Background:
Septic shock is a severe and common critical illness that is managed in the emergency department. Our current foundation of treatment includes IV fluids, empiric antibiotic coverage, vasopressor therapy, source control and corticosteroids for refractory shock. The levels of nitric oxide (NO) and hydrogen sulfide (H2S) are elevated in sepsis and associated with worse outcomes. Hydroxocobalamin is an inhibitor of NO activity and production and a scavenger of H2S [1,2]. Most of the current data is limited to observational studies looking at hydroxocobalamin in cardiac surgery related vasodilatory shock with few case series and reports for use in septic shock. The available data has shown an improvement in hemodynamics and reduction in vasopressor requirements in various vasodilatory shock states [2]. Chromaturia and self-limited red skin discoloration are common side effects but current data has not shown significant adverse events [3,4]. Patel et al, performed a phase 2 single-center trial to evaluate use of high dose IV hydroxocobalamin in patients with septic shock.
Study:
Results
Take home
There is a low risk of serious adverse events from high dose hydroxocobalamin use [3,4]. For now, it may be reasonable to consider in cases of septic shock refractory to standard care but there isn’t enough data to support its regular use yet.
Title: Albumin Versus Balanced Crystalloid for the Early Resuscitation of Sepsis: An Open Parallel-Group Randomized Feasibility Trial— The ABC-Sepsis Trial
Settings: 15 ED in the United Kingdom. This study is a feasibility study but it looked at mortality as a primary outcome.
Participants:
• Patients with Sepsis, with their National Early Warning Score (NEWS) ? 5 (These patients have estimated mortality of 20%). IV fluid resuscitation needs to be within 1 hour of assessment.
• 300 Patients were randomized to receive balanced crystalloids or 5% human albumin solution (HAS) only, within 6 hours of randomization.
Outcome measurement: 30-day mortality, Hospital length of stay (HLOS)
Study Results:
• The median time for receiving IV fluid from randomization was 41 minutes (HAS) vs. 36 minutes (crystalloids).
• Total volume of IV fluid per Kg in first 6 hours 14.5 ml/kg (HAS) vs. 18.8 ml/kg (crystalloids).
• Other interventions (vasopressor, Renal replacement therapy, invasive ventilation) were similar.
• Complications (AKI, pulmonary edema, allergy) were lower for Crystalloids group
• Median hospital LOS = 6 days for both groups.
• 90-day mortality: 31 (21.1%) (HAS) vs. 22 (14.8%) (Crystalloids), OR 1.54 (95% 0.8-2.8)
Discussion:
• Total volumes for resuscitation in the first 6 hours was 750 ml (HAS) and 1250 ml (crystalloids). This signified a trend toward lower total volume of resuscitation (remember that 30 ml/kg recommendation)
• The 2024 guidelines from Chest (REF 2) suggested that: “In Critically ill adult patients (excluding patients with thermal injuries and ARDS), intravenous albumin is not suggested for first line volume replacement or to increase serum albumin levels. Therefore, we should not give patients (except for cirrhosis or spontaneous bacterial peritonitis) albumin just to reduce the volume of fluid.
• The authors suggested that even a definitive trial in the future will not be able to demonstrate a significant benefit of using 5% albumin.
Conclusion:
There is lower mortality (numerical but not statistically) among the group with balanced crystalloids.
Some points from this narrative review:
Take home pearls:
I wanted to send out two websites curated in part by UMEM current and past faculty/residents/fellows which have a wealth of critical care lectures and resources:
Disclosure: *I am one of the webmasters for the STCMTCC, but have no affiliation with MCCP other than as an enthusiastic reader.
Airway management in the pre-hospital setting is a matter of much controversy, and overall I will defer to my EMS colleagues, but several previous studies have failed to show a benefit to endotracheal intubation in the field as opposed to alternate approaches like a supraglottic airway. Another nod in this direction has recently come out, with Battaglini et al performing a post-hoc analysis of one of the larger studies in the history of cardiac arrest, TTM-2, looking specifically at outcomes stratified by pre-hospital airway management strategy.
Do patients who undergo endotracheal intubation in the field do better than those who get a supraglottic airway?
No, they don't. TTM-2 included 1900 patients, of whom 1702 had enough data to be included in this re-analysis. 28% got supraglottic airways, and 72% got endotracheal intubation. The groups were reasonably well matched on most characteristics, and if anything most well-known prognostic factors favored the endotracheal intubation group (very slightly). It should be noted that several outcome metrics, including modified Rankin scale, did show slight signs of benefit for the endotracheal intubation group, even sometimes in a statistically significant fashion, but fell out when a multi-regression analysis, which was the primary endpoint, was done.
Bottom Line: In pre-hospital cardiac arrest, there remains limited data to support the notion that endotracheal intubation results in better outcomes than supraglottic airway placement. You should defer to your local protocols and continue to work with your paramedics and EMS directors as evidence continues to evolve. For now, I don't think there's sufficient data to suggest that a given patient should be intubated vs undergoing supraglottic airway placement, and it is probably best to defer to the judgement, training, and protocols of your folks on scene.
The incidence of opioid-overdose-related deaths has clearly increased in the past decade, with recent estimates of up to 17% of OHCA being opioid-related in 2023. [1,2] The use of naloxone for opiate reversal in overdose is well-established, with reasonable inference but no formal proof that its use could help in opioid-associated out of hospital cardiac arrest (OA-OHCA). [3] The August publication of two trials [4,5] retrospectively examining naloxone administration in OHCA offers some perspectives…
and
[View “Visual Diagnosis” for slightly more detail on the referenced studies.]
Bottom Line: While prospective trials are absolutely needed to offer more definitive evidence regarding the use of empiric naloxone in nontraumatic OHCA, the rising incidence of OA-OHCA in the U.S. and current findings are convincing enough to encourage early naloxone administration, especially in populations with higher incidence of opioid use.
U.S. Mortality due to Opioid Overdose (CDC data)
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Hepatorenal Syndrome
Euglycemic DKA (eDKA) is a medical emergency requiring prompt attention. It is caused by an imbalance of insulin and glucagon leading to ketone accumulation (1-3). In addition to typical risk factors for DKA, those for eDKA include SGLT-2 inhibitor use and pregnancy, with 30% of DKA cases in pregnancy presenting euglycemic (4, 5).
eDKA presents with an anion gap metabolic acidosis, ketosis/ketonuria, & blood glucose less than 250 mg/dL.
Diagnosis requires ruling out other causes of anion gap metabolic acidosis, including toxic ingestions.
The cornerstone of eDKA management is ensuring enough dextrose to allow needed insulin administration to reverse ketone accumulation.
Diabetic ketoacidosis (DKA) is a serious condition that carries the risk of significant morbidity and mortality if not managed appropriately. Typically managed with an infusion of regular insulin, IV fluids, and electrolytes, there is evidence to support treatment of mild to moderate DKA with a subcutaneous (SQ) regimen using a combo of fast-acting and long-acting insulin instead, decreasing the need for ICU admission without increasing adverse events [1].
What patients?
Adapted from Abbas et al.
How to manage?
Initial dose
Subsequent dosing:
If serum glucose is > 250 mg/dL
If serum glucose is < 250 mg/dL
Bottom Line
DKA management with a SQ insulin protocol is a reasonable approach for patients with mild to moderate DKA, is supported by the American Diabetes Association [5], and can be particularly helpful in this era of ED boarding and bed shortages. Give a long-acting insulin dose every 24 hours (or restart the patient’s home long-acting regimen) and short-acting insulin every 2 to 4 hours. Aggressive IV fluid resuscitation, electrolyte repletion, and treatment of underlying precipitating cause remain additional cornerstones of DKA management.
We heard it before. Continuous administration of antibiotics might be associated with better outcomes. However, results from smaller randomized controlled trials of beta-lactam showed inconsistent conclusions. Therefore, a large RCT was conducted
Settings: 31 ICUs in Croatia, Italy, Kazakhstan, Russia between June 2018 – August 2022.
Randomized, double-blind control trial.
Participants:
Outcome measurement:
Study Results:
Discussion:
Conclusion:
In critically ill patients with sepsis, continuous administration of meropenem did not improve mortality nor reduce the emergence of pandrug resistant bacteria.
Do Sepsis Alert Systems Work?
Researchers in Korea completed a high quality systematic review and meta-analysis of sepsis alert systems for adult ED patients
Using high quality methods, they identified over 3000 studies with 22 meeting criteria.
They found these systems were associated with:
Electronic alerts were further associated with:
Summary (+ a little editorialization)
As annoying as we may find these systems in our daily practice, there is growing evidence that they do provide some benefit with impacts on task saturation and decreasing cognitive load in addition to real patient benefit. While there is also recent evidence that physician gestalt performs well against these systems, there is a suggested benefit in their inclusion in clinical decision making as a safety net or as an “assist”.
The incorporation of rule-based algorithms like these in more advance machine learning methods are covered quite well in a recent opinion piece on “The AI Future of Emergency Medicine”. However, it is important to always know the source of any “algorithm” that you are using, whether rule or mathematically based, given real concerns for bias and error.
The CLOVERS trial (NEJM 2023) examined one of the eternal questions of critical care, liberal vs restrictive fluid management in sepsis… and found no difference. But there are criticism of CLOVERS, and while some other trials agreed with this result, there are also signals in the literature that restrictive fluid strategies are beneficial. Furthermore, we know that these trials suffer from issues of heterogeneity, and often lump together very different patients.
Jorda et al recently published in Critical Care a posthoc re-analysis of CLOVERS looking specifically at patients with advanced CKD (eGFR < 30). This is a challenging group of patients to manage. On the one hand their renal function is already marginal, so the last thing we want to do is potentially deprive starved kidneys of necessary intravascular volume, but on the flip side their septic shock puts them at high risk of full blown renal failure (transient or permanent) and they're thus at very high risk of fluid overload with aggressive resuscitative fluids and potentially limited ability to clear those fluids renally in the next few days. So how did these patients do in CLOVERS?
They did significantly better with the restrictive fluid strategy (mortality 22% vs 39%, HR CI 0.29-0.85). They also had more pressor free days and vent free days.
Bottom Line (my opinion): While a restrictive vs liberal fluid strategy in septic shock remains a bit up for debate, the evidence continues to slowly tip towards restrictive fluids (i.e. earlier pressors) as the preferred approach. In patients with advanced CKD (eGFR < 30), there is probably now sufficient evidence to favor vasopressors over IV fluid administration when resuscitating septic shock.
This May, the Society of Critical Care Medicine (SCCM) published new recommendations [1] for the use of corticosteroids in critical illness (separate from patients with known adrenal insufficiency or on chronic steroids), namely:
Bottom Line:
For severe bacterial pneumonia and septic shock, ED physicians should feel comfortable administering a dose of hydrocortisone 50mg IV as hydrocortisone 200mg/day is an accepted regimen for these disease processes.
For patients with ARDS who remain boarding in the ED, EM docs should discuss initiation of steroids with their intensivists, whether the institutional preference is for dexamethasone 20mg IV (per DEXA-ARDS) [6] or methylprednisolone 1mg/kg/day (per Meduri)[7].
Noninvasive Ventilation for Preoxygenation
Background: Sepsis remains a common entity associated with a relatively high rate of inpatient mortality, with timely recognition and treatment being key to improving patient outcomes. Various screening and warning scores have been created to attempt to identify sepsis and those patients at high risk of mortality earlier, but have limited performance because of suboptimal sensitivity and specificity.
A prospective observational study compared the performance of a variety of these scores (SIRS, qSOFA, SOFA, MEWS) as well as a machine learning model (MLM) against ED physician gestalt in diagnosing sepsis within the first 15 minutes of ED arrival.
Although not without its limitations, this study highlights the importance and relative accuracy of physician gestalt in recognizing sepsis, with implications for how to develop future screening tools and limit unnecessary exposure to unnecessary fluids and empiric broad spectrum antibiotics.
Bottom Line: In the era of machine learning models and AI, ED physicians are not obsolete. Even at 15 minutes, without lab results and diagnostics, our assessments lead to appropriate diagnoses and care. In this new normal of prolonged wait times and ED boarding, ED triage and evaluation models that optimize early physician assessment are of the utmost importance.
Magnesium is known to relax smooth muscles. Interestingly, there is also some literature using it as part of Rapid Sequence Intubation (RSI) pre-treatment in general, in hopes that this or other mechanisms might allow it to improve intubating conditions. Zouche et al recently published an RCT looking at giving IV magnesium as part of RSI pretreatment in cases where neuromuscular blockade (NMB) is not going to be given (e.g. scenarios where it is contraindicated). IV Magnesium Sulfate, 50 mg/kg in 100 mL of saline given 15 minutes before induction, significantly improved intubating conditions in those getting sedation but not NMB (95% vs 39%).
In 2013, Park et al did an RCT giving magnesium to all RSIs, even with the use of rocuronium in those patients, arguing that magnesium is also known to potentiate the effects of non-depolarizing NMB agents. They also found better intubating conditions in the magnesium patients.
In both trials, magnesium was associated with lower heart rates and less hypertension in the peri-intubation and immediate post-intubation periods (of note: high dose magnesium is known to be associated with lower blood pressures, and can induce overt hypotension). Neither study was really powered for more important measures like first pass success, mortality, or important side effects like peri-intubation hypotension.
Bottom Line: These are two small trials, and while more abundant literature should probably be obtained before we change our practice, one could consider giving magnesium sulfate, 50 mg/kg in 100 mL saline, prior to intubation in an attempt to improve intubating conditions. In my opinion, this is probably worth considering in the rare circumstance that your patient has a true contraindication to neuromuscular blockade, but I probably wouldn't start doing this in standard RSI where you're going to be giving NMB until more literature confirms the safety of this approach. Also, I would avoid this in situations where the patient is already hypotensive or at high risk of peri-intubation hypotension. This may be worth considering in the very rare patient you're not necessarily going to give NMB to right away (maybe awake fiberoptic intubations?) who are also very low risk for hypotension.
Title: Antipsychotics in the Treatment of Delirium in Critically Ill Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
We all do it. When our patients in the ICU develop delirium, we would give them an antipsychotic, commonly quetiapine (Brand name Seroquel), and all is good. However, results from this most recent meta-analysis may suggest otherwise.
Settings: This is a meta-analysis from 5 Randomized Control Trials. Intervention was antipsychotic vs. placebo or just standard of care.
Participants: The 5 trials included A total of 1750 participants. All trials used Confusion Assessment Method for the ICU or Intensive Care Delirium Screening Checklist to measure delirium.
Outcome measurement: Delirium – and Coma-Free days
Study Results:
The use of any antipsychotic (typical or atypical) did not result in a statistically significant difference in delirium- and coma-free days among patients with ICU delirium (Mean Difference of 0.9 day; 95% CI -0.32 to 2.12).
Similarly, atypical antipsychotic medication also did not result in difference of delirium- and coma-free days: Mean difference of 0.56 day; 95% CI -0.85 to 1.97).
ICU length of stay was also not different in the group receiving antipsychotic: Mean difference -0.47 day, 95% CI -1.89 to 0.95).
Discussion:
The authors used both delirium -free and coma-free days as a composite outcome because they reasoned that delirium cannot be evaluated in unresponsive patients. This composite outcome might have affected the true incidence of delirium and the outcome of delirium-free days.
This meta-analysis would be different from previous ones that aimed to answer the same question. Previous studies compared either haloperidol vs a broader range of other medication (atypical antipsychotic, benzodiazepines) (Reference 2) or included all ICU patients with or without delirium who received haloperidol vs. placebo (Reference 3). Overall, those previous studies also reported that the use of haloperidol has not resulted in improvement of delirium-free days.
Conclusion:
There is evidence that the use of anti-psychotic medication does not result in difference of delirium- or coma-free days among critically ill patients with delirium.
Many patients present to the ED with hypercarbic respiratory failure (i.e. COPD exacerbation, obesity hypoventilation syndrome etc.). Typically, our first line of treatment is the use of BiPAP, where we set an inspiratory pressure (IPAP) and an expiratory pressure (EPAP). The difference between these two pressures (as well as patient effort) determines the tidal volumes (and consequently minute ventilation) a patient receives in our attempts to help the patient “blow off CO2.”
If you are having trouble with continued hypercarbia despite the use of BiPAP, another NIPPV mode that can be trialed is Average Volume-Assured Pressure Support (AVAPS). With BiPAP the patient receives the same fixed IPAP no matter what, even if their tidal volumes are lower than what is needed. With AVAPS, the ventilator will self-titrate the IPAP and increase (or decrease) the IPAP to reach the tidal volumes that you set, increasing the odds the patient will achieve the minute ventilation you are trying to achieve.
(AVAPS is essentially a non-invasive version of PRVC)
Initial settings (ask your RTs for help!):
This really interesting study suggests that the classic site of CPR “in the middle of the chest” may actually not be the ideal place to perform CPR. Previous imaging studies demonstrate that the ventricles are primarily beneath the lower third of the sternum and that standard placement of CPR compressions may deform the aortic valve, blocking the LVOT, and theoretically limiting perfusion of the coronaries and brain.
This study compared a standard CPR group with those undergoing TEE-guided chest compressions to avoid aortic valve compression. Those in the non-AV compression group had significantly increased likelihood of ROSC, survival to ICU, and higher femoral arterial diastolic pressures. However, there was no difference in long-term outcomes or end-tidal CO2.
Summary: Avoiding AV compression during CPR significantly improved the chance at ROSC in adult OHCA, but this small observational study did not show any difference in long term outcomes when compared to standard practice. Lowering the point of chest compressions in CPR to the lower third of the sternum may be beneficial.
Historically, guideline recommendations have been to use a transfusion threshold of hemoglobin < 7 g/dL for patients unless they are a) undergoing orthopedic surgery or b) have cardiovascular disease (CVD).
Applefeld et al conducted a meta-analysis in 2018 which suggested that restrictive (i.e. lower hemoglobin trigger, typically 7-8) transfusion targets lead to worse outcomes in CVD patients than liberal (i.e. higher hemoglobin trigger, typically 9-10) targets, and those authors have updated this analysis to include data from newer trials. Interestingly, the conclusion remains similar: that when you look at the larger studies on restrictive vs liberal transfusion targets, CVD plays an important role, as patients with CVD tend to do better with liberal targets, and patients without CVD tend to do better with restrictive targets. Of note, CVD is variably defined in these studies, and sometimes limited only to active Acute Coronary Syndromes, and other times refers to all patients with acute or chronic CVD. However, according to their analysis, the aggregated data suggests that we should continue having higher transfusion targets in patients with CVD, and perhaps even more in the 9-10 range, as opposed to the goals of 7 or 8 which are common.
Bottom Line: We will likely continue to see different transfusion targets recommended for patients with cardiovascular disease (CVD), and may even see guideline and blood bank recommendations raise the target for these patients more into the 9-10 range, or expand this group to include chronic CVD. This would mean a substantial increase in recommended RBC transfusions, and as emergency physicians it is important for us to monitor these recommendations, especially since transfusions are not harmless and raising hemoglobin thresholds could lead to complications that are difficult to measure in the literature.
