Patrick Sorkine

Midazolam versus propofol for long-term sedation in the ICU: a randomized prospective comparison

Objective: To compare the efficacy, safety, and cost of midazolam and propofol in prolonged sedation of critically ill patients.Design: Randomized, prospective study.Setting: General intensive care unit (ICU) in a 1100-bed teaching hospital.Patients: 67 critically ill, mechanically ventilated patients.Interventions: Patients were invasively monitored and mechanically ventilated. A loading dose [midazolam 0.11 ± 0.02 (SEM) mg · kg−1, propofol 1.3 ± 0.2 mg · kg−1] was administered, followed by continuous infusion, titrated to achieve a predetermined sedation score. Sedation was continued as long as clinically indicated.Measurements and results: Mean duration of sedation was 141 and 99 h (NS) for midazolam and propofol, respectively, at mean hourly doses of 0.070 ± 0.003 mg · kg−1 midazolam and 1.80 ± 0.08 mg · kg−1 propofol. Overall, 68 % of propofol patients versus 31 % of midazolam (p<0.001) patients had a > 20 % decrease in systolic blood pressure after the loading dose, and 26 versus 45 % (p<0.01) showed a 25 % decrease in spontaneous minute volume. Propofol required more daily dose adjustments (2.1 ± 0.1 vs 1.4 ± 0.1, p<0.001). Nurserated quality of sedation with midazolam was higher (8.2 ± 0.1 vs 7.3 ± 0.1 on a 10-cm visual analog scale, p<0.001). Resumption of spontaneous respiration was equally rapid. Recovery was faster after propofol (p<0.02), albeit with a higher degree of agitation. Amnesia was evident in all midazolam patients but in only a third of propofol patients. The cost of propofol was 4–5 times higher.Conclusions: Both drugs afforded reliable, safe, and controllable long-term sedation in ICU patients and rapid weaning from mechanical ventilation. Midazolam depressed respiration, allowed better maintenance of sedation, and yielded complete amnesia at a lower cost, while propofol caused more cardiovascular depression during induction.

Metformin-associated lactic acidosis following acute kidney injury. Efficacious treatment with continuous renal replacement therapy

Diabet. Med. 29, 245–250 (2012)

Gray–white matter discrimination—a possible marker for brain damage in heat stroke?

INTRODUCTION/OBJECTIVEnHeat stroke (HS) is a common medical emergency which carries high morbidity and morality. This study was designed to describe the pattern of central nervous system (CNS) changes as detected by brain CT scan in a case series of six patients suffering from classical and exertional HS.nnnMETHODS AND PATIENTSnAll the patients were admitted in critical condition during the heat wave in the summer of 1999 in Israel. Each was in deep coma with a measured core temperature of over 40 degrees C upon admission to the emergency department.nnnRESULTSnAggressive cooling measures decreased the core temperature to <38 degrees C within 30 min following admission. Two patients (33.3%) died. One of the survivors remained in a vegetative state. Brain CT studies carried out within 4 days of admission in all the patients revealed severe loss of gray-white matter discrimination (GWMD) without signs of acute bleed or significant focal lesion, findings that persisted in repeated brain CTs in one patient who remained in a vegetative state.nnnDISCUSSION AND CONCLUSIONSnLoss of GWMD may represent an early and sensitive indication of severe brain damage in patients with severe HS. Further studies in larger groups of patients are warranted in order to determine whether the appearance of GWMD in brain CTs of patients with HS has prognostic value.

Vipera aspis venom reduces lethality and down-regulates tumor necrosis factor-α in a rat model of LPS-induced sepsis

OBJECTIVESnSepsis and septic shock are major causes of morbidity and mortality in critically-ill patients. Sepsis constitutes the systemic response to infection, that is predominantly mediated by the pro-inflammatory cytokines TNF-alpha and IL-1beta. Hence, cytokine modulation provides a promising target for the treatment of sepsis. In this work we evaluated the effect of a low-dose Vipera aspis venom (VAV) vaccine on survival and cytokine serum levels in a rat model of lipopolysaccharide (LPS)-induced septic shock.nnnMETHODSnAdult male Wistar rats were given either VAV vaccine or saline, and 2 weeks later half of each group received LPS challenge, and were monitored for mortality, cytokine levels, blood count and chemistry.nnnRESULTSnSurvival rate was significantly higher in venom-treated, compared to non-vaccinated septic rats. Furthermore, VAV treatment significantly reduced LPS-associated TNF-alpha and LDH, without affecting IL-6 and IL-10 levels, and modified WBC and platelet counts.nnnCONCLUSIONSnOur data suggest that sub-toxic doses of VAV have a protective effect against LPS-induced septic shock that may be mediated, at least partially, by the modulated TNF-alpha activity. This study thus offers a novel therapeutic approach for the attenuation of bacteremia-induced septic shock through the modulation of a central pro-inflammatory cytokine by VAV vaccination in mammals.

Antagonization of TNF attenuates systemic hemodynamic manifestations of envenomation in a rat model of Vipera aspis snakebite

Abstract Objectives: Tumor necrosis factor (TNF) has been reported as a mediator of local tissue injury following snake envenomation in an intact rat model. We investigated whether systemic release of TNF occurs following Vipera aspis envenomation. We further analyzed the possible connection between envenomation-related hemodynamic depression and TNF antagonization (TNF antibodies or soluble TNF receptor). Design: A prospective, randomized, controlled experimental study using a rat model for snake envenomation. Settings: A medical university hospital research laboratory. Intervention: Eighty rats (300–400xa0g) were divided into four groups (n=20): control and three experimental groups. Intramuscular injection of V. asis 500xa0µg/kg was administered to the three experimental groups: venom only (group 1), venom and 40xa0µg anti-TNF antibodies (group 2), venom and 250xa0µg soluble TNF receptor (p55-R; group 3). Hemodynamic parameters were monitored up to 4xa0h following venom injection. Measurements and results: A significant hemodynamic deterioration (reduction in heart rate and blood pressure) occurred 30xa0min following venom injection in group 1 compared to groups 2 and 3, where hemodynamic parameters remained stable throughout the 4xa0h observation period. Serum levels of TNF were detected 15xa0min after venom injection and peaked after 2xa0h at 485±12xa0pg/ml. Conclusions: The hemodynamic consequences of intramuscular injection of V. aspis venom can be blunted in a rat by systemic antagonization of TNF activity prior to venom injection. The poisonous hemodynamic effects of the V. aspis venom might be caused by systemic release of TNF.

Severe acidosis does not predict fatal outcomes in intensive care unit patients: A retrospective analysis☆ , ☆☆

PURPOSEnSevere acidosis is a potentially life-threatening acid-base imbalance. The outcome of patients with severe acidosis has only been anecdotally described. We therefore assessed the discharge rate of such patients from the intensive care unit (ICU) and survival time after the event.nnnMETHODSnA retrospective evaluation of medical records of patients admitted to the ICU of Tel Aviv Medical Center between 2005 and 2010, in whom arterial blood pH less than 6.8 was documented during their ICU stay, was performed.nnnRESULTSnTwenty-eight patients were suitable for study entry. Septic shock was the most common underlying medical condition (33%). Nine (32.1%) patients were either discharged alive or survived for at least 30 days in the ICU after their arterial blood pH measurement was less than 6.8. More than a quarter of the patients with life-threatening acidosis (n = 8; 28.6%) were discharged home and returned to their prehospitalization daily activity. Mean follow-up period for these patients was 132 ± 111 weeks. Multivariate analysis identified hyperkalemia, Acute Physiology and Chronic Health Evaluation II score, and Glasgow Coma Scale as determinants for ICU death after severe acidosis.nnnCONCLUSIONSnA significant number of patients can outlast severe acidosis and return to their prehospitalization status. Larger studies are needed to define the patient population most likely to benefit from aggressive resuscitation efforts during severe acidosis.

Cross-sensitivity between isoflurane and diazepam : Evidence from a bidirectional tolerance study in mice

We examined in mice the effect of chronic diazepam treatment on the sensitivity to isoflurane, and that of repeated isoflurane exposure on the sensitivity to diazepam. Mice were divided into four groups: group 1, treated with diazepam, 10 mg/kg i.p. twice daily; group 2, vehicle-treated controls; group 3, exposed to 3% isoflurane for 25 min twice daily; and group 4, untreated controls. After 14 days the effect of the treatment was assessed. Twenty-four hours after the last 10 mg/kg diazepam treatment, groups 1 and 2 received diazepam, 5 mg/kg i.p., and were subjected to the horizontal wire test (HWT). All control mice but only 10% of the diazepam-treated mice failed the HWT. Groups 1 and 2 were then exposed to increasing concentrations of isoflurane. Diazepam-treated mice (group 1) lost the HWT at 0.7+/-0.7%, compared with 0.6+/-0.1% in controls (group 2) (P<0.001); the ED50 was 0.75% vs. 0.65%. Group 1 mice lost the righting reflex at 0.94+/-0.07% isoflurane vs. 0.87+/-0.06% in group 2 (P<0.01); the ED50 was 0.93% vs. 0.82%. Recovery time was 175+/-161 s in group 1 vs. 343+/-275 s in group 2 (P<0.02). Twenty-four hours after the last of the repeated exposures to isoflurane, we examined the responses of groups 3 and 4 to increasing concentrations of isoflurane. Mice in group 3 lost the righting reflex at 1.0+/-0.06% isoflurane vs. 0.9+/-0.04% in controls (group 4) (P<0.001); the ED50 was 0.96% vs. 0.85%. Recovery time was 113+/-124 s vs. 208+/-126 s in groups 3 and 4 (P<0.09). Diazepam, 3 mg/kg i.p. administered to groups 3 and 4, caused loss of the HWT reflex in 33% of group 3 mice and in 82% of controls (group 4) (P<0.001). It appears that prolonged exposure to both diazepam and isoflurane caused reduced sensitivity to each drug separately, as well as to the other drug. This finding may strengthen the theory that inhalational anesthetics may act via the same mechanism as the benzodiazepines.

Low plasma C-reactive protein level as an early diagnostic tool for heatstroke vs central nervous system–associated infection in the ED

PURPOSESnHeatstroke (HS) is a life-threatening condition, manifested by systemic inflammation and multiorgan failure. Rapid recognition and treatment are life saving. We report a laboratory-oriented characterization of HS by low plasma C-reactive protein (CRP) level and propose its usefulness in distinguishing this type of hyperpyrexia from central nervous system-associated high core temperature.nnnMETHODSnAfter institutional review board approval, records of patients admitted to general intensive care unit between August 2008 and September 2011 with core temperature 39.0°C or higher due to HS or meningoencephalitis (ME) were reviewed. Patients demographics, CRP on admission and 24 to 48 hours later, serum creatinine, creatine phosphokinase, platelets count, international normalized ratio, alanine transaminase, serum pH, and lactate levels were retrieved.nnnRESULTSnThirty-six patients were admitted to the intensive care unit with high core temperature: 19 patients, aged 21 to 85 years, had HS; 17 individuals, aged 22 to 81 years, had ME. None of the HS individuals had infection. Twelve HS patients were previously healthy; in 13 patients, the event occurred postexercise. Mean admission CRP levels was 2.1 ± 3.3 mg/L in the HS group compared with 129 ± 84 mg/L in the ME patients (P < .0001); mean 24- to 48-hour CRP levels were 14.6 ± 16.8 vs 139 ± 98 mg/L, respectively (P < .0001). There were no clinically significant differences between the groups regarding laboratory parameters indicative of end-organ damage. Six HS patients underwent computed tomography and/or lumbar puncture before starting intensive cooling, due to misdiagnosis; 5 of them died subsequently.nnnCONCLUSIONSnLow serum CRP levels characterize non-central nervous system-associated HS. This available laboratory test could identify noninfectious hyperthermic patients upon admission, saving precious time until treatment and avoiding unnecessary diagnostic tests.