Aaron J. Weiss

Nutrition, Bone, and Aging: An Integrative Physiology Approach

Osteoporosis, a condition associated with significant morbidity and mortality, is prevalent in the growing elderly population. Aging is associated with characteristic changes in the complex pathways of bone remodeling and in patterns of food intake. Whereas the traditional focus of nutritional supplementation for protection of bone health has centered around calcium and vitamin D, a multitude of nutrients have been identified with effects on bone, both individually and in combination. An integrative physiology approach can assist in formulating a deeper understanding of the complex interactions of nutrition and aging with bone, with the goal of identifying modifiable risk factors for the prevention of bone loss.

IMPAIRED POSTOPERATIVE HYPERGLYCEMIC STRESS RESPONSE ASSOCIATED WITH INCREASED MORTALITY IN PATIENTS IN THE CARDIOTHORACIC SURGERY INTENSIVE CARE UNIT

OBJECTIVE To describe the association of tight glycemic control with intensive insulin therapy and clinical outcome among patients in the cardiothoracic surgery intensive care unit. METHODS All patients who underwent cardiothoracic surgery and were admitted to the cardiothoracic surgery intensive care unit between September 13, 2007, and November 1, 2007, were enrolled. Clinical and metabolic data were prospectively collected. All patients received intensive insulin therapy using a nurse-driven dynamic protocol targeting blood glucose values of 80 to 110 mg/dL. Four stages of critical illness were defined as follows: acute critical illness (intensive care unit days 0-2), prolonged acute critical illness (intensive care unit 3 or more days), chronic critical illness (tracheotomy performed), and recovery (liberated from ventilator). RESULTS One hundred fourteen patients were enrolled. Seventy-three (64%) recovered during acute critical illness, 26 (23%) recovered during prolonged acute critical illness, and 15 (13%) progressed to chronic critical illness. All 6 deaths were among patients in chronic critical illness. Admission blood glucose and average blood glucose values for the first 12 hours were lower in patients who developed chronic critical illness and died and were higher in patients who developed chronic critical illness and survived (P = .007 and P = .007, respectively). Severe hypoglycemia (blood glucose <40 mg/dL) occurred once (0.03% of all measurements). Lower initial blood glucose values, which reflect an impaired stress response immediately after surgery, were associated with increased mortality, and a significant delay in achieving tight glycemic control with intensive insulin therapy was associated with prolonged intensive care unit course, but no increase in mortality. CONCLUSION The study findings suggest that acute postoperative hyperglycemia and its prompt correction with intensive insulin therapy are associated with favorable outcomes in patients in the cardiothoracic surgery intensive care unit.

The Skeletal Subsystem as an Integrative Physiology Paradigm

Homeostatic bone remodeling depends on precise regulation of osteoblast-osteoclast coupling through intricate endocrine, immune, neuronal, and mechanical factors. The osteoblast-osteoclast model of bone physiology with layers of regulatory complexity can be investigated as a component of a local skeletal subsystem or as a part of a complete whole-body system. In this review, we flip the traditional investigative paradigm of scientific experimentation (“bottom–top research”) to a “top–bottom” approach using systems biology. We first establish the intricacies of the two-cell model at the molecular signaling level. We then provide, on a systems level, an integrative physiologic approach involving many recognized organ-level subsystems having direct and/or indirect effects on bone remodeling. Lastly, a hypothetical model of bone remodeling based on frequency and amplitude regulatory mechanisms is presented. It is hoped that by providing a thorough model of skeletal homeostasis, future progress can be made in researching and treating skeletal morbidities.

Quality of life and survival of septuagenarians and octogenarians after repair of descending and thoracoabdominal aortic aneurysms

OBJECTIVE We assessed quality of life and survival in elderly patients after complex aortic operations to aid in surgical decision making. METHODS A retrospective review was performed of 93 patients who underwent descending thoracic aneurysm or thoracoabdominal aortic aneurysm (TAAA) repair from 2002 to 2008. A Cox model was used for survival analysis. The SF-36 Item Health Survey was administered to assess postoperative quality of life in 39 patients and was compared with age- and gender-matched normal scores. RESULTS The mean age at operation was 75 ± 4.1 years; 51% of patients were male. In-hospital mortality was 15%. One-year survival was 69%, and 5-year survival was 45%. Only acute respiratory distress syndrome was a predictor of in-hospital mortality (hazard ratio = 3.75; P < .01) and 1-year mortality (hazard ratio = 4.61; P < .001). After 1 year, patients enjoyed longevity equivalent to that of a normal age- and gender-matched population (standardized mortality ratio = 1.06; P = .81). Being male is a predictor of long-term survival (hazard ratio = 0.18; P < .05). For women, extremely low and high body mass indexes (quadratic term = 0.020; P < .05) with an inflection point of body mass index of 28 is a risk factor of long-term survival. Quality of life scores were similar to those of the general population except for lower vitality scores, (s-score = -0.67, 95% CI, -1.09 to -0.26). CONCLUSIONS TAAA repair in this selected older surgical population yields acceptable survival beyond the first year. Among 1-year survivors, quality of life is similar to that of an age- and gender-matched population.

A systems approach to bone pathophysiology

With evolving interest in multiscalar biological systems one could assume that reductionist approaches may not fully describe biological complexity. Instead, tools such as mathematical modeling, network analysis, and other multiplexed clinical‐ and research‐oriented tests enable rapid analyses of high‐throughput data parsed at the genomic, proteomic, metabolomic, and physiomic levels. A physiomic‐level approach allows for recursive horizontal and vertical integration of subsystem coupling across and within spatiotemporal scales. Additionally, this methodology recognizes previously ignored subsystems and the strong, nonintuitively obvious and indirect connections among physiological events that potentially account for the uncertainties in medicine. In this review, we flip the reductionist research paradigm and review the concept of systems biology and its applications to bone pathophysiology. Specifically, a bone‐centric physiome model is presented that incorporates systemic‐level processes with their respective therapeutic implications.

Adjuvant Therapy With Methylene Blue in the Treatment of Postoperative Vasoplegic Syndrome Caused by Carcinoid Crisis After Tricuspid Valve Replacement

N INCREASING BODY of literature continues to show the benefits of methylene blue in cases of refractory hypotension caused by the systemic inflammatory response syndrome (SIRS), septic shock, or vasoplegic syndrome. 1,2 Methylene blue, by its indirect inhibition of bradykinin, may alleviate the hypotension associated with carcinoid crisis. The authors report the successful use of methylene blue to treat refractory hypotension in a patient with carcinoid syndrome who underwent a tricuspid valve replacement. CASE PRESENTATION A 74-year-old man was referred for tricuspid valve surgery after being diagnosed with tricuspid insufficiency as a result of carcinoid syndrome. His past medical history was significant for small intestinal carcinoid tumor resection 5 years prior and radiation for liver metastases secondary to carcinoid. His medications included octreotide (200 g subcutaneously, 3 times a day), tamsulosin, folic acid, furosemide, mometasone, and psyllium. His body mass index was 23 kg/m2. A transthoracic echocardiogram performed before surgery revealed severe tricuspid regurgitation, normal biventricular function, the absence of pulmonary hypertension, and thickening of the tricuspid valve leaflets. Before surgery, the patient had been experiencing New York Heart Association class IV symptoms. In addition, he also had complained of flushing and diarrhea over the past 4 months that were being controlled with octreotide. The patient was admitted to the hospital 2 days before surgery and was placed on 300 g of octreotide subcutaneously 3 times a day. On the day of the surgery, he was given his regular 300-g subcutaneous dose of octreotide followed by a 500-g dose subcutaneously 3 hours later. This was all done in an effort to reduce his risk of perioperative carcinoid crisis. The patient was taken to the operating room where general anesthesia was induced, and he was intubated without difficulty. On induction of anesthesia, an octreotride infusion was begun at 100 g/h. He also was given 11 g of the antifibrinolytic -aminocaproic acid during the case. On insertion of his pulmonary artery catheter, he had a baseline central venous pressure (CVP) of 20 mmHg and pulmonary artery pressures (PAP) of approximately 35/18 mmHg. An intraoperative tranesophageal echocardiogram (TEE) was performed that agreed with his preoperative echocardiographic findings. A median sternotomy was performed, and the patient was anticoagulated with 31,000 U of heparin and placed on cardiopulmonary bypass. A tricuspid valve replacement was performed through a right atriotomy. After bypass, the CVP was noted to be 22 mmHg, with PAPs of approximately 35/15 mmHg and systemic blood pressures of approximately 90/60 mmHg. The patient then was started on 100 ng/kg/min of epinephrine (7.7 g/min) and 150 ng/kg/min of norepinephrine (11.5 g/min), and his octreotide infusion was continued at 100 g/h. This resulted in a successful wean from cardiopulmonary bypass. To reverse his anticoagulation, 200 mg of protamine were given over 30 minutes. In the immediate post-bypass period, his CVP lowered to 18 mmHg, and his systemic mean blood pressure was maintained at 65 mmHg with this

Use of inhaled epoprostenol in transition to extubation in a patient after implantation of a ventricular assist device.

a a ULMONARY ARTERY HYPERTENSION (PAH) is a life-threatening condition characterized by an increase in rterial pressure and vascular resistance in the pulmonary cirulation.1 It is defined by a mean pulmonary artery pressure PAP) of more than 25 mmHg at rest or more than 30 mmHg uring exercise.2 PAH may aggravate right-heart failure, which s present in many patients after cardiac surgery requiring ardiopulmonary bypass. This is particularly important in paients who have had placement of a left ventricular assist device LVAD) as the right ventricle benefits from afterload reduction n the pulmonary circulation. Therefore, in these and other ituations, such as orthotopic heart transplant and either singler double-lung transplant, it is beneficial to lower pulmonary ressures by pharmacologic measures. However, treatment ith intravenous (IV) pulmonary vasodilators may reduce sysemic blood pressure as well, leading to systemic hypotension nd may impair coronary perfusion and right-heart perforance. Thus, these patients commonly are treated with inhaled gents such as epoprostenol or nitric oxide postoperatively to educe pulmonary afterload while avoiding reductions in sysemic pressure. To accomplish this, patients must remain intuated until their requirements for inhaled pulmonary vasodilaors decrease and can be safely discontinued. To date, there are no reports published describing extubation f patients before inhaled epoprostenol has been discontinued. e describe a patient who was safely extubated while on nhaled epoprostenol (Flolan; GlaxoSmithKline, Research Tringle Park, NC) after insertion of an implantable LVAD (Jarvik 000; Jarvik Heart Inc, New York, NY) for severe heart failure rom a massive myocardial infarction.

Deep versus mild hypothermia during thoracoabdominal aortic surgery

In 1950, Bigelow et al. (1) demonstrated that hypothermic canines tolerated circulatory exclusion of the heart for longer periods of time than normothermic canines. Shortly thereafter, F. John Lewis applied the ideas of hypothermia clinically by closing an atrial septal defect in a pediatric patient (2). In 1958, Sealy et al. (3) successfully combined hypothermia with cardiopulmonary bypass (CPB) in a wide range of patients undergoing cardiac surgery. Deep hypothermic circulatory arrest (DHCA) was first used in aortic surgery in 1975 in a series of patients undergoing aortic arch replacements (4). Since this time, DHCA has been broadened in its applications to all types of aortic surgery including descending thoracic aortic aneurysms (DTA) and thoracoabdominal aortic aneurysms (TAAA). Launched by these early experiences, hypothermia has become the single most effective tissue preservation adjunct necessary during specific cardiac and aortic surgeries that require reduced or even no blood flow. The rationale behind the use of hypothermia lies in its protective effect on organs via a reduction in metabolic rate and oxygen consumption, preservation of high-energy phosphate storages, and decreased central nervous system excitatory neurotransmitter release (5-7). One study investigating metabolic activity in experimental pigs found the cerebral metabolic rate to be 50% of baseline at 28 °C, 19% at 18 °C, and 11% at 8 °C. Thus, the relationship between cerebral metabolic rate as a function of temperature was exponential with a Q10 (degree of metabolic suppression with a 10 °C drop in temperature) to be approximately 2.46 (8). These findings demonstrated an appreciable temperature-dependent decrease in metabolic activity even between moderate hypothermia (18 °C) and deep hypothermia (8 °C). Later, McCullough and colleagues (9) in an elegant study in humans estimated a similar Q10 of 2.3 by calculating differences in metabolic activity during mild, moderate, and deep hypothermic circulatory arrest. These studies were based off of the clinical observation that return to baseline brain function is possible after cessation of blood flow at normothermia for no longer than five minutes. After a number of studies demonstrated short- and long-term neurological and cognitive dysfunction with longer ischemic times (10-13), this eventually led to the determination that the maximum safe DHCA time was approximately 30 minutes. Although most studies originally centered around the effects of hypothermia on brain tissue, it was soon discovered that acceptable ischemia times differed between organs, and that this difference was due to the baseline inherent ischemic tolerance of the specific organ tissue. Etz et al. (14) demonstrated in pigs that safe ischemic time for the spinal cord is close to that of the brain; however, the spinal cord has a baseline tolerance to ischemia that is about four times longer than that of the brain (20 versus 5 minutes). In other words, take away the baseline difference, and the time-temperature relationship for safe interruption of blood flow is the same for both the brain and the spinal cord. More precise ischemic times have not been borne out of the literature for the abdominal viscera, but clinical experience leads us to believe that the kidneys would have less ischemic tolerance than other intra-abdominal viscera.

Glycemic Control: How Tight in the Intensive Care Unit?

Determining the optimal level of glycemic control in critical illness has proven difficult since the original Leuven study conclusions were published in 2001. Conflicting evidence, scientific methodologies, hospital cultures, and a-priori biases have challenged many clinical practice patterns. Specifically, the prioritization of patient safety has resulted in many practitioners changing from a glycemic control target of 80-110 mg/dL to a more liberal target of 140-180 mg/dL. However, a detailed examination of the evidence can provide a more population-specific glycemic control strategy. This position paper presents an approach for cardiac surgery patients in the intensive care unit (ICU) consistent with extant evidence and real-life variables. We argue that in the cardiac surgery ICU, glycemic targets may be as low as 80-110 mg/dL when formal intensive insulin therapy and nutrition support protocols are used with low rates of hypoglycemia, patient safety mechanisms, properly trained staff, and a supportive hospital administration all in force. Cardiac surgery ICUs that already follow this model may continue with 80-110 mg/dL blood glucose targets, whereas others may advance their blood glucose targets in a stepwise fashion: from 140 to 180 mg/dL to 110-140 mg/dL to 80-110 mg/dL, on the basis of their performance.

Safety of parenteral nutrition in patients receiving a ventricular assist device.

Patients with advanced heart failure and poor nutritional status are predisposed to higher rates of infection, bleeding, and mortality. We have increasingly used perioperative parenteral nutrition (PN) in ventricular assist device (VAD) patients and now report our initial experience. We performed a retrospective review of 43 consecutive patients who received implantable VADs from 2006 to 2009. We compared outcomes for patients receiving PN for >7 days perioperatively vs ⩽7 days. In addition, we compared patients who received preoperative enteral nutrition (EN) with those who did not. Fourteen patients received perioperative PN in addition to EN for >7 days compared with 29 patients who received either PN for ⩽7 days or EN alone. Univariate analysis showed no differences in infection, bleeding, thrombus, stroke, length of stay, or mortality. Multivariate stepwise regression including EN, preoperative PN, Interagency Registry for Mechanically Assisted Circulation score, age, gender, and VAD indication showed that only EN was associated with infection. Prolonged use of perioperative PN appears to be safe and well tolerated in patients undergoing VAD implantation. Preoperative EN, while increasing infection risk, seems to have no harmful effect on survival.