Early hemostatic responses to trauma identified with hierarchical clustering analysis.

BACKGROUND: Trauma-induced coagulopathy is a complex multifactorial hemostatic response that is poorly understood. OBJECTIVES: To identify distinct hemostatic responses to trauma and identify key components of the hemostatic system that vary between responses. PATIENTS/METHODS: A cross-sectional observational study of adult trauma patients at an urban level I trauma center emergency department was performed. Hierarchical clustering analysis was used to identify distinct clusters of similar subjects according to vital signs, injury/shock severity, and comprehensive assessment of coagulation, clot formation, platelet function, and thrombin generation. RESULTS: Among 84 total trauma patients included in the model, three distinct trauma clusters were identified. Cluster 1 (N = 57) showed platelet activation, preserved peak thrombin generation, plasma coagulation dysfunction, a moderately decreased fibrinogen concentration and normal clot formation relative to healthy controls. Cluster 2 (N = 18) showed platelet activation, preserved peak thrombin generation, and a preserved fibrinogen concentration with normal clot formation. Cluster 3 (N = 9) was the most severely injured and shocked, and showed a strong inflammatory and bleeding phenotype. Platelet dysfunction, thrombin inhibition, plasma coagulation dysfunction and a decreased fibrinogen concentration were present in this cluster. Fibrinolytic activation was present in all clusters, but was particularly increased in cluster 3. Trauma clusters were most noticeably different in their relative fibrinogen concentration, peak thrombin generation, and platelet-induced clot contraction. CONCLUSIONS: Hierarchical clustering analysis identified three distinct hemostatic responses to trauma. Further insights into the underlying hemostatic mechanisms responsible for these responses are needed.

Intravenous perfluorocarbon emulsion increases nitrogen washout after venous gas emboli in rabbits.

Intravenous perfluorocarbon emulsion (IV-PFC) has been shown to provide hemodynamic protection from gas embolism (Venous-VGE or arterial-AGE). The objective of this study was to investigate the mechanism of PFC protection from controlled VGE by quantifying the effects of IV-PFC emulsion on pulmonary elimination of nitrogen (N2). All rabbits received an intravenous pretreatment of PFC emulsion (Oxygent, 2.7 g/kg) or saline, then either a continuous room air infusion (0.25 ml/kg for 10 minutes) or a bolus of air (0.8 ml/kg within 10 seconds) through the femoral vein. Expiratory N2 peaked higher with PFC infusion immediately after air injection. The recovery to baseline of end tidal N2 was faster for PFC-treated animals (40 +/- 4.7 vs. 58 +/- 6.5 minutes). In PFC-treated animals, expired CO2, O2, arterial pressure and central venous pressure returned to baseline faster than the saline group. This study demonstrated that PFC increased pulmonary N2 washout. Correspondingly, PFC treatment better preserved the animals' hemodynamics after VGE injury. The use of IV-PFC promises to be a breakthrough non-recompression therapy for gas embolism in the treatment of Decompression Sickness (DCS) and in surgery.

Use of ISO-NOP200 for measurement of NO in the gas phase under controlled humidity conditions.

A technique has been developed to measure nitric oxide (NO) in the gas phase using the ISO-NOP200 NO-specific probe, which was designed to only measure NO in solution. It was found that probe output was responsive to the relative humidity (RH) of the atmosphere. Increasing sensitivity of probe output to NO was observed with increasing RH but the time to achieve a stable output was also increased. The recommended method to give high sensitivity but an acceptable time between analyses was to hold the probe at a constant temperature (20 degrees C) in a sealed 20 ml glass vial containing 4 ml of a saturated solution of NaCl, which provides a constant RH of 75%. NO standards and samples were injected directly into the vial and provided good baseline stability and a limit of detection of 0.18 microl/L in the vial. The limit of detection of the analytical sample will depend on the volume of gas injected into the vial. Up to 4 ml could be injected without disturbing probe stability and this equates to a detection limit of 0.75 microl/L NO. However, analysis of the internal atmosphere of banana fruit could only consistently extract 1 ml of gas, which gave a detection limit of 3 microl/L NO.

Increased readthrough transcription across the simian virus 5 M-F gene junction leads to growth defects and a global inhibition of viral mRNA synthesis.

Recombinant simian virus 5 (rSV5) mutants containing substitutions in the M-F intergenic region were generated to determine the effect of increased readthrough transcription on the paramyxovirus growth cycle. We have previously shown, using an SV5 dicistronic minigenome, that replacement of the 22-base M-F intergenic region with a foreign sequence results in a template (Rep22) that directs very high levels of M-F readthrough transcription. An rSV5 containing the Rep22 substitution grew slower and to final titers that were 50- to 80-fold lower than those of wild-type (WT) rSV5. Cells infected with the Rep22 virus produced very low levels of monocistronic M and F mRNA, consistent with the M-F readthrough phenotype. Surprisingly, Rep22 virus-infected cells also displayed a global decrease in the accumulation of viral mRNA from genes located upstream and downstream of the M-F junction, and overall viral protein synthesis was reduced. Second-site revertants of the Rep22 virus that had regained WT transcription and growth properties contained a single base substitution that increased the M gene end U tract from four to eight residues, suggesting that the growth defects originated from higher-than-normal M-F readthrough transcription. Thus, the primary growth defect for the Rep22 virus appears to be in viral RNA synthesis and not in morphogenesis. A second rSV5 virus (G14), which contained a different foreign M-F intergenic sequence, grew to similar or slightly higher titers than WT rSV5 in some cell types and produced ~1.5- to 2-fold more mRNA and viral protein. The data support the hypothesis that inhibition of Rep22 virus growth is due to increased access by the polymerase to the 5' end of the genome and to the resulting overexpression of L protein. We propose that the elevated naturally occurring M-F readthrough which is characteristic of many paramyxoviruses serves as a mechanism to fine-tune the level of polymerase that is optimal for virus growth.

Systemic analgesia and sedation in managing orthopedic emergencies.

Many potent agents have become available in the emergency department for providing systemic analgesia and sedation for painful orthopedic procedures. This article details the pharmacology and principles of systemic analgesia and sedation, which will help the emergency physician provide maximal patient comfort with minimal complications during painful procedures. The use of an appropriate agent in these situations will optimize the outcome of the procedure itself and result in greater patient satisfaction.

Protection of the enzyme L-asparaginase during lyophilisation--a molecular modelling approach to predict required level of lyoprotectant.

Many novel therapeutic agents are proteins and peptides which need stabilisation due to their inherent instability in aqueous solution. Freeze-drying is an established method for protein stabilisation, although the use of additives is often necessary in order to preserve protein structure and activity during lyophilisation itself. The molecular interactions between protein and protective additive are as yet unclear. In this study, we examined the use of a range of saccharide additives to stabilise the model multi-subunit enzyme L-asparaginase during lyophilisation, assessed post-drying enzyme activity and quaternary structure, and related the extrapolated levels of additive necessary to provide full stabilisation to the theoretical levels predicted from an existing hypothesis using molecular modelling. It was found that each of the saccharides tested here displayed similar levels of protection towards L-asparaginase under the conditions used. Amounts of additive required to give full stabilisation to the enzyme were extrapolated from the activity data and were found to be in good agreement with theoretical amounts calculated from molecular modelling studies. Our data suggest that the existing hypothesis may be relevant to the prediction of optimum levels of lyoprotectant for the freeze-drying of proteins. However, further studies would be necessary in order to obtain a full picture of protein-additive interactions at the molecular level.

End-tidal carbon dioxide monitoring in emergency medicine, Part 1: Basic principles.

End-tidal carbon dioxide (PetCO2) monitoring is becoming more common in both the ED and the out-of-hospital setting. Its main use has been as an aid when confirming endotracheal intubation. However, since CO2 is intrinsically coupled with states of metabolism, circulation, and ventilation, PetCO2 monitoring along with analysis of its capnographic component is becoming increasingly valuable for other uses in the ED. This article reviews the physiology of CO2, the means by which end-tidal CO2 may be monitored, and the components and analysis of the capnogram.

End-tidal carbon dioxide monitoring in emergency medicine, Part 2: Clinical applications.

End-tidal carbon dioxide (PetCO2) monitoring is becoming more common in both the ED and the out-of-hospital setting. Its main use has been as an aid when confirming endotracheal intubation. Other uses in the ED include monitoring CPR efforts and monitoring the ventilatory and hemodynamic status of intubated and nonintubated patients. In addition, future uses may include using PetCO2 as an adjunct when monitoring the status of asthma treatment, when making the diagnosis of pulmonary embolism, and when measuring cardiac output noninvasively. This article reviews these specific uses of PetCO2 monitoring in emergency medicine.

Medical management of ectopic pregnancy--the role of methotrexate.

Ectopic pregnancy is an increasing health risk for women throughout the world. Recent advances in measurements of serum quantitative beta human chorionic gonadotropin and transvaginal ultrasonography have made it possible to diagnose ectopic pregnancy without laparoscopy. These developments have provided the atmosphere for trials using methotrexate as a nonsurgical treatment for ectopic pregnancy. This article briefly reviews the epidemiology and diagnosis of ectopic pregnancy. The medical management of ectopic pregnancy with methotrexate is then reviewed in more detail.

Norepinephrine-induced hypertension following cardiac arrest: effects on myocardial oxygen use in a swine model.

STUDY OBJECTIVE: Recent studies suggest that norepinephrine-induced hypertension early after cardiac arrest ameliorates cerebral hypoperfusion and improves neurologic outcome. The purpose of this study was to evaluate the effects of early norepinephrine-induced hypertension on postresuscitation myocardial blood flow and oxygen use. DESIGN: Prospective, controlled laboratory study. PARTICIPANTS: Ten swine. INTERVENTIONS: All animals underwent 10 minutes of ventricular fibrillation cardiac arrest followed by 5 minutes of low-flow cardiopulmonary bypass (10 mL/kg.min), norepinephrine (0.12 mg/kg), and defibrillation. Animals then were assigned to a hypertension group (mean aortic pressure, 95 mm Hg) or a control group (mean aortic pressure, 75 mm Hg) by titrating a norepinephrine infusion to attain the prescribed aortic pressure. RESULTS: Myocardial blood flow, perfusion pressure, and oxygen metabolism were compared between groups at different times using analysis of variance with a post-hoc Tukey test. Groups had similar myocardial blood flow during ventricular fibrillation, total defibrillation energy, and time to restoration of spontaneous circulation. Fifteen minutes after restoration of spontaneous circulation, the hypertension group had significantly elevated myocardial blood flow, 965 +/- 314 mL/min.100 g versus 325 +/- 67 mL/min.100 g in the control group (P < .001), myocardial oxygen consumption of 51.2 +/- 26.9 mL O2/min.100 g versus 6.4 +/- 3.4 mL O2/min.100 g (P < .001), and myocardial oxygen extraction of 46% +/- 20% versus 14% +/- 4% (P < .01). CONCLUSION: In the early resuscitation period, increasing the norepinephrine dose to induce mild hypertension significantly increases oxygen use in the postischemic myocardium.

Hemodynamics of interposed abdominal compression during human cardiopulmonary resuscitation.

OBJECTIVE: Clinical studies of interposed abdominal compression CPR (IAC-CPR) have had diverse outcomes. This study compared the hemodynamics of standard CPR and IAC-CPR in humans. METHODS: A 24-month prospective nonrandomized analysis of hemodynamic parameters was performed in a convenience cohort of 20 adults who had out-of-hospital, nontraumatic, normothermic cardiac arrests. The study took place in the resuscitation unit of a large urban hospital. Thoracic aortic and right atrial catheters were inserted and pressures were recorded during standard CPR and IAC-CPR. Coronary perfusion pressures (CPPs) were determined during standard CPR and IAC-CPR. The patients were separated into two groups based upon their responses to IAC-CPR. Responders had increases in CPP during IAC-CPR; nonresponders had decreases or no change in CPP during IAC-CPR. Aortic relaxation, right atrial relaxation, aortic compression, and right atrial compression phase pressures were compared between the two groups. RESULTS: CPPs increased in 13 patients and decreased in seven patients. The mean change in CPP with IAC-CPR was an increase of 5.8 +/- 15.1 torr. An elevated right atrial compression phase pressure (RaComp) during standard CPR was predictive of an increase in CPP during IAC-CPR (p = 0.047). In those patients who showed improvements in CPP during IAC-CPR, mean aortic relaxation phase pressures (AoRelax) increased by 9.5 +/- 14.2 torr (p = 0.026) and mean right atrial relaxation phase pressures (RaRelax) decreased by 2.6 +/- 6.2 torr (p = 0.099) during IAC-CPR. CONCLUSIONS: The variable effects of IAC-CPR on CPP appear to be multifactorial. The improvement in CPP that occurred in responders to IAC-CPR was secondary to an increase in AoRelax as well as a decrease in RaRelax.

Possible reasons for the variability of human responses to IAC-CPR.

OBJECTIVE: To propose reasons for the variability of the hemodynamic responses and survival data observed when interposed abdominal compression cardiopulmonary resuscitation (IAC-CPR) is performed on humans in cardiac arrest. METHODS: Critical content review of all studies performed in the United States examining IAC-CPR in humans and of selected animal studies addressing hemodynamic mechanisms of CPR. Articles in the English language dealing with human IAC-CPR studies from 1970-1993 were retrieved using the MEDLINE database of the National Library of Medicine. RESULTS: IAC-CPR does not consistently improve coronary perfusion pressure (CPP) over standard CPR in humans and is capable of decreasing as well as increasing CPP. This variability does not seem dependent on the manner in which abdominal compressions are performed. Because of the limited response to standard CPR, significant increases in return of spontaneous circulation would be expected with IAC-CPR if a large percentage of patients were to have favorable increases in CPP. However, other patients may be adversely affected by decreases in CPP during IAC-CPR, with unsuccessful resuscitation of those individuals. Return of spontaneous circulation also may be enhanced using IAC-CPR due to other factors reflected in the initial arrest rhythm and in arrest-population demographics. CONCLUSION: IAC-CPR should not be recommended for routine use until the mechanism of its beneficial effects is known and until those patients who are likely to benefit from the technique can be better identified.

Organ blood flow following cardiac arrest in a swine low-flow cardiopulmonary bypass model.

STUDY OBJECTIVE: To determine organ blood flow changes, relative to baseline, following cardiac arrest and resuscitation in a closed-chest cardiac arrest swine model using cardiopulmonary bypass to achieve reproducible return of spontaneous circulation (ROSC). INTERVENTIONS: Following 10 min of ventricular fibrillation (VF), animals (n = 10) received low-flow cardiopulmonary bypass at 10 ml/kg/min from 10-15 min. At 15 min of VF, norepinephrine (0.12 mg/kg) was given and bypass flow increased to 50 ml/kg/min, followed by countershocks at 16 min. Following ROSC, cardiopulmonary bypass was immediately weaned off with norepinephrine support. Organ blood flows were determined during normal sinus rhythm, during reperfusion of VF and during the early post-ROSC period while off cardiopulmonary bypass support. Organ blood flows during the early ROSC period were compared with organ blood flow at baseline and during VF. RESULTS: During early reperfusion of VF prior to any drug therapy, myocardial, cerebral and abdominal organ blood flows were all low. All animals achieved ROSC at 16.9 +/- 0.7 min and were weaned from bypass in < 5 min following ROSC. During the early post-ROSC period, blood flow to the myocardial, cerebral and adrenal vascular beds was significantly elevated relative to baseline. Simultaneously, blood flow to the kidneys, liver, spleen and lungs was reduced relative to baseline. CONCLUSIONS: This low-flow bypass model produces reproducible high resuscitation rates and ROSC times. Early post-resuscitation organ blood flow is characterized by a selective hyperemia involving the cerebral, myocardial and adrenal vascular beds, in contrast to hypoperfusion of the pulmonary and mesenteric vascular beds.

A comparison of chest compressions between mechanical and manual CPR by monitoring end-tidal PCO2 during human cardiac arrest.

STUDY OBJECTIVE: To compare the use of mechanical and manual chest compressions during cardiac arrest based on continuous monitoring of end-tidal PCO2 (PETCO2). DESIGN: Prospective, randomized, crossover design. SETTING AND PARTICIPANTS: Fifteen consecutive adults ranging in age from 33 to 78 years who presented in nontraumatic cardiac arrest to the emergency department of a large teaching hospital. INTERVENTIONS: Study protocols were begun late in the resuscitation after initial resuscitation attempts were unsuccessful. Patients received four alternating five-minute trials (two manual and two mechanical), being randomized to begin with either technique. Mechanical compressions were performed by a mechanical device at a compression depth of 2 in. Both mechanical and manual compressions were delivered at a rate of 80 with a ventilation delivered after every fifth compression. Persons performing manual CPR were experienced American Heart Association basic life support providers, and no person performed manual CPR more than once during the study period. No resuscitative drugs were administered during the study period. PETCO2 was monitored continuously; those performing manual CPR were blinded to the PETCO2 monitor. Data were analyzed with repeated-measures analysis of variance and Scheffé multiple comparisons with the alpha error rate set of .05. MEASUREMENTS AND RESULTS: Mean PETCO2 during mechanical CPR was 13.6 +/- 4.14 mm Hg compared with 6.9 +/- 2.42 mm Hg during manually performed CPR (P < .001), a difference of 97%. Average mechanical CPR PETCO2 was higher in all cases. No patient was resuscitated successfully. Capnography also indicated that most CPR providers were inconsistent in their chest compressions. CONCLUSION: This study suggests that cardiac output produced with mechanical chest compressions is greater than that produced with manual compressions as demonstrated by the significantly higher PETCO2 levels during mechanical CPR. Reasons for this are unclear. In addition, monitoring of PETCO2 may help optimize chest compressions during CPR.

Translaryngeal jet ventilation and end-tidal PCO2 monitoring during varying degrees of upper airway obstruction.

STUDY OBJECTIVES: To explore the ventilatory adequacy of translaryngeal jet ventilation (TLJV) during partial upper airway obstruction and the usefulness of monitoring end-tidal CO2 (PETCO2) during this condition. DESIGN: Prospective, nonrandomized, sequential crossover design. SETTING AND PARTICIPANTS: Apneic dog model (five dogs; mean weight, 23 kg). INTERVENTIONS: Animals were intubated with a 9.0-mm endotracheal tube with the tip positioned above the cricothyroid membrane. Upper airway obstructions of 40%, 69%, and 80% were created. TLJV was performed through the cricothyroid membrane using a 13-gauge catheter with 100% oxygen, 45 psi, 15 breaths per minute, and 30% inspiratory time for 15 minutes at each upper airway obstruction. Data collected at baseline (no upper airway obstruction) and one-minute intervals included arterial blood pressures, continuous PaCO2 measurements, and PETCO2 at the TLJV catheter tip and above the level of obstruction. Arterial blood gases were obtained at 0 and 15 minutes. Data were analyzed using Pearson's correlation, analysis of variance, and Turkey's multiple comparisons (significance, P less than .05). MEASUREMENTS AND RESULTS: Baseline values for all variables did not significantly differ at the onset of each testing phase. Mean pH increased significantly from baseline during 69% upper airway obstruction (7.36 to 7.54, P less than .05) and 80% upper airway obstruction (7.39 to 7.61, P less than .01). Mean PaCO2 decreased significantly from baseline during all upper airway obstructions: 40% upper airway obstruction (39.9 to 33.6 mm Hg, P less than .01), 69% upper airway obstruction (38.3 to 25.6 mm Hg, P less than .001), and 80% upper airway obstruction (36.2 to 18.2 mm Hg, P less than .001). PaCO2, PETCO2, and pH differed significantly between each level of upper airway obstruction (P less than .01). PETCO2 was significantly correlated with PaCO2 (r = .84, P less than .001) and did not significantly differ from PaCO2. No signs of barotrauma were observed in any animal at any degree of upper airway obstruction. CONCLUSION: TLJV during partial upper airway obstruction in our model provided safe and adequate-to-supranormal minute ventilation. In fact, marked hypocapnia and alkalemia occurred at levels of 69% and 80% upper airway obstruction, thus dispelling concepts that TLJV may cause hypercapnia during partial upper airway obstruction. PETCO2 correlates well with PaCO2 and may be valuable for monitoring ventilation when using TLJV in the nonobstructed or partially obstructed upper airway.

A comparison of interposed abdominal compression CPR and standard CPR by monitoring end-tidal PCO2.

Interposed abdominal compression CPR (IAC-CPR) has been demonstrated to significantly improve blood flow compared with standard (S)-CPR in animal and electrical models. Studies with IAC-CPR in human beings have not reported data regarding cardiac output. Animal and clinical studies have correlated end-tidal PCO2 (ETPCO2) with cardiac output produced with precordial compressions. We conducted a prospective, randomized study on 33 adult patients with nontraumatic cardiac arrest. Patients were randomized to initially receive either S-CPR or IAC-CPR. ETPCO2 was monitored continuously. After 20 minutes of resuscitation, the technique was reversed. The average ETPCO2 during IAC-CPR was 17.1 mm Hg while the average during S-CPR was 9.6 mm Hg, a difference of 78% (P less than .001). In patients arriving in cardiac arrest, return of spontaneous circulation was observed in six patients (30%) during IAC-CPR and in one patient (6%) during S-CPR (P = .07). Our study strongly suggests that cardiac output may be significantly increased in human beings with IAC-CPR as evidenced by the significantly greater increases in ETPCO2 with IAC-CPR compared with S-CPR. In addition, IAC-CPR appeared to demonstrate a trend toward increasing the return of spontaneous circulation.