Ang II: A Real Addition to the Critical Care Armamentarium or Just Another “Me Too” Vasopressor?

First, let me start by apologizing for the 7 month delay between blog posts.  It turns out that keeping up a blog is more work than I anticipated, and I have failed in keeping it up to date – epic failure.

So, in my first blog post in more than half a year, I thought I would write some comments on Angiotensin II (Ang II).  As many have seen, this new vasopressor made a bit of a splash with a NEJM publication in May of this year.

In the two decades I have been practicing medicine, we have essentially been limited to catecholamine vasopressors.  And, as much as we like to talk about the different effects of catecholamine pressors on different catecholamine receptors, the fact remains they are all still catecholamines. Continue reading “Ang II: A Real Addition to the Critical Care Armamentarium or Just Another “Me Too” Vasopressor?”

Is It Better to Have Seen and Failed or Never to Have Seen At All?

UPDATE:  The manuscript of the MACMAN study was simultaneously published in JAMA and presented at SCCM (Lascarrou JB, et al. JAMA. Published Online Jan 24, 2017).  While the peer reviewed primary results are unchanged, demonstrating that videolaryngoscopy improves the glottic view but does not improve the ability to pass the endotracheal tube compared to direct laryngoscopy, one of the secondary results deserves some mention.  It wasn’t presented in the brief late-breaker presentation at ESICM, so I hadn’t discussed it previously.  Lascarrou and colleagues also found a higher rate of severe life-threatening complications with videolaryngoscopy, namely severe hypoxemia, hypotension, and cardiac arrest.  While I am not entirely sure what to make of this finding, I do think it should cause us some pause.  If this is true (and it may just be a type 1 error that secondary analyses are prone to), then not only should we not use VL as the primary intubating device for all our intubations in the ICU, but we should think carefully about which ones we do use it for (and be selective in whom we use it in).  And, while these most recent studies have been informative on the risks and benefits of both VL and DL, there remain unanswered questions.  These studies do not include patients who the clinician believes they have to use VL for intubation, nor do they look exclusively at high risk populations such as morbid obesity or high Mallampati or MACHOCA scores.  I suspect additional studies will be forthcoming in the future and that this field will continue to evolve.  However, in the meantime, both of these most recent well-designed and conducted randomized controlled trials, make it apparent that we should not be using VL as the default intubation device in all our critically ill patients.


October 4, 2016;  08:55

In the last couple of decades, some of the biggest advances in medicine have involved technology.  The videolaryngoscopy represents one of these technological advances for assisting with endotracheal intubation.  FDA approval of devices simply requires demonstration that the device does what it claims to do, but does not require demonstration of improved outcomes or any clinical benefit. While there are a number of different videolaryngoscopes, they are all designed with a camera on the end of a laryngoscope connected to some form of a screen that displays the image the camera projects.  Numerous studies have demonstrated that videolaryngoscopes improve the view of the glottis and vocal cords (Cormack Lehane Glottic View Grade) over direct laryngoscopy during endotracheal intubation.  Some of these studies suggest that time to intubation may also be shorter using videolaryngoscope.  These data (probably combined with some allure of new technology) resulted in many opining that the videolaryngoscopy should be the standard of care for intubation in critically ill patients, and should be used in all intubations in the ICU, especially by inexperienced operators.  However, the studies providing the data supporting these recommendations were conducted in the operating room on patients undergoing intubation for surgical procedures.  And most of them studied experienced anesthesiologists as the operators.

Continue reading “Is It Better to Have Seen and Failed or Never to Have Seen At All?”

“I love sleep. My life has the tendency to fall apart when I’m awake, you know?” – Ernest Hemingway

How many times have you participated in this patient care scenario?

“My ICU patient on invasive mechanical ventilation is passing a spontaneous awakening and breathing trial, but isn’t waking up? I’m going to leave the patient intubated until he is more awake.”

Continue reading ““I love sleep. My life has the tendency to fall apart when I’m awake, you know?” – Ernest Hemingway”

How do the results of that clinical trial apply to this patient?

In the beginning, there was physiology.  Intensive care originated with the provision of invasive support for failing organs — and several decades of critical care practice were characterized by the use of increasingly sophisticated means to achieving physiologic ends.  Dobutamine and transfusion to improve systemic oxygen delivery in shock.  Mechanical ventilation to normalize PaO2 and PaCO2.  Physiology-guided critical care interventions were inherently logical and personalized.  Many improved patients’ appearance, silenced the alarming monitors, and stabilized the labsheet.  Unfortunately, a number of physiology-guided critical care interventions also killed patients1–3.  The arrival of randomized clinical trials to critical care in the mid-1990s4 heralded a new era in which the interventions provided in the ICU were placed back under the microscope with a new standard: improving patient outcomes.

The arrival of large-scale randomized trials in critical care, and the immediate recognition large trials could identify interventions capable of saving lives in the ICU1, gave rise to a novel challenge in critical care, one has persisted over the following two decades.  While physiology-based interventions apply naturally to a single patient or a small group of patients, trials require populations.  The results of any trial, therefore, require translation back from the population studied to individual patient in the ICU.

So how should one determine whether the results of a given clinical trial are likely to apply to a specific patient?  A common approach is to consider whether the patient in front of you would have been ‘eligible’ for the trial.  If the patient seems to meet the inclusion and exclusion criteria spelled out in the study methods, the intervention probably applies to them.  If not, laissez-faire.  Such an approach is encapsulated in an article in CCM this month by Dr. Ivie et al5.  In to “assess the generalizability of the most highly cited RCTs relevant to intensive care” the authors screened 93 ICU patients at two academic centers using the inclusion and exclusion criteria of 15 highly cited critical care trials.  Consistent with the author’s hypothesis, less than half of patients met criteria of any of the 15 landmark trials, largely due to not fulfilling inclusion criteria.  The authors conclude “Our work…suggests eligibility criteria used in [critical care] RCTs impose limitations on the generalizability of their findings.”

This approach misses the subtle but fundamental distinction between ‘study population’ and ‘domain’ when assessing to whom the results of a clinical trial apply.  The study population is the group of patients who are enrolled in a clinical trial – a product of the inclusion criteria (usually defining the disease of interest), the exclusion criteria (often focused on safety and targeting patients at the right amount of risk for the outcome), and the rate of ‘eligible-but-not-enrolled’ patients (patients for whom the patient, surrogates, or physician refuses participation)6.  The domain is the population of patients to whom the results of the trial apply.  These are not the same.  The study population is easy to determine…just read the methods and table 1.  The domain requires the reader to understand the study intervention, the population evaluated, and determine whether there is some physiologic reason why the same results seen in the trial would not apply in the patient in front of them.

A simple example is prisoners.  Prisoners are excluded from essentially every critical care trial for regulatory reasons.  Prisoners are therefore almost never in the study population.  But if a prisoner comes in with florid ARDS and septic shock, would the results of major ARDS and sepsis trials still apply to them?  Of course they would.  There is no physiologic difference between prisoners and non-prisoners with the same disease – and therefore, despite not being in the study population, they are in the domain…and the trial results apply.

This subtle difference between ‘study population’ and ‘domain’ has been highly problematic for the translation of critical care evidence into practice.  In 2001, the landmark ARMA trial showed that ventilation with lower tidal volume improved mortality among patients with ARDS1.  Only ARDS patients were in the study population, but a reasonable physiologic argument could be made that lung-protective ventilation would likely have the same benefit among other types of ventilated critically ill adults who didn’t meet strict ARDS criteria.  Some centers took the ‘domain’ approach and applied the ARDSNet protocol to all ventilated patients.  Others took the ‘study population’ approach and waited 15 years while the evidence was gradually expanded to support the benefit of protective ventilation among surgical patients7 and ventilated ICU patients generally8.

Of the 93 patients in the study by Ivie et al, only 4% had ARDS…but 66% were mechanically ventilated.  I would argue that the ‘domain’ of the ARMA trial alone means the results apply to at least two-thirds of the study patients…to say nothing of the other 14 trials.  There are legitimate arguments to be made that clinical trials should better deal with the patient heterogeneity inside9,10 and outside6 of the study.  But given the tremendous advances in ICU care the last 20 years have offered, I think the onus is on physicians to use the knowledge of physiology that was the original basis for critical care to determine whether there is any physiologic reason the intervention studied would have different results in your patient.  I would not discard high-quality RCT evidence based on the minutia of the inclusion and exclusion criteria.  After all, the study by Ivie et al only considered patients eligible who “were at least 18 years old…and were admitted to a participating ICU in November 2010 or July 2011”.  None of the patients in my ICU would have qualified.


  1. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342(18):1301-1308. doi:10.1056/NEJM200005043421801.
  2. Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367(2):124-134. doi:10.1056/NEJMoa1204242.
  3. Ferguson ND, Cook DJ, Guyatt GH, et al. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med. 2013;368(9):795-805. doi:10.1056/NEJMoa1215554.
  4. Bernard GR, Wheeler AP, Russell JA, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med. 1997;336(13):912-918. doi:10.1056/NEJM199703273361303.
  5. Ivie RMJ, Vail EA, Wunsch H, Goldklang MP, Fowler R, Moitra VK. Patient Eligibility for Randomized Controlled Trials in Critical Care Medicine: An International Two-Center Observational Study. Crit Care Med. October 2016. doi:10.1097/CCM.0000000000002061.
  6. Arabi YM, Cook DJ, Zhou Q, et al. Characteristics and Outcomes of Eligible Nonenrolled Patients in a Mechanical Ventilation Trial of Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2015;192(11):1306-1313. doi:10.1164/rccm.201501-0172OC.
  7. Futier E, Constantin J-M, Paugam-Burtz C, et al. A trial of intraoperative low-tidal-volume ventilation in abdominal surgery. N Engl J Med. 2013;369(5):428-437. doi:10.1056/NEJMoa1301082.
  8. Serpa Neto A, Cardoso SO, Manetta JA, et al. Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JAMA J Am Med Assoc. 2012;308(16):1651-1659. doi:10.1001/jama.2012.13730.
  9. Iwashyna TJ, Burke JF, Sussman JB, Prescott HC, Hayward RA, Angus DC. Implications of Heterogeneity of Treatment Effect for Reporting and Analysis of Randomized Trials in Critical Care. Am J Respir Crit Care Med. 2015;192(9):1045-1051. doi:10.1164/rccm.201411-2125CP.
  10. Prescott HC, Calfee CS, Thompson BT, Angus DC, Liu VX. Toward Smarter Lumping and Smarter Splitting: Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design. Am J Respir Crit Care Med. 2016;194(2):147-155. doi:10.1164/rccm.201512-2544CP.

Pulmonary “Steal” Syndrome

I wanted to share this fascinating and incredibly educational case – one where I learned an enormous amount about critical care medicine, pulmonary physiology, and ventilator management.

24 y.o. previously healthy female transferred from an OSH with ARDS.  She developed nausea and vomiting three days after sinus surgery with subsequent shortness of breath.  At presentation, had RLL infiltrate which progressed to diffuse bilateral infiltrates with some cavitary lesions, worse on the right.  Sputum culture grew MRSA – she is on vancomycin.  She also has developed a pneumothorax on the right and has a chest tube in place, although it was clamped during her medical flight to our hospital and she has developed lots of subcutaneous emphysema.  The sq emphysema slowly resolves over a couple of days with chest tube on -20 cm of water suction, but she continues to have a persistent air leak of moderate volume (about 30% of her tidal volume) consistent with a bronchopleural fistula (BPF).

Continue reading “Pulmonary “Steal” Syndrome”

IV Fluids in Critically Ill Patients: Business as “Normal” or Do We Need More Balance?

First, let me apologize for the long delay between posts.  We had a bit of a snafu in the blog, but things should be better now.

On to a discussion about isotonic crystalloids in our critically ill patients.  Administration of intravenous fluids represents the single most common intervention in critically ill patients.  And most of that iv fluids is given in the form of isotonic crystalloids.  So we are all on the same page, isotonic crystalloids include 0.9% NaCl (i.e. Normal Saline), Lactated Ringer’s solution, and Plasmalyte.  The use of one of these fluids is almost ubiquitous in our care of patients.

Intravenous fluids were first developed in the 1830’s for the treatment of Cholera.  They were refined in the 1880’s when Ringer’s solution was developed to bathe cardiac muscle ex vivo for physiology studies and 0.9% NaCl was found to avoid RBC lysis in vitro.  Use in patients began shortly thereafter and the argument about which iv fluid was best began.

Continue reading “IV Fluids in Critically Ill Patients: Business as “Normal” or Do We Need More Balance?”

ESICM – Hot Topics

Today was a big day at the European Society of Intensive Care Medicine (ESICM) International Conference.  Today was the Hot Topics session with the results from a number of studies being presented, many of which were published online simultaneously with the presentations.  I would like to take the opportunity to highlight four such trials presented in this Hot Topics session today:  1) The EMPIRICUS Trial (Empiric Micafungin in critically ill septic patients colonized with candida and with multiple organ dysfunction); 2) The OXYGEN-ICU Trial (Conservative vs. conventional oxygen therapy in ICU patients); 3) LeoPARDS Trial (Levosimendan in Septic Shock); and 4) High Flow Nasal Cannula vs Non-Invasive Ventilation Post-Extubation in High Risk Patients.

Continue reading “ESICM – Hot Topics”

ESICM ICU Clinical Trials (Part 2)

Yesterday, I blogged about the first group of clinical trials with results presented at European Society of Intensive Care Medicine International Conference (ESICM Update #1).  This blog will try to summarize some of the trials presented in the session on Tuesday, October 4.  The four studies from this session that I will briefly discuss include: Long-term outcomes of the TRISS randomized trial, the GRAVITY-VAP trial (lateral trendelenberg vs semirecumbent position to prevent VAP), the CLASSIC trial (restricting resuscitation fluid in patients with septic shock), and the OPERA trial (post-operative high flow nasal cannula vs conventional oxygen in patients after major abdominal surgery).

Continue reading “ESICM ICU Clinical Trials (Part 2)”

Update from ESICM – ICU Clinical Trials

The European Society of Intensive Care Medicine (ESICM) is conducting its international conference this week.  This conference has traditionally been a hotbed for breaking results from clinical trials.  In this post, I would like to briefly highlight four clinical trials whose results were presented during the President’s Session of Clinical Trials in Intensive Care yesterday.  Specifically, this post will briefly summarize the HYPRESS trial (Hydrocortisone for Prevention of Septic Shock), the DESIRE trial (Dexmedetomidine for ventilated septic patients in ICU), NAVA versus Pressure Support Ventilation, and the MACMAN trial (McGrath VL versus Macintosh DL for orotracheal intubation in intensive care patients).

Continue reading “Update from ESICM – ICU Clinical Trials”