Matthew W. Semler

Randomized Trial of Apneic Oxygenation during Endotracheal Intubation of the Critically Ill

RATIONALE Hypoxemia is common during endotracheal intubation of critically ill patients and may predispose to cardiac arrest and death. Administration of supplemental oxygen during laryngoscopy (apneic oxygenation) may prevent hypoxemia. OBJECTIVES To determine if apneic oxygenation increases the lowest arterial oxygen saturation experienced by patients undergoing endotracheal intubation in the intensive care unit. METHODS This was a randomized, open-label, pragmatic trial in which 150 adults undergoing endotracheal intubation in a medical intensive care unit were randomized to receive 15 L/min of 100% oxygen via high-flow nasal cannula during laryngoscopy (apneic oxygenation) or no supplemental oxygen during laryngoscopy (usual care). The primary outcome was lowest arterial oxygen saturation between induction and 2 minutes after completion of endotracheal intubation. MEASUREMENTS AND MAIN RESULTS Median lowest arterial oxygen saturation was 92% with apneic oxygenation versus 90% with usual care (95% confidence interval for the difference, -1.6 to 7.4%; P = 0.16). There was no difference between apneic oxygenation and usual care in incidence of oxygen saturation less than 90% (44.7 vs. 47.2%; P = 0.87), oxygen saturation less than 80% (15.8 vs. 25.0%; P = 0.22), or decrease in oxygen saturation greater than 3% (53.9 vs. 55.6%; P = 0.87). Duration of mechanical ventilation, intensive care unit length of stay, and in-hospital mortality were similar between study groups. CONCLUSIONS Apneic oxygenation does not seem to increase lowest arterial oxygen saturation during endotracheal intubation of critically ill patients compared with usual care. These findings do not support routine use of apneic oxygenation during endotracheal intubation of critically ill adults. Clinical trial registered with www.clinicaltrials.gov (NCT 02051816).

Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension: A Randomized Clinical Trial

Importance The effect of an early resuscitation protocol on sepsis outcomes in developing countries remains unknown. Objective To determine whether an early resuscitation protocol with administration of intravenous fluids, vasopressors, and blood transfusion decreases mortality among Zambian adults with sepsis and hypotension compared with usual care. Design, Setting, and Participants Randomized clinical trial of 212 adults with sepsis (suspected infection plus ≥2 systemic inflammatory response syndrome criteria) and hypotension (systolic blood pressure ⩽90 mm Hg or mean arterial pressure ⩽65 mm Hg) presenting to the emergency department at a 1500-bed referral hospital in Zambia between October 22, 2012, and November 11, 2013. Data collection concluded December 9, 2013. Interventions Patients were randomized 1:1 to either (1) an early resuscitation protocol for sepsis (n = 107) that included intravenous fluid bolus administration with monitoring of jugular venous pressure, respiratory rate, and arterial oxygen saturation and treatment with vasopressors targeting mean arterial pressure (≥65 mm Hg) and blood transfusion (for patients with a hemoglobin level <7 g/dL) or (2) usual care (n = 105) in which treating clinicians determined hemodynamic management. Main Outcomes and Measures The primary outcome was in-hospital mortality and the secondary outcomes included the volume of intravenous fluid received and receipt of vasopressors. Results Among 212 patients randomized to receive either the sepsis protocol or usual care, 3 were ineligible and the remaining 209 completed the study and were included in the analysis (mean [SD] age, 36.7 [12.4] years; 117 men [56.0%]; 187 [89.5%] positive for the human immunodeficiency virus). The primary outcome of in-hospital mortality occurred in 51 of 106 patients (48.1%) in the sepsis protocol group compared with 34 of 103 patients (33.0%) in the usual care group (between-group difference, 15.1% [95% CI, 2.0%-28.3%]; relative risk, 1.46 [95% CI, 1.04-2.05]; P = .03). In the 6 hours after presentation to the emergency department, patients in the sepsis protocol group received a median of 3.5 L (interquartile range, 2.7-4.0 L) of intravenous fluid compared with 2.0 L (interquartile range, 1.0-2.5 L) in the usual care group (mean difference, 1.2 L [95% CI, 1.0-1.5 L]; P < .001). Fifteen patients (14.2%) in the sepsis protocol group and 2 patients (1.9%) in the usual care group received vasopressors (between-group difference, 12.3% [95% CI, 5.1%-19.4%]; P < .001). Conclusions and Relevance Among adults with sepsis and hypotension, most of whom were positive for HIV, in a resource-limited setting, a protocol for early resuscitation with administration of intravenous fluids and vasopressors increased in-hospital mortality compared with usual care. Further studies are needed to understand the effects of administration of intravenous fluid boluses and vasopressors in patients with sepsis across different low- and middle-income clinical settings and patient populations. Trial Registration clinicaltrials.gov Identifier: NCT01663701

Randomized trial of automated, electronic monitoring to facilitate early detection of sepsis in the intensive care unit*

Objective:To determine whether automated identification with physician notification of the systemic inflammatory response syndrome in medical intensive care unit patients expedites early administration of new antibiotics or improvement of other patient outcomes in patients with sepsis. Design:A prospective randomized, controlled, single center study. Setting:Medical intensive care unit of an academic, tertiary care medical center. Patients:Four hundred forty-two consecutive patients admitted over a 4-month period who met modified systemic inflammatory response syndrome criteria in a medical intensive care unit. Intervention:Patients were randomized to monitoring by an electronic “Listening Application” to detect modified (systemic inflammatory response syndrome) criteria vs. usual care. The listening application notified physicians in real time when modified systemic inflammatory response syndrome criteria were detected, but did not provide management recommendations. Measurements and Main Results:The median time to new antibiotics was similar between the intervention and usual care groups when comparing among all patients (6.0 hr vs. 6.1 hr, p = .95), patients with sepsis (5.3 hr vs. 5.1 hr; p = .90), patients on antibiotics at enrollment (5.2 hr vs. 7.0 hr, p = .27), or patients not on antibiotics at enrollment (5.2 hr vs. 5.1 hr, p = .85). The amount of fluid administered following detection of modified systemic inflammatory response syndrome criteria was similar between groups whether comparing all patients or only patients who were hypotensive at enrollment. Other clinical outcomes including intensive care unit length of stay, hospital length of stay, and mortality were not shown to be different between patients in the intervention and control groups. Conclusions:Realtime alerts of modified systemic inflammatory response syndrome criteria to physicians in one tertiary care medical intensive care unit were feasible and safe but did not influence measured therapeutic interventions for sepsis or significantly alter clinical outcomes.

Balanced Crystalloids versus Saline in the Intensive Care Unit. The SALT Randomized Trial

Rationale: Saline is the intravenous fluid most commonly administered to critically ill adults, but it may be associated with acute kidney injury and death. Whether use of balanced crystalloids rather than saline affects patient outcomes remains unknown. Objectives: To pilot a cluster‐randomized, multiple‐crossover trial using software tools within the electronic health record to compare saline to balanced crystalloids. Methods: This was a cluster‐randomized, multiple‐crossover trial among 974 adults admitted to a tertiary medical intensive care unit from February 3, 2015 to May 31, 2015. The intravenous crystalloid used in the unit alternated monthly between saline (0.9% sodium chloride) and balanced crystalloids (lactated Ringers solution or Plasma‐Lyte A). Enrollment, fluid delivery, and data collection were performed using software tools within the electronic health record. The primary outcome was the difference between study groups in the proportion of isotonic crystalloid administered that was saline. The secondary outcome was major adverse kidney events within 30 days (MAKE30), a composite of death, dialysis, or persistent renal dysfunction. Measurements and Main Results: Patients assigned to saline (n = 454) and balanced crystalloids (n = 520) were similar at baseline and received similar volumes of crystalloid by 30 days (median [interquartile range]: 1,424 ml [500‐3,377] vs. 1,617 ml [500‐3,628]; P = 0.40). Saline made up a larger proportion of the isotonic crystalloid given in the saline group than in the balanced crystalloid group (91% vs. 21%; P < 0.001). MAKE30 did not differ between groups (24.7% vs. 24.6%; P = 0.98). Conclusions: An electronic health record‐embedded, cluster‐randomized, multiple‐crossover trial comparing saline with balanced crystalloids can produce well‐balanced study groups and separation in crystalloid receipt. Clinical trial registered with www.clinicaltrials.gov (NCT 02345486).

Balanced Crystalloids versus Saline in Critically Ill Adults

BACKGROUND Comparative clinical effects of balanced crystalloids and saline are uncertain, particularly in noncritically ill patients cared for outside an intensive care unit (ICU). METHODS We conducted a single‐center, pragmatic, multiple‐crossover trial comparing balanced crystalloids (lactated Ringers solution or Plasma‐Lyte A) with saline among adults who were treated with intravenous crystalloids in the emergency department and were subsequently hospitalized outside an ICU. The type of crystalloid that was administered in the emergency department was assigned to each patient on the basis of calendar month, with the entire emergency department crossing over between balanced crystalloids and saline monthly during the 16‐month trial. The primary outcome was hospital‐free days (days alive after discharge before day 28). Secondary outcomes included major adverse kidney events within 30 days — a composite of death from any cause, new renal‐replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to ≥200% of baseline) — all censored at hospital discharge or 30 days, whichever occurred first. RESULTS A total of 13,347 patients were enrolled, with a median crystalloid volume administered in the emergency department of 1079 ml and 88.3% of the patients exclusively receiving the assigned crystalloid. The number of hospital‐free days did not differ between the balanced‐crystalloids and saline groups (median, 25 days in each group; adjusted odds ratio with balanced crystalloids, 0.98; 95% confidence interval [CI], 0.92 to 1.04; P=0.41). Balanced crystalloids resulted in a lower incidence of major adverse kidney events within 30 days than saline (4.7% vs. 5.6%; adjusted odds ratio, 0.82; 95% CI, 0.70 to 0.95; P=0.01). CONCLUSIONS Among noncritically ill adults treated with intravenous fluids in the emergency department, there was no difference in hospital‐free days between treatment with balanced crystalloids and treatment with saline. (Funded by the Vanderbilt Institute for Clinical and Translational Research and others; SALT‐ED ClinicalTrials.gov number, NCT02614040.)

Dietary zinc alters the microbiota and decreases resistance to Clostridium difficile infection

Clostridium difficile is the most commonly reported nosocomial pathogen in the United States and is an urgent public health concern worldwide. Over the past decade, incidence, severity and costs associated with C. difficile infection (CDI) have increased dramatically. CDI is most commonly initiated by antibiotic-mediated disruption of the gut microbiota; however, non-antibiotic-associated CDI cases are well documented and on the rise. This suggests that unexplored environmental, nutrient and host factors probably influence CDI. Here we show that excess dietary zinc (Zn) substantially alters the gut microbiota and, in turn, reduces the minimum amount of antibiotics needed to confer susceptibility to CDI. In mice colonized with C. difficile, excess dietary Zn severely exacerbated C. difficile–associated disease by increasing toxin activity and altering the host immune response. In addition, we show that the Zn-binding S100 protein calprotectin has antimicrobial effects against C. difficile and is an essential component of the innate immune response to CDI. Taken together, these data suggest that nutrient Zn levels have a key role in determining susceptibility to CDI and severity of disease, and that calprotectin-mediated metal limitation is an important factor in the host immune response to C. difficile.

Randomized Trial of Video Laryngoscopy for Endotracheal Intubation of Critically Ill Adults.

Objective:To evaluate the effect of video laryngoscopy on the rate of endotracheal intubation on first laryngoscopy attempt among critically ill adults. Design:A randomized, parallel-group, pragmatic trial of video compared with direct laryngoscopy for 150 adults undergoing endotracheal intubation by Pulmonary and Critical Care Medicine fellows. Setting:Medical ICU in a tertiary, academic medical center. Patients:Critically ill patients 18 years old or older. Interventions:Patients were randomized 1:1 to video or direct laryngoscopy for the first attempt at endotracheal intubation. Measurements and Main Results:Patients assigned to video (n = 74) and direct (n = 76) laryngoscopy were similar at baseline. Despite better glottic visualization with video laryngoscopy, there was no difference in the primary outcome of intubation on the first laryngoscopy attempt (video 68.9% vs direct 65.8%; p = 0.68) in unadjusted analyses or after adjustment for the operator’s previous experience with the assigned device (odds ratio for video laryngoscopy on intubation on first attempt 2.02; 95% CI, 0.82–5.02, p = 0.12). Secondary outcomes of time to intubation, lowest arterial oxygen saturation, complications, and in-hospital mortality were not different between video and direct laryngoscopy. Conclusions:In critically ill adults undergoing endotracheal intubation, video laryngoscopy improves glottic visualization but does not appear to increase procedural success or decrease complications.

An Electronic Tool for the Evaluation and Treatment of Sepsis in the ICU: A Randomized Controlled Trial.

Objectives:To determine whether addition of an electronic sepsis evaluation and management tool to electronic sepsis alerting improves compliance with treatment guidelines and clinical outcomes in septic ICU patients. Design:A pragmatic randomized trial. Setting:Medical and surgical ICUs of an academic, tertiary care medical center. Patients:Four hundred and seven patients admitted during a 4-month period to the medical or surgical ICU with a diagnosis of sepsis established at the time of admission or in response to an electronic sepsis alert. Interventions:Patients were randomized to usual care or the availability of an electronic tool capable of importing, synthesizing, and displaying sepsis-related data from the medical record, using logic rules to offer individualized evaluations of sepsis severity and response to therapy, informing users about evidence-based guidelines, and facilitating rapid order entry. Measurements and Main Results:There was no difference between the electronic tool (218 patients) and usual care (189 patients) with regard to the primary outcome of time to completion of all indicated Surviving Sepsis Campaign 6-hour Sepsis Resuscitation Bundle elements (hazard ratio, 1.98; 95% CI, 0.75–5.20; p = 0.159) or time to completion of each element individually. ICU mortality, ICU-free days, and ventilator-free days did not differ between intervention and control. Providers used the tool to enter orders in only 28% of available cases. Conclusions:A comprehensive electronic sepsis evaluation and management tool is feasible and safe but did not influence guideline compliance or clinical outcomes, perhaps due to low utilization.

Saline Is Not the First Choice for Crystalloid Resuscitation Fluids.

Fluid resuscitation with crystalloid solutions is among the most common interventions for hospitalized patients. Currently, providers choose between two classes of available crystalloid solutions: 0.9% sodium chloride (saline) and “balanced” crystalloids (such as lactated Ringer solution [ Baxter, D

Flash Mob Research: A Single-Day, Multicenter, Resident-Directed Study of Respiratory Rate

BACKGROUND Vital signs are critical data in the care of hospitalized patients, but the accuracy with which respiratory rates are recorded in this population remains uncertain. We used a novel flash mob research approach to evaluate the accuracy of recorded respiratory rates in inpatients. METHODS This was a single-day, resident-led, prospective observational study of recorded vs directly observed vital signs in nonventilated patients not in the ICU on internal medicine teaching services at six large tertiary-care centers across the United States. RESULTS Among the 368 inpatients included, the median respiratory rate was 16 breaths/min for the directly observed values and 18 breaths/min for the recorded values, with a median difference of 2 breaths/min (P < .001). Respiratory rates of 18 or 20 breaths/min accounted for 71.8% (95% CI, 67.1%-76.4%) of the recorded values compared with 13.0% (95% CI, 9.5%-16.5%) of the directly observed measurements. For individual patients, there was less agreement between the recorded and the directly observed respiratory rate compared with pulse rate. CONCLUSIONS Among hospitalized patients across the United States, recorded respiratory rates are higher than directly observed measurements and are significantly more likely to be 18 or 20 breaths/min.