Mark A. Young

The child health epidemiology reference group reviews of the effectiveness of interventions to reduce maternal, neonatal and child mortality

This article consists of a short introduction to the reviews presented in this series. It focuses on the contribution of the work of the Child Health Epidemiology Reference Group (CHERG) to the Lives Saved Tool (LiST) through the development of estimates of key inputs to the model. These include previously estimated country-specific distribution of the main causes of under-5 deaths and of the proportion of these deaths that can be averted by specific interventions (affected fraction), along with the newly estimated efficacy/effectiveness of child survival interventions that are presented in detail in individual papers in this volume. This series reflects our efforts to make all data, materials and methods used in the estimation of parameters fully available and transparent.

Oxidation and haem loss kinetics of poly(ethylene glycol)-conjugated haemoglobin (MP4): dissociation between in vitro and in vivo oxidation rates

Haemoglobin-based oxygen carriers can undergo oxidation of ferrous haemoglobin into a non-functional ferric form with enhanced rates of haem loss. A recently developed human haemoglobin conjugated to maleimide-activated poly(ethylene glycol), termed MP4, has unique physicochemical properties (increased molecular radius, high oxygen affinity and low cooperativity) and lacks the typical hypertensive response observed with most cell-free haemoglobin solutions. The rate of in vitro MP4 autoxidation is higher compared with the rate for unmodified SFHb (stroma-free haemoglobin), both at room temperature (20-22 degrees C) and at 37 degrees C (P<0.001). This appears to be attributable to residual catalase activity in SFHb but not MP4. In contrast, MP4 and SFHb showed the same susceptibility to oxidation by reactive oxygen species generated by a xanthine-xanthine oxidase system. Once fully oxidized to methaemoglobin, the rate of in vitro haem loss was five times higher in MP4 compared with SFHb in the fast phase, which we assign to the beta subunits, whereas the slow phase (i.e. haem loss from alpha chains) showed similar rates for the two haemoglobins. Formation of MP4 methaemoglobin in vivo following transfusion in rats and humans was slower than predicted by its first-order in vitro autoxidation rate, and there was no appreciable accumulation of MP4 methaemoglobin in plasma before disappearing from the circulation. These results show that MP4 oxidation and haem loss characteristics observed in vitro provide information regarding the effect of poly(ethylene glycol) conjugation on the stability of the haemoglobin molecule, but do not correspond to the oxidation behaviour of MP4 in vivo.

Acute lung injury in critical neurological illness

Objective: Acute lung injury and acute respiratory distress syndrome have been reported in a significant proportion of patients with critical neurologic illness. Our aim was to identify risk factors for acute lung injury/acute respiratory distress syndrome in this population. Design: Prospective, observational study. Setting: A 22-bed, adult neurosciences critical care unit at a tertiary care hospital. Patients: Primary neurologic disorder, mechanical ventilation >48 hrs. Interventions: None. Measurements and Main Results: A total of 192 patients were enrolled with a range of neurologic disorders. Among these, 68 (35%) were diagnosed with acute lung injury/acute respiratory distress syndrome. In a multivariate logistic regression analysis, independent risk factors for acute lung injury/acute respiratory distress syndrome were pneumonia (odds ratio [95% confidence interval] 3.12 [1.5–6.0], p = .002), circulatory shock (2.2 [1.07–4.57], p = .03), and absence of a gag or cough reflex (3.41 [1.34–8.68], p = .01). Neither neurologic diagnosis nor neurologic severity, assessed with the Glasgow Coma Scale, was significantly associated with the development of acute lung injury/acute respiratory distress syndrome. Conclusion: Acute lung injury/acute respiratory distress syndrome occurred in more than one third of mechanically ventilated neurosciences critical care unit patients. Loss of the cough or gag reflex is strongly predictive of acute lung injury/acute respiratory distress syndrome, while neurologic diagnosis and Glasgow Coma Scale are not. Lower brainstem dysfunction, a clinical marker of neurologic injury not captured by the Glasgow Coma Scale, is a risk factor for acute lung injury/acute respiratory distress syndrome and could inform decisions regarding airway protection and mechanical ventilation.

Effect of maleimide-polyethylene glycol hemoglobin (MP4) on hemodynamics and acid-base status after uncontrolled hemorrhage in anesthetized swine: comparison with crystalloid and blood.

BACKGROUND Maleimide-polyethylene glycol hemoglobin, 4.3 g/dL (MP4), is a hemoglobin-based oxygen carrier consisting of native human hemoglobin modified with maleimide polyethylene glycol. This study evaluated resuscitation with MP4 after uncontrolled hemorrhage in anesthetized swine, and compared the effects of MP4 alone with those of standard-of-care crystalloid or crystalloid + blood. METHODS Pigs were anesthetized with isoflurane and hemorrhaged 250 mL by controlled withdrawal, which was followed by a 5-mm tear in the abdominal aorta. Three groups of pigs (n = 7 each) were randomized after aortic tear to receive 500 mL of MP4, unlimited Ringers acetate (RA), or 2 L of RA + 250 mL of autologous blood. Measurements included arterial and pulmonary artery pressures, central venous and pulmonary capillary wedge pressures, cardiac output, renal blood flow, urine output, arterial and venous blood gases, lactate concentration, and hemoglobin. Animals were monitored for 150 minutes after hemorrhage. RESULTS Average body weight (22-24 kg) and hemorrhage volume (28-34 mL/kg) were similar in the three groups. The nadir of mean arterial pressure (23-25 mm Hg) and base excess (-3 to -4 mEq/L) after hemorrhage were similar in all groups, indicating equivalent shock in the three groups. Two hours after administration of MP4, arterial pressure and base excess were significantly improved compared with those of animals administered RA or RA + blood, despite a significantly lower volume of infused fluids (MP4 = 36 +/- 2 mL/kg; RA = 224 +/- 28 mL/kg; RA + blood = 110 +/- 10 mL/kg), and a significantly lower total hemoglobin than achieved with RA + blood. Arterial pressure did not rise above baseline values, cardiac output was not diminished, and systemic vascular resistance was unchanged after administration of MP4, indicating the lack of cardiac effects or peripheral vasoconstriction. CONCLUSIONS These data demonstrate that resuscitation with a small volume of MP4 induces recovery from hemorrhage without vasoconstriction. Overall, the effects of MP4 alone on hemodynamic and acid-base indices appear to be of greater benefit than those observed with a large volume of RA alone or RA + blood.

Chief residency in PM&R : A balance of education and administration

The role of the Physical Medicine and Rehabilitation (PM&R) chief resident (CR) in physiatry residency education programs is the subject of annual deliberation in many academic centers. A national survey of PM&R programs was conducted to determine CR number, selection method, responsibilities, duration of service, and postresidency destiny. The questionnaire generated a response rate of 86% with 90% of programs reporting 1-3 CRs per year. A range of 1-11 CRs were selected annually per program. The most common methods of CR selection were faculty vote (45%), combined resident-faculty vote (22%), and other (33%). The prevalence of administrative responsibilities included orienting new residents (97%), formulating call schedules (92%), dispute mediation (88%), medical student-residency interviews (87%), rotation schedule configuration (64%), faculty meeting participation (61 %), social event promotion (59%), and elective and externship schedule development (31 %). Educational duties included teaching and organizing didactics (87%), organizing pharmaceutical and rehabilitation equipment inservices (77%), arranging didactics (77%), board review coordination (72%), arranging grand round speakers (66%), core curriculum lectures (61%), and facilitating resident research (37%). CR career goals included group practice (48%), academic faculty (29%), solo practice (5%), and fellowship (18%). Overall, PM&R CRs maintain considerable involvement in the educational aspects of residency training, although their clinical and administrative duties predominate. Although the PM&R CRs contribute significantly to the academic growth and development of their respective training programs, only a modest percentage (47%) of CRs choose to remain in academic physiatry via an attending (29%) or fellowship (18%) position.

Hemospan Improves Outcome in a Model of Perioperative Hemodilution and Blood Loss in the Rat: Comparison With Hydroxyethyl Starch

OBJECTIVES Hemospan (Sangart Inc, San Diego, CA) (MP4) is a hemoglobin-based oxygen carrier consisting of human hemoglobin modified with polyethylene glycol. This study evaluated the effects of MP4 on blood volume, hemodynamics, and metabolic stability in a rat model of hemodilution and hemorrhage. MP4 was compared with hydroxyethyl starch solutions of differing concentrations (ie, HES 260/0.45 and HES 130/0.4). DESIGN An open-label, randomized comparison of treatments. SETTING Pharmaceutical industry. PARTICIPANTS Sprague Dawley rats. INTERVENTIONS Rats underwent 50% hemodilution with one of the solutions. Control rats were not hemodiluted. Blood volume was determined at baseline and 0, 60, and 120 minutes after exchange. In separate groups, hemodilution and subsequent 60% hemorrhage were examined to determine effectiveness of hemodilution. MEASUREMENTS AND MAIN RESULTS Endpoints were blood volume after hemodilution and survival, hemodynamics, and acid-base status during hemorrhage. Volume expansion was similar with MP4 (159% of infused volume) and HES 260/0.45 (145%) and less with HES 130/0.4 (104%). The duration of expansion was longest with MP4 (1-2 hours). In the hemorrhage studies, 2-hour survival was 90% with MP4, 50% with controls, and 10% and 0% with HES 260/0.45 and HES 130/0.4, respectively. The severity of hemodynamic and acid-base changes paralleled the survival, with the least disturbance observed in MP4-treated animals. CONCLUSIONS Hemodilution with MP4 was more effective in maintaining hemodynamic and metabolic stability than starch solutions or no hemodilution before simulated intraoperative hemorrhage. The benefit of MP4 is not ascribed solely to volume expansion. The results suggest that perioperative administration of MP4 may improve outcomes in surgical settings.

History of Physical Medicine and Rehabilitation and Its Ethical Dimensions.

Physical medicine and rehabilitation has developed into a medical specialty that aims to restore optimal patient function in multiple dimensions of life with an interdisciplinary approach to care delivery.

Venous thrombosis: Diagnosis and treatment; new methods and strategies for management

Venous thrombosis most often attacks patients who have had alterations of venous stasis, endothelial damage, and/or hypercoagulability. Diagnosis generally depends on venography or duplex doppler ultrasonography; treatment is usually started with heparin and may proceed to warfarin alone.