Burks v. Allen

Panel: Eyler, Deborah S., Wright, Berger, JJ. * Eyler, Deborah S., J. ^{421 849} In the Circuit Court for Baltimore City, Cynthia Allen, individually and as Personal Representative of the Estate of Dennis Allen ("the Estate"), and seven of her adult children, appellees/cross-appellants, 1 brought medical malpractice wrongful death and survival actions against Allen Burks, M.D., and the University of Maryland Medical Systems Corporation ("UMMS"), appellants/cross-appellees. 2 The allegations arose out of Dr. Burks's treatment of Mr. Allen in March 2013, when he was an inpatient at the University of Maryland Medical Center ("UMMC"). Specifically, the Allens alleged that Dr. Burks breached the standard of care by treating Mr. Allen's ⁴²² elevated potassium levels with a formulation of Kayexalate 3 combined with 35.8 percent sorbitol and by doing so without obtaining his informed consent; and that the medication caused him to develop ischemic colitis and ultimately to die. They alleged that UMMS was liable for Dr. Burks's negligence under the doctrine of respondeat superior . Dr. Burks filed a pre-trial request for a Frye - Reed hearing, arguing that the Allens's theory that Kayexalate can cause ischemic colitis is not generally accepted in the relevant medical community, and therefore their expert witness testimony on that issue was not admissible.

The Allens opposed the request. The court held a hearing and ruled that a Frye - Reed hearing was not required but, even if it was and the court applied the Frye - Reed test to the evidence provided in the motion and opposition, the challenged evidence was admissible. After a ten-day trial, the jury returned a verdict in favor of the Allens, awarding $2,000,000 in non-economic damages to the Estate, and $1,000,000 in non-economic damages to Mr. Allen's wife and each of his seven children, for a total of $10,000,000 in damages. Dr. Burks filed a motion for new trial or, in the alternative, for remittitur.

The court did not grant a new trial but granted a remittitur, reducing the non-economic damages award to $906,250 pursuant to the cap on non-economic damages in Md. Code (1974, 2013 Repl. Vol.), section 3-2A-09 of the Courts and Judicial Proceedings Article ("CJP"). Dr. Burks noted an appeal, presenting three questions, which we have rephrased slightly: ⁸⁵⁰ I. Did the trial court abuse its discretion by denying his motion for a pretrial evidentiary Frye - Reed hearing on the Allens's causation theory? 4 ⁴²³ II. Did the trial court err by denying his motion to exclude certain evidence on informed consent?

III

Did the trial court err by permitting the Allens to introduce evidence about Dr. Burks's failure to order and administer calcium gluconate or calcium chloride and his failure to request a blood draw on the morning of March 18, 2013? The Allens noted a cross-appeal, presenting one issue: I. Does the cap on non-economic damages violate the equal protection clause of the 14 th Amendment and Article 24 of the Maryland Declaration of Rights? For the following reasons, we shall affirm the judgment of the circuit court. FACTS AND PROCEEDINGS Events of March 2013 On March 10, 2013, Dennis Allen, age 63, was transported by ambulance to Northwest Hospital Center in Randallstown for complaints of increasing "[w]eakness of the arms and legs." He was suffering from hepatitis C, cirrhosis of the liver, end stage liver disease, renal failure, and congestive heart failure, and already had been hospitalized twice in 2013-both times at UMMC-for a total of twenty-eight days.

Blood tests performed at Northwest Hospital Center revealed that Mr. Allen also was suffering from acute rhabdomyolysis, a condition in which muscle fibers break down, releasing muscle proteins into the bloodstream. Rhabdomyolysis causes muscle weakness and pain, can lead to kidney failure if untreated, and can cause elevated potassium levels, especially for patients with renal insufficiency. Mr. Allen was transferred from Northwest Hospital Center to UMMC the next day and was admitted to the intermediate care unit. Dr. Burks was the attending physician assigned to ⁴²⁴ him.

His primary admission diagnoses were rhabdomyolysis, chronic kidney disease, and hepatitis Ccirrhosis. Nephrology was consulted and from March 13 through 16, 2013, Mr. Allen underwent daily hemodialysis for his kidney failure. During that time, his bloodwork showed that his rhabdomyolysis was continuing to worsen. Mr. Allen did not receive dialysis on March 17, 2013.

On March 18, 2013, Dr. Burks arrived at UMMC sometime between 7 a.m. and 8 a.m. He had ordered routine laboratory tests for Mr. Allen to be performed in the early morning hours, but the results were not available. 5 Shortly after noon, Mr. Allen experienced a precipitous drop in heart rate, setting off the heart monitor alarms. Dr. Burks ordered an immediate EKG, which was performed at 12:18 p.m. It showed bradycardia (an abnormally slow heart rhythm) and life-threatening heart rhythms.

Dr. Burks made a preliminary diagnosis of hyperkalemia, i.e. , an elevated level of potassium in the blood. Hyperkalemia results when the kidneys are not able to excrete potassium in the urine. A potassium level over 5.5 mmol/L is hyperkalemic. 6 If left untreated, excess potassium can ⁸⁵¹ interfere with the electrical signals in the heart, causing a fatal cardiac arrhythmia. At 12:25 p.m., Dr. Burks ordered a stat blood draw to evaluate Mr. Allen's potassium level.

Given the emergency nature of the problem, he decided to begin the treatment protocol for hyperkalemia while awaiting the lab results. There are three phases to the hyperkalemia treatment protocol: stabilization, redistribution, and removal. The first phase addresses the danger of a fatal arrhythmia by stabilizing the heart muscle. Either calcium gluconate or calcium chloride is administered intravenously for this purpose and ⁴²⁵ works within 2 to 3 minutes.

In the redistribution phase, potassium in the blood stream is moved back into the cells to prevent it from interfering with the heart rhythm. Insulin, which works within 20 minutes, and sodium bicarbonate and albuterol, which work within 30 minutes, are prescribed in combination to achieve redistribution. Because insulin lowers blood sugar, dextrose is administered to counteract that effect. Insulin and dextrose are given intravenously; sodium bicarbonate is given orally; and albuterol is given through a nebulizer.

The third phase of the hyperkalemia treatment protocol is removal of the excess potassium from the body. There are three treatments by which potassium can be removed: diuretics, which cause the potassium to be excreted in the urine; hemodialysis, which removes the potassium directly from the bloodstream; and sodium polystyrene sulfonate ("SPS"), usually referred to by its brand name, Kayexalate, 7 which removes the potassium through the stool. Diuretics are not an option for a patient in renal failure, such as Mr. Allen. Dialysis begins to work within 30 minutes of being initiated and is very effective to remove potassium from the body.

The potassium stops being removed when the dialysis is stopped, however. Kayexalate, approved by the FDA in 1958 to treat hyperkalemia, is an "ion-exchange resin" medication, also known as a "cation exchange resin." The resin contains sodium ions that are exchanged for potassium ions in the bloodstream in the colon. The potassium ions bind to the resin and then are excreted in the stool. Because Kayexalate produces constipation and sometimes fecal impaction, it usually is given in combination with sorbitol, an osmotic laxative.

Osmotic laxatives increase the amount of water secreted into the bowels, which softens the stool, making it easier to pass. Kayexalate begins to work within 2 hours after it is administered. It reaches peak effectiveness approximately 4 to 6 hours after being administered and can continue to work for up to 24 ⁴²⁶ hours. It can be administered either in an oral suspension formula or by enema.

At 12:37 p.m., Dr. Burks used a UMMC electronic order set for hyperkalemia to order calcium gluconate stat, insulin stat, dextrose stat, sodium bicarbonate stat, and Kayexalate. 8 At 12:54 p.m., he ordered albuterol. At some time between 12:18 p.m. and 1:00 p.m., he also ordered a stat nephrology consult so hemodialysis could be started. Dr. Burks was advised by a UMMC pharmacist that calcium gluconate was not available due to a nationwide shortage. As we shall discuss, there was conflicting evidence ⁸⁵² at trial as to whether Dr. Burks gave an oral order to substitute calcium chloride for calcium gluconate.

In any event, neither drug was administered. It is undisputed that the failure to administer those drugs did not cause any injury to Mr. Allen. At 12:55 p.m., and continuing for 10 to 15 minutes, Mr. Allen received albuterol via a nebulizer. At 1:09 p.m., insulin and dextrose were administered intravenously.

At 1:15 p.m., Mr. Allen was given sodium bicarbonate and 30 milligrams of Kayexalate orally. The Kayexalate was in a suspension solution containing 35.8 percent sorbitol. Dr. Burks did not inform Mr. Allen about the risks and benefits of Kayexalate prior to its being administered. At 1:26 p.m., Mr. Allen's lab results were returned, revealing that his blood-potassium level was 7.3 mmol/L. That confirmed the diagnosis of hyperkalemia.

A blood potassium level of 7.3 mmol/L is considered dangerously high and can quickly lead to a fatal arrhythmia. At 1:30 p.m., a nephrologist assessed Mr. Allen and ordered hemodialysis on a stat basis. Dialysis began at 2:45 p.m. and was completed at 5:45 p.m. Mr. Allen had two bowel movements during dialysis.

After dialysis, Mr. Allen's potassium level was 4.5 mmol/L, which is within the normal range. ⁴²⁷ Dr. Burks left for the day around 8:00 p.m. Overnight, Mr. Allen had seven more bowel movements, several of them bloody, and began experiencing extreme abdominal pain. He told Cynthia he felt like he was "burning up inside." At 3:00 a.m., on March 19, 2013, Mr. Allen's lab results showed that his potassium levels were slightly elevated again, at 5.7 mmol/L. At 6:12 a.m., the physician assigned to Mr. Allen overnight wrote a note in his chart that he had had "several episodes of stool mixed with blood overnight." When Dr. Burks returned to UMMC around 7 a.m., he learned that Mr. Allen was experiencing "copious bloody bowel movements." Over the course of that morning, Mr. Allen's blood pressure dropped precipitously and could not be raised with fluid boluses. Around noon, Mr. Allen was transferred to the intensive care unit ("ICU") to be prepped for exploratory surgery.

Dr. Burks met with Cynthia and some of the Allen children. According to the family members, Dr. Burks told them he had "made a mistake" and was sorry. He said he had given Mr. Allen a drug that damaged his intestines, but that Mr. Allen was going to have surgery to correct it and everything would be all right. He estimated that the surgery would take 45 minutes to 2 hours.

After Mr. Allen was transferred to the ICU, Dr. Burks wrote a "discharge summary." In it, he noted that Mr. Allen's "differential diagnosis" included "intestinal ischemia due to hepatitis C related vasculitis versus intestinal ischemia due to concomitant Kayexalate and lactulose use versus hepatic decompensation with coagulopathy and lower GI bleed." 9 In other words, Dr. Burks listed Kayexalate use in the face of laxative use as a possible cause of Mr. Allen's intestinal ischemia, if that was what Mr. Allen was experiencing. ⁴²⁸ Mr. Allen's surgery lasted over six hours and confirmed the diagnosis of ischemic colitis. The exterior of his small intestine and colon (large intestine) appeared normal and there was a "palpable pulse" in the superior mesenteric artery, the largest artery supplying blood to the bowels. A ⁸⁵³ colonoscopy performed during the surgery revealed "multiple areas of mucosal ischemia with ulceration and bleeding," however. The severe ischemic ulceration necessitated removal of almost all of Mr. Allen's colon.

In his operative note, surgeon Ronald Tesoriero, M.D., wrote: [During the colonoscopy,] [w]e were able to advance the scope to the level of the transverse colon. There were multiple areas of mucosal ischemia with ulceration and bleeding in the colon. We were unable to pass beyond the transverse colon; however, it was clear at this point that the patient had significant mucosal level ischemic colitis. Given the overall state of the patient's perfusion, this may have likely been induced by the Kayexalate. [ 10 ] (Emphasis added.) Mr. Allen never regained consciousness.

He died the next day, March 20, 2013. His death certificate records the cause of death as "ischemic colitis." On autopsy, his cause of death was determined to be "[m]ultiple complications in the setting of hepatitis C /cirrhosis." In the "Discussion" section, pathologist Rupal I. Mehta, M.D., noted: Ischemic necrosis [was] seen within [Mr. Allen's] residual small intestine, with scattered basophilic crystals, consistent with recent [K]ayexalate use. The findings may be suggestive of [K]ayexalate colitis, which could have exacerbated the patient's underlying medical disease. (Emphasis added.) Because Mr. Allen's colon had been removed during surgery, it was not a part of the autopsy.

Dr. Mehta noted, however, that the "[p]rior colectomy specimen showed extensive bowel necrosis and hemorrhage." ⁴²⁹ Lawsuit by the Allens On June 25, 2015, the Allens filed suit against Dr. Burks and UMMS. Trial was scheduled to commence on September 7, 2016. On July 21, 2016, Dr. Burks filed a request for a Frye - Reed hearing, which was opposed. On the first day of trial, the court held a hearing and denied the request.

We shall discuss that hearing and the court's ruling in detail below. In their case-in-chief, the Allens called three expert witnesses: Richard Goldstein, M.D., a colorectal surgeon; James D. Leo, M.D., an internist; and Robert T. Odze, M.D., a pathologist. They also called thirteen fact witnesses: Siu Yan Amy Yeung, a clinical pharmacy specialist at UMMC; John Ashworth, III, the corporate designee for UMMS; Dr. Burks; Demetrius Jones, a phlebotomist at UMMC; Cynthia Allen; and all the Allen children. We summarize the pertinent testimony.

Ms. Yeung testified that in 2012 she served on the three-member UMMC team of pharmacists that developed internal guidelines for the treatment of hyperkalemia ("the UMMC Guidelines"). The UMMC Guidelines were reviewed by physicians in the nephrology department, the UMMC pharmacy committee, and the UMMC therapeutic committee. Upon approval, they were added to UMMC's internal computer database, which is accessible to doctors and nurses. The UMMC Guidelines, entitled "Management of Hyperkalemia," contain a table listing each "Agent" used to manage hyperkalemia; the dose; the mechanism; how to administer it; how quickly it works; how long it works; how its effectiveness is monitored; and any "Comments" about the use of the agent.

The table lists all the drugs ⁸⁵⁴ and treatments we have discussed above, including Kayexalate. The "Comments" column advises that the "[m]ajor complications" of Kayexalate are "intestinal necrosis and bowel perforation," and warns that Kayexalate" [s]hould not be used in patients with evidence of bowel obstruction, ileus or ischemia or to renal transplant patients in the early post operative phase." (Emphasis in original.) Ms. Yeung testified that these comments were included based on ⁴³⁰ medical literature she had reviewed that reported the risk of intestinal necrosis and bowel perforation from Kayexalate to be between 0.27 percent and 1.8 percent. In a flow chart for the management of hyperkalemia that appears in the UMMC Guidelines, Kayexalate is listed as the third agent to be used to treat acute severe hyperkalemia, after the stabilization and redistribution agents have been administered and before hemodialysis. According to Ms. Yeung, the only preparation of Kayexalate available for use at UMMC was the oral suspension in 35.8 percent sorbitol that Mr. Allen received.

Dr. Goldstein explained that the submucosal layer of the colon, which is beneath the lining of the colon (the mucosa), is filled with thin-walled blood vessels that absorb most of the water in the digestive fluid flowing into the colon from the small intestine, leaving solid stool. The celiac, superior mesenteric, and inferior mesenteric arteries supply blood to these vessels and to the small intestine, liver, appendix, and other organs. Compromised blood flow, i.e. , ischemia, to the submucosal vessels cuts off the oxygen supply to the lining of the colon. That causes the tissue in the mucosal layer to break down, ulcers to form, and bacteria from the colon to enter the bloodstream, further breaking down the surrounding tissue.

The loss of blood flow and the spread of bacteria throughout the submucosal layer of the colon causes necrosis, i.e ., tissue death. As the volume of bacteria in the bloodstream increases, the body attempts to fight off the infection, causing the blood pressure to fall. Dr. Goldstein opined that Mr. Allen died from intestinal necrosis caused by Kayexalate. In his view, the Kayexalate"cause[d] the[ ] blood vessels ... under the lining of the colon [to] stop working." He could not say "how [K]ayexalate damages the lining of the intestine and produces intestinal ischemia," only that it has been "observed over and over and over again with the use of [K]ayexalate." Dr. Goldstein was questioned about the defense theory that Mr. Allen's necrosis-producing ischemic colitis was caused by several periods of generalized decreased blood flow to the colon due to low blood pressure during dialysis.

He rejected that theory, explaining ⁴³¹ that the colon can sustain a 75 percent reduction in blood flow for up to 12 hours "without irreversible injury," and that the "very brief periods" of low blood pressure documented in Mr. Allen's chart would not have been sufficient to cause his severe necrosis. Moreover, Dr. Tesoriero's observation during surgery of a strong pulse and no clots in the superior mesenteric artery was inconsistent with generalized low blood flow having caused Mr. Allen's injury. Dr. Goldstein noted that other organs supplied by the same arteries-such as the appendix and the liver-were not necrotic, which was strong evidence of no general compromise of blood flow. On cross-examination, Dr. Goldstein acknowledged that there are "multiple causes of ischemic colitis" and that "99 out of 100 times when a patient has ischemic colitis it's idiopathic[,]" meaning the cause is unknown.

In reaching his opinion that Kayexalate caused Mr. Allen's ischemic colitis, Dr. Goldstein relied upon the medical literature, the UMMC Guidelines, Dr. Burks's differential diagnosis in his discharge note, and Dr. Tesoriero's observations ⁸⁵⁵ in his operative note. He also relied upon the "sequence of events," explaining that, until Mr. Allen was given Kayexalate, he did not have abdominal pain, diarrhea, or bloody stools. He viewed the timing of the onset of Mr. Allen's symptoms of ischemic colitis and the administration of Kayexalate as evidence of a causal link. Finally, Dr. Goldstein opined that although Mr. Allen was chronically ill none of his other health conditions was "imminently about to kill [him]." Dr. Leo, an expert in emergency medicine, internal medicine, and critical care medicine, testified that the standard of care for treating Mr. Allen's acute hyperkalemia was to stabilize his heart immediately with calcium gluconate or calcium chloride ; redistribute the potassium from his bloodstream into his cells by administering insulin (with dextrose), albuterol, and sodium carbonate; and remove the potassium by hemodialysis ordered urgently.

Because Mr. Allen already had a catheter for dialysis in place and was being treated by UMMC's nephrology team, there was no risk of delay in starting dialysis; and, in fact, dialysis was started just over an ⁴³² hour after the nephrology consult. Dr. Leo opined that given the availability and superior effectiveness of dialysis Kayexalate was unnecessary, and therefore its use was not in accordance with the standard of care. According to Dr. Leo, the "infrequent" but very serious risk of ischemic colitis from Kayexalate was not outweighed by any potential benefit from its use, given that dialysis was available and more effective. Dr. Leo also testified that Dr. Burks breached the standard of care by not obtaining Mr. Allen's informed consent before giving him Kayexalate.

After the stabilization and redistribution drugs had been administered, which resolved the emergency, Dr. Burks should have informed Mr. Allen that Kayexalate works more slowly and less effectively than dialysis and that it has a "very infrequent but very dangerous side effect that it can cause [a] condition called ischemic colitis in which the large intestine can basically die because of loss of blood flow." Dr. Leo further opined that the Kayexalate caused Mr. Allen's ischemic colitis and death. Mr. Allen had lived with his chronic medical conditions for some time, but never had "manifested evidence of ischemic colitis." "He did not have any other reasonable causes for ischemic colitis to occur during [the March 2013] hospital admission." Like Dr. Goldstein, Dr. Leo rejected the defense theory that episodes of low blood pressure caused Mr. Allen's ischemic colitis, opining that those episodes were "too short a duration, too mild in degree and too far in time prior to the development of the ischemic colitis for those to have been connected." Dr. Odze, an expert in pathology with a subspecialty in gastrointestinal and liver pathology, testified, based upon a review of Mr. Allen's pathology slides and medical records, that Mr. Allen's ischemic colitis and death were caused by Kayexalate or Kayexalate and sorbitol in combination. He explained that the "mechanism [of the bowel injury caused by Kayexalate and sorbitol] is poorly understood[, b]ut the consequence is very well understood." One theory is that sorbitol, a hyperosmotic agent, draws water out of the bloodstream and into the stool to counteract the constipating effects of Kayexalate and, in doing so, deprives the bowel tissue of oxygen. Dr. ⁴³³ Odze did not "find any evidence in this case ... that there was any other cause of ischemia in Mr. Allen's colon other than the ischemia caused by the Kayexalate." The "features in the tissue" showed an "acute injury" and there was no "lack of blood flow" from outside the colon that contributed to or caused the ischemia.

Had there been a generalized lack of blood ⁸⁵⁶ flow, one would expect to see "widespread ischemic injury," including to the small intestine and appendix, which are more susceptible to ischemic injury than the colon is. The "pattern of destruction" in Mr. Allen's case was "inconsistent" with "an overall lack of blood flow." In the prior 25 years, Dr. Odze had conducted pathology reviews in "more than a dozen cases" in which a patient had "ingested Kayexalate Sorbitol mixture and then died." He saw Mr. Allen's case as a "classic example of Kayexalate induced ischemic necrosis of the bowel." On cross-examination, in response to a series of questions about his understanding of the "mechanism" of injury caused by Kayexalate, Dr. Odze stated that it is not uncommon in medicine for the mechanism of a disease or condition to be poorly understood but for the "cause and effect" to be well understood. He opined that among gastrointestinal specialists, the causal connection between Kayexalate and ischemic colitis is well known. To the extent the defense experts would opine that there was insufficient evidence of a causal relationship, they were "[u]ninformed and incorrect." Dr. Burks (called adversely) testified that when he treated Mr. Allen for hyperkalemia he was unaware of any reported association between Kayexalate with sorbitol and ischemic colitis.

Ordinarily, he did not review UMMC Guidelines when considering treatment options for patients. Rather, he used "Up to Date," a peer-reviewed subscription website for physicians. Although an article about hyperkalemia on that website included information about the association between Kayexalate and ischemic colitis, it was not "something that [Dr. Burks] paid particular attention to." Dr. Burks could not "disagree with [the] statement [in the UMMC Guidelines that a major complication of Kayexalate use is intestinal necrosis and bowel ⁴³⁴ perforation ] at this point[.]" In his view, it did not matter that he was unaware of the rare risk of ischemic colitis from Kayexalate use because that would not have changed the course of treatment. Even if he had known that dialysis could be started in 10 minutes, he still would have ordered Kayexalate, because Kayexalate continues to remove potassium from the bloodstream for up to 24 hours, whereas dialysis only works during the several hours in which it is being administered.

After dialysis ends, the potassium levels can immediately begin to rise again. Dr. Burks further testified that he discussed Mr. Allen's hyperkalemia with Mr. Allen and his wife after the cardiac event but before Kayexalate was administered. He did not discuss any risks of Kayexalate with Mr. Allen and did not offer him the option to have dialysis only, instead of in conjunction with Kayexalate. After Mr. Allen was transferred to the ICU, he met with members of the Allen family.

He advised them that Mr. Allen had "developed injury to [his] intestines" and gave them an "incomplete list of possible reasons ... [including] ... Kayexalate." As of the time of trial, Dr. Burks's view remained that Kayexalate was a "possible but unlikely" cause of Mr. Allen's ischemic colitis. On cross-examination, Dr. Burks elaborated that treating hyperkalemia with Kayexalate in conjunction with dialysis satisfied the standard of care. In his opinion, Mr. Allen's elevated potassium levels were caused by rhabdomyolysis, an ongoing condition that warranted a multi-faceted approach to removing the excess potassium from his body.

Dr. Burks emphasized that even with the Kayexalate and dialysis Mr. Allen's potassium levels rose to 5.7 mmol/L (above normal) by 3:00 a.m. on March 19, 2013. Because of the emergency nature of Mr. Allen's condition, Dr. Burks did not ⁸⁵⁷ think he was required to obtain Mr. Allen's informed consent. Shelly testified that she was present when Dr. Burks spoke to the Allen family. He told them that the surgery would last about 2 hours.

Cynthia testified that she stayed with Mr. Allen overnight. She informed the nursing staff when she began ⁴³⁵ observing blood in her husband's stool. He was screaming and crying in pain. Dennis, Jr., Daniel, and Sarah also were present in the hospital on the evening of March 18, 2013, and the next morning.

They testified that they remembered their father being in severe pain and passing numerous bloody stools. On March 19, 2013, Dennis, Jr., was in the waiting area when Dr. Burks came to speak to him and some of his siblings. Dr. Burks told them that he had "administered some medicine to [Mr. Allen] that began to attack his bowels," but if it was "caught early enough ... he would be fine." He told them Mr. Allen would be having "routine surgery" lasting between "one to two hours." At the close of the Allens' case, counsel for Dr. Burks moved for judgment. He argued with respect to all the claims that although the Allens had presented evidence that Kayexalate had caused Mr. Allen's ischemic colitis they had failed to present any evidence that he would have survived if the drug had not been given to him.

With respect to the informed consent claim, he argued that the Allens had failed to present any evidence that Mr. Allen would have declined to take Kayexalate had Dr. Burks advised him of the risk of ischemic colitis, and that the evidence showed that the emergency exception to the informed consent doctrine applied. The court denied the motion. In his case, Dr. Burks called four expert witnesses: David Kaplan, M.D., an internist specializing in gastrointestinal and liver disease; Michael Schweitzer, M.D., a general surgeon; Michael Seneff, M.D., a critical care doctor; and Philip Buescher, M.D., an internist and critical care doctor. Dr. Kaplan, an expert in internal medicine, gastroenterology, and hepatology, including liver diseases and liver transplant medicine, opined that Dr. Burks complied with the standard of care for the treatment of severe hyperkalemia, which is to give Kayexalate and to begin dialysis as soon as possible.

According to Dr. Kaplan, Kayexalate is a "safe medication" that is "highly effective at removing potassium ⁴³⁶ from the body." Dr. Burks was not required to obtain Mr. Allen's informed consent before administering Kayexalate as this was a cardiac emergency and there was no significant risk associated with the drug. In Dr. Kaplan's view, the medical literature does not support the premise that Kayexalate causes ischemic colitis and, to the extent it does, the risk is so small that it is not material. It would have been a breach of the standard of care for Dr. Burks to have delayed giving Mr. Allen Kayexalate to obtain informed consent. Dr. Kaplan opined that Mr. Allen developed ischemic colitis from "multiple insults to the bowel" caused by repeated episodes of low blood pressure combined with his "overall clinical condition." He pointed to documented episodes of very low blood pressure during dialysis on March 13 and March 15, 2013, and noted that Mr. Allen may have experienced other episodes of low blood pressure that were not reflected in his chart because he was not on a continuous blood pressure monitor.

Dr. Kaplan testified that low blood pressure is "[t]he most common cause of ischemic colitis" and that low blood pressure lasting as little as 15 minutes can "lead to an episode of ischemic colitis... within 24, 48, even 72 hours [later.]" "Repeated bouts of low blood pressure can cause vasospasm meaning spasm of the small blood vessels that ⁸⁵⁸ feed the colon and that spasm if it continues causes the ... mucosa ... to not have enough blood flow and the cells die ...." Mr. Allen's cirrhotic liver also could have been a contributing factor. The colon "drain[s] into the liver," so when the liver is "under high pressure that drainage from the colon is also under high pressure ... [making the colon more sensitive] to changes in blood pressure." In Dr. Kaplan's opinion, there was not "sufficient evidence to claim that [K]ayexalate caused the injury" to Mr. Allen's colon. Mr. Allen was "predispose[d]" to ischemic colitis and the medical literature did not "substantiate[ ]" a causal relationship between Kayexalate and ischemic colitis. Moreover, Mr. Allen's medical prognosis at the time of his March 11, 2013 admission to UMMC was grim.

His likelihood of dying within 90 days was 85 percent. ⁴³⁷ On cross-examination, Dr. Kaplan was asked whether he would have expected to see ischemic injury to the appendix if the cause was a vasospasm occasioned by generalized low blood pressure. He replied, "[n]ot necessarily," elaborating that vasospasm often affects the small blood vessels in a "patchy" way and that it would not be "surprising" to see a patient with ischemic colitis and a normal appendix. Dr. Schweitzer, an expert in "general surgery including the care and treatment of ischemic colitis and multiple comorbidities that affect a patient's prognosis[,]" testified about causation. He had performed between 50 and 100 bowel surgeries for ischemic colitis.

He opined that there are many known causes of ischemic colitis, including scar tissue, vascular problems causing clotting in the arteries that supply the colon, episodes of very low blood pressure during dialysis, and certain medications, such as estrogen and diuretics. In his opinion, Mr. Allen's ischemic colitis was caused by "end stage liver disease, renal failure, rhabdomyolysis, [and] congestive heart failure [.]" Dr. Schweitzer explained that with liver failure the pressure in the abdominal veins increases, causing blood to be "shunted to other areas and [not to] go through the organs like the small and large bowel very well." Mr. Allen's rhabdomyolysis could have contributed because the inflammation and pain associated with that condition can cause small blood vessels to constrict. Similarly, congestive heart failure can restrict blood flow. Dr. Schweitzer agreed with Dr. Kaplan that episodes of hypotension during dialysis could have been a contributing cause.

Dr. Schweitzer further opined that Kayexalate was not a cause of Mr. Allen's ischemic colitis. The medical literature establishes a "very rare association[ ], not necessarily a cause" between "[K]ayexalate with high sorbitol" and ischemic colitis. The cases where such an association has been seen were in patients whose "bowels aren't moving[.]" It is for that reason that Kayexalate is not recommended for patients who are post-operative or otherwise are experiencing constipation. Mr. Allen was not postoperative, did not have constipation, and did not have a bowel obstruction.

Dr. Schweitzer testified that he ⁴³⁸ had treated five to ten patients who, like Mr. Allen, were not experiencing constipation (post-operative or otherwise) or an obstruction but were in renal failure, developed hyperkalemia, were treated with Kayexalate, and developed ischemic colitis. In his view, those patients did not develop ischemic colitis from Kayexalate. Dr. Schweitzer testified that Mr. Allen was not going to survive his hospitalization under any circumstance. His rhabdomyolysis was worsening, he had end stage liver disease, and he was in stage four renal failure.

In Dr. Schweitzer's view, Mr. Allen did not "have the reserve[s] to overcome" all those serious medical conditions. ⁸⁵⁹ On cross-examination, Dr. Schweitzer was asked about the lack of injury to the appendix. He replied that because the appendix is tiny, it "doesn't take much blood to fill [it]," whereas the colon requires much more blood flow. Dr. Seneff was accepted as an expert in critical care medicine, including the "diagnosis, care and treatment of ... liver disease, liver cirrhosis, kidney disease requiring dialysis, rhabdomyolysis, ... severe hyperkalemia [and other conditions]." He opined that giving Kayexalate in conjunction with dialysis, as Dr. Burks did, is within the standard of care for the treatment of severe hyperkalemia. It is Dr. Seneff's practice to order Kayexalate for patients with severe hyperkalemia "even [while] in the process of getting dialysis." He noted that the UMMC Guidelines direct that Kayexalate be administered before starting dialysis, i.e ., that both are to be given.

Dr. Seneff was aware of case reports showing an association between Kayexalate and ischemic colitis. He opined that the association is "very rare[,] ... [o]ne in 100,000, maybe less than that." It "primarily [was] reported with the 70 percent sorbitol solution," which no longer is used. He opined that he would not give Kayexalate to a patient with a bowel obstruction but otherwise he "would never hesitate to give it." For the same reasons, there was no obligation to obtain informed consent prior to administering Kayexalate. ⁴³⁹ In Dr. Seneff's opinion, Mr. Allen's ischemic colitis could not have been caused by Kayexalate because he "already had the ischemic colitis before the [K]ayexalate was administered[.]" This opinion was based upon Mr. Allen's lab results from March 18, 2013. His blood was drawn at 12:57 p.m., before the Kayexalate was given.

According to Dr. Seneff, the laboratory results from that blood draw showed that, over the preceding 30 hours, Mr. Allen's bicarbonate levels had dropped from a normal level of 24 to an abnormal level of 11. That change resulted from Mr. Allen's producing excess acid. Acid production rises when organs become ischemic. The change in Mr. Allen's acid production was an "om[ino]us sign" that the ischemic colitis already had begun.

Dr. Seneff opined that Dr. Burks would not have been able to determine prospectively from those lab results that Mr. Allen was ischemic, however, and, even if he had recognized the lab results as a sign of ischemia, there was no way to know where in Mr. Allen's body the ischemia was occurring. Dr. Seneff agreed with Drs. Kaplan and Schweitzer that Mr. Allen's ischemic colitis was caused by episodes of hypotension coupled with increased venous pressure in his intestines. Dr. Philip Buescher was accepted as an expert in internal medicine and critical care medicine, including, inter alia , the diagnosis and treatment of liver disease, kidney disease, and hyperkalemia, and the prescription of Kayexalate.

He opined that Dr. Burks did not breach the standard of care by ordering Kayexalate for Mr. Allen, even if dialysis was immediately available, and that Dr. Burks was not required to obtain informed consent before administering it. Dr. Buescher testified that he had ordered Kayexalate for patients with acute hyperkalemia at least 900 times in his career and had "not seen a single case of ischemic colitis" among his patients. He agreed with Dr. Seneff that Mr. Allen's ischemic colitis developed before the Kayexalate was administered to him, based upon his lab results showing low bicarbonate levels. He also agreed with Dr. Schweitzer that it was unlikely that Mr. Allen would have survived his hospitalization given his deteriorating condition overall.

On cross-examination, Dr. Buescher ⁴⁴⁰ acknowledged that he could not say whether the administration of Kayexalate to Mr. Allen accelerated and exacerbated the ischemic ⁸⁶⁰ colitis that, in his view, already was developing. He reiterated, however, that Mr. Allen would have died during this hospitalization regardless of whether he had been given Kayexalate. In their rebuttal case, the Allens played the video deposition of Carla Williams, the assistant director of UMMC's pharmacy clinical services. Her testimony, which we shall discuss in more detail, infra , was pertinent to the issue of the shortage of calcium gluconate.

At the close of all the evidence, Dr. Burks renewed his motion for judgment and the court denied it. On September 22, 2013, the case was sent to the jury on a special verdict. The jury returned a verdict that same day. It found that Dr. Burks had breached the standard of care by treating Mr. Allen with "Kayexalate Sorbitol mixture"; that that breach was a cause of injury to Mr. Allen and was the cause of Mr. Allen's death; that Dr. Burks had a duty to obtain informed consent before treating Mr. Allen with Kayexalate ; that a "reasonably prudent person in [Mr.] Allen's position would have withheld his consent" to that course of treatment had he been informed of the risks; and that the failure to obtain informed consent also was a cause of Mr. Allen's injury and was the cause of his death.

As noted previously, the jury awarded the Estate $2 million in non-economic damages and awarded Cynthia and Mr. Allen's seven biological children $1 million each in non-economic damages; and the court later reduced the damages award in accordance with the statutory cap on non-economic damages. The reduced damages award totaled $906,250 and was apportioned as follows: $181,250 to the Estate and $90,625 to Cynthia and to each of the seven children plaintiffs. This timely appeal followed. ⁴⁴¹ DISCUSSION APPEAL I. Frye - Reed (a) As mentioned, Kayexalate first was approved by the FDA in 1958 as a treatment for hyperkalemia. It was marketed in powder form.

Shortly after it was introduced, physicians found that Kayexalate frequently caused severe constipation that could result in life threatening intestinal impaction. That problem could be avoided by mixing the powder with sorbitol. As a result, the FDA approved labeling for Kayexalate powder encouraging it to be administered with sorbitol. In 1982, a premade suspension of Kayexalate in 33-36 percent sorbitol was approved for distribution.

The availability of the premade formulation contributed to an increase in the use of Kayexalate. Sometime thereafter, the FDA approved a premade suspension of Kayexalate in 70 percent sorbitol. Some of the history that followed is recounted in a 2010 "Clinical Commentary" published in the Journal of the American Society of Nephrology by Richard Sterns, M.D., et al ., titled Ion-Exchange Resins for the Treatment of Hyperkalemia: Are They Safe and Effective? (hereinafter Sterns ).

The Sterns commentary was cited by Dr. Burks in his motion for Frye - Reed hearing and by the Allens in their opposition. By 2005, the FDA had received 35 adverse event reports of serious bowel injuries following oral and rectal administration of Kayexalate in sorbitol. That year, the FDA removed the recommendation for concomitant use of sorbitol from the label for the powdered form of Kayexalate. In 2006, the largest manufacturer of the premixed oral suspensions met with the FDA and was permitted to continue ⁸⁶¹ manufacturing the 33-36 percent sorbitol and Kayexalate combination because, since 1982, it had not received any adverse reports of colonic necrosis with administration of that suspension; the only adverse ⁴⁴² reports concerned the 70 percent sorbitol suspension.

In September 2007, the FDA asked all manufacturers of the 70 percent suspension to reformulate their products. The 70 percent suspension has not been manufactured since. In 2009, the FDA issued a "black box" warning for Kayexalate powder, as follows: Cases of colonic necrosis and other serious gastrointestinal adverse events (bleeding, ischemic colitis, perforation) have been reported in association with Kayexalate use. The majority of these cases reported the concomitant use of sorbitol.

Risk factors for gastrointestinal adverse events were present in many of the cases including prematurity, history of intestinal disease or surgery, hypovolemia, and renal insufficiency and failure. Concomitant administration of sorbitol is not recommended. According to Dr. Sterns, that same year, an article was published reporting 11 new cases of colonic necrosis over a nine-year period in a single clinical center, four of them fatal, several in patients without end stage renal disease, and some in patients with noncritical illnesses. Some of the fatalities were in patients given the Kayexalate oral suspension with 33-36 percent sorbitol.

Dr. Sterns recommended: "Clinicians must weigh uncontrolled studies showing benefit against uncontrolled studies showing harm. It would be wise to exhaust other alternatives for managing hyperkalemia before turning to these largely unproven and potentially harmful therapies." Sterns , at 3. In 2011, the FDA revised its "black box" warning for powdered Kayexalate to state: WARNINGS Colonic Necrosis • Cases of intestinal necrosis, which may be fatal, and other serious gastrointestinal adverse events (bleeding, ischemic colitis, perforation) have been reported in association with Kayexalate use. ⁴⁴³ • Do not use in patients who do not have normal bowel function. This includes postoperative patients who have not had a bowel movement post surgery. • Do not use in patients who are at risk for developing constipation or impaction (including those with a history of impaction, chronic constipation, inflammatory bowel disease, ischemic colitis, vascular intestinal atherosclerosis, previous bowel resection, or bowel obstruction ). • Discontinue use in patients who develop constipation.

Do not administer repeated doses in patients who have not passed a bowel movement. PRECAUTIONS • Concomitant use of Sorbitol with Kayexalate has been implicated in cases of colonic intestinal necrosis, which may be fatal. (Bold in original.) (Italics added.) In the case at bar, on July 21, 2016, Dr. Burks filed a request for a Frye - Reed hearing, memorandum in support, and numerous exhibits. He sought to preclude the Allens from introducing their proposed expert medical causation testimony, which was based on the premise that Kayexalate can cause ischemic colitis.

He argued that although it is generally accepted in the relevant medical community that Kayexalate, in combination with sorbitol, has been associated with a small number of cases of ischemic colitis it is not generally accepted that Kayexalate, sorbitol, or some combination of the two actually cause ischemic colitis. Rather, there is considerable controversy over that general causation question. ⁸⁶² Moreover, they asserted that most of the adverse events reported in the medical literature involve a different formulation of Kayexalate (powder versus liquid suspension), a different concentration of sorbitol (70 percent versus 33-36 percent), and a different mode of administration (enema versus oral). Thus, even to the extent the medical literature supports a causal connection between that formulation of Kayexalate and ischemic colitis, that formulation was not used to treat Mr. Allen and therefore could not serve as the basis for the Allens' ⁴⁴⁴ medical experts to opine that the Kayexalate in sorbitol administered to Mr. Allen caused his ischemic colitis. Dr. Burks's exhibits included several articles and studies, the earliest of which was an experiment on rats published in 1987 in Surgery by Keith D. Lillemoe, M.D., et al. , Intestinal necrosis due to sodium polystyrene (Kayexalate ) in sorbitol enemas: Clinical and experimental support for the hypothesis (hereinafter Lillemoe ).

That study was performed after five patients suffered necrosis of the colon (four fatal) after receiving Kayexalate with sorbitol enemas. In the study, some of the rats were given Kayexalate with sorbitol, some were given sorbitol alone, and some were given Kayexalate alone. The mode of administration was enema for all of them. Seven out of ten of the rats who received sorbitol alone developed colonic necrosis, and six of the ten rats who received Kayexalate with sorbitol developed colonic necrosis.

None of the rats who received Kayexalate alone developed colonic necrosis. Also appended were articles by Maura Watson, D.O., et al. , in 2012, published in the American Journal of Kidney Disease , and Ziv Harel, M.D., et al. , in 2013, published in the American Journal of Medicine . See Association of Prescription of Oral Sodium Polystyrene Sulfonate With Sorbitol in an Inpatient Setting With Colonic Necrosis: A Retrospective Cohort Study (hereinafter Watson ); Gastrointestinal Adverse Events with Sodium Polystyrene Sulfonate (Kayexalate ) Use: A Systematic Review (hereinafter Harel ). Dr. Watson described colonic necrosis as a "rare but potentially fatal event" that has been reported after Kayexalate use, "most often in postoperative or intensive care settings and most frequently with rectal [Kayexalate ]/sorbitol (particularly 70% sorbitol), rather than [Kayexalate ] alone." Watson , at 409.

The estimated frequency among hospitalized patients is 0.27% in all cases occurring after surgery. Id. Because it is so rare, a very large population would be required to assess the risk factors and show an association between colonic necrosis and Kayexalate. Dr. Watson concluded that there is not enough evidence to show an association between colonic necrosis and ⁴⁴⁵ exposure to Kayexalate.

The precise mechanism of injury is unknown. She observed that use of Kayexalate may be associated with serious gastrointestinal adverse events, but a controlled trial is needed to make that determination. Dr. Harel conducted a literature review to "identify eligible reports of adverse gastrointestinal events associated with [Kayexalate ] use" and then applied the World Health Organization ("WHO") causality assessment system to those reports to determine inclusion in the review. Harel , at 264.e9.

Ultimately, out of 553 articles describing adverse events, 30 articles describing 58 cases were included because they "satisf[ied] at a minimum a possible level of certainty [under the WHO system]." Id. at 264.e10-e11. The study found evidence that Kayexalate, not sorbitol, might be the pathogenic agent causing adverse gastrointestinal events, but emphasized that the literature review could not "ensure that the relationship between ⁸⁶³ [Kayexalate ] and the described gastrointestinal adverse events is certain." Id. at 264.e14. Moreover, the authors could not calculate the risk of such an association because they lacked data on the prevalence of Kayexalate use. Id.

Dr. Burks also cited a 2015 rat experiment study by Isabelle Ayoub, published in PLOS One , that, unlike Lillemoe , showed that Kayexalate, not sorbitol, "is the main culprit for colon necrosis[.]" See Colon Necrosis Due to Sodium Polystyrene Sulfonate with and without Sorbitol: An Experimental Study in Rats , at 7. Dr. Burks argued that these contradictory studies show that the data is insufficient to support a generally accepted theory that the oral suspension of Kayexalate with 33-36 percent sorbitol is causally connected to ischemic colitis that produces necrosis of the colon. Dr. Burks's exhibits also included his expert witness designations; the deposition of Dr. Sterns, who had been identified as an expert by the Allens (but was not called to testify at trial); and the depositions of Drs. Leo, Goldstein, Buescher, Seneff, and Schweitzer.

The Allens filed an opposition to the request for a Frye - Reed hearing, in which they argued that the medical literature ⁴⁴⁶ establishes a general causal link between Kayexalate, given in conjunction with sorbitol, and ischemic colitis. They pointed to the 2009 and 2011 FDA "black box" warnings, and in particular to the 2011 warning, which states, " PRECAUTIONS Concomitant use of Sorbitol with Kayexalate has been implicated in cases of colonic intestinal necrosis, which may be fatal." (Emphasis in original.) The Allens maintained that, used in that context, "implicated" means causally connected, i.e ., that there is a cause and effect relationship between Kayexalate with sorbitol, given orally, and necrosis of the colon. The Allens provided as an exhibit the FDA "Guidance for Industry: Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products - - Content and Format," October 2011 ("FDA Guidance"), which states, in part, at page 3: The WARNINGS AND PRECAUTIONS section [of the label] is intended to identify and describe a discrete set of adverse reactions and other potential safety hazards that are serious or are otherwise clinically significant because they have implications for prescribing decisions or for patient management. To include an adverse event in the section, there should be reasonable evidence of a causal association between the drug and the adverse event, but a causal relationship need not have been definitively established.

(italics in original) (bold added) (footnote omitted). The Allens also relied upon the UMMC Guidelines, which, as noted, identify ischemic colitis as a "major complication" associated with Kayexalate, and the UMMC medical records for Mr. Allen, reflecting that Drs. Burks, Tesoriero, and Mehta all expressed the view that Mr. Allen's ischemic colitis may have been caused by Kayexalate. They attached the autopsy report as an exhibit.

The Allens argued that the medical literature cited by Dr. Burks in his request for a Frye - Reed hearing did not show the absence of a causal relationship but only showed that some researchers think there is a need for further study to quantify ⁴⁴⁷ more precisely the risk of colonic necrosis from Kayexalate administered in sorbitol. They attached as exhibits medical literature supporting a cause and effect relationship, including: • A 2001 article by Susan Abraham, M.D., published in the American Journal of Surgical Pathology , studying ⁸⁶⁴ 11 patients who were given Kayexalate and were found to have Kayexalate crystals on biopsy, which concluded that "Kayexalate in sorbitol can result in injury to the upper gastrointestinal tract in addition to the more commonly appreciated risk of colonic necrosis ." Upper Gastrointestinal Tract Injury in Patients Receiving Kayexalate ( [SPS] ) in Sorbitol , at 643 (emphasis added). The article, citing a 1997 study by Rashid and Hamilton, states: "Kayexalate... in sorbitol has been demonstrated to cause colonic necrosis in a subset of uremic [ 11 ] patients who are administered the cation exchange resin for hyperkalemia." Id. at 637. • A 2008 article by Lawrence Weisberg, M.D., in Critical Care Medicine , reviewing the medical literature pertinent to management of hyperkalemia and stating, with citations: There are numerous case reports of patients who have developed intestinal necrosis after exposure to [Kayexalate ] in sorbitol as an enema, and as an oral agent. A retrospective study estimated the prevalence of colonic necrosis to be 1.8% among postoperative patients receiving [Kayexalate ].

Thus, the slow onset of action and serious, albeit infrequent, toxicity make [Kayexalate ] a poor choice for the treatment of urgent hyperkalemia. Management of severe hyperkalemia , at 3249 (citations omitted). • A 2009 article by C.E. McGowan, M.D., in the Southern Medical Journal, studying pathology records of 29 patients ⁴⁴⁸ who received oral Kayexalate. Eleven patients had confirmed intestinal necrosis and four died. The article concluded: [Kayexalate ] in sorbitol has been implicated in the development of intestinal necrosis, primarily mediated by the sorbitol component.

Previous studies documented these findings almost exclusively in postoperative, renal transplant, and critically ill patients. Our study highlights that all patients are potentially susceptible, including those without previously described comorbidities. The indications for [Kayexalate ] use, as well as alternate vehicles for its delivery, should be re-evaluated. [Kayexalate ]-induced ischemia remains an under recognized, easily avoided complication, associated with significant morbidity and mortality. Physicians who routinely use this agent in sorbitol should be aware of its life-threatening complications.

Intestinal Necrosis due to Sodium Polystyrene Sulfonate (Kayexalate ) in Sorbitol, at 497. • A 2010 case study by Mohamad Erfani, in Practical Gastroenterology , documenting colonic necrosis in a patient who received oral Kayexalate in sorbitol for hyperkalemia. Sodium Polystyrene Sulfonate (SPS): Sorbitol-induced Colonic Necrosis . The study concluded: Intestinal necrosis following [Kayexalate ]-sorbitol administration is a rare clinical condition that may have significant morbidity and mortality. [Kayexalate ]-sorbitol should be used with caution, especially in the postoperative setting, in uremic or ill patients ... When clinically indicated other measures to treat hyperkalemia should be ⁸⁶⁵ considered instead of [Kayexalate ]-sorbitol.

Physicians need to be aware of [Kayexalate ]-sorbitol GI side effects while managing hyperkalemia. Id. at 49. • A 2015 "Up to Date" article by David Mount, M.D. (and edited by Dr. Sterns), generally reviewing the treatment and prevention of hyperkalemia in adults, and stating: "A major concern with [Kayexalate ] in sorbitol is the ⁴⁴⁹ development of intestinal necrosis, usually involving the colon and ileum, which is frequently a fatal complication." Treatment and prevention of hyperkalemia in adults, at 8 (citations omitted). In addition, the Allens attached as exhibits to their opposition deposition transcripts of Mrs. Allen and Drs.

Sterns, Kaplan, Goldstein, and Odze. In a reply memorandum, Dr. Burks argued that the conflicting medical opinions in the literature cited by the Allens and the literature he cited showed that there is disagreement about whether Kayexalate can cause intestinal necrosis; therefore, that proposition is not generally accepted in the relevant medical field, and expert testimony should not be permitted, under Frye - Reed . He argued further that the UMMC Guidelines do not establish a causal relationship either, as they are based on the same disputed literature, and his statement to the Allens about Mr. Allen's differential diagnosis and what might have caused his bowel problem merely was a repetition of what the medical community has not reached an agreement about. Nor, he argued, are the FDA "black box" warnings evidence of general acceptance by the medical community.

In a supplement, the Allens attached deposition testimony by Ms. Yeung, in which she stated that the UMMC Guidelines, listing intestinal necrosis as a major complication of Kayexalate use, were based on the FDA "black box" warnings. This case was not specially assigned, and the assignment office did not schedule a pre-trial hearing on Dr. Burks's request for a Frye - Reed hearing. Consequently, the request was taken up by the court at the outset of the first day of trial. The trial judge, who only was assigned the case that morning, first saw the request, opposition, and appended materials then.

Nevertheless, she held a comprehensive hearing for approximately one hour and fifteen minutes, during which she queried counsel about the medicine and the Frye - Reed cases. At one point, she remarked about the important distinction between a controversy over the means by which an agent causes a particular harm and a controversy over whether the agent can cause the harm at all. After counsel finished their arguments, ⁴⁵⁰ the judge took a twenty-minute recess to further review the materials provided, denied the request for a Frye - Reed hearing, and explained the reasons for her ruling. The ruling was made in the alternative.

First, relying primarily upon this Court's decisions in Myers v. Celotex Corporation , 88 Md. App. 442 , 594 A.2d 1248 (1991), cert. denied , 325 Md. 249 , 600 A.2d 418 (1992), and CSX Transportation, Inc. v. Miller , 159 Md. App. 123 , 858 A.2d 1025 (2004), cert. granted , 384 Md. 581 , 865 A.2d 589 , cert. dismissed , 387 Md. 351 , 875 A.2d 702 (2005), the judge concluded that the medical causation opinions being offered by the Allens' expert witnesses were not of the type requiring a Frye - Reed analysis. The judge emphasized that the Allens' experts were not using new or novel scientific techniques but were using the accepted differential diagnosis method to reach a conclusion about the etiology of Mr. Allen's ischemic colitis. The judge also distinguished cases such as ⁸⁶⁶ Blackwell v. Wyeth , 408 Md. 575 , 971 A.2d 235 (2009), which applied Frye - Reed to medical causation opinions, because, unlike in those cases, here there was no discernible