Acute and recurrent pericarditis are frequently diagnosed in the emergency department. Traditionally, treatment has consisted of anti-inflammatory medications (eg. ASA or NSAIDs) or corticosteroids. Colchicine is an underutilized therapy for pericarditis and provides significant benefit when combined with NSAIDs/ASA. Addition of colchicine to standard therapy results in earlier reduction in pericarditis symptoms, greater remission at 1 week, and reduces the rate of recurrent pericarditis. Let’s review the literature for colchicine for treatment of pericarditis.
What is Colchicine?
Colchicine is a plant derived compound that inhibits microtubule formation, thus effectively inhibiting mitosis. It also acts to inhibit neutrophil activity and has an anti-inflammatory effect. Known uses include treatment of gout and familial Mediterranean fever (FMF).
Studies of Colchicine for acute (1st Episode) pericarditis
The COPE (Imazio, 2005) and ICAP (Imazio, 2013) trials both studied the effects of adding colchicine to standard anti-inflammatory therapy for treatment of pericarditis.
CORP (Imazio, 2011) studied use of colchicine in the first episode of recurrent pericarditis.
Duration of Colchicine
|COPE 2005||Prospective RCT, Open-Label, Non-Blinded||Colchicine + ASA vs ASA alone||120 (60 per arm)||3 months|
|CORP 2011||Prospective RCT, Open-Label, Non-Blinded||Colchicine + ASA/NSAID vs ASA/NSAID alone||120 (60 per arm)||6 months (b/c recurrent pericarditis|
|ICAP 2013||Prospective, Double-Blind RCT||Colchicine + ASA or NSAID vs ASA or NSAID alone||240 (120 per arm||3 months|
What were the outcomes? (All reported as colchicine vs. placebo)
Incessant Pericarditis (Persistent Pain or Symptom Free < 6 Weeks)
Persistent Symptoms at 72 Hours
Remission at 1 Week
Recurrence at 18 Months
Recurrences per Patient
Time to First Recurrence
Pericarditis Related Hostpitalization
|COPE||NR||11.7% vs 36.7% (p=0.003, NNT = 4)||NR||10.7% vs 32.3% (p=0.004, NNT= 5)||NR||22.9 vs 17.2 months (p=0.009)||NR|
|CORP||NR||23% vs 53% (p=0.001, NNT = 3)||48% vs 82% (p<0.001, NNT = 3)||24% vs 55% (p<0.001, NNT = 3)||0.1 vs 1* (p<0.001)||2.5 vs 1 months (p<0.001)||5% vs 13% (p=NS)|
|ICAP||16.7% vs 37.5% (p<0.001, NNT = 5)||19.2% vs 40% (p=0.001, NNT = 5)||85% vs 58.3% (p<0.001, NNT = 4)||9.2% vs 20.8% (p=0.02, NNT = 9)||0.21 vs 0.52 (p=0.001)||24.7 vs 17.7 weeks (p<0.001)||5% vs 14.2% (p=0.02, NNT = 11)|
*Median number of recurrences at 20 months follow-up in CORP.
What dose of colchicine do you give?
In all trials, the dose was 1-2 mg on the first day, followed by 0.5 mg BID for patients > 70 kg or 0.5 mg once daily for patients < 70 kg.
What about side effects, especially diarrhea?
If patients on colchicine cannot tolerate due to GI upset, they should reduce the dose to once daily if > 70 kg, or stop it if < 70 kg.
What about using steroids for pericarditis?
Both COPE and ICAP performed multivariate analysis to determine risk factors for recurrence of pericarditis. In both trials, prednisone use was an independent risk factor for subsequent development of recurrences: COPE (OR 4.30, 95% CI 1.21-15.25; p=0.024) ICAP (OR 4.17; 95% CI, 1.28-13.53; p=0.02) In patients who cannot tolerate NSAIDs, have high GI bleed risk or have other contraindications for NSAID/colchicine use, steroids should be used. There should be solid clinical reasoning each time you prescribe steroids for pericarditis, and consideration for expert consultation should be given in these cases.
Who should get Colchicine for pericarditis?
Pretty much everyone in whom it is not contraindicated (see below).
What are the contraindications to Colchicine use?
Although it works well, many groups are excluded from studies of colchicine because of its side effects. In general, neoplastic pericarditis, bacterial pericarditis, significant liver or kidney disease, blood dyscrasias, and pregnancy are the big categories. Here is the list of exclusion criteria for ICAP:
Severe liver disease or aminotransferase levels ≥1.5x ULN
Serum creatinine >2.5 mg/dL (>221 umol/L)
Skeletal myopathy or CK >ULN
Blood dyscrasia IBD
Hypersensitivity to colchicine or other contraindication to its use
Life expectancy ≤18 months
Pregnancy or lactation
Women of childbearing potential not using contraception
Evidence of myopericarditis as evidenced by elevation in serum troponin
What other medication should everyone be prescribed?
A PPI (proton pump inhibitor). The combination of high dose NSAIDs/ASA + Colchicine or steroids is pretty much a recipe for gastritis/peptic ulcer disease, so PPIs were prescribed in all studies. Duration of PPI therapy was not disclosed, but I would prescribe it at minimum for the duration of NSAID use. Giving a PPI for the entire duration of colchicine use would also be reasonable.
Clinical Bottom Line
Unless there are contraindications to its use, colchicine should be prescribed in all cases of uncomplicated pericarditis, along with standard therapy of ASA/NSAID and a PPI. Glucocorticoids should be prescribed with caution, as they are an independent risk factor for pericarditis recurrence.
- Imazio M, et al. “A Randomized Trial of Colchicine for Acute Pericarditis”. The New England Journal of Medicine. 2013. 369(16):1522-1528. PMID:23992557
- Imazio M, et al. “Colchicine in Addition to Conventional Therapy for Acute Pericarditis : Results of the COlchicine for acute PEricarditis (COPE) Trial”Circulation. 2005;112:2012-2016. PMID:16186437
- Imazio M, et al. “Colchicine for Recurrent Pericarditis (CORP)” Ann Intern Med. 2011;155:409-414. PMID: 21873705
Misuse of prescription opioids is one of the defining health problems of our generation. The dramatic rise of opioid analgesic prescriptions in the US and Canada has been well documented, and opioids represent the most common cause of fatal prescription overdoses. On every shift, in every emergency department in the country, physicians struggle with the concerns of patients presenting with common pain complaints. Seeking to manage their patients’ symptoms in the face of dramatically rising prescription opioid misuse and fatal overdose, emergency physicians are challenged to distinguish those who are simply seeking pain relief, those who are seeking opioid prescriptions due to addiction, and those who fit both categories. Emergency care providers are also charged with balancing the pressures of meeting clinical care and patient satisfaction goals while fulfilling our moral obligation to provide primary and secondary prevention of opioid misuse.
Google Hangout with the Authors
On August 12, 2014 at 9 am EST, we will be hosting a 30 minute live Google Hangout on Air with Drs. Sabrina Poon and Margaret Greenwood-Ericksen, the authors of the Annals of Emergency Medicine Resident’s Perspective paper on the how the opioid prescription epidemic. Be sure to tune in! Later this year, a summary of this blog- and Twitter-based discussion will hopefully be published back into the journal.
- Sabrina Poon, MD (@sjpoon): resident physician, Harvard Affiliated Emergency Medicine Residency, Brigham and Women’s Hospital, Massachusetts General Hospital (Boston, MA)
- Margaret Greenwood-Ericksen, MD MPH: resident physician, Harvard Affiliated Emergency Medicine Residency, Brigham and Women’s Hospital, Massachusetts General Hospital (Boston, MA)
- David Juurlink, MD (@DavidJuurlink): medical toxicologist, internal medicine physician, Division of Clinical Pharmacology and Toxicology at Sunnybrook Health Sciences Centre (Toronto, ON)
- Maryann Mazer-Amirshahi, MD: medical toxicologist, emergency medicine physician, MedStar Washington Hospital Center (Washington, DC)
Twitter Feed with #ALiEMRP
Annals of EM Resident Perspective Article
In the June issue of Annals of Emergency Medicine, Drs. Poon and Greenwood-Ericksen published a Resident’s Perspective around this issue entitled “The Opioid Prescription Epidemic and the Role of Emergency Medicine.” The paper reviews the scope of the issue and describes the quandaries faced by ED physicians attempting to balance high-quality care with safe, appropriate care–resulting in high variability in ED prescribing practices. It also discusses some of the solutions that have been proposed to stem the tide of the epidemic, including prescription drug monitoring programs, prescribing guidelines, and physician education. Testament to the urgency and difficulty of these tasks are the number of blogs on this issue over the past year. A comprehensive review of FOAM resources produced during the last year was conducted using the FOAMSearch platform and targeted Google searches. Since 2013, 10 blog posts and 1 podcast concerning opioid prescribing trends in the emergency department have been published as the FOAM discussion of this issue continues to evolve. For some background on the paper discussion, review any of the resources listed in the table below.
FOAM Discussion to Date
EM Tutorials Oxy morons. Avoid prescribing oxycodone Chris Cresswell Podcast New Zealand 7/22/14
The Poison Review Counties in California sue manufacturers of opioid analgesics Leon Gussow Blog USA 5/24/14
Emergency Medicine Literature of Note Your Patients Will Abuse Opiates Ryan Radecki Blog USA 5/19/14
Emergency Physicians Monthly Opioids: Misuse and Abuse Ryan Radecki Blog USA 5/6/14
The Poison Review ED discharge prescriptions for opioid analgesics increased 49% from 2005 to 2010 Leon Gussow Blog USA 3/25/14
Emergency Medicine Literature of Note Nonsensical Opiate Overuse in Adolescent Headache Ryan Radecki Blog USA 3/2/14
The Skeptics Guide to Emergency Medicine Drugs in My Pocket (Opioids in the Emergency Department) Ken Milne Podcast Canada 11/28/13
The Poison Review Guidelines for Opioid Prescription: do emergency physicians need support? Leon Gussow Blog USA 4/9/13
The Poison Review NYC Recommendations for Prescribing Opioids in Emergency Departments Leon Gussow Blog USA 3/8/13
Emergency Medicine PharmD Opioid related deaths Craig Cocchio Blog USA 3/4/13
Emergency Physicians Monthly NYC Limits ED Opioid Prescriptions Kevin Klauer and Rick Bukata Blog USA 2/8/13
NJEmergencyDocs In the ER: Too Much or Too Little Pain Medication? David Adinaro Blog USA 10/1/13
In the June issue of Annals of Emergency Medicine, Drs. Poon and Greenwood-Ericksen published a Resident’s Perspective around this issue entitled “The Opioid Prescription Epidemic and the Role of Emergency Medicine.” The paper reviews the scope of the issue and describes the quandaries faced by ED physicians attempting to balance high-quality care with safe, appropriate care–resulting in high variability in ED prescribing practices. It also discusses some of the solutions that have been proposed to stem the tide of the epidemic, including prescription drug monitoring programs, prescribing guidelines, and physician education.
Testament to the urgency and difficulty of these tasks are the number of blogs on this issue over the past year.
A comprehensive review of FOAM resources produced during the last year was conducted using the FOAMSearch platform and targeted Google searches. Since 2013, 10 blog posts and 1 podcast concerning opioid prescribing trends in the emergency department have been published as the FOAM discussion of this issue continues to evolve. For some background on the paper discussion, review any of the resources listed in the table below.
Featured Discussion Questions
The ALiEM team poses the following questions to explore current practices with MMI, and perceptions about the benefits and drawbacks of this interview format. If you have additional questions, feel free to pose them!
- The authors cite the Joint Commission’s pain control mandate (i.e., “pain is the fifth vital sign”) and the emphasis on patient satisfaction scores as critical factors in the increase in opioid prescribing over the last decade. To what extent do these factors influence your use of opioid pain medications, both during the ED visit and upon discharge?
- The authors discussed potential barriers to prescription monitoring programs (PMPs). In your practice, are PMPs assisting in appropriate and safe opioid prescribing practices? If not, why? If so, how?
- Only three states have adopted formal guidelines for opioid prescribing from the ED. Do you think these are/will be helpful? Why do you think they have not been adopted more widely?
- The authors propose a resident curriculum for opioid prescribing in the ED, including lectures, journal club, case-based learning, and simulation. What have been your experiences with formal instruction around opioid prescribing? What do you think are the most effective ways to shape physician behavior around this issue?
Please participate in the discussion by answering either on the ALiEM blog comments below or by tweeting us using the hashtag #ALiEMRP. Please denote the question you are responding to by starting your reply with Q1, Q2, Q3, or Q4.
NEW! Contest for Best Blog Comment and Tweet
Thanks to Dr. Henry Woo and his colleagues in the Twitter-based International Urology Journal Club series (#urojc) hosted by @IUroJC, we are also implementing a contest for the Best Blog Quote and Best Tweet. What, emergency physicians – competitive? No… The winners will be announced in our Annals of EM publication curating this discussion.
Additional Reading / References
- Juurlink DN, Dhalla IA, Nelson LS. Improving opioid prescribing: the New York City recommendations. JAMA [Internet]. 2013 Mar 6 [cited 2014 Jul 28];309(9):879–80. Pubmed
- Kahan M, Gomes T, Juurlink DN, Manno M, Wilson L, Mailis-Gagnon A, et al. Effect of a course-based intervention and effect of medical regulation on physicians’ opioid prescribing. Can Fam Physician [Internet]. 2013 May [cited 2014 Jul 28];59(5):e231–9. PMC
- Mazer-Amirshahi M, Mullins PM, Rasooly IR, van den Anker J, Pines JM. Trends in prescription opioid use in pediatric emergency department patients. Pediatr Emerg Care [Internet]. 2014 Apr [cited 2014 Jul 28];30(4):230–5. Pubmed
- Mazer-Amirshahi M, Mullins PM, Rasooly I, van den Anker J, Pines JM. Rising Opioid Prescribing in Adult U.S. Emergency Department Visits: 2001-2010. Acad Emerg Med [Internet]. 2014 Mar [cited 2014 Mar 27];21(3):236–43. Pubmed
- Rosenau AM. Guidelines for opioid prescription: the devil is in the details. Ann Intern Med [Internet]. American College of Physicians; 2013 Jun 4 [cited 2014 Jul 28];158(11):843–4. Abstract
This blog post was co-authored by Scott Kobner (@skobner), New York University medical student and ALiEM-EMRA fellow, and Kevin Scott, MD (@K_ScottMD), University of Pennsylvania, Assistant Professor of Emergency Medicine.
Disclaimer: We reserve the right to use any and all tweets to #ALiEMRP and comments below in a commentary piece for an Annals of Emergency Medicine publication as a curated conclusion piece for this Resident’s Perspective publication. Your comments will be attributed, and we thank you in advance for your contributions.
The post The Opioid Prescription Epidemic: Annals of EM Resident Perspectives article appeared first on ALiEM.
I was a little apprehensive about undergoing HUET training, mostly due to some gentle winding up by the likes of Minh le Cong in Queensland & some of the GSA-HEMS mob. Comments about eliciting cremasteric reflexes, sinus douching and so on seemed to be setting the scene – made worse as undertaking HUET in the middle of Adelaide winter.
Actually, I don’t know why I was concerned about being dunked. ‘Back in the day’ I was a keen (and expert) whitewater canoeist. I rose through the ranks in both kayak and canadian classes, competing regularly at premier level in slalom events in the UK and representing my country overseas. Being flipped over in the dark whilst training in the ice cold waters of the Thames weirs or on the grade IV rapids of Scottish rivers was no problem.
Competing at that level of performance, the difference between boat-body-blade was indiscernible, with movements practiced and fluid such that one could quickly (<1 second) roll up from an inverted position with barely an interruption to forward paddling movement.
But that was a long time ago. Being stuck inside a metal airframe and dunked upside down is completely different. And unlike a low volume carbon-kevlar canoe, there’s no element of control when a helicopter ditches…
Training took place at the heated (27 degrees, thank you) pool at the Adelaide Dive Centre, under the expert guidance of the team from RHO aviation.
Why bother with HUET?
Brian Burns of Sydney HEMS tweeted this slide today from the concordant HUET exercise in Sydney, demonstrating why it is vital that anyone being transported by a helicopter platform knows what to do in the event of ditching in water.
Whilst it is possible to perform a controlled ditch on water, this will be subject to water conditions, aircraft performance and so on. Some helicopters have floats – but helicopters are inherently top heavy and are highly likely to invert. Or be attacked by sharks as in this clip below from Jaws 2 :
That said, helicopter transfer is reasonably safe. The most pertinent reference that I could find dates back almost 10 years and is from Dave Cooksley and (then registrar) Jim Holland when in Townsville, both nice FACEM chaps. However problems can occur and it makes to be prepared. Helicopter Underwater Escape Training (HUET) is designed to improve the chances of surviving a ditching episode.
As can be seen from the footage below, an uncontrolled ditch in water poses risks of disorientation, impact with unsecured equipment and debris from the impact. Add to this the confusing elements of inversion, cold water and poor/zero visibility, and it is easy to see why occupants can become disorientated and fail to survive. Add to this the myriad of different harness & door release mechanisms (over 35 of the latter, with no industry-standard!). HUET training is designed to increase chances of survival in an unlikely emergency.
US-Navy CH-46 Sea Knight crashes while landing on USNS Pecos
Controlled ditching onto water, then disaster as rotor blades enter water
So what did we learn?
The facilitators from RHO aviation were really good, working through educational material in a solid, stepwise manner with a clear goal (lessons there for meducationalists). They emphasised the importance of a pre-flight safety brief :
- seat belts
- loose items (secured)
- identifiying primary & secondary exits, with reference points
It;s no secret that I am a fan of checklists in a crisis – when there is time. But the regular performance of a safety brief reinforces safety, mitigates against complacency and is something that I try to instil into the resus bay of my local hospital when awaiting a patient – checkling O2, suction, confirming presence of airway and crash carts, setting up vent and anticipating likely clinical needs…as well as backup plans. Cliff Reid has talked about the value of having a resus room safety officer….perhaps it’s not such a bad idea, especially in EDs where the resus is performed by a flash team (members who may never have worked together, or are used to another ED’s equipment/procedures). Minh le Cong (who never sleeps) has proposed a pre-ED RSI safety brief, albeit tongue-in-cheek.
Once the aircraft inverts, the importance of WAITING for cessation of violent movement was emphasised (to reduce risk of disorientation, injury), then calm performance of a well-rehearsed sequence :
- orientate (use one hand to anchor as a fixed reference eg: underside of seat, with inboard hand)
- locate (primary exit, use body movement eg knee or shoulder to locate door, then use outboard hand to locate exit release)
- release (once exit open, keep outboard hand fixed on frame and then release inboard hand to undo safety harness)
- vacate (use a low profile, pull inboard hand to join outboard hand at exit & pull head through – body will follow)
- inflate (clear the surface of debris and inflate lifejacket if safe & appropriate to do so)
It was certainly easiest to perform this drill with eyes shut, avoiding the potential added disorientation of visual cues whilst inverted. Obviously an emergency ditching is a high stress environment – there will be a catecholamine surge and removing factors likely to add to panic is sensible
What’s the parallel in resus? There are probably a few. I was immediately reminded of similarity with CICO crisis training. I’ve had the misfortune of doing a few of these in real life, and have learned (by hard experience) to perform surgical airways as a tactile procedure (scalpel-finger-[bougie]-tube). But body mechanics are important in other things we do – threading a catheter onto a seldinger wire (use palmar aspect of both wrists to form a stable bridge, giving fine motor control) or effective laryngoscopy (understanding different mechanics of Mac 3 vs 4, elbow and wrist position to maximise force – a plug here for Rich Levitan’s airway course which certainly helped my airway technique).
Here’s a demo of the HUET in action – experimental test crash dummy Dr Francis Lockie uses his secondary exit, as the primary exit is blocked.
Despite the ‘wind up’ about HUET, I thought it was a well run course, delivered exactly what it was supposed to and has given a structure to dealing with a ditching crisis.
Could such lessons be applied to medicine? Absolutely – building muscle memory, relying on simple drills and regular sim are key.
Grammar, grammatical associations and context.
To make the test even more realistic, it is made up of nonsensical questions so that the largely uninformed, yet grammatically savant reader is capable of getting the correct answer even when the required factual knowledge is not present.
Select one response for each question – your time starts…now…
The answer is mentioned in stem.
This question can be defined as self referential.
The answer is in the stem...
This answer stands out as the longest distractor and the only response to use a qualifier
ALL, NONE and ALWAYS are absolute statements. Look for the distractor with a non-absolute qualifier.
Starting with a vowel, this is the only grammatically correct stem (question ends with 'an')
Being a plural, this is the only distractor that is grammatically correct
Narbit is present in all stems and logically must be correct. However any one of the other stems may also be correct...
This question references a previous question (Question 4)
Haemolytic Disease of the Newborn may occur if the mother produces antibodies that cross the placenta and attack the red blood cells of the foetus.
It can lead to anaemia in the baby, and in severe cases the foetus may die in utero, or suffer neurological damage after birth due to high levels of bilirubin (kernicterus).
Here is a simplified explanation to try to help you understand the concepts behind administration of anti-D. Check the links at the bottom of the post for more detailed reading.
We begin with mother and foetus.
Haemolytic Disease of the Newborn may occur
if we have a Rh (D) negative mother [RED dots] with an Rh (D) positive foetus [GREEN dots].
The Rh factor is the name given to a blood group protein, Rh (D), which is attached to red blood cells. Some people have this protein on their red blood cells and others do not.
On average, of every 100 people:
- 85 will have the Rh factor; their blood type is called ‘Rh (D) positive’
- 15 will not have the Rh factor; their blood type is called ‘Rh (D) negative’
Next, there is a sensitising event:
During (or at the end of) her pregnancy, Rh (D) blood cells from the foetus enter the mothers blood stream (known as a sensitising event). Reasons for this occurring include:
- tests such as amniocentesis
- ectopic pregnancy
- termination of pregnancy
- abdominal trauma.
- following delivery of Rh(D) positive baby.
A small number (1.5 – 1.8%) of Rh negative mothers are immunised by their Rh positive foetuses despite administration of anti-D immunoglobulin postpartum. Studies have shown that this number can be reduced to less than 1.0% by administering two doses of anti-D immunoglobulin, the first at 28 weeks gestation and the second following delivery. .
Mum produces antibodies:
This stimulates the mother to produce antibodies (the pink lines in the diagram) to destroy the Rh (D) positive blood cells in the maternal blood. This RH (D) antibody response may remain for many years.
Then there is an antibody response to subsequent pregnancy:
The NEXT time the mother falls pregnant with an Rh (D) positive foetus, these antibodies may cross the placenta and attack the foetal red blood cells.
This can lead to Haemolytic Disease of the Newborn (HDN).
Prevention of HDN with Rh (D) immunoglobulin. Anti D.
As before, Rh (D) positive blood cells from the foetus may cross into the mothers bloodstream.
Rh (D) immunoglobulin is given:
Within 72 hours, a dose of Rh(D) immunoglobulin is administered.
Rh (D) immunoglobulin is obtained form the fractionated plasma of blood donors.
Once administered, the Rh (D) immunoglobulin removes the Rh (D) positive red blood cells from the maternal bloodstream.
With these red blood cells removed, the mothers immune system is not activated and no maternal antibodies are produced.
Blood should be drawn from the mother prior to giving the immunoglobulin to assess the level of foetalmaternal hemorrhage. If the hemorrhage is larger than that covered by the initial dose of immunoglobulin additional dose(s) may be required.
Result: No immune response:
Therefore at the NEXT pregnancy there are no circulating antibodies to attack the foetal red blood cells.
In Australia Anti-D immunoglobulin is given to to all Rh negative women at 28 and 34 weeks gestation as prophylaxis against small amounts of foetal maternal bleeding that can occur in the absence of observable sensitising events.
This is known as routine antenatal anti-D prophylaxis (RAADP).
Giving Rh(D) immunoglobulin (Anti-D):
The recommended dose of anti-D immunoglobulin is
- 250 IU after sensitising events in the first trimester of pregnancy and
- 625 IU after sensitising events beyond the first trimester.
Should be given ASAP and within 72 hrs of sensitising event.
If the gestational age is not known with certainty and the possibility exists that the gestational age is 13 weeks or more, 625 IU should be given.
- Should be administered at room temp.
- Give IMI slowly.
- If dose more than 5ml then divide and give at different sites.
- Rh(D) Positive mother.
- individuals with isolated Immunoglobulin A (IgA) deficiency, unless they have been tested and shown not to have circulating anti-IgA antibodies
- Mothers with severe thrombocytopenia or coagulation disorders that would contraindicate IM injections.
- NOT to be administered IVI (high risk of anaphylactic reaction).
- Monitor closely if mother has history of allergic reactions following human immunoglobulin preparations.
Anti-D manufactured from human plasma. Potential risk of virus (inluding Hep B, HIV, Creutzfeldt-Jakob Disease), but this if very low due to screening process for donors and viral inactivation processes during the manufacturing process.
References: featured image via treehouse1977
- Haemolytic Disease of the Newborn.
- Guidelines on the propylactic use of RH (D) immunoglobulin (anit D) in obstetrics PDF.
- Full product information guide (PDF).