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Intramuscular Midazolam for Seizures – Part III

Mon, 20 Feb 2012 08:50:58 +0000 By Rogue Medic 1 Comment

Also posted over at Paramedicine 101 (now at EMS Blogs) and at Research Blogging. Go check out the excellent material at these sites.

I have already pointed out my disappointment with the references of this large double-blind, randomized, noninferiority trial comparing IM (IntraMuscular) midazolam (Versed) with IV (IntraVenous) lorazepam (Ativan). One of those criticisms appears to be just due to a typographical error. The footnote in the text was ¹¹, but the footnote should have been ¹.

The relationships among benzodiazepine dose, respiratory depression, and subsequent need for endotracheal intubation are poorly characterized, but higher doses of benzodiazepines may actually reduce the number of airway interventions. Our data are consistent with the finding that endotracheal intubation is more commonly a sequela of continued seizures than it is an adverse effect of sedation from benzodiazepines.¹¹ ^[1]

Here is some of the information from footnote ¹. One interesting aspect of this double-blind study is that there is a placebo group. Patients received 2 mg IV lorazepam, 5 mg IV diazepam (Valium), or IV placebo. Treatment could be repeated one time if seizures continued for more than 4 minutes or if seizures recurred.

Cardiorespiratory complications before arrival at the hospital and at the time of transfer were important secondary outcomes that relate to the safety of out-of-hospital therapy with intravenous benzodiazepines. Despite concern regarding the adverse effects of these agents, we found a trend toward lower rates of out-of-hospital complications (primarily respiratory compromise) in the active-treatment groups than in the placebo group. This suggests that respiratory complications associated with prolonged seizures may be more pronounced than those caused by intravenous lorazepam and diazepam given at relatively low doses.^[2]

The doses are low. The lorazepam dose is only half of the 4 mg used in the IV lorazepam vs. IM midazolam study.

The doses of midazolam and lorazepam used in this trial are consistent with the most effective doses for the treatment of status epilepticus that are reported in the literature.^9,10 Although these initial doses are higher than the ones used by many EMS systems and emergency physicians, they are the same as those approved for this indication and are in line with those used by epileptologists.^[1]

Is there added safety from the lower doses?

The epilepsy specialists and the FDA (Food and Drug Administration) do not recommend lower doses.

Were the low doses effective?

2 mg midazolam?

Does anyone really expect such a small dose to make a difference?

Despite the beneficial outcomes associated with intravenous lorazepam and diazepam, 41 to 57 percent of patients who received active treatment were still in status epilepticus at the time of arrival at the emergency department. These patients were more than twice as likely to require intensive medical care as those whose seizures ended outside the hospital. Differences in the causes of the episodes of status epilepticus are unlikely to account for this difference. These observations, coupled with the favorable risk–benefit profile associated with lorazepam and diazepam in this trial, suggest that higher doses should be studied to define the optimal therapy for patients with out-of-hospital status epilepticus.^[2]

An editorial refers to the study just published^[1] and to the benzodiazepine vs. placebo study.^[2] Describing the complications in the placebo study, the author wrote –

Successful termination was much more common in the two groups that received benzodiazepines (59% with lorazepam, 43% with diazepam, and 21% with placebo). Since respiratory distress was twice as common in the group given placebo as in either of the groups given a benzodiazepine, the best way to avoid the need for intubation is to stop seizure activity.^[3]

This presents an interesting conundrum. Doses of benzodiazepines (midazolam, lorazepam, diazepam, . . .) are often limited, due to a fear of causing respiratory complications.

When treating seizures, higher doses of benzodiazepines may actually protect patients from respiratory complications.

With a fatality rate around 10%, seizures are certainly not benign.

Maybe early treatment with high dose benzodiazepines can significantly decrease that fatality rate.

Finally, relatively few out-of-hospital interventions have been evaluated in randomized controlled trials,¹⁶ and when they have been evaluated carefully, therapies with intuitive appeal have often been found either to lack benefit or to cause harm to patients.^17-20 ^[2]

The irony is that we may be doing the opposite by limiting doses of benzodiazepines to less than what is recommended by the FDA.

What do you think?

See also Part I and Part II. To be continued in Part IV.

Footnotes:

^[1] Intramuscular versus intravenous therapy for prehospital status epilepticus.
Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, Barsan W; NETT Investigators.
N Engl J Med. 2012 Feb 16;366(7):591-600.
PMID: 22335736 [PubMed - in process]

^[2] A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus.
Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, Gottwald MD, O’Neil N, Neuhaus JM, Segal MR, Lowenstein DH.
N Engl J Med. 2001 Aug 30;345(9):631-7. Erratum in: N Engl J Med 2001 Dec 20;345(25):1860.
PMID: 11547716 [PubMed - indexed for MEDLINE]

Free Full Text from N Engl J Med. with link to PDF Download

^[3] Intramuscular versus intravenous benzodiazepines for prehospital treatment of status epilepticus.
Hirsch LJ.
N Engl J Med. 2012 Feb 16;366(7):659-60. No abstract available.
PMID: 22335744 [PubMed - in process]

Silbergleit, R., Durkalski, V., Lowenstein, D., Conwit, R., Pancioli, A., Palesch, Y., & Barsan, W. (2012). Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus New England Journal of Medicine, 366 (7), 591-600 DOI: 10.1056/NEJMoa1107494

Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, Gottwald MD, O’Neil N, Neuhaus JM, Segal MR, & Lowenstein DH (2001). A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. The New England journal of medicine, 345 (9), 631-7 PMID: 11547716

Hirsch LJ (2012). Intramuscular versus intravenous benzodiazepines for prehospital treatment of status epilepticus. The New England journal of medicine, 366 (7), 659-60 PMID: 22335744

Filed Under: Heresy, Midazolam, Paramedicine 101, Pharmacology, Research Blogging, Sedation

Intramuscular Midazolam for Seizures – Part II

Sun, 19 Feb 2012 06:30:47 +0000 By Rogue Medic 1 Comment

Also posted over at Paramedicine 101 (now at EMS Blogs) and at Research Blogging. Go check out the excellent material at these sites.

While there have been studies comparing IM (IntraMuscular) midazolam (Versed) with IV (IntraVenous) anti-epileptic medications, this is a large study that compares IM midazolam with the best IV anti-epileptic medication in a double-blind, randomized, noninferiority trial.

All adults and those children with an estimated body weight of more than 40 kg received either 10 mg of intramuscular midazolam followed by intravenous placebo or intramuscular placebo followed by 4 mg of intravenous lorazepam.^[1]

For the study, there were two different doses for the auto-injector (similar to an EpiPen auto-injector). The doses were not small.

Midazolam for seizures is an off-label use both when given IM and when given IV.^[2]

The lorazepam IV doses in the study are according to the FDA label –

For the treatment of status epilepticus, the usual recommended dose of Lorazepam Injection is 4 mg given slowly (2 mg/min) for patients 18 years and older. If seizures cease, no additional Lorazepam Injection is required. If seizures continue or recur after a 10- to 15- minute observation period, an additional 4 mg intravenous dose may be slowly administered.^[3]

Unfortunately, my protocols only permit 1/4 or 1/2 the dose of lorazepam for seizures, which may be repeated every 5 minutes up to a maximum of one full dose recommended as the initial dose by the FDA.^[4] There is no adult IM use of midazolam.

There is often a concern about carefully adjusting pediatric doses. How did they handle that in this study?

In children with an estimated weight of 13 to 40 kg, the active treatment was 5 mg of intramuscular midazolam or 2 mg of intravenous lorazepam.^[1]

But such high doses will lead to deadly outcomes

Except that this excuse to give low doses is not supported by the authors of this study.

The relationships among benzodiazepine dose, respiratory depression, and subsequent need for endotracheal intubation are poorly characterized, but higher doses of benzodiazepines may actually reduce the number of airway interventions. Our data are consistent with the finding that endotracheal intubation is more commonly a sequela of continued seizures than it is an adverse effect of sedation from benzodiazepines.¹¹ ^[1]

That is a very interesting comment. The authors believe that intubations are increased by not controlling the seizure, rather than by giving large doses of a benzodiazepine. Unfortunately. I did not see anything to support that statement in the paper they cited as footnote 11.^[5]

See also Part I. To be continued in Part III, and Part IV.

Footnotes:

^[2] MIDAZOLAM HYDROCHLORIDE injection, solution
[Hospira, Inc.]
DailyMed
NLM
FDA label

I checked all of the injectable formulations of midazolam. They are the same. None include recommended dosing for seizures, but all include warnings about midazolam possibly causing seizures.

^[3] Lorazepam (lorazepam) Injection, Solution
[Baxter Healthcare Corporation]
DailyMed
NLM
FDA label

^[4] Seizure
Pennsylvania Statewide Advanced Life Support Protocols
7007 – ALS – Adult/Peds
Page 100/128
Free Full Text PDF of All ALS Protocols

Titrate until seizure stops.

Split the dose in half. Repeat the dose in 5 minutes.

There is no option for adult IM dosing.

^[5] A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children.
Chamberlain JM, Altieri MA, Futterman C, Young GM, Ochsenschlager DW, Waisman Y.
Pediatr Emerg Care. 1997 Apr;13(2):92-4.
PMID: 9127414 [PubMed - indexed for MEDLINE]

Chamberlain JM, Altieri MA, Futterman C, Young GM, Ochsenschlager DW, & Waisman Y (1997). A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Pediatric emergency care, 13 (2), 92-4 PMID: 9127414

Filed Under: Heresy, Midazolam, Pharmacology, Research Blogging, Sedation

Intramuscular Midazolam for Seizures – Part I

Fri, 17 Feb 2012 12:10:30 +0000 By Rogue Medic 4 Comments

A study of IM (IntraMuscular) midazolam for EMS to treat seizures. The study looks at status epilepticus, but any seizure still present when EMS arrives should be treated. The terminology does not help. The only time I use the term status epilepticus is when teaching/writing about seizures; not when describing what I treated; not when thinking about what to do.

Many emergency medical services (EMS) systems, however, have begun to use intramuscular midazolam rather than an intravenous agent, largely because intramuscular administration is faster and is consistently achievable. ² This practice has become increasingly common despite the lack of clinical-trial data regarding the efficacy and safety of intramuscular midazolam.^[1]

Really?

In about an hour, using PubMed and Google, I found these. All of them examine the use of IM midazolam. Only one is not on humans.

1988

IM midazolam for status epilepticus in the emergency department.
Mayhue FE.
Ann Emerg Med. 1988 Jun;17(6):643-5.
PMID: 3377295 [PubMed - indexed for MEDLINE]

A 71-year-old man presented with a continuous generalized tonic-clonic seizure of 80 minutes duration. Multiple attempts to establish an IV line failed. Ten milligrams of midazolam hydrochloride was administered IM and was followed by prompt termination of seizure activity. This report discusses the pharmacokinetic and anticonvulsant properties of midazolam as an alternative to diazepam for the initial treatment of status epilepticus.

1991

A comparative pharmacokinetic study of intravenous and intramuscular midazolam in patients with epilepsy.
Bell DM, Richards G, Dhillon S, Oxley JR, Cromarty J, Sander JW, Patsalos PN.
Epilepsy Res. 1991 Nov-Dec;10(2-3):183-90.
PMID: 1817958 [PubMed - indexed for MEDLINE]

Since intravenous administration of AEDs including diazepam is not always feasible in status epilepticus there are obvious advantages in having an effective intramuscular formulation. Our data suggest that midazolam may be such a drug.

1992

Midazolam in treatment of epileptic seizures.
Lahat E, Aladjem M, Eshel G, Bistritzer T, Katz Y.
Pediatr Neurol. 1992 May-Jun;8(3):215-6.
PMID: 1622519 [PubMed - indexed for MEDLINE]

Midazolam (Versed), the first water-soluble benzodiazepine, has had widespread acceptance as a parenteral anxiolitic agent. Its antiepileptic properties were studied in adult patients with good results. Midazolam was administered intramuscularly to 48 children, ages 4 months to 14 years, with 69 epileptic episodes of various types. In all but 5 epileptic episodes, seizures stopped 1-10 min after injection. These results suggest that midazolam administered intramuscularly may be useful in a variety of epileptic seizures during childhood, specifically when attempts to introduce an intravenous line in convulsing children are unsuccessful.

1994

Intravenous versus intramuscular midazolam in treatment of chemically induced generalized seizures in swine.
Orebaugh SL, Bradford SM.
Am J Emerg Med. 1994 May;12(3):284-7.
PMID: 8179731 [PubMed - indexed for MEDLINE]

It is concluded that midazolam is effective in the control of tonic-clonic manifestations of generalized seizures when administered by the IV or the IM route

1997

Midazolam in treatment of various types of seizures in children.
Yakinci C, Müngen B, Sahin S, Karabiber H, Durmaz Y.
Brain Dev. 1997 Dec;19(8):571-2.
PMID: 9440805 [PubMed - indexed for MEDLINE]

No side effects were observed. These results suggest that i.m. administration of midazolam may be useful in a variety of seizures during childhood, especially in case of intravenous (i.v.) line problem.

A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children.
Chamberlain JM, Altieri MA, Futterman C, Young GM, Ochsenschlager DW, Waisman Y.
Pediatr Emerg Care. 1997 Apr;13(2):92-4.
PMID: 9127414 [PubMed - indexed for MEDLINE]

CONCLUSIONS:
IM midazolam is an effective anticonvulsant for children with motor seizures. Compared to IV diazepam, IM midazolam results in more rapid cessation of seizures because of more rapid administration. The IM route of administration may be particularly useful in physicians’ offices, in the prehospital setting, and for children with difficult IV access.

1999

Use of intramuscular midazolam for status epilepticus.
Towne AR, DeLorenzo RJ.
J Emerg Med. 1999 Mar-Apr;17(2):323-8. Review.
PMID: 10195494 [PubMed - indexed for MEDLINE]

The pharmacodynamic effects of midazolam can be seen within seconds of its administration, and seizure arrest is usually attained within 5 to 10 min. Case reports and a recent randomized trial that demonstrate the successful use of i.m. midazolam in the termination of epileptic seizures are reviewed.

2002

Midazolam for the treatment of out-of-hospital pediatric seizures.
Vilke GM, Sharieff GQ, Marino A, Gerhart AE, Chan TC.
Prehosp Emerg Care. 2002 Apr-Jun;6(2):215-7.
PMID: 11962570 [PubMed - indexed for MEDLINE]

CONCLUSION:
Prehospital IV midazolam is an effective intervention for pediatric seizures, while IM midazolam was associated with a 20% failure rate, with both having minimal risk of respiratory compromise.

This was the only study of midazolam cited as a midazolam study by the authors.

Controlling seizures in the prehospital setting: diazepam or midazolam?
Rainbow J, Browne GJ, Lam LT.
J Paediatr Child Health. 2002 Dec;38(6):582-6.
PMID: 12410871 [PubMed - indexed for MEDLINE]

CONCLUSION:
Midazolam controls seizures as effectively as diazepam in the prehospital setting. Furthermore, midazolam potentially reduces respiratory depression and time to treatment.

2005

Status epilepticus: an evidence based guide.
Walker M.
BMJ. 2005 Sep 24;331(7518):673-7. Review. No abstract available.
PMID: 16179702 [PubMed - indexed for MEDLINE]

Free Full Text from PubMed Central.

Intramuscular midazolam vs intravenous diazepam for acute seizures.
Shah I, Deshmukh CT.
Indian J Pediatr. 2005 Aug;72(8):667-70.
PMID: 16131771 [PubMed - indexed for MEDLINE]

CONCLUSION:
i.m. midazolam is an effective agent for controlling acute convulsions in children especially in children with febrile convulsions. It has relatively no side effects as compared to Intravenous diazepam and can be used as a first line agent for treatment of acute convulsions in patients with difficult intravenous access.

2010

Human safety and pharmacokinetic study of intramuscular midazolam administered by autoinjector.
Reichard DW, Atkinson AJ, Hong SP, Burback BL, Corwin MJ, Johnson JD.
J Clin Pharmacol. 2010 Oct;50(10):1128-35. Epub 2010 May 13.
PMID: 20466872 [PubMed - indexed for MEDLINE]

Midazolam in an autoinjector was evaluated in an open-label dose escalation study involving 39 healthy participants. Safety and pharmacokinetic parameters were determined for doses ranging from 5 to 30 mg. No serious adverse events were noted during the study.

2011

RAMPART (Rapid Anticonvulsant Medication Prior to Arrival Trial): a double-blind randomized clinical trial of the efficacy of intramuscular midazolam versus intravenous lorazepam in the prehospital treatment of status epilepticus by paramedics.
Silbergleit R, Lowenstein D, Durkalski V, Conwit R; Neurological Emergency Treatment Trials (NETT) Investigators.
Epilepsia. 2011 Oct;52 Suppl 8:45-7. doi: 10.1111/j.1528-1167.2011.03235.x.
PMID: 21967361 [PubMed - indexed for MEDLINE]

That is a preliminary release of information from the study that was just published in NEJM.

This practice has become increasingly common despite the lack of clinical-trial data regarding the efficacy and safety of intramuscular midazolam.^[1]

I haven’t looked at the rest of the study, but I hope that more thought went into the study design than went into the search for other research.

To be continued in Part II, Part III, and Part IV.

Footnotes:

^[1] Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus
Robert Silbergleit, M.D., Valerie Durkalski, Ph.D., Daniel Lowenstein, M.D., Robin Conwit, M.D., Arthur Pancioli, M.D., Yuko Palesch, Ph.D., and William Barsan, M.D. for the NETT Investigators
N Engl J Med 2012; 366:591-600February 16, 2012
Preview from NEJM

Apparently, there is no PubMed abstract, yet.

Late entry 02/18/2012 22:27 – Correction, there is a PubMed abstract for this study –

Intramuscular versus intravenous therapy for prehospital status epilepticus.
Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, Barsan W; NETT Investigators.
N Engl J Med. 2012 Feb 16;366(7):591-600.
PMID: 22335736 [PubMed - in process]

Filed Under: Heresy, Midazolam, Pharmacology, Research, Sedation

How Bad are the Drug Shortages

Wed, 15 Feb 2012 17:00:36 +0000 By Rogue Medic 1 Comment

I rant a bit about the misuse of many of these drugs, but there are a lot of drugs used in EMS on the current drug shortage list.

There is a lot written about the drug shortages, but what drugs are affected right now? I copied a list of what drugs are currently experiencing shortages as of today from the FDA (Food and Drug Administration).^[1], ^[2]

What about EMS drugs?

Alfentanil Injection (Alfenta, Rapifen) – An opioid that may be used in some EMS systems as a substitute for fentanyl. Or another reason for EMS to use ketamine.^[7]

Atracurium besylate (Tracrium) – A paralytic used in RSI (Rapid Sequence Induction/Intubation).

Atropine Sulfate Injection – Amphastar lists no delays, but other manufacturers list manufacturing delays and an increase in product demand. One manufacturer temporarily suspended production in April 2011.

The FDA search shows that there were drug shortages updates for atropine on 12/11/2008, 4/07/2009, and 9/30/2011 (the current shortage?), but all of the cached pages are the most recent, so the original information is not there.^[3]

Following concerns about possible terrorist attacks using poisons that may be treated with atropine, the long term stability of atropine, and the continuing lack of evidence of benefit of atropine in treating cardiac arrest.^[4]

How much did each of those contribute to another magic treatment biting the dust?

Caffeine, anhydrous (125 mg/mL) and Sodium benzoate (125 mg/mL) (Starbucks, Dunkin’ Donuts) – OK, that is not the kind of caffeine they are referring to. There might be true rebellion among EMS and hospital personnel if caffeine were not available.

What does that tell us about sleep deprivation, medicine, and the need for naps on the job?

Calcium Chloride Injection – If we are treating emergency hyperkalemia (which I recently saw written as hyperpotassiumemia ) with anything other than calcium chloride as the first line drug, we are not providing good patient care.^[5]

But calcium is dangerous!!

The danger of calcium is just another EMS myth.

What is dangerous is using much less effective treatments, such as sodium bicarbonate.

What is even more dangerous is using harmful, but ineffective treatments, such as sodium polystyrene sulfonate (Kayexalate)

Calcium Gluconate – A less concentrated form of calcium, that is safer in IV (IntraVenous) lines of questionable patency, not that this is the biggest concern in treating peri-arrest patients. IO (IntraOsseous) works for calcium chloride.^[6]

Desmopressin Injection (DDAVP, Stimate, Minirin) – Similar to vasopressin.

Dexamethasone Injection (Decadron) – Methylprednisolone (Medrol, Solu-Medrol) is a good alternative that is not listed as a current drug shortage.

Diazepam Injection (Valium, Diastat) – The common alternative benzodiazepine sedatives (lorazepam [Ativan] and midazolam [Versed]) are also listed as current drug shortages.

Maybe this is a good reason to start carrying ketamine.^[7]

Digoxin Injection – An inotrope alternative to catecholamines. The only inotrope not supposed to raise heart rate or myocardial oxygen demand at therapeutic levels. On the other hand, there is debate about whether digoxin improves outcomes.^[8], ^[9]

Diltiazem Injection (Cardizem) – Verapamil (Calan, Isoptin, and Verelan) is the common alternative calcium channel blocker that should be used in the place of diltiazem for A Fib (Atrial Fibrillation) or SVT (SupraVentricular Tachycardia).

Diphenhydramine Hydrochloride Injection (Benadryl) – A medication to treat dystonic reactions. For dystonia, it can be replaced by benztropine (Cogentin). The more common use of diphenhydramine is as an antihistamine, such as after IM (IntraMuscular) epinephrine for anaphylaxis. It may sedate and decrease itching, but do not expect diphenhydramine to reverse anaphylaxis.

An example of dystonia. Image credit.

Etomidate Injection (New!!) (Amidate) – Etomidate is commonly used for pseudo-RSI or DFI (Drug Facilitated Intubation). In Pennsylvania, we have a dose of 0.3 mg/kg, that is often restricted even more by some medical command doctors out of an apparent fear of giving a dose that might be effective. Should they want to give orders for more, the maximum dose listed in the protocol is 30 mg. The medical command doctor can order more, but few seem to realize that this is not a restriction on what they can order. Etomidate is only supposed to be used with a paralytic for RSI, but is expected to be both sedative and paralytic, when EMS uses it in Pennsylvania.

Why use a not-very-effective drug at a dose that is not expected to be effective?

Fentanyl Citrate Injection (Sublimaze) – The shortage of both benzodiazepines and opioids are just more reasons for EMS to use ketamine.^[7]

Furosemide Injection (Lasix) – A drug that EMS should not use. Furosemide is so far down on the list of treatments for CHF (Congestive Heart Failure), that it suggests we have been digging a grave for the patient, if we stay on scene long enough to give furosemide. A worthless EMS treatment.^[10], ^[11] Pennsylvania is ahead of most states in moving furosemide to medical command order only, but the better move is to remove it from EMS use completely.

Ketorolac Injection (Toradol) – A pain medicine related to aspirin, so not a good idea for trauma, but some people are less worried about interfering with the ability of trauma patients to stop bleeding than they are about the possibility that the 10/10 severe pain patient might stop screaming and, without anyone noticing, stop breathing.

One possible superiority is for calculi (kidney stones and gall stones). Of course, this is just another reason for EMS to use ketamine.^[7]

Labetalol Hydrochloride Injection (Normodyne, Trandate) – A beta blocker. Beta blockers have been de-emphasized since the CRUSADE trial, but there are still EMS indications in heart attack. Patients with signs of dramatic catcholamine release (they look as if someone gave them epinephrine) except for patients with tachycardia (greater than 110 beats per minute).

Lorazepam Injection (Ativan) – Not the best, or even the second best, EMS sedative, but one that is preferred by a lot of people. A much better idea is midazolam, because aggressive doses can be given and they should be wearing off at about the time the patient is being transferred to the ED (Emergency Department), so that one-on-one observation of a heavily sedated patient is not required and flumazenil (Romazicon) is not given. Another reason for EMS to use ketamine.^[7]

Magnesium Sulfate Injection – A safer antiarrhythmic than amiodarone and a treatment for some of the arrhythmias caused by amiodarone, such as torsades des pointes.-

Mannitol Injection – An osmotic diuretic used in some EMS systems.

Methylphenidate HCl (Ritalin) – Possibly the second most common EMS drug – after caffeine.

Metoclopramide injection (Reglan) – Anti-nausea medication.

Midazolam Injection (Versed) – This used to be my favorite EMS sedative, but this is one more reason for EMS to use ketamine.^[7]

Morphine Sulfate Injection – For pain management and another reason for EMS to use ketamine.^[7]

Nalbuphine Injection (Nubain) – A poor substitute for morphine and a pathetic excuse for risk management. Just another reason for EMS to use ketamine.^[7]

Naltrexone Oral Tablets (New!!) (Depade, ReVia) – With the use of nebulized naloxone, who knows what might be next? As long as we are treating something other than respiratory depression (patients unlikely to be able to use a nebulizer), maybe oral tablets will be next and the longer acting opioid antagonist may appeal to those terrified of any potential for respiratory depression.

NeoProfen (ibuprofen lysine) Injection – For treatment of PDA (Patent Ductus Arteriosus) in premature babies. Some EMS may use this, but it is more likely to be found in the ED or neonatal ICU.

Ondansetron Injection 2 mg/mL (Zofran) – One effective antiemetic.

Ondansetron Injection 32 mg/50 mL premixed bags (Zofran) – Same thing, different preparation.

Oxytocin Injection, USP (synthetic) (Pitocin) – For post-partum hemorrhage that is not otherwise controlled. Massage the fundus and consider direct pressure. Direct pressure is not in EMS protocols, but when the alternative is the death of the patient, do we want to stop the bleeding, or do we want to follow protocols?

Pancuronium Bromide Injection (Pavulon) – A paralytic used in RSI.

Phentolamine Mesylate for Injection (Regitine) – For treatment of extravasation of catecholamines (epinephrine, dopamine, dobutamine). Not usually carried by EMS (after all, it only happens in other EMS systems), but used in the ED (even to treat the extravasation of catecholamines from EMS IVs – but only from those other EMS systems).

Procainamide HCL Injection (Pronestyl) – An antiarrhythmic that is very effective, but it has a lot of side effects – just like the much less effective drugs that are used in its place.

Prochlorperazine Injection (Compazine) – Another anti-nause medication. This is also one of the drugs that may cause dystonic reactions.

Promethazine Injection (Phenergan) – Still another anti-nause medication. Another drug that may cause dystonic reactions.

Vasopressin Injection (Pitressin) – An alternative to epinephrine as a pressor to treat cardiac arrest, even though there is no evidence of improved survival. Also goes by the name “pit,” so that it can be easily confused with Pitocin (“pit”) used in OB/GYN.

Vecuronium Injection (Norcuron) – A paralytic used in RSI.

That is it for the drugs that are used in some EMS systems. Fortunately, a lot can be replaced by ketamine, or their use can be reduced by the use of ketamine. Pain management, sedation, RSI, excited delirium, DSI (Delayed Sequence Intubation), et cetera. One long list of reasons for EMS to use ketamine.^[7]

Also see Stressful Drug Shortage Update.

Footnotes:

^[1] Current Drug Shortages
Drug Shortages
FDA
02/15/2012
Drug shortage Update

^[2] List of medications from FDA drug shortages update on 02/15/2012

Acetylcysteine Inhalation Solution

Alcohol Dehydrated (Ethanol > 98%)

Alfentanil Injection

Amikacin Injection

Amino Acid Products (New!!)

Aminocaproic Acid

Ammonium Chloride Injection

Ammonium Molybdate Injection

Ammonul (sodium phenylacetate and sodium benzoate) Injection 10%/10%

Amphetamine Mixed Salts, ER Capsules

Amphetamine Mixed Salts Immediate-Release Tablets

Anadrol-50 tablets (Oxymetholone Tablets)

Aquasol A

Atracurium besylate

Atropine Sulfate Injection

Avalide (irbesartan and hydrochlorothiazide)Tablets

Bleomycin Injection

Bupivacaine Hydrochloride Injection

Buprenorphine Injection

Butorphanol Injection

Caffeine, anhydrous (125 mg/mL) and Sodium benzoate (125 mg/mL)

Calcitriol 1 mcg/mL Injection

Calcium Chloride Injection

Calcium Gluconate

Cerezyme (imiglucerase for injection)

Chromic Chloride Injection

Cisplatin injection 1 mg/mL solution

Corticorelin Ovine Triflutate (New!!)

Cosyntropin Injection

Cyanocobalamin injection

Daunorubicin hydrochloride solution for injection

Desmopressin Injection

Dexamethasone Injection

Dexrazoxane Injection

Dextroamphetamine Tablets

Diazepam Injection

Digoxin Injection

Diltiazem Injection

Diphenhydramine Hydrochloride Injection

Doxorubicin (adriamycin) lyophilized powder

Doxorubicin Liposomal (Doxil) Injection

Doxorubicin Solution for Injection

Ethiodol (ETHIODIZED OIL) ampules

Etomidate Injection (New!!)

Etoposide solution for injection

Fabrazyme (agalsidase beta)

Fentanyl Citrate Injection

Fluorouracil Injection

Foscarnet Sodium Injection

Fosphenytoin Sodium Injection

Furosemide Injection

Haloperidol Decanoate Injection

Indigo Carmine Injection

Insulin glulisine [rDNA origin] injection) solution for injection (Apidra SoloStar)

Intravenous Fat Emulsion

Isoniazid Tablets

Ketorolac Injection

Labetalol Hydrochloride Injection

L-cysteine hydrochloride

Leucovorin Calcium Lyophilized Powder for Injection

Leuprolide Injection

Levaquin Injection

Levofloxacin Injection

Levoleucovorin (Fusilev) 50 mg single use vials

Lorazepam Injection

Magnesium Sulfate Injection

Mannitol Injection

Mesna 100 mg/mL Injection

Methotrexate Injection

Methylphenidate HCl

Methyldopate Injection

Metoclopramide injection

Mexiletine Capsules (150mg, 200mg, and 250mg)

Midazolam Injection

Mitomycin Powder for Injection

Morphine Sulfate Injection

Multi-Vitamin Infusion (Adult and pediatric)

Mustargen (mechlorethamine HCl) injection

Nalbuphine Injection

Naltrexone Oral Tablets (New!!)

NeoProfen (ibuprofen lysine) Injection

Neupro (rotigotine transdermal system)

Ondansetron Injection 2 mg/mL

Ondansetron Injection 32 mg/50 mL premixed bags

Ontak injection

Opana ER (oxymorphone hydrochloride) Extended-Release Tablets CII (New!!)

Orphenadrine Citrate Injection

Oxsoralen (methoxsalen) 1% topical lotion

Oxytocin Injection, USP (synthetic)

Paclitaxel Injection

Pancuronium Bromide Injection

Phentolamine Mesylate for Injection

Phytonadione Injectable Emulsion (Vitamin K)

Potassium Phosphate

Primaquine Phosphate Tablets

Procainamide HCL Injection

Prochlorperazine Injection

Promethazine Injection

Selenium injection

Sodium Acetate Injection

Sodium Chloride 23.4%

Sodium Phosphate Injection

Sulfamethoxazole 80mg/trimethoprim 16mg/ml injection (SMX/TMP)

Telavancin (Vibativ) Injection

Tetracycline Capsules

Thiotepa for Injection

Thyrogen (thyrotropin alfa) injection 1.1mg/vial

Thyrolar Tablets

Ticlopidine Tablets

Tobramycin Solution for Injection

Vasopressin Injection

Vecuronium Injection

Vinblastine Sulfate Injection

Voltaren gel 1% (Diclofenac Sodium Topical Gel) (New!!)

^[3] Atropine Sulfate Injection
FDA
FDA Search

^[4] What Will We Do With All of That Atropine
Rogue Medic
Fri, 22 Oct 2010
Article

^[5] Management of severe hyperkalemia.
Weisberg LS.
Crit Care Med. 2008 Dec;36(12):3246-51. Review.
PMID: 18936701 [PubMed - indexed for MEDLINE]

Free Full Text PDF

^[6] Comparison study of intraosseous, central intravenous, and peripheral intravenous infusions of emergency drugs.
Orlowski JP, Porembka DT, Gallagher JM, Lockrem JD, VanLente F.
Am J Dis Child. 1990 Jan;144(1):112-7.
PMID: 1688484 [PubMed - indexed for MEDLINE]

^[7] Is Ketamine an EMS Wonder Drug
Rogue Medic
Sun, 01 Jan 2012
Article

^[8] Update on digoxin therapy in congestive heart failure.
Haji SA, Movahed A.
Am Fam Physician. 2000 Jul 15;62(2):409-16. Review.
PMID: 10929703 [PubMed - indexed for MEDLINE]

Free Full Text from Am Fam Physician.

For many more years, digitalis continued to be an important part of heart failure management. The detrimental aspects of digoxin therapy were not considered important until excess mortality was reported in survivors of myocardial infarction who received digitalis.^13,14 Uncontrolled observations that the withdrawal of digoxin produced no ill effects also raised concerns about the efficacy of the drug.^15,16

^[9] The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group.
[No authors listed]
N Engl J Med. 1997 Feb 20;336(8):525-33.
PMID: 9036306 [PubMed - indexed for MEDLINE]

Free Full Text from N Engl J Med.

In conclusion, digoxin had no effect on overall mortality in patients receiving diuretics and angiotensin-converting–enzyme inhibitors, but it did reduce the overall number of hospitalizations and the combined outcome of death or hospitalization attributable to worsening heart failure. In clinical practice, digoxin therapy is likely to affect the frequency of hospitalization, but not survival.

On the other hand, that is not a study of digoxin for emergency use.

^[10] Prehospital therapy for acute congestive heart failure: state of the art.
Mosesso VN Jr, Dunford J, Blackwell T, Griswell JK.
Prehosp Emerg Care. 2003 Jan-Mar;7(1):13-23. Review.
PMID: 12540139 [PubMed - indexed for MEDLINE]

Free Full Text PDF

^[11] Modern management of cardiogenic pulmonary edema.
Mattu A, Martinez JP, Kelly BS.
Emerg Med Clin North Am. 2005 Nov;23(4):1105-25. Review.
PMID: 16199340 [PubMed - indexed for MEDLINE]

Free Full Text PDF

Filed Under: FDA, Heresy, Pharmacology

Did Drugs Kill Whitney Houston

Mon, 13 Feb 2012 20:35:02 +0000 By Rogue Medic Leave a Comment

As with the death of Michael Jackson, this is not a call you want to be on, because everybody is going to be second-guessing everything that was done, but let’s assume that you are dispatched.

Law enforcement sources tell TMZ … multiple medicine bottles were found in the Beverly Hills hotel room where Whitney Houston died … but we’re told there were NOT a lot of pills at the scene.^[1]

there were NOT a lot of pills at the scene.

This suggests that a lot of pills were taken, but does not tell us over what time period?

How many pills should have been in the containers if the pills were taken as prescribed?

Among the pills … ibuprofen (painkiller), Xanax (anti-depressant), Midol (for menstrual cramps), amoxicillin (for treating bacterial infections) … and more.^[1]

Ibuprofen and Midol are sometimes the same thing, but Midol comes in so many different formulations, that you cannot tell without knowing the specific version.^[2] I did not know there were so many different drugs sold under essentially the same name. Besides, I use chocolate to keep my inner woman from PMSing.

The ones that catch my eye are – . . . Xanax … and more.

What is Xanax?

Xanax is the brand name for alprazolam, a benzodiazepine. Other benzodiazepines are drugs we commonly carry – diazepam (Valium), midazolam (Versed), and lorazepam (Ativan). Treatment of benzodiazepine overdose is supportive care (maintain oxygenation and ventilation, and maintain blood pressure). There is a competitive antagonist, flumazenil (Romazicon), but flumazenil does not bring benzodiazepine overdoses back from the dead any more than naloxone (Narcan) brings heroin overdoses back from the dead. The treatment for opioid overdose is also supportive care.

Absorption
Following oral administration, alprazolam is readily absorbed. Peak concentrations in the plasma occur in 1 to 2 hours following administration. Plasma levels are proportionate to the dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL were observed. Using a specific assay methodology, the mean plasma elimination half-life of alprazolam has been found to be about 11.2 hours (range: 6.3–26.9 hours) in healthy adults.^[3]

11+ hours can be a long time. Xanax XR (eXtended Release) does not appear to prolong the clearance of alprazolam, only the onset. What can affect the rate of elimination of alprazolam?

Metabolism/Elimination
Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam.^[3]

A lot of the technical drug information is not important, but the cytochrome P450 metabolism is important in the elimination of a lot of medications

CYP3A4 is a member of the cytochrome P450 superfamily of enzymes. . . . This enzyme is involved in the metabolism of approximately half the drugs that are used today, including acetaminophen, codeine, ciclosporin, diazepam, and erythromycin. . . . Most drugs undergo deactivation by CYP3A4, either directly or by facilitated excretion from the body. Also, many substances are bioactivated by CYP3A4 to form their active compounds, and many protoxins being toxicated into their toxic forms^[4]

Grapefruit juice can slow down metabolism by about half, so some consumer sites may recommend that people drink grapefruit juice to cut down on the cost of medications. This really is not a great idea, since it may affect other medications. It is something to discuss with a doctor, so that your doctor is aware of things that may interact with the medications you are taking, but doctors should do that anyway.

One interesting item that does not appear to be related to CYP3A4 metabolism. It makes me wonder about the effect flumazenil might have on smokers. There is no mention of smoking or cigarettes on the flumazenil label.^[5]

Cigarette Smoking
Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers.^[4]

We’re told some of the pills were old … some issued in 2011 … but some of the bottles were from 2012.^[1]

As long as a month and a half ago? Some people have milk and eggs that are that old, too. The medications should age much better than dairy products.

A prescription for alprazolam is often written as PRN (Pro Re Nata – Latin for according to the circumstances, or to be taken as needed). Alprazolam is an anti-anxiety drug that has addiction potential, just as with other GABA (GammaAminoButyric Acid) agonists (such as benzodiazepines and alcohol).

A PRN prescription that is more than a month old is not a problem. A prescription that is empty too soon is much more likely to be a problem. One problem with PRN prescriptions is that we usually do not know how quickly the patient has been taking them, so we do not know how many should be in the pill bottle. Some people do not want others to know that they are taking medication to manage anxiety (Tony Soprano), so their family may not even know they have a prescription for these medications.

In other words, with PRN medications, it is difficult to determine if too much has been taken

The acute oral LD50 in rats is 331–2171 mg/kg. Other experiments in animals have indicated that cardiopulmonary collapse can occur following massive intravenous doses of alprazolam (over 195 mg/kg; 975 times the maximum recommended daily human dose of 10 mg/day).^[3]

Prescriptions often come in a pill bottle that contains 100 pills of 0.5 mg, 1 mg, or 2 mg strengths. It is unlikely that a dose of even 200 mg would be enough by itself to kill a person.

General Treatment of Overdose
Overdosage reports with XANAX Tablets are limited. As in all cases of drug overdosage, respiration, pulse rate, and blood pressure should be monitored. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. If hypotension occurs, it may be combated by the use of vasopressors. Dialysis is of limited value. As with the management of intentional overdosing with any drug, it should be borne in mind that multiple agents may have been ingested.^[3]

With any potential overdose, always assume that other drugs/poisons have been taken.

We should use the Plus One Rule –

We should assume that there is at least one drug that we do not know about that the patient has taken. If we find out about more medication, wed still should assume that there is something that the patient has taken that we do not know about. The same rule applies to weapons. We should always assume that a violent/potentially violent patient has at least one weapon that we do not know about. Especially after they have been searched by police or prison personnel.

We should not expect antidotes to work the same way in dead patients as they do in living patients.^[6]

General supportive measures should be employed, along with immediate gastric lavage.

Lavage (pumping the stomach) is not something EMS should be doing. Inducing vomiting is a bad idea in a patient who may not be able to protect her airway – even with an endotracheal tube in place.

Intravenous fluids should be administered and an adequate airway maintained. If hypotension occurs, it may be combated by the use of vasopressors.

Always use fluids for hypotension before pressors, unless fluids are contraindicated, or unless a pressor is specifically indicated, even with acute CHF (Congestive Heart Failure).

Did drugs kill Whitney Houston?

I don’t know, but the drugs listed in this article probably did not kill her.

Footnotes:

^[1] Whitney Houston – Few Pills Recovered at Death Scene
TMZ
2/13/2012 7:45 AM PST by TMZ Staff
Article

^[2] Midol
Wikipedia
Article

As with cough and cold medicine, it is important to read the label to know what you are getting

The “Midol Complete” formulation consists of:

Acetaminophen 500 mg (Pain Reliever)
Caffeine 60 mg (Stimulant)
Pyrilamine Maleate 15 mg (Antihistamine)

The “Extended Relief” formulation consists of:

Naproxen Sodium 220 mg (NSAID, Pain Reliever/Fever Reducer)

The “Teen” formulation consists of:

Acetaminophen 500 mg (Pain Reliever)
Pamabrom 25 mg (Diuretic)

The “Liquid Gels” formulation consists of:

Ibuprofen 200 mg (Pain Reliever)

The “PM” formulation consists of:

Acetaminophen 500 mg (Pain Reliever)
Diphenhydramine citrate 38 mg (Sedative antihistamine)

^[3] XANAX (alprazolam) tablet
[Pharmacia and Upjohn Company]
DailyMed
NLM
FDA label

^[4] CYP3A4
Wikipedia
Article

Large list of drugs that affect CYO3A4 metabolism.

^[5] FLUMAZENIL injection, solution
[Baxter Healthcare Corporation]
DailyMed
NLM
FDA label

^[6] Dissecting the ACLS Guidelines on Cardiac Arrest from Toxic Ingestions
Rogue Medic
Tue, 01 Nov 2011
Article

Filed Under: ACLS, Heresy, Pharmacology

What should be the rules for safe drug administration – Part I

Fri, 03 Feb 2012 06:30:37 +0000 By Rogue Medic 3 Comments

There are the 5 Rights of drug administration, they are often cited as the defenders of the patients, but I do not think they are adequate. They can even cause harm.

The 5 Rights -

The Right Time.

This one is actually sometimes used to hurt patients. If we do interfacility transports and we have a patient who is in pain, or anxious, and we ask the doctor/nurse to give the patient some of the medication that they obviously have not received enough of – too often the response is, She’s not due for that yet.

Image credit.

Keeping to a schedule that requires harming the patient by refusing to treat the patient’s pain/anxiety is not good patient care. Pain and anxiety are both considered appropriate indications for medication. Undertreatment should result in malpractice law suits.

A foolish consistency is the hobgoblin of little minds, adored by little statesmen and philosophers and divines. – Ralph Waldo Emerson.

Is this consistency foolish? When it harms the patient, it certainly is.

If a patient is hyperventilating due to severe pain, should we be worried about respiratory depression?

But the order says to give the pain medicine every 6 hours. We can’t give it too early.

Then call the doctor. If you are a doctor, call your attending. If you have to wake them up, then maybe they will learn to write appropriate orders for when they want to sleep. If the medication wears off before the next dose is due, then that is an important assessment finding that the doctor should be informed about.

Why is the medication not working?

Has the patient’s medical condition changed? We get excited when the patient’s oxygen saturation drops, but is a change in the patient’s level of pain (or anxiety) any less important? Maybe the patient has never been given enough pain medicine.

If you think pain is less important than SpO₂ (Saturation of peripheral Oxygen – pulse oximetry reading), ask the patient what is more important. The patient’s priorities are not the same as our priorities, but we should be trying to come to some sort of agreement about priorities. The truth is that both pain and SpO₂ are important. So is anxiety.

The Right Time does not mean when it is convenient to document giving the medication in order to go along to get along. That isn’t patient care.

Some of you are thinking that I should just shut up and give the medication. As if patient care is not a responsibility of the hospital.

1. The patient is still the doctor’s patient until we leave.

2. Do the hospital staff really need to have EMS come in and do their work for them? The patient is supposed to be prepared for transport. Unless this is a sudden change, this is not prepared.

3. There is supposed to be a continuity of care, not abandonment of care. Would it be appropriate to transfer a patient within the hospital without treating the patient? I realize that this is done, but that does not make it right.

4. I may not have protocols that permit me to give the medication, but I will call medical command and ask for permission to give medication, if I need to. Also, I do not carry the doses that may be needed in treating patients with a tolerance to opioids. I do not have a pharmacy available to restock me. If I have other patients with severe pain, I may run out of opioids. I have before. I don’t even carry enough to treat a patient with severe burns.^[1]

What makes me thing that I know enough to question a doctor’s orders?

I am there, assessing the patient. Where is this omniscient doctor?

I am familiar with giving large doses of opioids, benzodiazepines, and combinations of opioids and benzodiazepines.

I am capable of assessing respiratory drive.

Oh, there is one other thing. I can ask the patient to talk to me, if there is any respiratory depression. Not that there is much chance of that with patients who have been deprived of care due to a foolish consistency to a schedule (Right Time is a schedule). This is not quantum physics.

Footnotes:

^[1] Who Carries Enough to Manage Severe Pain from Burns?
Rogue Medic
Sat, 15 Jan 2011
Article

Filed Under: Heresy, Mythology, Pharmacology

This is the Way to Bad Medicine – II

Thu, 02 Feb 2012 06:30:32 +0000 By Rogue Medic Leave a Comment

A post at EM Literature of Note provides another example of bad research. Not just bad, but deadly.

The benefit of tPA in acute stroke is linked to the speed and degree of clot lysis and artery recanalization. ^{16 –18} ^[1]

Speed does appear to be most important. The debate about the efficacy of tPA (tissue-type plasminogen activator) for stroke is not that tPA will not be a good treatment when given within 90 minutes (1 1/2 hours). The debate is about the whether there is benefit when tPA is given between 90 minutes and 180 minutes (between 1 1/2 hours and 3 hours). The AHA (American Heart Association) quickly made it part of the guidelines to give tPA to as many patients with embolic stroke within 3 hours as possible. Some places have even expanded the fibrinolytic window to 270 minutes (4 1/2 hours).

If the AHA does the same with this proposed treatment, our stroke patients might be better off if we took them to hospitals NOT equipped to treat strokes.

Why?

Let’s look at the study –

Purpose
The primary purpose of this study was to assess the safety of combined Argatroban and tPA in ischemic stroke as measured by the incidence of significant intracerebral hemorrhage (ICH). The secondary objective was to evaluate drug activity by determining the speed and completeness of arterial recanalization and reocclusion.^[1]

The primary purpose of this study is to determine safety.

Safety was defined as a rate of symptomatic ICH or Parenchymal Hematoma Type 2 intracranial hemorrhage not exceeding 10%. We hypothesized that a hemorrhage rate of 10% might be acceptable only in the setting of significant increases in arterial recanalization, which is highly associated with improved clinical outcomes. ^[1]

Highly associated with?

I love treatments that are highly associated with some surrogate endpoint, because that is what matters to the patient.

We achieved the surrogate endpoint. That surrogate endpoint is highly associated with improved outcome. Therefore, you’re cured. Don’t try to speak to thank us. Just trust us.

You are cured.

Your inability to speak is probably just a conversion disorder – and don’t try to get up. You are cured, but your inability to walk is probably just psychological. It’s all in your head.

Too much sarcasm? Am I being unfair? Keep reading.

All patients received intravenous tPA (0.9 mg/kg). There was no delay in starting intravenous tPA as a result of participation in this study. Informed consent and other qualifying activities for the study took place after the intravenous recombinant tPA bolus was given.^[1]

This is good. There is no change that affects the initiation of the standard treatment.

(3) baseline NIHSS score 17 (modified to 15 after the first 15 patients) for right hemisphere and 22 (modified to 20) for left hemisphere strokes;^[1]

Why modified?

The first 2 significant hemorrhages occurred with NIHSS scores of 15 and 21 (both right MCA strokes), prompting the data and safety monitoring board to reduce the upper limit of the NIHSS score to 15 (right hemisphere) and 20 (left hemisphere).^[1]

The lower the NIHSS (National Institutes of Health Stroke Scale^[2]) number, the less serious the stroke. Scores range from 0 to 42, with higher being worse, so these are not severe strokes. How much improvement is worth to each patient vs. the risk of worse neurological injury, or death, is difficult to state. Looking through the grading, very intoxicated might score around the 13 average for the patients in this trial. I would not classify that as mild.

A total of 32 serious adverse events occurred in 22 patients (see Table 3).^[1]

I do not know why they calculated these as percentages of the serious adverse events, rather than according to patients treated.

If you develop a serious adverse event, you have a 21% chance of death.

They appear to be assuming that this ratio will persist across serious adverse events, which is not a reasonable conclusion. This is just a derivative of what I want to know. What I want to know is –

If I receive the treatment, what are my odds of death, disability, et cetera.

Their categorization of only 3 (out of 32) serious adverse events as Probably related to treatment and none as Definitely related to treatment suggests that they are not being objective. How do they explain this in the discussion? They don’t. Maybe they aren’t referring to the serious adverse events, but are referring to deaths. I don’t know and since they do not explain, I can only speculate.

We know that tPA increases the risk of bleeding. We expect that giving an anticoagulant (argatroban is a thrombin inhibitor) with tPA increases that risk of bleeding. We conclude that the bleeding in our patients is just a coincidence, because that’s the way we roll, Yo!

You had a thrombotic stroke, but now you have so much bleeding that your brain is squeezing out through any orifice possible. This is just one of the improbably large number of coincidences during this study.

On discharge, 76% of patients went either home or to acute rehabilitation, and 7 patients died (10.8%). Five of the 7 deaths resulted from large hemispheric infarction with herniation, whereas the other 2 died from respiratory failure. Six of the 7 deaths occurred after the family requested withdraw of care.^[1]

Six of the 7 deaths occurred after the family requested withdraw of care.

I don’t know if they are just providing complete information or suggesting that the deaths are the fault of the families for not trying to keep their family members alive in nursing homes with zero quality of life.

long enough to prevent any reocclusion. ¹² However, 3 of our 4 significant hemorrhages occurred 18 hours into the infusion. A 12- to 18-hour infusion might produce even safer and equally effective results.^[1]

However, shortening the infusion to zero hours might produce even safer and equally effective results.

What does Dr. Radecki say about this trial?

Because NIHSS score predicts bleeding, we can compare to the NINDS trial TPA group, whose median NIHSS score of 14 compared with this trial’s median of 13. The NINDS trial showed a 10.8% rate of ICH and about 4% mortality at 7 days.^[3]

3 dead patients would have been 4.6%.

There were 7 dead – 10.8%.

Is it safe?

I guess that depends on how much life insurance you have on the person being treated and how much you dislike them.

These rates of bleeding are of the same order of magnitude seen with intravenous recombinant tPA alone and therefore low enough to justify further evaluation in more patients to arrive at a more confident assessment of the true risks of bleeding.^[1]

What is their point?

What if . . . ?

What if this really is beneficial? We wouldn’t want to miss out on this potentially useful, although potentially very dangerous, treatment.

They are ignoring the risks. The question, What if . . . ? can also be reversed –

What if the adverse events in this group are statistically much lower than what we should expect if we were to treat a large number of patients?

Do the authors understand the risks they are subjecting patients to?

Higher doses of Argatroban might also be safe and even more effective, but this will require careful evaluation.^[1]

Maybe the patients had all of these bleeds because we gave too much of our study drug that causes bleeding, but we aren’t going to rule out the possibility that we did not give enough.

Is this really that much different from presuming that blood-letting is not working because of not taking enough blood?^[4]

Further study of this treatment combination appears warranted.^[1]

No.

I hope that no IRB (Institutional Review Board) is ever impaired enough to come to the conclusion that this should be expanded to harm more patients.

Earlier, I asked if I was using too much sarcasm, but now I think I may have been too subtle. What do you think.

Footnotes:

^[1] The Argatroban and Tissue-Type Plasminogen Activator Stroke Study: Final Results of a Pilot Safety Study.
Barreto AD, Alexandrov AV, Lyden P, Lee J, Martin-Schild S, Shen L, Wu TC, Sisson A, Pandurengan R, Chen Z, Rahbar MH, Balucani C, Barlinn K, Sugg RM, Garami Z, Tsivgoulis G, Gonzales NR, Savitz SI, Mikulik R, Demchuk AM, Grotta JC.
Stroke. 2012 Jan 5. [Epub ahead of print]
PMID: 22223235 [PubMed - as supplied by publisher]

^[2] NIH Stroke Scale
NINDS
PDF Download of Stroke Scale with explanations of scoring

^[3] Helping TPA Help Patients Bleed
Wednesday, January 25, 2012
EM Literature of Note
Article

^[4] Answer to What is this Dangerous Treatment and How Long Did it Take to Stop Using it
Wed, 01 Feb 2012
Rogue Medic
Article

Barreto, A., Alexandrov, A., Lyden, P., Lee, J., Martin-Schild, S., Shen, L., Wu, T., Sisson, A., Pandurengan, R., Chen, Z., Rahbar, M., Balucani, C., Barlinn, K., Sugg, R., Garami, Z., Tsivgoulis, G., Gonzales, N., Savitz, S., Mikulik, R., Demchuk, A., & Grotta, J. (2012). The Argatroban and Tissue-Type Plasminogen Activator Stroke Study: Final Results of a Pilot Safety Study Stroke DOI: 10.1161/STROKEAHA.111.625574

Filed Under: Ethics, Heresy, Pharmacology, Research, Research Blogging, Science

Answer to What is this Dangerous Treatment and How Long Did it Take to Stop Using it

Wed, 01 Feb 2012 06:30:23 +0000 By Rogue Medic 6 Comments

Earlier I wrote What is this Dangerous Treatment and How Long Did it Take to Stop Using it. The first answer, from Jim Anderson, was the correct answer.

What we have learnt from the experience of the last few years is, that a great number of cases- which our predecessors thought and taught would die without Treatment X, may be spared Treatment X and yet live; and also, that many of the severe symptoms and risks in these cases were in reality the symptoms and risks arising out of Treatment X.^[1]

What was Jim Anderson’s answer?

Blood letting as a means to remove evil bodily humors that accumulate and manifest as a myriad of disease processes. E.G. Malaria, TB, Polio, Cancer among others…

Imagine if we were still in the days of ~~barbers~~ doctors bleeding patients to get rid of the bad humors.

Image credit.

What we have learnt from the experience of the last few years is, that a great number of cases- which our predecessors thought and taught would die without blood-letting, may be spared the operation and yet live; and also, that many of the severe symptoms and risks in these cases were in reality the symptoms and risks arising out of loss of blood.^[2]

Several people did answer spinal immobilization. While that is not the correct answer, that was what I was thinking of when I wrote this. There are many parallels between the paragraphs I quoted and spinal immobilization. This is also true for any other treatment that is based on wishful thinking or What if . . . ?

If there is no evidence that the treatment works, then we should DEMAND evidence.

If no attempts are made to provide evidence,

then we should PROHIBIT the treatment.

To do otherwise is to experiment on people without permission and without collecting the data that would allow us to learn from the experiment.

Many of those who habitually practised blood-letting as a daily means of cure in the last generation were careful and shrewd observers, as is shown bytheir writings; and it seems scarcely possible that such men should have been utterly mistaken in assigning advantages to this powerful means of modifying vital actions. It would be more reasonable to conclude that the advantages must be very great to have blinded their eyes to the accompanying evils.^[2]

When was this written?

1871.

But this paper, written thousands of years after we started using this treatment, was still defending blood-letting. The author was saying -

Don’t throw the baby out with the bathwater.

Physicians observed of old, and continued to observe for many centuries, the following facts concerning blood-letting.

1. It gave relief to pain. . . . .

2. It diminished swelling. . . . .

3. It diminished local redness or congestion. . . . .

4. For a short time after bleeding, either local or general, abnormal heat was sensibly diminished.

5. After bleeding, spasms ceased, . . . .

6. If the blood could be made to run, patients were roused up suddenly from the apparent death of coma. (This was puzzling to those who regarded spasm and paralysis as opposite states; but it showed the catholic applicability of the remedy.)

7. Natural (wrongly termed ” accidental”) hacmorrhages were observed sometimes to end disease. . . . .

8. . . . venesection would cause hamorrhages to cease.^[2]

That is a lot of misleading evidence of benefit, but these are just surrogate endpoints.

We harm patients because we think that surrogate endpoint studies are good enough to make a dangerous treatment the standard of care. We are fools.

Look – it’s scientific.^[3]

Points for blood-letting. Image credit.

Thousands of years later, in spite of repeated evidence of harm, this doctor (and many others) were still defending blood-letting.

It was found out that, if no patients were bled at all, more recovered than if all those were bled who had the collection of symptoms whose union gave certain names to diseases seen by experience often to justify vensection.^[2]

How long will it take to get rid of spinal immobilization?

How long will it take to get rid of epinephrine for cardiac arrest?

How long will it take to get rid of amiodarone for cardiac arrest?

How long will it take to start studying NTG (NiTroGlycerin) for cardiac arrest?^[4]

Without evidence of safety and efficacy, we must limit treatments to controlled trials.

Defined either by a symptomatic or an anatomical nomenclature, every class of disease, in which bleeding was put through the test of experience, was injured by it.^[2]

every class of disease was injured by it.

How little would it take for many doctors to return to this discredited traditional treatment?

Emptying the veins is, in point of fact, abnormally clearing the way for an abnormally weakened blood-stream; and there must be cases in which that will constitute the turning-point of life or death.^[2]

In spite of evidence of harm, blood-letting is still being defended as probably beneficial for something –

We just need to find the disease that isn’t made worse by this discredited traditional treatment!

The treatment is too good to get rid of.

The problem is not with the treatment, but with finding the right patients to inflict the treatment on.

Is this any way to treat patients?^†

Is this any different from harming patients with spinal immobilization?

Footnotes:

^[1] ?

^[2] Blood-Letting
Br Med J.
1871 March 18; 1(533): 283–291.
PMCID: PMC2260507

^[3] Scientific – It’s just a catchphrase
Rogue Medic
Sat, 21 Jan 2012
Article

^[4] High dose nitroglycerin treatment in a patient with cardiac arrest: a case report.
Guglin M, Postler G.
J Med Case Reports. 2009 Aug 10;3:8782.
PMID: 19830240 [PubMed - in process]

Free Full Text from PubMed Central . . . . . Free Full Text PDF from PubMed Central

^† Hemochromatosis is one illness for which removing blood, in order to remove the excess iron the body retains, is useful. That does not mean that we should look for illnesses to treat with discredited traditional treatments.