Drug Therapy and Vascular Access

Buffering Agents During Cardiac Arrest

Last Full Review: ILCOR 2025
Last Update: 2010

The routine administration of sodium bicarbonate during cardiac arrest has not been recommended by the International Liaison Committee on Resuscitation (ILCOR) since 2010. Historically, sodium bicarbonate was used to counteract metabolic acidosis, but it has not been shown to improve survival rates or neurological outcomes, and it may be associated with lower rates of sustained return of spontaneous circulation (ROSC) and favorable neurological outcomes (Alshahrani and Aldandan 2021, 21; Wu et al. 2020, 856). Despite the evidence against the use of sodium bicarbonate in cardiac arrest, studies suggest its use outside of cardiac arrest algorithms is prevalent in clinical practice. One survey (Ross et al. 2024) reported that up to 49% of physicians responding to a survey would administer sodium bicarbonate for indications not supported by current guidelines. Another study (Alsumait et al. 2022, 1653) of 147 inpatient cardiac arrests found that sodium bicarbonate was administered inappropriately 48.3% of the time (71/147 cases).

 

Evidence Summary

An ILCOR systematic review and Consensus on Science with Treatment Recommendations (CoSTR) (Lavonas et al. 2024; Drennan et al. 2025, S72) sought evidence with clinical outcomes for the use of buffering agents alone or in combination with other drugs in adults with cardiac arrest in any setting, compared with standard resuscitation. The systematic review was completed using the adolopment process (Schünemann et al. 2017, 101) and a recently completed systematic review (Xu et al. 2023, 40) on the effect of sodium bicarbonate on out-of-hospital cardiac arrest (OHCA) patients. That review included three random controlled trials (RCTs) and three propensity score matching cohort studies with a total of 21,402 patients. The systematic review by Xu et al. was assessed using the AMSTAR 2 appraisal tool (Shea et al. 2017, j4008). All studies had significant risk of bias and/or were conducted prior to the major changes in resuscitation algorithms in 2010. No RCTs were found for pediatric OHCA or in-hospital cardiac arrest (IHCA). ILCOR recalculated the effect estimates to obtain absolute risk differences and odds ratios, and ILCOR reassessed the included trials for risk of bias.

In short, no difference was shown between the group receiving sodium bicarbonate and the group without sodium bicarbonate for the outcome of short-term survival. While there was no difference between groups for the long-term survival rate, a sensitivity analysis performed after removing one study showed a lower long-term survival rate for the bicarbonate group than for the control group (Lavonas et al. 2024; Drennan et al. 2025, S72).

The updated treatment recommendation by ILCOR for 2025 suggests against the administration of buffering agents, such as sodium bicarbonate, in the treatment of OHCA, unless a special circumstance for its use is present (weak recommendation, very low certainty of evidence) and suggests against the administration of buffering agents, such as sodium bicarbonate, in the treatment of IHCA, unless a special circumstance for its use is present (weak recommendation, very low certainty of evidence) (Lavonas et al. 2024; Drennan et al. 2025, S72).

The review discussion emphasizes that the ILCOR treatment recommendations do not address the use of buffering agents in special circumstances, such as for the treatment of hyperkalemia or sodium channel blocker or tricyclic antidepressant poisoning.

Insights and Implications

Although evidence is limited in this review and included propensity score matching cohort studies that do not account for resuscitation time bias, data from the RCTs supports the Red Cross guideline that buffering agents, such as sodium bicarbonate, are not indicated in treatment of cardiac arrest, unless a special circumstance (e.g., tricyclic antidepressant or sodium channel blocker poisoning) for its use is present. The continued use of sodium bicarbonate as reported in studies and surveys may stem from long-standing clinical habits, varying interpretations of guidelines, and individual judgment of healthcare professionals during resuscitation efforts.

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.

Vasopressin Use with Corticosteroids for Cardiac Arrest

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

The use of vasopressin with corticosteroids after epinephrine for in-hospital cardiac arrest has been the subject of several studies and systematic reviews, but evidence has not shown beneficial long-term outcomes. A systematic review (Holmberg et al. 2022, 48) has been completed on this topic since the last American Red Cross Scientific Advisory Council review.

 

Evidence Summary

A 2021 American Red Cross Scientific Advisory Council Answer (American Red Cross Scientific Advisory Council: Resuscitation 2022c) on the combined use of vasopressin with corticosteroids for in-hospital cardiac arrest identified three randomized controlled trials (Andersen et al. 2021, 1586; Mentzelopoulos et al. 2009, 15; Mentzelopoulos et al. 2013, 270) reporting higher rates of return of spontaneous circulation (ROSC) with the combined use of vasopressin with corticosteroids. The most recent randomized controlled trial (RCT), however, failed to show a benefit for survival to hospital discharge or for favorable functional outcome at hospital discharge. A recent systematic review and International Liaison Committee on Resuscitation (ILCOR) Consensus on Science with Treatment Recommendations (Nicholson et al. 2022; Wyckoff et al. 2022, e483) on this topic included all three RCTs for meta-analysis and concluded that while intra-arrest administration of vasopressin with corticosteroids improved ROSC, this was not shown for outcomes of survival to hospital discharge and favorable functional outcome at hospital discharge. There continues to be no evidence specific to cardiac arrest in the out-of-hospital setting. This systematic review has been through the adolopment process (Schünemann et al. 2017, 101) by ILCOR and used to generate weak treatment recommendations that suggest against the combined use of vasopressin with corticosteroids in addition to the standard care for adult in-hospital cardiac arrest and out-of-hospital cardiac arrest (Nicholson et al. 2022; Wyckoff et al. 2022, e483).

Insights and Implications

The most recent systematic review (Holmberg et al. 2022, 48; Wyckoff et al. 2022, e483) includes the studies identified in the 2021 American Red Cross Scientific Advisory Council Answer (American Red Cross Scientific Advisory Council: Resuscitation 2022c). Additional studies are needed to determine if the increase in rates of ROSC reported with the combined use of vasopressin with corticosteroids for in-hospital cardiac arrest translate into long-term beneficial clinical outcomes. While the Red Cross guidelines continue to state that there is insufficient evidence to recommend the combined use of vasopressin with corticosteroids for in-hospital cardiac arrest, a new guideline clarifies that due to lack of evidence, the combined use of vasopressin with corticosteroids for out-of-hospital cardiac arrest is not recommended.

Vasopressor Use During Cardiac Arrest

Last Full Review: ILCOR 2025
Last Update: 2019

Vasopressors, such as epinephrine, vasopressin and norepinephrine, differ in the mechanisms and effects during resuscitation. Epinephrine stimulates both alpha- and beta-adrenergic receptors. Alpha-1 receptor activation causes vasoconstriction, increasing systematic vascular resistance and arterial blood pressure. This, in turn, enhances coronary and cerebral perfusion during cardiopulmonary resuscitation (CPR) (Callaway et al. 2013, 36). Beta-1 receptor stimulation increases heart rate and myocardial contractility, which can also increase myocardial oxygen consumption. Vasopressin is nonadrenergic and induces vasoconstriction by stimulating the vasopressin V1 receptors, leading to increased peripheral vascular resistance and arterial blood pressure but without stimulating the heart and thus without increasing myocardial oxygen demand and arrhythmias (Krismer et al. 2006, 51). Epinephrine, however, is the primary vasopressor in cardiac arrest due to its ability to increase coronary and cerebral perfusion pressures and improved rates of return of spontaneous circulation (ROSC) and survival (Jacobs et al. 2011, 1138; Perkins et al. 2018, 711).

Vasopressin has been suggested in the past as an alternative as it has fewer cardiac side effects and maintains efficacy during acidosis, but studies have not demonstrated superiority over epinephrine for survival. A 2020 International Liaison Committee on Resuscitation (ILCOR) systematic review and Consensus on Science with Treatment Recommendations (CoSTR) (Berg et al. 2020, S92) on vasopressor use during cardiac arrest recommended the use of epinephrine during CPR and suggested against the administration of vasopressin in place of, or in addition to, epinephrine. New studies have been published in the interim and the review was updated for 2025.

 

Evidence Summary

An ILCOR systematic review and CoSTR (Holmberg et al. 2024; Drennan et al. 2025, S72) and update to the 2019 systematic review (Holmberg et al. 2019, 106) and CoSTR (Welsford et al. 2019) evaluated clinical outcomes following vasopressor use or a combination of vasopressors administered through the intravenous (IV) or intraosseous (IO) route during CPR to adults with cardiac arrest in any setting, compared with no vasopressor, a different vasopressor, a different combination of vasopressors, a different vasopressor dose or a different timing of vasopressors. The updated literature search included only randomized clinical trials (RCTs) in humans. Data from identified studies were added to findings from included RCTs in the previous review.

The 2019 review (Holmberg et al. 2019, 106; Welsford et al. 2019) included 22 randomized clinical trials and 67 observational studies in adults. The observational studies were excluded for the updated review due to the available RCTs and concern for risk of bias in the observational studies. One RCT comparing epinephrine plus vasopressin to epinephrine alone (Kim et al. 2022, 378) was added to the previously included 22 RCTs. Two secondary analyses from a previous RCT of epinephrine versus placebo (Haywood et al. 2021, 84) and time to epinephrine administration (Perkins et al. 2020, 426) were also included. No trials were identified comparing high-dose epinephrine versus standard-dose epinephrine.

Analysis of data was reported by comparisons:

• Epinephrine versus no epinephrine, any rhythm
• Epinephrine versus no epinephrine, shockable rhythms
• Epinephrine versus no epinephrine, nonshockable rhythms
• Initial vasopressin versus epinephrine for out-of-hospital cardiac arrest, any rhythm
• Initial vasopressin versus epinephrine for in-hospital cardiac arrest, any rhythm
• Epinephrine plus vasopressin versus epinephrine only, any rhythm

 

The online CoSTR (Holmberg et al. 2024; Drennan et al. 2025 In Press, S72) and systematic review (Holmberg et al. 2019, 106) provide full details of studies also included in the 2019 review.

Of the studies included in the update, one substudy (Haywood et al. 2021, 84) of a prior RCT (Perkins et al. 2018, 426) with 7,997 patients found that the use of epinephrine was associated with improved survival at 6 and 12 months (RR, 1.37; 95% CI, 1.04–1.81 and RR, 1.33; 95% CI, 1.00–1.77, respectively) compared with placebo, although there was no improvement in favorable neurological outcome at 6 months with epinephrine. For the comparison of epinephrine plus vasopressin with epinephrine alone, results from one more recent RCT (Kim et al. 2022, 378) when combined with prior RCTs did not show a benefit from the administration of epinephrine plus vasopressin for outcomes of survival at different time points and for ROSC irrespective of the initial rhythm (Holmberg et al. 2024; Drennan et al. 2025, S72).

The ILCOR treatment recommendations for vasopressor use during cardiopulmonary resuscitation remain unchanged (Holmberg et al. 2024; Drennan et al. 2025, S72):

• We recommend administration of epinephrine during cardiopulmonary resuscitation (strong recommendation, low certainty of evidence).
• For patients with nonshockable rhythms (pulseless electrical activity [PEA] or asystole), we recommend administration of epinephrine as soon as feasible during cardiopulmonary resuscitation (strong recommendation, very low certainty of evidence).
• For patients with shockable rhythms (ventricular fibrillation [VF)] or pulseless ventricular tachycardia [pVT]), we suggest administration of epinephrine after initial defibrillation attempts are unsuccessful during cardiopulmonary resuscitation (weak recommendation, very low certainty of evidence).
• We suggest against the routine use of high-dose epinephrine in cardiac arrest (weak recommendation, very low certainty of evidence).
• We suggest against the administration of vasopressin in place of epinephrine during cardiopulmonary resuscitation (weak recommendation, very low certainty of evidence).
• We suggest against the addition of vasopressin to epinephrine during cardiopulmonary resuscitation (weak recommendation, very low certainty of evidence).

 

Insights and Implications

Results from the newly included studies support the prior recommendations for the use of epinephrine during CPR and against the addition of vasopressin to epinephrine during CPR. No studies were identified that addressed the question of dosing, timing or route of administration of epinephrine. High-dose epinephrine (e.g., 5 milligrams [mg] to 15 mg) has not been recommended since trials in the 1990s found improved short-term outcomes but no improvement in survival or neurological outcome (Stiell et al. 1992, 1045).

The Red Cross guidelines have been revised to recommend, as a good practice statement, the standard 1-mg dose of epinephrine during CPR, which is based historically and is the dose used in the trials evaluated in the ILCOR systematic review. There is insufficient evidence to suggest titrating epinephrine doses. The ILCOR CoSTR (Holmberg et al. 2024; Drennan et al. 2025, S72) notes that there is also limited data to guide the timing of epinephrine administration during CPR. For nonshockable rhythms, the chances of survival decrease rapidly (Perkins et al. 2020, 711) and there are limited alternative interventions; thus, administering epinephrine as early as possible is recommended during cardiac arrest. On the other hand, patients with cardiac arrest and a shockable rhythm benefit from early defibrillation, and thus guidelines recommend a strategy of epinephrine administration after initial defibrillation attempts have been unsuccessful.

However, the optimal timing of epinephrine administration in relation to defibrillation remains a knowledge gap. The route of epinephrine administration was not discussed in the current ILCOR review, however an analysis of data from the PARAMEDIC2 trial in 2020 (Nolan et al. 2020, 954) found that, among 3,631 patients with out-of-hospital cardiac arrest, there was no difference between IV and IO groups for odds ratio of ROSC at hospital handover, 30-day survival or favorable neurological outcome at discharge.

Calcium During Cardiac Arrest

Last Full Review: ILCOR 2023

The Red Cross does not recommend the routine administration of calcium during cardiac arrest in its guidelines, and its use has not been recommended by the International Liaison Committee on Resuscitation (ILCOR) since 2010. A recent study on this topic led to an updated systematic review by ILCOR (Hsu et al. 2022; Berg et al. 2023).

 

Evidence Summary

The 2023 ILCOR systematic review and Consensus on Science with Treatment Recommendations (Hsu et al. 2022; Berg et al. 2023) looked at the intravenous or intraosseous administration of calcium during cardiac arrest, compared with no administration of calcium. All years were included in the literature search. Three randomized controlled trials (RCTs) and eight observational studies in adults with out-of-hospital cardiac arrest did not show an improvement in outcomes with calcium administration for cardiac arrest. Of the RCTs, the largest trial was terminated early due to concern for harm. Results from two trials suggested worse functional outcomes at 90 days and 1 year with calcium administration (Vallentin et al. 2022, 21; Vallentin et al. 2021, 2268). The most recent trial (Vallentin et al. 2022, 21) of 391 adults reported that at 1 year, 9 patients in the calcium group (4.7%) were alive, compared with 18 (9.1%) in the placebo group (RR, 0.51; 95% CI, 0.24–1.09), and 7 (3.6%) were alive with a favorable neurological outcome, compared with 17 (8.6%) in the placebo group (RR, 0.42; 95% CI, 0.18–0.97). The updated ILCOR treatment recommendations include a strong recommendation against the routine administration of calcium for treatment of out-of-hospital cardiac arrest in adults, and a weak recommendation against calcium administration for treatment of in-hospital cardiac arrests in adults (Hsu et al. 2022; Berg et al. 2023).

Insights and Implications

No RCTs were identified that compared calcium administration with no calcium administration during in-hospital cardiac arrests (hence the weak recommendation against the use of calcium for adults with in-hospital cardiac arrests). Calcium is administered for special circumstances, such as hyperkalemic cardiac arrest, hypocalcemia and calcium channel overdose, but the ILCOR review notes that there is insufficient data from existing trials to evaluate these subgroups.

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 2022b) 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 identified 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 (Chen, Song, and Dennis 2020, Cd010904) 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. 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 (Kochanek et al. 2022, e220891). 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 an 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 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 a bolus of 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 except for mortality, which was not shown to be improved with hypertonic saline compared with mannitol. 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 the Red Cross guidelines related to the use of hypertonic saline in pediatric severe TBI and for avoiding complications related to hypernatremia.