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>.

Emergency Medical Symposium

Clinical Pearl 70 : Push Dose Nitroglycerin (PDN)

65 year old male with severe respiratory distress.

Initial impression presents an obese 65 year old male with gross respiratory distress, tripod, audible rales and with one word sentences, pale, diaphoretic and anxious. High flow nasal cannula underneath a CPAP mask with 10 cmH2O of PEEP is placed. Initial vital signs of RR 36 ppm, HR 118, irregular, BP 210/108, SpO2 93 % on 100% oxygen.

Primary survey is as above, GCS 15, no focal neurological deficits, unremarkable skin inspection, no s/s of trauma. SAMPLE history significant for increasing DOE with orthopnea and PND x 2 weeks, worse today. NKDA, Metformin, coreg, ASA, Lipitor, Glipizide, amlodipine, lasix and plavix. CAD s/p PCI with stents, AFib, DM2, hypercholesterolemia, HTN

12 lead ECG narrow-complex Afib with RVR @ 120 bpm, lateral T-wave inversion. Repeat VS unchanged. 

So what’s our next step…CPAP, IV Access, and maybe Lasix in select cases.  Nitroglycerin for preload reduction… Tabs, spray or paste is not going to work; leaves nitroglycerin infusion. NTG Infusions have been effective, depending on how aggressive the dosing schedule, nitro can rapidly reduce the blood pressure and after load.

KEY FACTS:

•    Standard NTG Infusion concentration is 200 mcg/mL; 50mg of Nitroglycerin in 250 mL of D5W either pre-mixed in a glass infusion vial or mixed at the beside.

•    Nitro infusions can be given using the 3/10 rule. Every 3 mL/hr is equal to 10 mcg/min of NTG infusion. For example: 50 mcg/min is 15 mL/hr infusion (3 x 5=15), 200 mcg/min is 60 ml/hr (3 x 20=60), 400 mcg/min is 120 mL/hr infusion (3 X 40=120).

•    Every 2 mL of Nitro Infusion is 400 mcg, equal to one SL tablet or spray pump.

•    If 1 tablet or 2mL bolus is given every 5 minutes, this equals 80 mcg/min.

•    Sublingual administration is very similar to IV infusion in bioavailability and time of onset.

•    Leave the pump in the cabinet and give 1 mL to 2 mL of the standard NTG Solution every minute, 200-400 mcg/min, titrated to effect.

•    Using a 10 fold dilution of the concentrated vial can be used as a Push Dose Nitro Solution. 5 mg (1 mL of the concentrated NTG Vial) mixed with 9 mL of Saline is 500 mcg/mL. Give 1 mL or 500 mcg every 60-90 seconds to lower the blood pressure.

Nitroglycerin lowers preload via venous vasodilation at low doses and lowers after load via arterial vasodilation at high doses, this makes our vascular container larger lowering the systemic pressure. Aggressive, high dose NTG paired with the recruitment of the alveoli using CPAP & PEEP make up the mainstay of pre-hospital treatment of APE and decompensated heart failure. Bolus doses as high as 2 mg (2000 mcg) of nitroglycerin have been given safely and effectively in previous studies.

In emergent resuscitations we need to focus on bolus dose medications in the acute phase versus starting and titrating critical care infusions while a patient is in extremis. The goal is to achieve clinical end points of treatment faster with bolus dosing at the bedside and then begin maintenance infusions once resuscitation goals are met and the hemodynamics are stable.

Stay tuned for a protocol

References:

Hsiao, R, et al. “Contemporary Treatment of Acute Heart Failure”. Progress in Cardiovascular Diseases. 2016;58:367-378.

Scott, MC & Winters, ME. “Congestive Heart Failure”. Emerg Med Clin N Am. 2015;33:553–562.

Mattu, A & Lawner B. “Prehospital Management of Congestive Heart Failure” Heart Failure Clin. 2009;5:19–24.

Weingart, S. “Sympathetic Crashing Acute Pulmonary Edema” EMCrit Podcast #1, 2009. http://emcrit.org/podcasts/scape

Levy, P; et al. “Treatment of Severe Decompensated Heart Failure With High-Dose Intravenous Nitroglycerin: A Feasibility and Outcome Analysis”. Ann Emerg Med. 2007;50:144-152.

Zalenski, RJ; et al. “The Feasibility of Treating Severe Acute Congestive Heart Failure With Bolus Intravenous Nitroglycerin”Ann Emerg Med. 2004;44.

Use of Beta-Blockers to Treat Patients with Ventricular Fibrillation

Ventricular fibrillation (VF) is the presenting cardiac rhythm in up to 40% of out-of hospital cardiac arrests. VF that does not respond to the first few defibrillation attempts is associated with high morality rates of up to 97%. ACLS guidelines recommend treating cardiac arrest patients with refractory VF with epinephrine, and amiodarone or lidocaine.  However these guidelines are often unsuccessful in achieving and maintaining return of spontaneous circulation (ROSC). Although not part of ACLS guidelines, some literature supports considering double sequence defibrillation as well as administering beta-blockers for VF refractory after standard ACLS protocol has been initiated.

Mechanism:

 

Refractory ventricular fibrillation is a severe form of electrical storm, defined as a clustering of destabilizing episodes of VF in a short period of time that does not respond to multiple defibrillation attempts. Cardiac arrest patients have high levels of catecholamines due to endogenous release and exogenous administration of epinephrine. Beneficial effects of these catecholamines are seen in the activation in of a1 receptors which cause vasoconstriction and increased coronary perfusion pressure. Adverse effects of epinephrine are seen through the activation of b1 and b2 receptors, which increase myocardial oxygen demand, worsen ischemic injury, lower VF threshold, and worsening post-resuscitation myocardial function. The use of beta-blockers is predicted to help terminate electrical storm and help prevent patients from re-entering into VF.

Evidence:

 

A small retrospective study (n=25) performed by Driver et al. (2014) demonstrated that the use of esmolol in refractory VF given after receiving at least three unsuccessful attempts at defibrillation, epinephrine 3 mg, and amiodarone 300mg. Esmolol was administered in a 500 mcg/kg bolus and followed by a drip of 0-100mcg/kg/min. Results showed that administration of esmolol was associated with higher rates of temporary ROSC, sustained ROSC, survival to hospital discharge, and discharge with favorable neurologic outcomes. Beta-blockers in refractory VF have been studied in animal and human models since the 1960’s. Though the existing literature supports a beneficial effect of beta-blockade in patients with VF/VT, high quality human trials are still lacking. Most studies have been evaluating the utility of propranolol or esmolol.

Interestingly, the ARREST and ALIVE trials showed that while amiodarone is associated with increased survival to hospital admission, it was not associated with a survival to discharge. However, in Driver et al. (2014) esmolol was associated with a survival benefit.

Conclusion:

 

            Beta-blockade should be considered in patients with refractory VF prior to the cessation of resuscitative efforts. 

References:

1.         Bourque, Daniel et al. B-Blockers for the treatment of cardiac arrest from ventricular fibrillation. Resuscitation 2007; 75:434-444.

2.        Carvalho de Oliveira, Felipe et al. Use of beta blockers for the treatement of cariac arrest due to ventricular fibrillation/pulseless ventricular tachycardia: A systemic review. Resuscitation 2012; 83: 674-683.

3.        Driver, Brian et al. Use of esmolol after failure of standard cardiopulmonary resuscitation to treat patients with refractory ventricular fibrillation. Resuscitation 2014; 85: 1337-1341.