NEW TREATMENTS IN CML

he outlook has never been better for patients with chronic myeloid leukemia (CML). Clinicians have an increasingly wide choice of drugs, between imatinib (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), bosutinib, and very likely ponatinib too, if it receives U.S. Food and Drug Administration (FDA) approval later this year.

The 17th Congress of the European Hematology Association (EHA), recently held in Amsterdam, The Netherlands, presented a wealth of new data on these second- and third-line tyrosine kinase inhibitors (TKIs).

"It's phenomenal. The overall survival has improved, with 93 to 95% of patients alive after 7 to 8 years of follow-up," said Daniel DeAngelo, MD, associate professor of medicine at Harvard Medical School, and clinical director of Adult Leukemia at the Dana-Farber Cancer Institute, Boston, Massachusetts, in an interview with Medscape Medical News. "There has been a dramatic improvement in outcome over the decade."

Data Round-Up on New Drugs

The EHA saw long-term follow-up and comparison data on bosutinib, dasatinib, nilotinib, and ponatinib presented.

Dasatinib data (Bristol-Myers Squibbs) showed that first-line treatment at 100 mg resulted in faster and deeper response rates compared with imatinib 400 mg, according to 3-year follow-up of the DASISION (Dasatinib versus Imatinib Study in Treatment-Naïve CML-CP Patients) trial. The median time to complete cytogenic response (CCyR) for dasatinib was 3.2 months, versus 6.0 months for imatinib. The median time to major molecular response (MMR) was 15 versus 36 months, respectively. By 3 years, MMR was achieved in 68% of dasatinib-treated patients and in 55% of imatinib-treated patients (P < .0001). Long-term follow-up for 5 years is planned as part of the original DASISION study design.

Pfizer's BELA trial compared bosutinib with imatinib and reported that after at least 30 months of follow-up, 79% of patients on bosutinib showed CCyR versus 81% on imatinib; 61% on bosutinib versus 52% on imatinib achieved MMR; and 30% on bosutinib versus 22% on imatinib achieved complete molecular response (CMR), according to an intent-to-treat analysis. The BELA trial is a phase 3 open-label comparison of the efficacy and safety of bosutinib combined with imatinib in patients with newly diagnosed chronic phase CML.

Nilotinib data (Novartis) showed superior results compared with imatinib in newly diagnosed patients in the ENESTnd 3-year follow-up. A significantly lower rate of progression to accelerated/blast phase CML, lower rates of mutation, and significantly higher rates of MMR and molecular response were observed for nilotinib versus imatinib. Differences in rates of molecular response between nilotinib and imatinib increased over time. Another study presented at EHA showed that nilotinib induced deeper molecular responses versus continued imatinib in patients with CML with detectable disease after 2 years on imatinib as seen in the ENESTcmr 12-month results.

Data on ponatinib (Ariad), an investigational pan-BCR-ABL inhibitor, showed that 54% of chronic-phase CML patients who were pretreated and were refractory to other TKIs, including 70% with a T315I mutation, achieved a major CyR (MCyR). CCyR was achieved by 44% of patients. The median follow-up of chronic phase CML patients is 10.1 months. Data were updated from the pivotal PACE trial in CML patients who were resistant or intolerant to dasatinib or nilotinib, or who had the T315I mutation.

Imatinib Sets the Stage

Imatinib was the first oral targeted drug in cancer therapy and the first in CML. "Imatinib sets the bar very high," reflects Dr. DeAngelo, "but that doesn't mean it's the best drug."

Patients who experience significant side effects, develop resistance to imatinib, or become intolerant warrant discontinuation of the drug. "These categories represent a small number of patients, but it is important to have alternative second- and now third-generation drugs available for patients," added Dr. DeAngelo.

In 2006, dasatinib received U.S. Food and Drug Administration (FDA) approval for CML in patients who were refractory or intolerant to imatinib; in 2010, it received approval for use in patients newly diagnosed with CML. Nilotinib (Tasigna) received FDA approval for previously treated CML in 2007, and for newly diagnosed patients in 2010. These 2 drugs represent the first 2 second-generation drugs for CML. They are more potent inhibitors of BCR-ABL than imatinib, and they exhibit significant activity against all resistant mutations except the T315Imutation.

Bosutinib Holds Long-Term Promise

Bosutinib is another second-generation TKI. Dr. Carlo Gambacorti, MD, hematologist-oncologist, from the University of Milano Bicocca, Monza, Italy, who presented findings at the EHA, commented on the BELA comparison trial with imatinib and noted that results reflected findings with other second-generation TKIs in that you get faster and deeper molecular remissions. "This translates into a reduced number of progressions to accelerated or blast/crisis phase, usually within the first year of treatment," said Dr. Gambacorti in an interview with Medscape Medical News.

At 30 months, 4% of patients in the bosutinib group progressed to accelerated or blast/crisis phase, compared with 6% of those taking imatinib. Overall survival at 30 months was achieved by 97% of patients in the bosutinib group versus 95% in the imatinib group, with 5 of 250 versus 10 of 252 drug-related deaths in each group, respectively.

"The comparator imatinib is a very effective drug, and most patients are well served by it. However, the small number who fail imatinib show a better response to bosutinib," pointed out Dr. Gambacorti.

It is notable that a small proportion of patients could not tolerate bosutinib and discontinued in the first few weeks. "Most discontinued because the physician was unfamiliar with the drug or the management of gastrointestinal effects like nausea and vomiting, but these can be effectively treated."

Because of these dropouts, the trial did not reach its primary endpoint of CCyR at 12 months but did show significant differences in MMR and CMR at 12 months. "The CMR is theoretically the response which could open the door for drug discontinuation," Dr. Gambacorti commented, and he added that no serious adverse toxicity was seen with bosutinib, unlike with other second-generation TKIs.

Reflecting more generally on CMR, Dr. Gambacorti stated that if a patient remained in CMR for an extended time, the patient would be likely to have a normal life expectancy, based on other data on imatinib. "This is the first disease in which we can return a patient to normal life expectancy. Patients on bosutinib with CMR at 24 months may have a similarly positive outlook."

Dr. Gambacorti concluded that bosutinib is most likely to be used in the approximately 20% of patients who do not respond well when taking imatinib. "In patients with a bad prognosis, bosutinib, like other second-generation TKIs, is likely to return over 50% of them to cytogenetic remission," said Dr. Gambacorti. "This is where these drugs are going."

However, he stood by the effectiveness of imatinib as first-line therapy. "It's difficult to beat a Ferrari, especially when it is a Ferrari that does not harm the patient," Dr. Gambacorti commented.

Ponatinib: A T315I Inhibitor

Ponatinib is a third-generation pan-BCR-ABL inhibitor drug. It marks another turning point in the therapeutic history of CML in that, in addition to other cases of refractory CML, it is under investigation for the treatment of patients with the gatekeeper T315I mutation, for which no other drug is currently available.

The study presented at this year's EHA represented patients who had failed treatment with a second-generation drug—dasatinib or niliotinib. Most had failed imatinib too.

"Imatinib, dasatinib, nilotinib, and bosutinib all fail to be effective in patients with the T315I mutation," commented Dr. DeAngelo. "Also, there are other mutations which render nilotinib ineffective, and others which render dasatinib ineffective; however, these mutations are sensitive to ponatinib."

Ariad, the company developing ponatinib, expects to file for regulatory approval of ponatinib in the European Union and in the United States in the third quarter of 2012 for patients who have failed dasatinib and nilotinib; it will also include patients who have the T315I mutation.

At some point in the near future, a randomized clinical trial (RCT) of ponatinib versus imatinib will be conducted in newly diagnosed patients; additional information will be obtained on toxicity profiles, and this will potentially lead to a first-line indication.

Asked where he would envisage using ponatinib if approval is granted, Dr. DeAngelo said, "Ponatinib offers a new approach in patients who fail dasatinib or nilotinib, as we currently have no good alternative option for them. With the exception of low-risk chronic phase CML, I typically use one of the second-generation TKIs as first line in the majority of my patients."

Dr. DeAngelo added that if a patient progressed while receiving imatinib and was found to have a T315I mutation, he would move straight to ponatinib. Mutation analysis still is not recommended in treatment-naïve patients.

Head-to-Head Comparisons

Three head-to-head RCTs have compared the following treatment agents: imatinib and niliotinib, imatinib and dasatinib, and imatinib and bosutinib. This information was presented at EHA.

Commenting on the dasatinib-imatinib trial results (3-year follow-up of the DASISION trial), Dr. DeAngelo said that dasatinib seemed to be better tolerated. "There was, in general, a slightly greater number of patients with pleural effusions in the dasatinib arm, but all other side effects were higher in the imatinib arm. Patients had a more rapid time to response, achieving complete cytogenetic remission on dasatinib, which was almost twice as fast," he said.

Furthermore, he added that more patients on dasatinib achieved an MMR. "On the face of it, dasatinib appears to be superior with these endpoints to imatinib."

Dr. DeAngelo said that the bosutinib BELA trial was powered to look at CCyR, and it was found identical to imatinib, but MMR was better in the bosutinib group. "Bosutinib had a higher MMR and complete molecular response rate, but the endpoint of CCyR was identical at 79% for bosutinib and 80% for imatinib. My assumption is that the drug is more active than imatinib, but CCR rate was the study's primary endpoint, and there was no difference," he said.

Dr. DeAngelo added that more patients experienced diarrhea in the bosutinib than in the imatinib group, but greater numbers of musculoskeletal issues and cases of edema were reported in the imatinib group. "It works in patients who fail imatinib, but also has a different toxicity profile to dasatinib and nilotinib. It would [be] good to have this as another treatment option."

Dr. DeAngelo has disclosed that he sat on the Novartis advisory board and received an honorarium from Ariad. Dr. Gambacorti has received research funding from Pfizer.

FDA clears first new weight-loss pill in 13 years

The Food and Drug Administration has approved Arena Pharmaceutical's anti-obesity pill Belviq, the first new prescription drug for long-term weight loss to enter the U.S. market in over a decade.

Despite only achieving modest weight loss in clinical studies, the drug appeared safe enough to win the FDA's endorsement, amid calls from doctors for new weight-loss treatments.

The agency cleared the pill Wednesday for adults who are obese or are overweight with at least one medical complication, such as diabetes or high cholesterol. The drug should be used in combination with a healthy diet and exercise.

Obesity Society President Patrick O'Neil said he's encouraged by the drug's approval because it underscores the notion that lifestyle changes alone are not enough to treat obesity.

"This is good news because it tells us that the FDA is indeed treating obesity seriously," said O'Neil, who teaches at Medical University of South Carolina and was the lead researcher on several studies of Belviq. "On the other hand, it's not the answer to the problem — or even a big part of the answer."

Even if the effects of Belviq are subtle, experts say it could be an important first step in developing new treatments that attack the underlying causes of obesity.

"The way these things tend to work is you have some people who do extremely well and other people don't lose any weight at all. But if we had 10 medicines that were all different and worked like this, we would have a real field," said Dr. Louis Aronne, director of the weight loss program at Weill-Cornell Medical College.

The FDA denied approval for Arena's drug in 2010 after scientists raised concerns about tumors that developed in animals studied with the drug. The company resubmitted the drug with additional data earlier this year, and the FDA said there was little risk of tumors in humans.

Arena and its partner Eisai Inc. of Woodcliff Lake, N.J., expect to launch the drug in early 2013.

With U.S. obesity rates nearing 35 percent of the adult population, many doctors have called on the FDA to approve new weight loss treatments.

But a long line of prescription weight loss offerings have been associated with safety problems, most notably the fen-phen combination, which was linked to heart valve damage in 1997. The cocktail of phentermine and fenfluramine was a popular weight loss combination prescribed by doctors, though it was never approved by the FDA.

In a rare move, the FDA explicitly stated in a press release that Belviq "does not appear to activate" a chemical pathway that was linked to the heart problems seen with fen-phen.

The FDA said the drug acts on a different chemical pathway in the brain, which is believed to reduce appetite by boosting feelings of satiety and fullness.

Belviq is one of three experimental weight-loss drugs whose developers have been trying for a second time to win approval, after the FDA shot them all down in 2010 or early 2011 because of serious potential side effects.

Vivus Inc.'s Qnexa is thought to be the most promising of the drugs, achieving the most weight loss. But the FDA has delayed a decision on that pill until July.

Shares of San Diego-based Arena Pharmaceuticals Inc. jumped $2.54, or 28.7 percent, to close at $11.39. Shares of Mountain View, Calif.-based Vivus rose $1.94, or 7.4 percent, to $28.33. Shares of Orexigen Therapeutics Inc., the third drugmaker with an obesity pill before the FDA, rose 20 percent to close at $4.92.

Arena's studies showed that patients taking Belviq, known generically as lorcaserin, had modest weight loss. On average patients lost just 3 to 3.7 percent of their starting body weight over a year. About 47 percent of patients without diabetes lost at least 5 percent of their weight or more, which was enough to meet FDA standards for effectiveness. By comparison, average weight loss with Qnexa is 11 percent, with more than 83 percent of patients losing 5 percent of their weight or more.

The FDA said patients should stop taking Belviq after three months if they fail to lose 5 percent of their body weight. Patients are unlikely to see any significant weight loss by staying with the drug.

Side effects with the drug include depression, migraine and memory lapses.

In May a panel of expert advisers to the FDA voted 18-4 to recommend approval of Arena's drug, concluding that its benefits "outweigh the potential risks when used long term" in overweight and obese people.

Experts say the challenge of weight loss drug development lies in safely turning off one of the body's fundamental directives: to eat enough food to maintain its current weight.

While several drugs are available for short-term weight loss, until Wednesday there was only one FDA-approved prescription drug for long-term weight loss: Xenical from Roche, which is seldom prescribed because of unpleasant digestive side effects and modest weight loss. Belviq is the first new prescription drug approved to treat obesity since Xenical's approval 13 years ago.

Other safety failures for diet pills have continued to pile up in recent years.

Four years ago Sanofi-Aventis SA discontinued studies of its highly anticipated pill Acomplia due to psychiatric side effects, including depression and suicidal thoughts. In 2010, Abbott Laboratories withdrew its drug Meridia after a study showed it increased heart attack and stroke.

ALCOHOL MAY TRIGGER AF EPISODES

Results of a new study suggest that patients with paroxysmal atrial fibrillation (PAF) should avoid consuming alcohol to reduce the risk of AF episodes, but the exact link between alcohol and arrhythmias is still poorly understood [1].

Dr Gregory Marcus (University of California, San Francisco) and colleagues previously reported trial results showing that daily consumption of alcohol by patients younger than 60 increases the risk of atrial fibrillation and flutter and that the risk of atrial flutter especially increases with greater alcohol consumption. "It looked like that might be related to a shorter atrial refractory period, which theoretically could have some causal mechanisms related to atrial fibrillation, but there's been very little research on understanding those mechanisms," Marcus toldheartwire .

"There's generally a perception out there that alcohol is good for your heart, but it looks like there's something going on that's probably important and could be detrimental electrically, so that's pertinent to everyone who drinks alcohol. Second, if we could really understand how alcohol triggers atrial fibrillation, we might learn something important about atrial fibrillation itself." He also suggested that this question is "ripe for a randomized study," comparing arrhythmia episodes of patients consuming alcohol with those not consuming alcohol.

Marcus and medical student Mala Mandyman (University of California, San Francisco) are the lead authors of a study, scheduled for the August 1, 2012 issue of the American Journal of Cardiology, comparing the self-reported frequency of PAF episodes in patients with previously documented PAF with the frequency of episodes of patients with other types of supraventricular tachycardia (SVT).

At a single center, 223 patients with a documented arrhythmia (133 with PAF and 90 with SVT) completed a survey detailing their alcohol-consumption pattern and arrhythmia episodes. Episodes were considered triggered by vagal activation if the subject's episodes usually began while the patient was resting or eating or if the symptoms terminated with exercise. If the episode was triggered after the patient was exercising, stressed, or consuming caffeine, the episode was considered triggered by sympathetic activation.

After multivariable adjustment, the patients with PAF had a 4.42 greater odds of reporting alcohol consumption (p=0.014) and a 2.02 greater odds (95% CI 1.02–4.00) of reporting vagal activity (p=0.044) as the arrhythmia trigger compared with patients with SVT. Younger age (odds ratio 0.68, p=0.022) and a family history of AF (OR 5.73, p=0.028) each were independently associated with vagal activation of episodes. Patients with PAF and alcohol triggers were more likely to report vagal triggers of arrhythmias (OR 10.32, p=0.045).

In patients with PAF, beer was the type of alcohol most commonly cited as a trigger (odds ratio 4.49, p=0.011), although the authors note that the questionnaire only asked what type of alcohol the subject drank the most, rather than what they were drinking before each episode. This association may be due to beer drinkers generally drinking more alcohol overall compared with those who prefer wine or spirits, but this association persisted after adjustment for average consumption and bingeing, Mandyam et al point out.

"It does appear that certain patients are more or less prone to alcohol triggering their symptoms. I don't think we know--there are conflicting data from large epidemiological studies--if alcohol actually causes atrial fibrillation," Marcus said. "So there are insufficient data to give a strong recommendation, [but] certainly in people in whom alcohol has triggered atrial fibrillation, I recommend abstinence [in the future]." With everyone else, Marcus advises moderation.

AVOID CHILDHOOD CT SCANS

Children undergoing computed tomography (CT) scans with cumulative radiation doses of about 50 mGy had about triple the risk for leukemia, and those who received doses of about 60 mGy had nearly triple the risk for brain cancer, according to the results of a retrospective cohort study published online June 7 in theLancet.

"We've been doing this particular study for about 8 years, and it's been about 20 years of research at Newcastle on radiation effects," lead author Mark Pearce, PhD, from Newcastle University and Royal Victoria Infirmary, United Kingdom, said in a news conference. "We found that radiation exposure from CT scans in childhood could triple the risk of leukemia and brain cancer."

The study authors note that CT scans are very useful diagnostically, but that children are more radiosensitive than adults and may therefore have additional potential risks for cancer from ionizing radiation. The study goal was to determine the excess risk for leukemia and brain tumors after CT scanning in a cohort of children and young adults.

Youth younger than 22 years and without previous diagnoses of cancer who first underwent CT scanning in National Health Service (NHS) centers in England, Wales, or Scotland between 1985 and 2002 were included in the analysis. The investigators estimated absorbed brain and red bone marrow radiation doses per CT scan in megagrays.

The NHS Central Registry provided data for cancer incidence, mortality, and loss to follow-up from January 1, 1985, to December 31, 2008. Use of Poisson relative risk models allowed assessment of excess incidence of leukemia and brain cancer. To exclude CT scans associated with cancer diagnosis, follow-up for leukemia started 2 years after the first CT, and for brain cancer 5 years after the first CT.

Diagnosis of leukemia during follow-up occurred in 74 of 178,604 patients, and diagnosis of brain tumor in 135 of 176,587 patients. There was a positive association between radiation dose from CT scans and leukemia (excess relative risk [ERR] per mGy, 0.036; 95% confidence interval [CI], 0.005 - 0.120; P = .0097) and brain tumors (ERR, 0.023; 95% CI, 0.010 - 0.049; P < .0001).

Compared with patients who received a radiation dose of less than 5 mGy, those who received a cumulative dose of at least 30 mGy (mean dose, 51.13 mGy) had a relative risk of leukemia of 3.18 (95% CI 1.46 - 6.94). For patients who received a cumulative dose of 50 to 74 mGy (mean dose, 60.42 mGy), the relative risk of brain cancer was 2.82 (95% CI, 1.33 - 6.03).

"Our main findings were confined to children under the age of 15 years, and showed that the risk of brain cancer is tripled with 2 or 3 CT scans, and the risk of leukemia is tripled with 5 to 10 CTs," Dr. Pearce said. He added that the risks vary with age and with radiation exposure of a particular type of CT scan to a given target organ.

Limitations and Implications

The investigators suggest that applying the dose estimates for 1 head CT scan before the age of 10 years would translate into about 1 excess case of leukemia and 1 excess brain tumor per 10,000 patients.

Limitations of this study include the lack of data about the reasons for CTs, exposure to radiography, and other clinical variables.

"The immediate benefits of CT outweigh the potential long­term risks in many settings, and because of CT's diagnostic accuracy and speed of scanning, notably removing the need for anaesthesia and sedation in young patients, it will, and should, remain in widespread practice for the foreseeable future," Dr. Pearce said in a news release. "Further refinements to allow reduction in CT doses should be a priority, not only for the radiology community but also for manufacturers.”

"Alternative diagnostic procedures that do not involve ionizing radiation exposure, such as ultrasound and [magnetic resonance imaging], might be appropriate in some clinical settings," Dr. Pearce concluded. "Of utmost importance is that where CT is used, it is only used where fully justified from a clinical perspective."

In an accompanying comment, Andrew J. Einstein, MD, from New York Presbyterian Hospital and Columbia University Medical Center, New York City, noted that new CT scanners now have dose-reduction options and that clinical awareness is increasing of potential risks from radiation exposure.

"[This study] should reduce the debates about whether risks from CT are real, but the specialty has anyway changed strikingly in the past decade, even while the risk debate continued," Dr. Einstein writes. "Pearce and colleagues confirm that CT scans almost certainly produce a small cancer risk. Use of CT scans continues to rise, generally with good clinical reasons, so we must redouble our efforts to justify and optimise every CT scan."

The US National Cancer Institute and UK Department of Health funded this study. The study authors have disclosed no relevant financial relationships. Dr. Einstein is supported by the US National Heart, Lung, and Blood Institute; a Victoria and Esther Aboodi Assistant Professorship; and the Louis V. Gerstner Jr Scholars Program. He has also received research support from GE Healthcare and Spectrum Dynamics and has been a consultant for Kyowa Hakko Kirin Pharma and the International Atomic Energy Agency.

NORMAL SALINE IS NOT SO NORMAL

In a study from England published ahead of print in Annals of Surgery, healthy volunteers given two liters of so-called "normal" saline intravenously showed signs of decreased kidney perfusion and increased fluid retention compared to infusion of a balanced salt solution. The work builds on previous research suggesting that normal saline, in use intravenously for over 100 years, is not "normal" and may not be the best fluid to use, especially in patients who are susceptible to renal dysfunction.

In an email to Reuters Health, lead author Dr. Dileep N. Lobo of the University of Nottingham said, "Had normal saline been formulated in recent times, it is debatable whether it would have survived a phase 1 trial."

Dr. Lobo's group carried out a randomized, double-blind cross-over trial involving 12 healthy male volunteers who were given two-liter infusions over one hour of either "normal" 0.9% saline or the balanced salt solution Plasma Lyte-148, several days apart. Plasma Lyte-148 contains sodium and chloride in physiologic amounts, compared to the higher amounts of those two ions found in normal saline.

During the four hours following the infusions, subjects underwent sequential blood and urine tests as well as magnetic resonance imaging (MRI) of their kidneys.

The main results: when the men received normal saline, they retained significantly more fluid in the extravascular space (1,484 vs 1,155 mL; p=0.031) and gained more weight (1.2 vs 0.84 kg, p=0.22). With the balanced solution, they produced significantly higher urine volumes and had a significantly shorter time to first voiding.

Furthermore, in the normal saline trials, serum chloride was significantly higher from the first hour on (p=0.0001), and a low strong ion difference indicated acidemia (p=0.025).

MRI showed that normal saline significantly decreased renal artery flow velocity (p=0.045) and renal cortical tissue perfusion (p=0.008) compared to the balanced solution - differences that could matter in patients with kidney disease.

The authors point out that some 200 million liters of normal saline are used in the U.S. every year. The paper doesn't address the issue of costs, but Dr. Lobo said, "Plasma-Lyte 148 is more expensive but this is likely to be because it is not widely used. Just because a product is more expensive does not mean that it should not be used in the clinical setting."

Dr. Lobo pointed out that a paper this year by Shaw et al, also in Annals of Surgery, showed that complications and resource use are less with Plasma-Lyte than with 0.9% saline.

Another inexpensive option, lactated Ringer's solution, has nearly normal amounts of sodium and chloride. Dr. Lobo said, "It is likely that similar results could be achieved with Ringer's lactate, however, we chose Plasma-Lyte 148 as it has a chloride content in the normal physiological range."

Dr. Laurence Weinberg of the Department of Anesthesia, Austin Hospital and Senior Fellow, Department of Surgery, University of Melbourne was not a contributor to the study. Regarding lactated Ringer's, he said, "It contains lactate. In shock conditions if lactate cannot be metabolized by the liver, it will be unable to be converted to bicarbonate. This can also result in elevated lactate levels which, if being used as a marker of effective resuscitation, can lead to misinterpretation of the cause of the hyperlactatemia."

According to Dr. Lobo, "It is clear that many patients continue to receive large quantities of intravenous fluid especially in the perioperative period. We suggest that large quantities of saline may not be beneficial for those with pre-existing renal disease or those at risk of developing renal impairment."

Dr. Lobo thinks that normal saline is not appropriate for use for resuscitation or in the operating room. He said, "There is an increasing body of evidence to suggest that saline may lead to harmful effects. This study, building on evidence first obtained in animal studies, suggests that hyperchloremia associated with saline infusion may have an unfavorable effect on renal perfusion."

Dr. Weinberg said, "For many operations we only use 1000 mL of fluid. Choice of fluid for these cases is less important. However there is now overwhelming evidence that a balanced solution is better than an unbalanced and given that the costs of normal saline and Ringer's lactate are the same I would advocate Ringer's lactate as a preference."

When massive amounts of fluid are needed, however, Dr. Weinberg would advocate Plasma-Lyte 148 over both normal saline and lactated Ringer's solution. He added, "Many critically ill patients do require significant fluid/volume intervention as part of their care; the type and correct amount of fluid patients receive is paramount. The study by Lobo now gives us information that is clinically important, and I am certain that we will see many more studies examining the clinical effects of different fluid solutions."

Dr. Lobo and one other member of his group have received financial support from Baxter Healthcare, maker of Plasma-Lyte 148. Baxter Healthcare also supported the study but did not participate in its conduct or analysis.

Dr. Weinberg's department has received funding from Baxter Healthcare, which has no input or oversight of its research.