A study of Professor Bellomo's contribution to cardiac arrest research

1. The ripple effect of cardiac arrest

Cardiac arrest (CA) is a common and catastrophic event with an estimated incidence of 30,000 events per year in Australia and New Zealand.¹ It is a traumatic experience for the patient, is profoundly distressing for family members, and has undesirable impacts on the community and broader society.^2,3 Among comatose adults who are resuscitated after CA, the leading cause of death and disability is hypoxic–ischaemic encephalopathy,⁴ proven by neuroimaging, neurophysiology, chemical biomarkers, bedside assessment, and not least by long-term clinical outcomes.[5], [6], [7], [8] Like us, Professor Bellomo recognised that interventions to reduce brain injury following CA are desperately needed and remain foremost in actions of researchers in the field of CA.

Professor Bellomo's vision, stature, achievements, and character are well described elsewhere in the journal.⁹ For over 20 years, he had published across a breadth of topics related to CA. His output, borne out of curiosity and achieved through collaboration, challenged existing practices and revealed new insights. This editorial uses selected publications to illustrate Professor Bellomo's significant contribution to CA research, with a particular emphasis on programmatic and collaborative research.

2. Professor Bellomo's contribution to CA research

Professor Bellomo made meaningful contributions to the field CA research through editorials, literature reviews, clinical trial publications, and presentation at critical care conferences. His work spanned a wide range of areas, including the following:

• •Animal and experimental studies[10], [11], [12]
• •Prehospital studies¹³
• •In-hospital (in and outside intensive care) CA[14], [15], [16]
• •Physiological effects of CA[17], [18], [19], [20], [21], [22]
• •Oxygenation, ventilation, and temperature management[23], [24], [25], [26]
• •Postresuscitation care and guideline adherence[27], [28], [29]

Table 1 provides a snapshot of the breadth and nature of Professor Bellomo's contribution to CA research.

Table 1.

Snapshot of Professor Bellomo's contribution cardiac arrest research.

Lead author	Year	Study type	Population	Topic
Animal studies and experimental research
Pilcher J et al.10	2012	SR and MA	Animal	Describe the effect of hyperoxia following CA
Bellomo R et al.11	2016	Proof-of-concept	Animal	Direct cerebral perfusion and cooling in experimental CA
Lucchetta L et al.12	2019	SR	Animal	Carotid artery and cerebral blood flow during experimental CPR
Prehospital
Young P et al.13	2014	RCT	OHCA	Evaluation of hyperoxic therapy or normoxic therapy after OHCA
In-hospital (in and outside intensive care)
Rozen TH et al.14	2014	Retrospective	ICU	Antecedents to CAs in a teaching hospital ICU
Ratnayake H et al.15	2021	Retrospective	Acute care	Use of laboratory-derived early warning score for the prediction of in-hospital mortality, ICU admission, medical emergency team activation, and CA in general medical wards
Jones D et al.16	2023	Prospective	Acute care	Rapid response system components and in-hospital CAs rates 21 years after introduction into an Australian teaching hospital
Physiological effects
Makino J et al.17	2005	Observational	CA	Quantitative analysis of the acidosis of CA
Chua HR et al.18	2012	Observational	CA	Describe the incidence and characteristics of acute kidney injury after CA
Bellomo R et al.19	2015	Literature review	CA	Evaluate metabolic and electrolyte disturbance after CA
Melberg MB et al.20	2023	TAME sub-study	OHCA	Evaluate cardiovascular changes induced by targeted mild hypercapnia after OHCA
Melberg MB et al.21	2024	TAME sub-study	OHCA	Evaluate the effects of mild hypercapnia on myocardial injury after OHCA
Eastwood G et al.22	2025	TAME sub-study	OHCA	Evaluate of the impact of mild hypercapnia on renal function after OHCA
Oxygenation, ventilation and temperature management
Bellomo R et al.23	2011	Observational	CA	Arterial hyperoxia and in-hospital mortality after resuscitation from CA
Eastwood GM et al.24	2016	Retrospective	CA	Conservative oxygen therapy in mechanically ventilated patients following CA
Dankiewicz J et al.25	2021	MC-RCT	OHCA	Hypothermia versus normothermia after OHCA
Eastwood G et al.26	2023	MC-RCT	OHCA	Mild hypercapnia or normocapnia after OHCA
Post-resuscitation care and guideline adherence
Casamento A et al.27	2016	Before after study	CA	Comparison of therapeutic hypothermia and strict therapeutic normothermia after CA
Salter R et al.28	2018	Retrospective	OHCA	Describe changes in temperature management of ANZ CA patients after the TTM trial
Eastwood GM et al.29	2025	TAME sub-study	OHCA	Use of MRI in adults resuscitated after OHCA

ANZ, Australia and New Zealand; CA, cardiac arrest; CPR, cardiopulmonary resuscitation; ICU, intensive care unit; MA, meta-analysis; MC-RCT, multicentre randomised controlled trial; MRI, magnetic resonance imagining; OHCA, out-of-hospital cardiac arrest; SR, systematic review; TAME trial, Targeted Therapeutic Mild Hypercapnia after Cardiac Arrest trial (NCT03114033); TTM2 trial, Targeted Hypothermia versus Targeted Normothermia after out-of-Hospital Cardiac Arrest trial (NCT01020976).

3. Involvement in the pivotal CA trials

Two landmark studies exemplify Professor Bellomo's influence in the field of CA research: the Targeted Therapeutic Mild Hypercapnia after Cardiac Arrest (TAME) trial²⁶ and the Targeted Hypothermia versus Targeted Normothermia after out-of-Hospital Cardiac Arrest (TTM2) trial.²⁵ The TAME trial explored whether targeted mild hypercapnia could enhance cerebral perfusion and improve neurological outcomes in comatose CA survivors. This nuanced approach to postresuscitation ventilation reflects Professor Bellomo's commitment to physiological precision as it challenged conventional thinking related to the effect of arterial carbon dioxide on cerebrovascular control during critical illness. Coled by Professor Bellomo, this trial aimed to determine whether mildly elevated carbon dioxide levels could reduce cerebral injury and enhance recovery.²⁶ More detail of the TAME trial's program of research, including findings and impact, is provided later in this editorial.

Equally transformative is the TTM2 trial which questioned the routine use of therapeutic hypothermia, comparing it to normothermia in comatose adults resuscitated following CA and admitted to the intensive care unit (ICU).²⁵ The findings of the TTM2 trial,²⁵ which showed no significant benefit of cooling to 33 °C, have informed international guidelines and prompted ongoing evaluation of long-held practices, as evidenced by the actively recruiting STEPCARE trial (NCT05564754). Professor Bellomo's role in the harmonisation of the TAME and TTM2 trials is discussed in the following.

4. TAME trial: A masterclass in programmatic research

Professor Bellomo valued programmatic research for its ability to systematically follow data through to an evidence-based, practice-informing conclusion. The TAME trial provides an exemplar of Professor Bellomo's skill in evolving a research question into a research project and a project into a research program. Shown in Fig. 1 and described in the following paragraphs are the steps and milestones that took the TAME trial from its initial question to a definitive phase III trial and beyond, all under Professor Bellomo's careful stewardship.

Fig. 1.

The TAME trial research program including key milestones and achievements. Shown are the key milestones and events spanning the 13+-year TAME trial research program. These touch on the research question being defined, the conduct of the foundational observational study, pivotal phase II and physiological studies, successful multinational grant funding, conduct of the definitive phase III TAME trial, including TTM2 trial harmonisation. Followed by the primary publication of results in the New England Journal of Medicine (N Engl J Med 2023;389:45–57) and the succeeding post hoc studies. ANZ, Australia and New Zealand; Australian NHMRC, National Health and Medical Research Council of Australia; CA, cardiac arrest; CO₂, carbon dioxide; ICU, intensive care unit; Irish HRB, Health Research Board of Ireland; MRI, magnetic resonance imaging; NEJM, New England Journal of Medicine, New Zealand HRC, Health Research Council of New Zealand; QOL, quality-of-life; TAME trial, Targeted Therapeutic Mild Hypercapnia after Cardiac Arrest trial; and, TTM2 trial, Targeted Hypothermia versus Targeted Normothermia after out-of-Hospital Cardiac Arrest trial.

The initial concept that would evolve into the TAME trial research program occurred in early 2011. It began with a brief conversation among a small group of clinician-researchers at the Austin Hospital, on the physiological role of carbon dioxide. The research question that arose centred on exploring the potential therapeutic role that arterial carbon dioxide management may have in specific clinical scenarios. Among these, patients resuscitated from CA were swiftly identified as a key population of interest.

In 2013, using data from the Australian New Zealand Intensive Care Society “Adult Patient Database”, an observational cohort study was conducted to examine the association between arterial carbon dioxide tension and outcome following CA.³⁰ From data of 16,542 patients, this study found that both hypocapnia and hypercapnia were common. Most patients were typically hypercapnic on arrival to the ICU, and notably, compared to hypocapnia, hypercapnia increased the likelihood of being discharged home.

Building on these findings, the results of a multicentre, binational phase II study were published in 2016.³¹ This study demonstrated that patients in the mild hypercapnia group showed reduced levels neuron-specific enolase, a brain injury biomarker, coupled with a trend towards improved neurological outcome at 6 months. Later in 2016, the results of a double-crossover physiological study were published.³² This study demonstrated that deliberate short-term exposure to periods of mild hypercapnia, compared to normocapnia, led to increased cerebral oxygenation as assessed using near-infrared spectroscopy. Put together, the observational, physiological, biomarker, and clinical outcome data led to the successful awarding of multinational grants and the conduct of the phase III TAME trial, overseen by a multidisciplinary management committee.

Findings of the TAME trial showed that patients with coma following out-of-hospital CA and targeted mild hypercapnia did not improve neurological outcomes at 6 months.²⁶ Additionally, there was no statistically significant difference between groups in terms of death within 6 months or health-related quality of life.²⁶ For Professor Bellomo, publishing the primary results was just one step along the continuum of evidence generation and practice change. As such, the TAME research program continues beyond this phase III trial, as demonstrated by several post hoc studies that have explored areas including acute myocardial injury,²¹ cardiovascular,²⁰ renal,²² and intracranial pressure³³ change in response to targeted mild hypercapnia, and neuroimaging with magnetic resonance imaging.²⁹

5. TAME trial and TTM2 trial collaboration: The power and sensibility of harmonisation

Clinical trials involving CA patients present distinct ethical, operational, and scientific challenges which can be compounded when multiple trials target the same patient population. This was the case for the TAME and TTM2 trials. Faced with this scenario, Professor Bellomo's modus operandi was to seek a path forward that would optimise the success for all concerned.

Achieving harmonisation between the TAME and TTM2 trials exemplifies Professor Bellomo's scientific acumen and his collaborative spirit. For over a year, Professor Bellomo and the authors of this editorial held weekly discussions that led to almost complete harmonisation of trial protocols. Notably, during one of the early meetings, author Nielsen recalled a 15-year-old email exchange that highlighted Professor Bellomo's collaborative nature, generosity, and altruism (see personal reflection in Fig. 2).

Fig. 2.

A personal reflection on Professor Bellomo's collaborative nature, generosity, and altruism by Professor Nielsen.

In a remarkable fashion, from March 2018 through September 2021, the TAME trial enrolled 1700 patients at 63 ICUs in 17 countries. More remarkably, 370 patients were coenrolled into the TTM2 trial.²⁶ This represents 21% and 19% of the overall TAME and TTM2 trial populations, respectively.^25,26

As poetically stated by Parke et al.,³⁴ the case for coenrolment of patients into TAME and TTM2 trials was always going to be the correct “cerebral option”.

6. Professor Bellomo's legacy: Ongoing and planned CA research

Independent of the TAME and TTM2 trial research programs, several related ongoing and planned studies continue to deepen the knowledge base of CA care and patient management. Of note, research projects into pharmaceutical interventions for neuroprotection have commenced and research concepts are coalescing into formal questions in relation to harnessing computerised technologies and artificial intelligence to optimise neuroprognostication.

In addition, we await the findings of two actively recruiting large, multicentre, multinational trials. The first is the LOGICAL nested-cohort study of the MEGA-ROX trial (ACTRN12620000391976), a 40,000-patient trial comparing conservative versus liberal oxygen therapy in mechanically ventilated ICU patients.³⁵ The second is the STEPCARE trial, a 3500-patient trial comparing sedation, temperature and blood pressure strategies for comatose adults resuscitated following out-of-hospital CA.³⁶

From here, in the spirit of Professor Bellomo, we are uniquely placed to (i) evaluate current practice; (ii) to identify early neuroprognostic indicators to improve patient selection for future CA trials and; (iii) to seek and then implement new physiological insights to guide therapeutic target selection for cerebral protection after CA.

7. Summary

In the evolving field of CA research, all efforts to reduce brain injury and improve patient outcomes are to be pursued pragmatically and systematically. Through his breadth of work and commitment, Professor Bellomo challenged long-standing assumptions and expanded our understanding and management of patients following CA. His enthusiastic leadership, programmatic approach, and collaborative nature have informed international guidelines and clinical practice, reinforcing the importance of evidence-based postarrest care. His contributions to CA research will influence the field for years to come.

CRediT authorship contribution statement

GE: Conceptualisation, Writing – original draft, Writing – review & editing Validation, Visualisation.

NN: Formal analysis, Writing – review & editing, Visualisation.

Data availability

Not applicable.

Declaration of generative artificial intelligence usage

During the preparation of this work, the authors used Microsoft 365 Copilot to improve language and readability. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.