Jacqueline M. Leung

Altering the Intestinal Microbiota during a Critical Developmental Window Has Lasting Metabolic Consequences

Acquisition of the intestinal microbiota begins at birth, and a stable microbial community develops from a succession of key organisms. Disruption of the microbiota during maturation by low-dose antibiotic exposure can alter host metabolism and adiposity. We now show that low-dose penicillin (LDP), delivered from birth, induces metabolic alterations and affects ileal expression of genes involved in immunity. LDP that is limited to early life transiently perturbs the microbiota, which is sufficient to induce sustained effects on body composition, indicating that microbiota interactions in infancy may be critical determinants of long-term host metabolic effects. In addition, LDP enhances the effect of high-fat diet induced obesity. The growth promotion phenotype is transferrable to germ-free hosts by LDP-selected microbiota, showing that the altered microbiota, not antibiotics per se, play a causal role. These studies characterize important variables in early-life microbe-host metabolic interaction and identify several taxa consistently linked with metabolic alterations. PAPERCLIP:

Postoperative myocardial ischemia. Therapeutic trials using intensive analgesia following surgery

Recent data suggest that postbypass and postoperative myocardial ischemia are related to adverse cardiac outcome following myocardial revascularization. Therapeutic trials to suppress postoperative ischemia are warranted. Because anesthetics can suppress a variety of physiologic responses to stress as well as myocardial ischemia intraoperatively, we examined whether use of intensive analgesia in the stressful postoperative period could decrease postoperative ischemia. In 106 patients undergoing elective myocardial revascularization, we standardized the anesthetic prior to bypass (sufentanil 5-10 micrograms/kg [induction] and 4.2-6.0 micrograms.kg-1.h-1 [infusion] supplemented with up to 0.5 mg/kg of diazepam). During bypass, patients were randomly assigned to receive either morphine sulfate (group M, n = 54, up to 2 mg/kg) or sufentanil (group S, n = 52, 1 microgram/kg and 1 microgram.kg-1.h-1). In the intensive care unit (ICU), group M received low-dose analgesia (morphine sulfate 1-10 mg intravenously every 30 min, average dose = 2.2 +/- 2.1 mg/h), while group S continued to receive intensive analgesia (infusion of sufentanil at 1 microgram.kg-1.h-1). Both groups received supplemental midazolam in the ICU (group M = 1.1 +/- 1.1 mg/h; group S = 0.6 +/- 0.6 mg/h; P = 0.01). All analgesic and sedative-hypnotic medications were discontinued at 18 hours following myocardial revascularization. Using continuous two-channel electrocardiographic (ECG) monitoring (CC5 and CM5), we documented and characterized ECG changes consistent with ischemia during the preoperative, intraoperative (pre- and postbypass), and postoperative (on- and off-treatment) periods. The total ECG monitoring time was 8,486 h, averaging 81 h per patient. During the prebypass (anesthetic control) period, groups M and S had a similar incidence, but group S episodes were more severe: maximum ST-segment change (median), S versus M: -1.8 mm versus -1.4 mm (P = 0.04). During the postbypass period, both groups had a similar incidence of ischemia, but episodes in group S were less severe: maximum ST-segment change, S versus M: -1.8 mm versus -2.7 mm (P = 0.0005). During the ICU-on-therapy period, the incidence of ischemic episodes was less in group S patients, and the severity was less: area-under-the-ST-time curve, S versus M: -21 mm.min versus -161 mm.min (P = 0.05). After discontinuation of the drug regimen in the ICU, the incidence and severity of ischemic episodes was similar. The incidence of hypotension, hypertension, and tachycardia was similar in both groups in both the intraoperative and ICU periods.(ABSTRACT TRUNCATED AT 400 WORDS)

Relative importance of preoperative health status versus intraoperative factors in predicting postoperative adverse outcomes in geriatric surgical patients.

OBJECTIVES To determine the prevalence and predictors of adverse postoperative outcomes in older surgical patients undergoing noncardiac surgery. DESIGN Prospective cohort study of consecutive patients undergoing noncardiac surgery in 1997. SETTING A medical school-affiliated teaching community hospital. PARTICIPANTS Patients age 70 and older undergoing noncardiac surgery. Patients presenting for surgery requiring only local anesthesia or monitored anesthesia care were excluded. MEASUREMENTS Potential pre- and intra-operative risk factors were measured and evaluated for their association with the occurrence of predefined in-hospital postoperative adverse outcomes. Univariate predictors of postoperative outcomes were first measured using the chi-square or Fishers exact tests followed by multivariate logistic regression. Odds ratios (OR) with 95% confidence interval (CI), and two-sided P-values were reported. RESULTS Five hundred forty-four consecutive patients were studied. Overall, 21% of patients developed one or more postoperative adverse outcomes and 3.7% died during the in-hospital postoperative period. Of all the adverse outcomes, cardiovascular complications (10.3%) were the leading cause of morbidity, followed by neurological (7.7%) and pulmonary complications (5.5%). By multivariate logistic regression analysis, American Society of Anesthesiologists (ASA) classification (OR = 2.7, CI = 1.6-4.4), emergency surgery (OR = 2.0, CI = 1.1-3.4), and intraoperative tachycardia (OR = 3.8, CI = 1.9-7.6) were the most important predictors of postoperative adverse outcomes. Of all the preoperative physical symptoms and signs, decreased functional status (OR = 3.0, CI = 1.4-6.4) and clinical signs of congestive heart failure (OR = 2.1, CI = 1.1-5.1) were the two most important predictors of postoperative adverse neurological and cardiac outcomes, respectively. The median hospital stay was 4 days. The patients who developed postoperative adverse outcomes had significantly longer median hospital stays (9 days) than those without complications (3 days), (P < .0001). CONCLUSION Our study demonstrates that the postoperative mortality rate in geriatric surgical patients undergoing noncardiac surgery is low. Despite the prevalence of preoperative chronic medical conditions, most patients do well postoperatively. The ASA classification (a reflection of the severity of preoperative comorbidities), emergency surgery, and intraoperative tachycardia increase the odds of developing any postoperative adverse events. Future studies aimed at modifying some of the potentially reversible risk factors, such as preoperative heart function and intraoperative heart rate are warranted.

Prognostic Importance of Postbypass Regional Wall-Motion Abnormalities in Patients Undergoing Coronary Artery Bypass Graft Surgery

Regional wall motion abnormalities (RWMA) detected by intraoperative transesophageal echocardiography (TEE) are thought to be sensitive markers of myocardial ischemia. To assess the prognostic significance of RWMA as compared with other less costly technologies such as electrocardiography (ECG) and hemodynamic measurements [blood pressure (BP) and pulmonary artery (PA) pressure], 50 patients were prospectively studied who were undergoing elective coronary artery bypass graft (CABG) surgery using continuous TEE, ECG (Holter), and hemodynamic measurements during the prebypass, postbypass, and early postoperative intensive care unit (ICU) periods (first 4 h). Echocardiographic and ECG evidence of ischemia was characterized during each of these three periods and related to adverse clinical outcomes (postoperative myocardial infarction, ventricular failure, and cardiac death). Clinicians were blinded to the TEE and ECG information. The prevalence of myocardial ischemia during the perioperative periods was as follows: prebypass, 20% (TEE) versus 7% (ECG); postbypass, 36% (TEE) versus 25% (ECG); ICU 25% (TEE) versus 16% (ECG). Neither prebypass TEE ischemia nor ECG ischemia occurring in any of the three periods predicted adverse outcome. In contrast, postbypass TEE ischemia was predictive of outcome: six of 18 patients with postbypass TEE ischemia had adverse outcomes versus 0 of 32 without TEE ischemia (P = 0.001). Seventy-three percent of the echocardiographic ischemic episodes occurred without acute change (+/- 20% of control) in heart rate, BP, or PA pressure. The authors conclude that: 1) prebypass myocardial ischemia was relatively uncommon, 2) the incidence of ECG and TEE ischemia was highest in the postbypass period, and 3) postbypass RWMA were related to adverse clinical outcome.

The Role of Postoperative Analgesia in Delirium and Cognitive Decline in Elderly Patients: A Systematic Review

Postoperative delirium and cognitive decline are adverse events that occur frequently in elderly patients. Preexisting patient factors, medications, and various intraoperative and postoperative causes have been implicated in the development of postoperative delirium and cognitive decline. Despite previous studies identifying postoperative pain as a risk factor, relatively few clinical studies have compared the effect of common postoperative pain management techniques (IV and epidural) or opioid analgesics on postoperative cognitive status. A systematic search of the PubMed and CINAHL databases identified six studies comparing different opioid analgesics on postoperative delirium and cognitive decline and five studies comparing IV and epidural routes of administering analgesia. Meperidine was consistently associated with an increased risk of delirium in elderly surgical patients, but the current evidence has not shown a significant difference in postoperative delirium or cognitive decline among other more frequently used postoperative opioids such as morphine, fentanyl, or hydromorphone. The available studies also suggest that IV or epidural techniques do not influence cognitive function differently. However, future investigations of sufficient study size and more standardized methods of defining outcomes are necessary to confirm the current findings.

Postoperative Delirium: The Importance of Pain and Pain Management

Postoperative delirium is common in geriatric patients. Few studies have examined events in the postoperative period that may contribute to the occurrence of postoperative delirium. We hypothesized that postoperative delirium is related to postoperative pain and/or pain management strategy. Patients aged ≥65 years who were scheduled for major noncardiac surgery were studied. A structured interview was conducted preoperatively and for the first 3 postoperative days to determine the presence of delirium using the Confusion Assessment Method. The method of postoperative pain management, as well as pre- and postoperative medications for the first 3 days, was collected. Pre- and postoperative pain at rest and with movement was recorded using the Visual Analog Scale. Three hundred thirty-three patients, with a mean age of 74 ± 6 years, were studied. After surgery, 46% of patients developed postoperative delirium. By multivariate logistic regression, age (odds ratio [OR], 2.5; 95% confidence interval [CI] 1.5 to 4.2), moderate (OR, 2.2; 95% CI 1.2 to 4.0) and severe (OR, 3.7; 95% CI 1.5 to 9.0) preoperative resting pain, and increase in level of pain from baseline to postoperative day one (OR, 1.1; 95% CI 1.01 to 1.2) were independently associated with a greater risk for the development of postoperative delirium. In contrast, patients who used oral opioid analgesics as their sole means of postoperative pain control were at decreased risk of developing delirium in comparison with those who used opioid analgesics via IV patient-controlled analgesia technique (OR, 0.4; 95% CI 0.2 to 0.7). These results validate our hypothesis that pain and pain management strategies are important factors related to the development of postoperative delirium in elderly patients.

Effects of Perioperative Dexmedetomidine Infusion in Patients Undergoing Vascular Surgery

Background Dexmedetomidine, a highly selective alpha2 ‐adrenergic agonist, increases perioperative hemodynamic stability in healthy patients but decreases blood pressure and heart rate. The goal of this study was to evaluate, in a preliminary manner, the hemodynamic effects of perioperatively administered dexmedetomidine in surgical patients at high risk for coronary artery disease. Methods Twenty‐four vascular surgery patients received a continuous infusion of placebo or one of three doses of dexmedetomidine, targeting plasma concentrations of 0.15 ng/ml (low dose), 0.30 ng/ml (medium dose), or 0.45 ng/ml (high dose) from 1 h before induction of anesthesia until 48 h postoperatively. All patients received standardized anesthesia and hemodynamic management. Blood pressure, heart rate, and Holter ECG were monitored; additional monitoring included continuous 12‐lead ECG preoperatively, anesthetic concentrations and myocardial wall motion (echocardiography) intraoperatively, and cardiac enzymes postoperatively. Results Preoperatively, there was a decrease in heart rate (low dose 11%, medium dose 5%, high dose 20%) and systolic blood pressure (low dose 3%, medium dose 12%, high dose 20%) in patients receiving dexmedetomidine. Intraoperatively, dexmedetomidine groups required more vasoactive medications to maintain hemodynamics within predetermined limits. Postoperatively, dexmedetomidine groups had less tachycardia (minutes/monitored hours) than the placebo group (placebo 23 min/h; low dose 9 min/h, P = 0.006; medium dose 0.5 min/h, P = 0.004; high dose 2.3 min/h, P = 0.004). Bradycardia was rare in all groups. There were no myocardial infarctions or discernible trends in the laboratory results. Conclusions Infusion of dexmedetomidine up to a targeted plasma concentration of 0.45 ng/ml appears to benefit perioperative hemodynamic management of surgical patients undergoing vascular surgery but required greater intraoperative pharmacologic intervention to support blood pressure and heart rate.

Predicting Adverse Postoperative Outcomes in Patients Aged 80 Years or Older

OBJECTIVE: The identification of reversible factors that are associated with postoperative morbidity in geriatric surgical patients is critical to improving perioperative outcomes in such patients. Our study aimed to compare the relative importance of intraoperative versus preoperative factors in predicting adverse postoperative outcomes in geriatric patients.

Critical Oxygen Delivery in Conscious Humans Is Less Than 7.3 ml O2· kg−1· min−1

Background The “critical” level of oxygen delivery (DO2) is the value below which DO2 fails to satisfy the metabolic need for oxygen. No prospective data in healthy, conscious humans define this value. The authors reduced DO2 in healthy volunteers in an attempt to determine the critical DO2. Methods With Institutional Review Board approval and informed consent, the authors studied eight healthy, conscious volunteers, aged 19–25 yr. Hemodynamic measurements were obtained at steady state before and after profound acute isovolemic hemodilution with 5% albumin and autologous plasma, and again at the reduced hemoglobin concentration after additional reduction of DO2 by an infusion of a &bgr;-adrenergic antagonist, esmolol. Results Reduction of hemoglobin from 12.5 ± 0.8 g/dl to 4.8 ± 0.2 g/dl (mean ± SD) increased heart rate, stroke volume index, and cardiac index, and reduced DO2 (14.0 ± 2.9 to 9.9 ± 2.0 ml O2 · kg−1 · min−1; all P < 0.001). Oxygen consumption (VO2; 3.0 ± 0.5 to 3.4 ± 0.6 ml O2 · kg−1 · min−1;P < 0.05) and plasma lactate concentration (0.50 ± 0.10 to 0.62 ± 0.16 mM;P < 0.05; n = 7) increased slightly. Esmolol decreased heart rate, stroke volume index, and cardiac index, and further decreased DO2 (to 7.3 ± 1.4 ml O2 · kg−1 · min−1; all P < 0.01 vs. before esmolol). VO2 (3.2 ± 0.6 ml O2 · kg−1 · min−1;P > 0.05) and plasma lactate (0.66 ± 0.14 mM;P > 0.05) did not change further. No value of plasma lactate exceeded the normal range. Conclusions A decrease in DO2 to 7.3 ± 1.4 ml O2 · kg−1 · min−1 in resting, healthy, conscious humans does not produce evidence of inadequate systemic oxygenation. The critical DO2 in healthy, resting, conscious humans appears to be less than this value.

The prevalence and predictive value of abnormal preoperative laboratory tests in elderly surgical patients.

Because data to determine which preoperative laboratory tests are important in elderly surgical patients are limited, we performed a prospective cohort study to evaluate the prevalence and predictive value of abnormal preoperative laboratory tests in consecutive patients ≥70 yr old who were undergoing noncardiac surgery. Patients presenting for surgery requiring only local anesthesia or monitored anesthesia care were excluded. Preoperative risk factors and laboratory test results were measured and evaluated for their association with the occurrence of predefined in-hospital postoperative adverse outcomes. In 544 patients, the prevalence of preoperative electrolytes and platelet count abnormalities (<115 ×109/L) was small (0.5%–5%), and abnormal creatinine (>1.5 mg/dL), hemoglobin (<10 g/dL), and glucose (>200 mg/dL) values were 12%, 10%, and 7%, respectively. Univariate predictors for adverse outcome of abnormal sodium and creatinine were not as predictive as ASA classification and surgical risk. By multivariate logistic regression, only ASA classification (>II) (odds ratio [OR], 2.55; 95% confidence interval [CI], 1.56–4.19;P < 0.001) and surgical risk (OR, 3.48; 95% CI, 2.31–5.23;P < 0.001) were significant independent predictors of postoperative adverse outcomes. The prevalence of abnormal preoperative electrolyte values and thrombocytopenia was small and had low predictive values. Although more prevalent, abnormal hemoglobin, creatinine, and glucose values were also not predictive of postoperative adverse outcomes. Routine preoperative testing for hemoglobin, creatinine, glucose, and electrolytes on the basis of age alone may not be indicated in geriatric patients. Rather, selective laboratory testing, as indicated by history and physical examination, which will determine patient’s comorbidities and surgical risk, seems to be indicated.