salsburey and Brown62,Reference Hvarfner, Mörlin, Wide and Ljunghall63} A retrospective cohort study on calcium administration in 82 infants found that the administration of parenteral calcium was associated with a decrease in post-operative cardiac arrest compared with historical controls.^{Reference Murray, Alford and Haney26} The mean ionised calcium level was 1.33 mmol/L in the study group compared to 1.24 mmol/L in the control group.

Levosimendan is a calcium sensitiser, binding to the cardiac troponin C protein and preventing binding of troponin I for sustained cardiac myocyte contraction.^{Reference Sorsa, Heikkinen and Abbott64–Reference Bowman, Haikala and Paul66} We examined 13 studies on 867 patients focused on the administration of levosimendan^{Reference Ferrer-Barba, Gonzalez-Rivera and Bautista-Hernandez10,Reference Ebade, Khalil and Mohamed16,Reference Amiet, Perez and Longchamp28–Reference Giordano, Palma and Palumbo30,Reference Wang, Cui and Fan32–Reference Basto-Duarte, Flores-Rodriguez, Bermon and Mendoza-Crespo34,Reference Jadhav, Bobhate and Garekar36–Reference Thorlacius, Suominen and Wahlander38} : 7 studies were retrospective, and 6 were prospective randomised controlled trials. The dosing range was 0.05–0.2 µg/kg/minute for 48–72 hours with or without a loading dose of 12–15 µg/kg. The median dose was 0.1 µg/kg/minute. There was mixed data on the effects of levosimendan on heart rate, mean arterial blood pressure, cerebral oxygenation, and lactate level. Overall, three studies showed that levosimendan may be effective at preventing low cardiac output syndrome when used as an adjunct therapy to other vasopressors.^{Reference Ricci, Garisto, Favia, Vitale, Di Chiara and Cogo27,Reference Amiet, Perez and Longchamp28,Reference Giordano, Palma and Palumbo30}

Milrinone inhibits phosphodiesterase type III which increases levels of cyclic adenosine monophosphate and calcium uptake into cells, leading to inotropy and peripheral vasodilation.^{Reference Farah and Frangakis67–Reference Silver, Lepore and O’Connor70} Milrinone has been studied in 12 prospective and 3 retrospective studies, both as a primary agent and as rescue therapy in children after cardiopulmonary bypass, totaling 1476 patients. Dosing was variable, with a range of 0.25–1.0 µg/kg/minute with or without a loading dose of 20–50 µg/kg. Two studies suggested that milrinone may prevent low cardiac output syndrome^{Reference Duggal, Pratap, Slavik, Kaplanova and Macrae39,Reference Hoffman, Wemovsky and Atz40} ; however, another study measured milrinone levels and found that 16% of treated patients had supratherapeutic levels, which was associated with higher rates of low cardiac output syndrome.^{Reference Garcia Guerra, Joffe, Senthilselvan, Kutsogiannis and Parshuram41} Milrinone has also been studied in children with pulmonary hypertension, and was found to decrease pulmonary arterial pressure in 2 studies.^{Reference Barnwal, Umbarkar, Sarkar and Dias42,Reference Chu, Lin and New43}

Nine trials on milrinone and levosimendan reported rates of low cardiac output syndrome as an endpoint. In a randomised, double-blind, placebo-controlled trial of 238 post-operative children, milrinone was shown to significantly decrease the risk of low cardiac output syndrome.^{Reference Hoffman, Wemovsky and Atz40} Milrinone also significantly increased biventricular function in 15 post-operative children who were at risk or developed low cardiac output syndrome.^{Reference Duggal, Pratap, Slavik, Kaplanova and Macrae39} Levosimendan showed no decrease in low cardiac output syndrome or mortality in a randomised, double-blind, placebo-controlled trial of 187 post-operative children.^{Reference Wang, Cui and Fan32} However, 6 studies compared levosimendan to milrinone and showed mixed data regarding superiority.^{Reference Momeni, Rubay and Matta33–Reference Thorlacius, Suominen and Wahlander38} Three studies were randomised controlled trials and 3 were retrospective for a total of 236 patients. There were no consistent differences in inotropic requirements or rates of low cardiac output syndrome between the levosimendan group and milrinone groups, and there was mixed data comparing rates of renal failure with levosimendan versus milrinone.^{Reference Lechner, Hofer, Mair, Moosbauer, Sames-Dolzer and Tulzer19,Reference Basto-Duarte, Flores-Rodriguez, Bermon and Mendoza-Crespo34,Reference Lechner, Hofer and Leitner-Peneder37,Reference Thorlacius, Suominen and Wahlander38} Nevertheless, five out of the six studies suggested that levosimendan is as safe and effective as milrinone. These studies had wide age variance, as well as variation in cardiac defects.

There is mixed evidence as to whether milrinone is associated with arrhythmias. A double-blind placebo-controlled study of 238 children found no association with arrhythmias, even with a loading dose followed by a high continuous infusion of milrinone at 0.75 µg/kg/minute.^{Reference Hoffman, Wemovsky and Atz40} Yet, a larger observational study of 603 paediatric patients after cardiac surgery found that milrinone administration is an independent risk factor for arrhythmias.^{Reference Smith, Owen, Borgman, Fish and Kannankeril44}

Nitric oxide and cyclic guanosine monophosphate pathway targeting agents

Modulators of the cyclic guanosine monophosphate pathway have been studied both independently and in comparison to cyclic adenosine monophosphate modulators. Nesiritide is a synthetic brain natriuretic peptide that inhibits the renin–angiotensin aldosterone system and stimulates cyclic guanosine monophosphate, causing vasorelaxation.^{Reference Song, Kohse and Murad71,Reference Zhou and Fiscus72} There were 2 studies of nesiritide in 106 children. Dosing was variable, with a loading dose followed by infusion up to 0.03 µg/kg/minute. A loading dose of nesiritide decreased mean arterial pressure by 7% in a study of 17 children after cardiac surgery,^{Reference Simsic, Scheurer and Tobias46} and was found to be equivocal when compared to milrinone in preventing low cardiac output syndrome in 106 children.^{Reference Costello, Dunbar-Masterson and Allan45} Nitroprusside releases nitric oxide, which increases the formation of cyclic guanosine monophosphate, causing vasorelaxation.^{Reference Gmeiner, Riedl and Baumgartner73–Reference Kamisaki, Waldman and Murad75} There were two retrospective studies on nitroprusside. Dosing was not prescribed but the mean starting dose was between 1 and 2 µg/kg/minute in these studies. One study found no increase in outcomes of complications compared to phentolamine.^{Reference Furck, Hansen, Uebing, Scheewe, Jung and Kramer18} In terms of safety, one study found that 11% of patients treated with nitroprusside were found to have toxic levels of cyanide.^{Reference Moffett and Price47}