Home            Past Issues            About IP            About IAP           Author Information            Subscription            Advertisement              Search  

   
Review ARTICLE

Indian Pediatr 2012;49: 297-305

Therapeutic Applications of Vasopressin in Pediatric Patients


Amit Agrawal, *Vishal K Singh, *Amit Varma and #Rajesh Sharma

From the Departments of Pediatrics, Chirayu Medical College and Hospital, Bhopal, MP, *Department of Critical Care Medicine, and #Department of Pediatric Cardiac Surgery, Escorts Heart Institute and Research Center, New Delhi.

Correspondence to: Dr Amit Agrawal, H. No. 28, Ravidas Nagar, Near Nizamuddin Colony, Indrapuri,
Bhopal 462 023, MP, India.
Email: [email protected]

 

Abstract

Context: Reports of successful use of vasopressin in various shock states and cardiac arrest has lead to the emergence of vasopressin therapy as a potentially major advancement in the management of critically ill children.

Objective: To provide an overview of physiology of vasopressin, rationale of its use and dose schedule in different disease states with special focus on recent advances in the therapeutic applications of vasopressin.

Data Source: MEDLINE search (1966-September 2011) using terms "vasopressin", "terlipressin", "arginine-vasopressin", "shock", "septic shock", "vasodilatory shock", "cardiac arrest", and "resuscitation" for reports on vasopressin/terlipressin use in children and manual review of article bibliographies. Search was restricted to human studies. Randomized controlled trials, cohort studies, evaluation studies, case series, and case reports on vasopressin/terlipressin use in children (preterm neonates to 21 years of age) were included. Outcome measures were analysed using following clinical questions: indication, dose and duration of vasopressin/terlipressin use, main effects especially on systemic blood pressure, catecholamine requirement, urine output, serum lactate, adverse effects, and mortality.

Results: 51 reports on vasopressin (30 reports) and terlipressin (21 reports) use in pediatric population were identified. A total of 602 patients received vasopressin/terlipressin as vasopressors in various catecholamine-resistant states (septic - 176, post-cardiotomy - 136, other vasodilatory/mixed shock - 199, and cardiac arrest - 101). Commonly reported responses include rapid improvement in systemic blood pressure, decline in concurrent catecholamine requirement, and increase in urine output; despite these effects, the mortality rates remained high.

Conclusion: In view of the limited clinical experience, and paucity of randomized controlled trials evaluating these drugs in pediatric population, currently no definitive recommendations on vasopressin/terlipressin use can be laid down. Nevertheless, available clinical data supports the use of vasopressin in critically ill children as a rescue therapy in refractory shock and cardiac arrest.

Key words: Cardiac arrest, Children, Shock, Terlipressin, Vasopressin.


Vasopressin (AVP) was one of the first synthesized peptide hormones, used to treat diabetes insipidus (DI) and gastrointestinal (GI) hemorrhage for the last five decades [1]. It was discovered by Oliver and Schafer in 1895 by demonstrating the vasopressor effects of posterior pituitary extracts, while Farini and Velden described its antidiuretic effects by successfully treating DI with neurohypophyseal extracts, providing the name antidiuretic hormone [2]. Later, Vigneaud and Turner isolated vasopressin and proved that the same neurohypophyseal hormone possessed both antidiuretic and vasopressor activity [1,3].

Currently, vasopressin and terlipressin (AVP/TP) have emerged as promising agents for the management of refractory shock in critically ill children. However, their effects on various vascular beds and tissues are complex and sometimes apparently paradoxical.

Physiology AND Pharmacology

Synthesis and metabolism of vasopressin

Vasopressin, a nonapeptide with a disulphide bridge between two cysteines, is synthesized in the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei as a prohormone "preprovasopressin". It is degraded to provasopressin before reaching posterior pituitary along the neuronal axons, and is finally converted to the active vasopressin releasing neurophysin-II and co-peptin [4].

Only 10-20% of the intracellular stores are available for immediate release in response to appropriate stimuli; however, secretion diminishes on sustained stimulus. Vasopressin synthesis, transport and storage takes about 1-2 hours [4]. It is metabolised by renal and hepatic vasopressinase enzymes with 5-15% urinary excretion. Vasopressin has a short half life (5-15 minutes) and pressor effect lasts for 30-60 minutes.

Mean serum levels usually remain below 4 pg/ml under normal conditions, which can go upto 10-20 pg/mL as an antidiuretic response [4-5]. In vasodilatory shock, a biphasic response is observed and initial high levels (upto 30-300 pg/mL) gradually fall as the shock progresses so as to reach as low as 4-30 pg/mL after 36 hours of established shock [4-5].

Regulation of vasopressin secretion

In healthy subjects, AVP secretion is primarily regulated by changes in the plasma osmolarity sensed by peripheral osmoreceptors near hepatic portal veins and central osmoreceptors in the subfornical organ nuclei of the brain. Low plasma volume and arterial blood pressure (BP) increase AVP levels without disrupting normal osmoregulation. Atrial and ventricular baroreceptors sense change in plasma volume while aortic arch and carotid sinus receptors signal BP changes. More than 10% reduction in BP is needed to induce a response, as against 1% change in plasma osmolarity [4-6].

Other important stimuli include pain, hypoxia, nausea, pharyngeal stimuli, and hormones (e.g. norepinephrine, acetylcholine, histamine, dopamine and angiotensin-II), endotoxins and pro-inflammatory cytokines. Vasopressin release is inhibited by opioids, γ-aminobutyric acid (GABA), atrial natriuretic peptide (ANP) and nitric oxide (NO) [4-5].

Vasopressin Receptors

Vasopressin acts via G-protein coupled receptors, which are classified according to the location and second messenger pathways into V1 (Vascular), V2 (Renal), and V3 (Pituitary). Additionally, AVP also exerts some action via OTR (Oxytocin) and P2 (Purinergic) receptors [4,7]. (Table I)

TABLE I  Vasopressin Receptors Physiology
Receptor s Organs/Tissues Effects Intracellular Signaling/ transmitters
V1 R (V1 receptors, Vascular smooth muscle Vasoconstriction? Increased intracellular Ca++
 previously via Phosphoinositide pathway
 V1a  receptors) Myocardium Inotropy Increased intracellular Ca++
Platelets Platelet Aggregation Selective renal efferent arteriolar
Kidney Diuresis constriction via local NO release
  Myometrium Uterine contraction
Liver Glycogenolysis
Bladder,  spleen, adipocytes, Vasodilation
testis
Brain Role in social memory,
circadian rhythm,
emotional learning,
stress adaptation
V2 R (V2 receptors) Renal collecting duct Increased permeability  Increased cAMP via adenylate
Vascular smooth muscles to water cyclase
Vascular endothelium Vasodilation NO mediated
Release of von-willebrand
factor/VIII
V3 R (Previously Pituitary Neurotransmitter ACTH release Phosphokinase C pathway, Increased
 V1b receptors) cAMP via G protein
Oxytocin (OTR) Uterus, mammary gland Smooth muscle contraction  Phospholipase C mediated increased
 receptors intracellular  Ca++
Vascular endothelium Vasodilation Increase in intracellular Ca++
Heart ANP release mediated NO release
Purinergic (P2 R) Myocardium Increased cardiac contractility Increase in intracellular  Ca++
 receptors Cardiac endothelium Selective coronary vasodilation NO mediated
 ACTH – Adrenocorticotrophic Hormone, ANP – atrial natriuretic peptide, NO – nitric oxide, cAMP – cyclic adenosine mono phosphate, cGMP – cyclic guanosine monophosphate

Systemic Effects

The major functions of vasopressin include osmoregulation and vasoconstriction. Under normal conditions, its main role is in regulation of water balance with minimal effect on BP. Vasopressin also plays a role in other physiological functions e.g. hemostasis, temperature regulation, memory, sleep cycle, and insulin and corticotrophin release [8-9].

Vasoconstrictor effects

Vasopressin binds to vasopressin specific membrane bound V1 receptors (AVPR1A) in vascular smooth muscles and leads to vasoconstriction by increasing intracellular calcium levels via phosphoinositide pathway. In septic shock, AVP also restores vascular tone, by blocking K+-sensitive ATP channels in dose dependent manner, and via amelioration in increased c-GMP levels by decreasing inducible NO-synthase enzymes [4-5,7].

Vasodilator effects

Unlike catecholamines, vasopressin induces vasodilatation in pulmonary, renal and cerebral circulation through V2R or OTR mediated NO release [10-11]. Vasodilator effect is exhibited particularly at low doses unlike its dose dependent vasoconstrictor effect.

Pulmonary vascular effects

Vasopressin induces pulmonary vasodilatation via V1R mediated release of endothelium derived NO [11]. This is particularly relevant in septic shock, where increased pulmonary vascular tone and resistance is usually seen. Vasopressin also decreases pulmonary arterial pressure in normal or hypoxic conditions mediated via ANP [12].

Renal effects

The complex renal effects are determined by interplay between osmoregulatory and renovascular effects. Antidiuretic effect is mediated via V2R, located on the basolateral membrane of tubular epithelium of the collecting ducts, increasing intracellular c-AMP levels through adenylate cyclase pathway. It leads to fusion of aquaporin vesicles with luminal membrane increasing intracellular water content, which further equilibrates osmotically with interstitial fluid resulting in concentrated urine [4,7]. Paradoxically, low dose vasopressin in septic shock exhibit diuretic effect, possibly through V1R mediated selective renal efferent arteriolar constriction, NO mediated afferent arteriolar vasodilatation, and down regulation of V2R [7,13].

Endocrine effects

In pharmacologic doses, AVP increases plasma cortisol level through V3R mediated ACTH release, effect most likely mediated via NO and c-GMP [9]. This is particularly important in critically ill children, given the prevalence of adrenocortical dysfunction. Vasopressin is reported to mediate ANP and angiotensin-II secretion as well as stimulate prolactin and endothelin-I release [9].

Effects on coagulation system

Vasopressin causes aggregation of human platelets. Selective V2-agonist desmopressin stimulates factor VIIIc, von Willebrand factor, and plasminogen activator release from vascular endothelial cells, promoting effective platelet adhesion. Based on this effect vasopressin has been used to treat bleeding due to functional platelet disorders [14].

Vasopressin Analogues

Terlipressin

Terlipressin (triglycyl lysine-vasopressin) is a longer-acting analogue containing 12 amino acids, and is slowly cleaved to lysine-vasopressin by endo-and exopeptidases in liver and kidney over 4-6 hrs, making intermittent bolus use feasible rather than continuous infusion.

Relative to AVP, its affinity for V1R is higher than V2R (2.2:1 compared to 1:1). Additionally, terlipressin does not appear to increase fibrinolytic activity, unlike vasopressin [15]. Terlipressin has been extensively studied and used in adults with acute variceal bleeding and hepatorenal syndrome, before emerging as potential therapeutic option in a variety of shock states [16].

Desmopressin

Desmopressin or DDAVP (1-deamino-8-D-arginine vasopressin) is selective V2-agonist with an antidiuretic-to-vasopressor ratio 4000 times than that of AVP [17,18].

Therapeutic Applications

Approved uses for vasopressin and analogs include DI, nocturnal enuresis, gastrointestinal bleeding, hemophilia-A, von-Willebrand disease, and bleeding due to platelet dysfunction. Currently, vasopressin is emerging as a potent vasopressor to treat vasodilatory shock states and cardiac arrest; however, it is still not recognized as a standard of care and is being evaluated in trials. Indications and doses of vasopressin/analogs are given in Table II and various studies evaluating its therapeutic uses in children are summarized in Web Table I.

TABLE II Indications and Doses of Vasopressin and Analogs [63-64]
Indication Drug Dose
Nocturnal enuresis DDAVP Intranasally: 5-20 µg (in children > 6 years)Orally: 0.2-0.4  mg/d at bedtime
Central diabetes insipidus DDAVP Intranasally: 5-30 µg/d Q 8-12 hr Orally: 0.05-0.2 mg/d Q 8-12 hr IV/SC: 2-4 µg/d Q 8-12 hr
AVP IM/SC: 2.5-10U/dose 2-4 times/day IV infusion: 0.0005 U/kg/hr initially, double every 30 min upto 0.01 U/kg/hr
Hemophilia-A, von Willebrand  DDAVP Intranasally: <50 kg - 150 µg;
disease, platelet dysfunctions    >50 kg - 300 µg IV: 0.3 µg/kg (>3 months), repeat if needed, give 30 min before procedure
 
Bleeding esophageal varices AVP Initial IV bolus 0.3 U/kg (maximum: 20 U) followed by infusion: 0.002-0.01 U/kg/min
TP IV: 10 – 20 µg/kg every 4 – 6 hrs or 1 – 2 mg Q 4 – 6 hr (in adolescents & adults)
Refractory vasodilatory shock AVP IV infusion: 0.0005-0.002 U/kg/min (variable, from as low as 0.00005 U/kg/min upto 0.008 U/kg/min)
TP IV bolus: 10 – 20 µg/kg every 4 – 6 hrs
IV infusion: 10 µg/kg/hr
Cardiac arrest AVP IV bolus: 0.4 U/kg
TP IV bolus: 10 – 20 µg/kg
DDAVP – Desmopressin, AVP – Arginine Vasopressin, TP – Terlipressin, IV – intravenous, IM – intramuscular, SC – subcutaneous

Nocturnal enuresis

DDAVP is used to treat nocturnal enuresis, caused by maturational delay in normal nocturnal increase in AVP secretion [18].

Diabetes insipidus

In DI, renal tubular collecting ducts are unable to concentrate urine which can be Central or Nephrogenic. Central DI is due to congenital or acquired deficiency of AVP secretion. Nephrogenic DI arises from defective or absent vasopressin receptor sites or aquaporins with resultant inappropriate response to vasopressin.

In Central DI, vasopressin increases cellular permeability of collecting ducts, resulting in renal reabsorption of water and forms the mainstay of treatment [19]. Vasopressin may also be used safely to diagnose type of DI due to shorter half life with lesser risk of volume overload. Doses are variable and titrated according to serum/urinary sodium and osmolality, and urine output [20].

Bleeding esophageal varices

Upper GI bleeding is reported in 6-25% of PICU admissions [21-22]; however, incidence of serious lower GI bleeding has not been well established [23]. Use of vasopressin is intended to decrease portal venous pressure and optimize clotting and hemostasis. Although it may provide effective control of bleeding, vasopressin is still a secondary treatment option, as evidence supporting improved survival is scarce [24].

Presently, endoscopic sclerotherapy or band ligation is considered to be the first-line therapy for bleeding esophageal varices followed by vasoactive drugs i.e. octreotide (somatostatin analogue), vasopressin and terlipressin [25].

Vasodilatory shock states

Vasodilatory shock can be the final common pathway in a variety of shock states including sepsis, post-perfusion syndrome following CPB, prolonged hemorrhage, hypovolemia, anaphylaxis, cardiogenic shock and carbon monoxide poisoning. They share common pathogenic mechanisms responsible for vascular smooth muscle dysfunction and hyporesponsiveness to catecholamines e.g. activation of ATP sensitive K+-channels, NO-synthase stimulation and vasopressin deficiency [26-27]. This relative deficiency is attributable to (i) depleted neurohypophyseal AVP stores, (ii) autonomic dysfunction leading to impaired baro-reflex mediated release, (iii) increased neurohypophyseal NO production, and (iv) central inhibitory effects of increased norepinephrine on AVP production [5,7,27].

Vasopressin has emerged as a useful therapeutic option in vasodilatory shock to reverse the mechanisms responsible for vasoplegia and catecholamine resistance.

Dose in pediatric shock is not very well documented and is extrapolated from adult data. In various studies, vasopressin was used in a dose of 0.00005 to as high as 0.008 U/kg/min [28,29]; however, in a RCT evaluating vasopressin in pediatric shock, vasopressin was used in dose range of 0.0005-0.002 U/kg/min [30]. TP dose used in the RCT was 20 µg/kg/6h for maximum 96 hours [31].

Septic shock

In septic shock, catecholamines often have a diminished vasopressor action and more than half of the patients succumbing to sepsis die from advanced cardiovascular failure, which is refractory to conventional therapy. In these patients, vasopressin hypersensitivity is observed with significant increase in BP, mediated via: (i) direct V1R mediated vasoconstriction;(ii) unlike catecholamine receptors, absolute or relative AVP deficiency allow V1R to remain available and block mechanisms inducing their downregulation; (iii) absent bradycardia reflex in critically ill patients with autonomic failure; (iv) potentiating vasopressor efficacy of catecholamines through blockage of ATP sensitive K+-channels and resulting membrane hyperpolarization and vasodilation; and (v) finally, increased ACTH and cortisol release [4-5,7,9,27]. Vasopressin induced selective pulmonary, coronary, cerebral vasodilatation, and improved urine output and creatinine clearance, make it more beneficial in preserving vital organ functions in sepsis as compared to catecholamines [10-13].

However, judicious use of AVP/TP is warranted, as characteristic vasodilation seen in adult septic shock is a late feature of pediatric septic shock, where myocardial dysfunction is more common and the majority of septic shock cases have low cardiac index with only about 20% presenting in the typical warm shock [32]. Additionally, children in septic shock often change hemodynamic profile and as the disease progresses, transformation from vasodilatory shock to a hypodynamic shock with high systemic vascular resistance (SVR) is not uncommon. Therefore, AVP/TP should be used with cardiac output (CO) and central venous oxygen saturation (ScvO2) monitoring, as they can reduce CO due to potent vasoconstriction [33].

Post-cardiopulmonary bypass vasodilatory shock

Post CPB vasodilatory hypotension, not associated with primary cardiogenic or septic shock, has been reported in nearly 10% of cardiac surgeries [34]. This is attributed mainly to systemic inflammatory response activated by CPB via endothelial injury, release of cytokines and other inflammatory mediators, as well as to nonspecific activators e.g. surgical trauma, blood loss or transfusion, and hypothermia. Other contributory factors include prolonged CPB, long term ACE inhibitor or beta blocker therapy, or post-bypass amiodarone and phosphodiestrase-III inhibitors.

Apart from these mechanisms, inappropriately low AVP secretion may be another important factor in producing low SVR hypotension. Low dose vasopressin therapy in this condition has been shown to improve BP as well as restore catecholamines sensitivity by a mechanism similar to that seen in septic shock [34].

Anaphylactic shock

Acute cardiovascular collapse in anaphylaxis results from immune mediated release of inflammatory mediators producing systemic vasodilation and increased capillary permeability, resulting in mixed distributive-hypovolemic shock [35]. Optimal vasoactive action of vasopressin i.e. vasoconstriction in skin, skeletal muscle, intestine and fat, with relatively less coronary and renal vasoconstriction, and cerebral vasodilatation, has supported the use of AVP in adrenaline refractory anaphylactic shock.

Currently, no controlled trials or guidelines on AVP use in anaphylactic shock are available, and its use is recommended on the basis of case reports and laboratory experiences, In different cases reports, 2-15 U (0.03-0.15U/kg) vasopressin have been used [36-38].

Hemorrhagic shock

Patients with advanced hemorrhagic shock usually respond poorly to both volume and catecholamine therapy due to resistant vasodilation secondary to accumulated vasodilatory metabolites produced by ischemic-reperfusion injury and coexisting severe acidosis inactivating catecholamine receptors. These patients with complete cardiovascular collapse have an extremely poor prognosis and AVP has been used as a rescue therapy in such cases considering its inherent vasopressor effect. Vasopressin also decreases bleeding by shifting the blood away from the subdiaphragmatic site of injury to the vital organs. This specific effect may be life-saving in patients with uncontrolled hemorrhage resulting from subdiaphragmatic injury [39].

As RCTs evaluating the role of vasopressin in hemorrhagic shock are currently unavailable, even limited clinical and laboratory data available may support its use in selected patients, who would otherwise rapidly collapse [40-42].

Pediatric cardiopulmonary resuscitation

Cardiac arrest in children is often the terminal result of progressive respiratory failure or shock rather than sudden primary cardiac event as commonly seen in adults. Prolonged CPR often has dismal prognosis, along with severe neurological impairment among survivors. For more than four decades, epinephrine has been the drug of choice in cardiac arrest for restoring spontaneous circulation based on its ability to maintain diastolic BP and subsequent blood flow to heart. However, adult and pediatric studies have shown no clear survival benefit of epinephrine and rather elucidated adverse effects [43-44].

Vasopressin causes profound vasoconstriction with shunting of blood to heart and brain, and unlike epinephrine, this vasoconstriction continues even in presence of severe acidosis that accompanies cardiopulmonary arrest. Additionally, vasopressin has shown to improve cerebral perfusion during CPR with better neurologic outcome in animal studies. It also enhances myocardial oxygen delivery without marked increase in consumption observed with catecholamine mediated β1-adrenergic receptor activation.

In RCTs of in-hospital and out-of-hospital arrests in adults, vasopressin had comparable efficacy to epinephrine [45,46]. Although improved return of spontaneous circulation (ROSC) with vasopressin therapy was demonstrated in a few pediatric reports [47-49], two other reports failed to demonstrate any survival benefit [50,51]. Therefore, further research is necessary to evaluate the long term outcome and safety of vasopressin in pediatric CPR. During CPR, vasopressin can also be given endotracheally in the same IV dose, if IV/IO route can not be accessed rapidly [52].

Vasopressin during organ recovery

Low dose AVP infusion has been evaluated as a vasopressor in critically ill children treated for DI during brain death and organ recovery in a retrospective matched-controlled study. AVP has shown good pressure effects and they were more likely to wean from alpha agonists than controls, without adverse affect on transplant organ function [53].

Pulmonary hypertension

Vasopressin has been successfully used in infants with pulmonary hypertension secondary to congenital diaphragmatic hernia [54-56] and after correction of total anomalous pulmonary venous return [57] refractory to other conventional therapies, to improve BP and to decrease pulmonary artery pressure.

Sedation related hypotension

One RCT evaluated the role of low-dose vasopressin infusion to prevent sedation/analgesia related hypotension in non-septic, hemodynamically stable but critically ill children, considering the fact that vasopressin leads to redistribution of mesenteric blood. However, AVP therapy was associated with decreased urine output, hyponatremia, and rebound hypotension, thus limiting the prophylactic vasopressin use for sedation-related hypotension [58].

Current recommendations on vasopressin use

American College of Critical Care Medicine Clinical Guidelines 2007 for hemodynamic support of pediatric and neonatal septic shock recommended that AVP/TP can be used in catecholamine-resistant shock with high cardiac index and low SVR. However, as these agents can reduce CO, they should be used with CO/ScvO2 monitoring [33]. Pediatric Sepsis Guidelines for resource-limited countries developed by Intensive Care Chapter of Indian Academy of Pediatrics recommended AVP therapy as a last resort in patients with catecholamine-resistant warm shock [59].

Although, latest American Heart Association guidelines have recommended the use of one dose of vasopressin to replace either the first or second dose of epinephrine in treatment of adult cardiac arrest, no recommendations were made on its routine use in pediatric patients [60,61]. European Resuscitation Council guidelines 2010 also did not support or refute the use of AVP/TP as an alternative to or in combination with adrenaline in any cardiac arrest rhythm; however, these drugs could be used in cardiac arrest refractory to several adrenaline doses [62].

Cost-effectiveness

Cost of the vasopressin may be an inhibiting factor at current market values, as it costs around 25-30 times than that of adrenaline. Still, AVP therapy is not as expensive as extended ICU stay of even one day with costlier antibiotics, and it would help in lowering the overall long-term cost in patient care [63-64]. As no RCT is currently available to determine the cost-effectiveness of vasopressin, significant clinical benefits would need to be demonstrated to cost-justify the routine substitution of adrenaline with vasopressin in cardiac arrest.

Adverse Effects

Due to potent vasoconstrictor action, there is always a concern that vasopressin therapy may impair capillary blood flow and tissue oxygenation. Safety data of vasopressin in pediatric patients are limited and a number of adverse effects were reported depending upon dose and duration, underlying disease process, co-morbidities, and concurrent use of other vasopressors. Complications are more common when vasopressin is co-administered with moderate to high dose of norepinephrine [5].

Cardiac complications include coronary ischemia, myocardial infarction, ventricular arrhythmias (ventricular tachycardia and asystole), and severe hypertension [64]. Other reported adverse effects include severe GI ischemia leading to bowel necrosis, hyponatremia, anaphylaxis, bronchospasm, urticaria, angioedema, rashes, venous thrombosis, local irritation at injection site, and peripheral vasoconstriction leading to cutaneous gangrene [65].

Conclusion

While vasopressin continues to be a useful agent to treat DI and GI hemorrhage, it is emerging as a potentially life saving therapy in critically ill children with a variety of vasodilatory shock. Both adult and pediatric studies have demonstrated the efficacy of rescue AVP therapy in reversing shock due to sepsis or following cardiotomy/CPB, when other vasopressors are escalated to high infusion rates with potential adverse effects. Limited laboratory and adult data along with a few pediatric reports support the use of vasopressin as an adjunctive therapy for prolonged cardiac arrest and irreversible hypovolemic and anaphylactic shock. However, large controlled trials are necessary to define the efficacy, dosage, ideal initiation time, and safety profile in children, as evidence is limited due to the retrospective nature of existing studies and small numbers of patients.

Thus, vasopressin is not a standard of care as of now and it should be considered as a rescue therapy in situations like catecholamine-refractory shock and cardiac arrest in children, with close monitoring for adverse effects.

Competing interests: None stated; Funding: None.

References

1. Du Vigneaud V, Gash DT, Karsoyannis PG. A synthetic preparation possessing biological properties associated with arginine vasopressin. J Am Chem Soc. 1954;76:4751-2.

2. Oliver H, Schafer E. On the physiological action of extracts of the pituitary body and certain other glandular organs: preliminary communication. J Physiol (Lond). 1895;18:277-9.

3. Turner RA, Pierce JG, Du Vigneaud V. The purification and the amino acid content of vasopressin preparation. J Biol Chem. 1951;191:21-8.

4. Holmes CL, Landry DW, Granton JT. Science Review: Vasopressin and the cardiovascular system part-I – receptor physiology. Crit Care. 2003;7:427-34.

5. Holmes CL, Patel BM, Russell JA, Walley KR. Physiology of vasopressin relevant to management of septic shock. Chest. 2001;120:989-1002.

6. Bourque CW, Oliet SH, Richard D. Osmoreceptors, osmoreception and osmoregulation. Front Neuroendocrinol. 1994;15:231-74.

7. Barrett LK, Singer M, Clapp LH. Vasopressin: mechanisms of action on the vasculature in health and in septic shock. Crit Care Med. 2007;35:33-40.

8. Treshcan TA, Peters J. The vasopressin system: Physiology and clinical strategies. Anesthesiology. 2006;105:599-612.

9. Dunser MW, Hasibeder WR, Wenzel V, Schwarz S, Ulmer H, Knotzer H, et al. Endocrinologic response to vasopressin infusion in advanced vasodilatory shock. Crit Care Med. 2004;32:1266-71.

10. Okamura T, Ayajiki K, Fujioka H, Toda N. Mechanisms underlying arginine vasopressin-induced relaxation in monkey isolated coronary arteries. J Hypertens. 1999;17:673-8.

11. Russ RD, Walker BR. Role of nitric oxide in vasopressinergic pulmonary vasodilatation. Am J Physiol. 1992;262:743-7.

12. Tayama E, Ueda T, Shojima T, Akasu K, Oda T, Fukunaga S, et al. Arginine vasopressin is an ideal drug after cardiac surgery for the management of low systemic vascular resistant hypotension concomitant with pulmonary  hypertension. Interact Cardiovasc Thorac Surg. 2007;6:715-9.

13. Morelli A, Rocco M, Conti G, Orecchioni A, De Gaetano A, Cortese G, et al. Effects of terlipressin on systemic and regional haemodynamics in catecholamine-treated hyperkinetic septic shock. Intensive Care Med. 2004;30:597-604.

14. Haslam RJ, Rosson GM. Aggregation of human blood platelets by vasopressin. Am J Physiol. 1972;223:958-67.

15. Douglas JG, Forrest JA, Prowse CV, Cash JD, Finlayson ND. Effects of lysine vasopressin and glypressin on the fibrinolytic system in cirrhosis. Gut. 1979;20:565-7.

16. Solanki P, Chawla A, Garg R, Gupta R, Jain M, Sarin SK, et al. Beneficial effects of terlipressin in hepatorenal syndrome: A prospective, randomized placebo controlled clinical trial. J Gastroenterol Hepatol. 2003;18:152-6.

17. Richardson D, Robinson A. Desmopressin. Ann Intern Med. 1985;103:228-39.

18. Key DW, Bloom DA, Sanvordenker J. Low-dose DDAVP in nocturnal enuresis. Clin Pediatr (Phila). 1992;31:299-301.

19. Bichet DG, Razi M, Lonergan M, Arthus MF, Papukna V, Kortas C, et al. Hemodynamic and coagulation responses to 1-desamino [8-d-arginine] vasopressin in patients with congenital nephrogenic diabetes insipidus. N Engl J Med. 1988;318:881-7.

20. Wise-Faberowski L, Soriano SG, Ferrari L, McManus ML, Wolfsdorf JI, Majzoub J, et al. Perioperative management of diabetes insipidus in children. J Neurosurg Anesthesiol. 2004;16:220-5.

21. Cochran EB, Phelps SJ, Tolley EA, Stidman GL. Prevalence of, and risk factors for upper gastrointestinal tract bleeding in critically ill pediatric patients. Crit Care Med. 1992;20:1519-23.

22. Lacroix J, Nadeau D, Laberge S, Gauthier M, Lapierre G, Farrell CA. Frequency of upper gastrointestinal bleeding in a pediatric intensive care unit. Crit Care Med. 1992;20:35-42.

23. Teach SJ, Fleisher GR. Rectal bleeding in the pediatric emergency department. Ann Emerg Med. 1994;23:1252-8.

24. Darcy M. Treatment of lower gastrointestinal bleeding: Vasopressin infusion versus embolization. J Vasc Interv Radiol. 2003;14:535-43.

25. Molleston JP. Variceal bleeding in children. J Pediatr Gastroenterol Nutr. 2003;37:538-45.

26. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001;345:588-95.

27. Landry DW, Levin HR, Gallant EM, Ashton RC Jr., Seo S, D’Alessandro D, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997;95:1122-5.

28. Lechner E, Dickerson HA, Fraser CD Jr, Chang AC. Vasodilatory shock after surgery for aortic valve endocarditis: Use of low-dose vasopressin. Pediatr Cardiol. 2004;25:558-61.

29. Liedel JL, Meadow W, Nachman, J, Koogler T, Kahana M. Use of vasopressin in refractory hypotension in children with vasodilatory shock: Five cases and a review of the literature. Pediatr Crit Care Med. 2002;3:15-8.

30. Choong K, Bohn D, Fraser DD, Gaboury I, Hutchison JS, Joffe AR, et al. Vasopressin in pediatric vasodilatory shock: A multicenter randomized controlled trial. Am J Resp Crit Care Med. 2009;180:632-9.

31. Yilidzdas D, Yapicioglu H, Celik U, Setdemir Y, Alhan E. Terlipressin as a rescue therapy for catecholamine-resistant septic shock in children. Intensive Care Med. 2008; 34:511-7.

32. Ceneviva G, Paschall JA, Maffei F, Carcillo JA. Hemodynamic support in fluid-refractory pediatric septic shock. Pediatrics. 1998;102:e19.

33. Brierley J, Carcillo JA, Choong K, Cornell T, DeCaen A, Deymann A, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med. 2009;37:666-88.

34. Argenziano M, Chen JM, Choudhri AF, Cullinane S, Garfein E, Weinberg AD, et al. Management of vasodilatory shock after cardiac surgery: identification of predisposing factors and use of a novel pressor agent. J Thorac Cardiovasc Surg. 1998;116:973-80.

35. Schummer C, Wirsing M, Schummer W. The pivotal role of vasopressin in refractory anaphylactic shock. Anesth Analg. 2008;107:620-4.

36. Williams SR, Denault AY, Pellerin M, Martineau R. Vasopressin for treatment of shock following aprotinin administration. Can J Anaesth. 2004;51:169-72.

37. Chiara LD, Stazi GV, Ricci Z, Polito A, Morelli S, Giorni C, et al. Role of vasopressin in the treatment of anaphylactic shock in a child undergoing surgery for congenital heart disease: a case report. J Med Case Reports. 2008;2:36.

38. Meng L, Williams EL. Case report: treatment of rocuronium-induced anaphylactic shock with vasopressin. Can J Anaesth. 2008;55:437-40.

39. Stadlbauer KH, Wenzel V, Krismer AC, Voelckel WG, Lindner KH. Vasopressin during uncontrolled hemorrhagic shock: Less bleeding below the diaphragm, more perfusion above. Anesth Analg. 2005;101:830-2.

40. Voelckel WG, Raedler C, Wenzel V, Lindner KH, Krismer AC, Schmittinger CA, et al. Arginine vasopressin, but not epinephrine, improves survival in uncontrolled hemorrhagic shock after liver trauma in pigs. Crit Care Med. 2003;31:1160-5.

41. Haas T, Voelckel WG, Wiedermann F, Wenzel V, Lindner KH. Successful resuscitation of a traumatic cardiac arrest victim in hemorrhagic shock with vasopressin: a case report and brief review of the literature. J Trauma. 2004;57:177-9.

42. Erkek N, Senel S, Hizli S, Karacan CD. Terlipressin saved the life of a child with severe nonvariceal upper gastrointestinal bleeding. Am J Emerg Med. 2011;29:133. e5-6.

43. Woodhouse SP, Cox S, Boyd P, Case C, Weber M. High dose and standard dose adrenaline do not alter survival compared with placebo in cardiac arrest. Resuscitation. 1995;30:243-9.

44. Perondi MB, Reis AG, Paiva EF, Nadkarni VM, Berg RA. A comparison of high-dose and standard dose epinephrine in children with cardiac arrest. N Engl J Med. 2004;350:1722-30.

45. Stiell IG, Hébert PC, Wells GA, Vandemheen KL, Tang AS, Higginson LA, et al. Vasopressin versus epinephrine for in hospital cardiac arrest: a randomised controlled trial. Lancet. 2001; 358:105-9.

46. Wenzel V, Krismer AC, Arntz HR, Sitter H, Stadlbauer KH, Lindner KH. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med. 2004;350:105-13.

47. Yilidzdas D, Horoz OO, Erdem S. Beneficial effects of terlipressin in pediatric cardiac arrest. Pediatr Emerg Care. 2011;27:865-8.

48. Gil-Antón J, López-Herce J, Morteruel E, Carrillo Á, Rodríguez-Núńez A. Pediatric cardiac arrest refractory to advanced life support: Is there a role for terlipressin? Pediatr Crit Care Med. 2010;11:139-41.

49. Mann K, Berg RA, Nadkarni V. Beneficial effects of vasopressin in prolonged pediatric cardiac arrest: a case series. Resuscitation. 2002;52:149-56.

50. Carroll TG, Dimas VV, Raymond TT. Vasopressin rescue for in-pediatric intensive care unit cardiopulmonary arrest refractory to initial epinephrine dosing: A prospective feasibility pilot trial. Pediatr Crit Care Med. 2011 Sep 15. [Epub ahead of print]

51. Duncan MJ, Meaney P, Simpson P, Berg RA, Nadkarni V, Schexnayder S. Vasopressin for in-hospital pediatric cardiac arrest: Results from the American Heart Association National Registry of Cardiopulmonary Resuscitation. Pediatr Crit Care Med. 2009;10:191-5.

52. Wenzel V, Lindner KH, Prengel AW, Lurie KG, Strohmenger HU. Endobronchial vasopressin improves survival during cardiopulmonary resuscitation in pigs. Anesthesiology. 1997;86:1375-81.

53. Katz K, Lawler J, Wax J, O’Connor R, Nadkarni V. Vasopressin pressor effects in critically ill children during evaluation for brain death and organ recovery. Resuscitation. 2000;47:33-40.

54. Papoff P, Caresta E, Versacci P, Grossi R, Midulla F, Moretti C. The role of terlipressin in the management of severe pulmonary hypertension in congenital diaphragmatic hernia. Pediatr Anaesth. 2009;19:805-6.

55. Stathopoulos L, Nicaise C, Michel F, Thomachot L, Merrot T, Lagier P, et al. Terlipressin as rescue therapy for refractory pulmonary hypertension in a neonate with a congenital diaphragmatic hernia. J Pediatr Surg. 2011;46:19-21.

56. Filippi L, Gozzini E, Daniotti M, Pagliai F, Catarzi S, Fiorini P. Rescue treatment with terlipressin in different scenarios of refractory hypotension in newborns and infants. Pediatr Crit Care Med. 2011;12:e237-41.

57. Scheurer MA, Bradley SM, Atz AM. Vasopressin to attenuate pulmonary hypertension and improve systemic blood pressure after correction of obstructed total anomalous pulmonary venous return. J Thorac Cardiovasc Surg. 2005;129:464-6.

58. Baldasso E, Garcia PCR, Piva JP, Branco RG, Tasker RC. Pilot safety study of low-dose vasopressin in non-septic critically ill children. Intensive Care Med. 2009;35: 355-9.

59. Khilnani P, Singhi S, Lodha R, Santhanami I, Sachdev A, Chugh K, et al. Pediatric Sepsis Guidelines : Summary for resource-limited countries. Indian J Crit Care Med. 2010;14:41-52.

60. Kleinman ME, Chameides L, Schexnayder SM, Samson RA, Hazinski MF, Atkins DL, et al. Part 14: Pediatric Advanced Life Support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122:876-908.

61. Neumar RW, Otto CW, Link MS, Kronick SL, Shuster M, Callaway CW, et al. Part 8. Adult advanced cardiovascular life support. American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122:729-67.

62. Biarent D, Bingham R, Eich C, López-Herce J, Maconochie I, Rodríguez-Nunez A, et al. European Resuscitation Council Guidelines for Resuscitation 2010 Section 6. Paediatric life support. Resuscitation. 2010;81:1364-88.

63. Wenzel V, Lindner KH. Employing vasopressin during cardiopulmonary resuscitation and vasodilatory shock as a lifesaving vasopressor. Cardiovasc Res. 2001;51:529-41.

64. Vasopressins – Compound summary. Available from: URL: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=11979316&loc=ec_rcs. Accessed August 30, 2011.

65. Dünser MW, Mayr AJ, Tür A, Pajk W, Barbara F, Knotzer H, et al. Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine resistant vasodilatory shock: Incidence and risk factors. Crit Care Med. 2003;31:1394-8.

66. Rodriguez-Nunez A, Oulego-Erroz I, Gil-Anton J, Perez-Caballero C, Lopez-Herce J, Gaboli M, et al. Continuous terlipressin infusion as rescue treatment in a case series of children with refractory septic shock. Ann Pharmacother. 2010;44:1545-53.

67. Bidegain M, Greenberg R, Simmons C, Dang C, Cotten MC, Smith BP. Vasopressin for refractory hypotension in extremely low birth weight infants. J Pediatr. 2010;157:502-4.

68. Ikegami H, Funato M, Tamai H, Wada H, Nabetani M, Nishihara M. Low-dose vasopressin infusion therapy for refractory hypotension in ELBW infants. Pediatr Int. 2010;52:368-73.

69. Papoff P, Mancuso M, Barbara CS, Moretti C. The role of terlipressin in pediatric septic shock: A review of the literature and personal experience. Int J Immunopathol Pharmacol. 2007;20:213-21.

70. Rodriguez-Nunez A, Lopez-Herce J, Gil-Anton J, Hernandez A, Rey C. RETSPED: Working Group of the Spanish Society of Pediatric Intensive Care. Rescue treatment with terlipressin in children with refractory septic shock: a clinical study. Crit Care. 2006;10:20.

71. Meyer S, Loffler G, Polcher T, Gottschling S, Gortner L. Vasopressin in catecholamine-resistant septic and cardiogenic shock in very-low-birth weight infants. Acta Paediatr. 2006;95:1309-12.

72. Meyer S, Gottschling S, Baghai A, Wurm D, Gortner L. Arginine- vasopressin in catecholamine-refractory septic versus non-septic shock in extremely low birth weight infants with acute renal injury. Crit Care. 2006;10:71.

73. Vasudevan A, Lodha R, Kabra SK. Vasopressin infusion in children with catecholamine resistant septic shock. Acta Pediatr. 2005;94:380-3.

74. Matok I, Vard A, Efrati O, Rubinshtein M, Vishne T, Leibovitch L, et al. Terlipressin as rescue therapy for intractable hypotension due to septic shock in children. Shock. 2005;23:305-10.

75. Rodriguez-Nunez A, Fernandez-Sanmartin M, Martinon- Torres F, Gonzalez-Alonso N, Martinon-Sanchez JM. Terlipressin for catecholamine-resistant septic shock in children. Intensive Care Med. 2004;30:477-80.

76. Tobias JD. Arginine vasopressin for refractory distributive shock in two adolescents. J Intensive Care Med. 2002;17:48-52.

77. Agrawal A, Singh VK, Varma A, Sharma R. Intravenous arginine vasopressin infusion in refractory vasodilatory shock: A clinical study. Indian J Pediatr. 2011 Sep 16 [E-pub ahead of print].

78. Burton GL, Kaufman J, Goot BH, da Cruz EM. The use of arginine vasopressin in neonates following the Norwood procedure. Cardiol Young. 2011;21:536-44.

79. Alten JA, Borasino S, Toms R, Law MA, Moellinger A, Dabal RJ. Early initiation of arginine vasopressin infusion in neonates after complex cardiac surgery. Pediatr Crit Care Med. 2011 Sep 15 [Epub ahead of print].

80. Mastropietro CW, Rossi NF, Clark JA, Walters HL III, Delius R, Lieh-Lai M, et al. Relative deficiency of arginine vasopressin in children after cardiopulmonary bypass. Crit Care Med. 2010;38:2052-8.

81. Matok I, Rubinshtein M, Levy A, Vardi A, Leibovitch L, Mishali D, et al. Terlipressin for children with extremely low cardiac output after open heart surgery. Ann Pharmacother. 2009;43:423-9.

82. Mastropietro CW, Clark JA, Delius RE, Walters HL III, Sarnaik AP. Arginine-vasopressin to manage hypoxic infants after stage I palliation of single ventricle lesions. Pediatr Crit Care Med. 2008;9:506-10.

83. Lechner E, Hofer A, Mair R, Moosbauer W, Sames-Dolzer E, Tulzer G. Arginine –vasopressin in neonates with vasodilatory shock after cardiopulmonary bypass. Eur J Pediatr. 2007;166:1221-7.

84. Rosenzweig EB, Starc TJ, Chen JM, Cullinane S, Timchak DM, Gersony WM, et al. Intravenous arginine-vasopressin in children with vasodilatory shock after cardiac surgery. Circulation. 1999;100(19 Suppl):II182-II186.

85. Jerath N, Frndova H, McCrindle BW, Gurofsky R, Humpl T. Clinical impact of vasopressin infusion on hemodynamics, liver and renal function in pediatric patients. Intensive Care Med. 2008;34:1274-80.

86. Masutani S, Senzaki H, Ishido H, Taketazu M, Matsunaga T, Kobayashi T, et al. Vasopressin in the treatment of vasodilatory shock in children. Pediatr Int. 2005;47:132-6.

87. Efrati O, Modan-Moses D, Vardi A, Matok I, Bazilay Z, Paret G. Intravenous arginine vasopressin in critically ill children: Is it beneficial? Shock. 2004;22:213-7.

88. Matok I, Vardi A, Augarten A, Efrati O, Leibovitch L, Rubinshtien M, et al. Beneficial effects of terlipressin in prolonged pediatric cardiopulmonary resuscitation. A case series. Crit Care Med. 2007;35:1161-4.

 

Copyright © 1999-2012  Indian Pediatrics