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Wednesday, October 4, 2017

BY FRANK DEL VECCHIO, MD

When I first heard of the shooting in Las Vegas a few days ago, it sounded as if only a few people were injured. I was preparing for bed, but as soon as I realized the scope of the incident, I went immediately to the emergency department. I ran several red lights as ambulances do, exceeded speed limits by a factor of 2+, and was quickly waved through police barricades when I showed my hospital ID.

I would like to say that I heroically saved dozens of lives by performing numerous invasive bloody procedures, but that was not the case. Most of the serious cases were already handled when I got there. We had one DOA, and all the others are expected to survive, but many will have permanent injuries.

When I arrived, I was immediately struck by how quiet it was. Nothing moved me more than how patients with horrific injuries heroically suffered in silence while the staff worked diligently to care for all. They knew we would get to them as soon as possible and in order of priority. None of the providers yelled or so much as raised their voices. They walked briskly, but never ran. With the exception of one neurosurgeon who did not want to be bothered, specialists and ancillary services responded quickly and efficiently.

It was truly an inspirational scene, once you could get beyond the depravity of what just happened.

The worst cases I saw were an 18-year-old girl with a spinal injury who will be permanently paralyzed, and a young man whose hip was pulverized and femoral artery lacerated. He may keep his leg, but probably will never walk well again.

I didn't perform any dramatic invasive procedures, but I would like to think that coordinating complex evaluations among the surgeons, technicians, and nurses was just as life-saving.

I offered many reassurances to patients as honestly as I could. I touched many foreheads, gently placed my cheek on a few, and gave hugs to others, including family members. It was all graciously and emotionally received.

It was deeply moving to see the help offered to others by non-medical people. Bystanders used makeshift stretchers to carry people out of harm's way, drivers allowed bloodied victims to pile into their nice cars for transport to the hospital, and pickup trucks were also used to transport more serious victims. Long lines, up to six hours, formed with those waiting to give blood. Many delivered food and drink to the donors.

Out of evil and chaos came goodness and beauty.

I believe there is a God, but even if you don't and even if you are correct, there is God-like charity in all of us should we choose to practice it.

I felt emotionally detached from it all, until the following day, at which time I must admit, I needed a few moments alone.

We may never know what motivated the perpetrator, but he was obviously a tortured soul. I believe that almost all human beings are innately good. Children raised in loving and supportive environments, even with disparate financial resources, will almost always become loving and contributing adults. Providing children with a moral compass, regardless of religious beliefs, is an important part of the same process.

Beyond raising children, we can all play a part in this. Please consider donating your time to charities, especially those working with underprivileged children. Also, set up affordable automatic monthly donations to the charities of your choice. Remote Area Medical (https://ramusa.org), Safe Nest (https://safenest.org), and Three Square, a service feeding poor children (https://www.threesquare.org), are among my favorites.

Savor your relationships with family and friends and those things you enjoy. In less than a second, it can all be taken away from you.

Spread goodwill and generosity to others, every day, even in small ways. Be kind to others, even when they don't deserve it.

Dr. Del Vecchio is an emergency physician in Las Vegas and a retired U.S. Navy captain and flight surgeon.​


Thursday, September 28, 2017

BY STEPHEN HAIRE, MD

​Rapidly treating sepsis patients with antibiotics is absolutely vital to their survival. Even an hour or two of delay could cost a patient his life. But as U.S. hospitals are striving to implement effective sepsis protocols, many feel torn between that and a parallel and equally important national effort—our need to reduce antibiotic overuse and misuse, which is a primary driver of our growing antibiotic resistance problem. Ironically, we at Morton Plant Hospital BayCare Health System (MPMHC) learned that these two goals don't have to be at cross-purposes. The key to optimizing these essential goals is the biomarker procalcitonin or PCT.

No one has ever said to me in my 20 years as an emergency physician, "Doctor, I think I may have sepsis." In fact, more than 40 percent of those surveyed said they had never heard of the term "sepsis," according to a 2015 survey by the Sepsis Alliance. (
http://bit.ly/2xaoL5v.) Have we done a poor job explaining this syndrome? Perhaps, but sepsis is a difficult concept to convey. It's always secondary to a preceding condition, such as pneumonia and urinary tract and gastrointestinal infections. But the fact remains that when these patients die, sepsis is what usually kills them. As a consequence of patients living longer with serious chronic conditions and the crisis of antimicrobial resistance, the incidence of sepsis is growing and affecting younger and younger patients. (JAMA 1995;273[2]:117.)

Our ED, ICU, pharmacy, and other departments decided in 2008 to see what we could do to reverse these trends within our health system. The sepsis protocol at MPMHC is built on a team approach that involves every clinical department and caregiver who comes into contact with a potential sepsis patient from the ED until discharge.

 sepsis fig 1.JPG

Our goal was simple: We wanted to pull patients into our sepsis protocol as early in the sepsis inflammatory cascade as possible. Interventions that save lives are thoroughly proven and documented: Fluids, antibiotics, and vasopressors can save the majority of patients. This is not the problem. The problem is discerning who to put on this track with a syndrome that shares symptoms with many other conditions. Only sepsis accelerates with terrifying speed and morbidity, however.

Figure 1 illustrates how fast septic patients can deteriorate. We could save many of them if we could identify sepsis patients before the initial organ failure. (
JAMA 1995;273[2]:117; Critical Care Med 2001;29[7]:1303; Intensive Care Med 2002;28[10]:1440.) We included the biomarker procalcitonin (PCT) in our protocol so we could utilize the earliest possible signals that a patient is at risk for sepsis because it provides us with vital clues that often go undetected until the sepsis cascade is well underway.

Sepsis Defined
The 1992 guidelines from the American College of Chest Physicians and the Society of Critical Care Medicine defined systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock. (Chest 1992;101[6]:1644.) SIRS is defined as a patient having two of the following four symptoms:

n Temperature higher than 38°C (100.4°F) or lower than 36°C (96.8°F)
n Heart rate above 90 beats per minute
n Respiratory rate higher than 20 breaths per minute or arterial carbon dioxide tension (PaCO2) of less than 32 mm Hg
n Abnormal white blood cell count (>12,000/µL or <4,000/µL or >10% immature [band] forms)

Because SIRS is nonspecific with infection as its root cause, along with other noninfectious etiologies such as ischemia, inflammation, and trauma, the definition of sepsis depends on the diagnosis of SIRS plus a new set of criteria:

n Sepsis is defined as SIRS plus a new infection.
n Severe sepsis is sepsis plus organ dysfunction.
n Septic shock is severe sepsis plus hypotension that persists despite fluid resuscitation or lactate great than 4.

​ED Sepsis Alert
Our sepsis protocol allows emergency physicians to screen for sepsis and to place likely septic patients on a track designed to reduce its effects of sepsis and make these patients better sooner. This begins in the ED, but the protocol is a team approach that relies on those with skills and experience across the entire treatment continuum for a septic patient. The team includes registration, ED and ICU nurses, intensivists, emergency and critical care physicians, respiratory therapy, and unit clerks.

We integrated our new screening tool with our EMR software. We evaluate all patients for sepsis, and roughly 30 to 40 patients per day are detected by our sepsis screening tool in the ED. Two to three of those patients end up on the sepsis protocol based on that screening process. Our screen looks at lactate level, blood pressure, tachycardia, CBC, BNP, and PCT levels.

PCT is the key to the success of this screening program. An elevated PCT is a powerful indicator that a severe bacterial infection has occurred and that sepsis is possible. A normal PCT score, particularly one that remains normal for several days, allows us to look for other etiologies sooner than we would have without PCT. Once we identify a patient with sepsis, the emergency physician initiates the sepsis alert, which is sent to the operator and issued as a stat page to the admitting team and the transfer center that tele-tracks bed control. The administrator on duty is also made aware of the patient, and will assist in the ED or the ICU if the patient has already been transferred. The stat page also goes to the ICU charge nurse and the respiratory therapist on duty. Labs are done stat so the turnaround time is efficient. We also draw blood cultures and send these to the lab.

sepsis fig 2.JPG

Rapid Antibiotics
A study by Kumar, et al., documented the correlation between delayed antibiotics for those in septic shock and mortality. (Crit Care Med 2006;34[6]:1589.) Figure 2 is one of the most compelling graphics that explains the horrible and all too predictable consequences of delayed treatment in septic shock patients. Kumar concluded that the survival rate for effective antibiotics in the first hour of documented hypotension was 79.9 percent, but this drops dramatically with each passing hour. The survival rate with antibiotics five to six hours post-documented hypotension was 42 percent. Survival plummets to 25.4 percent by hours nine to 12. In fact, each hour of delay in giving antibiotics to these patients translated into a decrease in the survival rate of 7.6 percent. The median time to effective antibiotic delivery was six hours, which has a mortality rate of nearly 60 percent.

Procalcitonin testing can help you stay ahead of this vicious spiral. PCT elevation is very responsive to bacterial challenge so the biomarker begins to rise almost immediately. Figure 3 shows that PCT levels of 0.05 ng/mL or below represent the normal range; 0.05-0.5 ng/mL is indicative of a local infection; 0.5 to 2.0 ng/mL indicates a systemic infection; 2-10 ng/mL is severe sepsis, and anything over 10 ng/mL is strongly indicative of septic shock. PCT does not respond at all to viral or fungal infections, which is why we began to use it as a tool to assist in antibiotic stewardship several years ago.


sepsis fig 3.JPG
Overusing Antibiotics
Initiating our sepsis response in the ED made us quickly realize that there was great value in testing for PCT in the ED, regardless of whether the patient had a blood infection or sepsis. A 68-year-old man, for instance, was admitted to our emergency department with lethargy, headache, neck stiffness, disorientation, and rising blood pressure. The patient was a smoker with type 2 diabetes and a past history of cardiac issues, including a heart attack. Tests showed a high white blood cell count, normal cardiopulmonary function, and negative neurological exam results.

The initial PCT level taken in the ED was low, and it remained normal for several days. His symptoms and normal PCT level led the ICU team to look for other possible causes. A lumbar puncture revealed that he was suffering from viral meningitis. Thanks to a normal PCT level that remained well within the normal range for several days, antibiotic exposure was dramatically limited in this patient. The viral meningitis was effectively treated, and he was discharged.

sepsis 4.JPG

Another patient, an elderly man, arrived in the ICU via the emergency department, presumed to have pneumonia, suggested by a bilateral perihilar infiltrates. The patient had a fullness of the right hilum, which was possibly vascular but also suspicious for lymph node enlargement. Follow-up clearance was recommended to ensure no underlying pathology. His white blood cell count was high, so he was treated aggressively with antibiotics and fluids. He remained symptomatic of pneumonia for three days, and his physicians began to consider other causes, so they took a second look at his serial PCT levels. Figure 4 shows his WBC, troponin-L, and PCT levels over three days. His initial ED PCT level was 0.10 ng/ml—well within the normal range. It never exceeded 0.15, also normal, over the course of three days. PCT made it clear that we were not likely dealing with an infection. A chest x-ray taken on the third day confirmed heart failure. Antibiotics were stopped, and he was successfully treated for this cardiac crisis.

The negative predictive value of PCT cannot be understated. Without PCT, we may never have realized the patient was suffering from heart failure. Three days of antibiotics are three days too many for a patient without an infection, this patient may have been treated for
a week, possibly 10 days were it not for the information provided by PCT.

Serial PCT testing—starting in the ED—is now central to our sepsis protocol and our antibiotic stewardship program. The test provides us with much more confidence when deciding whether to start antibiotics or when looking for a noninfectious underlying cause of the patient's symptoms. It also is of enormous benefit in discontinuing antibiotics. PCT closely follows the trajectory of a severe bacterial infection, so we use an algorithm based on the percentage decrease in PCT from its highest measurement to help us determine when we can safely begin to curtail IV antibiotics. Until PCT, most U.S. hospitals used the football score approach to antibiotic duration: 3, 7, 10, or 14 days. Virtually no evidence supports this approach, however. We must avoid giving antibiotics to patients who are without bacterial infections in this age of rampant antibiotic resistance, but we also must reduce or discontinue powerful IV antibiotics when the patient's infection has abated.

I would like to thank Devendra Amin, MD, the medical director for critical care services at Morton Plant Hospital, who spearheaded the effort to bring PCT testing to our hospital, who has worked tirelessly to help educate other clinicians at Morton Plant and across the country, and who helped me collect data for the case studies presented in this article.

haire.JPG 
Dr. Haire is an emergency physician and the medical director at Morton Plant Hospital, BayCare Health System, in Clearwater, FL, the chairman and CEO of Bay Area Emergency Holdings Corp., and the chairman of the EMS advisory board for Pinellas County. He disclosed that he wrote this article for bioMérieux, though he did not receive compensation for it. He does, however, receive remuneration for bioMérieux speaking engagements.

Tuesday, September 12, 2017

BY MARTHA ROBERTS, ACNP, PNP

News stories flooding social media, the internet, and television sparked outrage after a police officer's body camera video showed the arrest of a Salt Lake City, UT, nurse, Alex Wubbels, in July. Ms. Wubbels, who said she was protecting the rights of her unconscious patient, was arrested for obstruction of justice for refusing to provide the police with blood samples without a warrant, the patient's consent, or a stated intent to arrest the patient. Recordings of the scene showed Ms. Wubbels being dragged out of the hospital by a police officer. (NBC News. Sept. 4, 2017; http://nbcnews.to/2xbHZYM.)

This story generated questions about police brutality against patients and health care workers involved in their care, as well as about the communication between medical providers and the police. Patients and health care workers are at risk of police maltreatment, and it is a growing threat and issue.

Police brutality and medical negligence are concerns nationwide, like the case of Freddie Carlos Gray Jr., a 25-year-old African-American man arrested on April 12, 2015, by the Baltimore police for possessing what the police alleged was an illegal switchblade. (PBS NewsHour. May 1, 2015; http://to.pbs.org/2w8rqb6.) When Mr. Gray was being transported in a police van to central booking, he became comatose and died from severe neck and spinal cord injuries.

The medical investigation found that Mr. Gray had "sustained the injuries while in transport," and did not receive timely medical attention after he had asked for help and said twice that he couldn't breathe. (CNN. April 24, 2015; http://cnn.it/2w8u1So.) The media and the courts questioned the police's role in Mr. Gray's death, and the officers involved in the case were later convicted of second-degree murder and manslaughter for delaying Mr. Gray's medical care. (New York Times. May 1, 2015; http://nyti.ms/2w7N5A0.).

At least 4,813 people died in the process of being arrested by local police between 2003 and 2009, according to data from the Bureau of Justice Statistics. (http://bit.ly/2w7U1gN.) The bureau classified 2,876 of those deaths as law enforcement homicides, and 1,643, or 57.1 percent, of those were minorities. (http://bit.ly/2w7Hiup.) Police brutality isn't limited to beatings, Tasers, shackles, trauma, shootings, and wrongful arrests. Assault and battery are also issues. In Mr. Gray's case, he was placed in metal ankle braces even though he was shown to be completely motionless on a cell phone recording. (The Baltimore Sun. May 20, 2015; http://bsun.md/2w7NfaO.)

It is difficult to advocate for patients when the police are involved. Sometimes the patient does not get timely medical care, or their medical rights are not protected. Ms. Wubbels was advocating for a patient who was not under arrest, and she ended up in handcuffs.

As emergency department providers, we often see patients who are in the ED to be cleared to go back to jail or those who may be involved in complicated judicial matters. There are times when our patients are drunk, high, hostile, and incorrigible. But what about those who need further evaluation or whose medical rights are ignored? This includes patients from whom you must collect belongings or even blood samples. How do we protect these patients and ourselves?

We must be aware of what happens in the police's field and in ours. All patients brought in by the police deserve a full examination, privacy, an appropriate treatment plan, and the protection of their rights. Proper protocols must be followed, especially if the rights of the patients are being denied. We cannot step between the law and official police business, but we can advocate for appropriate care. You must always be concerned for the safety of the patient.

The bottom line is patients' rights are a serious matter and should always be on your radar, according to Ms. Wubbels. "The only job I have is to keep my patient safe," she said at a press conference. "Blood is your blood. That is your property. When a patient comes in a critical state, that blood is extremely important, so I don't take it lightly."(CBS. Sept. 1, 2017; http://cbsn.ws/2w7LudD.)​

Ms. Roberts is an acute care nurse practitioner at Medstar Montgomery Medical Center in Olney, MD, an adjunct faculty associate and clinical instructor of nursing at the Malek School of Health Professions, Marymount University in Arlington, VA.


Monday, July 3, 2017

BY PAUL MARIK, MBBCh


Below is a list of the most common questions that have been asked in response to our paper, "Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study" (
Chest 2016), and our best answers.

Q1. Why was the mortality rate in your control group so high relative to world averages?

A. When we began using this "cocktail," we were unsure of its benefits (and risks), and we therefore only used the cocktail in patients at highest risk of dying and developing progressive organ failure. To receive the cocktail, patients must be admitted via our emergency department with severe sepsis or septic shock and an initial procalcitonin (PCT) >2. (We routinely measure PCT in all our patients suspected of having sepsis.)

The median procalcitonin in the treatment and control groups were 25 ng/ml and 15 ng/ml respectively. The median PCT in the MOSES study, the largest study to date to evaluate the time course of PCT in patients with severe sepsis and septic shock, was 5 ng/ml. (Crit Care Med 2017;45[5]:781.) In the MOSES study, nearly 50 percent of patients had a PCT <2. PCT is a very good quantitative marker of sepsis severity. We therefore selected a subgroup of patients with sepsis at highest risk of complications and death, i.e., we include the sickest half of the patients with sepsis.

When we performed the retrospective, case-controlled study, we matched the control group patients based on PCT and severity of illness, meaning we used the same selection criteria for the treatment and control groups, which was indicated in the manuscript. After completing the study and once we analyzed the data for efficacy and safety, we changed our indications for use: We now treat every patient with sepsis who is sick enough to be admitted to the ICU with the cocktail, starting in the ED and at the same time as antibiotics. This may explain the progressive decline in sepsis mortality at our hospital from January 2016 to January 2017, which has been reported by an independent data analytics company. (See YouTube video at http://bit.ly/2rdozj9.)

Furthermore, the exact incidence and mortality of sepsis in the United States (or elsewhere) is difficult to determine. It depends on the selection criteria and whether the data are severity-adjusted. Administrative databases have been shown to be notoriously unreliable. In addition, one cannot extrapolate from the mortality reported in "large" clinical trials due to the large number of exclusion criteria. They do not represent real-world practice. It is noteworthy that in the Surviving Sepsis Campaign Database, which includes more than 130,000 patients, the overall mortality was 32.8 percent.


Q2. How do you mix and administer vitamin C, and what is its shelf life and cost?

A. Vitamin C is provided by the manufacturer as a 50 ml vial at a concentration of 500 mg/ml. We add 3 ml of vitamin C into a 50 ml bag of normal saline (1,500 mg vitamin C in 50 ml bag), which is then infused over one hour. The dosing schedule is 1,500 mg every six hours for four days or until discharge from the ICU.

Once the vial is open, it is only stable for six hours. The resulting product has given 24 hours of stability. When first ordered, four doses are made and sent to the nurse. For the next day, we will wait until one hour prior to make the next batch. The acquisition cost of IV vitamin C as sold by Mylan Institutional is $81 per vial. KRS Global Biotechnology in Boca Raton, FL, compounds a vitamin C formulation (Tapioca) 500 mg/ml 50ml at $20 per vial, which has a 90-day shelf life from the time made and a seven-day shelf life after opening the vial.


Q3. What about the use of vitamin C and spurious blood glucose levels using point-of-care glucose monitors?

A. Vitamin C and glucose have very similar molecular structures, both being six-carbon molecules with glucose-6-phospate being the precursor molecule of vitamin C. Spuriously elevated POC glucose levels have been reported in patients with burns, who have received large pharmacologic doses of vitamin C (more than 50 g/day). (Psych Res 1989;30[2]:165; J Burn Care Res 2015;36[1]:50.) This phenomenon has been reported with vitamin C and other compounds with POC glucose devices that incorporate the glucose-dehydrogenase-pyrroloquinoline quinone (PQQ) amperometric method of testing. The pharmacologic doses of vitamin C used in patients with burns (PsychRes 1989;30[2]:165; J Burn Care Res 2015;36[1]:50) and those with malignancy (Proc Natl Acad Sci U S A 2005;102[38]:13604; PLoS One 2015;10[4]:e0120228; Science 2015;350[6266]:1391) result in millimolar concentrations of vitamin C.

Our dosing strategy (1.5 g IV q 6 hourly) results in blood vitamin C levels that are in the 200 umol/l range, which should not cause significant cross-reaction with blood glucose concentrations that are in the millimolar range (6-11 mmol). To validate this, we measured blood glucose levels with POC testing (Accu-Chek Inform, Roche, Indianapolis) and simultaneously with our central laboratory at the end of the vitamin C infusion, and noted minimal differences in the measured levels. We, therefore, believe that in the dosage used in our study, the interaction between vitamin C and POC glucose testing is not a clinically significant problem.


Q4. Why did you apply a protocol that had not yet been tested?

A. As clinicians responsible for the care of patients who are at an exceedingly high risk of death, one "has to think outside the box" because our current approach is unsatisfactory. The three agents that we combined in our "cocktail" are widely available, safe, and cheap, and have been used individually to treat sepsis. All patients with severe sepsis/septic shock have low or undetectable levels of vitamin C. The vitamin C was dosed according to the indications and dosage of the approved package insert. (See below.) We combined these three agents on the presumption that the sum would be greater than the individual components.

sepsis 1.jpg

Q5. If our intensivists begin using vitamin C for our sepsis patients, would the IRB need to oversee this as research? Did you obtain IRB approval for your study?

A. No, IRB approval is not required. As is clear from our paper, we performed a retrospective, before-after study approved by our IRB. This treatment approach has now become standard of care in our ICU and in many ICUs across the world, although the selection criteria may be different. The use of the cocktail in the clinical context is not research; the cocktail consists of three widely available and approved drugs with a long safety record.

Many of the drugs used in the ICU in the United States do not having supporting scientific data based on large RCTs, nor do they have specific FDA labeling for that indication. Haloperidol is a good example. The use of haloperidol for a patient with delirium in the ICU does not require IRB approval. It should be noted that haloperidol has significant risks and toxicity. When using "nonstandard" treatments or a drug for non-approved indications, however, the clinician must balance the potential benefits of the intervention with the consequences of the disease (untreated) and the safety of the proposed therapy.

It is our opinion based on an extensive review of the literature as well as our experience and that of others that vitamin C, thiamine, and hydrocortisone are exceedingly safe and have no known side effects in a disease without alternative treatments and an exceedingly high mortality. Indeed, we believe that clinicians have an ethical obligation to treat overwhelmingly septic patients with this cocktail. The balance of beneficence, nonmaleficence, and social justice clearly supports this treatment approach.


Q6. Are patients still consistently responding well to your therapy?

A. We have now treated more than 250 patients with this cocktail, and received the same reproducible response. During this time (over 16 months), only one patient has died while receiving this therapy. That patient was a complicated surgical patient with inadequate source control who died within hours of surgery. Our therapeutic cocktail has been used in hundreds of patients across the globe with strikingly similar positive results.

Here's a typical example: "An elderly man with ischemic cardiomyopathy and EF 15% pacer/AICD at baseline presented to outside hospital with shock and BP 60/30 mm Hg.He was given two-three liters of fluid, and immediately went into respiratory failure requiring intubation. He was transferred to us intubated on four vasopressors with AKI (Cr 3). Eventually he ended up growing Group B Strep from his blood with procalcitonin 43. He was started on the vitamin C cocktail, and within a day his pressor requirements melted away, and he was extubated. His kidneys have improved, and he is walking around the ICU. Tomorrow he will probably leave the ICU with no residual organ dysfunction, no volume overload, and no ICU complications."


Q7. After the publication of your work, how has your protocol been extended? What experience have you gathered from the other centers?

A. More than 30 medical centers across the United States and the world are now using this protocol in daily practice. As already indicated, the results are reproducible time and time again, and hundreds of lives have been saved.


Q8. Do you think adopting your treatment is a matter of patents and money?

A. The wonderful thing about our novel intervention is that nobody will become rich from this therapy, including me, because it is cheap and readily available. It is not possible to patent these drugs or the combination, as I understand it. This is important because sepsis is common in resource-limited countries that cannot afford expensive designer pharmaceutical drugs.


Q9. What do you think about the opinion of those who have criticized your protocol?

A. Criticism and skepticism are an essential part of scientific discourse, but it must be professional, scientific, and not personal. Our protocol was not "sucked out of thin air." There is an enormous body of scientific research to support using all three components; all we did was put them together.


​Q10. From your critical care experience, do you think it is currently the best treatment in cases of sepsis or septic shock?

A. I believe this treatment is an important component for treating sepsis and septic shock, but it cannot be applied in isolation. The important components are:

  • Early identification of sepsis
  • Early prescription of the right antibiotic(s) in the right dose
  • Adequate source control (very important)
  • A physiologic, restrictive fluid strategy with the early use of norepinephrine ( very important)
  • The "metabolic resuscitation protocol:" steroids, vitamin C, and thiamine
  • State-of-the-art supportive care based on the best scientific evidence
  • A multidisciplinary, team approach to patient care

 

Q11. Do you think it is important to know to what degree each protocol component works?

A. As indicated previously, each component has some benefits, but together the sum is more than the parts. This is no different from the approach oncologists use to treat cancer; almost every oncology protocol uses multiple drugs that target different pathways.


Q12. What about the safety of IV vitamin C, particularly in patients with renal impairment?

A. Vitamin C in the doses we recommend is extremely safe, even in patients with renal impairment. We have checked serum oxalate levels in patients with chronic renal failure who are not receiving hemodialysis (HD) at the end of treatment with the cocktail, and they are all in the safe range. Vitamin C is a small molecule that is freely dialyzable and safe in the doses we recommend in patients receiving renal replacement therapy (continuous renal replacement therapy or conventional HD). We have closely followed the serum creatinine (Cr) in our patients with acute kidney injury (AKI) treated with the cocktail, and the creatinine has fallen in all of them. (See graph.)

​ sepsis 2.jpg

Dosages of 150 g (100 times the dose we use) have been safely given to patients with cancer. The only precaution with such high doses is chronic renal impairment that increases the risk of hyperoxalosis and worsening renal function. Hyperoxalosis and acute kidney injury have not been reported in patients receiving less than 10 g/day. These facts are well documented in the literature. The only other potential complication with these pharmacologic doses of vitamin C is hemolysis in patients with G6PD deficiency. (See Q14.)


Q13. Is there a risk of oxalate accumulation in patients with chronic renal failure (CRF) on dialysis? Is there a level of renal failure beyond which you would advise dose-reducing the vitamin C?

A. This is the one area that did concern us, and we have explored in much detail (also see answer to the previous question). In patients with CRF on HD, there is no issue with oxalate. AKI is common in patients with sepsis; we have found that the Cr comes down in all cases. (See graph above.) What's trickier is the situation in which patients have CRF and AKI, as well as septic shock. We had one such patient at the very beginning. We tried a dosage adjustment in him, but he failed to respond to the cocktail.

We have subsequently used the standard dose (1.5 g IV q 6) in all patients with CRF, and the Cr has fallen in all. We monitored oxalate levels in the first half-dozen or so of these patients; the levels were in the safe range. In patients at highest risk of kidney injury, I would suggest that the Cr be closely monitored, and if the Cr increases, it is not unreasonable to stop the vitamin C on day 3 and measure the serum oxalate level until further safety data are available on these patients. We believe, however, it is safe to continue treatment with vitamin C in patients receiving CRRT.

 

Q14. What about the risk of hemolysis in patients with G6PD deficiency?

A. Low-dose vitamin C is protective against hemolysis in patients with G6PD deficiency. It only causes hemolysis in very high doses. We have not had any issue with hemolysis or any other complications.

 

Q15. "Twenty-eight of 47 (59.6%) patients in the control group were treated with hydrocortisone.'' Was an analysis done on the mortality outcome for these 28 patients?

A. During the control period, hydrocortisone was used at the discretion of the treating physician. While the sample size is very small, the use of hydrocortisone compared with no hydrocortisone did not appear to affect any of the outcome measures.

 

Q16. It would have been interesting to have a prospective study comparing the effects of vitamin C and thiamine with a hydrocortisone group alone. I do believe this might be the variable that may have created such a gap between the primary outcome results.

A. As already indicated and as supported by our bench research currently in press (Chest 2017), we believe that vitamin C and hydrocortisone act synergistically on multiple metabolic pathways to limit and reverse the multiple derangements in cellular and organ dysfunctions that occur in sepsis. The added benefit of IV thiamine requires further study. Additional basic science and clinical studies are required to confirm our preliminary findings.

 

Q17. Our surgeons will not let us use this cocktail because they believe it impairs wound healing and increases the risks of secondary infections.

A. This is a common and absurd myth. There are multiple mechanistic reasons why the cocktail may actually promote wound healing and prevent secondary infections. Septic patients have critically low vitamin C levels. It is well known that vitamin C is essential for collagen formation and wound healing. In addition, vitamin C improves macrophage and T cell function, and prevents the development of post-sepsis immunosuppression. (Arch Surg 1997;132[2]:129.) It is important to emphasize that the metabolic resuscitation protocol uses stress doses of hydrocortisone, which are equivalent to those produced by a normally functioning adrenal gland during stress; these are not immunosuppressive doses of corticosteroids that impair immune function or wound healing. On the contrary, this dose of hydrocortisone is likely to promote resolution of tissue inflammation and wound healing.

Schulze, et al., performed a randomized, double-blind, placebo-controlled trial that investigated the effects of acute, preoperative corticosteroid administration on cutaneous wound healing. (Arch Surg 1997;132[2]:129.) The 24 patients in this study received a single dose of 30 mg/kg methylprednisolone (equivalent to 10,000 mg of hydrocortisone; 100 times the dose used in our protocol) or placebo intravenously 90 minutes prior to colon resection. There was no difference in wound healing between the two groups. Proline levels in the collagen and the amount of collagen accumulation within the wounds over 10 postoperative days were also evaluated, with no difference between the groups. These results suggest that acute, high-dose steroid administration does not significantly affect wound healing, as measured by both clinical and biochemical parameters. Audrey Wang, MD, and colleagues reviewed the literature on the use of corticosteroids in the perioperative period and wound healing. (Am J Surg 2013;206[3]:410.) These authors concluded that "the preponderance of human literature found that high-dose corticosteroid administration for less than10 days has no clinically important effect on wound healing."


Q18. We believe that the findings from your study are spurious, that the results are biased, and the conclusion overstated. There is no high-quality evidence that any of the three interventions individually improves survival in patients with sepsis. The substantial methodological flaws of the study undermine its external validity and veracity. We highly recommend meticulous assessment of all patient-important benefits and harms of vitamin C, hydrocortisone, and thiamine prior to adopting this unproven strategy in clinical ICU practice. (Synopsis of letter to Chest by Moller, et al.)

A. First and foremost, it is important to state that we do not refute nor did we attempt to mask the nature of our study: retrospective, single-center, nonrandomized, and unblinded. We initiated this therapy after our review of small trials in similar populations. (J Transl Med 2014;12:32; Crit Care Med 2016;44[2]:360.) We agree that the supporting data on efficacy were not robust, but felt that the available safety data on these particular interventions justified their introduction as salvage therapy in septic patients who were unlikely to survive. Our anecdotal experience was impressive, and led us to use this treatment in a number of consecutive patients.

Our decision to describe and publish our experience occurred afterwards; thus the methodological characteristics were unmodifiable. As a result of this study design, we understand why the results of our study have been met with some skepticism by the scientific community. We agree with Moller, et al., that additional trials should be performed to support or refute the findings of our study. As stated in our conclusion, "…additional studies are required to confirm our preliminary findings." Given our experience, however, we felt that publication of these results was necessary, and it's our ethical responsibility to do so.

Sepsis is common, debilitating, and often lethal. Despite exhaustive attempts at therapies to interrupt the mechanism of a dysregulated immune response and subsequent organ damage, we are currently limited to antibiotics and supportive care as our only consensus therapeutic measures. We recognize that the decision to use three readily available pharmacologic agents, each with limited supporting clinical data, can be viewed as unconventional, but therapeutic interventions in the absence of high-quality, randomized, controlled trials are commonplace in the ICU. When using such interventions, the clinician must balance the potential consequences of the disease with the safety of the proposed therapy. It is our opinion that the safety profile of vitamin C, thiamine, and hydrocortisone for a disease without alternative treatments and an exceedingly high mortality allows clinicians to use this therapeutic intervention to prevent death and limit the complications and long-term sequelae of this devastating disease. (J Transl Med 2014;12:32; Crit Care Med 2016;44[2]:360; Ann Surg 2002;236[6]:814; J Res Pharm Pract 2016;5[2]:94; Crit Care Med 2008;36[6]:1937.)

We continue to support the effort to investigate this therapy further in studies. The mortality reductions described in retrospective studies are often not reproduced in large, multicenter RCTs. A therapy that effectively targets pivotal pathways in patients with sepsis, however, could plausibly result in a large reduction in mortality. The associated reduction in the dose of vasopressors, qSOFA score, and procalcitonin clearance in our treated patients, all independent markers of the successful treatment of sepsis (Crit Care Med 2017;45[5]:781) , suggests a true biologic effect. In addition, we have independent validation that the sepsis mortality in our hospital has been dramatically reduced since the introduction of this novel therapeutic intervention.

It has previously been suggested that "the best hope for therapeutic advances [in sepsis] will depend on broad-base targeting, in which multiple components are targeted at the same time." (Blood 2003;101[10]:3765.) Such combination "chemotherapy" targeting multiple biological pathways is the standard approach in treating malignant diseases. The benefits of vitamin C, hydrocortisone, and thiamine alone are likely limited, but we believe that these medications act synergistically to effect the desired outcomes. Laboratory evidence of a synergistic interaction between hydrocortisone and vitamin C in preserving endothelial integrity supports this claim. (Chest 2017; in press.)

Read "Vitamin C for Sepsis Remains a Hypothesis" at http://bit.ly/2uDwzaR.

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Dr. Marik is a professor of internal medicine and the chief of pulmonary and critical care medicine at Eastern Virginia Medical School in Norfolk.


Friday, June 16, 2017

BY SETH COLLINGS HAWKINS, MD; JUSTIN SEMPSROTT, MD; & ANDREW SCHMIDT, DO, MPH

Earlier this month a young child died following days of vomiting. He had been in shallow water in a Texas dike about a week before his death. The story was picked up as an alleged case of a rare condition called dry drowning or secondary drowning. (CNN. June 9, 2017; http://cnn.it/2rECrOV.) The media accounts went viral, spreading significant fear in parenting communities and among those learning about these alleged conditions from the news or social media.

Every death is tragic, especially when it is a child's. Our heartfelt sympathies go out to the family and to those who treated the patient. Drowning deaths are a common cause of pediatric death, and we need to be particularly vigilant about sharing correct, meaningful, and medically credible information.

Unfortunately, there is significant misinformation in the media reports of this case, and we hope this evidence-based discussion of drowning and the best practice medical care of drowning patients will help set the record straight.

1. The medical definition of drowning is "the process of experiencing respiratory impairment from submersion/immersion in liquid." (Definition of Drowning: A Progress Report. Bierens J, Drowning 2e. Berline: Springer, 2014.) Drowning has only three outcomes: fatal drowning, nonfatal drowning with injury or illness, or nonfatal drowning without injury or illness.

2. There are no medically accepted conditions known as near-drowning, dry drowning, and secondary drowning. The World Health Organization, the International Liaison Committee on Resuscitation, the Wilderness Medical Society, the Utstein Style system, the International Lifesaving Federation, the International Conference on Drowning, Starfish Aquatics Institute, the American Heart Association, the American Red Cross, and the U.S. Centers for Disease Control and Prevention (CDC) all discourage the use of these terms. (WHO, http://bit.ly/2rECxWT; Circulation 2003;108[20]:2565; Wilderness Environ Med 2016;27[2]:236, http://bit.ly/2sAR3nL; International Life Saving Federation, http://bit.ly/2s9hi33; Handbook on Drowning: Prevention, Rescue, Treatment. Berlin: Springer, 2006; Starfish Aquatics Institute, http://bit.ly/2sACGQd; Circulation 2005;112:IV-133, http://bit.ly/2tb2pLU; American Red Cross Statement on Secondary Drowning, 2014; Morb Mortal Wkly Rep 2004;53:447; Snopes, http://bit.ly/2sHayL1; CDC, http://bit.ly/2sxCsZh.)

Unfortunately, these terms still slip past the editors of major medical journals, allowing their use to be perpetuated. These terms are most pervasive in the nonmedical press and social media, where the term drowning seems to be synonymous with death. We must find a better way to educate the public on how to discuss drowning as a process, with a spectrum ranging from mild to moderate to severe with fatal or nonfatal outcomes.

Near-drowning. Historically, drowning was used to indicate death, while near-drowning was used to describe patients who survive. But many people suffer from strokes, cardiac arrest, or car collisions every year, and we wouldn't consider them near-strokes, near-cardiac arrest, or near-car collisions just because the person survived. The same is true for drowning and near-drowning. A person can drown and survive the same way that a person can have a cardiac arrest and survive.

Dry drowning. Dry drowning is a term that has never had an accepted medical definition, and has been used at different times to describe different parts of the drowning process. Many media reports use it as a synonym for secondary drowning (described below), but in the past, it was used to describe the finding that the lungs of drowning victims contained no water in about 10 to 20 percent of autopsies. About 10 to 20 percent of the time, no water is found in the lungs at autopsy. Laryngospasm may play a role in some of these cases. During the drowning process, very little water actually enters the lungs, typically less than 2 mL/kg body weight.

This would mean only 30 mL, or one ounce, of water would enter the lungs of an average 15 kg (33 lb.) 3-year-old. If a child is underwater for more than a minute or so, then the main problem is a lack of oxygen to the brain, and CPR should be started to restore oxygen to the brain. If the person is rescued before the brain runs out of oxygen, then that small amount of water in the lungs is absorbed and causes no problems, or it can cause excessive coughing that gets better or worse over the next few hours. The management is the same regardless of whether small amounts of water are present, so this distinction between wet and dry drownings was abandoned as clinically meaningless years ago by drowning specialists.

Secondary drowning. Sometimes known as delayed drowning, this term also has no currently accepted medical definition. Its historical use reflects the reality that patients may sometimes worsen after water exposure. The take-home point is that anyone who experiences respiratory symptoms after a drowning incident (using the modern definition above) should seek medical care. There has never been a case published in the medical literature of a patient who received a clinical assessment, was initially without symptoms, and who later deteriorated and died. People who have drowned and have minimal symptoms will either get better or worse within two to three hours.

We know from a study of more than 41,000 lifeguard rescues that 0.5 percent of patients with initially minimal symptoms and five percent of patients with initially moderate symptoms ultimately died of drowning. (Chest 1997;112[3]:660.) This is the valid part of the concern about drowning patients who initially have only minimal symptoms: They should seek medical care. What are minimal symptoms? Using an experience familiar to almost everyone, we recommend that care be sought if symptoms seem any worse than the experience of a drink going down the wrong pipe at the dinner table or severe coughing that does not resolve in minutes.

Usually these patients can be observed for four to six hours in an emergency department and be released if normal. More significant symptoms would be persistent cough, foam at the mouth or nose, confusion, or abnormal behavior, all of which warrant attention. Drowning deaths do not occur due to unexpected deterioration days or weeks later with no preceding symptoms. The lungs and heart or their passages do not fill up with water, and water does not need to be pumped out of the lungs.

As noted earlier, only small amounts of water are needed to disrupt the surfactant that lines the cells in the lung responsible for exchanging oxygen and other gases. The problem in drowning, especially in cases of mild drowning that worsens, is surfactant disruption, not a measurable level of fluid in the lungs that fills up like a cup and prevents breathing. After a mild or moderate drowning, inflammation and infections in the lungs can cause the initial symptoms to get worse. Parents should seek additional care whenever a child has an excessive cough, isn't breathing normally, or isn't acting right immediately after being pulled from the water. If the child is 100 percent normal upon exiting the water and concerning symptoms develop more than eight hours later, then parents should seek care and providers should consider diagnoses other than primary drowning. In our experience, spontaneous pneumothorax, chemical pneumonitis, bacterial or viral pneumonia, head injury, asthma, heart attack, and chest trauma have been misattributed to delayed drowning.

3. Nonfatal drownings of this sort are common. Cases where a person has mild to moderate symptoms after a drowning incident, such as cough, pulmonary edema (fluid in the lungs), or confusion, are far more common than fatal drownings. It is often quoted in the media that this type of drowning is rare, but that is incorrect. It is actually the most common presentation of drowning. It is estimated that there are five nonfatal drownings for every fatal drowning in children. (AHRQ; http://bit.ly/2ta8RTxCDC; http://bit.ly/2rz1d85.) There are almost 13,000 emergency department visits per year for drowning (AHRQ; http://bit.ly/2ta8RTx), with only about 3,500 drowning deaths in the United States. (CDC; http://bit.ly/2rz1d85.) In fact, 95 to 99.5 percent of patients who have mild to moderate symptoms and a normal blood pressure survive. (New Engl J Med 2012;366[22]:2102; http://bit.ly/2sGEU02.)

What is rare is for these minimally symptomatic cases to progress to death. Similarly, this is also true of heart attacks: Most cases don't progress to death. Nonetheless, they can certainly deteriorate or progress, which is why we encourage people to seek care immediately when they have warning signs like chest pain. The warning signs for drowning are submersion or immersion followed by difficulty breathing, excessive coughing, foam in the mouth, and not acting normally. Subsequent death or complication from drowning is no more a secondary or delayed drowning than subsequent death or complication from heart attack is a secondary or delayed heart attack.

4. How do we communicate better information through the media? Some media reports noted that the terms dry drowning and secondary drowning are discredited in the medical community, but they went on to use them throughout their story. Often, we hear that these terms are more familiar to the public, which is likely true. Of more concern is that some physicians continue to use these terms (and older definitions of drowning that equate drowning exclusively with death) during media interviews and in clinical care and publications. The paradox is that the medical community invented these terms, not patients. The novelty of this storyline—and its appeal to media outlets—is precisely the unfamiliarity of these terms to the general public and the perceived mysterious looming threat. As clinicians and researchers, we should drive popular culture definitions, not the other way around. Rather than discuss these terms as semantics or technicalities, we have an opportunity to present facts, highlight the dangers of drowning and the importance of prevention, and to promote simpler but correct language that is easier for us and our patients to understand.

5. The bottom line. Near, dry, wet, delayed, and secondary drownings are not medically accepted diagnoses. We urge you to abandon these terms in favor of understanding and communicating drowning as a process that can be mild, moderate, or severe with fatal or nonfatal outcomes. Someone who drowns and survives has suffered a nonfatal drowning.

Drowning is a leading cause of preventable pediatric death. The danger is real and not esoteric or rare, and we should use this as an opportunity to discuss with the media and our patients the most important tool for treating drowning—primary prevention. Such prevention includes swimming lessons, touch supervision for toddlers, life jacket usage, appropriate pool fencing (four-sided with a locking gate), and continuous, uninterrupted supervision while kids are in the water, even if a lifeguard is present. If a drowning incident still occurs, anyone with symptoms should receive medical attention. Alternative diagnoses should be sought for those with an asymptomatic period of more than eight hours followed by other symptoms developing. Health care providers should understand and share modern drowning science and best practices, which will reduce fear, improve resource utilization, and prevent potentially deadly consequences due to misunderstanding or misinterpretation of incorrect terminology.


​Additional Resources

Find peer-reviewed information in the practice guidelines from the Wilderness Medical Society (Wilderness Environ Med 2016;27[2]:236; http://bit.ly/2sAR3nL) and an excellent review from the New England Journal of Medicine. (2012;366[22]:2102; http://bit.ly/2sGEU02.) There are also good review articles specifically written for pediatric (PEMNetwork Blog; http://bit.ly/2rEm9Wh) and rural emergency medicine providers (J Rural Emerg Med 2015;2[1]:1; http://bit.ly/2sH9nev) as well as for family practitioners (Am Fam Physician 2016;93[7]:576; http://bit.ly/2roz8w2) and lifeguards. (Starfish Aquatics Institute; http://bit.ly/2sACGQd.)


A​bout the Authors

Dr. Hawkins is an emergency physician in active clinical practice, an assistant professor at Wake Forest University School of Medicine, and a lifelong competitive swimmer. He is the medical director of Starfish Aquatics Institute, Landmark Learning, the Burke County EMS Special Operations Team, and the North Carolina State Parks system. He is an author of numerous medical textbook chapters about drowning and of the Wilderness Medical Society's evidence-based practice guidelines for drowning. He serves as a board member of Lifeguards Without Borders, and is a certified wilderness lifeguard instructor. Follow him on Twitter @hawk_sc.

Dr. Sempsrott is an emergency physician who started out as a beach lifeguard in 1996, and was a founder of the nonprofit Lifeguards Without Borders, now serving as its executive director. He also serves as the medical director for the International Surf Lifesaving Association, Starfish Aquatics Institute, and Innovative Attraction Management Starguard Elite. He is a founding member of the International Drowning Research Alliance and a frequent author and lecturer on drowning prevention, rescue, and treatment.

​Dr. Schmidt is an assistant professor with the University of Florida-Jacksonville Department of Emergency Medicine, where he also serves as deputy medical director for the TraumaOne Flight Program. His specific areas of research and teaching are drowning resuscitation and prehospital medicine. Other positions held include the medical director for Jacksonville Beach Ocean Rescue and a director of Lifeguards Without Borders.