The Patient in Front of You

It’s 2 AM.

A 72-year-old woman arrives in your Emergency Department with new-onset atrial fibrillation. Her CHA₂DS₂-VASc score is 4.

A few bays away, a 55-year-old man is diagnosed with a segmental pulmonary embolism.

Meanwhile, the oncology service calls regarding a patient with metastatic colon cancer and recurrent DVT despite anticoagulation.

Three patients. Three thrombotic problems. One recurring question:

Which anticoagulant should we choose ?

Not long ago, the answer was usually warfarin.

Today, Direct Oral Anticoagulants (DOACs) have fundamentally changed how we prevent and treat thromboembolic disease. The recently released 2026 ACC Scientific Statement represents perhaps the most comprehensive modern review of DOAC use across atrial fibrillation, venous thromboembolism, cancer-associated thrombosis, stroke prevention, and special populations (Kumbhani et al., 2026).

But while DOACs have become standard therapy, their optimal use remains surprisingly misunderstood. This article explores what has changed, what hasn’t, and how acute care physicians should approach anticoagulation in 2026.

Why DOACs Changed Everything

For decades, warfarin dominated anticoagulation. It worked, but it came with significant challenges:

• Narrow therapeutic window

• Frequent INR monitoring

• Numerous food interactions

• Multiple drug interactions

• High variability between patients

DOACs were developed to overcome these limitations and now account for nearly 80% of oral anticoagulant prescriptions in many regions (Kumbhani et al., 2026).

The currently available DOACs include:

Factor Xa inhibitors

• Apixaban

• Rivaroxaban

• Edoxaban

Direct thrombin inhibitor

• Dabigatran

(Kumbhani et al., 2026)

Unlike warfarin, these agents provide predictable pharmacokinetics, fixed dosing, and generally do not require routine laboratory monitoring (Kumbhani et al., 2026).

The result?

A simpler, safer, and often more effective approach to anticoagulation.

The Most Important Update: Think Risk, Not Scores

One of the subtle but important shifts highlighted in the ACC statement is that anticoagulation decisions should increasingly be based on absolute thromboembolic risk rather than rigid dependence on CHA₂DS₂-VASc alone (Kumbhani et al., 2026).

Historically, clinicians memorized:

• CHA₂DS₂-VASc ≥2 → anti-coagulate

• CHA₂DS₂-VASc <2 → don’t

Reality is more nuanced. Patients with similar scores may have markedly different actual stroke risks depending on AF burden, cardiac substrate, renal function, and co-morbidities.

The modern approach emphasizes:

• Shared decision-making

• Individualized risk assessment

• Consideration of additional modifiers beyond traditional scoring systems

(Kumbhani et al., 2026).

Atrial Fibrillation: DOACs Are the New Default

For most patients with atrial fibrillation requiring anticoagulation, DOACs are now unequivocally preferred over warfarin (Kumbhani et al., 2026).

The reasons are straightforward:

• Similar or better stroke prevention

• Less intracranial hemorrhage

• Easier use

• No INR monitoring

The ACC Scientific Statement strongly supports DOACs as first-line therapy for non-valvular AF.

But There Are Two Major Exceptions

1. Mechanical Heart Valves

Despite years of hope, DOACs remain unsuitable. The RE-ALIGN trial demonstrated excess thromboembolic events and bleeding with dabigatran compared with warfarin in mechanical valve patients (Eikelboom et al., 2013).

More recently, the PROACT Xa trial showed higher rates of valve thrombosis and thromboembolic events with apixaban compared with warfarin (Kumbhani et al., 2026).

For mechanical valves:

Warfarin remains king.

2. Rheumatic Mitral Stenosis

The INVICTUS trial demonstrated superior outcomes with vitamin K antagonists compared with rivaroxaban among patients with rheumatic heart disease and AF (Connolly et al., 2022; Kumbhani et al., 2026).

This remains another domain where warfarin continues to outperform DOACs.

Acute VTE: The Era of DOAC Dominance

The management of DVT and PE has changed dramatically. Multiple pivotal trials and meta-analyses have demonstrated that DOACs achieve similar efficacy with less major bleeding than warfarin (Kumbhani et al., 2026).

Today:

DOACs are first-line treatment for most patients with acute VTE.

(Kumbhani et al., 2026)

Is Apixaban Becoming the Preferred DOAC?

If one theme repeatedly emerges throughout contemporary literature, it is the growing prominence of apixaban.

The 2026 ACC statement notes that recent evidence suggests an apixaban-based strategy may be associated with lower bleeding compared with rivaroxaban during VTE treatment (Kumbhani et al., 2026).

The COBRRA trial further strengthened this observation, showing lower bleeding rates with apixaban in acute VTE management (Kumbhani et al., 2026).

Additionally, the ACC consensus highlights apixaban as the preferred option in:

• Frailty

• Advanced age

• Prior bleeding

• Chronic kidney disease

(Kumbhani et al., 2026).

This does not mean rivaroxaban is obsolete. It means that when uncertainty exists, apixaban increasingly appears to offer the best balance between efficacy and safety.

The Most Common Mistake: Stopping Too Early

Many clinicians continue to think of anticoagulation as a 3–6 month treatment. For many patients, this is no longer true.

The ACC statement emphasizes extended anticoagulation for:

• Unprovoked VTE

• Recurrent VTE

• Persistent risk factors

• High recurrence risk profiles

(Kumbhani et al., 2026).

In these patients:

The question is not whether treatment lasts beyond six months.

The question is whether treatment should ever stop.

Cancer-Associated Thrombosis: One of the Biggest Changes in Modern Medicine

Perhaps no area has evolved faster than cancer-associated thrombosis (CAT). For years, LMWH was the unquestioned standard.

That paradigm has shifted. A 2022 meta-analysis by Frère et al. demonstrated significantly lower recurrent VTE rates with DOACs compared with LMWH, without differences in mortality.

Similarly, Schrag et al. (2023) reported recurrent VTE rates of 6.1% versus 8.8% in favor of DOACs during a randomized trial involving cancer patients.

The strongest contemporary evidence supports:

• Apixaban

• Edoxaban

• Rivaroxaban

for selected cancer patients (Masini et al., 2023; Fujisaki et al., 2024).

But Not Every Cancer Patient Is the Same

Bleeding risk remains highly tumor-specific. The literature consistently identifies:

• Gastrointestinal cancers

• Gastroesophageal tumors

• Some genitourinary malignancies

as populations where bleeding risk may outweigh benefits (O’Connell et al., 2020; Sabatino et al., 2020; Masini et al., 2023).

This is where individualized medicine still matters.

Chronic Kidney Disease: A Persistent Challenge

Anticoagulation in advanced CKD remains difficult. Evidence remains limited, particularly in dialysis populations.

The ACC statement concludes:

• Apixaban may be considered in dialysis patients

• Dabigatran should generally be avoided

(Kumbhani et al., 2026).

For acute care physicians, this often translates into one practical rule:

If severe renal dysfunction is present, pause before reflexively prescribing a DOAC.

Obesity: Time to Retire an Old Myth

Many clinicians remain hesitant to prescribe DOACs in severe obesity. Current evidence no longer strongly supports this concern.

The ACC statement specifically endorses:

• Apixaban

• Rivaroxaban

for patients with BMI ≥40 kg/m² (Kumbhani et al., 2026). The assumption that obesity automatically requires warfarin is increasingly outdated.

What If Your Hospital Doesn’t Have Reversal Agents?

This question frequently arises in low- and middle-income settings. Can DOACs still be used if idarucizumab or andexanet alfa are unavailable?

The literature suggests yes.

Reviews by Weitz (2017), Chaudhary et al. (2019), and Grottke et al. (2024) conclude that most DOAC-associated bleeding can be managed through supportive care, temporary drug interruption, and standard resuscitative measures.

Specific antidotes are primarily reserved for:

• Life-threatening bleeding

• Catastrophic hemorrhage

• Emergency surgery

(Gómez-Outes et al., 2023; Grottke et al., 2024).

When antidotes are unavailable, PCCs remain a reasonable rescue strategy despite lower-quality evidence (Pozzi et al., 2024; Tran et al., 2025).

The practical message:

DOACs do not require onsite antidotes to be prescribed safely.

However, hospitals should maintain protocols for catastrophic bleeding management.

The Future: Beyond AF and DVT

The 2026 ACC Scientific Statement hints at the future direction of anticoagulation.

Emerging areas include:

• Device-detected subclinical AF

• Atrial myopathy

• Post-ablation anticoagulation

• Left atrial appendage closure strategies

• Expanded cancer-associated thrombosis pathways

(Kumbhani et al., 2026).

Many of tomorrow’s anticoagulation decisions may depend less on rhythm and more on underlying atrial disease biology.

Pulse Check

A decade ago, anticoagulation was largely a warfarin-versus-not-warfarin discussion.

In 2026, the conversation has evolved.

DOACs have become the default anticoagulants for most patients with atrial fibrillation and venous thromboembolism. Yet success lies not in prescribing them blindly, but in selecting the right drug, at the right dose, for the right patient.

The emergency physician’s challenge is no longer:

“Should I anticoagulate?”

It is:

“Which anticoagulant offers this patient the greatest net clinical benefit?”

Increasingly, the answer is a DOAC.

And more often than not, it may be apixaban.

References

• Kumbhani DJ, et al. 2026 ACC Scientific Statement on Direct Oral Anticoagulants.

• Frère C, et al. 2022.

• Schrag D, et al. JAMA. 2023.

• Fujisaki T, et al. JACC CardioOncology. 2024.

• Grottke O, et al. Eur J Anaesthesiol. 2024.

• Tran HA, et al. Internal Medicine Journal. 2025.

• Weitz JI. Semin Respir Crit Care Med. 2017.

• Chaudhary R, et al. J Thromb Thrombolysis. 2019.

• Masini M, et al. Curr Oncol Rep. 2023.

• O’Connell C, et al. The Oncologist. 2020.

• Sabatino J, et al. JACC CardioOncology. 2020.

It’s 2:17 a.m.

A 58-year-old man arrives clutching his chest. The ECG leaves little room for doubt, an anterior STEMI. While the cath lab is being activated, the nurse turns to you.

“Doctor, which anti-platelet should I load?”

Before you’ve answered, another patient rolls in. A 72-year-old woman with a minor ischemic stroke, well within 4.5 hours of symptom onset.

Should she receive aspirin alone? Or dual anti-platelet therapy? or nothing at all?

As you’re reviewing her CT, the surgical registrar calls.

“We’ve got a patient with a perforated bowel. He’s on aspirin and ticagrelor after a stent placed three months ago. Can we stop them?”

Three patients. Three anti-platelet decisions. Three completely different answers.

Yet every one of them starts with the same question.

Why is this patient need an anti-platelet?

Not which drug. Not how long they’ve been taking it. But why?

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Because modern anti-platelet therapy is no longer about memorizing drugs. It’s about understanding the balance between thrombosis and bleeding, and recognizing that this balance changes with time (Kumbhani et al., 2026).

In the ED, we are often the first physicians to influence that balance. We decide what gets loaded, what gets withheld, what should continue before surgery, and what should never be stopped. This article isn’t a cardiology review.

It’s a practical guide to the anti-platelet decisions emergency and acute care physicians make every shift.

A Mental Model Before We Begin

Whenever you encounter a patient on anti-platelets, pause and ask three questions.

1. Why was it started?

• Acute coronary syndrome?

• PCI?

• Stroke?

• Peripheral arterial disease?

• Primary prevention?

2. How recent was the event?

Hours? Days? Weeks? Years?

A patient one week after PCI is very different from one who had a stent placed five years ago.

3. What is the biggest threat today?

Bleeding? Or thrombosis?

Everything else follows from these three questions.

Decision 1

Which Anti-platelet Should I Load in the Emergency Department?

This is probably the most common and one of the most important antiplatelet decisions we make.

The answer depends entirely on where the patient is going next.

• Primary PCI?

• Fibrinolysis?

• Early invasive NSTEMI?

• Conservative management?

Each pathway has a different strategy.

Scenario 1: STEMI Going for Primary PCI

Imagine you’re in the resuscitation bay. The ECG shows a large anterior STEMI. The cath lab has accepted the patient. Your priority is simple:

Achieve rapid and potent platelet inhibition before coronary instrumentation.

The current standard is:

• Chewed aspirin 162–325 mg

• Plus a P2Y12 inhibitor

For most patients undergoing primary PCI, ticagrelor or prasugrel are preferred over clopidogrel because they produce faster, more potent, and more predictable platelet inhibition, reducing ischemic events and stent thrombosis (Wallentin et al., 2009; Wiviott et al., 2007; Kumbhani et al., 2026).

Which P2Y12 Inhibitor Should I Choose?

Ticagrelor

Ticagrelor has become the default choice in many emergency departments. Why?

• Rapid onset

• No metabolic activation required

• Potent platelet inhibition

• Reversible receptor binding

The PLATO trial demonstrated lower cardiovascular mortality compared with clopidogrel without increasing overall major bleeding, making it an attractive first-line agent in ACS (Wallentin et al., 2009).

Prasugrel

Prasugrel is equally potent and in PCI-treated patients may even outperform ticagrelor in selected populations (Schüpke et al., 2019).

However, remember its major limitations. Avoid prasugrel in patients with:

• Previous stroke or TIA

• Age ≥75 years (unless benefits clearly outweigh risks)

• Weight <60 kg

Unlike ticagrelor, many operators prefer administering prasugrel after coronary anatomy has been defined, particularly if there is a realistic possibility the patient will require CABG.

Clopidogrel

Clopidogrel still has an important place. It remains reasonable when:

• Ticagrelor or prasugrel are unavailable

• Bleeding risk is high

• Cost is a major issue

• Potent P2Y12 inhibitors are contraindicated

Think of clopidogrel not as an “inferior” drug—but as the right drug for selected patients.

Frontline Pearl

PCI favors potent platelet inhibition. If the patient is heading to the cath lab, think ticagrelor or prasugrel first.

Scenario 2: STEMI Receiving Thrombolysis

Now imagine a different hospital. No PCI capability. Transfer will take four hours. The patient is receiving tenecteplase. Should you still load Ticagrelor or Prasugrel?

No.

This is one of the most common misconceptions among junior doctors. The evidence supporting fibrinolysis was built around clopidogrel, not the newer P2Y12 inhibitors.

Recommended Strategy

Why Not Ticagrelor?

Could ticagrelor work? Possibly.

Should it replace clopidogrel routinely with thrombolysis? Not yet.

The strongest evidence for pharmaco-invasive STEMI still supports aspirin plus clopidogrel after fibrinolysis, and contemporary guidelines continue to recommend this approach (Kumbhani et al., 2026).

Scenario 3: NSTE-ACS

Very High Risk or High Risk NSTE- ACS , continue same approach as of STEMI requiring PCI.
but for others,
This is where things become less straightforward. For years, many of us loaded clopidogrel as soon as we diagnosed NSTEMI. That practice has changed.

Modern evidence suggests routine pretreatment before coronary anatomy is known offers little benefit and may complicate patients who ultimately require CABG (Kumbhani et al., 2026).

My Practical Approach

If early angiography (<24 hours) is planned:

• Give aspirin.

• Discuss P2Y12 timing with cardiology.

• In many patients, defer loading until coronary anatomy is defined.

If angiography will be delayed or the patient is managed conservatively:
Loading with ticagrelor or clopidogrel when appropriate is reasonable.

Common ED Pitfalls

❌ Giving prasugrel to a patient with previous stroke.

❌ Loading ticagrelor in a patient receiving thrombolysis because “it’s newer.”

❌ Automatically loading every NSTEMI before discussing the invasive strategy.

❌ Forgetting that patients over 75 years receiving fibrinolysis do not receive a clopidogrel loading dose.

Decision 2

Does Every ACS Patient Still Need 12 Months of Dual Anti-platelet Therapy?

For years, the answer was simple. Every patient with ACS received 12 months of dual antiplatelet therapy (DAPT)—usually aspirin plus a P2Y12 inhibitor.

It was easy to remember. It was also easy to teach. But like many “rules” in medicine, it turned out to be only partly true. Over the past decade, improvements in stent technology, PCI techniques, and the availability of more potent anti-platelet agents have fundamentally changed the conversation. Today’s question is no longer:

“Should every patient receive 12 months of DAPT?”

Instead, we ask:

“How long does this particular patient need protection from thrombosis before the risk of bleeding becomes the greater threat?”

That shift—from fixed-duration therapy to individualized therapy—is perhaps the biggest conceptual change in modern anti-platelet management (Kumbhani et al., 2026).

The first month after an ACS is a dangerous time. Platelets are highly activated. The stent is still endothelializing. The culprit plaque remains biologically unstable.

This is precisely when dual antiplatelet therapy (DAPT) provides its greatest benefit. But as weeks turn into months, something interesting happens—the risk of stent thrombosis falls rapidly, while the cumulative risk of bleeding continues to rise.

That’s why modern antiplatelet therapy is no longer about one duration for everyone. It is about matching the duration of DAPT to the patient’s evolving balance between ischemic and bleeding risk (Kumbhani et al., 2026).

The New Way to Think About DAPT

Instead of asking:

“Should I stop DAPT at 12 months?”

Ask:

“Has the patient’s bleeding risk now become greater than their ischemic risk?”

If the answer is yes, shortening DAPT may be safer. If the answer is no, prolonged therapy may still provide benefit.

When Can We Shorten DAPT?

Several contemporary trials have shown that selected patients can safely transition to P2Y12 inhibitor monotherapy after 1–3 months of DAPT, reducing bleeding without a significant increase in ischemic events (Mehran et al., 2019; Valgimigli et al., 2021).

Who should you think about?

• Older adults

• Previous GI bleeding

• Chronic kidney disease

• Frailty

• Need for future surgery

• Concurrent anticoagulation

De-escalation: Less Can Be More

Imagine your patient returns three months after PCI. No recurrent ischemia. Now they develop upper GI bleeding.

Do they still need potent DAPT? Maybe not.

In carefully selected patients, switching from ticagrelor or prasugrel to clopidogrel, or stopping aspirin and continuing a P2Y12 inhibitor alone, can substantially reduce bleeding while maintaining acceptable ischemic protection (Kumbhani et al., 2026).

Decision 3

The Patient Has an Acute Ischemic Stroke. Should I Give Aspirin, Dual Antiplatelet Therapy, or Neither?

A 69-year-old man presents 90 minutes after sudden right arm weakness and aphasia. His CT brain shows no hemorrhage.

Before you think about aspirin or clopidogrel, ask yourself one question:

Is this patient a candidate for reperfusion therapy?

This is arguably the most important antiplatelet decision in acute stroke care. Giving anti-platelets too early in a patient proceeding for intravenous thrombolysis or mechanical thrombectomy can increase bleeding risk without improving outcomes.

Step 1: Is the Patient Eligible for Reperfusion?

Intravenous thrombolysis

Eligible?
Do NOT administer aspirin or any P2Y12 inhibitor before thrombolysis.

Following alteplase or tenecteplase, all antiplatelet and anticoagulant therapy should be withheld for the first 24 hours.

A repeat CT (or MRI) demonstrating no intracranial hemorrhage is required before initiating antiplatelet therapy (Powers et al., 2019; European Stroke Organisation, 2023).

Mechanical thrombectomy

Patients proceeding directly for thrombectomy without thrombolysis similarly should not receive routine antiplatelet loading before reperfusion, unless there is another specific indication (such as emergent intracranial stenting).

Once post-procedure imaging excludes hemorrhage, antiplatelet therapy can be started according to the underlying stroke mechanism and procedural findings.

(Kumbhani et al., 2026)

Minor Stroke: Aspirin Alone or Dual Antiplatelet Therapy?

A 69-year-old man presents with sudden right arm weakness that resolved within 20 minutes. His CT brain is normal. He has a National Institutes of Health Stroke Scale (NIHSS) score of 1.

Should he receive aspirin? Or dual antiplatelet therapy? The answer depends on stroke severity.

Minor Stroke and High-Risk TIA

Three landmark trials—CHANCE, POINT, and THALES—changed our practice. For patients with:

• Minor ischemic stroke (NIHSS ≤3)

• High-risk TIA (ABCD² ≥4)

Early initiation of DAPT reduces recurrent stroke, particularly during the first three weeks (Wang et al., 2013; Johnston et al., 2018).

Why Only 21 Days?

Because recurrent stroke risk is highest immediately after the event. After three weeks, the incremental benefit of DAPT diminishes, while bleeding risk continues to increase. Unlike ACS, where DAPT is measured in months, stroke DAPT is measured in weeks. (Kumbhani et al., 2026)

Decision 4

The Surgeon Wants to Stop the Anti-platelets

Few phone calls create more anxiety than this one.

“Doctor, can we stop the aspirin before surgery?”

The answer isn’t simply yes or no. It depends on why the patient is taking it. A patient taking aspirin for primary prevention is very different from one who underwent PCI six weeks ago.

Elective Surgery After PCI

Whenever possible:

• Delay surgery at least 6 months after PCI for chronic coronary disease.

• Delay surgery 12 months after PCI for ACS.

(Kumbhani et al., 2026)

Emergency Surgery

Sometimes surgery simply cannot wait.

Options include:

• Proceeding despite antiplatelet therapy when delay would be more dangerous.

• Platelet transfusion in selected life-threatening bleeding scenarios.

• Bridging with intravenous cangrelor in carefully selected recent PCI patients.

(Kumbhani et al., 2026)

Decision 5

The Patient Is Already Taking a DOAC

An 80-year-old patient with atrial fibrillation undergoes PCI.

Should you prescribe:

Aspirin + Clopidogrel + Apixaban?

That used to be standard practice. Today, prolonged triple therapy has largely disappeared.

Modern Strategy

For most patients:

• Short course of triple therapy (1–4 weeks)

• Then discontinue aspirin

• Continue DOAC + clopidogrel

This strategy substantially reduces bleeding while preserving ischemic protection (Kumbhani et al., 2026).

Final Thoughts

Antiplatelet therapy has become far more nuanced than it was a decade ago. Yet the bedside approach remains surprisingly simple. Understand why the therapy was started. Recognize how the patient’s risk changes with time. And remember that the best antiplatelet strategy is rarely the most aggressive one—it is the one that strikes the right balance between preventing thrombosis and avoiding harm.

As emergency and acute care physicians, we are often the first to make that decision. It may be as simple as choosing the correct loading dose in a STEMI, or as difficult as deciding whether to stop DAPT before emergency surgery. Either way, our decisions shape what happens long after the patient leaves the Emergency Department.

References

1. Kumbhani DJ, Gibson CM, Kinlay S, et al. Antiplatelet Therapy in the Management of Atherosclerotic Cardiovascular Disease: 2026 ACC Scientific Statement. J Am Coll Cardiol. 2026.

2. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009.

3. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in ACS undergoing PCI. N Engl J Med. 2007.

4. Schüpke S, Neumann FJ, Menichelli M, et al. Ticagrelor or prasugrel in patients with acute coronary syndromes. N Engl J Med. 2019.

5. Mehran R, Baber U, Sharma SK, et al. Ticagrelor with or without aspirin after PCI (TWILIGHT). N Engl J Med. 2019.

6. Valgimigli M, Frigoli E, Heg D, et al. Dual antiplatelet therapy after PCI in high bleeding risk patients (MASTER DAPT). N Engl J Med. 2021.

7. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or TIA (CHANCE). N Engl J Med. 2013.

8. Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA (POINT). N Engl J Med. 2018.

One of the most preventable harms in emergency and critical care occurs after successful intubation—not during it. A patient receives induction with etomidate, ketamine, or propofol. A paralytic is administered. The airway is secured. The team celebrates a successful intubation.

But then the sedative wears off. The paralysis does not. For the next 30–60 minutes, the patient may be awake, aware, unable to move, unable to communicate, and unable to breathe independently.

Few experiences in medicine are more terrifying. Post-intubation sedation is not an optional intervention. It is the continuation of the intubation procedure itself.

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The Goal Is Not Deep Sedation

Before discussing drugs, we must define the target.

Modern acute care has shifted away from routine deep sedation. Multiple studies have demonstrated that excessive sedation is associated with longer mechanical ventilation, increased delirium, prolonged ICU stays, and worse long-term outcomes.

For most mechanically ventilated patients, the target should be:

RASS -2 to 0

• 0 = Alert and calm

• -1 = Drowsy

• -2 = Light sedation

Patients should be comfortable, cooperative when appropriate, and free from pain—not chemically comatose.

Deep sedation (RASS -4 to -5) should be reserved for specific indications:

• Severe ARDS requiring ventilator synchrony

• Neuromuscular blockade

• Refractory intracranial hypertension

• Status epilepticus

• Severe agitation threatening patient safety

The question is not “How deeply sedated can I make my patient?”, The question is “What is the lightest level of sedation that safely achieves my goals?”

This seemingly small shift in philosophy has transformed modern ICU practice.

You Can’t Target What You Don’t Measure

Post-intubation sedation, like shock resuscitation, must be goal-directed. (Baumgartner K, 2026)

Yet studies show sedation assessment in mechanically ventilated ED patients remains inconsistent, with documentation rates varying dramatically between institutions (Steel et al., 2021; Fuller et al., 2019).

Every intubated patient should have two explicit targets:

• Pain target: Critical Care Pain Observation Tool (CPOT) if possible

• Sedation target: Richmond Agitation-Sedation Scale (RASS), must

These assessments should be repeated regularly and tied to nursing-driven titration protocols. Because sedation is not a drug order. Consider it as a treatment target.

For most patients:

• CPOT: As low as possible

• RASS: -2 to 0

Without structured assessment, clinicians frequently default to over-sedation—a practice consistently associated with more delirium, longer ventilation, longer ICU stays, and higher mortality (Shehabi et al., 2012; Tanaka et al., 2014; Shehabi et al., 2018). What gets measured gets managed.

Sedation Begins the Moment the Tube Goes In

The most dangerous misconception after rapid sequence intubation is assuming that induction agents provide ongoing sedation. They do not. Typical durations are remarkably short:

This creates a potentially devastating mismatch. The patient may regain awareness long before they regain movement. Every clinician who performs RSI should develop a habit:

Before the intubation begins, know what your post-intubation sedation plan will be.

Not afterward. Not when the chest X-ray returns. Not when the nurse reminds you. Before.

Awareness With Paralysis: The Complication We Don’t Measure Enough

Awareness during neuromuscular blockade is not rare. Prospective emergency department studies demonstrate unacceptably high rates of recall among mechanically ventilated patients (Pappal et al., 2021; Driver et al., 2023).

Risk factors include:

• Rocuronium use

• Delayed sedation initiation

• Lack of sedation monitoring

• Deeply sedated appearance masking inadequate analgesia

Patients who are paralyzed cannot demonstrate distress. Silence is not comfort.

The most effective prevention strategy is simple: Plan post-intubation sedation before intubation.

Build Sedation Into Your Airway Checklist

One of the simplest ways to prevent awareness with paralysis is to stop treating post-intubation sedation as an afterthought. Before administering induction drugs, ask:

“What is our sedation plan after the tube goes in?”

The answer should include:

• Target RASS

• Initial analgesic

• Initial sedative

• Vasopressor strategy if needed

• Planned reassessment interval

Ideally, post-intubation medications should be prepared before laryngoscopy begins. (Baumgartner K, 2026). Multiple quality-improvement initiatives have shown that incorporating sedation into peri-intubation checklists reduces delays in analgesia and sedation initiation (Irwin et al., 2022; Ayers et al., 2024).

The patient should never wait for a chest radiograph, ICU bed assignment, or medication order reconciliation before receiving analgesia and sedation. Airway management does not end at endotracheal tube confirmation. It ends when the patient is comfortable.

The Rise—and Nuance—of Analgosedation

(Baumgartner K, 2026)

For decades, sedation-focused strategies dominated critical care. Patients received sedatives first, with analgesia added later if needed. Modern practice has shifted toward an analgesia-first philosophy.

Why?

Because many mechanically ventilated patients are not agitated because they need more sedation. They are agitated because they are in pain.

Pain increases:

• Tachycardia

• Hypertension

• Ventilator dyssynchrony

• Oxygen consumption

• Agitation

• Sedative requirements

Treating pain first often reduces the amount of sedative required. This approach is known as analgosedation.

However, post-intubation analgesia and sedation are linked—but distinct—interventions. (Baumgartner K, 2026)

Not every patient benefits from opioid escalation, and pain assessment can be challenging in critically ill, non-communicative patients. Current guidelines have softened earlier recommendations for strict analgesia-first approaches, emphasizing individualized care based on patient physiology and validated assessment tools (Devlin et al., 2018).

The practical message remains unchanged:

Do not mistake pain for a need for more sedation.

And do not mistake analgesia for sedation. Fentanyl may make patients more comfortable. It does not reliably make them unaware.

Fentanyl: The Most Misunderstood Drug in Post-Intubation Care

One concept deserves particular emphasis. Fentanyl is an analgesic. It is not primarily a sedative. This distinction is frequently misunderstood in emergency departments.

Mechanism

Fentanyl is a potent μ-opioid receptor agonist.

Its primary effects are:

• Analgesia

• Blunting of sympathetic responses

• Reduction of pain-related agitation

At high doses, fentanyl can certainly contribute to sedation. However, sedation is not its principal therapeutic role.

Typical Dosing

Loading dose
25–100 mcg IV

Continuous infusion
25–200 mcg/hour

or approximately

0.5–3 mcg/kg/hour

Advantages

• Rapid onset

• Reliable analgesia

• Familiarity

• Minimal histamine release

Limitations

• Respiratory depression

• Chest wall rigidity with rapid high-dose administration

• Drug accumulation during prolonged infusions

The practical takeaway is straightforward:
If your patient is receiving fentanyl alone, they may have excellent analgesia while remaining inadequately sedated.

Pain control and sedation are not synonymous.

Midazolam: The Old Workhorse

Midazolam remains one of the most commonly used sedatives worldwide.

Mechanism

Midazolam enhances GABA-A receptor activity, producing:

• Sedation

• Anxiolysis

• Amnesia

• Anticonvulsant effects

Typical Dosing

Loading
2–5 mg IV

Infusion
1–10 mg/hour

(approximately 0.02–0.1 mg/kg/hour)

When Midazolam Still Shines

Despite its declining popularity, midazolam remains valuable in:

• Hemodynamically unstable patients

• Status epilepticus

• Alcohol withdrawal

• Situations requiring profound amnesia

• Deep sedation requirements

The Problem

The major issue with benzodiazepines is not inadequate sedation. It is excessive sedation.

Accumulation, particularly during prolonged infusions, contributes to:

• Delayed awakening

• Prolonged ventilation

• Increased delirium

• Longer ICU stays

Meta-analyses comparing midazolam with propofol and dexmedetomidine consistently demonstrate slower extubation and higher delirium rates with benzodiazepine-based strategies (Garcia et al., 2021; Chen & Ho, 2025).

Intermittent bolus doses of midazolam for breakthrough agitation are unlikely to carry the same risks as prolonged continuous infusions. The adverse outcome data are driven primarily by infusion-based benzodiazepine strategies.

For this reason, contemporary guidelines generally favor non-benzodiazepine sedatives whenever feasible.

Dexmedetomidine: Cooperative Sedation

If benzodiazepines represent traditional ICU sedation, dexmedetomidine represents the modern philosophy.

Mechanism

Dexmedetomidine is a selective alpha-2 adrenergic agonist. Unlike GABAergic sedatives, it produces a unique form of sedation. Patients often appear asleep but awaken easily and interact appropriately when stimulated.

Typical Dosing

Loading dose
Often omitted in critically ill patients due to hemodynamic effects.
Infusion
0.2–1.5 mcg/kg/hour

Advantages

• Reduced delirium

• Easier neurological assessment

• Preserved respiratory drive

• Improved patient interaction

• Shorter time to extubation compared with benzodiazepines

Large meta-analyses demonstrate lower delirium rates and modest reductions in ventilation duration compared with traditional sedatives (Wen et al., 2023; Walsh et al., 2025).

Dexmedetomidine has a delayed onset. Without a loading dose, peak sedative effect may take 30–60 minutes. When rapid sedation is required, dexmedetomidine should be bridged with a faster-acting agent such as propofol.

Limitations

The trade-off is predictable:

• Bradycardia

• Hypotension

As with every sedative in critical care, benefits must be balanced against physiology.

Ketamine: More Than an Induction Agent

Most emergency physicians are comfortable using ketamine for induction.

Fewer use it as part of a post-intubation strategy.

Mechanism

Ketamine acts primarily through NMDA receptor antagonism.

Unlike most sedatives, it provides:

• Analgesia

• Sedation

• Relative preservation of airway reflexes

• Sympathomimetic effects

Typical Dosing

Loading
0.25–1 mg/kg

Infusion
0.1–2 mg/kg/hour

Where Ketamine Excels

Ketamine is particularly attractive in:

• Severe bronchospasm

• Opioid-tolerant patients

• Hemodynamic instability

• Patients requiring opioid-sparing strategies

Ketamine may be particularly useful in severe bronchospasm, polytrauma with difficult-to-control pain, refractory status epilepticus, or when propofol intolerance limits sedation options.

Recent reviews suggest ketamine’s greatest strength is as an adjunctive agent that reduces overall sedative and opioid requirements rather than as routine monotherapy (Hendrikse et al., 2023; Amer et al., 2024).

What About Propofol?

No discussion of post-intubation sedation would be complete without propofol. In many ICUs, propofol remains the default sedative.

Why?

Because it is:

• Rapidly titratable

• Predictable

• Short acting

• Associated with faster awakening and extubation

Typical dosing ranges from:

5–80 mcg/kg/min

Its major limitations are equally familiar:

• Hypotension

• Bradycardia

• Hypertriglyceridemia

• Propofol infusion syndrome (rare)

Compared with midazolam, propofol consistently shortens ventilation duration and accelerates extubation in mechanically ventilated patients (Garcia et al., 2021).

Propofol should be dosed using ideal body weight rather than actual body weight, particularly in obesity, to reduce the risk of hypotension. (Baumgartner K, 2026)

Rather than abandoning propofol when hypotension develops, clinicians should first consider reducing the infusion rate and initiating vasopressor support. Given its short duration of action, persistent hypotension despite dose reduction should prompt evaluation for alternative causes. (Baumgartner K, 2026)

For many patients, a combination of:

Fentanyl + Propofol

remains an excellent starting strategy.

This article focuses on emergency department management during the immediate post-intubation period. Sedation strategies should always be individualized based on patient physiology, institutional protocols, and evolving ICU goals.

Choosing the Right Sedative

There is no universally superior sedative.

The best agent depends on the physiology in front of you. The goal is not to find the perfect drug. The goal is to match the drug to the patient.

The Bottom Line

The airway is not secured when the tube passes the cords.

The airway is secured when the patient is:

• Adequately analgesed

• Adequately sedated

• Appropriately monitored

• Maintained within a defined sedation target

Post-intubation sedation is not an afterthought.

It is not an ICU issue.

It is not something to “sort out later.”

It is a core component of airway management.

Because a patient who is awake, frightened, and paralyzed behind an endotracheal tube has not received complete care.

They have received an incomplete intubation.

References

1. Baumgartner K, Fuller BM. Postintubation sedation and analgesia in the emergency department: the basics and beyond. Emergency Medicine Clinics of North America. 2026. doi:10.1016/j.emc.2026.02.004.

2. Devlin JW, Skrobik Y, Gélinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Critical Care Medicine. 2018;46(9):e825-e873. doi:10.1097/CCM.0000000000003299

3. Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after critical illness. New England Journal of Medicine. 2013;369(14):1306-1316. doi:10.1056/NEJMoa1301372

4. Shehabi Y, Bellomo R, Reade MC, et al. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. American Journal of Respiratory and Critical Care Medicine. 2012;186(8):724-731. doi:10.1164/rccm.201203-0522OC

5. Tanaka LMS, Azevedo LCP, Park M, et al. Early sedation and clinical outcomes of mechanically ventilated patients: a prospective multicenter cohort study. Critical Care. 2014;18(4):R156. doi:10.1186/cc13941

6. Shehabi Y, Bellomo R, Kadiman S, et al. Sedation intensity in the first 48 hours of mechanical ventilation and 180-day mortality: a multinational prospective longitudinal cohort study. Critical Care Medicine. 2018;46(6):850-859. doi:10.1097/CCM.0000000000003071

7. Boncyk C, Rolfsen M, Richards D, et al. Management of pain and sedation in the intensive care unit. BMJ. 2024;387:e079789. doi:10.1136/bmj-2024-079789

8. Garcia R, Salluh J, Andrade TR, et al. A systematic review and meta-analysis of propofol versus midazolam sedation in adult intensive care patients. Journal of Critical Care. 2021;64:91-99. doi:10.1016/j.jcrc.2021.04.001

9. Chen Y, Ho MH. Comparative risks and clinical outcomes of midazolam versus other intravenous sedatives in critically ill mechanically ventilated patients: a systematic review and meta-analysis of randomized trials. Intensive & Critical Care Nursing. 2025;103945. doi:10.1016/j.iccn.2025.103945

10. Wen J, Ding X, Liu C, et al. A comparison of dexmedetomidine and midazolam for sedation in patients with mechanical ventilation in ICU: a systematic review and meta-analysis. PLOS One. 2023;18:e0294292. doi:10.1371/journal.pone.0294292

11. Walsh TS, Parker RA, Aitken LM, et al. Dexmedetomidine- or clonidine-based sedation compared with propofol in critically ill patients: the A2B randomized clinical trial. JAMA. 2025. doi:10.1001/jama.2025.7200

12. Lewis K, Alshamsi F, Carayannopoulos K, et al. Dexmedetomidine versus other sedatives in critically ill mechanically ventilated adults: a systematic review and meta-analysis of randomized trials. Intensive Care Medicine. 2022;48:811-840. doi:10.1007/s00134-022-06712-2

13. Kawazoe Y, Miyamoto K, Morimoto T, et al. Effect of dexmedetomidine on mortality and ventilator-free days in patients requiring mechanical ventilation with sepsis: a randomized clinical trial. JAMA. 2017;317(13):1321-1328. doi:10.1001/jama.2017.2088

14. Hendrikse C, Ngah V, Kallon I, et al. Ketamine as adjunctive or monotherapy for post-intubation sedation in patients with trauma on mechanical ventilation: a rapid review. African Journal of Emergency Medicine. 2023;13:313-321. doi:10.1016/j.afjem.2023.10.002

15. Amer M, Møller MH, Alshahrani M, et al. Ketamine analgosedation for mechanically ventilated critically ill adults: a rapid practice guideline from the Saudi Critical Care Society and the Scandinavian Society of Anesthesiology and Intensive Care Medicine. Anesthesia & Analgesia. 2024. doi:10.1213/ANE.0000000000007173

16. Matchett G, Gasanova I, Riccio CA, et al. Continuous infusion ketamine for adjunctive analgosedation in mechanically ventilated, critically ill patients. Pharmacotherapy. 2019;39(3):288-296. doi:10.1002/phar.2223

17. Pappal RD, Roberts BW, Mohr NM, et al. The ED-AWARENESS study: a prospective observational cohort study of awareness with paralysis in mechanically ventilated patients admitted from the emergency department. Annals of Emergency Medicine. 2021;77(5):532-544. doi:10.1016/j.annemergmed.2020.09.026

18. Driver BE, Prekker ME, Wagner E, et al. Recall of awareness during paralysis among emergency department patients undergoing tracheal intubation. Chest. 2023;163(2):313-323. doi:10.1016/j.chest.2022.09.035

19. Fuller BM, Roberts BW, Mohr NM, et al. The ED-SED study: a multicenter, prospective cohort study of practice patterns and clinical outcomes associated with emergency department sedation for mechanically ventilated patients. Critical Care Medicine. 2019;47(11):1539-1548. doi:10.1097/CCM.0000000000003956

20. Fuller BM, Roberts BW, Mohr NM, et al. The feasibility of implementing targeted sedation in mechanically ventilated emergency department patients: the ED-SED pilot trial. Critical Care Medicine. 2022;50(8):1224-1235. doi:10.1097/CCM.0000000000005559

21. Steel TL, Lokhandwala S, Caldwell ES, et al. Variability in sedation assessment among intubated patients in the emergency department. Academic Emergency Medicine. 2021;28(10):1173-1176. doi:10.1111/acem.14329

22. Ely EW, Truman B, Shintani A, et al. Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale. JAMA. 2003;289(22):2983-2991. doi:10.1001/jama.289.22.2983

23. Gélinas C, Fillion L, Puntillo KA, et al. Validation of the Critical-Care Pain Observation Tool in adult patients. American Journal of Critical Care. 2006;15(4):420-427.

24. Irwin WW, Berg KT, Ruttan T K, et al. Initiative to improve postintubation sedation in a pediatric emergency department. Journal for Healthcare Quality. 2022;44(1):31-39. doi:10.1097/JHQ.0000000000000304

25. Ayers C, Johnson DP, Noffsinger L, et al. Reducing time to postintubation sedation in a pediatric emergency department. Pediatrics. 2024;153(4):e2023062665. doi:10.1542/peds.2023-062665

This article synthesizes current evidence and recommendations from the 2018 SCCM PADIS Guidelines, recent emergency medicine literature, and the review by Baumgartner and Fuller (2026), “Postintubation Sedation and Analgesia in the Emergency Department: The Basics and Beyond.” It is intended for educational purposes and should complement—not replace—local protocols and clinical judgment.

Dr Arihant Jain, MD | lifeonthefrontline.com
Instagram: @humans.of.em
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PART 1 — Understanding Diuretic Resistance

The problem

Loop diuretics are the cornerstone of decongestion—yet:

• 20–30% of patients fail to respond adequately

• Associated with longer hospital stay, ICU need, and mortality

What is Diuretic Resistance?

Failure to achieve negative sodium and fluid balance despite adequate dosing

• Often misdiagnosed

• Many cases are actually a result of:

  • Under-dosing

  • Poor drug delivery

  • Wrong physiology

PART 2 — Mechanisms of Diuretic Resistance

(This is the key to everything that follows)

Diuretic resistance is multifactorial, driven by 3 major pathways:

1️⃣ Pharmacokinetic Failure (Drug never reaches kidney)

• Gut edema → ↓ oral absorption

• Low cardiac output → ↓ renal perfusion

• High CVP → renal congestion

• Hypoalbuminemia → altered drug delivery

👉 Result: insufficient drug at site of action

2️⃣ Tubular Adaptation (“Nephron fights back”)

• Chronic loop use → distal nephron hypertrophy

• ↑ Na-Cl cotransporter (NCC)

• ↑ ENaC activity

👉 Result: distal sodium reabsorption overrides loop effect

3️⃣ Neurohormonal Activation (“Body wants sodium”)

• RAAS activation

• Sympathetic activation

• Vasopressin

👉 Creates a state of “basal sodium avidity”
👉 Kidney is primed to retain sodium despite diuretics

The Forgotten Player — Chloride

• Hypochloremia → activates WNK kinases

• ↑ Sodium reabsorption

• ↓ Diuretic response

👉 Diuretics worsen chloride depletion → vicious cycle

Diuretic resistance is NOT just “need more dose”
It’s a mismatch between drug, kidney, and physiology

Read further about pathophysiology behind Diuretic Resistance here

PART 3 — How to Monitor Diuretic Therapy in ED

(Where most clinicians go wrong)

❌ What NOT to rely on:

• Weight

• Fluid balance charts

• “Urine looks good”

👉 These do NOT reflect sodium removal

✅ What actually matters:

1. Urinary Sodium (U. Na+) — THE GOLD STANDARD

⏱ Check 1–2 hours after IV diuretic

• >70 mmol/L → Adequate response

• <50–70 mmol/L → Resistance

👉 This predicts response before clinical deterioration

2. Urine Output

• Target: >100–150 mL/hour (first 6 hours)

3. Bedside Ultrasound

• Lung B-lines → pulmonary congestion

• VExUS → systemic venous congestion

Dynamic Monitoring with all 3 adjuncts.

Assess → Adjust → Reassess every 2–6 hours

Not next morning. Not after ward transfer.

PART 4 — The Shift: Phenotype-Based Diuretic Therapy

Same drug. Same dose. Different patients → different failures.

👉 That’s because different mechanisms dominate in different phenotypes

PHENOTYPE 1 — RIGHT HEART FAILURE

“Venous congestion is the problem”

🔬 Mechanism

• ↑ CVP → renal congestion

• ↓ renal perfusion gradient

• ↓ drug delivery

Strategy

• Aggressive decongestion (even if borderline BP)

• Higher loop doses

• Early combination therapy

If low output:

• Add inotropes (dobutamine/milrinone)

• Use norepinephrine if hypotensive

👉 Decongestion improves renal function

PHENOTYPE 2 — ADVANCED CKD

“Delivery + tubular resistance”

Mechanism

• ↓ tubular secretion

• Chronic sodium retention

• Distal nephron adaptation

Strategy

• Use higher loop doses (expected)

• Prefer IV route

Early add-ons:

• Acetazolamide → if metabolic alkalosis

• Thiazide → if chronic loop use

👉 Sequential nephron blockade is essential

Critical points:

• Correct chloride

• Accept mild creatinine rise

PHENOTYPE 3 — OBESITY

“Hidden congestion + neurohormonal activation”

Mechanism

• Adipose tissue → RAAS + SNS activation

• ↑ plasma volume

• ↑ intra-abdominal pressure → ↓ renal perfusion

Strategy

• Assume underestimated congestion

• Use higher doses early

• Early combination therapy

Add:

• SGLT2 inhibitors (if appropriate)

Clinical pearl

BNP & exam are unreliable → rely on physiology

PHENOTYPE 4 — ELDERLY / FRAIL

“Balance between diuresis and harm”

Mechanism

• Altered pharmacokinetics

• ↓ renal reserve

• High vulnerability

Strategy

• Gradual decongestion

• Close monitoring

Use:

• Urine output

• UNa

• Ultrasound

Goal:

👉 Not aggressive fluid removal
👉 Stable euvolemia + preserved function

Putting It All Together (ED Algorithm)

Based on :-

1. Aletras G, Bachlitzanaki M, Stratinaki M, Foukarakis E, Petrakis I, Pantazis Y, Hamilos M and Stylianou K (2026) Diuretic resistance in cardiorenal syndrome: mechanisms, monitoring and phenotype-tailored management. Front. Cardiovasc. Med. 12:1731305. doi: 10.3389/fcvm.2025.1731305
   
   

FINAL TAKEAWAY

Diuretic resistance is not about the drug.
It is about which physiological barrier is dominant.

When you:

• Monitor early

• Identify mechanism

• Treat phenotype

👉 Diuretics start working again.

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Etomidate is one of the most commonly used induction agents for:

• Rapid Sequence Intubation (RSI)

• Short procedural sedation (e.g., cardioversion)

Its appeal lies in:

• Rapid onset (10–20 sec)

• Short duration (4–10 min)

• Minimal cardiovascular depression

This makes it particularly valuable in critically ill or hypotensive patients, where even small drops in blood pressure can be dangerous.

Dosing essentials

• RSI: 0.3 mg/kg IV (max ~40 mg)

• Unstable / elderly: 0.2 mg/kg

• Procedural sedation: 0.1 mg/kg

Always dose using actual body weight to avoid awareness during paralysis.

Clinical advantages

• Preserves hemodynamic stability better than most induction agents

• Maintains cerebral perfusion pressure → useful in head injury

• Reliable intubating conditions with high first-pass success

• Rapid recovery profile for short procedures

Adrenal suppression: the central controversy

Mechanism

Etomidate inhibits 11β-hydroxylase, impairing cortisol synthesis:

• Leads to reduced endogenous cortisol production

• Effect occurs even after a single dose

Duration:

• Suppression may last 6–72 hours

Biochemical vs clinical significance

• Biochemical suppression:
  Almost universal → low cortisol levels after administration

• Clinical adrenal insufficiency:
  Variable → may present as:

  • Persistent hypotension

  • Increased vasopressor requirement

Key point:
Not all patients with low cortisol develop clinically significant instability.

Adrenal effects in real-world ED practice

In the emergency setting, etomidate-induced adrenal suppression is best understood as a transient physiologic trade-off rather than a definitive clinical harm.

While cortisol levels drop predictably after a single dose, most patients do not manifest overt adrenal crisis.

The effect becomes clinically relevant primarily in septic shock, where endogenous cortisol is crucial for maintaining vascular tone and catecholamine responsiveness.

In such patients, etomidate may contribute to vasopressor dependence or delayed shock reversal, even though a clear increase in mortality has not been consistently demonstrated. In contrast, in undifferentiated shock or cardiogenic instability, the immediate hemodynamic stability provided during intubation often outweighs this transient endocrine effect, making etomidate a reasonable and frequently preferred choice.

What the evidence shows

General ED population

• No consistent increase in mortality after single-dose use

• Benefits in maintaining hemodynamics often outweigh risks

Sepsis and septic shock

• Higher rates of adrenal suppression

• Increased vasopressor requirement seen in several studies

• No clear mortality difference compared with alternatives

Interpretation:

• The signal is physiologic (pressor need) rather than definitively outcome-driven

Other important adverse effects

• Myoclonus (~30%) → limits use in procedural sedation

• No analgesia → must combine with appropriate agents

• Transient apnea/hypoventilation possible

• Injection site pain (~20%)

• Avoid repeat dosing

Etomidate vs Ketamine: bedside decision-making

Outcomes between agents are largely similar—choice depends on physiology and context rather than superiority

Steroids after etomidate?

• Routine steroid use is not recommended

• No clear improvement in outcomes

• Reserve steroids for established refractory septic shock, not prophylaxis

Practical ED approach

Use etomidate when:

• Patient is hemodynamically unstable

• Concern for peri-intubation hypotension

• Need for neuroprotection

Consider alternatives when:

• Septic shock with high vasopressor requirement

• Concern for adrenal insufficiency impact

Take-home message

• Etomidate provides rapid, reliable, hemodynamically stable induction

• It causes predictable, transient adrenal suppression

• Clinical impact is usually limited, but context matters in sepsis

• The decision is not about the drug alone—it’s about the patient in front of you

“Etomidate protects the pressure upfront—just be mindful of the cortisol trade-off.”

1️⃣ Ketamine for Acute Pain (Sub-dissociative Dosing)

IV Analgesia

• 0.1–0.3 mg/kg IV infusion over 15–30 min

• Repeat in 1–2 hours if needed

• Consider infusion 0.05–0.25 mg/kg/h for ongoing pain
  (Engstrom et al., 2025)

  Ketamine _ CorePendium

What’s new:
Recent ED trials confirm that ~0.3 mg/kg IV provides comparable analgesia to opioids with fewer respiratory events (Beaudrie-Nunn et al., 2023; Lovett et al., 2020). Infusion is preferred over rapid IV push to reduce dizziness and psychoperceptual effects (Engstrom et al., 2025)

Alternative Routes

• Intranasal: 0.75–1 mg/kg

• Nebulized: 0.75–1 mg/kg
  (Engstrom et al., 2025)

  Ketamine _ CorePendium

Clinical Pearl: Excellent option when IV access is delayed (pediatrics, trauma, behavioral emergencies).

2️⃣ Procedural Sedation (PSA)

IV Dissociative Sedation

• 1 mg/kg IV, repeat 0.5 mg/kg as needed
  (Engstrom et al., 2025)

  Ketamine _ CorePendium

IM Dissociation

• 4–5 mg/kg IM

• Repeat 2–5 mg/kg if required
  (Engstrom et al., 2025)

  Ketamine _ CorePendium

Pediatric Safety Update

• Large pediatric ED registry: critical AEs 0.016%

• Meta-analysis (8,282 children): airway events increase with ≥2.5 mg/kg IV initial dose or ≥5 mg/kg total dose
  (Green et al., 2009; Green et al., 2025)

Emerging trend (2024–2025):

• Moderate dosing (0.5–1 mg/kg IV) achieves adequate sedation with fewer adverse effects than higher dosing (Türkücü et al., 2025).

• Structured sedation programs significantly reduce complications (Erumbala et al., 2023).

3️⃣ Acute Agitation & Behavioral Emergencies

IM for Severe Agitation

• 3–4 mg/kg IM initial agent

• 2 mg/kg IM if adjunctive or sedative intoxication
  (Engstrom et al., 2025)

  Ketamine _ CorePendium

IV (if access available)

• 1–2 mg/kg IV (less well studied for agitation)

Key Updates:

• ED airway intervention rates are significantly lower than early EMS reports when dosing is standardized (Mankowitz et al., 2018; Kwong et al., 2025).

• Avoid polypharmacy with opioids or benzodiazepines unless clinically indicated — airway events increase with co-administration.

4️⃣ Airway Management: RSI, DSI & Post-Intubation

RSI Induction

• 1–2 mg/kg IV push

• In shock: 0.5–1 mg/kg IV, titrate
  (Engstrom et al., 2025)

Delayed Sequence Intubation (DSI)

• ~1 mg/kg IV to achieve dissociation while preserving respirations
  (Merelman et al., 2019)

Post-Intubation Sedation

• Bolus 1–2 mg/kg

• Infusion 1–5 mg/kg/h

Hemodynamic Advantage:
Ketamine supports blood pressure via indirect sympathomimetic activity (Engstrom et al., 2025)

Important nuance (2025 update):
Higher induction doses (2 mg/kg) in shock have been associated with post-intubation hypotension — titrated dosing (0.5 mg/kg increments) is recommended

5️⃣ Status Asthmaticus

Non-intubated

• 0.5–1 mg/kg IV bolus

• 0.25–0.5 mg/kg/h infusion

Intubated

• Up to 0.75–3 mg/kg/h infusion

Bronchodilation is clinically useful, though meta-analyses show mixed outcome benefit (Engstrom et al., 2025)

6️⃣ Refractory Status Epilepticus

• 1–2 mg/kg IV bolus

• 0.1–4 mg/kg/h infusion

• Continuous EEG recommended
  (Engstrom et al., 2025)

Ketamine’s NMDA antagonism is particularly valuable in late-phase refractory seizures.

7️⃣ Special Populations & Safety Pearls

Pregnancy

• Should not be withheld if clinically indicated

• Single ED dose unlikely to cause fetal harm
  (Engstrom et al., 2025)

Breastfeeding

• Avoid for 6–12 hours post-dose

Intracranial Pressure

• Contemporary data suggest ketamine does not increase ICP and may reduce it.

Adverse Effects to Anticipate

• Emergence reactions (10–20%)

• Laryngospasm - < 3 months (rare; manage with Larson maneuver)

• Increased secretions (consider glycopyrrolate 0.2 mg IV)

• Nausea/vomiting

  

📌 2026 Clinical Takeaways

1. Think in a dose continuum — analgesia (0.1 mg/kg) → dissociation (1 mg/kg) → airway control (1–2 mg/kg).

2. Moderate IV dosing (0.5–1 mg/kg) often balances efficacy and safety for PSA.

3. In shock, titrate (0.5 mg/kg increments) rather than reflexively giving 2 mg/kg.

4. Avoid unnecessary co-administration of respiratory depressants.

5. Pediatric safety remains excellent when high doses are avoided.

Ketamine remains one of the most hemodynamically stable induction agents in ED airway management.

References

1. Mirfazaelian H, Fazel A, Azizi N, et al. Non-injectable ketamine for pediatric sedation in the emergency department: a systematic review. Acad Emerg Med. 2025;32:1344-1355. doi:10.1111/acem.70163

2. Sharif S, Kang J, Sadeghirad B, et al. Pharmacological agents for procedural sedation and analgesia in the emergency department and intensive care unit: a systematic review and network meta-analysis of randomized trials. Br J Anaesth. 2024. doi:10.1016/j.bja.2023.11.050

3. Esmaillian M, Kouhestani S, Azizkhani R, et al. Dexmedetomidine versus propofol: an effective combination with ketamine for adult procedural sedation: a randomized clinical trial. Am J Emerg Med. 2023;73:95-101. doi:10.1016/j.ajem.2023.08.025

4. Türkücü Ç, Parlak I, Kokulu K, Sert E, Mutlu H. Comparison of the incidence of recovery agitation with two different doses of ketamine in procedural sedation: a randomized clinical trial. Acad Emerg Med. 2025;32:857-862. doi:10.1111/acem.15116

5. Ghojazadeh M, Sanaie S, Paknezhad S, et al. Using ketamine and propofol for procedural sedation of adults in the emergency department: a systematic review and meta-analysis. Adv Pharm Bull. 2019;9:5-11. doi:10.15171/apb.2019.002

6. De Vries L, Veeger N, Van Roon E, Lameijer H. Low-dose ketamine or opioids combined with propofol for procedural sedation in the emergency department: a systematic review. Eur J Emerg Med. 2023;30:244-251. doi:10.1097/MEJ.0000000000001046

7. Nasir H, Zahid M, Saleh M, et al. Use of ketamine, propofol and their combination (ketofol) for procedural sedation in emergency department: a review. Pak J Health Sci. 2023;4(02). doi:10.54393/pjhs.v4i02.539

8. Poonai N, Canton K, Ali S, et al. Intranasal ketamine for procedural sedation and analgesia in children: a systematic review. PLoS One. 2017;12:e0173253. doi:10.1371/journal.pone.0173253

9. Jamal D, Powell C. Paediatric procedural sedation in the emergency department: is ketamine safe? Arch Dis Child. 2020;106:120-124. doi:10.1136/archdischild-2019-318610

10. Dilip T, Chandy G, Hazra D, et al. The adverse effects of ketamine on procedural sedation and analgesia in the emergency department. J Fam Med Prim Care. 2021;10:2279-2283. doi:10.4103/jfmpc.jfmpc_2140_20

11. M S, S J, A B, et al. A randomized controlled trial comparing ketamine versus fentanyl for procedural sedation in the emergency department for adults with isolated extremity injury. Malays Orthop J. 2024;18:116-124. doi:10.5704/moj.2403.015

12. Elsaeidy A, Ahmad A, Kohaf N, et al. Efficacy and safety of ketamine-dexmedetomidine versus ketamine-propofol combination for periprocedural sedation: a systematic review and meta-analysis. Curr Pain Headache Rep. 2024;28:211-227. doi:10.1007/s11916-023-01208-0

13. Anoumandane A, Murugesan V, Jayabalan K, et al. Comparison of ketamine-dexmedetomidine and ketamine-propofol for procedural sedation in adults – a single-center prospective randomized control study. Asian J Med Sci. 2025. doi:10.71152/ajms.v16i10.4770

14. Dehne L, Foertsch M, Bradshaw P, et al. Evaluation of subdissociative-dose ketamine for procedural sedation in the emergency department. Crit Care Med. 2022. doi:10.1097/01.ccm.0000908972.43680.39

15. Rached-d’Astous S, Finkelstein Y, Bailey B, et al. Intranasal ketamine for procedural sedation in children: an open-label multicenter clinical trial. Am J Emerg Med. 2023;67:10-16. doi:10.1016/j.ajem.2023.01.046

16. Erumbala G, Anzar S, Deiratany S, et al. Procedural sedation programme minimising adverse events: a 3-year experience from a tertiary paediatric emergency department. Arch Dis Child. 2023;109:88-92. doi:10.1136/archdischild-2023-326021

17. Strayer RJ, Nelson LS. Adverse events associated with ketamine for procedural sedation in adults. Am J Emerg Med. 2008;26:985-1028. doi:10.1016/j.ajem.2007.12.005

18. Green SM, Roback MG, Krauss B, et al. Predictors of airway and respiratory adverse events with ketamine sedation in the emergency department: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med. 2009;54:158-168.e1-4. doi:10.1016/j.annemergmed.2008.12.011

19. Green SM, Tsze DS, Roback MG. Emergency department ketamine sedation: frequency and predictors of critical and high-risk adverse events. Ann Emerg Med. 2025. doi:10.1016/j.annemergmed.2025.05.003

20. White N, Wendt W, Drendel A, Walsh P. Sedation with ketamine, propofol, and dexmedetomidine in pediatric emergency departments. Am J Emerg Med. 2025;93:21-25. doi:10.1016/j.ajem.2025.03.027

21. Merelman AH, Perlmutter MC, Strayer RJ. Alternatives to rapid sequence intubation: contemporary airway management with ketamine. West J Emerg Med. 2019;20:466-471. doi:10.5811/westjem.2019.4.42753

22. Mankowitz SL, Regenberg P, Kaldan J, Cole JB. Ketamine for rapid sedation of agitated patients in the prehospital and emergency department settings: a systematic review and proportional meta-analysis. J Emerg Med. 2018;55:670-681. doi:10.1016/j.jemermed.2018.07.017

23. Kwong J, Verbeek PR, Leong Y, et al. Paramedic use of ketamine for severe agitation and violence. Can J Emerg Med. 2025;27:653-660. doi:10.1007/s43678-025-00963-w

24. Beaudrie-Nunn A, Wieruszewski E, Woods E, et al. Efficacy of analgesic and sub-dissociative dose ketamine for acute pain in the emergency department. Am J Emerg Med. 2023;70:133-139. doi:10.1016/j.ajem.2023.05.026

25. Lovett S, Reed T, Riggs R, et al. A randomized, noninferiority, controlled trial of two doses of intravenous subdissociative ketamine for analgesia in the emergency department. Acad Emerg Med. 2020;28. doi:10.1111/acem.14200

26. Engstrom K, Nordt SP, Acquisto NM, Won K, Rech MA, Swadron S, Mattu A. Ketamine. In: CorePendium. EM:RAP; Updated August 2, 2025.

    Ketamine _ CorePendium

Where Bicarbonate Is NOT Your First Move

Most metabolic acidosis cases in ED:

❌ Pure lactic acidosis from shock
❌ Sepsis without AKI
❌ Respiratory acidosis
❌ “pH <7.2 ⇒ Give bicarb” reflex

In lactic acidosis from hypoxia, bicarbonate does not improve perfusion, may worsen intracellular acidosis, and adds sodium + fluid load [1,3].

Fix shock → perfusion → lactate first.
Not the ABG.

Where Bicarbonate Actually Helps

Use bicarb when acidemia is no longer adaptive — when it starts hindering organs, especially the kidneys and heart.

Most evidence-supported ED indications:

These are targeted, not routine use cases.

Sodium bicarbonate is not a universal antidote to low pH. Its most evidence-supported role is in severe metabolic acidemia with acute kidney injury (AKI) — particularly when pH ≤ 7.1–7.2 and the acidosis is contributing to hemodynamic instability or dialysis risk. The original BICAR-ICU trial (2018) showed reduced KRT requirement and a survival signal in the AKI subgroup, while the more recent BICAR-ICU-2 trial (2025) did not demonstrate mortality benefit overall but did show delayed and reduced KRT use, at the cost of higher sodium load and earlier vasopressor exposure.
Evidence summaries therefore recommend targeted use — not routine buffering — with bicarbonate reserved for patients where organ support and hyperkalemia management are parallel goals. Patients with hyperchloremic acidosis may particularly benefit, as bicarbonate therapy directly reverses chloride-driven acidemia and avoids further saline burden.

Isotonic vs Hypertonic Bicarbonate — Not interchangeable

Hypertonic bicarb does not reliably reduce K⁺ due to solute drag [5].

How to Make Isotonic Bicarbonate at the Bedside (ED/ICU Use) [6]

When bicarbonate is indicated as a resuscitation fluid (e.g., hyperkalemia + metabolic acidosis + hypotension), isotonic bicarbonate is preferred over hypertonic boluses. The standard preparation:

Isotonic Bicarbonate Formula:

• Add 3 amps of Sodium Bicarbonate (50 mEq each = 150 mEq total)

• Into 1 liter of D5W

This results in:

• 150 mEq/L NaHCO₃ (≈ normal sodium concentration)

• Osmolarity ~300 mOsm/L (near-isotonic)

• Safe for peripheral IV infusion

Typical ED/ICU infusion rates:

• 50–150 mL/hr for gradual pH correction

• Up to 250 mL/hr in severe metabolic acidosis with shock (close monitoring required)

Key benefits vs hypertonic bicarbonate:

• Provides volume + alkali without the osmotic sodium load

• Avoids solute drag that can paradoxically raise potassium

Always monitor:

• pH, Na⁺, K⁺, Ca²⁺, lactate, and volume status

• Repeat blood gases every 2–4 hours

Isotonic bicarbonate = the right tool when volume resuscitation AND acidosis correction are both needed.

Why Undiluted (Hypertonic) Bicarbonate Can Be Harmful in Hyperkalemic Arrest

In cardiac arrest from hyperkalemia, it may be tempting to push undiluted 8.4% sodium bicarbonate (1 mEq/mL) as a rapid fix — but this can worsen serum potassium rather than help. The hypertonic bicarbonate creates a steep extracellular osmotic shift, pulling potassium out of cells and into the bloodstream (“solute drag”), counteracting the desired intracellular driving effect. [5]

Additionally:

• Rapid CO₂ generation can worsen intracellular acidosis

• Sudden alkalinization can drop ionized calcium, impairing contractility and resuscitation success

• Hypernatremia & volume-independent sodium load can worsen neurologic outcomes

• Extravasation risk → severe tissue injury

🛑 Hypertonic bicarbonate should not be used as routine push-dose therapy in hyperkalemic arrest.

✔ Best practice during arrest:

• IV calcium to stabilize the myocardium

• Insulin + dextrose (or beta-agonists) to shift K⁺

• Definitive K⁺ removal (dialysis) as soon as feasible

• Consider isotonic bicarbonate infusion (not pushes) only if severe metabolic acidosis is present

If you must give bicarbonate in cardiac arrest — know why you are giving it, and ensure the physiology supports it.

What did BICAR-ICU Trials Actually Show?

—> BICAR-ICU [7]

No mortality benefit overall, benefit in AKI subgroup

Use selectively in AKI

—> BICAR-ICU 2 [8]

↓ & delayed dialysis use but ↑ fluid balance + pressors

Organ support > survival

Bicarbonate is not a mortality drug —
it is an organ protection strategy in the right patient.

When Bicarb Can Harm

Situations to avoid or minimize use:

• Pure lactic acidosis from early shock [1,3]

• Respiratory acidosis (CO₂ retention makes pH worse) [1]

• Volume overload (HF, pulmonary edema) [1,2]

• Hypernatremia — worsens sodium load [1]

• Hypocalcemia — alkalosis ↓ ionized Ca [1]

• Hypokalemia [1]

If there is no AKI and no hyperkalemia →
Bicarb is probably not helping.

The Physiology Takeaway

Acidemia is often a protective mechanism.
We intervene only when it becomes maladaptive.

✔️ Better perfusion
✔️ Better potassium handling
✔️ Better organ function

Not:
✘ “prettier ABG”

This is pH-guided resuscitation [6].

Final Take-Home

🩺 Bicarbonate is a precision therapy — not a reflex.
Use it when it meaningfully corrects physiology, avoid when it only adds risk.

Where it helps most

• Severe metabolic acidosis with AKI/oliguria

• Hyperkalemia with metabolic acidosis (as an adjunct — not primary therapy)

• Select toxicology: TCA + sodium-channel blocker toxicity, salicylate poisoning

• Significant hyperchloremic acidosis after large-volume NS

Where to avoid

• Pure lactic acidosis from hypoperfusion

• Respiratory acidosis

• Hypernatremia, fluid overload, hypocalcemia

• When pH is already >7.2 and patient clinically improving

🚨 Critical Caution

Do NOT push undiluted bicarbonate for hyperkalemia —
it may worsen intracellular acidosis, shift K⁺ out of cells, drop ionized calcium, and delay proven therapies like insulin/dextrose and dialysis.

Think beyond the number (pH) — treat the cause, use bicarbonate only when it changes outcomes.

Buffer the right patient — not the number.

References:-

1. Kraut JA, Lew SQ, Amlal H, et al. A review of bicarbonate use in common clinical scenarios. J Emerg Med. 2023;64(4):e377–e385.

2. Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med. 2018;378(9):829–839.

3. Dubin A, Otero J, Martín LC, et al. International Fluid Academy (IFA) recommendations. Ann Intensive Care. 2020;10(Suppl 1):79.

4. Wang Z, Zheng H, Deng J, et al. Hemorrhagic shock resuscitated with Ringer’s (bicarbonate vs lactate): randomized controlled trial. J Inflamm Res. 2022;15:6123–6133.

5. Xu J, Walline JH. Treatment of hyperkalemic emergencies. J Thorac Dis. 2022;14(5):1455–1462.

6. Farkas JD. Fluid selection & pH-guided fluid resuscitation. EMCrit Project. Updated Oct 2024. Accessed Dec 2025.

7. Jaber S, Paugam-Burtz C, Dupres G, et al. Sodium bicarbonate therapy in severe metabolic acidaemia in ICU: the BICAR-ICU randomized trial. Lancet. 2018;392:31–40.

8. Jung B, Jabaudon M, De Jong A, et al. Sodium bicarbonate for severe metabolic acidemia and acute kidney injury: the BICAR-ICU-2 randomized clinical trial. JAMA. 2025; e2520231.

9. Blank S, Blank R, Laupland K, et al. Sodium bicarbonate administration for metabolic acidosis in the ICU: target trial emulation. Intensive Care Med. 2025;51:1078–1086.

10. Sabatini S, Kurtzman N. Bicarbonate therapy in severe metabolic acidosis. J Am Soc Nephrol. 2009;20:692–695.

11. Fujii T, Udy AA, Licari E, et al. Sodium bicarbonate therapy in critically ill metabolic acidosis: review. J Crit Care. 2019;51:184–191.

12. Fujii T, Udy A, Nichol A, et al. International observational study of metabolic acidosis treatment with bicarbonate in ICU. Crit Care. 2021;25:108.

13. Arieff AI. Indications for bicarbonate use in metabolic acidosis. Br J Anaesth. 1991;67:165–177.

14. Yang T, Lin H, Wang H, et al. Sodium bicarbonate treatment and outcomes in CKD with metabolic acidosis. Clin J Am Soc Nephrol. 2024;19:959–969.

15. Tong L, Wu S, Li D, et al. Hyperchloremic acidosis benefiting from sodium bicarbonate therapy. Eur J Intern Med. 2024.

16. Navaneethan S, Shao J, Buysse J, Bushinsky DA. Treating metabolic acidosis in CKD: systematic review. Clin J Am Soc Nephrol. 2019;14:1011–1020.
    

But here’s what’s NOT controversial:

➡️ We clearly know when not to use one.
➡️ And in the ED, those contraindications matter more than theoretical superiority.

Both agents work. Both reduce ICP. But their safety profiles, contraindications, and dosing nuances are the real decision-makers.

This article focuses on the evidence that your shift actually needs:

• Which one works better when

• Who should never get one or the other

• Practical bedside dosing (adults + paediatrics)

• Sodium & osmolality cutoff values

• Updated literature you can trust

1. Efficacy & Safety: What the Evidence Really Shows

Both work — but hypertonic saline often performs better in the sickest patients.

Across RCTs and meta-analyses:

• HTS is as effective or superior to mannitol

• HTS shows better ICP reduction in refractory or severe TBI

• HTS is especially beneficial in:
  ✔ unstable hemodynamics
  ✔ paediatric CNS infections
  ✔ dehydration
  ✔ renal compromise

(Gu et al., 2018; Mangat et al., 2019; Ashraf et al., 2024; Kamel et al., 2011; Rameshkumar et al., 2020; Hemmati et al., 2025)

Safety: HTS has fewer problems than mannitol

Hypertonic Saline advantages

• More stable blood pressure

• Less renal injury

• No over-diuresis

• Fewer electrolyte swings

• Can be used when hypotensive

Mannitol risks

• Hypotension

• Hypovolemia

• Renal failure

• Rebound ICP

• Dilutional hyponatremia

(Ashraf, 2024; Kamel, 2011; Kumar, 2024)

Patient Outcomes

Outcomes like mortality and neurological recovery are similar, but:

➡️ HTS may reduce ICU stay and ventilator duration.
(Ashraf, 2024; Karamian, 2024)

2. Absolute Contraindications (The REAL Deciding Factor)

Agent

This is the cleanest bedside rule:

—> If the patient is dehydrated, hypotensive, or renally compromised → avoid mannitol.
—>If sodium is already high or the patient is in heart failure → avoid HTS.

3. Serum Sodium & Osmolality Cutoffs (Critical Numbers)

Mannitol

• Absolute contraindication: Serum osmolality >320 mOsm/L

• Avoid in severe hyponatremia
  (Fink, 2012; Park & Ko, 2023)

Hypertonic Saline

• Avoid if serum sodium >160–165 mEq/L

• Caution if osmolality >320–350 mOsm/L
  (Fink, 2012; Shao, 2015)

4. Practical Bedside Doses (Adults & Paediatrics)

Clinical Notes

• 3% HTS can be given peripherally if monitored (Khasiyev, 2024).

• Higher concentrations → central line preferred.

• Repeat boluses or infusions depend on ICP response & protocols.

5. Key Takeaways for Busy ED Clinicians

✔ Both agents work — but HTS is safer in high-risk patients

✔ Mannitol should NOT be used above 320 mOsm/kg

✔ HTS should NOT be used above Na 160–165 mEq/L

✔ Dosing is similar in adults & paediatrics

✔ The real ED decision is guided by contraindications, NOT preference

✔ HTS may outperform mannitol in refractory ICP

Bottom line:

References

1. Rameshkumar et al., 2020

Randomized Clinical Trial of 20% Mannitol vs 3% HTS in Children With Raised ICP. Pediatric Critical Care Medicine, 21:1071–1080.
https://doi.org/10.1097/pcc.0000000000002557

2. Ashraf et al., 2024

Comparison of Mannitol vs HTS for ICP Management. Biological and Clinical Sciences Research Journal.
https://doi.org/10.54112/bcsrj.v2024i1.1010

3. Gu et al., 2018

Meta-analysis: HTS vs Mannitol in TBI. Neurosurgical Review, 42:499–509.
https://doi.org/10.1007/s10143-018-0991-8

4. Kamel et al., 2011

Meta-analysis of HTS vs Mannitol. Critical Care Medicine, 39:554–559.
https://doi.org/10.1097/ccm.0b013e318206b9be

5. Hemmati et al., 2025

Systematic Review: Complications of HTS vs Mannitol.
https://doi.org/10.1101/2025.04.25.25326424

6. Kochanek et al., 2022

ICP Response to HTS vs Mannitol in Severe Pediatric TBI. JAMA Network Open, 5.
https://doi.org/10.1001/jamanetworkopen.2022.0891

7. Harutjunyan et al., 2005

RCT comparing 7.2% HTS HES vs 15% Mannitol in Neurosurgery. Critical Care, 9:R530–R540.
https://doi.org/10.1186/cc3767

8. Mangat et al., 2019

HTS superior to Mannitol for ICP & CPP burden. Neurosurgery.
https://doi.org/10.1093/neuros/nyz046

9. Alfarhan et al., 2023

HTS vs Mannitol in Children: Systematic Review.
https://doi.org/10.5742/mewfm.2023.95256187

10. Kumar et al., 2024

20% Mannitol vs 3% HTS in Non-Traumatic ICP: Meta-analysis. Indian J Crit Care Med, 28:686–695.
https://doi.org/10.5005/jp-journals-10071-24746

11. Susanto & Riantri, 2022

Optimal HTS Dose & Concentration in TBI. Medeniyet Medical Journal, 37:203–211.
https://doi.org/10.4274/mmj.galenos.2022.75725

12. Karamian et al., 2024

Systematic Review: HTS vs Mannitol in severe TBI. Neurological Research, 46:883–892.
https://doi.org/10.1080/01616412.2024.2360862

13. Huang et al., 2020

Equimolar Hypertonic Agents for ICP. Medicine, 99.
https://doi.org/10.1097/md.0000000000022004

14. Vialet et al., 2003

7.5% HTS vs 20% Mannitol in Refractory ICP. Critical Care Medicine, 31:1683–1687.
https://doi.org/10.1097/01.ccm.0000063268.91710.df

15. James, 2005

Methodology for ICP control using mannitol. Acta Neurochirurgica, 51:161–172.
https://doi.org/10.1007/bf01406742

16. Patil & Gupta, 2019

Comparison of HTS, Mannitol, and Combination Therapy. World Neurosurgery.
https://doi.org/10.1016/j.wneu.2019.01.051

17. Su et al., 2020

10% HTS vs 20% Mannitol in Large Infarction ICP. Clinical Neurology and Neurosurgery, 200.
https://doi.org/10.1016/j.clineuro.2020.106359

18. Khasiyev et al., 2024

Safety of 3% HTS Peripheral Bolus. Neurocritical Care.
https://doi.org/10.1007/s12028-024-01941-3

19. Holden et al., 2022

HTS Use in Neurocritical Care: Dosing, Safety, Administration. AJHP.
https://doi.org/10.1093/ajhp/zxac368

20. Kolsen-Petersen, 2020

Osmotherapy chapter in Management of Severe TBI.
https://doi.org/10.1007/978-3-030-39383-0_61

Sodium & Osmolality Cutoff References

21. Fink, 2012

Osmotherapy: Mannitol vs HTS. Continuum, 18:640–654.
https://doi.org/10.1212/01.con.0000415432.84147.1e

22. Barkas et al., 2023

Hyponatremia Management in Stroke. Ther Adv Endocrinol Metab.
https://doi.org/10.1177/20420188231163806

23. Shao et al., 2015

HTS for Brain Relaxation & ICP: Meta-analysis. PLOS ONE.
https://doi.org/10.1371/journal.pone.0117314

24. Park & Ko, 2023

Adverse effects & monitoring in Hyperosmolar Therapy. JKMA.
https://doi.org/10.5124/jkma.2023.66.5.303