Medical Devices — Balancing Regulation and Innovation. Part 2

21 September, 2011 (11:46) | Medications | By: Health news

The ASR is a class III device — the FDA’s highest risk classification. Clearance through the 510(k) process is especially inappropriate for such risky devices. Congress envisioned that class III devices would be approved through the more stringent premarket approval (PMA) process, which does require clinical testing, and the Safe Medical Devices Act of 1990 requires that the FDA either use the PMA process for class III devices or reclassify them in a lower-risk category. Despite the clear intent of Congress, high-risk devices continue to slip by this requirement.

On July 20, 2011, the U.S. House Energy and Commerce Subcommittee on Oversight and Investigations held a hearing entitled “Medical Device Regulation: Impact on American Patients, Innovation, and Jobs.” The subcommittee’s chairman, Congressman Cliff Stearns (R-FL), argued that FDA regulation of medical devices is too burdensome, stifles innovation, and drives device manufacturers overseas. But the disastrous outcomes of the use of DePuy ASRs show that rushing untested and potentially dangerous medical devices into the marketplace carries serious risks; our regulators should not be in the business of creating jobs in the manufacture of dangerous devices.

On July 29, 2011, the Institute of Medicine (IOM) released an FDA-commissioned report on the 510(k) clearance process.4,5 The report concluded that it was impossible for 510(k) clearance to assure safety and effectiveness, because it assesses neither, instead establishing only “substantial equivalence” to an existing device. The report therefore recommended that 510(k) clearance be eliminated. In addition, it recommended monitoring medical devices throughout their life cycle, especially during the postmarketing period. Despite its reasonable (and relatively modest) recommendations, the report has been aggressively attacked by the device industry and by politicians from states where device companies are located. In fact, the attacks began even before the report was released, which is highly unusual for an IOM report.

We believe that the IOM report is insightful, judicious, sensible, and long overdue. The 510(k) clearance process was established 35 years ago, and although it may have been a reasonable approach then, it surely is not today. We support the IOM committee’s recommendation that the 510(k) process be replaced with an evaluation of safety and effectiveness. It is important to maintain and encourage innovation in medical devices. But true innovation requires that safety and effectiveness be proven by scientific study in clinical trials.

Unfortunately, the FDA leadership has already suggested that it does not intend to implement this key recommendation of the report, although it may be open to other changes. As the best long-term improvements are contemplated, there are important steps that the agency can take now.

Medical Devices — Balancing Regulation and Innovation

19 September, 2011 (16:01) | Medications | By: Health news

Many Americans benefit from the implantation of medical devices, such as artificial joints and lifesaving defibrillators. Tragically, many also suffer or even die from complications related to medical devices that were never studied in clinical trials before being implanted in patients. As devices have evolved and become more complex, our device-approval system has become incapable of assuring safety and effectiveness. The system we use today was created 35 years ago in an era of much simpler and fewer devices, and it is now outdated.

A recent, but not rare, example provides a cautionary tale about the challenges of ensuring that complex medical devices are both effective and safe. Osteoarthritis of the hip joint is a common and debilitating disorder. Each year, nearly a quarter of a million patients with advanced painful arthritis receive a total hip replacement in the hope that it will restore mobility and improve their quality of life. Conventional artificial hip implants consist of a metal ball inserted into a plastic cup. In 2005, a new metal-on-metal design was introduced in which both components were made from a metal alloy. The design was touted as a major innovation that would improve durability and reduce the risk of hip dislocation — advantages that were especially appealing to younger patients but were never tested.

One metal-on-metal design is the DePuy (Johnson & Johnson) ASR XL Acetabular System, which was introduced into the U.S. market in 2005. The ASR was cleared by a Food and Drug Administration (FDA) process known as 510(k), which refers to the section of the 1976 Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act that created it. Under that section, the criterion for clearance of a new medical device is that it be “substantially equivalent” to an already-marketed device (a “predicate”); clinical data are not required.

The ASR was constructed by borrowing a metal alloy cup from a different hip device known as the ASR Hip Resurfacing System and retrofitting it onto a standard hip implant. The manufacturer successfully made the case that the re-engineered implant was “substantially equivalent” to a predicate device. Its marketing clearance was therefore based not on clinical trials or other clinical data but on bench testing in a laboratory, which was inadequate to simulate the stresses that would be placed on it in patients’ bodies.

It soon became clear that the device failed at the astonishing rate of at least one in eight. According to a recent report presented at the British Hip Society Annual Conference, 21% of these hips have had to be replaced (revised) by 4 years after implantation, and the revision rate rises to 49% at 6 years, as compared with 12 to 15% at 5 years for other devices. Failure appears to be due to erosion of the metal in the articular surfaces and migration of metallic particles into the surrounding tissues and the bloodstream. Thus, the innovation led to tragedy for many patients. Before it was recalled in 2010, the ASR had been implanted in nearly 100,000 patients, and the result was a public health nightmare.

Enrollment and Randomization. Part 3

19 September, 2011 (14:21) | Heart Diseases | By: Health news

Given the complex clinical circumstances of out-of-hospital cardiac arrest, precise control of the time to the first analysis of cardiac rhythm is difficult to achieve. In our trial, the duration of CPR before the first analysis of rhythm did not fall within the assigned target for 36% of the patients. Although this observation raises the question of quality control in training and trial supervision, the participating EMS agencies were high-functioning services with advanced-level paramedics; in addition, they had collected high-quality patient data before the start of the trial, and they made continuous efforts to reinforce performance targets. Thus, although implementation of the protocol was imperfect, it nonetheless represents the degree of precision with which such therapies are likely to be practiced in the clinical setting of out-of-hospital cardiac arrest. Furthermore, despite this limitation, there was very good separation between the two study groups in the duration of CPR, and a variety of data analyses confirmed the primary finding of no significant difference in the outcome between patients who had early rhythm analysis and those who had later rhythm analysis.

Our results indicate that in most cases, the outcome is similar with as few as 30 seconds and as many as 180 seconds of EMS-administered CPR before the analysis of cardiac rhythm. The exception is the case of cardiac arrest witnessed by EMS responders, which was not evaluated in this study and for which rapid defibrillation remains the standard of care.13 Our results also do not address the strategy of immediate analysis of cardiac rhythm without any preceding CPR, since we deliberately insisted on some CPR for the early-analysis group, in the belief that good patient care required cardiopulmonary support while the defibrillator was being prepared.

Exploratory examination of our data suggests that a strategy of brief CPR and early analysis may be more appropriate than longer CPR and later analysis for patients who have received CPR from a bystander before the arrival of professional responders. Conversely, for patients who have not received CPR from a bystander, there is no approach that is clearly advantageous with respect to the time to analysis of rhythm. The 2010 guidelines of the AHA–ILCOR give little direction as to the preferred period of CPR before analysis of cardiac rhythm. Each EMS system should consider its operational situation when deciding on its strategy for initial EMS-administered CPR. We believe that it is important to administer CPR for some period while the defibrillator pads are being applied and that compressions should be of high quality with minimal interruptions.

In conclusion, in a large clinical trial, we evaluated the timing of the analysis of cardiac rhythm during CPR in patients who had an out-of-hospital cardiac arrest that was not witnessed by EMS personnel. We found no difference in the outcome between the EMS strategy of a brief period of CPR before early rhythm analysis and that of a longer period of CPR before delayed rhythm analysis.

Enrollment and Randomization. Part 2

17 September, 2011 (21:42) | Heart Diseases | By: Health news

In this randomized trial, we tested the hypothesis that patients with an out-of-hospital cardiac arrest might benefit from the administration of CPR by EMS personnel for approximately 3 minutes before the first analysis of cardiac rhythm (with delivery of a defibrillator shock as appropriate). We found that there was no significant difference in the rate of survival with satisfactory functional status between the two EMS strategies of a brief period of CPR with early analysis of cardiac rhythm and a longer period of CPR with delayed analysis of rhythm. Subgroup and adjusted analyses also did not show any significant differences in the outcomes between the two study groups. We further explored the relationship between the rate of survival and the actual time to rhythm analysis and found that outcomes did not improve with increasing time to analysis. This finding suggests that there is no advantage of delaying the analysis of cardiac rhythm during EMS-administered CPR. Indeed, the data suggest that there may be a disadvantage of delaying the rhythm analysis in the subgroup of patients with a first rhythm of either ventricular tachycardia or ventricular fibrillation who have received CPR from a bystander. Overall, our data suggest that the administration of 2 minutes of CPR by EMS personnel before the first analysis of rhythm, which was suggested in the 2005 guidelines of the AHA–ILCOR, is unlikely to provide a greater benefit than CPR of shorter duration.
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The hypothesis that a brief period of initial CPR before analysis of cardiac rhythm could be beneficial is based primarily on the concept that a few minutes of chest compressions may increase myocardial perfusion, thus improving the metabolic state of the cardiac myocytes and enhancing the likelihood of successful defibrillation. Several studies in animals with experimentally induced ventricular fibrillation showed that the outcomes with delayed countershock after a period of chest compressions were better than the outcomes with earlier countershock, whereas other studies failed to show a benefit of CPR before shock. Five previous clinical studies also attempted to evaluate this issue, but all five had limitations involving the design or sample size, and none had findings that were definitive. Cobb et al., in a before-and-after study, showed that the rate of survival increased after the implementation of a policy that required 90 seconds of CPR before analysis of cardiac rhythm when an automated external defibrillator was used. Wik et al. conducted a randomized trial and found no significant difference between the outcomes after immediate defibrillation and those after 3 minutes of basic CPR before defibrillation, but the outcomes in a subgroup with response times exceeding 5 minutes were better after initial CPR than after immediate defibrillation. Randomized trials reported by Jacobs et al. and Baker et al. showed no significant difference in outcomes with early as compared with late defibrillation. Bradley et al. performed an observational analysis and found that CPR by EMS personnel for 46 to 195 seconds before defibrillation was weakly associated with an improved rate of survival.

Enrollment and Randomization

17 September, 2011 (17:31) | Heart Diseases | By: Health news

The first site commenced the run-in phase in June 2007. All the sites stopped enrollment in November 2009, when the data and safety monitoring board recommended that the trial be stopped early because continuing recruitment was unlikely to change the outcome of the study. Of 13,460 patients screened, 10,365 were enrolled, and 10,153 underwent randomization. Of these, 195 were excluded from the data analysis when their cardiac arrest was confirmed to be due to drowning, strangulation, or electrocution, and 25 were excluded because the outcome with respect to the primary end point was unknown. Thus, 9933 patients were included in the primary data analysis.

Characteristics of the Two Study Groups

The early-analysis group comprised more patients than the later-analysis group (5290 vs. 4643) owing to early termination of the trial. The two study groups were evenly balanced with respect to baseline characteristics except that there were small group imbalances in the distribution of patients across sites; however, these would not have any appreciable effect on the results because of the cluster-crossover design, which yields treatment comparisons within clusters. Not all the scheduled cluster crossovers had occurred at the time of termination, although each cluster had crossed over at least once.

The median time to the analysis of cardiac rhythm was 42 seconds (interquartile range, 27 to 80) in the early-analysis group and 180 seconds (interquartile range, 151 to 190) in the later-analysis group. A majority of patients in each group received rhythm analysis within the targeted range for that group: 68% of patients in the early-analysis group received analysis of cardiac rhythm within the targeted range of 0 to 60 seconds and 60% of patients in the later-analysis group received analysis of cardiac rhythm within the targeted range of 150 to 210 seconds.

Primary and Secondary Outcomes

A total of 310 patients in the early-analysis group (5.9%) and 273 patients in the later-analysis group (5.9%) survived to hospital discharge with a modified Rankin score of 3 or less, with a cluster-adjusted difference between later cardiac analysis and early cardiac analysis of −0.2 percentage points. There was also no significant difference between the study groups with respect to any of the secondary outcomes. An analysis adjusted for potential confounders evaluated the effect of study group on survival and showed a difference of −0.3 percentage points (95% CI, −1.3 to 0.7) between later cardiac analysis and early cardiac analysis (P=0.61).

When the outcomes were analyzed on an as-treated basis, the rates of survival with satisfactory functional status were 6.0% among the 3982 patients in whom the analysis of cardiac rhythm was performed between 0 and 60 seconds and 5.9% among the 3115 patients in whom the analysis of cardiac rhythm was performed between 150 and 210 seconds (P=0.97). In an additional exploratory analysis, we evaluated the rate of survival as a function of the actual time to the first rhythm analysis, regardless of the study group. The chance of survival with satisfactory functional status did not improve with increasing time to the first analysis of cardiac rhythm, and among patients with an initial rhythm of ventricular tachycardia or ventricular fibrillation who received CPR from a bystander, the rate of survival tended to decline with increasing time to the first rhythm analysis.

Outcome Measures and Statistical Analysis

15 September, 2011 (18:03) | Heart Diseases | By: Health news

Outcome Measures

The primary outcome was survival to hospital discharge with satisfactory functional status, defined as a score of 3 or less on the modified Rankin scale. This is a validated scale, ranging from 0 to 6, that is commonly used for measuring the performance of daily activities by people who have had a stroke. Lower scores represent better performance; scores of 4 or higher represent severe disability or death. Secondary outcomes were survival to discharge, survival to hospital admission, and return of spontaneous circulation at the time of arrival at the emergency department.

Statistical Analysis

We estimated that with enrollment of 13,239 patients who could be evaluated, the study would have 99.6% power to detect an improvement in the primary outcome from 5.4% with early analysis of heart rhythm to 7.4% with later analysis, assuming a group-sequential stopping rule at a two-sided alpha level of 0.05 with up to three interim analyses (O’Brien–Fleming boundaries). This calculation took into consideration the concurrent ITD portion of the trial, which required the enrollment of 14,154 patients who could be evaluated, in order to have 90% power to detect a 25% difference in the outcome between the two groups in that trial.

Analyses of the primary and secondary effectiveness outcomes were performed on the basis of a modified intention-to-treat principle with data from eligible patients in whom the cardiac arrest was not due to drowning, strangulation, or electrocution and for whom the primary outcome was known. An independent data and safety monitoring board reviewed the data at prespecified intervals and used a group-sequential stopping rule. The primary analysis compared the outcomes between the groups with the use of the Wald statistic for the treatment group in a generalized linear mixed model. The model included random effects for each of the clusters, accommodated the binary distribution of the outcome variable, and used a linear-link function to estimate an absolute difference in risk.

The between-group difference in the primary outcome, adjusted for baseline characteristics, was calculated with the use of a multiple linear regression model, with robust standard errors to accommodate clustering and the binary distribution of the outcome. Analyses of binary secondary outcomes and subgroup analyses were performed with the use of generalized-estimating-equation models to estimate differences in risk. Mean scores on the modified Rankin scale were compared between the two treatment groups with the use of a linear model.

We conducted further exploratory analyses of the data using kernel density estimators to estimate the distribution of time from the start of CPR to the actual analysis of cardiac rhythm, separately within treatment groups. The association between the primary outcome and the time of cardiac-rhythm analysis was explored with the use of smoothing splines, and confidence intervals were computed with the use of the bootstrap method.

Early versus Later Rhythm Analysis in Patients with Out-of-Hospital Cardiac Arrest. Part 2

15 September, 2011 (10:02) | Heart Diseases | By: Health news

The protocol was approved by the institutional review or research ethics boards at each participating site. The trial protocol, including the statistical analysis plan, is available at All the authors vouch for the completeness and accuracy of the data and the analyses and for the fidelity of the study to the trial protocol.
Study Setting and Population

The trial was conducted at 150 of the 260 EMS agencies participating in the ROC. The trial agencies were selected because they had the capability to provide advanced cardiac life-support interventions and to record CPR process measures and because they met prespecified quality criteria during an initial run-in phase.

We included all persons 18 years of age or older who had an out-of-hospital cardiac arrest that was not the result of trauma and who were treated with defibrillation, delivery of chest compressions, or both by EMS providers. Persons were excluded if the arrest was witnessed by EMS personnel; if they had a blunt, penetrating, or burn-related injury; if the arrest was due to exsanguination; if they were pregnant; if they were prisoners; if they had an “opt-out” bracelet, indicating that they wished to opt out of the study; if they had “do not attempt resuscitation” orders; if the rhythm analysis was performed by police or a lay responder; or if they received initial treatment by an EMS agency that was not in the ROC. Patients were not required to provide informed consent; according to the regulations of the Food and Drug Administration and the Canadian Tri-Council agreement, this study qualified for exception from the requirements for informed consent because it involved research conducted during an emergency situation.

Each of the 10 participating ROC centers (or sites) was divided into approximately 20 subunits, designated as “clusters,” according to EMS agency or geographic boundaries or according to defibrillator device, ambulance, station, or battalion. Randomization of clusters was stratified according to site. All episodes of cardiac arrest in a cluster were randomly assigned to one CPR strategy; after a set period of time, ranging from 3 to 12 months, all episodes in that cluster were then assigned to the other strategy. All the clusters were assigned to cross over to the other strategy one or more times during the study at fixed intervals; we estimated that approximately 100 patients would be included during each interval.
Study Intervention

Patients in the early-analysis group were assigned to receive 30 to 60 seconds of chest compressions and ventilations (sufficient time to place defibrillator electrodes) before electrocardiographic (ECG) analysis, and those in the late-analysis group were assigned to receive 3 minutes of chest compressions and ventilations before ECG analysis. The assigned intervention was implemented by the first qualified EMS provider to arrive at the scene (defibrillation-capable firefighter, emergency medical technician, or paramedic). The start and stop times for CPR were recorded by the responders, and the information was supplemented by the recording of defibrillator time.

The training of participating EMS providers emphasized uninterrupted chest compressions except for required ventilations, with compressions and ventilations applied in a 30:2 ratio, and specified that advanced airway devices were to be placed with minimal interruptions to compressions. Every 6 months, the EMS providers underwent some retraining that included written reminders, slide presentations, and Web-based modules. All ROC sites implemented high-quality electronic monitoring of the CPR process with the use of defibrillator hardware and software. Adherence to the protocol-specified performance targets and to the requirements for data submission was monitored throughout the study by a study monitoring committee, which provided regular feedback to sites.

Early versus Later Rhythm Analysis in Patients with Out-of-Hospital Cardiac Arrest

14 September, 2011 (21:44) | Heart Diseases | By: Health news

Out-of-hospital cardiac arrest is a common and lethal problem, leading to an estimated 330,000 deaths each year in the United States and Canada. Overall, the rate of survival to hospital discharge among patients with an out-of-hospital cardiac arrest who are treated by emergency medical services (EMS) personnel is low but varies greatly, with rates ranging from 3.0% to 16.3%. This variation in the rate of survival can be attributed partly to local variations in the five key links in the chain of survival: rapid EMS access, early cardiopulmonary resuscitation (CPR), early defibrillation, early advanced cardiac life support, and effective care after resuscitation. Concerted efforts by EMS personnel to strengthen these links have led to only a slight increase in survival rates in recent years.
The traditional approach to out-of-hospital cardiac arrest has been to emphasize early analysis of cardiac rhythm, with delivery of defibrillatory shocks, if indicated, as quickly as possible. It has been suggested, however, that many patients may benefit from a period of CPR before the first analysis of rhythm. The 2005 resuscitation guidelines from the American Heart Association–International Liaison Committee on Resuscitation (AHA–ILCOR) departed from its previous “shock first” strategy by suggesting that responders could provide 2 minutes of CPR before analysis of cardiac rhythm. These changes in the guidelines are supported by the findings of three clinical studies but are not supported by two others, and in the 2010 guidelines, the recommendation was modified to say that “there is inconsistent evidence to support or refute” such a delay in the analysis of cardiac rhythm. Therefore, the preferred initial approach remains uncertain. Our objective was to compare two approaches to the timing of CPR by EMS personnel — a brief period of manual chest compressions and ventilations with prompt initiation of rhythm analysis and defibrillation (early analysis) versus a longer period of compressions and ventilations before the first analysis of cardiac rhythm (later analysis).

Study Design and Oversight

A detailed description of the methods has been published previously. The Resuscitation Outcomes Consortium (ROC) is a clinical trial consortium comprising 10 U.S. and Canadian universities and their regional EMS systems. The ROC investigators designed the Prehospital Resuscitation Impedance Valve and Early Versus Delayed Analysis (ROC PRIMED) trial to study two randomized comparisons. The first comparison, in which early analysis of cardiac rhythm was compared with later rhythm analysis, is the subject of this article. The second, concurrent comparison, in which the use of an impedance threshold device (ITD) was compared with the use of a sham ITD, is reported elsewhere in this issue of the Journal. Most patients were enrolled simultaneously in both the early-analysis-versus-later-analysis component and the active-ITD-versus-sham-ITD component of the ROC PRIMED trial, although the two components had slightly different eligibility criteria.

A Problem in Gestation. Commentary – Part 2

14 September, 2011 (10:42) | Diseases | By: Health news

The approach to the management of hyperparathyroidism during pregnancy varies, depending on the presence or absence of symptoms and their severity; the gestational age; and the patient’s preference. Conservative management with watchful waiting is often most reasonable for patients with mild, asymptomatic hypercalcemia (i.e., calcium levels that are slightly about the normal range for pregnancy). Increased oral intake of salt and fluids is recommended to prevent volume depletion. In more severe cases, intravenous hydration with isotonic saline is warranted; furosemide promotes urinary calcium excretion and may help in the treatment of patients with initial hypercalcemia, but it should be used only after volume repletion. Calcitonin, which is classified by the Food and Drug Administration as a category C medication for pregnant patients (i.e., a medication for which animal studies have shown an adverse effect on the fetus, but no adequate, well-controlled studies have been conducted in humans; potential benefits may warrant use of the drug in pregnant women despite potential risks), may bring about rapid reductions in calcium levels when administered intravenously or intramuscularly, but it is not a viable option for prolonged treatment, since tachyphylaxis rapidly develops. Bisphosphonates cross the placenta and are contraindicated in pregnancy owing to concern about their interference with fetal bone development.

Parathyroidectomy is the only definitive therapy and is generally recommended for cases of symptomatic and severe hypercalcemia. The second trimester is generally preferred for surgery, but for patients in whom medical management is ineffective, surgical intervention may be necessary irrespective of the stage of gestation. In all cases of maternal hyperparathyroidism, neonates should be followed closely for evidence of hypocalcemia resulting from suppression of PTH production by the neonatal parathyroid gland, which may not appear until several hours after delivery.

This case underscores the need to consider a broad differential diagnosis for problems in pregnancy and to interpret laboratory tests in the context of the complex metabolic alterations associated with pregnancy. In this patient, back and abdominal pain proved to be attributable to pancreatitis, which was probably caused by hypercalcemia associated with hyperparathyroidism. The detection of hypercalcemia and an inappropriately “normal” intact PTH level led to the identification of primary hyperparathyroidism, and surgical intervention in the second trimester resulted in a good outcome for both mother and infant.

A Problem in Gestation. Commentary

9 September, 2011 (23:52) | Diseases | By: Health news

An association between hyperparathyroidism and an increased prevalence of hypertension has been reported in nonpregnant patients, but the mechanism has not been identified. The effects of parathyroidectomy on blood-pressure levels in such patients have been inconsistent.


Primary hyperparathyroidism occurs rarely during pregnancy — the true incidence is unknown. Since many cases are asymptomatic, they are not recognized in pregnant patients. In addition, pregnancy is associated with alterations in the levels of calcium and calcitropic hormones such as PTH, which may obscure the hyperparathyroidism. In this case, the presence of hypercalcemia was an important clue — a finding that was in clear contrast to the reduction in total serum calcium levels expected in pregnancy.

The morbidity associated with primary hyperparathyroidism during pregnancy is substantial, with complications reported in up to 67% of affected mothers and 80% of fetuses and neonates, usually in the presence of severe hypercalcemia (an increase in calcium levels of approximately 2 mg per deciliter [0.5 mmol per liter] or more above the normal range for pregnancy). Fetal complications associated with maternal hyperparathyroidism include restriction of intrauterine growth, low birth weight, preterm delivery, stillbirth, miscarriage, and neonatal tetany. The maternal complications are similar to those seen outside of pregnancy, including nephrolithiasis, pancreatitis, bone disease, changes in mental status, and hypercalcemic crisis. Pancreatitis during pregnancy is rare, occurring in 0.03% of pregnancies.8 Whereas some reports — most of them based on case series — have suggested an association between primary hyperparathyroidism and pancreatitis, a community-based study showed no increase in the incidence of pancreatitis among patients with primary hyperparathyroidism as compared with matched controls.

An understanding of the normal pregnancy-induced alterations in levels of calcium and vitamin D is important in the assessment of a patient with hypercalcemia in pregnancy. During pregnancy, calcium is shunted from the maternal circulation to the fetus, in order to mineralize the developing fetal skeleton. The fetal calcium demand increases primarily in the third trimester, but the maternal adaptations to meet this demand start early in pregnancy. Maternal shunting of calcium to the fetus may contribute to relative maternal hypocalcemia, but the reduction in total maternal serum calcium levels observed in pregnancy is mainly a reflection of a decrease in serum albumin levels and, consequently, a decrease in the albumin-bound fraction of calcium; ionized calcium levels remain in the normal range during pregnancy. Longitudinal measurements of intact PTH levels have revealed decreases to the low-to-normal range during early pregnancy, with a subsequent increase to the midnormal range by term.

A major maternal adaptation to the increased fetal calcium demand is increased intestinal absorption of calcium, mediated by an increase in 1,25-dihydroxyvitamin D levels. Maternal 1,25-dihydroxyvitamin D levels increase early in pregnancy and remain about twice as high as prepregnancy levels throughout pregnancy. The increase is attributed to PTH-independent up-regulation of 1α-hydroxylase in the maternal kidneys, with the placenta, decidua, and fetal kidneys possibly contributing additional amounts. The glomerular filtration rate also increases during pregnancy, as does urinary calcium excretion; the increased calcium excretion is probably a response to the increased intestinal absorption of calcium. Urinary calcium levels are commonly two to three times as high as they are in nonpregnant women and may be in a range that would be frankly hypercalciuric for nonpregnant women. PTH-related protein stimulates placental calcium transport in the fetus14 and may also have a role in protecting the maternal skeleton. Calcitonin may play a role in protecting the maternal skeleton from increased resorption.

A Problem in Gestation. Part 4

9 September, 2011 (23:12) | Diseases | By: Health news

Instructions were given for the patient to receive nothing by mouth, and she was treated with intravenous hydration, furosemide, and nasally administered calcitonin, with improvement in her calcium levels to a range of 1.32 to 1.38 mmol of ionized calcium per liter. Her pain subsided. Levels of amylase and lipase gradually fell. Methyldopa was discontinued, since pancreatitis is a rare side effect of this treatment. Treatment with oral labetalol was started for blood-pressure control. Fetal well-being was monitored by tracking the fetal heart rate, performing daily ultrasound examinations, and checking biophysical profiles, which remained normal.

It is likely that the patient’s hyperparathyroidism led to her pancreatitis. Her history of nephrolithiasis suggests that hypercalcemia may have been present for years. Although her symptoms have subsided and her calcium levels have improved, she continues to have mild hypercalcemia and is at risk for worsening hypercalcemia and attendant pregnancy-associated complications, including intrauterine growth retardation, preterm delivery, intrauterine fetal death, and neonatal tetany. Consequently, surgery should be considered in this patient. Preoperative imaging for identification and localization of an adenoma will reduce the duration and invasiveness of surgery. Since sestamibi scanning is contraindicated during pregnancy, ultrasonography of the neck would be the preferred imaging technique. After further abatement of the pancreatitis, when the patient could tolerate oral intake, she underwent parathyroid exploratory surgery and resection of a left lower parathyroid adenoma under general anesthesia, without complications. Blood samples were obtained from the internal jugular vein before and 10 minutes after resection of the adenoma, and analysis showed that the PTH level decreased from 344 to 60.7 pg per milliliter.
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The majority of cases of primary hyperparathyroidism are caused by solitary parathyroid adenomas. Intraoperative PTH monitoring takes advantage of the short half-life of PTH in plasma (3 to 4 minutes) and the availability of a rapid assay for PTH. A reduction in PTH levels of more than 50% is considered to be an indicator of successful removal of the adenoma. Postoperative monitoring of this patient’s serum calcium levels should be continued.

After resection, the patient’s serum calcium levels normalized and remained normal for the duration of her pregnancy. Maintenance doses of 600 mg of calcium carbonate with 200 IU of vitamin D twice daily were prescribed, in addition to 400 IU of vitamin D3 daily. The amylase and lipase levels gradually normalized. The patient remained in the hospital for continued monitoring because of mild preeclampsia. Labor was induced at 37.5 weeks’ gestation, after her blood pressure rose further, to 152/104 mm Hg, despite the administration of labetalol. She delivered a healthy girl by means of cesarean section, which was performed because of the failure of labor to progress. The postpartum serum calcium levels remained normal. After a course of 50,000 units of ergocalciferol weekly for 8 weeks, the 25-hydroxyvitamin D level increased to 30 ng per milliliter. The patient had persistent postpartum hypertension, requiring the continuation of antihypertensive therapy, but was otherwise well.

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