Drug Therapy and Vascular Access

Vasopressor Use During Pediatric Cardiac Arrest

Last Full Review: ILCOR 2025
Last Update: 2020

Pediatric cardiac arrest differs significantly from adult cardiac arrest in both etiology and outcomes. In children, cardiac arrest is most commonly precipitated by respiratory failure or shock, leading to hypoxia and bradycardia, whereas in adults, it often results from primary cardiac causes like ventricular fibrillation or myocardial infarction. Survival rates vary depending on the setting; in-hospital pediatric cardiac arrests have a higher survival rate (approximately 36.2%) compared to out-of-hospital arrests (around 11.3%) (Fovaeus et al. 2024, 110103). The vasopressor epinephrine plays an important role in cardiac arrest due to its alpha-adrenergic effects resulting in peripheral vasoconstriction, increased aortic diastolic pressure, and enhanced coronary and cerebral perfusion pressures (Goug et al. 2018, 139; Williams et al. 2024, 1904). Activation of beta receptors increases heart rate and myocardial contractility. These hemodynamic effects are beneficial for restoring circulation, but may also cause vasoconstriction in the cerebral microvasculature, potentially reducing cerebral perfusion (Lin et al. 2014, 732). This has raised concerns about neurological outcomes post-resuscitation. A recent International Liaison Committee on Resuscitation (ILCOR) systematic review compares outcomes following resuscitation of children and infants with epinephrine versus without epinephrine during cardiopulmonary resuscitation (CPR).

 

Evidence Summary

A 2025 ILCOR systematic review and Consensus on Science with Treatment Recommendations (CoSTR) (Kurosawa et al. 2025; Scholefield et al.2025, S116) examined clinical outcomes in infants and children experiencing cardiac arrest who received chest compression in any setting. The review sought to assess the impact from the use of vasopressors (epinephrine, vasopressin, combination of vasopressors) compared to no vasopressor use on survival or neurological outcomes and return of spontaneous circulation (ROSC). Two studies were included in the review (Amoak et al. 2023, e235187; Matsuyama et al. 2020, 194).

One cohort study (Matsuyama et al. 2020, 194) involving 608 patients from the out-of-hospital setting was propensity score matched for children 9 to 17 years old and compared epinephrine administration with no epinephrine. Although epinephrine administration was associated with ROSC, no significant difference was found for survival at 1 month and favorable neurological outcome at hospital discharge with epinephrine administration compared with no epinephrine for cardiac arrest. A second cohort study (Amoak et al. 2023, e235187) involving 1,432 patients with propensity score matching for children less than 18 years old in cardiac arrest showed no significant difference when epinephrine was administered compared to no epinephrine administration for the outcomes of favorable neurological survival at hospital discharge and for survival to hospital discharge. Both studies in meta-analysis (2,034 patients less than 18 years old) showed a benefit with pre-hospital ROSC when epinephrine was administered, compared to no epinephrine (63 more patients with ROSC per 1,000 resuscitations; 95% CI, 28 more patients with ROSC to 145 more) (Kurosawa et al. 2025; Scholefield et al.2025, S116).

The previous ILCOR treatment recommendation (2020) suggested that the initial dose of epinephrine in pediatric patients with nonshockable in-hospital and out-of-hospital cardiac arrest be administered as early in the resuscitation as possible.

For 2025, the ILCOR treatment recommendations have been revised to:

• We suggest the use of epinephrine in pediatric out-of-hospital cardiac arrest (weak recommendation, very low-certainty evidence).

 

The task force considers the indirect evidence from out-of-hospital cardiac arrest to support the administration of epinephrine in pediatric in-hospital cardiac arrest (good practice statement) (Kurosawa et al. 2025; Scholefield et al.2025, S116).

Insights and Implications

The ILCOR review did not consider the evidence from the adult review on this topic as indirect evidence because of the differences between adults and children in the etiology of cardiac arrest. Both pediatric studies included in the 2025 systematic review were conducted in the out-of-hospital setting, which led to a change in the recommendation for in-hospital patients with cardiac arrest to a good practice statement. While there is an association between epinephrine administration and prehospital ROSC in children with cardiac arrest, its use may not translate to meaningful neurological recovery. Randomized controlled trials are needed in different settings to further clarify the efficacy of epinephrine in cardiac arrest as well as dosing and timing of use.

An ILCOR evidence update in 2025 (Scholefield et al.2025, S116) on the timing of the first dose of epinephrine in pediatric patients with cardiac arrest did not find evidence for patients with a shockable rhythm. Based on the evidence update, the initial dose of epinephrine should be administered as early as possible in the resuscitation of pediatric patients with nonshockable in-hospital cardiac arrest and out-of-hospital cardiac arrest. This evidence update on timing of the initial dose has been integrated into the Red Cross guidelines.

 

Intravenous Versus Intraosseous Administration of Drugs During Cardiac Arrest

Last Full Review: ILCOR 2015
Last Update: 2021

The intraosseous (IO) route is commonly used for cardiac arrest when intravenous (IV) access is not readily available or following failed attempts at IV access.

 

Evidence Summary

 

An International Liaison Committee on Resuscitation (ILCOR) systematic review (Granfeldt et al. 2020, S222) and Consensus on Science with Treatment Recommendations (Berg et al. 2020, S92) compared placement of an IO cannula and drug administration through this IO access during cardiac arrest with placement of an IV cannula and drug administration through the IV access during cardiac arrest in adults in the in-hospital or out-of-hospital setting. Outcomes included return of spontaneous circulation (ROSC) and survival to hospital discharge. Studies included in the review are all observational, providing very low-certainty evidence. Three studies (Feinstein et al. 2017, 91; Kawano et al. 2018, 588; Body et al. 2019, 69) including 24,686 adult out-of-hospital cardiac arrests were reported to show 61 fewer per 1,000 cardiac arrests with ROSC associated with use of IO access compared with IV access (aOR, 0.74; 95% CI, 0.67–0.81; aRD, -6.1%; 95% CI, -2.7 to -0.5). These same three studies showed 17 fewer per 1,000 cardiac arrests survived to hospital discharge (95% CI, 27 fewer to 5 fewer) with IO access compared with IV access (aOR, 0.79; 95% CI, 0.66–0.93; aRD, -1.7%; 95% CI, -2.7 to -0.5) (Granfeldt et al. 2020, S222).

A weak recommendation is made by ILCOR for the use of IV access compared with IO access as the first attempt for drug administration during adult cardiac arrest. If attempts at IV access are unsuccessful or IV access is not feasible, IO access is suggested as a route for drug administration during adult cardiac arrest (Berg et al. 2020, S92).

Insights and Implications

Very low-certainty evidence from three observational studies suggests improved outcomes with the administration of medications intravenously during resuscitation from cardiac arrest compared with intraosseous administration. Thus, for adults, the intraosseous route should be reserved for cases where IV access is difficult, impossible, or not readily available.

Treatment of Bradycardia: Drugs and Transcutaneous Pacing

Last Full Review: ILCOR 2020
Last Update: 2022

Sinus bradycardia with adequate perfusion typically does not require immediate intervention beyond supportive care and treatment of reversible causes. When bradycardia is accompanied by inadequate perfusion, a first step is to ensure that oxygenation and ventilation are adequate. When the heart rate is 60 beats per minute or less, chest compressions should be started. Epinephrine is the cornerstone of drug therapy when bradycardia with inadequate perfusion is present despite adequate oxygenation and ventilation, while transcutaneous or transvenous pacing may be needed for some types of bradycardias and/or if there is no response to drug therapy. Evidence updates were recently completed on these topics by the International Liaison Committee on Resuscitation (ILCOR) (Wyckoff et al. 2022, 1095).

 

Evidence Summary

The topic of drugs for pediatric bradycardia with hemodynamic compromise was last reviewed by ILCOR in 2020, (Maconochie et al. 2020, S140) with no new evidence to add to a 2010 Consensus on Science with Treatment Recommendations (CoSTR)  (Kleinman et al. 2010, S466). ILCOR treatment recommendations have been unchanged since 2010 and state: (Kleinman et al. 2010, S466)

• Epinephrine may be used for infants and children with bradycardia and poor perfusion that is unresponsive to ventilation and oxygenation.
• It is reasonable to administer atropine for bradycardia caused by increased vagal tone or cholinergic drug toxicity.
• There is insufficient evidence to support or refute the routine use of atropine for pediatric cardiac arrest.

 

A 2022 ILCOR evidence update (Maconochie et al. 2020, S140) on this topic identified three relevant observational retrospective studies (Khera et al. 2019, 370; Holmberg et al. 2020, 180; Morgan et al. 2020, 881). Two studies (Khera et al. 2019, 370; Holmberg et al. 2020, 180) used the same population, with one (Holmberg et al. 2020, 180) adding 2 more years of data analyzed with a time-dependent propensity score matching. An association was found between epinephrine use and a worse prognosis with the Holmberg study, (Holmberg et al. 2020, 180) although it was noted by the evidence update authors that the study analysis was complex and there were many confounders. The third review (Morgan et al. 2020, 881) used a different population, reporting no differences epinephrine use between patients with bradycardia compared with patients with other rhythms. The ILCOR Pediatric Task Force discussed the evidence and concluded that the new evidence does not impact current recommendations or prompt a formal updated systematic review. ILCOR 2010 treatment recommendations for pharmacotherapy of bradycardia remain unchanged (Wyckoff et al. 2022, 1095).

A separate evidence update was completed by ILCOR on the topic of transcutaneous pacing for symptomatic bradycardia in pediatric patients (Wyckoff et al. 2022, 1095). No pediatric-specific literature was identified, and treatment recommendations remain unchanged since a 2000 ILCOR and American Heart Association review (Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care 2000, I291) that noted in select cases of bradycardia caused by complete heart block or abnormal function of the sinus node, emergency transthoracic pacing may be lifesaving. Pacing is not helpful in children with bradycardia secondary to a post-arrest hypoxic/ ischemic myocardial insult or respiratory failure. In addition, pacing was not shown to be effective in the treatment of asystole in children (Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care 2000, I291).

Insights and Implications

The Red Cross guidelines for drug therapy and pacing of pediatric bradycardia with inadequate perfusion are informed by the ILCOR CoSTR (Maconochie et al. 2020, S140). With the latest evidence updates, the current guidelines are reaffirmed.

Sodium Bicarbonate Administration for Cardiac Arrest

Last Full Review: ILCOR 2010
Last Update: 2022

Sodium bicarbonate was once proposed to reduce metabolic acidosis during cardiopulmonary resuscitation but has not been shown to improve outcomes with resuscitation. The routine use of sodium bicarbonate in the management of pediatric cardiac arrest has not been recommended since 2010. Evidence updates were completed by International Liaison Committee on Resuscitation (ILCOR) most recently in 2020 (Maconochie et al. 2020, S140) and 2022 (Wyckoff et al. 2022, 1095).

 

Evidence Summary

A 2022 evidence update (Wyckoff et al. 2022, 1095) by ILCOR on the use of sodium bicarbonate for children in cardiac arrest did not identify new evidence since the previous update in 2020 (Maconochie et al. 2020, S140). When first reviewed by ILCOR in 2010, no randomized controlled trials in infants and children evaluating the use of sodium bicarbonate in pediatric cardiac arrest were identified (Kleinman et al. 2010, S466).

A 2015 retrospective review (Raymond et al. 2015, 106) of sodium bicarbonate use during in-hospital pediatric cardiac arrest using data adjusted for confounders found that sodium bicarbonate was associated with decreased survival to hospital discharge; however, for patients with metabolic and electrolyte abnormalities, hyperkalemia, and toxic syndromes, sodium bicarbonate was not associated with decreased survival.

The 2022 evidence update identified an American Heart Association guideline noting observational studies that reported that sodium bicarbonate administration during in-hospital cardiac arrest and out-of-hospital cardiac arrest was associated with worse survival outcomes (Topjian et al. 2020, S469). The guideline noted that sodium bicarbonate may be indicated in cardiac arrest with special circumstances, such as hyperkalemia and sodium channel blocker toxicity. A 2021 systematic review with meta-analysis of non-randomized studies between 2006 and 2018 evaluated sodium bicarbonate administration during 4,877 pediatric in-hospital cardiac arrests, finding decreased survival to hospital discharge (OR, 0.40; 95% CI, 0.25–0.63, P=0.0003) (Chang et al. 2021, 188). The authors of the current ILCOR Evidence Update concluded that this study supports current guidelines.

Insights and Implications

While routine administration of sodium bicarbonate is not recommended by the Red Cross for pediatric cardiac arrest, it is recognized that there may be situations in which sodium bicarbonate may be considered, despite a lack of significant evidence. This includes cardiac arrest associated with hyperkalemia and sodium channel (i.e., tricyclic antidepressant) toxicity and with severe metabolic acidosis, including after prolonged cardiac arrest/resuscitation, that persists despite adequate oxygenation and ventilation.

Mannitol or Hypertonic Saline for Acute Major Traumatic Brain Injury

Last Full Review: American Red Cross Scientific Advisory Council 2019
Last Update: 2022

Mannitol and hypertonic saline are osmotic diuretics commonly used to treat cerebral edema and increased intracranial pressure (ICP) in patients with traumatic brain injury (TBI). The choice of which agent to use is frequently based on local protocol. Are clinical outcomes improved with the use of hypertonic saline compared with mannitol for patients with acute major TBI and elevated ICP?

 

Evidence Summary

A 2022 triennial review of a 2019 American Red Cross Scientific Advisory Council scientific review (American Red Cross Scientific Advisory Council: Resuscitation 2022) of this topic identified two systematic reviews (Boone et al. 2015, 177; Chen, Song, and Dennis 2020, Cd010904) and two randomized trials of pediatric patients (Upadhyay et al. 2010, 18; Kochanek et al. 2022, e220891). The first systematic review from 2015 included seven relevant manuscripts comparing hypertonic saline to mannitol in TBI (Boone et al. 2015, 177). The authors found that both agents were effective osmolar diuretics, however, there was heterogeneity between studies and the findings were inconclusive regarding which agent was more effective.

A 2020 Cochrane systematic review (Boone et al. 2015, 177) included six trials with 91% of participants having severe TBI. Meta-analysis for outcomes of mortality at final follow-up and for a poor outcome was only possible for two trials but was challenged by a high loss to follow-up with survivors at 6 months. Based on calculated worst-case, best-case and per-protocol results, no difference in mortality at 6 months or for poor outcome based on Glasgow Outcome Scale was shown for hypertonic saline versus mannitol. Meta-analysis for the outcome of change in ICP was not possible due to heterogeneity between studies, including variation in modes of drug administration, follow-up times, and ways of reporting changes in ICP. Results of trials were reported narratively. Both hypertonic saline and mannitol tended to be reported as effective in reducing elevated ICP, but greater benefits were noted in some studies with hypertonic saline. Rebound phenomenon following use of mannitol was reported in one trial, and no other adverse effects were reported in the remaining trials.

A randomized trial of 200 pediatric intensive care unit patients with elevated ICP found that 3% sodium chloride decreased coma in patients compared to mannitol, however without a mortality benefit (Upadhyay et al. 2010, 18). Mannitol was associated with acute tubular necrosis in this trial.

A 2022 trial, Approaches and Decisions for Acute Pediatric TBI (ADAPT) compared the effect of bolus doses of 3% hypertonic saline versus mannitol on ICP and included data from 518 children with severe TBI (Kochanek et al. 2022, e220891). The data showed a statistically significant decrease in ICP and increase in cerebral perfusion pressure (CPP) with hypertonic saline bolus administration, while mannitol was observed to increase CPP. Hypertonic saline was associated with a greater reduction in ICP compared with mannitol using unadjusted data, but after adjusting for confounders, associations of both agents with ICP and CPP were not different. During periods of increased ICP, greater improvements in outcomes were observed with 3% hypertonic saline than with mannitol. This difference persisted with adjusted data for ICP greater than 25 mmHg.

The Brain Trauma Foundation Guidelines for the Management of Pediatric Severe TBI, published in 2019, is based on a systematic review and synthesis of the literature with evidence-based recommendations (Kochanek et al. 2019, S1). Recommendations include the use of a bolus dose of 3% hypertonic saline for acute intracranial hypertension, while a continuous infusion is suggested using the minimum dose needed to maintain an ICP of less than 20 mmHg. No studies using mannitol were identified as meeting inclusion criteria in the development of the pediatric severe TBI guidelines.

Insights and Implications

The ADAPT trial is the first to compare bolus 3% hypertonic saline with mannitol in pediatric patients with severe TBI (Kochanek et al. 2022, e220891). Results from this trial demonstrated a modest decrease in ICP and increase in CPP with hypertonic saline and increased CPP with mannitol. The Cochrane review (Chen, Song, and Dennis 2020, Cd010904) also noted that improved outcomes of ICP reduction were reported with hypertonic saline. Long-term clinical outcomes with treatment, however, are lacking with the exception of mortality, which was not shown to be improved with hypertonic saline compared with mannitol (Upadhyay et al. 2010, 18).

When choosing an osmolar diuretic, one must consider that the hyperosmolar state induced by hypertonic saline can be associated with a higher risk of kidney injury, congestive heart failure, pulmonary edema and, after repeated doses, with hyperchloremic acidosis (Dabrowski et al. 2021). Mannitol was associated with acute tubular necrosis in one included study (Upadhyay et al. 2010, 18). Hypertonic saline may thus be more appropriate in patients with decreased renal perfusion. Additional controlled trials are needed comparing hypertonic saline with mannitol to determine efficacy for lowering ICP, short- and long-term neurologic and survival outcomes, and adverse effects or limitations. Future studies that demonstrate a definitive improvement in outcomes or harmful effects may result in a change in recommendations.

The most recent (2019) Brain Trauma Foundation guidelines (Kochanek et al. 2019, S1) were used to inform Red Cross guidelines related to use of hypertonic saline in pediatric severe TBI and for avoiding complications related to hypernatremia.