The safety of hyperbaric oxygen treatment--retrospective analysis in 2,334 patients.

INTRODUCTION: Hyperbaric oxygen (HBO2) therapy is applied in a growing number of cases for patients with different comorbidities and is considered a generally safe therapy. The main side effects related to HBO2 therapy are barotrauma, central nervous system- and pulmonary oxygen toxicity, claustrophobia, anxiety and visual disturbances. The aim of this study was to evaluate the incidence of side effects associated with HBO2 therapy and risk factors in a large cohort of patients treated for different indications. METHODS: We conducted a retrospective analysis of 2,334 patients treated in the Sagol Center of Hyperbaric Medicine and Research, Assaf Harofeh, Israel, between June 2010 and December 2014. Patients were classified to one of three categories of indications: Category A--non-neurological indications; Category B--neurotherapeutic indications; and Category C--acute indications. RESULTS: From a total of 2,334 patients, 406 (17.4%) experienced adverse event(s) (one or more) during HBO2 therapy sessions. The overall per-session incidence was 721:100,000 events:sessions (0.72%). The main complication was middle ear barotrauma, which occurred in 9.2% of patients and in 0.04% of sessions. Females and children under the age of 16 years had increased risk for barotrauma. Other complications--hypoglycemia, oxygen toxicity, dizziness, anxiety reactions, dyspnea and chest pain--occurred in 0.5-1.5% of patients. CONCLUSIONS: Strict operational protocols, including pre-HBO2 therapy evaluations and in-chamber monitoring, are essential and improve patient safety. When applied, HBO2 therapy can be considered one of the safest medical treatments available today.

Seizures during hyperbaric oxygen therapy: retrospective analysis of 62,614 treatment sessions.

INTRODUCTION: Hyperbaric oxygen (HBO2) therapy is considered to be a generally safe therapy. However, data regarding seizure incidence during HBO2 therapy as a clinical presentation of central nervous system- (CNS) related oxygen toxicity are conflicting (ranging from 1:10,000 to 1:600 seizures:hyperbaric sessions). The risk for seizures is of significant importance for the growing population of patients suffering from chronic neurological disorders such as traumatic brain injury and stroke who are treated with HBO2. The aim of this study was to evaluate the incidence of seizures during HBO2 therapy in a large cohort of patients and determine whether patients with known chronic neurological disorders are at increased risk. METHODS: Retrospective analysis of 2,334 patients treated at the Sagol Center of Hyperbaric Medicine and Research, Assaf Harofeh Medical Center, Israel, between June 2010 and December 2014. Patients were grouped into one of three categories according to indication for HBO2 therapy: Category A--non- neurological indications; Category B--neurological indications; and Category C--acute indications. RESULTS: A total of 62,614 hyperbaric sessions, administered to 2,334 patients, were included in the analysis. The overall incidence of seizures during hyperbaric sessions was 0.011% (1:8,945), occurring in seven (0.3%) patients. Only one patient had a clear oxygen toxicity-induced seizure, with an overall incidence of 1:62,614. CONCLUSIONS: Seizures induced by oxygen toxicity during HBO2 therapy are extremely rare. Moreover, in relation to oxygen-induced seizures, HBO2therapy can be considered safe for patients suffering with chronic neurological disorders except for uncontrolled epilepsy.

Hyperbaric oxygen can induce neuroplasticity and improve cognitive functions of patients suffering from anoxic brain damage.

PURPOSE: Cognitive impairment may occur in 42-50% of cardiac arrest survivors. Hyperbaric oxygen therapy (HBO2) has recently been shown to have neurotherapeutic effects in patients suffering from chronic cognitive impairments (CCI) consequent to stroke and mild traumatic brain injury.The objective of this study was to assess the neurotherapeutic effect of HBO2 in patients suffering from CCI due to cardiac arrest. METHODS: Retrospective analysis of patients with CCI caused by cardiac arrest, treated with 60 daily sessions of HBO2. Evaluation included objective computerized cognitive tests (NeuroTrax), Activity of Daily Living (ADL) and Quality of life questionnaires. The results of these tests were compared with changes in brain activity as assessed by single photon emission computed tomography (SPECT) brain imaging. RESULTS: The study included 11 cases of CCI patients. Patients were treated with HBO2, 0.5-7.5 years (mean 2.6 ± 0.6 years) after the cardiac arrest. HBO2 was found to induce modest, but statistically significant improvement in memory, attention and executive function (mean scores) of 12% , 20% and 24% respectively. The clinical improvements were found to be well correlated with increased brain activity in relevant brain areas as assessed by computerized analysis of the SPECT imaging. CONCLUSIONS: Although further research is needed, the results demonstrate the beneficial effects of HBO2 on CCI in patients after cardiac arrest, even months to years after the acute event.

Comprehensive Approach to Lower Blood Pressure (CALM-BP): a randomized controlled trial of a multifactorial lifestyle intervention.

Complementary medicine advocates the use of a multifactorial approach to address the varied aspects of hypertension. The aim of this study was to compare the blood pressure (BP) effect and medication use of a novel Comprehensive Approach to Lowering Measured Blood Pressure (CALM-BP), based on complementary medicine principles, with the standard recommended Dietary Approach to Stop Hypertension (DASH). A total of 113 patients treated with antihypertensive drugs were randomly assigned to either CALM-BP treatment (consisting of rice diet, walks, yoga, relaxation and stress management) or to a DASH+exercise control group (consisting of DASH and walks). Ambulatory 24-h and home BP were monitored over a 16-week programme, followed by 6 months of maintenance period. Medications were reduced if systolic BP dropped below 110 mm Hg accompanied by symptoms. In addition to BP reduction, medications were reduced because of symptomatic hypotension in 70.7% of the CALM-BP group compared with 32.7% in the DASH group, P<0.0001. After 6 months, medication status was not altered in the majority of individuals. Significant reductions in body mass index, cholesterol and improved quality-of-life scores were observed only in the CALM-BP group. Lifestyle and diet modifications based on complementary medicine principles are highly effective with respect to BP control, medication use and cardiovascular risk factors.

Hyperbaric oxygen, oxidative stress, NO bioavailability and ulcer oxygenation in diabetic patients.

BACKGROUND: Hyperbaric oxygen therapy (HBO2) increases tissue oxygenation, thus serving as an adjunct therapy for diabetic wounds. However, in some patients there is insufficient increase in tissue O2. AIMS: To investigate the pathophysiology of insufficient HBO2 and the possible role of N-acetylcysteine (NAC). METHODS: Prospective, randomized, cross-over trial included 50 diabetic patients with non-healing ulcers. Each patient received two treatments with 100% oxygen/2ATA. NAC was administered i.v. at one of the two treatments. Basal and post-treatment peri-wound transcutaneous O2 (TcPO2) pressure, malondialdehyde (MDA), total anti-oxidant status (TAOS) and nitric oxide (NO) were assessed. An ulcer oxygenation increase above 200 mmHg was accepted as sufficient. RESULTS: During HBO2, 17 patients (34%) demonstrated insufficient increase in TcPO2. Concomitantly, their TAOS and NO decreased, while MDA increased. NAC administration attenuated these parameters, thus improving the HBO2 outcome. In those affected by NAC, the cure rate was 75%. By contrast, in 66% of patients with sufficient increase in TcPO2 TAOS was increased and MDA decreased irrespective of NAC administration. The cure rate in this subgroup was 82%. CONCLUSIONS: Insufficient increase of ulcer oxygenation during HBO2 results from exaggerated oxidative stress and decreased NO bioavailability. NAC administration-induced modulation of both parameters and may improve ulcer oxygenation during HBO2.

Gentamicin-induced ototoxicity in hemodialysis patients is ameliorated by N-acetylcysteine.

Aminoglycoside (AG) antibiotics are associated with several side effects, including a reversible nephrotoxicity and a permanent ototoxicity. Oxidative stress is thought to contribute to the pathophysiology of both conditions. We studied the possible protective effect of the antioxidant N-acetylcysteine (NAC) in gentamicin-induced hearing loss in hemodialysis patients. This study includes 53 hemodialysis patients scheduled to receive gentamicin for dialysis catheter-related bacteremia that were randomized to receive the antibiotic with or without NAC. Hearing function was assessed by the standard technique of pure-tone audiograms over a range of frequencies. Audiometric evaluations were performed at baseline, 1 week and at 6 weeks after the completion of gentamicin therapy. A total of 40 patients completed the study protocol with a mean duration of therapy of almost 15 days. At both 1 and 6 weeks after the completion of antibiotic therapy, there were significantly more patients exhibiting ototoxicity in the control group compared with the group receiving NAC. Additionally, significantly more patients in the control group had bilateral ototoxicity. The greatest otoprotective effect of NAC was noticed in the high audiometric tone frequencies. Taken together, our study suggests that NAC treatment may ameliorate gentamicin-induced ototoxicity in hemodialysis patients.

The effect of simvastatin, ezetimibe and their combination on the lipid profile, arterial stiffness and inflammatory markers.

OBJECTIVE: Arterial stiffness and highly sensitive C-reactive protein (hsCRP) serum level predict the risk for cardiovascular events. The most commonly used drugs for lowering cholesterol levels, the statins, also have anti-inflammatory effects and can decrease arterial stiffness. Ezetimibe is the first drug of a new class of cholesterol absorption inhibitors in common use and, to date, its effect on arterial stiffness has not yet been studied. The aim of this study was to compare the effect of simvastatin and ezetimibe, both singly and in combination, on arterial stiffness and hsCRP serum concentration in hypercholesterolemic patients. METHODS: Forty hypercholesterolemic patients were studied. Group1 comprised previously untreated patients, who received simvastatin at doses of 40 mg/day during the study; group 2 comprised patients previously treated with simvastatin at 40 mg/day, who received simvastatin at 80 mg/day during the study; group 3 consisted of patients previously untreated, who received ezetimibe at doses of 10 mg/day during the study; group 4 comprised patients previously treated with simvastatin at 40 mg/day, who received simvastatin at 40 mg/day and ezetimibe at 10 mg/day during the study. Arterial stiffness expressed as the Augmentation Index (AIx) (assessed by pulse wave analysis), the lipid profile and the hsCRP level were measured at baseline and after 3 months of treatment. RESULTS: The reduction in low-density lipoprotein (LDL) after treatment was significantly greater in groups 1 and 4 (39.9 and 35.7%) than in groups 2 and 3 (17.7 and 16.9%; p = 0.005). The AIx decreased significantly only in group 1 patients, from 30.2 +/- 8.3% before treatment to 21.6 +/- 6.5% after treatment (p < 0.001). Changes in hsCRP paralleled the changes in AIx, with a significant decrease in patients in group 1 only, from 2.8 +/- 2.5 mg/L before treatment to 1.6 +/- 1.5 mg/L after treatment (p = 0.016). CONCLUSION: Ezetimibe as a monotherapy had no effect on arterial stiffness or hsCRP, while the administration of simvastatin at 40 mg per day improved arterial stiffness and CRP. However, increasing the dose of simvastatin or administering ezetimibe in combination with simvastatin had no beneficial effects on arterial stiffness.

Hyperbaric oxygen therapy for nonhealing vasculitic ulcers.

BACKGROUND: Cutaneous nonhealing ulceration is a threatening manifestation of vasculitis. Hyperbaric oxygen (HBO), frequently used as adjuvant therapy for patients with ischaemic ulcers, exerts additional beneficial effects on the vascular inflammatory response. AIM: To evaluate the effect of HBO on vasculitis-induced nonhealing skin ulcers. METHODS: The study population comprised 35 patients aged >or= 18 years with severe, nonhealing, vasculitis-induced ulcers that had not improved following immunosuppressive therapy. Baseline ulcer tissue oxygenation was evaluated at room air concentration (21% O2), at 1 atmosphere absolute (ATA) breathing 100% O2, and at 2 ATA breathing 100% O2. The baseline treatment protocol consisted of a 4-week course of 100% O2 for 90 min at 2 ATA, five times/week. RESULTS: The mean baseline ulcer tissue oxygenation (3.1 +/- 2.4 kPa at room air concentration), was significantly increased to 13.9 +/- 11.9 kPa at 1 ATA breathing 100% O2 (P < 0.001), and subsequently increased further to 59.1 +/- 29.8 kPa at 2 ATA breathing 100% O2 (P < 0.001). At the end of the hyperbaric therapy, 28 patients (80%) demonstrated complete healing, 4 (11.4%) had partial healing and 3 (8.6%) had no improvement. None of the patients had any side-effects related to the HBO therapy. CONCLUSION: HBO therapy may serve as an effective safe treatment for patients with vasculitis having nonhealing skin ulcers. Further studies are needed to evaluate its role as primary therapy for this group of patients.

Total cellular calcium and magnesium content of cultured human peripheral blood mononuclear cells following exposure to antidiabetic drugs.

Drugs modulating the ATP-sensitive potassium (K(ATP)) channel activity are widely used for the treatment of diabetes mellitus, the target being pancreatic beta-cells. However, any cell type possessing K(ATP) channels might be concomitantly affected. We investigated the metabolic effect of glibenclamide, a K(ATP) channel closer, and/or diazoxide, a K(ATP) channel opener, on total intracellular content of calcium (Ca) and magnesium (Mg) of cultured peripheral blood mononuclear cells (PBMC). Metformin and rosiglitazone, acting via cellular mechanisms other than K(ATP) channels, were also tested. Ca and Mg were assessed in PBMC from healthy subjects following 72 h in vitro treatment with the respective drugs. Ca content increased significantly in PBMC treated with glibenclamide or rosiglitazone, however apparently via different intracellular pathways. Mg increased only following treatment with rosiglitazone. Metformin had no effect on intracellular Ca or Mg. Pretreatment with diazoxide resulted in a significant intracellular Ca and Mg loss in each experimental situation. If verified clinically, rosiglitazone-induced increase in Mg content of PBMC might prove beneficial beyond hypoglycaemic control. On the other hand, loss of intracellular Ca/Mg content following K(ATP) channel opening by diazoxide might eventually result in significant intracellular Ca and/or Mg depletion.

Clonal variability of group B Streptococcus among different groups of carriers in southern Israel.

A high prevalence of maternal group B Streptococcus (GBS) carriage and an extremely low incidence of invasive neonatal disease have been reported from southern Israel. In order to obtain insight into this discrepancy, this study was performed to determine the population structure of GBS from asymptomatic pregnant women living in this area. Seventy-two strains from maternal GBS carriers were characterized using multilocus sequence typing (MLST). Epidemiologic characteristics of the carriers and their newborns, including demographic variables, obstetric status, and general health parameters, were collected by means of a postpartum interview and a review of the relevant medical records. The MLST analysis grouped the bacteria into six different lineages (clonal complexes). Lineage ST-2 was prevalent among Bedouin-Arabs (p=0.01) and lineage ST-22 among Jews (p=0.001). Lineage ST-17 was prevalent among carriers who emigrated after 1997 from western nations of the former USSR (p<0.001). Lineage ST-22 was associated with carriage of surface-protein C (p=0.01) and lineage ST-17 with surface-protein R (p<0.01). Lineage ST-2 was prevalent among consumers of antibiotics (p=0.02) and was associated with erythromycin-resistant strains (p<0.001). Each subgroup of the southern Israeli maternal population has a different distribution of GBS clones. The clones prevalent among the Bedouin-Arabs and the Jews are known to be of low virulence. Lineage ST-17, which is associated with invasive disease, is prevalent among women who emigrated from western Soviet nations. Therefore, a different policy of GBS prophylaxis, resembling the one executed in endemic areas, should be considered in this population.

The effect of sildenafil on gastric emptying in patients with end-stage renal failure and symptoms of gastroparesis.

BACKGROUND: Delayed gastric emptying is a common disorder among patients with end-stage renal failure (ESRF). Pyloric relaxation, a major determinant of gastric emptying, is a nitric oxide (NO)-mediated process. NO-induced smooth muscle relaxation is mediated through its second messenger cyclic guanosine monophosphate, which is broken by tissue phosphodiesterases (PDEs). Thus the inhibition of cyclic guanosine monophosphate breakdown by PDE inhibitors can potentiate NO-mediated responses and facilitate pyloric relaxation. In an animal model of diabetes mellitus, treatment with sildenafil (a PDE-5 inhibitor) restored NO-mediated pyloric relaxation and improved gastric emptying. The aim of our study was to examine the hypothesis that sildenafil may improve gastric emptying in patients with ESRF and symptoms of gastric paresis. METHODS: We studied 12 patients with ESRF (6 men; age range, 54-80 years; 5 with diabetic nephropathy; 4 +/- 1 years receiving long-term renal replacement therapy) after either placebo or a 25-mg tablet of sildenafil (Viagra; Pfizer Inc). Gastric emptying of a solid meal (one medium-sized fried egg mixed with 37 MBq [1 mCi] technetium Tc 99m phytate plus 1 slice of bread and 150 mL of water at the end of the meal) was assessed 1 hour after dosing by use of a single-headed camera. Images were acquired every 30 seconds for 90 minutes immediately after patients ate. RESULTS: The gastric emptying rate was decreased at baseline (after placebo), to 33% +/- 6% (normal, > or =50%). Treatment with sildenafil had no effect on gastric emptying rates after 90 minutes (from 33% +/- 6% after placebo to 30% +/- 6% after sildenafil, P =.9). CONCLUSIONS: Sildenafil did not improve gastric emptying in patients with ESRF and gastric paresis. Sildenafil may have opposing effects on gastric peristalsis (causing gastric relaxation) compared with its effects on pyloric relaxation. Studies combining sildenafil with prokinetic drugs are of interest.

Adverse drug events in hospitalized patients treated with cardiovascular drugs and anticoagulants.

PURPOSE: To evaluate the incidence of serious adverse drug events (ADEs) caused by cardiovascular drugs during hospitalization in a department of internal medicine, and to identify patients at highest risk. PATIENTS AND METHODS: All the patients treated with cardiovascular drugs and/or anticoagulants in the department between November 1999 and January 2000 were recruited into the study. During hospitalization the patients' charts were reviewed by a pharmacist and a clinician, and the occurrence of serious ADEs was assessed using the Naranjo algorithm. 'Possible' and 'doubtful' ADEs were not counted. RESULTS: Of 496 patients who were enrolled in the study, 20 (4%) had serious ADEs. Compared to patients without ADEs, patients in the ADE group were older (72 +/- 12.6 years (mean +/- SD) vs. 65 +/- 13 years, p = 0.048), their average stay in hospital was longer (7.3 +/- 5.5 days vs. 5.2 +/- 3.7 days, p = 0.018) and their mean urea levels were higher (10.8 +/- 9.3 mmol/l vs. 7.8 +/- 5.3 mmol/l, p = 0.027). The most frequent background pathologies of the 20 patients with ADEs were hypertension (in 18 (90%)) and atrial fibrillation (in nine (45%)). In 50% of the the ADE group there was a history of drug allergies. The ADEs recorded were bleeding in four (20%), arrhythmias in six (30%), orthostatic hypotension in six (30%) and skin necrosis, paranoid reaction, acute hepatitis and acute renal failure in four (20%). The causative drugs were warfarin (which accounted for 25% of the ADEs), beta-blockers (15%), propafenone (5%), amiodarone (5%), and Ca(2+)-channel blockers, nitrates and diuretics (together accounting for 50% of ADEs). Drug combinations were implicated in 50% of ADE. CONCLUSIONS: Serious ADEs were developed by 4% of hospitalized patients taking cardiovascular drugs. Those at highest risk were older, were receiving multiple drug therapy and had higher urea levels. Warfarin and beta-blockers were the drugs causing the largest number of adverse effects. ADEs are an important cause of preventable morbidity, often with serious economic implications and special attention should be given to their prevention.

Placental transfer of valproic acid after liposome encapsulation during in vitro human placenta perfusion.

Valproic acid (VPA) is an antiepileptic drug that crosses the placenta freely. Because its use in pregnancy is associated with an increased incidence of fetal malformation and toxic effects, this study was designed to check whether the placental transfer of VPA entrapped in liposomes was reduced. VPA was encapsulated in dehydrated-rehydrated liposomes prepared with equimolar concentrations of phosphatidylcholine, cholesterol and alpha-tocopherol. Liposomes were analyzed for their physicochemical characteristics, their stability and percentage of encapsulation of VPA. A system of dual perfusion of an isolated lobule of term human placenta was used. Six placentas were perfused with liposome-VPA and six with free VPA for 180 min using recirculating maternal and fetal circuits. The rate of transfer and time to reach equilibrium of VPA was similar in placentas perfused with free VPA and with liposome-encapsulated VPA. Liposomes significantly reduced VPA transplacental transfer and placental uptake. This was confirmed by FMM at equilibrium, that was 0.548 +/- 0.058 in free VPA and 0.393 +/- 0.075 in liposome-VPA. The ratio of fetal to maternal concentrations at equilibrium was 0.90 +/- 0.10 in controls and 0.66 +/- 0.13 in liposome-VPA. The amount of VPA recovered in fetal circulation and in placental tissue were 28 +/- 4 and 7 +/- 3% in controls and 19 +/- 4 and 3 +/- 2% in liposome-VPA. In conclusion, our data indicate that encapsulating VPA in liposomes significantly reduces the fetal amount and exposure, and further in vitro and in vivo investigations are needed to optimize the use of liposomes, particularly in pregnancy.

Mefloquine transfer during in vitro human placenta perfusion.

Mefloquine (MQ) is highly effective in the treatment and prophylaxis of chloroquine-resistant Plasmodium falciparum malaria. Despite its widespread use, scant information is available on the transplacental profile and time course of MQ transfer across the human placenta. Six human placentas were perfused with human plasma for 180 min using recirculating maternal and fetal circuits. The viability of the placental preparation was validated measuring oxygen and carbon dioxide balance and the rates of glucose consumption and lactate production. MQ data were compared with antipyrine, a routine marker in placental perfusions. Disappearance of MQ from the maternal circulation after a dose of 0.8 mg/liter was biexponential, with a first, rapid distribution phase into the placental tissue. The apparent first-order distribution (lambda 1) and elimination (lambda z) rate constants were 0.043 +/- 0.014 min-1 and 0.020 +/- 0.007 min-1, respectively. The fetomaternal mass ratio became constant (0.46 +/- 0.07) after 120 min of perfusion and the time needed to achieve equal concentrations on both sides of the placenta was 178 +/- 31 min. MQ clearance was 3.36 +/- 0.38 ml/min. About 40% of the MQ maternal dose was recovered in tissue and 11% appeared in the fetal circulation. These data provide support for using MQ in pregnant women for both the treatment and prophylaxis of Plasmodium malaria, although comparison with other compounds are needed.

Placental transfer of theophylline in an in vitro closed perfusion system of human placenta isolated lobule.

Theophylline (TH) is a methylated xanthine widely used in the treatment of asthmatic pregnant women. Because of the scant available information on the transplacental profile, the time course of TH transfer was studied by an in vitro human placental perfusion. 6 placentas were perfused with Earle's enriched bicarbonate buffer for 180 min using recirculating maternal and fetal circuits. The physiological and biochemical properties of the tissue were well maintained. TH data were compared to those of antipyrine (AP), an usual marker in placental perfusions. The disappearance of TH from the maternal circuit was studied after administration of 15 mg/l in maternal perfusate. TH appeared in the fetal circuit within 5 min. Equilibrium was achieved in both circuits. TH fetomaternal mass ratio became constant (FMM = 0.45 +/- 0.01) after 80 min of perfusion and maternal to fetal clearance was 2.59 +/- 0.24 ml/min. About 16% of TH maternal dose was recovered in the tissue, while 18% appeared in fetal circulation. TH recovery was 89 +/- 9%. On the basis of our results, similar concentrations could be predicted in mother and fetus after maternal TH intake. The TH transfer profile is consistent with in vivo values reported in humans and animals at delivery.