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Comparison of intraosseous and intravenous epinephrine administration during resuscitation of asphyxiated newborn lambs
  1. Calum T Roberts1,2,3,
  2. Sarah Klink1,
  3. Georg M Schmölzer4,
  4. Douglas A Blank1,2,3,
  5. Shiraz Badurdeen1,5,
  6. Kelly J Crossley1,
  7. Karyn Rodgers1,
  8. Valerie Zahra1,
  9. Alison Moxham1,
  10. Charles Christoph Roehr6,7,8,
  11. Martin Kluckow9,
  12. Andrew William Gill10,
  13. Stuart B Hooper1,11,
  14. Graeme R Polglase1,11
  1. 1 The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia
  2. 2 Department of Paediatrics, Monash University, Clayton, Victoria, Australia
  3. 3 Monash Newborn, Monash Health, Clayton, Victoria, Australia
  4. 4 Centre for the Studies of Asphyxia and Resuscitation, University of Alberta, Royal Alexandra Hospital, Edmonton, Alberta, Canada
  5. 5 Newborn Research Centre, Royal Women's Hospital, Parkville, Victoria, Australia
  6. 6 National Perinatal Epidemiology Unit, Nuffield Department of Population Health, Medical Sciences Division, University of Oxford, Oxford, UK
  7. 7 Newborn Care, Division of Women and Children, University of Bristol, Southmead Hospital, North Bristol NHS Trust, Bristol, UK
  8. 8 Newborn Care, Southmead Hospital, North Bristol NHS Trust, Bristol, UK
  9. 9 Department of Neonatology, Royal North Shore Hospital, St Leonards, New South Wales, Australia
  10. 10 Centre for Neonatal Research and Education, University of Western Australia, Perth, Western Australia, Australia
  11. 11 Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
  1. Correspondence to Dr Calum T Roberts, The Ritchie Centre at Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; calum.roberts{at}monash.edu

Abstract

Objective Intraosseous access is recommended as a reasonable alternative for vascular access during newborn resuscitation if umbilical access is unavailable, but there are minimal reported data in newborns. We compared intraosseous with intravenous epinephrine administration during resuscitation of severely asphyxiated lambs at birth.

Methods Near-term lambs (139 days’ gestation) were instrumented antenatally for measurement of carotid and pulmonary blood flow and systemic blood pressure. Intrapartum asphyxia was induced by umbilical cord clamping until asystole. Resuscitation commenced with positive pressure ventilation followed by chest compressions and the lambs received either intraosseous or central intravenous epinephrine (10 μg/kg); epinephrine administration was repeated every 3 min until return of spontaneous circulation (ROSC). The lambs were maintained for 30 min after ROSC. Plasma epinephrine levels were measured before cord clamping, at end asphyxia, and at 3 and 15 min post-ROSC.

Results ROSC was successful in 7 of 9 intraosseous epinephrine lambs and in 10 of 12 intravenous epinephrine lambs. The time and number of epinephrine doses required to achieve ROSC were similar between the groups, as were the achieved plasma epinephrine levels. Lambs in both groups displayed a similar marked overshoot in systemic blood pressure and carotid blood flow after ROSC. Blood gas parameters improved more quickly in the intraosseous lambs in the first 3 min, but were otherwise similar over the 30 min after ROSC.

Conclusions Intraosseous epinephrine administration results in similar outcomes to intravenous epinephrine during resuscitation of asphyxiated newborn lambs. These findings support the inclusion of intraosseous access as a route for epinephrine administration in current guidelines.

  • resuscitation
  • neonatology
  • emergency care

Data availability statement

Data are available upon reasonable request. Data are available to qualified researchers upon reasonable request to the authors.

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What is already known on this topic?

  • Epinephrine is required during resuscitation at a small proportion of births, but these infants are at high risk of adverse outcomes.

  • Intraosseous access is included as an alternative to umbilical venous cannulation for drug administration in newborn resuscitation guidelines.

  • There are no clinical or preclinical trials comparing the effectiveness of intraosseous and intravenous epinephrine during newborn resuscitation.

What this study adds?

  • Asphyxiated lambs effectively achieve return of spontaneous circulation with intraosseous epinephrine, at similar rates and administered doses as with intravenous epinephrine.

  • Plasma epinephrine levels measured after intraosseous and intravenous epinephrine administration are similar, suggesting effective distribution into the intravascular space.

  • Given the similar physiological response, speed of access may be an important determining factor in choosing intraosseous or intravenous epinephrine in the clinical setting.

Introduction

Worldwide, approximately 10 million infants per year require resuscitation at birth, which may include interventions such as stimulation, oxygen and positive pressure ventilation, or in the most severe cases chest compressions (CC) and drugs such as epinephrine.1 The proportion of infants receiving epinephrine during neonatal resuscitation is difficult to define. Reports from a large tertiary centre in the USA suggest epinephrine use occurs at approximately 0.05% of births,2 3 whereas resuscitation guidelines quote figures of 1–3 per 1000 term and late preterm births.4 On a global scale this would equate to tens of thousands of infants annually, in settings where advanced neonatal resuscitation is available. Although representing a small proportion of births, these infants are at particularly high risk of major adverse outcomes such as neurodisability and death.5

While not clearly understood, the critical action of epinephrine during newborn resuscitation is thought to be the same as that derived from work in infant and adult animal models, specifically its effect on alpha-adrenergic receptors, resulting in systemic vasoconstriction.6 Vasoconstriction, in conjunction with forward flow from CC,7 results in increased aortic and coronary perfusion pressure, which correlates with myocardial perfusion and is a positive predictor of return of spontaneous circulation (ROSC).8 9

Neonatal resuscitation guidelines include several potential routes for epinephrine administration, with intravenous administration via an umbilical venous catheter (UVC) preferred.10 11 Alternatives include administration via endotracheal tube, which may be placed early during resuscitation for airway management, or via intraosseous needle. Intraosseous access is an established alternative to intravenous access in resuscitation guidelines for adults and older children,12 13 but has featured less prominently in neonatal guidance, potentially reflecting a lack of evidence, availability or familiarity in neonatal settings. A review of intraosseous versus UVC epinephrine, conducted by the International Liaison Committee on Resuscitation (ILCOR) in 2020, identified no evidence comparing these two treatments in newborns.10 The current ILCOR treatment recommendation is that intraosseous access ‘is a reasonable alternative for vascular access during newborn resuscitation’ at birth if umbilical access is unavailable, and that outside the delivery room ‘either umbilical venous access or the IO [intraosseous] route may be used’.

Preclinical research can provide a vital understanding of the physiological effects of clinical treatments and, particularly in the context of a lack of clinical evidence, may influence treatment recommendations. We aimed to evaluate the efficacy of intraosseous epinephrine administration during resuscitation, compared with intravenous administration, in a near-term lamb model of birth asphyxia.

Methods

Instrumentation and delivery

Pregnant Border Leicester ewes (Ovis aries) at 139±2 days’ gestation (mean±SD; term ~148 days) were anaesthetised with intravenous thiopentone sodium (20 mg/kg), followed by tracheal intubation and delivery of inhaled anaesthesia (isoflurane 1.5%–2.5%).

The fetus was partially exteriorised (head and chest) from the uterus and flow probes were placed around the left main pulmonary artery, femoral artery and carotid artery (Transonic Systems, Ithaca, New York, USA). Catheters were inserted into a carotid artery and jugular vein (PD10; DTX Plus Transducer, Becton Dickinson, Singapore) as described previously.14 Arterial pressures and blood flows were digitally recorded (1 kHz, Powerlab; ADInstruments, Castle Hill, New South Wales, Australia). The fetal trachea was intubated with a 4.5 mm cuffed endotracheal tube and lung liquid drained passively. A peripheral oxygen saturation (SpO2) probe (Masimo, Radical 4, California, USA) was placed around the right forelimb and a near-infrared spectroscopy (NIRS) Optode (Casmed Foresight, CAS Medical Systems, Branford, Connecticut, USA) placed over the left frontal cortex to measure cerebral tissue oxygen saturation. For lambs allocated to intraosseous treatment, an intraosseous needle (Arrow EZ-IO 15 mm 15 ga intraosseous needle; Teleflex Medical, Wayne, Pennsylvania, USA) was inserted in the distal right rear femur.

After delivery, asphyxia was induced by umbilical cord clamping, and continued until the mean blood pressure was reduced to ~0 mm Hg and no discernible activity was visible on the blood pressure trace.14 Resuscitation was initiated in air with a 30 s sustained inflation to 30 cmH2O, followed by positive pressure ventilation using a T-piece device (Neopuff; Fisher and Paykel Healthcare, Auckland, New Zealand), with peak inflation pressure of 30 cmH2O and end-expiratory pressure of 5 cmH2O, targeting 60 breaths per minute. One minute after ventilation onset, if heart rate remained <60 beats per minute, CC were initiated with a target of 90 CC and 30 ventilation breaths per minute, and fraction of inspired oxygen increased to 1.00 as per resuscitation guidelines.11 Intravenous (jugular vein, n=12) or intraosseous (n=9) epinephrine (50 μg, equivalent to 10 μg/kg based on estimated weight of 5 kg) was given 1 min after CC were initiated, and every 3 min thereafter if ROSC had not been achieved, for a maximum of four doses. Treatment allocation to intravenous or intraosseous epinephrine was determined by the investigators prior to surgery (not random) and was unblinded. In the intraosseous group, after three intraosseous epinephrine doses, a fourth and final ‘rescue’ intravenous dose was administered. Each epinephrine dose (by either route) was flushed with 5 mL of 0.9% saline.

After ROSC, lambs received pressure-limited volume guarantee ventilation at tidal volume of 7 mL/kg,15 with heated humidified gas (Dräeger Babylog 8000+, Dräeger, Lübeck, Germany). Ventilation parameters were digitally recorded (Powerlab). Lambs were sedated to maintain comfort (Alfaxan 5–15 mg/kg/hour intravenously in 5% dextrose). Blood gas samples (ABL 30; Radiometer, Copenhagen, Denmark) were collected every 3 min until 15 min, and every 5 min thereafter. Ventilation settings were adjusted to target an SpO2 of 90%–95% and a partial pressure of arterial carbon dioxide (PaCO2) of 35–45 mm Hg.

Plasma samples were collected from the carotid artery before cord clamping (fetal), at end asphyxia, and at 3 and 15 min after ROSC, and epinephrine concentrations were determined by enzyme immunoassay (Adrenaline 162 Research ELISA, catalogue #BA E-5100; LDN, Germany).16 Lambs were humanely euthanised (sodium pentobarbitone >100 mg/kg intravenously) at 30 min after ROSC.

Statistical analysis

Baseline fetal and physiological data were compared using Student’s t-test, or Mann-Whitney rank-sum test if data were not normalised (GraphPad Prism; GraphPad Software, California, USA). A two-way repeated measures analysis of variance with Holm-Sidak post-hoc comparison was used to compare serial physiological data (SigmaPlot; Systat Software, California, USA). Statistical significance was accepted at p<0.05. A minimum of seven survivors per group was regarded as sufficient to determine differences in serial physiological variables, based on previous studies conducted by our group.

Results

Fetal characteristics

Fetal characteristics are outlined in table 1. PaO2 was significantly higher in intraosseous animals compared with intravenous animals prior to initiation of studies. All other variables were similar in the two groups. The weights in each group were similar, but were slightly lower than the working weight used to calculate the epinephrine dose (5 kg). As a result, the administered mean epinephrine dose was 12.2 μg/kg in the intravenous group and 11.1 μg/kg in the intraosseous group.

Table 1

Characteristics of all lambs and those achieving ROSC

Resuscitation and return of circulation

Achievement of ROSC occurred in 10 of 12 intravenous lambs and 7 of 9 intraosseous lambs. The number of epinephrine doses received was similar in both groups: a single dose was required by 7 of 10 survivors in the intravenous group (range 1–3 doses) and 6 of 7 survivors in the intraosseous group (range 1–2 doses). There was no difference in the time taken to achieve ROSC (figure 1), with eight lambs and six lambs achieving ROSC within 5 min in the intravenous and intraosseous groups, respectively.

Figure 1

Time to return of spontaneous circulation (ROSC) in intravenous and intraosseous lambs. Individual animals are shown with mean (95% CI) included. This original figure was created by GRP.

Plasma epinephrine levels

Plasma epinephrine was elevated at 3 min in comparison with the fetal and asphyxia levels, but was reduced again at 15 min. Plasma epinephrine concentrations were similar in the two groups at all measured time points (figure 2).

Figure 2

Plasma concentration of epinephrine in intravenous (IV) and intraosseous (IO) lambs measured in the fetal state (F), at end asphyxia (A), and at 3 and 15 min after return of spontaneous circulation. Mean values are shown with error bars representing SD. This original figure was created by GRP.

Blood gas, oxygenation and ventilation parameters

At 3 min, pH and PaO2 were significantly higher, and PaCO2 was significantly lower, in intraosseous lambs compared with intravenous lambs (figure 3). No differences were identified at other time points. Arterial lactate was significantly higher in the intravenous lambs compared with intraosseous lambs throughout the study (group effect p=0.0032). Peripheral SpO2 and cerebral oxygenation, measured by pulse oximetry and NIRS, respectively, were not different between the groups at any time point, nor was fraction of inspired oxygen. The mean airway pressure was significantly higher in intravenous lambs than in intraosseous lambs throughout the study.

Figure 3

pH, PaO2, PaCO2 and lactate measured in arterial blood samples, and peripheral oxygenation (SpO2), cerebral oxygenation (SctO2), fraction of inspired oxygen (FiO2) and mean airway pressure measured prior to asphyxia (control, F), at end asphyxia (A) and regularly after return of spontaneous circulation in lambs receiving intraosseous (IO) or intravenous (IV) epinephrine. Error bars denote SD. *Significant difference at p<0.05. This original figure was created by GRP. SctO2, cerebral tissue oxygen saturation; SpO2, oxygen saturation.

Physiological parameters

Blood pressure was not different between the groups before or after ROSC (figure 4). A pronounced overshoot in blood pressure beyond fetal values was observed in both groups (mean blood pressure increase: intraosseous 24.2±11.3 mm Hg, intravenous 23.6±21.0 mm Hg), and the degree of overshoot was similar. Pulmonary and carotid blood flow were not different between the groups. The overshoot in mean carotid blood flow was similar in the two groups (intraosseous: 1134.5±721.7 mL/min/g brain weight vs intravenous: 716.5±420.0 mL/min/g brain weight).

Figure 4

Mean blood pressure, mean pulmonary blood flow (PBF) and mean carotid blood flow measured prior to asphyxia (control, F), at end asphyxia (A) and regularly after return of spontaneous circulation in lambs receiving intraosseous or intravenous epinephrine. Error bars denote SD. This original figure was created by GRP.

Discussion

Using asphyxiated near-term lambs, we have shown intraosseous and intravenous epinephrine administrations result in similar outcomes, in terms of achievement of ROSC and in the physiological responses seen shortly after resuscitation. The number of epinephrine doses required to achieve ROSC was similar in both groups, as were the measured plasma epinephrine levels at all time points before and after ROSC. These data support the concept that medications administered via an intraosseous device are rapidly distributed into the central venous circulation.

We found that blood gas parameters in the intraosseous group improved more rapidly, with higher pH and PaO2 and lower PaCO2. These differences did not persist beyond 3 min after ROSC, so are unlikely to be clinically meaningful. Lactate was persistently higher in intravenous lambs than in intraosseous lambs throughout the study, although this was also true at the end of asphyxia, despite other blood gas parameters in the two groups being similar. The reasons for this difference are unclear and may represent random variation between lambs. Similarly, it was not apparent why the intraosseous group required lower mean airway pressures, despite a consistent approach to ventilation in both groups.

Both groups had a marked increase in blood pressure and carotid blood flow in the minutes immediately after ROSC. This may be a reflection of the combined effect of systemic vasoconstriction due to epinephrine administration, and the physiological response of the fetus to asphyxia, which results in preferential maintenance of brain perfusion.17 18 Previous studies have shown a correlation between the overshoot in blood pressure and degree of cerebrovascular injury as assessed by protein leakage from subcortical white matter and grey matter.17 The strategy of physiologically based cord clamping (PBCC), in which ventilation is commenced prior to cord clamping, reduces both blood pressure overshoot and cerebrovascular injury, in comparison with immediate cord clamping prior to resuscitation, as was used in this study. Resuscitation with the umbilical cord intact is currently restricted to clinical trials. Should this approach become more widely adopted into clinical practice, it is a scenario in which intraosseous access may prove very advantageous as the cord is not available for UVC insertion during PBCC.

Previous data on the use of intraosseous access in the neonatal population are extremely limited. A recent systematic review identified one neonatal case series of 30 infants and several case reports.19 This review summarised the reported complications of intraosseous placement, which include malposition, fracture, infection, compartment syndrome and limb ischaemia. Although these complications are important, if the alternative is failure to administer epinephrine, likely resulting in death, in most situations they would be deemed acceptable. UVC insertion has also been associated with complications, including infection, thrombi, hepatic injury, cardiac tamponade and death.20 21

This is the first study, in either the clinical or preclinical setting, to compare the intraosseous and intravenous routes for epinephrine administration during newborn resuscitation. The strengths of this study include the use of a well-established model that replicates the transitional physiology seen at birth in humans, including the liquid-filled newborn lung, changing pulmonary vascular resistance, and the presence of structural fetal shunts including a patent ductus arteriosus. Limitations in applicability to clinical care include that this study was conducted in lambs, which although of similar size to a term infant have certain anatomical differences, and the lack of randomised treatment allocation. We used jugular rather than umbilical venous epinephrine administration, but both routes similarly provide central venous access. The controlled environment in which this study was conducted is a strength in terms of providing reliable physiological data, but cannot accurately replicate the stressful environment of a newborn resuscitation, where a variety of clinical, equipment and human factors will influence outcome.22

Comparisons of intraosseous and intravenous access via UVC have previously been described in simulation studies. These studies reported that intraosseous access was achieved in a significantly shorter time than UVC placement, including when participants were practitioners specialising in newborn care, with greater experience of UVC placement than intraosseous placement.23–25 While it would be expected that these clinicians will preferentially choose a more familiar procedure (UVC) over an unfamiliar one (intraosseous), and that complications of an unfamiliar procedure may be more frequent, both uptake in use and success rate without complication would be expected to increase with appropriate training. Including intraosseous access more prominently in neonatal resuscitation training, alongside UVC insertion, may change decision making in clinical practice. Many infants who require resuscitation at birth are born outside of tertiary neonatal units and resuscitated by clinicians such as general paediatricians, midwives, anaesthetists, emergency clinicians, general practitioners or paramedics. These clinicians may have limited exposure to neonatal resuscitation, particularly UVC insertion. However, if regularly involved in resuscitation of adults or older children, they may be familiar with intraosseous insertion as this approach is more prominent in resuscitation guidelines for these patient groups.12 13 It may be appropriate that treatment recommendations place more emphasis on prioritising either intraosseous or intravenous access based on whichever route is likely to be achieved more rapidly, depending on the training and experience of the treating clinician. European guidelines, updated in 2021, feature the option of intraosseous access more prominently than in past versions.11

While ideally clinical trials should be used to guide practice recommendations, there are situations where conducting such research is particularly difficult. The use of epinephrine during newborn resuscitation typically occurs unpredictably at a small minority of births and must be administered as an emergency treatment, creating a particularly challenging environment for clinical research. In such situations, the use of alternative approaches to study design, such as cluster trials, or the use of a waiver of informed consent may be necessary to allow effective study recruitment. While clinical randomised trial data on the use of intraosseous epinephrine are the optimal scenario, even additional observational clinical data would be informative, given the minimal existing evidence in the neonatal population.

Conclusions

In the absence of clinical evidence from human trials, appropriately designed preclinical research may influence treatment recommendations. In this study, conducted in asphyxiated near-term lambs, we found intraosseous epinephrine administration resulted in similar outcomes to intravenous epinephrine, in terms of required dosage and plasma level, achievement of ROSC, and physiological parameters measured after ROSC. The results of this study provide reassurance that the physiological responses seen with intraosseous epinephrine use during newborn resuscitation are very similar to those seen with intravenous epinephrine, currently regarded as the ‘gold standard’ route of administration, and support the inclusion of intraosseous access as a route for epinephrine administration in current consensus guidelines.

Data availability statement

Data are available upon reasonable request. Data are available to qualified researchers upon reasonable request to the authors.

Ethics statements

Ethics approval

Experimental procedures were approved by the Monash Medical Centre Animal Ethics Committee A, Monash University (MMCA/2018/10), were conducted in accordance with the National Health and Medical Research Council of Australia’s guidelines, and are reported in accordance with the ARRIVE guidelines.

Acknowledgments

We acknowledge the support of Teleflex Medical, which loaned the EZ-IO Power Driver and donated the Arrow EZ-IO needles used in this study.

References

Footnotes

  • Twitter @calumtheroberts

  • Contributors CTR, GMS, DAB, SB, CCR, MK, AWG, SBH and GRP made substantial contributions to study conception and design, or analysis and interpretation of the data. SK, KJC, KR, VZ and AM contributed to data collection and analysis. CTR and GRP cowrote the first draft of the manuscript.

  • Funding This research was supported by the National Health and Medical Research Council (NHMRC) Project Grant APP1158494 and Fellowships (GRP: APP1173731; SBH: APP545921; CTR: APP1175634), a National Heart Foundation of Australia Vanguard Grant (103022), and the Victorian Government’s Operational Infrastructure Support Programme.

  • Disclaimer Teleflex Medical had no input in study design, conduct, or analysis or in manuscript preparation.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.