Arbor Pharmaceuticals Announces FDA Approval of Nymalize...

FDA Approves Nymalize

Arbor Pharmaceuticals Announces FDA Approval of Nymalize

FDA: May 13, 2013 - Atlanta, GA - Arbor Pharmaceuticals announced today that the U.S. Food and Drug Administration (FDA) has approved its New Drug Application (NDA) for Nymalize (nimodipine) oral solution. Nymalize was previously granted Orphan designation which provides seven years of market exclusivity.

Nymalize is the first and only nimodipine oral solution indicated for the improvement of neurological outcome in adult patients with subarachnoid hemorrhage (SAH).

Prior to the approval of Nymalize, nimodipine was only available in gel capsule form. Since the product is commonly administered to patients through a nasogastric tube healthcare providers would extract the product from the gel capsule with a syringe. This has resulted in accidental administrations of nimodipine intravenously instead of via the intended enteral (oral) syringe.

In 2010, the FDA issued a "drug safety communication" to healthcare professionals titled “Nimodipine Oral Capsules: Medication Errors - IV Administration May Result in Death, Serious Harm.” In this communication they reported twenty-five intravenous nimodipine prescribing or administration errors and that four of the patients who mistakenly received nimodipine intravenously died and five had near-death events. The Institute for Safe Medication Practice reported an additional death due to improper nimodipine administration in February 2013.

Ed Schutter, President & CEO of Arbor stated, “I am pleased that Arbor’s first NDA approval has the potential to save lives by reducing the opportunity for hospital administration errors. To further ensure that we minimize the potential for administration error, each Nymalize unit dose cup will be packaged with an oral syringe. Nymalize adds to our growing portfolio of approved prescription products that can improve the lives of our patients.”

Dr. Laurence Downey, VP of Medical & Scientific Affairs added, “Approval of our first NDA is an important milestone in the evolution of Arbor Pharmaceuticals. This is the first of what we hope will be multiple NDA approvals over the next several years. I would like to thank and congratulate our team that worked on the Nymalize NDA.”

Arbor Pharmaceuticals will launch Nymalize in the next few months.

About Nymalize

Nymalize (nimodipine) oral solution is indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in adult patients with SAH from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition (i.e., Hunt and Hess Grades I-V).

Important Safety Information About Nymalize

Blood pressure should be carefully monitored during treatment with Nymalize (nimodipine) oral solution. Nimodipine may increase the blood pressure lowering effect of concomitantly administered anti-hypertensives such as diuretics, beta-blockers, ACE inhibitors, angiotensin receptor blockers, other calcium channel blockers, α-adrenergic blockers, PDE5 inhibitors, and α-methyldopa.

Patients with cirrhosis are at a higher risk of adverse reactions and should be monitored closely and administered a lower dose.

Concomitant use of strong inhibitors of CYP3A4 with nimodipine should generally be avoided due to risk of significant hypotension. These include some macrolide antibiotics (e.g. clarithromycin, telithromycin), some HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, saquinavir), some HCV protease inhibitors (e.g., boceprevir, telaprevir), some azole antimycotics (e.g., ketoconazole, itraconazole, posaconazole, voriconazole), conivaptan, delaviridine, and nefazadone.

Concomitant use of strong CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s wort) and nimodipine should generally be avoided, as nimodipine plasma concentration and efficacy may be significantly reduced.

Nimodipine plasma concentration can also be increased in the presence of moderate and weak inhibitors of CYP3A4. If nimodipine is concomitantly administered with these drugs, blood pressure should be monitored, and a reduction of the nimodipine dose may be necessary.

Grapefruit juice inhibits CYP3A4. Ingestion of grapefruit/grapefruit juice is not recommended while taking nimodipine.

Moderate and weak inducers of CYP3A4 may also reduce the efficacy of nimodipine. Patients on these should be closely monitored for lack of effectiveness, and a nimodipine dosage increase may be required.

Common Adverse Reactions

Most common adverse reactions (incidence ≥ 1% and ≥1% placebo) were hypotension, headache, nausea, and bradycardia.

About Arbor Pharmaceuticals

Arbor Pharmaceuticals, headquartered in Atlanta, Georgia, is a specialty pharmaceutical company currently focused on the hospital, cardiovascular and pediatric markets. The company has 175 sales professionals in the field which promote its products to hospitals and physicians. Arbor intends to become a leading specialty pharmaceutical company by actively licensing, developing and commercializing late-stage products for specialty focused conditions. Arbor currently markets fifteen NDA and ANDA approved products with twenty-eight more in development.

Source: Arbor Pharmaceuticals

Accidental Awareness During Anesthesia Is Rare.

Accidental Awareness During Anesthesia Is Rare.

A Very few surgical patients experience accidental awareness while under general anesthesia.

The survey of the senior anesthetists at National Health Service hospitals in the United Kingdom about cases of accidental awareness during general anesthesia encountered in 2011.

Previous research has suggested a high rate of accidental awareness, occurring in about one in 500 patients.

But this study found that the rate was one in 15,000.

The researchers also found that only about 2 % of anesthetists routinely use brain-monitoring equipment to keep tabs on patients during surgery.

The findings, published in the journals Anesthesia and The British Journal of Anaesthesia, appeared online March 12.

"Anesthesia is a medical specialty very much focused on safety and patient experience," study lead author Jaideep Pandit, a consultant anesthetist in Oxford, said in an Anesthesia news release. "We identified accidental awareness during anesthesia as something which concerns patients and the profession. The profession is therefore undertaking this major study so that we can better understand the problem and work to reduce the likelihood of it happening to patients."

"We are particularly interested in patient experiences of awareness," Pandit added. "Although we know that some patients do suffer distress after these episodes, our survey has found that the vast majority of episodes are brief and do not cause pain or distress."

The researchers plan to investigate why their findings are so different from the results of previous studies.

"Risks to patients undergoing general anesthesia are very small and have decreased considerably in the last decades," study co-author Tim Cook, a consultant anesthetist in Bath, said in the news release. "Of the 3 million general anesthetics administered in [National Health Services hospitals] each year, only a very small number of patients experience awareness during anesthesia, with the majority of these occurring before surgery starts or after it finishes."

"While our findings are generally reassuring for patients and doctors alike, we recognize that there is still more work to be done," Cook said. "We are spending the next year studying as many of the cases as possible to learn more from patients' experiences."

THE ANAESTHETIC MANAGEMENT OF THE OBESE CHILDREN Alisher Agzamov, A.M. Al Qattan, Asmahan Al Mulla, A. Y. Dubikaitis Department of Anaesthesiology & ICU, Al Sabah Hospital, Kuwait City, Kuwait More than 42 million children under 5 years of age are overweight across the world. In Asia, in Middle East and in the Gulf region, the number of overweight children and adolescents has doubled in the last two to three decades, and similar doubling rates are being observed worldwide, including in developing countries and regions where an increase in Westernization of behavioral and dietary lifestyles is evident. The definition of childhood obesity has not been standardized in the past, making studies difficult to compare. In spite of this, the increase in the incidence of childhood obesity is evident and has now reached epidemic proportions. Obese children experience few of the medical complications seen in obese adults. 1. Respiratory System is most affected, the degree of which is determined by the level of obesity. 2. A considerable amount of information on the anaesthetic management of the obese adult, but a very little has been written concerning the obese child. 3. There is less pathology in the obese child when compared with the adult but some evidence shows a higher likelihood of a critical incident occurring when anaesthetizing such children. 4. We need to be as worried about anaesthetizing the obese child as we are for the obese adult. This concern should increase with increasing body mass index. Anaesthesia consideration must be given to family behavior patterns, diet after weaning, and the use of new methods of information dissemination to help reduce the impact of childhood obesity worldwide.

THE ANAESTHETIC MANAGEMENT OF THE OBESE CHILDREN

Alisher Agzamov, A.M. Al Qattan, Asmahan Al Mulla, A. Y. Dubikaitis

Department of Anaesthesiology & ICU, Al Sabah Hospital, Kuwait City, Kuwait

More than 42 million children under 5 years of age are overweight across the world.

In Asia, in Middle East and in the Gulf region, the number of overweight children and adolescents has doubled in the last two to three decades, and similar doubling rates are being observed worldwide, including in developing countries and regions where an increase in Westernization of behavioral and dietary lifestyles is evident.

The definition of childhood obesity has not been standardized in the past, making studies difficult to compare. In spite of this, the increase in the incidence of childhood obesity is evident and has now reached epidemic proportions.

Obese children experience few of the medical complications seen in obese adults.

1. Respiratory System is most affected, the degree of which is determined by the level of obesity.

2. A considerable amount of information on the anaesthetic management of the obese adult, but a very little has been written concerning the obese child.

3. There is less pathology in the obese child when compared with the adult but some evidence shows a higher likelihood of a critical incident occurring when anaesthetizing such children.

4. We need to be as worried about anaesthetizing the obese child as we are for the obese adult.

This concern should increase with increasing body mass index. Anaesthesia consideration must be given to family behavior patterns, diet after weaning, and the use of new methods of information dissemination to help reduce the impact of childhood obesity worldwide.

The tougher guidelines on research conduct. Dr. Alisher Agzamov MD PhD

The tougher guidelines on research conduct. Dr. Alisher Agzamov MD phD

Geoff Watts. Research Councils UK issues tougher guidelines on research conduct. BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f1565 (Published 8 March 2013)

Cite this as: BMJ 2013;346:f1565

Research Councils UK has issued more explicit guidelines on the conduct that it expects from holders of its members’ research grants.¹ 

Unlike the document it replaces, published in 2009, it also outlines the likely penalties facing individuals and institutions that knowingly break the rules.

“We want to be seen to be tougher, but there’s a balance to be struck,” said Dr Tony Peatfield, director of corporate affairs at the Medical Research Council. “The more you threaten sticks rather than carrots, the greater the temptation for institutions to bury stuff. I think we’ve got the right balance.”

In the case of proven research misconduct the report lists the sanctions that might be applied. For the individuals concerned the research councils would reserve the right to withdraw funding and disallow future applications for grants for any fixed period of time, or even indefinitely. A researcher’s institution might also be required to return all the money awarded to the individual.

Research Councils UK is the strategic partnership of all seven of the country’s research councils. The new guidelines are now in line with a set of recommendations already laid out in a 2012 concordat on research conduct organised by Universities UK and approved by most of the country’s main funding bodies.

The new guidance sets standards of good research practice and also defines unacceptable research conduct. It explains how alleged misconduct should be reported and investigated and clarifies the responsibilities of the research councils, as opposed to research institutions, in fostering high standards.

The report emphasises the importance, where relevant, of clear procedures for obtaining ethical approval for intended work; seeking the informed consent of subjects; and ensuring that all staff are aware of these procedures.

“Peer reviewers,” it says, “must declare any conflicts of interest, including professional, personal or commercial conflicts, and must not take advantage of any information received as a result of their peer reviewing role.”

Commenting on what it considers to be unacceptable research conduct, the report says, “The spectrum of inappropriate behaviour is wide, ranging from minor misdemeanours which may happen occasionally and inadvertently, to significant acts of misappropriation or fabrication.”

Unacceptable conduct includes the creation of false data, the inappropriate manipulation of data and images, plagiarism, and misrepresentation. The last of these covers the suppression of relevant findings and/or data, the undisclosed duplication of published reports, the failure to declare material interests, false claims about qualifications and/or experience, and inappropriate claims to authorship.

The report suggests that any preliminary investigation of suspected misconduct should be carried out informally, and outlines how this might be done. If the suspicion is substantiated, it describes how a more formal procedure should be conducted.

Notes: Cite this as: BMJ 2013;346:f1565

References

1.    Research Councils UK. RCUK policy and guidelines on governance of good research conduct. www.rcuk.ac.uk/documents/reviews/grc/RCUKPolicyandGuidelinesonGovernanceofGoodResearchPracticeFebruary2013.pdf

General anesthesia.

General anesthesia.

Alisher Agzamov MD PhD.

Introduction

General anesthesia is a treatment that puts you into a deep sleep so you do not feel pain during surgery. When you receive these medications, you will not be aware of what is happening around you.

Description

You will receive general anesthesia in a hospital or outpatient office. Most times, a doctor called an anesthesiologist will put you to sleep. Sometimes, a certified registered nurse anesthetist will take care of you.

The doctor will give you medication into your vein. You may be asked to breathe in (inhale) a special gas through a mask. Once you are asleep, the doctor may insert a tube into your windpipe (trachea) to help you breathe and protect your lungs.

You will be watched very closely while you are asleep. Your blood pressure, pulse, and breathing will be monitored. The doctor or nurse taking care of you can change how deeply asleep you are during the surgery.

You will not move, feel any pain, or have any memories of the procedure because of this medicine.

Why the Procedure Is Performed

General anesthesia is a safe way to stay asleep and pain-free during procedures that would:

·         Be too painful

·         Take a long time

·         Affect your ability to breathe

·         Make you uncomfortable

·         Cause too much anxiety

You may also be able to have conscious sedation for your procedure, but sometimes it isn’t enough to make you comfortable. Children may need general anesthesia for a medical or dental procedure to handle any pain or anxiety they may feel.

Risks

General anesthesia is usually safe for healthy people. The following people may have a higher risk of problems with general anesthesia:

·         People who abuse alcohol or medications

·         People with allergies or a family history of being allergic to medicine

·         People with heart, lung, or kidney problems

·         Smokers

Ask your doctor about these complications:

·         Death (rare)

·         Harm to your vocal cords

·         Heart attack

·         Lung infection

·         Mental confusion (temporary)

·         Stroke

·         Trauma to the teeth or tongue

·         Waking during anesthesia (rare)

Before the Procedure

Always tell your doctor or nurse:

·         If you could be pregnant

·         What drugs you are taking, even drugs or herbs you bought without a prescription

During the days before the surgery:

·         An anesthesiologist will take a complete medical history to determine the type and amount of anesthesia you need. This includes asking you about any allergies, health conditions, medications, and history of anesthesia.

·         Several days before surgery, you may be asked to stop taking aspirin, ibuprofen, warfarin (Coumadin), and any other drugs that make it hard for your blood to clot.

·         Ask your doctor which drugs you should still take on the day of your surgery.

·         Always try to stop smoking. Your doctor can help.

On the day of your surgery:

·         You will usually be asked not to drink or eat anything after midnight the night before the surgery. This is to prevent you from vomiting while you are under anesthesia. Vomiting during anesthesia can be dangerous.

·         Take the drugs your doctor told you to take with a small sip of water.

·         Your doctor or nurse will tell you when to arrive.

After the Procedure

You will wake up tired and groggy in the recovery or operating room. You may also feel sick to your stomach, and have a dry mouth, sore throat, or feel cold or restless until the anesthesia wears off. Your nurse will monitor these side effects. They will wear off, but it may take a few hours. Sometimes nausea and vomiting can be treated with other medicines.

Follow your doctor's recommendations while you recover and care for your surgical wound.

Outlook (Prognosis)

General anesthesia is generally safe because of modern equipment, medications, and safety standards.

Most people recover completely and do not have any complications.

A target-controlled infusion (TCI) Propofol in major trauma patients.

A target-controlled infusion (TCI) Propofol in major trauma patients.

Alisher Agzamov, A. M. Al Qattan, M. Hashti, M. Bahzad.

Department of Anesthesiology & ICU, Al Aabah & Zain Hospitals, MOH, Kuwait City, Kuwait.

BACKGROUND:

Many pathophysiologic alterations in major trauma patients can cause changes in the distribution of, and perhaps response to, drugs commonly used in anesthesia practice. This study was conducted to assess changes in bispectral index (BIS) caused by increasing the target Propofol effect-site concentration during a target-controlled infusion (TCI) in major trauma patients.

METHODS:

120 patients, ASA physical status II, III - IV, aged from 19 to 65 years old, weighing 50-170 kg, with poly multiple major trauma, scheduled for emergency surgery less than a 2 – 10 hours after injury were recruited. A further 120 ASA physical status class II, III - IV, emergency non- trauma surgical patients, age, sex- and weight-matched adult patients scheduled for emergency surgery under general anesthesia were recruited as controls. During anesthesia induction, target propofol effect-site concentrations were increased by increments of 0.5 mcg/ml  up to 5.0 mcg/ml. The BIS responses to each target concentration using TCI were compared in both groups.

RESULTS:

In the trauma group, significantly greater BIS values relating to increasing propofol TCI were noted at deeper anesthesia when compared with controls; at > or =3.0 – 5.0 mcg/ml; mean BIS remained at a plateau of about 40. Patients with traumas had higher cardiac indices, and lower hemoglobin and albumin concentrations than the controls. They consumed more cisatracurium to maintain the same degree of neuromuscular blockade than the controls.

CONCLUSIONS:

In major trauma patients, the final biphasic BIS responses appeared to be determined by numerous other variables such as BIS algorithm, TCI performance, and altered Propofol pharmacokinetics and pharmacodynamics.

According to our results the importance of an individually tailored approach, including careful anesthetic titration, based upon the patient's clinical condition and responses can not be overemphasized.

Acute therapy and outcome of sudden cardiac death. Dr. Alisher Agzamov MD PhD

Acute therapy and outcome of sudden cardiac death.

Dr. Alisher Agzamov MD PhD

The treatment of sudden cardiac death (SCD) consists of acute resuscitation followed, in survivors, by attempted long-term prevention of recurrence by pharmacologic and nonpharmacologic means. However, despite advances in treatment of heart disease, the outcome of patients experiencing SCD remains poor. In a study of 515 patients with out-of-hospital sudden death from 1991 to 1994, cardiac resuscitation was attempted in 51 percent and 13.5 percent were subsequently discharged alive from the hospital, resulting in an overall survival rate of 6.2 percent [1].

Furthermore, a relatively good quality of life can be achieved in the patient who survives. In one study of 827 resuscitated patients, 20 percent survived to hospital discharge and 12 percent were alive at six months [2]. Most of the survivors (75 percent) were independent in daily life.

This card will review the issues related to acute therapy, including the guidelines for cardiopulmonary resuscitation. Issues related to prevention of recurrent sudden cardiac death are discussed separately. (See "Pharmacologic therapy in survivors of sudden cardiac death" and see "Nonpharmacologic therapy in survivors of sudden cardiac death: Role of surgery and radiofrequency ablation").

ARRHYTHMIC ETIOLOGY AND OUTCOME OF RESUSCITATION — There is an association between the arrhythmic mechanism for SCD and the outcome of resuscitation. (See "Pathophysiology and etiology of sudden cardiac death" for a review of the arrhythmic mechanisms).

  •  When the initial rhythm is asystole, the likelihood of successful resuscitation is low and, when performed out of hospital, very few of these patients (less than 10 percent) survive to hospitalization [3]. Furthermore, a number of studies have found that virtually none of these patients survive to be discharged from the hospital [4].

  •  The outcome is much better when the initial rhythm is a sustained ventricular tachyarrhythmia. Approximately 25 percent of patients with ventricular fibrillation (VF) survive to be discharged; in the majority of these patients an acute myocardial infarction is the underlying mechanism [5]. In comparison, survival of those with hemodynamically unstable ventricular tachycardia (VT) is 65 to 70 percent [6]. The prognosis may be better in patients found in monomorphic VT because of the potential of some systemic perfusion during this more organized arrhythmia. In addition, patients with VT tend to have a lower incidence of a remote myocardial infarction and a higher ejection fraction when compared to those with VF [7].

The poor outcome in patients with bradycardia due to a very slow idioventricular rhythm or asystole probably reflects the prolonged duration of the cardiac arrest, usually more than four minutes, and the presence of severe and irreversible myocardial damage. The myocardial damage and extinction of electrical activity result from severe tissue hypoxemia, a metabolic acidosis and hyperkalemia which develop rapidly. Ultimately there is also irreversible damage of other organs.

Patients who have SCD due to electrical-mechanical dissociation (pulseless electrical activity) also have a poor outcome. In one study of 150 such patients, 35 patients (23 percent) were resuscitated and survived to hospital admission [8]. However, 19 patients died in hospital and only 16 (11 percent) were discharged.

End-tidal carbon dioxide levels have excellent correlation with very low cardiac outputs when measured after at least 10 minutes CPR, and may provide prognostic information during a cardiopulmonary resuscitation. One study reported that an end-tidal carbon dioxide level 10 mmHg, measured after 20 minutes of standard cardiopulmonary resuscitation (CPR), identified individuals who did not survive to hospitalization discharge with a sensitivity and specificity of 100 percent [8]. The end-tidal carbon dioxide level did not discriminate between patients who survived to hospital discharge or those who died in hospital.

OUTCOME OF NONCARDIAC SUDDEN DEATH — While the most frequent mechanism for sudden death is a ventricular tachyarrhythmia due to underlying heart disease, one study reported that noncardiac causes accounted for 34 percent of cases [9]. (See "Pathophysiology and etiology of sudden cardiac death"). Trauma, nontraumatic bleeding, intoxication, near drowning, and pulmonary embolism were the most common noncardiac etiologies of sudden death in this study, and 40 percent of patients were successfully resuscitated and hospitalized. However, only 11 percent were discharged from the hospital and only 6 were neurologically intact or had mild disability.

FACTORS RELATED TO THE OUTCOME OF RESUSCITATION — Sudden cardiac death is a catastrophic event. Ventricular fibrillation in the human heart does not terminate spontaneously and survival is therefore dependent upon prompt cardiopulmonary resuscitation. The only effective way to reestablish organized electrical activity and myocardial contraction is prompt electrical defibrillation (show figure 1).

It has been estimated that ischemic changes begin with the onset of the ventricular arrhythmia due to the absence of tissue perfusion. Organ damage becomes irreversible after approximately four minutes of VF and cessation of cardiac output [10]. As a result, the longer the duration of the cardiac arrest, the lower the likelihood of resuscitation or survival even if initial resuscitation is successful (see below).

The Seattle Heart Watch program has reported on the outcome of patients resuscitated at the scene by a bystander trained in cardiopulmonary resuscitation (CPR) compared with CPR initiated by emergency medical personnel [11]. While there was no difference in the percentage of patients resuscitated at the scene and admitted alive to the hospital (67 versus 61 percent), the percentage discharged alive was significantly higher among those with bystander-initiated CPR (43 versus 22 percent, p< 0.001) (show figure 2).

The most important reason for the improvement in survival was that earlier CPR and prompt defibrillation were associated with less damage to the central nervous system. More patients with bystander-initiated CPR were conscious at the time of hospital admission (50 versus 9 percent), and more regained consciousness by the end of hospitalization (81 versus 52 percent) [11].

These observations were confirmed by a second larger study which analyzed data from 1872 patients with a witnessed cardiac arrest due to ventricular fibrillation [12]. Overall, 31 percent of patients survived to hospital discharge. Lower age, bystander-initiated CPR, and shorter intervals between collapse, CPR, and defibrillation were significantly associated with survival. Another study found that performing CPR for at least 90 seconds prior to defibrillation improves survival, especially in patients for whom the initial response interval was over four minutes (27 versus 17 percent without prior CPR) [13].

Optimizing the emergency medical system within a community and reducing the response interval to within eight minutes can improve the survival to hospital discharge. This was observed in one study of 6331 patients who had an out-of-hospital cardiac arrest; the overall survival to hospital discharge improved by 33 percent after the response time was shortened (5.2 versus 3.9 percent), representing an additional 21 lives saved [14].

Causes of in-hospital mortality — The cause of death in hospital is most often noncardiac, usually being due to anoxic encephalopathy or to respiratory complications from long-term respirator dependence [15]. Only about 10 percent of patients die from recurrent arrhythmia, while approximately 30 percent die from a low cardiac output or cardiogenic shock [16]. Recurrence of severe arrhythmia in the hospital is associated with a poor outcome [17].

Risk factors for mortality — Despite the efforts of emergency personnel, resuscitation is successful in only one-third of patients, and only about 10 percent of all patients are ultimately discharged from the hospital [18,19,20,21,22]. In addition to later onset of CPR, there are a number of other factors that are associated with a poor outcome with CPR [5,23,24,25,26,27]:

  •  Absence of any vital signs
  •  Sepsis
  •  Cerebrovascular accident with severe neurologic deficit
  •  Cancer or Alzheimer's disease
  •  History of more than two chronic diseases
  •  A history of cardiac disease
  •  An initial rhythm of asystole or pulseless electrical activity (electromechanical dissociation)
  •  CPR lasting more five minutes

There are also several poor prognostic features in survivors of CPR:

  •  Persistent coma after CPR
  •  Hypotension, pneumonia, renal failure after CPR
  •  Need for intubation or pressors
  •  Class 3 or 4 congestive heart failure
  •  Older age

In order to identify those patients who will survive and recover neurologically, one study reviewed the records of 127 patients who underwent CPR [28]. A cardiac arrest score was developed, based upon the time to return of spontaneous circulation (<25 minutes=1, 25 minutes=0), the initial systolic blood pressure (90 mmHg=1, <90 mmHg=0), and initial neurologic status (alert, arousable, spontaneous movement=1; unresponsive or comatose=0) [28]. Scores of 0, 1, 2, and 3 predicted in-hospital mortality rates of 90, 71, 42, and 18 percent, respectively and neurologic recovery in 3, 17, 57, and 89 percent, respectively.

ACUTE THERAPY FOR THE SUDDEN CARDIAC DEATH VICTIM — As noted above, ventricular fibrillation in the human heart does not spontaneously terminate; as a result, survival is dependent upon prompt successful defibrillation and CPR and the reestablishment of organized electrical activity with a stable sinus or supraventricular rhythm.

The only effective approach for terminating VF is defibrillation using 200 to 400 J of energy delivered transthoracically in a nonsynchronized fashion [29]. Biphasic waveforms, truncated rectilinear exponential waveform with an initial positive phase followed by a phase of opposite polarity or a quasi-sinusoidal biphasic waveform, have been investigated for transthoracic applications and found to be superior to monophasic exponential waveforms (show figure 3) [30,31]. One study demonstrated fewer postshock arrhythmias and less contractile dysfunction when using biphasic compared with monophasic waveforms [32]. (See "Basic principles and technique of cardioversion and defibrillation").

While defibrillation is life-saving, direct current shock to the heart delivered transthoracically or epicardially can generate free radicals which may be in part responsible for defibrillation injury [33]. The generation of free radicals is related to the peak energy of an individual shock, not the cumulative energy delivered.

The initial success of defibrillation depends upon the duration of the arrhythmia and promptness of defibrillation (show figure 4) [34]:

  •  When VF has been present for seconds to a few minutes and the fibrillatory waves are coarse, the success rate is high.

  •  As VF continues for a longer period of time, the fibrillatory waves become finer, possibly due to depletion of myocardial epinephrine stores, and the ability to terminate the arrhythmia is reduced [35].

  •  When VF continues for more than four minutes, there is irreversible damage to the central nervous system and other organs which will impact on survival even if there is initially successful defibrillation [36].

Guidelines for CPR have been established by the American Heart Association and are depicted in the accompanying figures (show figure 5A-5D) [37].

Intravenous amiodarone — VF or VT that persists despite defibrillation or which recurs promptly after successful defibrillation is not uncommon. The current guidelines recommend therapy with an intravenous antiarrhythmic drug, although benefit from such therapy is not certain. The ARREST trial randomized 504 patients with a cardiac arrest due to VF or pulseless VT who were not resuscitated after at least three defibrillation shocks to intravenous amiodarone (300 mg) or placebo [38]. Although the mean time to resuscitation and number of shocks  delivered were the same, survival to hospitalization was greater in the amiodarone group (44 versus 34 percent, p = 0.03), especially in patients who had a transient return of pulse during defibrillation and then received amiodarone (64 versus 41 percent) (show figure 6). Time to therapy with the study drug was an independent predictor of survival to hospital; faster treatment was associated with a better outcome (show figure 7). However, the incidence of hypotension (59 versus 48 percent) and bradycardia requiring therapy (41 versus 25 percent) was greater with amiodarone therapy compared to placebo. More than 50 percent of patients who survived to discharge had no neurological impairment. (See "Clinical use of amiodarone" and see "Major side effects of amiodarone").

Intravenous amiodarone is also effective for acute suppression of life-threatening, hemodynamically significant ventricular tachyarrhythmias that recur despite therapy with other agents. Amiodarone has been reported to prevent recurrence of sustained spontaneous VT or VF in more than 50 percent of patients, and has been approved for the acute treatment and prevention of ventricular fibrillation and hemodynamically destabilizing VT that is refractory to other agents [39,40]. Patients who respond to intravenous amiodarone and are discharged on oral drug have a good outcome. As an example, in one study of 107 patients surviving hospitalization, the one-year survival was 80 percent [41].

Left ventricular dysfunction — After cardiac resuscitation there is a variable period of global left ventricular systolic and diastolic dysfunction, perhaps representing myocardial "stunning" as a result of prolonged hypoxemia [42]. In an animal model, left ventricular dysfunction begins 15 minutes after resuscitation, peaks at five hours, and recovers by 48 hours [43]. In this model, dobutamine begun within 15 minutes of resuscitation prevents the development of left ventricular dysfunction resulting from prolonged cardiac arrest and cardiopulmonary resuscitation [44].

LONG-TERM OUTCOME OF SUDDEN DEATH SURVIVORS — The long-term mortality of the sudden death survivor is high, regardless of the therapy received [45,46]. In one series of 227 survivors, the mortality rate was 20 percent at one year and 50 percent at three years [46].

Similar considerations apply to patients with life-threatening ventricular arrhythmia in the absence of sudden death. This issue was addressed in the AVID registry, which enrolled 4219 patients with life-threatening ventricular arrhythmia or syncope felt to be due to a ventricular arrhythmia [47]. After an average follow-up of 17 months, the morality was high regardless of the arrhythmic mechanism or therapy received (eg, implantable device, antiarrhythmic drug, both, or neither) and regardless of whether the arrhythmia was ventricular fibrillation, ventricular tachycardia with syncope, symptomatic ventricular tachycardia, asymptomatic ventricular tachycardia, a ventricular tachyarrhythmia due to a transient/correctable cause, or unexplained syncope (12.3 to 21.2 percent).

Interestingly the mortality is higher for patients with an in-hospital presentation of life threatening ventricular arrhythmia not due to a reversible cause compared to those presenting with out-of-hospital arrhythmia, perhaps because in-hospital patients are sicker with more concomitant diseases [48]. The one and two year adjusted mortality rates were 15 and 21 percent versus 8.4 and 14 percent for out-of-hospital arrhythmia; the adjusted long-term relative risk for in-hospital versus out-of-hospital presentation was 1.6.

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