Article Reviews - CRIT CLOUD

Manage Critical Bleedings in Anticoagulated Patients like a Pro!

5/12/2018

Anticoagulated patients are common, and the amount of available oral anticoagulants is becoming more diverse and confusing. Anticoagulation is the cornerstone in the treatment of thrombosis and thromboembolic complications in a variety of diseases. Lixiana, Pradaxa, Eliquis and Xarelto are some of these pretty-sounding drugs that many doctors know but find it difficult to keep up.

So if you work in an emergency room, anaesthesia or intensive care, there's a good chance you will be facing an anticoagulant patient with potentially critical bleeding that could require urgent treatment... And this leaves you with the following questions:

- What is a critical bleed (apart from obvious massive bleeding)? Does this bleeding need imminent reversal?

- Do I need any laboratory testing before?

- What treatment should I actually give the patient?

If you do not have a guideline in your institution, it may be time to create one, and the following publication is indeed very useful for this purpose!

The 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants very nicely summarises current evidence and expert opinion on these issues. But the very best are their excellent figures, providing all the answers you need: simple and very understandable!

What is a Critical Bleeding?

Do I Need any Laboratory Tests Before?

What Treatment Should I Give the Patient for Reversal?

2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants, Volume 70, Issue 24, December 2017

Out-of-Hospital Cardiac Arrest: The Power of Adrenaline and Amiodarone

29/7/2016

For the resuscitation out-of-hospital one of the mainstays besides compression and defibrillation ist the application of adrenalin and amiodarone. According to the new ACLS guidelines 2015 these are the only drugs remaining in the treatment for shockable rhythms.

While adrenaline is given for maximum vasoconstriction in order to promote coronary perfusion pressure CPP, amiodarone and sometimes lidocaine are used to promote successful defibrillation of shock-refractory ventricular fibrillation VF or pulseless ventricular tachycardia VT. While the usage of these drugs is undoubtedly very effective in patients with existing circulation the effectiveness during resuscitation remains a matter of debate.

The Effect of Adrenaline

As a matter of fact it has never been proven that adrenalin actually improves long-term outcome. In 2014 Steve Lin and colleagues published a systemativ review on the efficacy of adrenaline in adult out-of-hospital cardiac arrest (OHCA). They were able to show that according to current evidence standard dose adrenaline (1mg) improved rates of survival to hospital admission and return of spontaneous circulation (ROSC) but had no benefit in means of survival to discharge or neurologic outcomes.

What about Amiodarone and Lidocaine?

Kudenchuck et al. now made the effort to look into the efficacy of amiodarone and lidocaine in the setting of OHCA. Used according to the ACLS guidelines 2016 amidarone is given after the third shock applied when treating a shockable rhythm. Two rather small controlled trials have shown so far that using amidarone actually does increase the likelihood of ROSC and the chance to arrive at a hospital alive. It's impact on survival to hospital discharge and neurologic outcome though remains uncertain.

In this randomized, double-blind trial, the investigators compared parenteral amiodarone, lidocaine and saline placebo in adult, non-traumatic, OHCA. They ended up with 3026 patients meeting inclusion criteria and which were randomly assigned to receive amiodarone, lidocaine or saline placebo for treatment. They finally found that neither amiodarone nor lidocaine improved rate of survival to discharge or neurologic outcome significantly. There were also no differences in these outcomes between amiodarone and lidocaine. Across these trial groups also in-hospital care like frequency of coronary catheterisation, therapeutic hypothermia and withdrawal of life-sustaining treatments did not really differ, making a bias due to treatments after admission unlikely.

Take Home

- This study was not able to show any benefit of amiodarone or lidocaine in the the setting of OHCA in terms of survival to hospital discharge and neurologic outcome

- Amiodarone seems to improve the likelihood of ROSC and survival to hospital admission (similar to adrenaline)

- As there are no other options, I believe amiodarone should remain part of the standard treatment for shockable rhythms in OHCA

- Lidocaine can be safely removed from CPR sets as there is no benefit of over amiodarone

Read here:

N Engl J Med 2016;374:1711-22

Resuscitation, June 2014, Vol 85, Issue 6, p 732-740

New ACLS Guidelines 2015, The Changes

Lactate - From Bad to Good? An Explanation Trial

14/2/2016

The discussion on the so-called lactic acidosis and its causes have become increasingly attractive over the last couple of years as several biochemical explanations are challenged. A significant confusion persists on the various relationships between lactate, lactic acid and metabolic acidosis.

Most clinicians continue to refer to the traditional understanding of impaired tissue oxygenation causing increased lactate production, impaired lactate clearance and therefore resultant metabolic acidosis. Just recently we had a discussion on our ward round on this topic when a team member presented the most recent article of UpToDate online on the causes of lactic acidosis. The authors state that 'Lactic acidosis is the most common cause of metabolic acidosis in hospitalised patients' and that 'Lactic acidosis occurs when lactate production exceeds lactate clearance. The increase in lactate production is usually caused by impaired tissue oxygenation...'... finally suggesting that lactate is no good!

These statements support the classical understanding that:
- Hyperlactatemia is caused by tissue hypoxemia, and
- This in turn then leads to a metabolic acidosis called lactic acidosis

This biochemical understanding has persisted for decades, but there are some good reasons to vigorously challenge this traditional aspect on the 'bad' lactate. Lactate turns out to be by far more complex in its characteristics and functions, so I decided to try and make a short but comprehensive overview of this molecule.

What is lactate?

Lactate is a small organic molecule with the chemical formula CH3CH(OH)CO2H and structurally looks like on the image to the left. It is produced in the cytoplasm of human cells mainly by anaerobic glycolysis by the conversion of pyruvate to lactate by LDH. This chemical reaction results typically in a blood lactate to pyruvate ratio of about 10:1. And while lactate is produced, NAD+ also is incurred, and this actually can accept protons itself, so does not result in acidosis itself.

Lactate arises from the production of energy by consuming glycogen and glucose.

Where does it come from?

Typically most people think of muscles first as an origin of lactate. As a matter of fact lactate originates from many other organs, including our red blood cells. Red blood cells always produce lactate as they lack the mitochondria required to regenerate NAD+ needed for glycolysis. In general, you can say that tissues with lots of LDH are the primary producers of lactate. Around 20mmol/kg/day of lactate are produced under normal circumstances.

Lactate is not only produced in skeletal muscle.

Muscle: 25%
Skin: 25%
Brain: 20%
RBC: 20%
Intestine: 10%

What happens with it?

Lactate is not just for nothing. After its production by anaerobic glycolysis lactate is reutilised, for instance in the liver and the cortex of the kidneys. As an example: under the influence of cortisol it is used for gluconeogenesis in hepatocytes and restores glucose and glycogen. Also, it is a part of oxidative phosphorylation in the liver, kidney, muscles, the heart and the brain. Like this lactate helps conserve glucose levels in our blood.

Lactate actually serves as a fuel for oxidation and glucose regeneration and therefore is a source for energy itself.

From The Lancet Endocrinology 2013

How does hyperlactatemia develop?

In general, you can assume that there is a balance between lactate production and its consumption or usage. The classical understanding that tissue hypoxia leads to overproduction and underutilisation by impaired mitochondrial oxidation is correct.

The critical point though is that lactate is also produced via aerobic glycolysis as a response to stress. This happens in septic patients, asthmatic exacerbations, trauma and other critical conditions. In these situations, the trigger for lactate production is adrenergic stimulation and NOT tissue hypoxia. There are also several other reasons for hyperlactatemia other than tissue hypoxia:

Sepsis: Adrenergic drive
Asthma: Adrenergic drive
Trauma: Adrenergic drive
Cardiogenic and haemorrhagic shock: Adrenergic drive
Pheochromocytoma: Adrenergic drive
Inflammation: Cytokine drive
Alkalosis, antiretroviral medication and others

Also, there is good evidence showing that organs like the lungs are an important producer of lactate during stress. And of course in all these conditions hypoxic and non-hypoxic hyperlactatemia might also co-exist.

In critically ill patients often other reasons than tissue hypoxia are responsible for hyperlactatemia (e.g. adrenergic drive).

Is lactate harmful?

In contrast to the classical understanding of lactate and lactic acidosis more and more evidence comes up indicating that lactate during stress actually serves as a fuel for energy production. Various tissues, e.g. the myocardium increase their lactate uptake during stress significantly. Also, our brain consumes more lactate during stress which is used for oxidation. Research has shown that lactate infusions improve cardiac output in pigs and even in patients with heart failure.

Experimental work on isolated muscles suggests that circulating catecholamines and development of acidic conditions during exhaustive exercise may improve muscles' tolerance to elevated K+ levels. This implies that during high-intensity activity with high extracellular K+ and adrenaline, lactate serves as a performance-enhancing chemical, rather than being the cause of muscle fatigue.

Lactate is not harmful to our organism. On the contrary, recent compelling evidence suggests that lactate might be beneficial, rather than detrimental, during high-intensity activity and to force development in working heart and skeletal muscle.

Why do critically ill patients with hyperlactatemia die more often then?

In critical care hyperlactatemia indeed is a marker of illness severity and a strong indicator of mortality. This is especially true for patients with sepsis. However, as described above, hyperlactatemia often doesn't indicate hypoperfusion or tissue hypoxia. Hyperlactatemia rather reflects the severity of illness by representing the degree of our body's activation to stress. A fall in lactate concentration following treatment of critically ill patients is due to an attenuation of the stress response rather than to correction of oxygen debt.

Hyperlactatemia reflects a severe disease and the patients' response to stress. Patients die due to their illness, not because of high lactate.

What about Ringer's lactate?

Ringer's lactate (RL) is not harmful in patients with hyperlactatemia.

As a matter of fact RL turns out to be superior compared to normal saline in hyperlactatemia, acidotic patients and patients with hyperkalemia.

The bottom line

- Lactate is an indicator of stress, a marker of illness severity and a strong predictor of mortality, but not harmful as a molecule itself.

- Lactate is helpful as an essential source of energy and an important fuel for oxidation and glucose generation.

- During conditions like septic shock, there is no proof that lactate is produced only due to tissue hypoxia. In fact, well-ventilated lungs provide a large amount of lactate during sepsis. Lactate in sepsis and other critical conditions is mostly not due to hypoxemia or hypoperfusion.

- Ringer's lactate contains sodium lactate, but not lactic acid. Lactate itself, as mentioned above, is beneficial in severe disease. Therefore RL remains the fluid of choice during severe disease like for instance septic shock.

- Ringer's lactate is superior to normal saline in patients with metabolic acidosis, hyperlactatemia and also hyperkalemia.

Got interested in some better understanding? START READING HERE:

Emmettt et al. UpToDate online, August 2015, Causes of lactic acidosis

Garcia-Alvarez et al. Critical Care 2014, 18:503

Marik PE, Bellomo R. OA Critical Care 2013 Mar 01;1(1):3

Garcia-Alvarez et al. Lancet Diabetes Endocrinol. 2014 Apr;2(4):339-47.

Andersen JB et al. Journal of Experimental Biology 2007 210: vii doi: 10.1242/jeb.001107

Bakker J et al. Intensive Care Med (2016) 42:472–474

Also, have a listen to Bellomo's review on lactate:

Click in image to listen to podcast

OUT NOW: New and Updated ILCOR 2015 Treatment Recommendations on Cardiopulmonary Resuscitation

23/10/2015

Since the year 2000 the International Liaison Committee on Resuscitation (ILCOR) continues to evaluate all evidence and updates their recommendations in 5-year cycles. The most recent ILCOR 2015 International Consensus Conference was held in Dallas last February and the new treatment recommendation are out now.

Resuscitation remains one of the most challenging situations in health care. Providing basic and advanced cardiac life support gives you the opportunity to virtually safe a patients life but in a very limited period of time. It is an enormous challenge to consider all emerging evidence and pack this into simple and useful guidelines.

It is imperative to for any health care provider to get familiar with the updated guidelines and major changes. Below you can find all relevant links to get the reading going.

The team of BoringEM.org in Canada have provided some excellent infographics to visualise all important changes in the new treatment guidelines since 2010. You should also note that the Canadian Heart & Stroke Association and the American Heart Association have just published the 'HIGHLIGHTS of the 2015 American Heart Association Guidelines Update for CPR and ECC', an excellent summary of the new recommendations and changes. So if you can't find the time to read all of the publication in 'Circulation', this will certainly provide all information you need to know.

Summary of the Canadian Heart & Stroke Association and the American Heart Association: HIGHLIGHTS of the 2015 American Heart Association Guidelines Update for CPR and ECC

The original publication in Circulation, October 20, 2015, Volume 132, Issue 16 suppl 1
OPEN ACCESS

The Most Important Changes (Click to Enlarge)

The Updated Algorithms (Click to Enlarge)

ERC and ESICM 2015 Guidelines for Post-Resuscitation Care

Based on the the 2015 ILCOR treatment recommendations the European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM) have produced these post-resuscitation care guidelines on October the 13th. Recent changes here are the greater emphasis for urgent PCI when indicated, target temperature management at 36°C, prognostic evaluation using a multimodal strategy and an increased emphasis on rehabilitation after survival.

Nolan JP, Resuscitation, October 2015, Pages 202 - 222

Don't Throw Away your Cooling Devices!

20/8/2015

When performing a kidney transplantation nowadays up to 50% of recipients developed a delayed graft function which is defined as the need of dialysis within seven days. The authors of this recently published NEJM-article asked themselves whether mild hypothermia might influence outcome in this regard.

In order to answer this question the investigators assigned organ donors after declaration of death according to neurologic criteria into two groups. They were either treated with mild hypothermia (34 to 35°C) or with normothermia (36.5 to 37.5°C). The target temperature was maintained until the patients were transferred to theatre for transplantation.

Primary outcome of this trial was delayed graft function among recipients. Secondary outcomes included the rates of individual organs transplanted into each treatment group at the total number of organs transplanted from each donor.

This trial had to be stopped early as an interim analysis showed significant efficacy of mild hypothermia. Up to this point a total of 572 patients received a kidney transplant (285 in the hypothermia group and 287 in the normothermia group). 28% of recipients in the hypothemia group developed delayed graft function compared to 39% in the normothermia group.

The authors therefore conclude that mild hypothermia significantly reduces the rate of delayed graft functions among recipients.

This study suggests that potential organ donors after declaration of death according to neurologic criteria should be treated with mild hypothermia.

Intensive care units that continue to treat patients with mild hypothermia after cardiac arrest might have two rewarm their patients for the diagnosis of neurological death before re-cooling them for organ transplantation

Anyhow, it seems reasonable not to get rid of your cooling devices!

Read more about the controversies of hypothermia in the ICU:

The Targeted Temperature Management Trial: Nielsen N, et al. New Engl J Med. 2013 Dec;369(23):2197-206

The 2 trials that introduced therapeutic hypothermia into ICU practice:
The Hypothermia After Cardiac Arrest Study Group, Holzer at al. New Engl J Med. 2002 Feb;346(8):549-556

Bernard S.A. et al. New Engl J Med. 2002 Feb;346(8):557-563

Review article on therapeutic hypothermia for non-VF/VT cardiac arrest:
Sandroni S. et al. Crit Care Med; 2013;17:215

Pyrexia and neurological outcome:
Leary M. et al. Resuscitation. 2013 Aug;84(8):1056-61

BIJC post on: The Effect of Pre-Hospital Cooling: Rather Worrying Results

Another Hole in the Ballon (-Pump)!

7/5/2015

In the late 1960's the technology of counter-pulsation by using an intra-aortic balloon pump (IABP) was introduced into clinical work. Based on the principle of diastolic inflation and systolic deflation, IABP counter-pulsation improves diastolic coronary artery blood flow and decreases left ventricular afterload. Up to the year 2009, 2012 respectively, the usage of an IABP in patients with ST-segment elevation myocardial infarction and cardiogenic shock was considered a class IC recommendation (reminder: levels of evidence).

Since then a couple of well conducted, larger trials have failed to show a positive impact of IABP especially on mortality. In regards of the most recent meta-analysis in JAMA we provide a short overview of the most important publications. It's interesting to see that the balloons undermining started with a meta-analysis and for the the time being ends with one.

Stitch no.1

The first notable hole in the ballon was caused by Sjauw et al.'s systematic review and meta-analysis in the European Heart Journal in 2009. Their pooled randomized data consisting of two separate meta-analyses did not support the use of an IABP in patients with high risk STEMI. They concluded that there is insufficient evidence endorsing the current guideline recommendation for the use of IABP therapy in the setting of STEMI complicated by cardiogenic shock.

This publication was one of the main reasons for the expert panel of the European Society of Cardiology to change the recommendation (ESC Guidelines 2012) to use an IABP in patients with STEMI from IC to IIB.

Stitch 2 and 3

In the same year 2012 Thiele et al. published their first IABP-SHOCK II results in the NEJM. Their
randomized, prospective, open-label, multicenter trial showed no reduction in the 30-day mortality compared to the best available medical therapy alone in patients with myocardial infarction-induced cardiogenic shock and planned early revascularization (PCI or CABG).

One year later the IABP-SHOCK II investigators published their final 12-months results in The Lancet. They came to the final conclusion that in patients undergoing early revascularization for myocardial infarction with cardiogenic shock, IABP did not reduce 12-month all-cause mortality.

Stitch no. 4

In 2013 Ranucci at al. presented the results of their single-center prospective randomized controlled trial looking at the usage of a preoperative IABP in high-risk patients undergoing surgical coronary revascularization. By looking at a total of 110 patients with an ejection fraction below 35% and no hemodynamic instability there was no improvement in outcome when inserting an IABP preoperatively.

Preliminary Final Stitch

So finally Ahmad and his team decided to assess IABP efficacy in acute myocardial infarction by performing an updated meta-analysis. Main outcome was 30-day mortality. They included 12 eligible RCTs randomizing 2123 patients and found no improvement in mortality among patients with acute myocardial infarction... regardless of whether patients had cardiogenic shock or not!
A look at another 15 eligible observational studies with a total of 15 530 patients showed basically conflicting results which was explained by the differences between studies in the balance of risk factors between IABP and non-IABP groups.

It seems that the IABP fails to show its assumed efficacy in patients with myocardial infarction and cardiogenic shock, especially when early revascularization (PCI or CABG) is available.

As a general consideration and also when no early revascularisation is available the use of another left-ventricular assist device like the Impella pump might prove to be a good and easy to use alternative (see blow).

Sjauw KD et al. Eur Heart J 30: 459-468

ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 33: 2569-2619 OPEN ACCESS

Thiele et al. N Engl J Med 2012; 367:1287-1296 OPEN ACCESS

Thiele et al. The Lancet, Volume 382, Issue 9905, Pages 1638 – 1645

Crit Care Med. 2013 Nov;41(11):2476-83

JAMA Intern Med. Published online March 30, 2015

Short film on the principle of the Impella pump 2.5. Bare in mind that this device can actually be easily inserted in the environment of ICU and positioned by using transthoracic echo TTE.

Excellent Review on IV Fluid Resuscitation for the End of the Year 2014

11/1/2015

Again we have picked a review article looking at fluid resuscitation in the ICU. This article by Lira et al. in the Annals of Intensive Care looks at all the new literature available in regards of fluid therapy during resuscitation. Also review current recommendations and recent clinical evidence. This results in an excellent systematic review that leaves us with following conclusions:

- Currently no indications exist for the routine use of colloids over crystalloids

- In regards of current evidence (including the Albios trial), the cost and limited shelf time the use of albumin as a resuscitation fluid is not recommended

- The use of hydroxy-ethyl-starch (HES) during resuscitation should be avoided

- In light of the lack of evidence, and the theoretical potential for adverse effect, the suggestion is to avoid gelatine or dextran

- The use of 0.9% normal saline is associated with the development of hyperchloremic metabolic acidosis and increased risk of AKI in susceptible patients. Therefore balanced crystalloid solutions should be considered/ preferred

- Current literature supports the use of balanced crystalloid solutions (e.g. Hartmann's solution, Ringer's lactate) whenever possible

This makes things quite simple actually... but of course opinions differ!

Lira and Pinsky, Annals of Intensive Care Dec 2014, 4:38 OPEN ACCESS

Read here: The Albios trial

Early Systematic Coronary Angiography in All Out-Of-Hospital Cardiac Arrests Seems Reasonable

9/6/2014

The most recent guidelines of the European Resuscitation Council and the American Heart Association recommend that resuscitated patients of presumed cardiac cause should undergo immediate coronary angiography with subsequent PCI if indicated, regardless of clinical symptoms and/or ECG criteria. However, this approach is discussed controversially as we don't know if there is any benefit on performing an angiography in every out-of-hospital cardiac arrest (OHCA). Additionally such an approach might be associated with quite some logistical and organisational problems for certain institutions.

In this noteworthy and open access review article Geri et al. discuss current literature and state that there are no randomised studies looking at acute coronary angiography in OHCA patients. A large number of observational studies though supports feasibility and a possible survival benefit of an early invasive approach.

They conclude that even in the absence of large randomised studies, it is probable that an early coronary revascularization is associated with a significant clinical benefit in OHCA survivors.

Providing the patient had no other obvious reason for OHCA (sepsis, haemorrhage, metabolic disorder etc.) current literature strongly encourages performing a systematic coronary angiography in all OHCA patients.

Geri G et al., Current Opinion in Critical Care, June 2014, Vol 20, Issue 3 (Open Access)

Challenging another Dogma: Time for Drug-Free Cardiopulmonary Resuscitation?

30/4/2014

Guidelines on advanced cardiopulmonary resuscitation around the world, including the ACLS guidelines, are based on four important concepts: mechanical resuscitation (CPR), defibrillation, airway management and also application of vasoactive drugs. The application of these drugs is intended to improve hemodynamics and the heart's responsiveness to defibrillation.

What some of us might not be aware of though, but has already been mentioned by the '2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations' and the 'European Resuscitation Council Guidelines' in 2010: There is actually no definitive evidence that the application of these drugs provides any long-term benefit for these patients.

While vasopressors are intended to improve coronary and cerebral perfusion and therefore successful defibrillation and neurological outcome, there is actually some concern (animal and registry studies) that this might actually decrease microcirculation and cerebral blood flow as well as increase myocardial oxygen consumption and cause post-defibrillation ventricular arrhythmias. Also the use of anti-arrhythmic drugs as well as their combination with vasopressors lacks evidence of any impact on survival. Another interesting fact is that we have no idea about ideal dosage or optimal timing of these drugs... should they be given continuously?

This and many more questions and facts are discussed in an interesting review article by Sunde and Olasveengen in Current Opinion in Critical Care. They conclude that there is no evidence to support any specific drugs during cardiac arrest and that healthcare systems should not prioritise implementation of unproven drugs before good quality of care can be documented.

Are we heading towards an era of drug-free resuscitation?

Sunde K et al. Curr Opin Crit Care. 2014 April 16

Article accessible here

The Effect of Pre-Hospital Cooling: Rather Worrying Results

24/3/2014

JAMA just published another interesting puzzle piece on the topic of post arrest cooling. In this interesting, randomized trial, the authors addressed the question wether prehospital cooling aiming for 34°C improves outcomes after resuscitation from cardiac arrest in patients with ventricular fibrillation (VF) and non-VF. A total of 1359 patients were enrolled within 5 years. Primary outcomes were survival at hospital discharge and neurological status at discharge.

In regards of primary outcomes no differences were found between the intervention and control group. Also when looking at patients who awakened from coma or died without awakening again no significant differences between the intervention and control group were found. Also length of stay, access to early coronary angiography and reduction in level or withdrawal of life support did not differ.

When looking at patient safety issues though the investigators noted a higher incidence of rearrest during transport to the hospital. The intervention group (cooled out of hospital) also showed significantly lower oxygenation on arrival, increased pulmonary edema on the first chest x-ray and a greater use of diuretics during the first 12 hours after admission. During further hospitalization though the number of days ventilated, the incidence of re-intubation and the use of antibiotics did not differ.

The study results don’t support the practice of out-of-hospital cooling but show some worrying implications for patients safety.

Cobb LA et al. JAMA. 2013;311(1):45-52

Open access on JAMA Network Reader (Need for sign up)

Recent BIJC blog on Targeted Temperature Management Trial: Targeted Temperature Management Trial: Is it Time to Stop Cooling Patients after Cardiac Arrest?

ABOUT US

The Crit ☁ supports free access medical eduction. The content of this website can be used and reproduced by stating a reference to our site.
Read our statements here

SEARCH US

CONTACT US

If you have any interesting article or news to be posted on this website, please contact us here

FOLLOW US

TRUST US

TWEET US

This site complies with the HONcode standard for trustworthy health information:
verify here.

Follow @BIJCorg

WEBSITES WE SUPPORT