Clinical Pearl 74: Why 30 ml/kg fluid bolus in Sepsis?

Recently Winters et al in a 2016 AAEM clinical practice guidelines concluded that “There is no difference in mortality between current usual care and the goal-directed approach recommended by current international guidelines for patients with severe sepsis and septic shock.”  This statement is based on the ARISE, PROMISE and PROCESS TRIALS.  As such more scientific evidence is being sought for the treatment of sepsis. The current recommendation per the “Surviving Sepsis Campaign” recommends the administration of 30 ml/kg crystalloid for hypotension or lactate > 4 mmol/L.  The Severe Sepsis 3-hour Resuscitation bundle recommends the 30 ml/kg fluid bolus therapy for the targeted guidelines are to have the CVP of ≥8 mm Hg, ScvO2 of ≥70 percent, and normalization of lactate. It is important to site there is no restriction for additional fluids but the minimal 30 ml/kg should be administered within 30-60 minutes of identification of septic patient.    There is no data to support the amount fluid resuscitation prospectively or retrospectively… only expert opinions.  Maitland et al studied pediatric patients presenting in shock in Sub-saharan Africa evaluating resuscitation with either saline or albumin compare to a no-bolus strategy in terms of all-cause mortality at 48 hours.  The Fluid Expansion as Supportive Therapy (FEAST) study published in 2011 and enrolled 3,141 Sub-Saharan children with severe febrile illness and impaired organ perfusion, and randomized them to receive either albumin, saline, or no volume resuscitation  At 48 hours, mortality was higher with albumin (10.6%) and saline (10.5%) as compared to no volume resuscitation (7.3%). Half of the participants had malaria and may not yield similar results as undifferentiated hypovolemic shock.

In the Journal of Critical Care, Hilton et al did a critique of fluid bolus in sepsis.  The author argue that 30 ml/kg has “weak physiologic support and limited experimental support.”  This interesting review for the ICU community questions why “nobody has ever challenged this dogma.”  This review cites many animal studies concluding that not even animal models show benefit for large volume fluid resuscitation. 

So if we do not have clear evidence of “help”  do we have evidence of “harm.”   The answer is yes.. in some models.  We know that fluid resuscitation boluses worsens outcome in penetrating torso trauma and positive fluid balances worsen outcome in Acute kidney injury, ARDS and recent colorectal surgery.  Also at cited above we know that NSS or Albumin in children with no significant cofounders has a 50 percent mortality increase. (FEAST STUDY)

In another 2017 study, Seethala et al evaluated the risk of developing ARDS in septic patients base on early fluid resuscitation.  2534 patients were evaluated using multivariate models.  6.2 percent of patient developed ARDS. In the first 6 hours in patients without shock, the amount of fluid resuscitation was associated with greater risk of developing ARDS 

But Why Is This? Several mechanisms exist regarding why Fluid Bolus Therapy worsens outcomes.  One model suggests rapid fluid infusion can also damage the endothelial glycocalyx leading to endothelialdisruption and organ dysfunction. Also expansion of blood volume in septic shock might increase distribution of harmful cytokines to end organs

In conclusion, of the 47 papers identified in the literature, we still have no support for 30 ml/kg.  In fact a better academic approach is to utilize repeat ultrasound evaluating the IVC, very early vasopressors, and frequent evaluations after several small bolus.  However in the true hypovolemic, hypotensive septic shock patient, fluid bolus therapy should still remain the mainstay of treatment until further randomized trials guide us.  

References:

1. Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for  uid resuscitation in the intensive care unit. New England Journal of Medicine. 2004;350:2247-2256.
2. Choi PTL, Yip G, Quinonez LG, et al. Crystalloids vs. colloids in  fuid resuscitation: A systematic review. Critical Care Medicine. 1999;27:200-210.
3. Cook D, Guyatt G. Colloid use for  fluid resuscitation: Evidence and spin. Annals of Internal Medicine. 2001;135:205-208.
4. Schierhout G, Roberts I. Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: A systematic review of randomized trials. British Medical Journal. 1998;316:961-964.
5. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. New England Journal of Medicine. 2001;345:1368-1377.
6. Reinhart K, Kuhn HJ, Hartog C, et al. Continuous central venous and pulmonary artery oxygen saturation monitoring in the critically ill. Intensive Care Medicine. 2004;30:1572-1578.
7. Maitland K, et al. Mortality after fluid bolus in African children with severe infection. NEJM 2011. 364:2483-2495.
8. Wan L, Bellomo R, May CN: A comparison of 4% succinylated gelatin solution versus normal saline in stable normovolaemic sheep: global haemodynamic, regional blood fl ow and oxygen delivery effects. Anaesth Intensive Care 2007, 35:924-931.
9. Payen D, de Pont AC, Sakr Y, Spies C, Reinhart K, Vincent JL; Sepsis Occurrence in Acutely Ill Patients (SOAP) Investigators: A positive fluid balance is associated with a worse outcome in patients with acute renal failure. Crit Care 2008;12:74.
10. NHLBI ARDS Clinical Trials Network: Comparison of two fluid management strategies in acute lung injury. NEJM 2006, 354:2564-2575.
11. Durairaj L, Schmidt GA: Fluid therapy in resuscitated sepsis: less is more. Chest 2008, 133:252-263.
12. Bickell WH, Wall MJ Jr, Pepe PE, Martin RR, Ginger VF, Allen MK, Mattox KL: Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injury. NEJM 1994;331:1105-1109.
13  Brandstrup B, Tønnesen H, Beier-Holgersen R et al. Danish Study Group on Perioperative Fluid Therapy: Effects of intravenous fluid restriction on postoperative complications: comparison of two perioperative fluid regimens: a randomized assessor-blinded multicenter trial. Ann Surg 2003, 238:641-648.
14. Burke-Gaffney A, Evans TW: Lest we forget the endothelial glycocalyx in sepsis. Crit Care 2012;16:121.
15.Woodcock TE, Woodcock TM: Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy. Br J Anaesth 2012;108:384-394.

16. Boyd JH, Forbes J, Nakada TA, Walley KR, Russell JA. Fluid resuscita- tion in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med. 2011;39:259–265.
17. Hilton AK,  Bellomo . A critique of fluid bolus resuscitation inssevere sepsis. Critical Care 2012;16:1-5.
18.Brandt S, Regueira T, Bracht H, et al. Effect of fluid resuscitation on mortality and organ function in experimental sepsis models. Crit Care. 2009;13:186.
19.Durairaj L, Schmidt GA. Fluid therapy in resuscitated sepsis: less is more. Chest. 2008;133:252-63.
20.Glassford NJ, Eastwood GM, Bellomo R. Physiological changes after fluid bolus therapy in sepsis: a systematic review of contemporary data. Critical care. 18(6):696.
21.Madhusudan P, Tirupakuzhi Vijayaraghavan BK, Cove ME. Fluid resuscitation in sepsis: reexamining the paradigm. BioMed research international. 2014:984082..
22.Malbrain ML, Marik PE, Witters I, Cordemans C, Kirkpatrick AW, Roberts DJ, Van Regenmortel N. Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiol Intensive Ther. 2014 Nov-Dec;46:361-80

Clinical Pearl 72: GCSm: A New Standard Of Care In Assessing The Trauma Patient

The standard GCS score consists of visual, verbal and motor subscores. A randomized controlled trial published in Annals of Emergency Medicine in 2015 assessed the accuracy of EMS providers' GCS scoring as well as the improvement in the GCS score assessment with the use of a scoring aid. 178 completed the study. Overall, 41% gave a GCS score that matched the expert consensus score. GCS score was correct in 25% cases without the scoring aid. GCS was correct in 57% cases with the scoring aid. Differences in accuracy were most pronounced in scenarios with a correct GCS score of 12 or below. In summary, 60% of the EMS participants provided inaccurate GCS score estimates and the use of a GCS scoring aid improved accuracy of their score assessments.  So, instead of using a scoring aid why not just implement a simplified version of the GCS scoring system to minimize inaccuracy?

Another study published in Annals of Emergency Medicine in 2007 aimed to validate the Simplified Motor Score in a large heterogeneous trauma population. This was a secondary analysis of a prospectively maintained trauma registry with consecutive trauma patients who presented to a Level I trauma center from 1995 through 2004. Test performance of the GCS and the Simplified Motor Score relative to 4 clinically relevant traumatic brain injury outcomes (emergency intubation, clinically significant brain injury, neurosurgical intervention, and mortality) was evaluated with areas under the receiver operating characteristic curves (AUCs). The AUCs for the GCS and its components ranged from 0.76 to 0.92 across the 4 outcome measures. The AUCs for the Simplified Motor Score ranged from 0.71 to 0.89, and the relative differences from the GCS AUCs ranged from 3% to 7%, with a median difference of 5%. In this external validation study, the 3-point Simplified Motor Score (SMS) demonstrated similar test performance when compared with the 15-point GCS score and its components for the prediction of 4 clinically important traumatic brain injury outcomes. A second study of nearly 20,000 ICU trauma patients from 2011 found that the SMS acted equally to the GCS in predicting select trauma outcomes, offering it as an easier tool for pre-hospital providers to utilize in their trauma assessment.

In 2014, a study published in Journal of trauma and Acute Care Surgery, evaluated performance of the National Trauma Triage Protocol if GCm is substituted for the classic GCS score. GCSm score ≤ 5 increases specificity at the expense of sensitivity compared with GCS score ≤ 13.

In 2016, Doug Kupas and colleagues, in an evaluation of trauma outcomes from the Pennsylvania trauma data base, found that patients with a GCS- motor component less than 6 (“patient does not follow commands”) was equally effective in predicting select trauma outcomes (intubation, surgery, ICU admission, craniotomy, etc) as GCS, and again would serve as simple binary tool for EMS providers to utilize in their trauma assessment.

GCSm is superior to Total GCS.  Having a patient follow a motor command provides the easiest method to determine GCSm in a rapid accurate way.

References:

Brown JB, Forsythe RM, Stassen NA, Peitzman AB, Billiar TR, Sperry JL, Gestring ML. Evidence-based improvement of the National Trauma Triage Protocol: The Glasgow Coma Scale versus Glasgow Coma Scale Motor Subscale. J Trauma Acute Care Surg. 2014 Jul;77(1):95-102

Jaukoos JS, Gill MR, Rabon RE, Gravitz CS, Green SM. Validation of the Simplified Motor Score for the prediction of brain injury outcomes after trauma. Ann Emerg Meg. 2007 Jul;50(1):18-24.

Thompson DO, Hurtado TR, Liao MM, Byyny RL, Gravitz C, Haukoos JS. Validation of the simplified motor score in the out-of-hosptial setting for the preduction of outcomes after traumatic brain injury. Anne Amerg Med. 2011 Nov;58(5):417-25.

Feldman A, Hart KW, Lindsell CJ, McMullan JT. Randomized controlled trial of a scoring aid to improve Glasgow Coma Scale Scoring by emergency medical services proviers. Ann Emerg Med. 2015 Mar;65(3):325-329.e.2

Kuppas DF, Melnychuk EM, Young AJ. Glasgow Coma Scale Motor Component (“Patient Does Not Follow Commands”) Performs Similarly to Total Glasgow Coma Scale in Predicting Serve Injury In Trauma Patients. Ann Emerg Med. 2016 Dec.68(6):744-750.

Clinical Pearl 71: Fentanyl for ICP/CPP

You have 54 y/o male in an MVC who is is found with GCS of 5, with extensor posturing and obvious head trauma.  Concerned for traumatic brain injury, the paramedics at the scene performed successful rapid sequence intubation using fentanyl, ketamine and succinylcholine.  The patient was transported to a trauma center. A CT scan of the brain revealed multiple parenchymal hemorrhages. The medical director at the local hospital called to question the use of fentanyl in the setting of traumatic brain injury and the possibility of hypotension. Does Fentanyl during the perintubation period effect cerebral perfusion pressure (CPP)??

Larygnoscopy and tracheal intubation cause hypertension and tachycardia, which may lead to increases in intracranial pressure, a problem of serious consequence in vulnerable patients. Of special interest here are the acute head trauma patients who undergo rapid sequence intubation, and for who changes in cerebral perfusion pressure may have deleterious effects [1, 2]. Various drugs such as fentanyl have been used to modify these changes in hemodynamics, including lidocaine, beta-blockers and fentanyl and have been studied extensively [3].  A prospective, randomized, double-blinded study of healthy ASA I & II patients undergoing elective intubation with appropriate NPO status evaluated the efficacy of esmolol (1.5mg/kg), fentanyl (1mcg/kd) and lidocaine (1.5mg/kg) in blunting the catecholamine response of laryngoscopy as measured by heart rate, mean arterial blood pressure, and a derived rate-pressure product. In this study of 120 patients, esmolol was shown, with statistical significance to be superior to both fentanyl and lidocaine[4]. This study is interesting but somewhat limited in the emergency setting where patients are rarely NPO, healthy, with a low-grade ASA status, and stable enough to tolerate the 2-3 minutes of pre-medication utilized in the study protocol.

The use of opioids for rapid sequence intubation in trauma has been extensively reviewed in the literature. In 2014, Pouraghaei et al evaluated 90 patients who required emergent intubation following trauma. Patients were randomized into three different groups, those receiving alftentanil (20microgm/kg), fentanyl (2microgm/kg) and sufentanil (0.2microgm/kg), respectively [5]. Vital signs such as heart rate, blood pressure, oxygen saturation and end-tidal carbon dioxide were measured 5 minutes before and 3, 5 and 10 minutes after intubation. No statistically significant differences were observed in the hemodynamic parameters (systolic and diastolic blood pressure, heart rate, oxygen saturation and end tidal carbon dioxide) during intubation and up to ten minutes after successful endotracheal intubation. While small in sample size, this study did further support the use of fentanyl as a safe sedating agent during RSI. 

In the SHRED study (1998), the authors sought to compared thiopental, fentanyl, and midazolam for rapid-sequence induction intubation [6].  In this double-blinded study, 86 patients undergoing RSI in the emergency department were randomly selected to receive thiopental (5 mg/kg), fentanyl (5 microg/kg), or midazolam (0.1 mg/kg) before paralysis was induced. Outcome measures were mortality, speed and ease of intubation, and hemodynamic changes. In all three groups, patients exposed to multiple attempts at intubation manifested pronounced hypertension. Fentanyl proved to have the most neutral hemodynamic profile during RSI, with  minimal changes in heart rate, systolic and diastolic blood pressure when administered in the peri-intubation period.

In his 1993 review in Annals of Emergency Medicine, Wall described the role of opioids in the performance of rapid sequence intubation in the patient with acute traumatic brain injuries [7]. Wall cite’s that the use of fentanyl is advantageous in that it is readily available in most emergency departments, has a rapid rate of onset and has favorable cardiovascular effects. Fentanyl may be administered 3-5microgrms/kg about one to three minutes before laryngoscopy and intubation. Larger doses of fentanyl may lead to hypoventilation thus leading to hypercarbia in the spontaneously breathing patient. If a patient is hypotensive, fentanyl should be highly considered due to its proven stable hemodynamic profile.

Despite it’s excellent sedating quality and favorable hemodynamic profile, questions remain about the actual effect of fentanyl on ICP. While some studies have suggested that the administration of opioids in bolus dosing results in transient increases in ICP, the clinical ramifications of such transient rises is unclear.  One proposed mechanism for this subtle rise in the ICP has been that a drop in MAP results in the initiation of autoregulatory processes in the brain meant to preserve brain function which, lead to vasodilation in the cerebral vasculature [8].

So? The end-game is that Fentanyl is likely safe to use in patients was suspected rises in ICP, and may in fact be beneficial in the peri-intubation phase to reduce the risk for increased ICP associated with direct laryngoscopy. 

Bibliography

1. Cardiovascular and catecholamine responses to laryngoscopy with and without tracheal intubation. Schribman AJ, Smith G, Achola KJ. British Journal of Anaesthesia. 1987;59:295-9.
2. Neurocirculatory responses to intubation with either an endotracheal tube or laryngeal mask airway in humans. Akbar AN, Muzi M, Lopatka CW, Ebert TJ. Journal of Anesthesia 1996;8:194-7
3. Use of lidocaine and fentanyl premedication for neuroprotective rapid sequence intubation in the emergency department. Kuzak N, Harrison DW, Zed PJ - CJEM - March 1, 2006; 8 (2); 80-4
4.  Effects of Esmolol, Lidocaine and Fentanyl on Haemodyamic Responses to Endotracheal Intubation: A Comparative Study. Bakiye U, Mustafa O, Erdal G, Osman NA, Feray G. Clinical Drug Investigation. 2007;27 (4): 269-277
5. Comparison between the effects of alfentanil, fentanyl and sufentanil on hemodynamic indices during rapid sequence intubation in the emergency department. Pouraghaei M, Moharamzadeh P, Soleimanpour H, Rahmani F, Safari S, Mahmoodpoor A, Ebrahimi Bakhtavar H, Mehdizadeh Esfanjani R - Anesth Pain Med - February 1, 2014; 4 (1); e14618
6. Randomized, double-blind study on sedatives and hemodynamics during rapid-sequence intubation in the emergency department: The SHRED Study. Sivilotti ML, Ducharme J - Ann Emerg Med - March 1, 1998; 31 (3); 313-24
7. Rapid Sequence Intubation in Head Trauma. Walls, R. Ann Emerg Med – June 1993. Accessed online September 2016.
   
8. Effects of Fentanyl on Intracranial Pressure and Cerebral Perfusion Pressure during Hypocapnia Moss E, Powell D.  Clinicalkey.com – September 15; 50, 779 Br. F Anaesth (1978) Macmillan Journals. 1978

Clinical Pearl 71: The TOXIC EKG

25 y/o M is found unresponsive surrounded by empty pill bottles. Intranasal naloxone was administered by police without improvement in mental status.

Vitals: RR 18/min, HR 110, BP 96/52, SpO2 100 % on 15L NRB.  BGL is 102.
Exam: Sternal rub produces eye opening, moaning, and he reaches towards his chest (GCS 9). Pupils are large and reactive, dry oral mucosa, and lungs are clear.
Medical history: Depression and bipolar disorder as per family.
Meds:  Zyprexa ™ (olanzapine), Elavil™ (amitriptyline), and Benadryl™ (diphenhydramine).

12-lead EKG:  negative for STEMI, shows an incomplete right bundle branch block, QRS duration as interpreted by the monitor is 140ms.

Treatment: saline bolus. Discussion results orders for 2 amps of sodium bicarb. Repeat EKG reveals a narrow QRS and the right bundle branch block has disappeared.

Why do an EKG in overdose?
Numerous prescription medications can produce fatal cardiac arrhythmia with overdose. Logically beta blockers and calcium channel blockers produce bradycardia with varying degrees of AV blocks. Diagnosis and treatment of these medications will be discussed elsewhere. Two much more subtle, but equally deadly cardiac toxicities exist. Widened QRS and prolonged QT. Let’s focus on the widened QRS as its treatment. 

• Blockade of sodium channels produces a widened QRS (may be subtle), right axis deviation, and predisposition to ventricular arrhythmias (VT and VF).
• QRS > 100 ms is predictive of seizures (blocks sodium channels in brain)
• QRS > 160 ms is predictive of ventricular arrhythmias (VT/VF)

Sodium channel blockade by medications such as:

Tricyclic antidepressants (Amitriptyline, Desipramine, Imipramine, Nortriptyline)
Antiarrhythmics (Procainamide, Quinidine Encainide, Flecainide)
Local anesthetics (Bupivacaine, Cocaine, Ropivacaine)
Antipsychotics (Thioridazine, and many others)
Antimalarials (Chloroquine, Hydroxychloroquine, Quinine)
Miscellaneous (Amantadine,  Diltiazem,  Diphenhydramine, Carbamazepine)

• Consider a bicarbonate challenge and repeat EKG in overdose patients with a QRS of greater than 100ms. (These patients deteriorate fast so don’t wait for the arrhythmia or seizure to start treatment.)

• EKG Findings in Sodium  Channel Blockade

• Interventricular conduction delay — QRS > 100 ms in lead II
• Right axis deviation of the terminal QRS:

• Terminal R wave > 3 mm in aVR
• R/S ratio > 0.7 in aVR

TREATMENT:

• Give IV sodium bicarbonate 100 mEq (1-2 mE /kg), (50 mEq in each amp). Repeat every 3 to 5 minutes until QRS narrows. (It’s the sodium part of sodium bicarbonate that “bumps off” the blocker from the sodium channel)Treat hypotension with IV fluid boluses initially.
• Treat ventricular arrhythmias with repeated doses of sodium bicarbonate, early intubation with hyperventilation.
• If bicarb and hyperventilation fail to stop the arrhythmia give lidocaine (1.5mg/kg) IV (competes with the sodium channel blocker for sodium channels)
• Consider giving magnesium sulfate if above treatments are not working.
• AVOID beta-blockers and amiodarone as they may WORSEN  both hypotension and cardiac conduction abnormalities.

Pre-treatment EKG

Post-sodium bicarbonate EKG:

References:
Burns, Edward. "Sodium Channel Blocker Toxicity." LIFEINTHEFASTLINE.com. N.p., 16 Mar. 2011. Web. 25 Apr. 2016.


Liebelt, Erica L. "Cyclic Antidepressants." Goldfrank's Toxicologic Emergencies, 10e. Eds. Robert S. Hoffman, et al. New York, NY: McGraw-Hill, 2015. n. pag. AccessEmergency Medicine. Web. 25 Apr. 2016. <http://accessemergencymedicine.mhmedical.com/content.aspx?bookid=1163&Sectionid=65097419>.

LoVecchio, Frank. "Cyclic Antidepressants." Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e. Eds. Judith E. Tintinalli, et al. New York, NY: McGraw-Hill, 2016. n. pag. AccessEmergency Medicine. Web. 25 Apr. 2016. <http://accessemergencymedicine.mhmedical.com/content.aspx?bookid=1658&Sectionid=109413513>.