UMEM Educational Pearls - Critical Care

Background: The use of steroids in pneumonia has long been controversial with conflicting data, and the recent ESCAPe randomized controlled trial by Meduri et al. showing no mortality benefit with their use, but likely underpowered due to recruitment issues. The recently published CAPE COD study by Dequin et al. may change the game.

Design: Double-blind, placebo-controlled, multicenter, RCT

• 31 hospitals in France, 2015 to March 2020
• Adults with severe (P:F <300 on 50% FiO2 or NRB, mechanical ventilation, or pulmonary severity index >130) CAP (+symptoms and imaging)
• Notable exclusion criteria: vasopressors, aspiration-related, influenza, chronic steroids (equiv to >15mg prednisolone)

Intervention: Early hydrocortisone within 24 hrs, 200mg/day x 4-8 days depending on improvement, then preset taper

• 800 patients: 401 hydrocortisone, 399 placebo

Primary outcome:  Death at 28 days

• Hydrocortisone 6% vs Placebo 12% (p = 0.006)

Secondary outcomes:

• Death at 90 days: Hydrocortisone 9.3% vs placebo 14.7%
• Decreased cumulative incidence of endotracheal intubation by day 28 (if not initially intubated)
• Decreased cumulative incidence of vasopressor initiation by day 28
• Higher median daily dose insulin in hydrocortisone group
• No difference in rate of hospital acquired infections or GIB

Bottom Line:  The addition of hydrocortisone to antibiotics in severe CAP may decrease need for intubation and development of shock, and in this well-done study, decreased 28 and 90-day mortality. 

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The classic teaching is that patients with acute pancreatitis should be aggressively hydrated with IV fluids.  But as we increasingly question heavy handed fluid strategies in other areas such as sepsis, should we look at pancreatitis management too?

Li et al did a systematic review of the literature on aggressive fluid resuscitation (the exact protocol/definition varied per study, but we're mostly talking 15-20 mL/kg boluses followed by 3-5 mL/kg/hr infusion) vs less aggressive fluid resuscitation (mostly 10 mL/kg boluses followed by 1.5 mL/kg/hr infusion).  They found that aggressive resuscitation worsened mortality in severe pancreatitis (RR 2.45) and trended towards worse mortality in non-severe pancreatitis (RR 2.26, but CI crossed 1).  Aggressive was associated with more complications in both severe and non-severe pancreatitis pancreatitis.

Multiple society guidelines still call for aggressive IVF resuscitation for acute pancreatitis, but probably need to be updated given mounting evidence that this is harmful.  More recent guidelines suggest "goal-directed therapy", but no one is completely sure what that means.  

Bottom Line:  In acute pancreatitis, a more conservative empiric IVF resuscitation is probably better than the clasically taught aggressive approach.  Whether even less fluids would be better or worse is not known, but for now it's probably best to stick to a 10 mL/kg bolus and 1-2 mL/kg/hr infusion when ordering fluids for these patients unless you have another indication.

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Things to Consider for Persistent or Worsening Septic Shock

• Septic shock is one of the most common critical illnesses in emergency medicine and critical care.
• Norepinephrine is recommended as the initial vasopressor of choice for patients with septic shock, with vasopressin or epinephrine commonly added as a second vasopressor for patients with refractory shock.
• While vasopressors are being added and titrated, it is important to consider additional diagnoses in patients with worsening or persistent septic shock.  Some of these diagnoses include:
  • Undetected infection that requires emergent source control
  • Concomitant causes of shock: cardiogenic, PE, abdominal compartment syndrome, tamponade, adrenal insufficiency
  • Severe acidosis
  • MAP underestimation by a radial arterial line

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Title: Electrocardiographic Changes at the Early Stage of Status Epilepticus: First Insights From the ICTAL Registry.

As the song goes: “the thigh bone is connected to the hip bone, the hip bone is connected to the back bone.” It turns out that the brain electrical activities are also connected to the heart conduction activities.

In a multi-center (23 French ICUs) retrospective analysis of 155 critically ill patients with status epilepticus, ECGs were done within 24 hours of onset of status epilepticus, and were independently reviewed by cardiologists showed abnormalities in 145 (93.5%) of patients.

Below is a list of events that occurred more than 10% of events.

Abnormal rate (<60 or > 100 beats/min         64 (44%)

Negative T-waves                                           61 (42%)

Flattened T-waves                                           18 (12%)

ST elevation                                                    24 (16.6%)

ST depression                                                 26 (17.9%)

Left axis deviation                                          22 (15.9%)

Discussion:

Major ECG abnormalities were not associated with 90-day functional outcome in multivariable logistic regression.

The brain-heart axis could be affected by antiseizure medication. For example, phenytoin, lacosamide are sodium channel blockers while benzodiazepines, propofol, barbiturates with their GABAnergic effects will also display cardiac side effects.  This current study was not able to tease out whether the cardiac effects were from medication. Therefore, further studies are needed to figure out the cardiac effect for patients with status epilepticus.

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Background: 

There have been a few studies that suggested that there may be some neuroprotective effect with a higher MAP goal in post-arrest patients. However, these studies were small and/or observational. 

Intervention:

-The BOX trial was a double-blind, dual-center (Denmark), randomized trial 

-Study population: >18 yo, OHCA of presumed cardiac cause

-Pts randomized to higher (77 mmHg) vs. lower (63 mmHg) MAP goal

-double-blinded by attaching a module that reported a BP that was 10% higher or lower than the pt’s actual BP

-Notable exclusion criteria:

-unwitnessed asystole or suspected intracranial bleeding/stroke

Results/Primary outcome:

-No sig difference in composite of death + Cerebral Performance Category of 3 or 4  (3= severe disability, 4= coma) within 90 days

-133 patients (34%) in the high-target group vs 127 patients (32%) in the low-target group (hazard ratio, 1.08;95%CI, 0.84 to 1.37; P=0.56)

Caveats/Takeaways:

-Mean difference in BP was 10.7 mmHg (95[CI], 10.0 to 11.4) which is still relatively clinically significant, but was lower than their goal difference of 14 mmHg

-They used IVF to target a CVP of 10 mmHg prior to initiation of norepi and used dopamine "if necessary"

-Consider generalizability given study population was patients with presumed cardiac cause of arrest

-Keeping a lower MAP goal of >65 mmHg is reasonable in post-arrest patients

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Given my previous post on APRV (11/6/2022) and while I take issue with many of the author's statements, I wanted to share a very well referenced article with an excellent discussion on the current gaps in the knowledge around APRV and its use.

One statement I do agree with is the need for a well-designed and adequately powered trial of this mode in an admittedly difficult-to-study population.

Fortunately, this article has an invited rebuttal pending from Dr. Habashi which I am sure will appear in the Educational Pearls in short order. 

Good luck to the residents on the ITE!

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Sympathetic Crashing Acute Pulmonary Edema (SCAPE) (also known as flash pulmonary edema) is an extreme form of hypertensive acute heart failure where a surge of high blood pressure from catecholamine surge and sudden vascular redistribution causes sudden onset decompensated heart failure hallmarked by rapid pulmonary edema and symptoms of hypoxia and dyspnea.

This is treated by systolic blood pressure control and venous vasodilation with IV nitroglycerine, bilevel positive airway pressure (BPAP), and diuretics if needed. A common error in treatment is administration of the traditional IV nitroglycerine infusion dosing protocol in which the nitroglycerine infusion is started at 5 mcg/min and slowly increased by 5 mcg/min increments until the clinical response is seen. However, in this syndrome, rapid blood pressure control and correction of vascular redistribution is critically important to reverse the central factor for patient decompensation. Lack of blood pressure control places the patient at risk of further cardiac decompensation or respiratory failure ultimately requiring intubation.

Increasing literature has been published on the concept of high dose or push dose IV nitroglycerine for the treatment of this syndrome. Many of these studies show decreased rates of intubation, decreased ICU admissions, and shorter hospital length of stays with high dose or push dose nitroglycerine, while also demonstrating low risk of hypotension.

The actual dose of the high-dose nitroglycerine administered in these trials is variable, with some trials administering nitroglycerine 1-2 mg IV pushes every 3-5 minutes, and other trials using a nitroglycerine infusion at a much higher starting rate (between 200-400 mcg/min) with rapid down-titration as blood pressure is controlled.

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Question

Background: The use of sodium bicarbonate in the treatment of out-of-hospital cardiac arrest (OHCA) has been longstanding despite conflicting data regarding its benefit, outside of clear indications such as toxic ingestion or hyperkalemic arrest.

Study: A recent retrospective cross-sectional study by Niederberger et al.¹ examined prehospital EHR data for ALS units responding to nonpregnant adults with nontraumatic OHCA, noting use of prehospital bicarb and the outcomes of 1) ROSC in the prehospital encounter and 2) survival to hospital discharge. They created propensity-matched pairs of bicarb and control patients, with a priori confounders: age, sex, race, witnessed status, bystander CPR, prearrival instructions, any defibrillation attempt, use of CPR feedback devices, any attempted ventilation, length of resuscitation, number of epi doses.

There were 23,567 arrests (67.4% asystole, 16.6% PEA, 15.1% VT/VF), 28.3% overall received sodium bicarb. 

Results: 

In the propensity-matched sample, survival was higher in bicarb group (5.3% vs. 4.3%; p=0.019).

• Asystole (bicarb 3.3 vs 2.4%; p = 0.020)
• PEA (bicarb 8.1% vs 5.4%; p=0.034)

There were no differences in rate of ROSC overall, but looking at the different rhythms, ROSC was higher in the bicarb group with asystole as the presenting rhythm (bicarb 10.6 vs 8.8%; p=0.013) but not PEA or VT/VF.

*There is no indication by the authors as to the dosing of bicarb most associated with survival to hospital discharge (or ROSC in asystole) in the study, however a previous study has indicated that a single amp of bicarb is unlikely to significantly improve severe metabolic acidosis (pH <7.1),² so the general recommendation of at least 1-2mEq/kg should be employed.

Bottom Line: The use of sodium bicarb may increase survival in OHCA with initial PEA/asystole. The recommended initial dose is 1-2mEq/kg; giving at least 2 amps of bicarb (rather than the standard 1) should achieve this in many patients.

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When managing a hypotensive patient who may have some element of cardiogenic shock, it has long been debated whether it is better to start an inodilator like dobutamine, and use a true vasopressor like norepinephrine to offset the vasodilation, or start an inopressor like epinephrine.  Currently, this is largely a practice pattern issue, with different providers and specialties tending to make different choices (in my anecdotal experience, medical intensivists tend to do norepi+dobutamine, whereas cardiac surgeons and intensivists tend to use epi).  

Banothu et al recently studied this question in children with "cold" septic shock (they do not specify how this was defined) and found quicker time to resolution of shock with norepi+dobutamine vs epinephrine.  It should be noted that this was a secondary outcome, was a small study, was in children (who I'm told are not just little adults), and no difference in mortality or patient oriented outcomes was found.  However, this is a good opportunity to review what is known on this topic:

-A small RCT in Lancet 2007 by Annane et al found no difference

-A very small RCT in Acta Pharmacologica Sinica 2002 by Zhou et al suggested norepi-dobutamine has favorable effects on gastric mucosa and tissue oxygenation relative to epi or dopamine

-A small RCT in Intensive Care Medicine 1997 similarly suggested that oxygenation in the splanchnic circulation may be better with norepi+dobut than epi.

Take Home: There is very limited evidence in either direction when choosing between an inodilator + vasopressor (e.g. norepi + dobutamine) vs single inopressor (e.g. epi) strategy for a hypotensive patient in which inotropy is desired.  There is some weak evidence that norepi + dobutamine may be better for maintaing gut oxygenation and may resolve shock faster.  Personally, I would weakly recommend norepi + dobutamine over epinephrine, but continuing to follow provider preference and go with the agent(s) you're most comfortable with is also very reasonable.  If using the inodilator/vasopressor combination, it is recommended to titrate the vasopressor (e.g. norepi) to MAP and inodilator (e.g. dobutamine) to a measure of cardiac function such as CO/CI.  

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An Uncommon Cause of Shock

• Sepsis is the most common cause of distributive shock encountered in the emergency department and intensive care unit.
• Notwithstanding, it is important to consider other etiologies of shock, especially when the patient is not responding to resuscitation.
• Adrenal crisis is one uncommon etiology of distributive shock whereby the diagnosis is often delayed.
• Risk factors for adrenal crisis can include recent GI illness, thyrotoxicosis, recent surgery, and physical or psychological stress.
• Patients often have nonspecific symptoms of generalized weakness, abdominal pain, vomiting, fever, and altered mental status.
• Current guidelines recommend the administration of 100 mg of hydrocortisone in adults suspected of having adrenal crisis.   

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Title:

The Impact of Thoracic Ultrasound on Clinical Management of Critically Ill Patients (UltraMan): An International Prospective Observational Study

Settings: 4 hospitals (3 in Netherlands and 1 in Italy)

Participants: All adults patients who were admitted to the ICU but patients who died within 8 hours of thoracic ultrasound were excluded.

Thoracic ultrasound procedure: cardiac, lung, diaphragm, inferior vena cava. The main indicators were Respiratory, Cardiac and Volume status.

Study Results:

725 thoracic ultrasound examinations and 534 patients.  Clinical management occurred in 247 (88.5%) patients within 8 hours of ultrasound.

Thoracic ultrasound was performed by 111 operators, ranging from inexperienced to very experienced.

Common findings from thoracic ultrasound among these ICU patients.

• Atelectasis 233 (32.1%)
• Pleural effusion 221 (30.5%)
• Pulmonary edema 120 (16.6%)
• Pneumonia 107 (14.8%)

Discussion:

• There was a major impact in fluid management.
  • Patients who needed more fluid (N=63) would have a balance of +907 ml within 8 hours.
  • Patients who need euvolemia (N = 28) would have a balance of +80ml within 8 hours.
  • Patients who need less fluid (N=45) would have a balance of -411ml within 8 hours.
• There was no information regarding management change according the experience of the operators.
• The authors did not assess patient-centered outcomes from these management changes.

Conclusion: Thoracic ultrasound provided a significant change in management of critically ill patients.

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Thrombolytic-induced angioedema is a known complication of alteplase or tenecteplase administration, occurring in 0.9-5.1% of patients who received thrombolytics due to ischemic stroke. Angioedema occurs due to activation of the kinin and complement pathway by plasminogen, leading to both bradykinin and histamine release.

Swelling most commonly occurs acutely while the t-PA is infusing, but can have a delayed presentation up to 24 hours post administration. It normally has an orolingual distribution, although in severe cases there can be laryngeal involvement as well. There is a 4-fold-increase occurrence in patients who take ACE inhibitor medications ^[1] with some studies noting a high prevalence in strokes involving the right insular brain region ^[2].

Once identified, the t-PA infusion should be immediately discontinued. As there may be histamine involvement in angioedema formation, patients are initially treated with steroids, H1, and H2 blockers with as needed epinephrine injections.

Given the orolingual predominance, airway obstruction must be ruled out and the patient closely monitored with emergent intubation performed if necessary.

As the kinin pathway (bradykinin) appears to play the largest role in angioedema formation, C1 esterase inhibitors and bradykinin inhibitors can be used in severe or refractory cases ^[3,4].

However, most cases are mild and resolve with t-PA discontinuation and the initial steroid and histamine blockade.

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Although extubation has historically been the purview of critical care, as ED lengths of stay continue to worsen, and as we see more and more rapidly reversible respiratory failure (e.g. opioid overdose), it is valuable for ED providers to be facile in extubating patients.  In addition, a longstanding debate in critical care has revolved around the proper device to extubate patients to, specifically: regular nasal cannula (NC) vs high flow nasal cannula (HFNC) vs noninvasive positive pressure ventilation (NIPPV).  Although data are mixed, the literature suggests extubation to HFNC or NIPPV may reduce risk of reintubation, esspecially in patients at a high risk of reintubation, but doesn't show a clear difference between HFNC and NIPPV.  

Hernandez et al recently conducted an RCT in two Spanish ICUs looking at HFNC vs NIPPV upon extubation for high risk patients.  NIPPV was associated with a lower reintubation rate (23%) as opposed to HFNC (39%).  Hospital LOS was also shorted in the NIPPV group, but no other differences were observed.  

It should be noted that this study, and pretty much the entirety of this literature base, is in ICU patients.  In fact, in this study, patients were excluded if they were intubated less than 24 hours.  Generally speaking, patients with shorter intubation tend to be lower risk for reintubation and other post-extubation negative outcomes, so I would use caution extrapolating this too much to the ED.  Unfortunately however, there is very limited literature to guide ED extubation practices.  

Bottom Line:

1) Know how to assess readiness for extubation and consider extubation in the ED if they meet  criteria

2) For patients at higher risk of reintubation (older, sicker, CHF, COPD, obesity, airway issues) who you are considering extubating, you may wish to extubate them to Noninvasive Positive Pressure Ventilation, even though there is little solid literature showing best practices in terms of post-extubation respiratory support in the ED.

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Transcutaneous Cardiac Pacing

• Transcutaneous cardiac pacing (TCP) is often attempted while preparing for transvenous cardiac pacing in critically ill patients with symptomatic bradycardia unresponsive to medical therapy.
• For TCP, pacer pads can be placed in either the anterolateral (AL) or anteroposterior (AP) positions.  
• Current resuscitation guidelines from the American Heart Association and the European Resuscitation Council do not identify a preferred pacer pad placement for TCP.
• In a recent study of patients who received TCP following cardioversion from atrial fibrillation or flutter, Moayedi and colleagues found that pacer pads placed in the AP position required less mA to capture and chest wall contractions were less severe when compared to the AL position.
• In fact, capture was approximately 80% more likely with pacer pads placed in the AP position compared to the AL position.
• Take Home Point: Consider placing the pacer pads in the AP position the next time you need to initiate TCP.

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This was a cross-sectional survey for the Diversity-Related Research Committee of the Women in Critical Care (WICC) Interest Group of the American Thoracic Society.

Settings: 62 sites in Canada and the US

Participants: Attending physicians who worked in ICUs

Questionaire:

·         Measure of Moral Distress for healthcare professionals (27 items),

·         Maslach burnout inventory (2 items),

·         Stanford Professional Fulfilment Index (14-items), Brief Cope scale (14-items)

Study Results:

1.       Demographics:

·         431 participants (approximately 43.3% response rate).

·         334 (65%) participants worked at University-affiliated hospitals

·         387 (89.0%) worked in Adult ICUs.

·         Pre-pandemic, clinical days/months was 10.1 (± 14) days, and increased to 13.1 (± 16) days during the pandemic.

2.       Measure of moral distress: Average score 95.6 ± 66.9 (maximum 417).

·         The highest score (mean 8.5 ± 4.8), for distress, came from the item: “Follow the family insistence to continue aggressive treatment even though it is not in the best interest of the patient.” ((Family wanted to do everything).

3.       Stanford Fulfillment Index:

·         387 (91.9%) intensivists found their work meaningful and 365 (86.5%) felt worthwhile at work, although most felt physically (297, 71.6%), emotionally (266 [63.8%]) exhausted.

4.       Coping strategies:

·         Participants resorted to a wide variety of scoping strategies ranging from Acceptance (90%), Self-distraction (85%) to Substance abuse (32%) and Denial (18%).

·         Most physicians (231 [55.9%]) reported that their coping remained the same before and during the pandemic.

Discussion:

·         Physicians are quite resilient. The authors found that physicians who worked more days experienced significantly more moral distress but with similar Stanford Professional Fulfillment score.

·         This finding was similar to an exploratory analysis from a meta-analysis that showed physicians, among other healthcare workers, were less likely to have severe symptoms of PTSD (2).

·         Women and physicians who were persons of color experienced significantly higher moral distress and burn-out.

Conclusion:

There was moderate moral distress and burn-out, although physicians who worked in ICUs still achieved moderate professional fulfillment.  Up to 20% of ICU physicians used a maladaptive coping strategy

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DOSE VF (DOuble SEquential External Defibrillation for Refractory VF) Trial 

Background - High quality data regarding the use of double sequential external defibrillation (DSED) and vector-change (VC) defibrillation in refractory vfib is limited

Study

-Three-group, cluster-randomized, controlled trial in six Canadian paramedic services

-Study population: 

-OHCA with refractory vfib (initial presenting rhythm of vfib or pulseless VT that was still present after three consecutive rhythm analyses and standard defibrillations separated by 2 minute intervals of CPR) of presumed cardiac etiology (405 patients)

-Some notable exclusion criteria: 

-suspected drug overdose, hypothermia, traumatic cardiac arrest

-Protocol:

-First 3 defib attempts in the standard (anterior-lateral) position

-If remained in vfib after three consecutive shocks randomized to one of:

1. Standard defib for all subsequent attempts (136 pts)

2. VC defib (all subsequent attempts in anterior-posterior position) (144 pts)

3. DSED (applied second set of pads in AP position) with near simultaneously (<1 sec) defib shocks (125 pts)

Results

-Primary outcome: survival to hospital discharge

-38 patients (30.4%) in the DSED group vs. 18 (13.3%) in the standard group (RR 2.21; 95% CI, 1.33 to 3.67) (Fragility index of 9)

-31 patients (21.7%)  in the VC group (RR [vs. standard], 1.71; 95% CI, 1.01 to 2.88) (Fragility index of 1)

-Notable secondary outcome: survival with a good neurologic outcome

-34 patients (27.4%) who received DSED vs. 15 patients (11.2%)  with standard defibrillation (RR, 2.21; 95% CI, 1.26 to 3.88)

Takeaways/Caveats:

-68% of arrests witnessed, 58% received bystander CPR, median response time of 7.4-7.8 min

-Did not reach planned sample size 2/2 COVID pandemic

-No reporting of post-arrest care (e.g. TTM, PCI)

-Overall rates of survival and good neuro outcome on the higher side even with standard of care

-More/larger studies needed, but can consider DSED for refractory vfib, particularly if you are in a setting without more advanced circulatory support/resources

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Airway Pressure Release Ventilation (APRV) is an "advanced" mode of mechanical ventilation that has long been considered a "rescue" mode of ventilation and has recently garnered much more attention during the COVID pandemic.  Given the long boarding times of critical care patients in the ED with widespread improvement in sight, I wanted to send out some great resources that have come out recently delineating the difference in thought process between APRV as a "rescue" mode and as a "primary" mode.

Rory Spiegel of EMNerd and former UMMC CCM fellow has recently given a great talk on APRV and its use as a rescue mode of ventilation. See also Phil Rola's recent paper listed on that webpage.

https://emcrit.org/emcrit/aprv-for-lung-rescue/

APRV as a primary mode of ventilation has been used in the STC for years and is often referred to in the literature according to the basic ventilatory philsophy called Time Controlled Adaptive Ventilation. I realize this may be heresy to some and perhaps a curiousity to others. I recommend you take some time to peruse the following resources:

1. Dr. Habashi has done a great deal of work in the basic and translation literature on APRV and TCAV. His recent review dispels many myths and concerns surrounding APRV

Myths and Misconceptions of Airway Pressure Release Ventilation: Getting Past the Noise and on to the Signal - https://www.frontiersin.org/articles/10.3389/fphys.2022.928562/full

2. The TCAV Network has great resources for those who want to do a deeper dive into this topic. 

https://www.tcavnetwork.org/

(Can also find their recommended protocols at the Multi Trauma Critical Care education website: https://stcmtcc.com/handouts/)

Attachments

2211021655_fphys-13-928562_(2).pdf (5,575 Kb)

2211021655_Standard_Settings_for_APRV_using_the_TCAV_Method.pdf (1,525 Kb)

2211021655_APRV_TCAV_Rescue_Strategy_Strategy_Guidelines_2020.pdf (1,614 Kb)

Question

Arterial line waveform interpretation and troubleshooting are essential skills for any physician caring for critically ill patients. Overdamping and underdamping of the arterial line waveform leads to inaccurate systolic and diastolic blood pressure readings which can lead to unidentified hypertension or hypotension. In addition to scrutiny of the arterial waveform pattern, the square-wave test is a tool to identify overdamped or underdamped arterial lines. 

Overdamped arterial waveforms will underestimate systolic blood pressure and overestimate diastolic blood pressure. Underdamping will have the opposite effect and overestimate systolic blood pressure and underestimate diastolic blood pressure. In both cases, the mean arterial pressure (MAP) often remains the same.  

The square-wave test is a rapid flush that is applied to the arterial line for approximately 1 second. This rapid high-pressure surge results in vibration and oscillation of the arterial catheter. These oscillations are then read by the pressure transducer and the number and amplitude of these oscillations can be measured. 0 or 1 oscillations is suggestive of overdamping. 3 or more oscillations is suggestive of an underdamped system. 

Major causes of an overdamped arterial line waveform include low infusion bag pressure, loose connectors, air bubbles in the tubing, blood clot in the circuit, or kinking of vascular catheter. An underdamped arterial line, however, is caused by overly stiff circuit tubing or a defective transducer.   

Scrutiny of the arterial waveform and utilization of the square-wave test can be helpful to both identify erroneous arterial line blood pressure readings as well as suggest likely corrective measures.  

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Attachments

2210242137_Arterial_line_overdamped_and_underdamped_examples.jpg (112 Kb)

Emergency physicians are familiar with posterior reversible [leuko]encephalopathy syndrome as an entity associated with untreated hypertension. It also happens to be a well-documented entity amongst solid organ transplant patients.  

While the exact pathophysiology remains unclear, PRES is characterized by posterior subcortical vasogenic edema due to blood-brain barrier disruption, usually in the setting of elevated blood pressure with loss of cerebral autoregulation and/or endothelial dysfunction.

The immunosuppressants used in this population, namely calcineurin inhibitors (CNI) such as tacrolimus and cyclosporine, are thought to contribute most to this endothelial dysfunction and development of PRES in transplant patients, although high-dose corticosteroids, ischemia-reperfusion injury during surgery, and antibiotics have also been implicated. 

Presentation of PRES post-transplant:

Clinical symptoms:

• Seizures (75-85%)
• AMS - confusion/somnolence (30-40%)
• Headache (25-50%)
• Vision disturbance (20-40%)

Time course:

• Within weeks to a year posttransplant, rarely after a year
• Rapid onset once it starts, can develop over hours to days

Diagnostics:

• Labs nonspecific, although supratherapeutic CNI levels are often associated with:
  • Acute renal injury
  • Hyperchloremic metabolic acidosis
  • Hyperkalemia
  • Hypomagnesemia
  • Hypercalciuria
• Thoughts on checking FK506 (tacrolimus) levels
  • For transplant patients, usually advise only checking troughs (~12 hrs after last dose)
  • A low random level may rule out CNI toxicity but not PRES
  • A high random level isn't really helpful
• MRI is diagnostic modality of choice >> subcortical edema, usually bilateral, symmetric, in parieto-occipital regions

Management:

1. Stabilization via supportive care – seizure, cerebral edema, BP management as applicable, etc.
2. Withdrawal/holding of offending agent – will require consultation with transplant physician and pharmacist usually by inpatient team
   • Mixed data re: use of CYP-inducers to lower CNI levels in CNI toxicity

Bottom Line: 

Patients with a history of solid organ transplant are at risk for PRES. While ED stabilization of these patients remains the same, recognition of PRES as a potential etiology for a transplant patient's presentation is crucial to proceed with important testing and necessary changes to their immunosuppressive regimen. 

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Needless to say, therapeutics for COVID-19 pneumonia have been controversial.  From hydroxychloroquine to ivermectin to remedesivir to steroids to bleach (sorry, but it had to be said...),  it depends on who you ask whether medications make a difference in COVID, how much of a difference, when they should be given, and what the correct dose is. 

Dexamethasone, however, ala the RECOVERY trial, is one of the relatively few therapies supported by the majority of the literature and guidelines, and generally is recommended when respiratory support is required for COVID-19 pneumonia.  Further add to this that steroids for ARDS is a long-running point of critical care controversy (e.g. DEXA-ARDS, Meduri, etc), and all you need to say to an intensivist is "how much steroid should I give this patient?" and you can walk away and come back 10 minutes later to find them having not noticed you had ever left.

Wu et all did a fairly small (n=107) single-centered RCT looking at dexamethasone 6 mg daily vs dexamethasone 20 mg daily for COVID-19 requiring O2.  There are several notable limitations to this study, but in short it did NOT add support to the notion that higher dose dexamethasone is a good thing for COVID-19 pneumonia.  In fact, the 20 mg group trended towards worse outcomes.  Small sample size, single-center, limited follow up, variable use of biologics between the groups, and failure to investigate intermediate doses between 6 and 20 are all significant limitations of this trial. Of note, DEXA-ARDS, which was conducted before COVID (2013-2018), looked at 20 mg x 5 days followed 10 mg x 5 days and DID find a significant benefit, as well as pretty darn good NNT and p values (and was a higher quality trial), so in my opinion it is also not unreasonable to use DEXA-ARDS dosing if the patient meets moderate-severe ARDS (P:F < 200) criteria, even though of course DEXA-ARDS was before COVID and Wu et al slightly contradicts it. 

When faced with a very sick COVID-19 pneumonia patients many intensivists will do either RECOVERY or DEXA-ARDS dexamethasone (with relatively limited basis to choose one vs the other), and some will do Meduri protocol methylprednisolone (1-2 mg/kg/day).  Relatively few nowadays will omit steroids unless there's a contraindication.

Bottom Line: It probably remains a good idea to give dexamethasone to your COVID-19 pneumonia patients with hypoxia, but you can probably stick to RECOVERY (see reference below; 6 mg daily x 10 days) dosing as opposed to higher doses.  If they're REALLY sick (P:F < 200), consider DEXA-ARDS (20 mg x 5 days followed by 10 mg x 5 days) dosing.