AMA after Narcan – Is it safe?

In comes a 34-year-old male who is obtunded with pinpoint pupils and breathing at five times a minute; likely due to heroin abuse.  He wakes up after Narcan is appropriately administered, but now he wants to leave.  What is the risk of death if he leaves?  Do we restrain him against his will to monitor him for possible recurrent respiratory depression?

We have some pre-hospital literature that looked into this issue.  The studies looked at patients who refused care after pre-hospital providers administered Narcan for a suspected opiate overdose.  They then searched the death registry to see if those patients later died after refusing care (transport to the hospital).

Wampler et al. looked at 552 patients and found that no one died until at least 4 days later (1).  These deaths four days later were unlikely to be from the initial overdose.  A second study recently published in March of 2016 had 205 patients and showed only one death in 24 hours (2).  Two others died in the 30-day follow up period which again were not likely due to the initial overdose.  Combining the numbers from these two studies equates to 1/757 (0.13%) deaths.

There are limitations with all studies, but death seems unlikely after refusal of care post-narcan administration.  However, our practice should not change as it relates to monitoring patients for about 4 hours to those willing.  Recurrent respiratory depression is a real concern particularly seen in those patients who abuse long acting opiates.  Despite this, some patients who have the capacity to make decisions may not choose the wisest care plan and may leave AMA.  We must still make considerable attempts at providing substance abuse referrals and other appropriate resources as these patients are in great need of help.

Post by: Joe Bove  (@jjbove08)

  1. Wampler D, Molina D, McManus J, Laws P, Manifold C. No deaths associated with patient refusal of transport after naloxone-reversed opioid overdose. Prehosp Emerg Care. 2011;15(3):320-324.
  2. Levine M, Sanko S, Eckstein M. Assessing the Risk of Prehospital Administration of Naloxone with Subsequent Refusal of Care. Prehosp Emerg Care. March 2016:1-4.

Tox Box Journal Club

In this installment of the Tox Box Journal Club we are going over three articles reviewed at the NYC Poison Control Center in Manhattan last week.  Two of the articles discuss utility of lipid emulsion therapy in animal models and a third on the deleterious effects of methotrexate dosing errors in Australia.
Background: LAST = Local Anesthetic Systemic Toxicity is a well described phenomenon which can occur from accidental intravenous administration of anesthetics during peripheral nerve blocks or other procedures. Seizures are often described following accidental intravenous administration, which can then lead to cardiovascular collapse in the setting of severe acidosis and hypoxia. This study was designed to see if there exists a role for lipid emulsion therapy for LAST. Prior animal models did not account for the acidosis / hypoxemia that is known to occur, and this model was able to simulate these settings
Methods: 20 pigs separated into 2 groups of 10. All were anesthetized/paralyzed/intubated. Then infusions of levobupivicaine were administered to each at a dose of 3mg/kg, then five minutes of hypoventilation, then 1mmol/kg of lactic acid infusion (to simulate aforementioned settings). One arm was given Lipid emulsion, the other arm was given Ringer’s acetate. Mean arterial pressure / HR / EKG/QRS/ and plasma concentrations of the anesthetic were all monitored and compared. 
Results: The data show that there was no effect of lipid emulsion compared to that of the ringer’s acetate. QRS took similar amounts of time to narrow in both arms. Pharmacokinetics of Levobupivicaine were the same in both groups. 
Bottom Line: Although there have been case reports describing successful resuscitation of patients who suffer from LAST who were given lipid emulsions during resuscitation, this particular model which simulates acidosis and hypoxemia in pigs, does not support the use of lipid emulsion therapy for local anesthetic toxicity. There seems to be a growing body of lack of support based on this study and others like it. 
 
 
Background: Intravenous lipid emulsion (ILE) is a potential antidote for severe overdoses and its use in cocaine toxicity has been suggested; however, it is not well characterized. Its potential use as an antidote during cocaine toxicity was the focus of this study to see if cocaine-induced cardiac arrest in rats was able to be reversed using this therapy.
Methods: 12 rats were given lethal doses of cocaine IV over 30 seconds, and mechanical chest compressions were initiated once asystole was noted. One arm was given ILE, while the other arm was given a similar bolus rate of 0.9% NS. 
Results: The data show that ILE had no affect in the terminal outcome in cocaine-induced cardiac arrests in this particular rat model, suggesting that this is not an appropriate toxin/antidote pairing. Only 1 of 12 rats received ROSC and was found to be statistically not significant. This rat was in the ILE arm of the study.
Bottom Line:  This article demonstrates some potential design flaws including small sample size,  and withholding ACLS medications post cardiac arrest which potentially would have aided in resuscitation. 
This was a retrospective review article which sheds light upon the fatal errors which can occur as a result of accidental, improper dosing of methotrexate (MTX).  After looking at the Australian database for reported poisonings, errors occurred for a number of reasons and the ones most commonly identified were: 
  •  mistaking medication for another medication
  •  care-giver/nursing home error
  •  MTX was newly prescribed medication
  •  pharmacy dosing packet error
  •  misunderstood directions
  •  patient believing it would improve efficacy
  •  prescribing error by physician
  •  dispensing error
  •  labeling error 
As a result there were 22 deaths noted to be linked to MTX administration errors
Bottom Line:  These medication errors are not uncommon, and because MTX is a high risk medication which can become fatal if taken incorrectly, further care is warranted in dealing safely with this medicine. A multi-faceted approach should be considered and suggestions are still ongoing. Some recent suggestions have been to change packet size, to increase education/awareness, mandatory weekly dosing labeling on packaging, including software alerts for prescribers and dispensers
Post by: Dr. Ray Brancato (@drrayfields)

Fixed dose PCC?

In the past, vitamin K and FFP were the mainstays of reversing warfarin, but now we have fancy new drugs like four-factor prothrombin complex concentrate (4F-PCCs).  4F-PCCs can rapidly reverse the INR of warfarin induced coagulopathy with less volume and quicker than FFP.  Many of the dosing regimens base the dose on the patient’s presenting INR and body weight, with ranges from 25-50 IU/kg.  A few problems arise with this approach, first the INR is not immediately available.  Second, 4F-PCCs are not cheap; costing up to $7,000 per patient in some cases.  Is there a fixed-dose regimen that we can give to patients on vitamin K antagonists without having to wait for the INR?

Some studies have looked at using 500 IU and 1000 IU fixed dose regimens for reversing the INR.  The 500 IU only corrected the INR in 43% of the patients, whereas the 1000 IU fixed dose study showed better clinical outcomes in 83.5% of the patients, but there is concern that the obesity epidemic in the United States will dilute the IU/kg concentration of the 4F-PCC and not be as efficacious.  Klein et al looked at using a fixed dose of 1500 IU of 4F-PCC for reversal of warfarin in 2015.  It was a relatively small sample of 38 patients on warfarin with the vast majority of them presenting with an intracranial hemorrhage.  Each patient had their INR drawn and then 1500 IU given before the result of the INR returned.  92.3% of the patients had their INR lowered to less than 2.0 after the 1500 IU of 4F-PCC and they reported no thrombotic events within the subsequent 7 days.  The presenting INR median was 3.3 (2.5-4.0) which was reduced to 1.4 (1.2-1.6) after administration of the 4F-PCC.  Additionally, this saved $40,273 dollars when compared to the typical INR and weight based dosing regimen for their patient sample.

We’ll have to figure out whether this fixed dose regimen of 1500 IU is the way to go, or should we base the dose solely on the patient’s weight and not worry about waiting on the INR.  Does waiting the extra 20 minutes for the INR lead to improved clinical outcomes?  And if we are going to start using a standard dose, is there a role for pre-hospital administration of the 4F-PCCs?

Post by: Terrance McGovern DO, MPH (@drtmcg13)

Octreotide for sulfonylurea poisoning

Newer second generation sulfonylureas are used extensively for treating type-2 diabetes mellitus (i.e. glyburide, glipizide, glimepiride and gliclazide). They are rapidly absorbed and reach peak plasma concentration typically within 2-4 hours; and have a duration of action up to 24 hours long. In 2010, the American Association of Poison Control centers reported nearly 4,000 cases of sulfonylurea exposures that led to no reported fatalities. Previous treatment has revolved around IV dextrose and glucagon for treatment of sulfonylurea associated hypoglycemia, but octreotide is another option for treating these exposures.

Mechanism of Octreotide and Sulonylureas

Sulfonylureas help to increase the amount of endogenous insulin release from the pancreatic beta cells. They bind to sulfonylurea receptors that are associated with ATP dependent potassium channels on the pancreatic beta cell membrane. By inhibiting potassium efflux, the membrane depolarizes causing influx of calcium and subsequent exocytosis of insulin. Octreotide counters this mechanism by closing the calcium channels after binding to somatostatin receptors, which prevents the secretion of the insulin.

Dosing

For adults we can use 50-100ug SC every 6-12h and for children 1-2 ug/kg SC up to 50ug q6-12h. Typically the patient will received 3 doses of octreotide as well as supplemental IV dextrose which can be gradually tapered off as tolerated. An extended length of observation may be needed for patients with renal impairment as sulfonylureas and insulin clearance will be impaired.

Check out The Poison Review for a couple posts on using octreotide for sulfonylurea poisoning here and here.

Post by: Terrance McGovern DO, MPH (@drtmcg13)