The final nail in the Paxlovid coffin?

Butler CC, Pinto AD, Harris V, Holmes J, Rahman NM, Cureton L, Hayward G, Richards DB, Lowe DM, Standing JF, Breuer J, Hood K, Png ME, Petrou S, Dorward J, Patel MG, Thomas NPB, Evans P, Hart ND, Jani BD, Hosseini B, Murthy S, McBrien K, Condon A, McDonald EG, Daley P, Greiver M, da Costa BR, Selby P, Jüni P, Lee TC, Shi H, Detry MA, Saunders CT, Fitzgerald M, Berry NS, Saville BR, Khoo SH, Nguyen-Van-Tam JS, Hobbs FDR, Yu LM, Little P; PANORAMIC Trial and CanTreatCOVID Trial Collaborative Groups. Oral Nirmatrelvir-Ritonavir for Covid-19 in Higher-Risk Outpatients. N Engl J Med. 2026 Apr 23;394(16):1583-1594. doi: 10.1056/NEJMoa2502457. PMID: 42019019

This paper actually describes two separate open-label adaptive platform RCTs: PANORAMIC out of the UK and CanTreatCOVID out of Canada. The trials are pretty similar. If you want the full details you can read Justin’s full rant on here.

Bottom line: Maybe Paxlovid should join Tamiflu on the shelves of the medical misadventure museum?

Minocycline, for stroke?

Lu Y, Guan L, Wu J, Yang Q, Zhang M, Zhou D, Yang H, Pan Y, Wang L, Qiu B, Liu C, Wang Y, Yang Y, Zhou X, Qu H, Liao X, Liu L, Zhao X, Bath PM, Johnston SC, Amarenco P, Turc G, Shi FD, Wang Y, Wang Y; EMPHASIS Investigators. Efficacy and safety of minocycline in patients with acute ischaemic stroke (EMPHASIS): a multicentre, double-blind, randomised controlled trial. Lancet. 2026 Feb 14;407(10529):679-688. doi: 10.1016/S0140-6736(25)01862-8. Epub 2026 Jan 30. PMID: 41628627

So, now acne medication has about the same level of evidence for acute stroke as does tPA?

Bottom line: In this high quality double-blind RCT, minocycline improved functional outcomes from ischemic stroke. 

They are still trying to make recombinant factor VII a thing??

Broderick JP, Naidech AM, Elm JJ, Toyoda K, Dowlatshahi D, Demchuk AM, Khatri P, Steiner T, Bath PM, Audebert HJ, Vagal A, Yoshimura S, Mayer SA, Wang LL, Sabagha N, Mocco JD, Molina C, Aviv R, Stinson E, Quadri SA, Carrozzella J, Huynh T, Phan A, Beall J, Davis I, Sakai N, Ohta T, Yokosawa M, Hara T, Sangha N, Morita K, Dominc Tse MY, Streib CD, Miyashita F, Silva Y, Nagakane Y, Gheorghiu T, Sun CH, Hirano T, Poli S, Izumo T, Fukuda-Doi M, Ihara M, Koga M, Buck B, Walsh KB, Spokovny I, Grotta JC; FASTEST Investigators. Recombinant factor VIIa versus placebo for spontaneous intracerebral haemorrhage within 2 h of symptom onset (FASTEST): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet. 2026 Feb 21;407(10530):773-783. doi: 10.1016/S0140-6736(26)00097-8. Epub 2026 Feb 4. PMID: 41653933

Recombinant factor VIIa seems like a great idea in principle, yet we know that is rarely one that translates into real world benefits…

Bottom line: An expensive drug that probably does nothing and may cause harm. Sounds like something we should avoid but probably won’t!

Strike 2 for whole blood

Sperry JL, Guyette FX, Cotton BA, Luther JF, Utarnachitt RB, Kutcher ME, Daley BJ, Peetz AB, Patel MB, Goodman MD, Claridge JA, Patel N, Harbrecht BG, Hashmi ZG, Zarychanski R, Neal MD, Yazer MH, Martin-Gill C, Vincent LE, Harner AM, Meyer DE, Latimer AJ, Robinson BR, McKnight CL, Hinckley WR, Miller KR, Jansen JO, Martin D, Fox EE, Rosario-Rivera BL, Wisniewski SR; TOWAR Study Group. Prehospital Resuscitation with Type O Whole Blood for Trauma and Hemorrhage. N Engl J Med. 2026 May 18. doi: 10.1056/NEJMoa2602167. PMID: 42150044

Last episode we looked at the SWIFT trial out the UK which was asking the same question and came up negative. So this new trail from the United States (that’s the country just below Canada on a map) is more data that keeps our Bayesian needle exactly in the same place… meh!

Bottom line: It is not unexpected, but this cluster RCT shows no benefit from whole blood, and the point estimate is a major red flag. 

HI-PEITHO – widely misunderstood

Rosenfield K, Klok FA, Piazza G, Sharp ASP, Ní Áinle F, Jaff MR, Barco S, Goldhaber SZ, Kucher N, Lang IM, Schmidtmann I, Sterling KM, Araszkiewicz A, Arora V, Cires-Drouet R, Coghlan J, Hobohm L, Ito WD, Jacobson K, Kaiser C, Kopec G, Marx K, McElwee S, Meneveau N, Monteleone P, Montero-Cabezas JM, Olivier CB, Park J, Roik M, Sakhuja R, Tego A, Theurl M, Visveswaran G, Vos JA, Young MN, Asch FM, Konstantinides SV; HI-PEITHO Investigators. Ultrasound-Facilitated, Catheter-Directed Fibrinolysis for Acute Pulmonary Embolism. N Engl J Med. 2026 Mar 28. doi: 10.1056/NEJMoa2516567. PMID: 41910345

We have heard a lot from the interventional folk about invasive devices for the management of biggish PEs in recent times. I wrote an overview earlier this year.

(You can listen to Weingart and Justin argue about HI-PEITHO over on EmCrit.) It is a fun chat between a polite American and a ranty Canadian (i.e. equally polite…)

Bottom line: Despite widely being discussed as a positive trial, there were no real differences – peripheral IV tPA is probably still the more available and reliable treatment option.

So should we be aggressive with clots in the legs instead?

Vedantham S, Kahn SR, Marston WA, Weinberg I, Sista AK, Magnuson EA, Cohen DJ, Wasan SM, Razavi MK, Goldhaber SZ, Sanfilippo KM, Comerota AJ, Azene EM, Chaar CIO, Leung DA, Kolli KP, Kalva SP, Rostambeigi N, Desai A, Desai KR, Tafur AJ, Khalsa B, Majerus E, Wang B, Wang Y, Nieters P, Derfler MC, Oliver A, Hardy C, Bashir R, Winokur R, Weger N, Khaja MS, Sharma A, Mani N, Kavali P, Thukral S, Lake LL, Mikkelsen K, Parpia S; C-TRACT Trial Investigators. Endovascular Therapy for Post-Thrombotic Syndrome – A Randomized Trial. N Engl J Med. 2026 Apr 13:10.1056/NEJMoa2519001. doi: 10.1056/NEJMoa2519001. PMID: 41972998

Bottom line: Fractional benefits and possible harms… not really a fair fight as one group got dual anticoags. But good to know what is on offer for our chronic post DVT patients.

The dose of iodinated contrast required for a CT scan is below the toxicological threshold of concern for nephrotoxicity

Phillips A, Blumenberg A. The dose of iodinated contrast required for a CT scan is below the toxicological threshold of concern for nephrotoxicity: a toxicological perspective. JEM Rep. 2026 Jun;5(2). doi: 10.1016/j.jemrpt.2026.100220

The best evidence that we have tells us that CT contrast simply does not cause kidney injury.

This is an interesting Toxicological perspective on the debate about AKI due to contrast.

Short answer: for diagnostic CT studies we are well below the “Threshold of Toxicologic Concern.” Carry on and contrast.

Yes, peripheral pressors are safe

Greaves RL, Quay A, Bolot R, King J, Gibbs C. Safety of Peripheral Vasoactive Drug Administration in Prehospital and Retrieval Medicine (SPOTLESS-2): A Prospective Observational Cohort Study. Acad Emerg Med. 2026 Apr;33(4):e70271. doi: 10.1111/acem.70271. PMID: 41947342

This is one of my passion projects… the safety and efficacy of peripheral vasopressors can make a big difference to rural Resus patients. This data out of Queensland supports all of my biases and backs up my beliefs!

Bottom line: Peripheral vasopressors are safe to use, and considering the harms of central lines, are honestly the preferred option for early resuscitation in almost all patients. 

Diagnostic accuracy of tongue coating in identifying acute appendicitis

Mori H, Yamasaki K, Saishoji Y, Torisu Y, Mori T, Nagai Y, Izumi Y. Diagnostic accuracy of tongue coating in identifying acute appendicitis: a prospective cohort study. Emerg Med J. 2025 Jul 22;42(8):519-525. doi: 10.1136/emermed-2024-214210. PMID: 40169241

The TCI (Tongue Coating Index) is probably about as useful as any other clinical decision score in acute appendicitis. It is very cheap and fast, so why not have a look. Worst case scenario is second-hand halitosis?

I will leave it up to you to decide whether that is because the tongue coating index is valuable, or because most of the clinical decision rules in existence are absolute garbage and are probably making you worse at your job.

Justin says he will buy a pint for anyone who calls a surgeon without imaging and tries to convince them that there is an acute appendicitis based primarily on your tongue exam. Challenge accepted.

Bottom line: Glossal Gestalt for the win?

Neanderthal Dentistry – how hard can it be?

Zubova AV, Zotkina LV, Olsen JW, Kulkov AM, Moiseyev VG, Malyutina AA, Davydov RV, Markin SV, Maksimovskiy EA, Chistyakov PV, Krivoshapkin AI, Kolobova KA. Earliest evidence for invasive mitigation of dental caries by Neanderthals. PLoS One. 2026 May 13;21(5):e0347662. doi: 10.1371/journal.pone.0347662. Erratum in: PLoS One. 2026 Jun 5;21(6):e0351227. doi: 10.1371/journal.pone.0351227. PMID: 42127021

A fascinating insight into the culture of our Neanderthal cousins – they were likely doing dentistry – planning, making tools and carrying out prolonged procedures in Siberia nearly 60,000 years ago

Given the relative unavailability of acute dental services in most rural places in the world – it is a relief to know that our ancient cousins managed to do this sans anaesthesia with some rock tools. Much cheaper if you have the will power and pain tolerance.

Peake SL, Macdonald SPJ, et al; the ARISE FLUIDS Investigators, the ANZICS Clinical Trials Group, and the ACEM Clinical Trials Network. Vasopressors or Fluids in Early Septic Shock. N Engl J Med. Published online June 11, 2026. DOI: 10.1056/NEJMoa2516225. (FREE PDF COPY HERE)

We’ve spent fifteen years slowly walking back the idea that septic shock is a problem you solve by drowning it. ARISE FLUIDS is the latest, biggest, and most carefully done step in that walk-back from our part of the world. It is, on its primary outcome, resoundingly negative. I want to argue that the negative result is a useful one. For those of us working a long way from a tertiary ICU, it quietly describes an approach we should probably already be using.

The clinical question:
Once a patient with septic shock has had their first litre or two, what do you reach for next? More fluid, or noradrenaline? The Surviving Sepsis Campaign still gives a weak recommendation for at least 30 mL/kg in the first three hours, on evidence everyone agrees is… watery. ARISE FLUIDS set out to test the alternative head-on in the emergency department, before that 30 mL/kg had been committed.

PICO
ARISE FLUIDS is an investigator-initiated, open-label RCT at 51 sites (Australia / NZ), Oct 2021–Nov 2025. 1000 randomised 1:1 → 963 ITT (481 vasopressor, 482 fluids). The allocated strategy ran for a minimum 6 h and up to 24 h in a critical care area (ED or ICU); after that, both arms reverted to usual care.

Patients — Adult ED septic shock (Sepsis-3 phenotype):

Clinically suspected infection, and
SBP <90 mmHg or MAP <65 mmHg despite ≥1000 mL fluid given as boluses (a bolus = 500–1000 mL over ≤60 min, including prehospital fluid), and Lactate >2.0 mmol/L, and
IV antimicrobial already commenced
Excluded: already received >2000 mL IV fluid; >6 h since ED presentation; a reason fluid restriction or the intervention was inappropriate (cardiac failure and other fluid-restriction states, imminent surgery, care limitations, clinician-judged unsuitability)

Intervention — Restricted fluids + early vasopressors:

Resuscitation fluids stopped at randomisation
Vasopressor started immediately and titrated to a clinician-chosen MAP target; agent, route and dosing all at clinician discretion
Further fluid given only as 250 mL boluses, and only for a defined trigger: refractory hypotension, persistent hypoperfusion (e.g. delayed cap refill), lactate >4 mmol/L or rising from the previous value despite ≥2 h resuscitation, persistent tachycardia, or oliguria (UO <0.5 mL/kg/h for ≥2 h) Maintenance fluids discouraged

Control — Liberal fluids + later vasopressors:

Initial bolus of up to 1000 mL over the first hour after randomisation Further 500 mL boluses for persistent hypotension or hypoperfusion A total of 30 mL/kg by 3 h from ED presentation recommended unless contraindicated (i.e. the current Surviving Sepsis target) Fluid type, fluid-responsiveness assessment, maintenance and MAP target all at clinician discretion Vasopressors started only once the target MAP wasn’t met and the clinician judged the patient fluid-replete or fluid-unresponsive; for the minority already on a pressor at randomisation, dosing was left to clinician judgement (no mandated weaning) Both arms: if critically hypotensive, concurrent fluids + vasopressors were allowed; patients reassessed at least hourly for 6 h, then as needed.

Outcomes:

Primary: “days alive and out of hospital” to day 90

Secondary: 28- & 90-day mortality, survival time, days alive & at home, organ-support–free days to day 28

Safety: peripheral-vasopressor complications, pulmonary oedema, organ ischaemia

What they found:

Good separation. This wasn’t a trial that failed because the two arms blurred together. Over 24 hours the vasopressor group received about 1.1 L less fluid (median 1140 vs 2248 mL; difference −1108 mL, 95% CI −1395 to −850), with most of the gap opening in the first 6 hours (500 vs 1500 mL). Vasopressors were used in 86.5% vs 67.6% (an 18.9 percentage-point difference), started about an hour earlier (median 0.4 vs 1.4 h), and were given peripherally in most patients in both arms – arms of the trial – not both arms of each patient ! (71.9% vs 55.4%).

The primary outcome was as flat as it gets. Median number of “days alive and discharged” at day 90 was 76 days in both groups (difference 0.0 days, 95% CI −2.7 to 2.7, P = 1.00). Adjustment, sensitivity analysis, and every prespecified subgroup told the same story.

Mortality — read this honestly. 90-day death was 16.4% (vasopressor) vs 14.4% (fluids), RR 1.14 (95% CI 0.85–1.54); 28-day death 12.9% vs 10.0%, RR 1.29 (0.91–1.85). Not statistically significant, and the trial wasn’t powered for mortality — but the point estimates sit on the wrong side for the vasopressor strategy, and intellectual honesty means saying so.

More patients in the vasopressor arm were admitted to ICU (76.5% vs 67.8%) – this tells us more about hospital protocols than actual patient factors…

The one signal that did separate: pulmonary oedema. 0.6% in the vasopressor group vs 5.0% in the fluids group (RR 0.12, 95% CI 0.03–0.39, P <0.001). The authors fairly note this may be partly reporting bias in an open-label trial — but a roughly eight-fold difference is difficult to wave away entirely, and it’s biologically exactly what you’d predict from a litre-plus of extra crystalloid.

Bottom line as written: restricted fluids with early vasopressors did not increase days alive and out of hospital. A clean null.

So, why is a null result important for a rural hospital? Here’s the thing about a genuinely flat primary outcome with tight confidence intervals: it doesn’t tell you the strategy is better, but it does tell you it’s not worse. And once two strategies are equivalent on patient-centred outcomes, the tie-breaker becomes everything else — deliverability, safety profile, and the resources you actually have in the room. That’s where this gets interesting for those of us in places where the nearest ICU is a retrieval flight away.

This is the end of a fifteen-year arc, and the arc points one way. Rivers’ EGDT (2001) gave us aggressive front-loaded fluids, central lines and ScvO2 targets.

Then ProCESS, ARISE and ProMISe (2014) showed the elaborate protocol and the invasive monitoring added nothing over good usual care.

CLASSIC and then CLOVERS (NEJM 2023) tested fluid restriction directly and found — like ARISE FLUIDS — no mortality benefit and no convincing harm.

ARISE FLUIDS now extends that to the earliest, ED-based, pre-30 mL/kg window in well-defined Sepsis-3 shock. Every one of these trials is “negative.”

Read together, they are a fifteen-year accumulation of evidence that less fluid is safe. Meanwhile, the two traditional objections to an early-vasopressor strategy have evaporated as the evidence evolved.

The first was “you need a central line” — no longer true. Peripheral noradrenaline is now the most-studied peripheral vasopressor, used safely in thousands of patients, with extravasation events that are uncommon (~5%) and almost always minor (a bit of blanching and local oedema). In ARISE FLUIDS itself, the majority of vasopressor patients in both arms were managed peripherally. I have just rewritten the local peripheral vasopressor guidelines to reflect this reality.

The second objection was “you need an arterial line to run pressors.” EVERDAC (Muller et al, NEJM 2025) randomised 1010 ICU shock patients to invasive versus non-invasive BP and found NIBP non-inferior for 28-day mortality (34.3% vs 36.9%), with arterial-line exposure slashed from 98% to 15%. Importantly – the complications of arterial lines also dropped significantly. You can run noradrenaline through a good peripheral line, titrated to an automated cuff, and the evidence says your patient does just as well.

Put those three threads together, and you have a resuscitation strategy that is purpose-built for a rural setting: a peripheral line, a bag of noradrenaline and a NIBP cuff cycling every few minutes, and a deliberate decision not to keep pouring in fluid you may not be able to get back out. None of that requires a central line, an art line, or an ICU bed you don’t have. And the downside of the liberal-fluid alternative is concentrated exactly where we’re least equipped to deal with it.

ARISE FLUIDS standout safety signal was pulmonary oedema — five times more common in the fluids arm. In a tertiary centre, fluid-overload pulmonary oedema is an inconvenience: more oxygen, some diuresis, a CPAP circuit, an ICU review, maybe some renal-replacement (aka dialysis). In a remote ED with a single doctor, a sick septic patient, and a retrieval team six hours away, iatrogenic pulmonary oedema in an already-shocked patient is a genuinely dangerous complication that can turn a stabilisation into an intubation. If two strategies give the same days alive and out of hospital, but one of them is far less likely to flood the lungs of a patient we then have to keep alive overnight – no retrieval flight in sight – that asymmetry matters enormously to me.

So what am I actually claiming? Not that early vasopressors save lives — ARISE FLUIDS clearly does not support that, and the numerically higher mortality in the vasopressor arm is a reason for humility – we need to be wary. This science will continue to evolve.

The defensible claim is narrower and, I think, more useful: early, peripheral, NIBP-monitored vasopressor support, with judicious rather than liberal fluids, is now a safe and reasonable first-line approach to ED septic shock — and in the rural and remote context its risk-benefit balance tilts further in its favour than the headline equivalence suggests.

Less (fluids, invasive lines, intubations) is not more, but it is probably just as good.

A note on US / echocardiography in this context. Stop deciding in the dark: ultrasound should be the go-to tool in septic shock.

Here’s what nags at me about the whole fluids-versus-vasopressors literature, ARISE FLUIDS included. These are pragmatic trials that deliberately treat septic shock as one thing and randomise everyone to the same lever. ARISE FLUIDS says so explicitly — neither resuscitation targets nor any specific measure of fluid responsiveness was mandated; the decision was left to clinician discretion. That’s a legitimate design choice and it’s why the result generalises. But it also means the trial answers “fluids or pressors for the average septic patient?” when the question I’m actually asking at 2am is “what does this patient in front of me need?”

Septic shock isn’t one average patient. Some are warm, vasodilated and genuinely empty — they’ll take fluid and improve. Others have a heart that’s already struggling — septic cardiomyopathy, or a long-standing poor ventricle — and every extra bag just backs up into the lungs. A single randomised lever can’t be right for both, which is probably a fair part of why these trials keep landing on “no difference”: benefit in one group is being cancelled by harm in the other. The good news is you don’t need to be a sonographer to get useful information at the bedside. The skill that matters here isn’t measuring anything — it’s recognising the patient who shouldn’t get more fluid. Three quick looks, all well attainable for a generalist with basic POCUS training.

Lungs. B-lines are extravascular lung water, and they appear before the sats drop or you hear crackles. A couple in isolation is normal; bilateral B-lines spreading across the chest mean the lungs are getting wet — stop the fluid. It’s the easiest view to learn and the most directly actionable, and it speaks straight to that 5% pulmonary-oedema signal: much of that is preventable if someone’s putting the probe on the chest between boluses.

The heart, eyeball it. Forget ejection fractions. You’re answering one question: is this ventricle squeezing down briskly, or is it sluggish and barely moving? A poorly contracting LV is your warning that fluid will pool behind it instead of boosting output — lean towards pressors and go very easy on volume. More experienced echonerds may also be able to spot dynamic LVOT obstruction. Which is not that rare and not too hard once you know how. This might be the patient who does need a little more fluid.

The IVC, at the extremes it can be useful. A full, non-collapsing IVC suggests the tank probably isn’t empty. One data point only — never in isolation, never the headline — but a plump IVC plus B-lines plus a tired-looking heart is three arrows pointing the same way: no more fluid. A small, hard-to-see IVC is also useful; this suggests low filling pressures, which both fluids and vasopressors may help fix. A flat IVC should not mandate a fluid bolus on its own.

That’s the whole kit. You don’t need VExUS, formal fluid-responsiveness manoeuvres or a cardiology-grade study to make this call — they’re fine if you have them and the training, but they’re beyond what most of us need, and chasing them is how people talk themselves out of scanning at all. Wet lungs, a weak heart, a full IVC: that’s enough to tell you the fluids arm of this trial is the wrong arm for this patient.

To be honest about the evidence: POCUS-guided resuscitation hasn’t been shown to lower mortality in sepsis, IVC variation is unreliable on its own, and the 2026 reviews say the same — no proven survival signal yet. So I’m not claiming the probe saves lives. The claim is more modest: when the big trials tell you the average choice doesn’t matter, the only way left to beat the average is to look at the patient in front of you — and three simple views let even a novice spot the one who’ll be harmed by another litre.

Reversibility in the bush: the beautiful thing about peripheral pressors is that they are entirely “switch-off-able” – if you had to make an error, this is the error to make. I would much rather call the ICU to say that the first-line pressors are not working than to call them to say that the patient is needing to be intubated after 4 litres. The morbidity and mortality (not to mention the cost) of an intubated aero-medical retrieval are not insignificant.

The honest caveats. This was open-label, so the pulmonary-oedema signal carries some ascertainment risk. The exclusions matter for our patients: anyone already past 2000 mL or with a fluid-restriction reason like cardiac failure was out, which is a meaningful slice of remote presentations. The mortality point estimates favour fluids, even if non-significantly, and nobody should run a vasopressor-first protocol believing it’s superior. And the findings explicitly may not generalise to low-resource settings — an irony worth sitting with, given that’s precisely the setting I’m arguing they help. But equipoise was the whole premise of the trial, and ARISE FLUIDS has largely resolved it: do whichever you can do well and safely. For a lot of us north of the Tropic of Capricorn, the thing we can do well and safely — without a central line, an art line, or an ICU — is start the noradrenaline early and ease off the fluids.

This trial gives us permission to keep doing exactly that. As always — read the paper, argue with me in the comments, and tell me where the Kimberley reality differs from the trial.

References

1. Peake SL, Macdonald SPJ, et al; ARISE FLUIDS Investigators. Vasopressors or Fluids in Early Septic Shock. N Engl J Med 2026. DOI: 10.1056/NEJMoa2516225.
2. The NHLBI PETAL Network (CLOVERS); Shapiro NI, Douglas IS, et al. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. N Engl J Med 2023;388:499–510.
3. Meyhoff TS, Hjortrup PB, et al (CLASSIC). Restriction of Intravenous Fluid in ICU Patients with Septic Shock. N Engl J Med 2022;386:2459–70.
4. Muller G, Contou D, Ehrmann S, et al; EVERDAC Trial Group. Deferring Arterial Catheterization in Shock. N Engl J Med 2025;393:1875–88.
5. Permpikul C, Tongyoo S, et al (CENSER). Early Use of Norepinephrine in Septic Shock: A Randomised Trial. Am J Respir Crit Care Med 2019;199:1097–105.
6. Munroe ES, Co IN, Douglas I, et al. Peripheral Vasopressor Use in Early Sepsis-Induced Hypotension. JAMA Netw Open 2025;8(8):e2529148.
7. Prescott HC, Antonelli M, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines 2026. Crit Care Med 2026;54:725–812.
8. Dunay Silva AAA, Medina Tovar S, Usma Gutierrez JS, et al. Impact of Point-of-Care Ultrasound-Guided Resuscitation Protocols in the Treatment of Septic Shock: A Systematic Review of Hemodynamic Outcomes and Mortality. Cureus 2026;18(1):e100850.
9. Wang J, Blake LM, Orozco N, et al. Dynamic Measures of Fluid Responsiveness to Guide Resuscitation in Patients with Sepsis and Septic Shock: A Systematic Review and Meta-Analysis. Crit Care Explor 2025;7(9):e1303.

Then the VBG comes back.

Lactate: 3.1 mmol/L.

And suddenly Gary is getting a sepsis workup, a 30ml/kg fluid bolus is being contemplated, and someone is calling the ICU at a regional centre three hours away.

His chest X-ray shows a right lower lobe consolidation. He has pneumonia. He is, by the loosest technical definition, septic.

Here’s the thing. Gary has also been huffing away on his salbutamol inhaler for two hours.

What Lactate Actually Is

Lactate is produced constantly, by nearly every cell in your body. It’s not a waste product — it’s a fuel. The heart, brain, and skeletal muscle all use lactate as an energy substrate. At rest, a healthy person produces around 1500 mmol of lactate per day, clearing it mostly through the liver and to a lesser degree the kidneys and heart.

The normal serum range is up to around 2 mmol/L, though this varies by lab and method.

The classic teaching — lactate rises when tissues are underperfused, switch to anaerobic metabolism, pyruvate backs up, and lactate floods the blood — is Type A lactic acidosis. Shock. Ischaemia. Real badness.

But Type A is only a small part of the story, and arguably the less interesting part. To be honest, picking a patient with type A lactic acidosis is pretty easy in practice.

The Fallacies

Fallacy 1: Elevated lactate = tissue hypoxia = underperfusion = needs more fluid.

This is the one that causes the most harm. Type B lactic acidosis has nothing to do with oxygen delivery. Lactate rises in the absence of any perfusion problem at all. Common culprits:

• Beta-agonists — salbutamol, adrenaline. To understand why, it helps to know about the Cori cycle: the normal housekeeping loop where lactate produced in peripheral tissues — working muscle, red blood cells — is shuttled to the liver, converted back to glucose via gluconeogenesis, and returned to circulation. It’s an elegant recycling system, and under normal conditions it keeps lactate levels tightly controlled.
• Beta-2 receptor stimulation short-circuits this. Activation of beta-2 receptors on skeletal muscle cells drives Na⁺/K⁺-ATPase activity, which ramps up ATP consumption and in turn accelerates glycolysis. More pyruvate is produced than the mitochondria can handle — so lactate dehydrogenase mops up the excess, converting it to lactate. This happens with adequate oxygen delivery — it’s aerobic glycolysis, the same metabolic trick tumour cells use (the Warburg effect). The Cori cycle tries to keep up, but hepatic clearance has a ceiling. A few salbutamol nebs and a lactate of 2.5–4 mmol/L is a completely expected pharmacological consequence. It is not a distress signal from your patient’s tissues — it’s a readout of their medication.
• Infection and systemic inflammation — activated neutrophils, macrophages, and other immune cells are metabolically ravenous. They upregulate aerobic glycolysis as part of their inflammatory response — producing lactate not because they’re starved of oxygen, but because rapid ATP generation via glycolysis suits their function. Add the endogenous catecholamine surge of any acute illness and you have another beta-2 mediated push on top. A lactate of 2–3 in a patient with pneumonia who is otherwise haemodynamically stable may simply reflect an immune system doing its job.
• Thiamine deficiency — blocks pyruvate dehydrogenase, pyruvate can’t enter the Krebs cycle, and shunts instead to lactate. Relevant in your malnourished, alcohol-dependent, or post-bariatric patients.
• Metformin toxicity — inhibits complex I of the mitochondrial respiratory chain, again shunting pyruvate away from oxidative metabolism.
• Liver disease — impaired clearance. The Cori cycle depends on a functioning liver. In cirrhosis or acute hepatic failure, lactate may be elevated simply because the recycling system is broken, not because production is excessive.
• Malignancy — Warburg physiology again. Tumour cells produce lactate aerobically as a feature, not a bug.
• Seizures — transient massive rise from muscular activity, self-resolving within an hour or so.

In Gary’s case — COPD exacerbation, pneumonia, salbutamol nebs — he has at least three concurrent Type B mechanisms running simultaneously. The lactate is over 3 – the result of multiple pathways, none type A hypoxemia. Gary himself is sitting up, talking in full sentences, and asking when he can have a cup of tea.

Fallacy 2: Lactate clearance is a resuscitation target.

The Surviving Sepsis Campaign’s use of serial lactate as a guide to resuscitation adequacy has embedded this deeply. And there is an association between lactate normalisation and improved outcomes in septic shock. But association is not mechanism, and lactate clearance is almost certainly a marker of physiological recovery, not a driver of it. Treating the number — giving more fluid, more pressors — because the lactate hasn’t normalised yet is treating a proxy, not the patient.

The most recent (2026) Surviving Sepsis guidelines reframed lactate clearance to specifiy that it only applies in patients who are already in septic shock. So the sickest of the sick. Not Gary.

The ANDROMEDA-SHOCK trial found peripheral perfusion targets were non-inferior to lactate-guided resuscitation. The point is not that lactate is useless — it’s that it tells you something has gone wrong somewhere, not specifically that you need to pour in more saline.

Fallacy 3: Any lactate above 2 is clinically significant.

The Sepsis-3 criteria use >2 mmol/L as a criterion for septic shock in a patient with suspected infection and vasopressor requirement. That’s an appropriate clinical context with a narrow application. It is not a population-level trigger for aggressive resuscitation in any undifferentiated patient who looks vaguely unwell.

Spurious elevations from delayed sample processing, tight tourniquet application, prolonged transport in the sample tube — these are all real. Lab artefact can push a normal lactate into the “abnormal” range without a single struggling mitochondrion involved.

What to Actually Do

When you see an elevated lactate, ask yourself five questions before you reach for the fluid bag:

1. Is this patient in shock? Not the number — the patient. Mentation, skin perfusion, cap refill, pulse pressure, urine output. Treat the human.
2. What’s the clinical context? Beta-agonists on board? Liver disease? Metformin? Seizure in the last hour? Known malignancy? Active infection driving an inflammatory response?
3. Is there a perfusion problem I’m missing? Mesenteric ischaemia, massive PE, cardiogenic shock — these do cause Type A lactataemia and deserve urgent attention.
4. What does the trajectory look like? A lactate trending down in a patient who is improving clinically is reassuring. A lactate climbing despite initial resuscitation in a sick patient is alarming. Context and direction matter more than a single value.
5. Will volume actually help, or possibly harm my patient? Before embarking on a large volume resuscitation it behooves us to spend a minute thinking about where our patient sits on the spectrum of fluid tolerance and the possible downsides of “another litre”. This does require one to get off of one’s chair, but it can save a lot of time down the line if we get this right.

Back to Gary

Gary got a salbutamol cease, appropriate antibiotics for his pneumonia, a repeat lactate two hours later of 1.8, and admission for treatment of his chest infection. He did not need 3L of normal saline, a central line, or an ICU transfer.

He had pneumonia. He needed antibiotics. His lactate told us his immune system and his puffer were both working — not that his organs were failing.

Lactate is a useful tool with a narrow range of meaningful applications. It is not a substitute for clinical assessment, and a mildly elevated result should prompt thinking, not reflexive escalation.

Know what the number means. Know what it doesn’t.

Casey

Further reading

A fantastic PK presentation on Lactate in ED by Dr Laura Castle in 2013 CLICK HERE

• Garcia-Alvarez et al.: Garcia-Alvarez M, Marik P, Bellomo R. Sepsis-associated hyperlactatemia. Crit Care. 2014;18(5):503. doi: 10.1186/s13054-014-0503-3. PMID: 25394679
• Hernandez et al. (ANDROMEDA-SHOCK): Hernández G, Ospina-Tascón GA, Petri Damiani L, et al. Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA. 2019;321(7):654–664. doi: 10.1001/jama.2019.0071. PMID: 30772908
• Levy B. Lactate and shock state: the metabolic view. Curr Opin Crit Care. 2006;12(4):315–321. doi: 10.1097/01.ccx.0000235208.77542.39. PMID: 16810041
• Kraut & Madias: Kraut JA, Madias NE. Lactic acidosis. N Engl J Med. 2014;371(24):2309–2319. doi: 10.1056/NEJMra1309483. PMID: 25494270
• Prescott HC, Antonelli M, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2026. Crit Care Med. 2026;54(4):725–812. DOI: 10.1097/CCM.0000000000007075

Not your standard SMACC talk. This one ranges over the neurobiology of empathy, the social science and the more practical modern application of empathy in clinical medicine. You can learn a lot of history too – its a bit of a whistle-stop tour through some of the dark days of western culture.

So grab a cuppa and sit down for this 30 minute chat.

And somewhere in the room, the hesitation begins.

Not in you, necessarily. But you’ve felt it. The half-second of oh when a young woman arrives after a significant mechanism. The faintly spoken concern from a nurse. The instinct — culturally baked in, not evidence-based — to go carefully because of a possible early pregnancy. The creeping thought: what if I harm the baby?

I want to talk about that hesitation. Because it has a body count.

The problem isn’t radiation. The problem is us.

In 2024, a study of emergency department physicians found that 88.7% reported finding the management of pregnant trauma patients challenging, and expressed a preference to avoid these cases. Nearly nine in ten. Not first-year residents — physicians. And the consequence was exactly what you’d predict: delays, selective under-imaging, and practice variability that had nothing to do with the evidence and everything to do with discomfort.

Trauma is the leading non-obstetric cause of maternal death. Motor vehicle collisions account for more than half of trauma in pregnant women. The fetus does not survive maternal exsanguination. There is no version of this story where protecting the fetus means under-resuscitating and under-imaging the mother.

The best treatment for the fetus is optimal treatment of the mother. This isn’t a controversial statement. It’s in ATLS. It’s in the ACOG guidelines. It’s in the ACEM/RANZCR joint imaging guidelines. It’s the unanimous position of every relevant professional body on the planet. And yet here we are, with 88.7% of emergency physicians describing a preference to avoid these patients.

That’s not caution. That’s a knowledge gap dressed up as sensitivity.

Let’s actually talk about the radiation.

The fear is deterministic effects — the real, measurable harm that radiation causes to a developing embryo. Microcephaly. Organ malformation. Growth restriction. Death of the conceptus. These are real. They happen. And they have a threshold below which they simply do not occur.

That threshold is 100 mGy to the fetus.

Above 100 mGy, the risk curve climbs steeply. Below it, deterministic effects are not observed. This isn’t a comfortable regulatory threshold with a safety factor bolted on — it’s based on the actual biology of radiation-induced tissue damage. Below 100 mGy, there are no fetal anomalies, no increase in pregnancy loss. The ACR, ACOG, and the National Council on Radiation Protection all say so explicitly.

Now. What does a trauma CT actually deliver to the fetus?

The RANZCR, in their Diagnostic Radiology and Pregnancy position statement, cites Australian data: CT of the abdomen delivers a mean uterine dose of 7.1 mGy. Range 1–40 mGy. A whole-body trauma CT in a pregnant patient in a French multicentre study delivered a median fetal dose of 38 mGy. A single CT scan — even a full whole-body study — cannot reach 100 mGy.

Not won’t in most cases. Cannot. The ICRP states explicitly that the 100 mGy threshold cannot be reached with a single CT examination.

So the conversation about deterministic effects from a single trauma CT is over. Done. The risk does not exist at diagnostic doses.

But what about stochastic risk?

Here’s where people get tangled. Stochastic effects — principally childhood leukaemia and solid cancers — have no known safe threshold. Risk increases linearly with dose. There is no floor. And this is where the ALARA principle lives: as low as reasonably achievable, not because diagnostic doses cause deterministic harm, but because we should minimise cumulative stochastic burden where we can do so without compromising the diagnostic objective.

Here’s the important word: where we can.

The background rate of childhood leukaemia is approximately 1 in 3,000. A 10–20 mGy fetal exposure may double that risk. Which means an absolute risk of perhaps 2 in 3,000. An additional 1 in 3,000. In a child who will only exist if their mother survives long enough to deliver them.

ALARA does not mean avoid. ALARA does not mean hesitate when a woman’s spleen is haemorrhaging. ALARA means apply dose reduction techniques, involve your radiographer, document the estimated dose, and have a counselling conversation — after the scan, not instead of it.

The β-hCG question

Should you check a β-hCG before scanning? Sure, if it’s immediately available and won’t delay anything. It may be useful for counselling. It tells you nothing about whether to image.

A positive β-hCG at four weeks does not lower the CT threshold. A negative β-hCG does not raise it. The clinical question is the same regardless: does this mechanism and these clinical signs warrant cross-sectional imaging? Answer that question using standard trauma criteria, and then scan if indicated. The pregnancy status is relevant to the conversation you have afterward, not the decision you make now.

If the woman is haemodynamically unstable, you don’t have time for the conversation anyway. You have time for the scan.

So what is the risk of missing an injury if we do not CT?

This is a tricky question to answer. There is not a lot of data on pregnant women specifically. However if we look at the best, most recent Australian data (11) – the numbers are convincing. The risk of an important occult chest or abdominal injury in patients (even those with normal exam and CXR) is high – someting like 20 -25%.

Up to 19% of patients with normal abdominal examinations were later found to have evidence of injury on their CT scan, and significant injuries detected were otherwise clinically occult, including blunt aortic injury. This is corroborated by non-Australian data that nonetheless speaks directly to the clinical argument.

In population-level studies of pregnant women involved in motor-vehicle collision, maternal death occurred in 3.6 per 1,000 women and fetal death or stillbirth in 6.6 per 1,000. These numbers are about 10-20 times higher than the theoretical risk of CT-induced future childhood malignancy.

In blunt trauma patients with normal sensorium and normal physical examination, 15% were found to have an occult chest injury on CT despite a normal chest exam, 35% had occult injuries on chest CT despite a negative chest exam and negative chest X-ray, and 16% had occult abdominal injuries despite a negative abdominal exam. Overall, 25% of patients with normal chest, abdomen, and pelvis examinations had occult injuries detected on CT.

So, keep that in mind when thinking about risk. We are comparing a possible 1:3000 risk of future badness to a 1:4 or 1:5 risk of missing current real badness. Not even close.

Why not Ultrasound?

Ultrasound is awesome.  No radiation, no risk right?  Unfortunately, even in the best hands ultrasound cannot give us the answers that we need in women suffering traumatic injury.  We know that US is inferior to CT for injuries such as solid organ and visceral bleeding.  However, it is also very insensitive for uterine injury and abruption – which are common (30-40%) of major trauma in the 3rd trimester.  CT actually has a very high pick up rate for uterine injury and placental abruption.  Obviously we do not use CT to diagnose abruption in non-traumatic scenarios as we can use clinical assessment, CTG and US to guide the management.  However, when trauma happens in later pregnancy the risk:benefit ratio is definitely towards CT as it can pick all the other injuries as well as abruption.  So it is a no-brainer really

The rural reality

I want to be direct about something that doesn’t appear in the guidelines, because guidelines are written for trauma centres with consultant radiologists on call, obstetric teams available, and someone to second-guess you in a collegial way.

In remote practice, you are the protocol.

You are the trauma team, the intensivist, the obstetrician, and the surgeon. There is no second opinion arriving in twenty minutes. The RFDS is on its way and the window for definitive diagnosis is the window you create right now, with the tools you have.

Withholding a CT because of radiation anxiety in that setting doesn’t make you cautious. It makes you blind. An occult solid organ injury, an aortic haematoma, a mesenteric tear — missed because someone was worried about a stochastic risk of 1 in 3,000 in a fetus that may not even implant — is an entirely avoidable tragedy.

The senior emergency physicians in the study above were the ones most likely to scan regardless of gestational age. The hesitancy was concentrated in those without specific training or experience in this area. That’s important information about where the educational gap is.

A note on shielding

The lead apron on the abdomen of a pregnant trauma patient is well-intentioned and often unhelpful. Most of the fetal dose in trauma CT comes from internal scatter — radiation that has already passed through the maternal body and is bouncing around internally. External shielding does not significantly reduce that scatter. More importantly, some modern CT scanners use automated dose modulation — if the detector senses lead shielding, it may increase tube current to compensate, actually raising the dose.

Shielding is not harmful, and if it reassures the patient and clinician without delaying or compromising the scan, fine. But it is not a mitigation strategy. It’s a ritual comfort.

The synthesis

The RANZCR position statement says it plainly: most diagnostic radiological procedures pose no substantial risk to the fetus. The ACEM and RANZCR joint imaging guidelines support CT as the investigation of choice in the trauma context. The WA statewide cohort data — from Fiona Stanley and Royal Perth — found that even in trauma populations receiving multiple CTs, the excess cancer signal was modest against the background of trauma mortality itself.

The literature is not ambiguous. The guidelines are not equivocal. The professional bodies are aligned. And the 88.7% of emergency physicians who describe this as challenging are not reflecting on a genuinely difficult evidence question — they are describing a gut reaction that is costing lives.

Scan her.

Reference List

Australian and New Zealand Sources

1. Royal Australian and New Zealand College of Radiologists. Diagnostic Radiology and Pregnancy — Clinical Radiology Position Statement. Version 2.0. November 2017. [Under review May 2026.] Available: https://www.ranzcr.com/college/document-library/diagnostic-radiology-and-pregnancy-policy (PDF direct link: https://www.ranzcr.com/wp-content/uploads/edocman/professional-documents/policies/Diagnostic%20Radiology%20and%20Pregnancy%20Position%20Statement.pdf)

2. Australasian College for Emergency Medicine (ACEM); Royal Australian and New Zealand College of Radiologists (RANZCR). Guidelines on Diagnostic Imaging. NSW Agency for Clinical Innovation. Available: https://aci.health.nsw.gov.au/__data/assets/pdf_file/0007/273715/ACEM-Guidelines-diagnostic-imaging.pdf

3. Yaw LK, Song S, Ho KM. Dose-related association between radiation exposure from computed tomography (CT) scans during trauma hospitalisations and subsequent risk of developing new-onset cancers: statewide cohort study, Western Australia 2004–2020. Communications Medicine 2026 Jan 5. doi: 10.1038/s43856-025-01354-z PMC: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12881511/ (Fiona Stanley Hospital / Royal Perth Hospital, WA)

International Guidelines and Position Statements

4. American College of Obstetricians and Gynecologists. Committee Opinion No. 723: Guidelines for Diagnostic Imaging During Pregnancy and Lactation. Obstet Gynecol 2017;130(4):e210–e216. doi: 10.1097/AOG.0000000000002355 PMID: 28937575 Available: https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2017/10/guidelines-for-diagnostic-imaging-during-pregnancy-and-lactation

5. Qamar SR, Green CR, Ghandehari H, Holmes S, Hurley S, Khumalo Z, Mohammed MF, Ziesmann M, Jain V, Thavanathan R, Berger FH. CETARS/CAR Practice Guideline on Imaging the Pregnant Trauma Patient. Can Assoc Radiol J 2024 Nov;75(4):743–750. doi: 10.1177/08465371241254966 PMID: 38813997 PubMed: https://pubmed.ncbi.nlm.nih.gov/38813997/

6. McCollough CH, Schueler BA, Atwell TD, Braun NN, Regner DM, Brown DL, LeRoy AJ. Radiation exposure and pregnancy: when should we be concerned? RadioGraphics 2007 Jul–Aug;27(4):909–917. doi: 10.1148/rg.274065149 PMID: 17620458 Available: https://pubs.rsna.org/doi/10.1148/rg.274065149

Epidemiology and Clinical Practice Data

7. Abback PS, Benchetrit A, Delhaye N, Daire JL, James A, Neuschwander A, Boutonnet M, Cook F, Vinour H, Hanouz JL, Cotte J, Pastene B, Jouffroy V, Gauss T; Traumabase Group. Multiple trauma in pregnant women: injury assessment, fetal radiation exposure and mortality. A multicentre observational study. Scand J Trauma Resusc Emerg Med 2023 May 2;31(1):22. doi: 10.1186/s13049-023-01084-y PMID: 37131266 PMC: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10152762/

8. Karaaslan A, Ipekci A, Karaaslan Y. A Flowchart to Guide Emergency Physicians to Order Radiological Imaging in Pregnant Patients: Findings from an Emergency Department Questionnaire. Healthcare 2025 Dec 2;13(23):3138. doi: 10.3390/healthcare13233138 PMC: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12692375/ (Source of the 88.7% hesitancy figure)

9. MacDermott R, Berger FH, Phillips A, Robins JA, O’Keeffe ME, Abu Mughli R, MacLean DB, Liu G, Heipel H, Nathens AB, Qamar SR. Initial Imaging of Pregnant Patients in the Trauma Bay — Discussion and Review of Presentations at a Level-1 Trauma Centre. Diagnostics 2024 Jan 26;14(3):276. doi: 10.3390/diagnostics14030276 PMID: 38337792 PMC: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10855036/

10. Lucas AN, Tay-Lasso E, Zezoff DC, Fierro N, Dhillon NK, Ley EJ, et al. Significant variation in computed tomography imaging of pregnant trauma patients: a retrospective multicenter study. Emerg Radiol 2024;31:69–77. doi: 10.1007/s10140-023-02195-w PMID: 38148383 PMC: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10830714/

11. Salam Findakly, Adil Zia, Helen Kavnoudias, Joseph Mathew, Dinesh Varma, Bruno Di Muzio, Robin Lee, Heather K Moriarty, Tim Joseph, Warren Clements.
The use of whole-body trauma CT should be based on mechanism of injury: A risk analysis of 3920 patients at a tertiary trauma centre, Injury, Volume 54, Issue 7, 2023, 110828,
https://doi.org/10.1016/j.injury.2023.05.059.

Justin also has a great schema for discussing radiation risk with women over at First10EM