Which septic patients should receive empiric antifungal therapy?

Patients with fungemia only make up about 5% of patients presenting with septic shock, but invasive fungal infections are associated with increased hospital mortality (40-50%), prolonged ICU and hospital length of stay, and increased costs of care.¹

The EMPIRICUS trial showed no mortality benefit to empiric antifungals for all, even patients with candidal colonization and recent exposure to antibiotics. (It demonstrated decreased rate of new invasive fungal infection, but did not increase survival).²

Risk factors for invasive fungal infections include:³

• Immunosuppresion
• Prolonged central venous catheter
• Total parenteral nutrition (TPN)
• Renal failure/dialysis
• Recent broad spectrum antibiotics
• Yeast colonization (as noted by previous urine or bronch cultures)
• Recent abdominal surgery (especially with disruption of intestinal wall)
• Severe pancreatitis

Which antifungal agent should we use?

Although older studies have not shown benefits to echinocandin, such as micafungin, over fluconazole as initial empiric antifungal therapy,^4,5 a recent study by Garnacho-Montero et al. demonstrated improved 30 and 90-day mortality in patients with candidemia whose initial antibiotic was an echinocandin rather than fluconazole.⁶  

1. Xie GH, Xiang-Ming F, Qiang F, et al. Impact of invasive fungal infection on outcomes of severe sepsis: a multicenter matched cohort study in critically ill surgical patients.
2. Timsit JF, Azoulay E, Schwebel C, et al. Empirical micafungin treatment and survival without invavsive fungal infection in adults with ICU-aquired sepsis, candida colonization, and multiple organ failure: the EMPIRICUS randomized clinical trial. JAMA 2016;316(15): 1555-64.
3. Muskett H, Shahin J, Eyres G, et al. Risk factors for invasive fungal disease in critically ill adult patients: a systematic review. Crit Care 2011;15(6): R287.
4. Murri R, Scoppettuolo G, Ventura G, et al. Initial antifungal strategy does not correlate with mortality in patients with candidemia. Eur J Clin Microbiol Infect Dis 2016; 35:187–93.
5. López-Cortés LE, Almirante B, Cuenca-Estrella M, et al. Empirical and targeted therapy of candidemia with fluconazole versus echinocandins: A propensity score-derived analysis of a population-based, multicentre prospective cohort. Clin Microbiol Infect 2016; 22:733.e1–733.e8
6. Garnacho-Montero J, Díaz-Martín A, Cantó-Bulnes L, et al. Initial antifungal strategy reduces mortality in critically ill patients with candidemia: a propensity score-adjusted analysis of a multicenter study.  Crit Care Med 2018;46(3): 384-93.

1. Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002; 288(7):862-71.
2. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008; 358(2): 111-24.
3. Balasubramanian V, Finfer S, Cohen J, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018; doi: 10.1056/NDJMoa1705835. [Epub ahead of print]

References

1.     Heffner AC, Swords DS, Neale MN, Jones AE. Inicidence and factors associated with cardiac arrest complicating emergency airway management. Resuscitation. 2013; 84(11):1500-4. 

2.     Kim WY, Kwak MK, Ko BS, et al.  Factors associated with the occurrence of cardiac arrest after emergency tracheal intubation in the emergency department. PLoS One. 2011; 9(11):e112779.

3.     Wardi G, Villar J, Nguyen T, et al. Factors and outcomes associated with inpatient cardiac arrest following emergent endotracheal intubation. Resuscitation. 2017; 121:76-80.

1. Taylor SP, Karvetski CH, Templin MA, et al. Initial fluid resuscitation following adjusted body weight dosing is associated with improved mortality in obese patients with suspected septic shock. J Crit Care. 2017;43: 7-12.
2. Rhodes A, Evans LE, Alhazzani, et al. Surviving Sepsis Campaign: International guidelines for management of sepsis and shock: 2016. Crit Care Med. 2017;45(3): 486-552.

1. Farley, H, Zubrow MT, Gies J, et al. Emergency department tachypnea predicts transfer to a higher level of care in the first 24 hours after ED admission. Acad Emerg Med. 2010;17(7): 718-22.
2. Boerma LM, Reijners EPJ, Hessels RA, et al. Risk factors for unplanned transfer to the intensive care unit after emergency department admission. Am J Emerg Med. 2017;35(8): 1154-8.
3. Wardi G, Wali AR, Villar J, et al. Unexpected intensive care transfer of admitted patients with severe sepsis. J Intensive Care. 2017;5: 43.
4. Tam V, Frost SA, Hillman KM, Salamonson Y. Using administrative data to develop a nomogram for individualizing risk of unplanned admission to intensive care. Resuscitation. 2008;79: 241-8.

Molecular Adsorbent Recirculating System (MARS) is an artificial liver support system colloquially known in the medical field as "dialysis for the liver."   

Its use demonstrates apparent effective replacement of liver function, with consistently-proven improvements in hemodynamics, hepatic encephalopathy, hepatorenal syndrome, drug clearance, hyperbilirubinemia, and other markers of hepatic homeostasis.

It has been repeatedly demonstrated to work well as a short-term bridge to liver recovery or liver transplant in severe ALF of various causes, especially those that are generally reversible with support and time severe trauma, toxic ingestions, and acute alcoholic hepatitis.

Mortality benefit remains unclear and may be dependent on the subtype of acute liver failure. Most of the current literature is made up of case reports, or case studies with small study populations. In acute on chronic liver failure, the 23-patient randomized, controlled RELIEF trial failed to show survival advantage at 28 days.  Gerth et al, however, found a 14-day mortality benefit in ACF patients by retrospective analysis, which may indicate that MARS use as a bridge to transplant is the most appropriate utilization in this patient population.

• Bañares R, Nevens F, Larsen FS, et al. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial. Hepatology. 2013;57(3): 1153-62.
• Gerth HU, Pohlen M, Thölking G, et al. Molecular adsorbent recirculating system (MARS) in acute liver injury and graft dysfunction: Results from a case-control study.  PLoS One. 2017;12(4):e0175529.
• Gerth HU, Pohlen M, Thölking G, et al. Molecular adsorbent recirculating system can reduce short-term mortality among patients with acute-on-chronic liver failure—a retrospective analysis. Crit Care Med. 2017;45(10): 1616-1624.
• Hanish SI, Stein DM, Scalea JR, et al. Molecular adsorbent recirculating system effectively replaces hepatic function in severe acute liver failure. Ann Surg. 2017;266(4):677-684.

Negative-pressure pulmonary edema (NPPE), also called post-obstructive pulmonary edema, can occur after any event in which a patient exerts strong inspiratory effort against an obstructed airway. This obstruction can be essentially due to any cause; in adults it is most well-documented secondary to post-extubation laryngospasm, in children the etiology is usually infectious, such as in epiglottitis. It has also been documented secondary to laryngeal edema, tumor, trauma, biting on an endotracheal tube, vent dyssynchrony,  as well as disruptions to breathing mechanics during generalized seizures, among other causes.

It is noted that many of the documented cases involve patients who are relatively young and otherwise healthy, and thus capable of creating a strong negative intrathoracic pressure. The pathophysiology is thought to be related to hydrostatic mechanisms rather than a “leaky-capillary” permeability edema, and it usually resolves quickly if managed appropriately, within 24-48 hours. Diffuse alveolar hemorrhage, related to capillary rupture from the negative pressure, has been documented to occur in severe cases but is rare.

Consider the diagnosis in patients with an appropriate clinical picture or witnessed event leading to abrupt respiratory distress and/or failure. The diagnosis is even more strongly supported if they had absence of respiratory symptoms, or a clear chest x-ray prior to the event, with a chest x-ray demonstrating pulmonary edema afterwards.

Appropriate management of these patients includes:  

1.     Alleviation or bypass of the upper airway obstruction, which usually requires intubation.

·      Depending on the etiology of obstruction (e.g. epiglottitis), endo/nasotracheal intubation may be difficult and a surgical airway may be necessary. Be prepared for this possibility.

·      Ventilated patients who develop NPPE may require sedation to prevent biting on the ETT or to promote vent synchrony

2.     Provide with positive-pressure ventilation to counteract the negative airway pressures, and oxygen supplementation to decrease pulmonary vascular resistance.

3.     Lung-protective ventilation with low tidal volumes is generally accepted as the preferred ventilation strategy in these patients, extrapolated from data regarding its use in acute lung injury.

4.     In cases of moderate to severe hypoxemia without the presence of shock, add a diuretic agent.

5.     For refractory hypoxemia, consider early utilization of additional therapies, including neuromuscular blockade, proning, and ECMO. 

Bhattacharya M, Kallet RJ, Ware LB, Matthay MA. Negative-pressure pulmonary edema. Chest. 2016;150(4):927-33. 

Contou D, Voiriot G, Djibre et al. Clinical features of patients with diffuse alveolar hemorrhage due to negative-pressure pulmonary edema. Lung. 2017;195(4):477-487. 

Stephens, R.J., et al., Analgosedation Practices and the Impact of Sedation Depth on Clinical Outcomes Among Patients Requiring Mechanical Ventilation in the ED: A Cohort Study. Chest, 2017 [Epub ahead of print].

Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta JF, Davidson JE, Devlin JW, Kress JP, Joffe AM, et al.; American College of Critical Care Medicine. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013;41:263–306.

Kazzaz NM, McCune WJ, Knight JS. Treatment of catastrophic antiphospholipid syndrome. Curr Opin Rheumatol. 2016;28(3):218-27. 

Cervera R, Rodriguez-Pinto I, Colafrancesco S, et al. 14th International Congress on Antiphospholipid Antibodies Task Force. Report on catastrophic antiphospholipid syndrome. Autoimmun Rev 2014; 13:699–707.

Several studies have demonstrated benefits to patient family members who are offered the opportunity to witness ongoing CPR when their loved one develops cardiac arrest.  These benefits--decreased rates of PTSD-related symptoms, anxiety, depression (including need for medication, professional treatment, and suicide attempts), and complicated grief--have been shown to persist at 1 year post-resuscitation event.

Themes that arise when discussing the resuscitations with family members afterward include:

1. The feeling of active involvement in the resuscitation process

• The importance of being emotionally present for their loved one
• The ability to see the efforts of the resuscitation team

2. Communication with the resuscitation team

• Providing medical information on the loved one’s behalf
• Explanation from the team of what was happening

3. Perception of the reality of death

• Understanding actual death as the cause for CPR
• Seeing the failure of CPR and even nonverbal communication between participants of the team

4. Experience of and reaction to witnessing (or not witnessing) the resuscitation

• Examples given when witnessed:

1. Relief that the patient did not or would not suffer
2. Feeling that there was even excessively heroic treatment

• Examples given when not witnessed:

1. Feeling of brutality and dehumanization
2. The inability to say goodbye

Twelve percent of family members who chose to NOT be present during CPR expressed regret at their choice, versus three percent of relatives who chose to be present.

Negative outcomes cited by family members who witnessed CPR involved feeling like they were not being communicated with, or that their loved one was being over-zealously resuscitated. 

1. Bradley C, Keithline M, Petrocelli M, et al. Perceptions of adult hospitalized patients on family presence during cardiopulmonary resuscitation. Am J Crit Care. 2017;26(2):103-110.
2. Jabre P, Belpomme V, Azoluay E, et al. Family presence during cardiopulmonary resuscitation. N Engl J Med. 2013;368(11):1008-18.
3. Jabre P, Tazarourte K, Azoulay E, et al. Offering the opportunity for family to be present during cardiopulmonary resuscitation: 1-year assessment. Intensive Care Med. 2014;40(7):981-7.
4. Goldberger Z, Nallamothu B, Nichol G, et al.  Policies allowing family presence during resuscitation and patterns of care during in-hospital cardiac arrest. Circ Cardiovasc Qual Outcomes. 2015;8(3):226-34.
5. De Stefano C, Normand D, Jabre P, et al. Family presence during resuscitation: A qualitative analysis from a national multicenter randomized clinical trial. PLoS ONE.  2016;11(6): e0156100.

Background Info:

While the ACLS algorithm does recommend initial defibrillation followed by 2 minutes of CPR and repeated shock if the shockable rhythm persists, the 2015 AHA Guidelines update admits that there is insufficient evidence to comment on “optimal timing” of epinephrine administration in these patients.

A 2016 study of 2794 patients across 310 hospitals looked at patients with cardiac arrest with initial shockable rhythm and found that compared to patients who received epinephrine after the second defibrillation attempt, patients who received epinephrine in the first 2 minutes before the 2nd shock had:

• decreased rate of ROSC (67 v. 79%, p<0.001)
• decreased rate of survival (31 v. 48%, p<0.001)
• decreased functional outcome (25 vs. 41%, p<0.001)

The benefit of 2^nd-shock-first was maintained when groups were matched using a propensity score accounting for baseline characteristics of the patients, events, and hospitals. 

References:

Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Link MS, Berkow LC, Kudenchuk PJ, et al. Circulation. 2015;132(18 Suppl 2):S444-64.

Early administration of epinephrine (adrenaline) in patients with cardiac arrest with initial shockable rhythm in hospital: propensity score matched analysis. Andersen LW, Kurth T, Chase M, et al. BMJ. 2016;353:i1577.

For patients with acute hypoxic respiratory failure without hypercapnia, the FLORALI trial demonstrated that high flow nasal cannula (HFNC) therapy increases ventilator-free days, reduces 90-day mortality, and is associated with better comfort and lower dyspnea severity when compared to conventional oxygen therapy and non-invasive ventilation (NIV). Failure of HFNC, however, may result in delayed intubation and worse clinical outcomes in patients with acute hypoxic respiratory failure. So how do we predict in the ED which patients are going to fail?

Sztrymf et al. evaluated patients placed on HFNC for nonhypercapneic acute hypoxic respiratory failure, who later went on to require endotracheal intubation. The cohort who failed HFNC had significantly:

-     higher RR at 30 & 45 minutes after initiation of HFNC

-     lower SpO2% at 15, 30, and 60 minutes

-     higher incidence of paradoxical breathing (thoracoabdominal dyssynchrony) at 15, 30, 60, and 120 minutes

In an observational study of patients with ARDS,* Messika et al. found that factors predicting HFNC failure included:

-     a higher Simplified Acute Physiology Score II (SAPS II; 46 v. 29, p=.001)

-     additional organ system failure (mostly hemodynamic or neurological)

-   trends towards lower PaO2:FiO2 ratios and higher RR

So don’t set it and forget it! Consider a different method of respiratory support if your patient has multi-organ system failure, especially if they are in shock or have altered mental status. If you do use HFNC, reevaluate your patient at 15 minutes and again at 30 minutes to make sure their respiratory rate and SpO2 have improved and that there is no paradoxic breathing (or it is resolving). If not, move on to NIV or invasive mechanical ventilation. 

*acute respiratory failure occurring within 1 week of known clinical insult with PaO2:FiO2 <300mmHg and bilateral opacities on chest x-ray not attributable to cardiac failure/volume overload

1.   Frat JP, Thille AW, Mercat A, et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med. 2015;372:2185–96.

2.   Sztrymf B, Messika J, Bertrand F, et al. Beneficial effects of humidified high flow nasal oxygen in critical care patients: a prospective pilot study. Intensive Care Med. 2011;37:1780–6.

3.   Messika J, Ben Ahmed K, Gaudry S, et al. Use of high-flow nasal cannula oxygen therapy in subjects with ARDS: a 1-year observational study. Respir Care. 2015;60(2):162-9.

4.   Hernandez G, Roca O, Colinas L. High-flow nasal cannula support therapy: new insights and improving performance. Crit Care. 2017;21(1):62.

It makes sense that it’s going to be faster for you to use that internal jugular/subclavian central venous catheter (CVC) you just placed if you confirm with bedside ultrasound instead of waiting for the radiology tech to get the chest x-ray. But what’s the data?

Using pooled data from of 15 studies with 1553 CVC placements, Ablordeppey et al. found that ultrasound had a sensitivity of 86% and 98% specificity for detecting catheter malposition, with a positive likelihood ratio (LR) of 31.1 and a negative LR of 0.25. There was an almost 100% sensitivity and specificity for pneumothorax detection, and reduced confirmation time by 58 minutes.These findings are generally consistent across the board for the other studies out there.

1.     Ablordeppey EA, Drewry AM, Beyer AB, et al. Diagnostic accuracy of central venous catheter confirmation by bedside ultrasound versus chest radiography in critically ill patients: a systematic review and meta-analysis. Crit Care Med. 2017; 45(4): 715-24.

2.     Gekle R, Dubensky L, Haddad S, et al. Saline flush test: Can bedside sonography replace conventional radiography for confirmation of above-the-diaphragm central venous catheter placement? J Ultrasound Med. 2015;34(7):1295-9.

3.     Weekes AJ, Johnson DA, Keller SM. Central vascular catheter placement evaluation using saline flush and bedside echocardiography. Acad Emerg Med. 2014; 21:65-72.