Ibuprofen improves survival and neurologic outcome after resuscitation from cardiac arrest

Post-ischemic inflammatory changes in the central nervous system (CNS) following cardiac arrest and resuscitation are potentially responsible for ultimate survival and much of the neurologic damage, producing greater morbidity and mortality in successfully resuscitated patients. This study was undertaken to assess the non-steroidal anti-inflammatory agent, ibuprofen, in a controlled and monitored experimental model of canine cardiac arrest and resuscitation. With the investigator blinded as to the intervention, eight of 21 dogs were randomly assigned to receive ibuprofen as an i.v. bolus (10 mg/kg) and a 6-h i.v. infusion (5 mg/kg per h). The other 13 dogs received an equivalent volume of 0.9% NaCl to serve as controls. No statistically significant differences between the two groups were detected in any pre-arrest variables. All 21 dogs were successfully resuscitated. At 24 h, dogs receiving ibuprofen exhibited 100% survival, while control dogs exhibited only 54% survival (P = 0.03). The majority of deaths for the control group occurred within the first 6 h. Neurologic deficit scores were assigned at 1, 2, 6 and 24 h after resuscitation. A general trend occurred such that dogs treated with ibuprofen improved over time, while the control dogs remained severely impaired. A significant difference in neurologic deficit score was detected at 6 h (P = 0.01). At 24 h the ibuprofen group exhibited minimal neurologic deficit (5.9 +/- 3.2), and the control group exhibited significantly more severe neurologic impairment (52.2 +/- 13.0, P = 0.01). These results suggest that ibuprofen may be helpful in the pharmacologic management of cardiac arrest as a means of increasing survival and decreasing neurologic impairment.     

Open-chest CPR improves survival and neurologic outcome following cardiac arrest

STUDY OBJECTIVE: To determine if 15 min of open-chest cardiac massage (OC-CPR) versus closed-chest compressions (CC-CPR) improves 72-h survival and neurologic outcome (behavioral and histologic) after 5 min of untreated cardiac arrest. METHODS: Mongrel dogs were anesthetized and instrumented. Cardiac arrest was induced by KCl injection and after a 5-min period of non-intervention, dogs were randomized to receive either CC-CPR (N = 7) or OC-CPR (N = 5) performed for 15 min. The dogs were then resuscitated and physiologic data was recorded. Surviving dogs were scored at 72 h using canine neurodeficit score of Safar et al. (NDS; 0 = behaviorally normal, 500 = brain death). Dogs that could not be resuscitated or died before 72 h were assigned a score of 500. Brain histology was performed on all survivors. RESULTS: All OC-CPR dogs were successfully resuscitated and were behaviorally normal at 72 h (NDS = 0). Histology in OC-CPR dogs showed little to no injury. Only three out of the seven CC-CPR dogs survived to 72 h. Of the survivors, one dog exhibited minor ataxia (NDS = 15), and two had incapacitating deficits (both NDS = 180). Two dogs died within 24 h after extubation, and one could not be resuscitated and the other could not be weaned from the ventilator (each NDS = 500). Histology of the CC-CPR survivors revealed moderate to severe lesions. NDS between groups was statistically significant (p < 0.0079). CONCLUSION: In our canine model of cardiac arrest, OC-CPR significantly improved 72-h survival and neurologic outcome when compared to CC-CPR.     

Predictors of poor neurologic outcome in patients after cardiac arrest treated with hypothermia: a retrospective study

Introduction

Outcome studies in patients with anoxic-ischemic encephalopathy focus on the early and reliable prediction of an outcome no better than a vegetative state or severe disability. We determined the effect of mild therapeutic hypothermia on the validity of the currently used clinical practice parameters.

Methods

We conducted a retrospective cohort study of adult comatose patients after cardiac arrest treated with hypothermia. All data were collected from medical charts and laboratory files and analyzed from the day of admission to the intensive care unit until day 7, discharge from the intensive care unit or death using the Utstein definitions for the registration of the data.

Results

We analyzed the data of 103 patients. The combination of an M1 or M2 on the Glasgow Coma Scale or absent pupillary reactions or absent corneal reflexes on day 3 was present in 80.6% of patients with an unfavourable and 11.1% of patients with a favourable outcome. The combination of M1 or M2 and absent pupillary reactions to light and absent corneal reflexes on day 3 was present in 14.9% of patients with an unfavourable and none of the patients with a favourable outcome. None of the patients with a favourable outcome had a bilaterally absent somatosensory evoked potential of the median nerve. The value of electroencephalogram patterns in predicting outcome was low, except for reactivity to noxious stimuli.

Conclusions

No single clinical or electrophysiological parameter has sufficient accuracy to determine prognosis and decision making in patients after cardiac arrest, treated with hypothermia.     

NSE and S-100B are not sufficiently predictive of neurologic outcome after therapeutic hypothermia for cardiac arrest

Introduction

Prognostication of cardiac arrest survivors is challenging since therapeutic hypothermia (TH) has been introduced. We evaluated serum biomarkers and motor response.

Methods

This was a retrospective data analysis including patients in the years 2007–2012. Blood was drawn and a neurological examination was performed on admission and every morning. Outcomes were evaluated 6 months after discharge and dichotomized into good (cerebral performance category (CPC) = 1 or 2) and poor (CPC = 3, 4 or 5).

Results

123 patients (79.7% male, 63 ± 14 years) received TH; 50% had a good outcome. On admission, S-100B (P = 0.004) was significantly associated with the outcome, as well as neuron-specific enolase (NSE; P = 0.020) and S-100B (P = 0.004) on day 1 after admission. NSE on day 2, NSE progression from day 1 to 2 and motor response on day 3 also predicted the outcome (all P < 0.001).NSE > 33 μg l⁻¹ only predicted a poor outcome with a specificity of 76%. An absent motor response on day 3 was the most sensitive marker (94%). NSE > 41.1 μg l⁻¹ combined with S-100B > 0.461 μg l⁻¹ on day 1 was the most specific marker (96%).

Conclusion

Although NSE and S-100B levels are associated with the outcome, the use of previously described cut-off values was insufficiently predictive of neurologic outcome. Caution should be exercised in the use of these tests to provide neuroprognostication.     

Pyrexia and neurologic outcomes after therapeutic hypothermia for cardiac arrest

Objective

Therapeutic hypothermia, also known as targeted temperature management (TTM), improves clinical outcomes in patients resuscitated from cardiac arrest. Hyperthermia after discontinuation of active temperature management (“rebound pyrexia”) has been observed, but its incidence and association with clinical outcomes is poorly described. We hypothesized that rebound pyrexia is common after rewarming in post-arrest patients and is associated with poor neurologic outcomes.

Methods

Retrospective multicenter US clinical registry study of post-cardiac arrest patients treated with TTM at 11 hospitals between 5/2005 and 10/2011. We assessed the incidence of rebound pyrexia (defined as temperature >38 °C) in post-arrest patients treated with TTM and subsequent clinical outcomes of survival to discharge and “good” neurologic outcome at discharge, defined as cerebral performance category (CPC) 1–2.

Results

In this cohort of 236 post-arrest patients treated with TTM, mean age was 58.1 ± 15.7 y and 106/236 (45%) were female. Of patients who survived at least 24 h after TTM discontinuation (n = 167), post-rewarming pyrexia occurred in 69/167 (41%), with a median maximum temperature of 38.7 (IQR 38.3–38.9). There were no significant differences between patients experiencing any pyrexia and those without pyrexia regarding either survival to discharge (37/69 (54%) v 51/98 (52%), p = 0.88) or good neurologic outcomes (26/37 (70%) v 42/51 (82%), p = 0.21). We compared patients with marked pyrexia (greater than the median pyrexia of 38.7 °C) versus those who experienced no pyrexia or milder pyrexia (below the median) and found that survival to discharge was not statistically significant (40% v 56% p = 0.16). However, marked pyrexia was associated with a significantly lower proportion of CPC 1–2 survivors (58% v 80% p = 0.04).

Conclusions

Rebound pyrexia occurred in 41% of TTM-treated post-arrest patients, and was not associated with lower survival to discharge or worsened neurologic outcomes. However, among patients with pyrexia, higher maximum temperature (>38.7 °C) was associated with worse neurologic outcomes among survivors to hospital discharge.     

Prognostication of neurologic outcome in cardiac arrest patients after mild therapeutic hypothermia: a meta-analysis of the current literature

Purpose

To assess the sensitivity and false positive rate (FPR) of neurological examination and somatosensory evoked potentials (SSEPs) to predict poor outcome in adult patients treated with therapeutic hypothermia after cardiopulmonary resuscitation (CPR).

Methods

MEDLINE and EMBASE were searched for cohort studies describing the association of clinical neurological examination or SSEPs after return of spontaneous circulation with neurological outcome. Poor outcome was defined as severe disability, vegetative state and death. Sensitivity and FPR were determined.

Results

A total of 1,153 patients from ten studies were included. The FPR of a bilaterally absent cortical N20 response of the SSEP could be calculated from nine studies including 492 patients. The SSEP had an FPR of 0.007 (confidence interval, CI, 0.001–0.047) to predict poor outcome. The Glasgow coma score (GCS) motor response was assessed in 811 patients from nine studies. A GCS motor score of 1–2 at 72 h had a high FPR of 0.21 (CI 0.08–0.43). Corneal reflex and pupillary reactivity at 72 h after the arrest were available in 429 and 566 patients, respectively. Bilaterally absent corneal reflexes had an FPR of 0.02 (CI 0.002–0.13). Bilaterally absent pupillary reflexes had an FPR of 0.004 (CI 0.001–0.03).

Conclusions

At 72 h after the arrest the motor response to painful stimuli and the corneal reflexes are not a reliable tool for the early prediction of poor outcome in patients treated with hypothermia. The reliability of the pupillary response to light and the SSEP is comparable to that in patients not treated with hypothermia.     

Better lactate clearance associated with good neurologic outcome in survivors who treated with therapeutic hypothermia after out-of-hospital cardiac arrest

Introduction

Several methods have been proposed to evaluate neurological outcome in out-of-hospital cardiac arrest (OHCA) patients. Blood lactate has been recognized as a reliable prognostic marker for trauma, sepsis, or cardiac arrest. The objective of this study was to examine the association between initial lactate level or lactate clearance and neurologic outcome in OHCA survivors who were treated with therapeutic hypothermia.

Methods

This retrospective cohort study included patients who underwent protocol-based 24-hour therapeutic hypothermia after OHCA between January 2010 and March 2012. Serum lactate levels were measured at the start of therapy (0 hours), and after 6 hours, 12 hours, 24 hours, 48 hours and 72 hours. The 6 hour and 12 hour lactate clearance were calculated afterwards. Patients’ neurologic outcome was assessed at one month after cardiac arrest; good neurological outcome was defined as Cerebral Performance Category one or two. The primary outcome was an association between initial lactate level and good neurologic outcome. The secondary outcome was an association between lactate clearance and good neurologic outcome in patients with initial lactate level >2.5 mmol/l.

Results

Out of the 76 patients enrolled, 34 (44.7%) had a good neurologic outcome. The initial lactate level showed no significant difference between good and poor neurologic outcome groups (6.07 ±4 .09 mmol/L vs 7.13 ± 3.99 mmol/L, P = 0.42), However, lactate levels at 6 hours, 12 hours, 24 hours, and 48 hours in the good neurologic outcome group were lower than in the poor neurologic outcome group (3.81 ± 2.81 vs 6.00 ± 3.22 P <0.01, 2.95 ± 2.07 vs 5.00 ± 3.49 P <0.01, 2.17 ± 1.24 vs 3.86 ± 3.92 P <0.01, 1.57 ± 1.02 vs 2.21 ± 1.35 P = 0.03, respectively). The secondary analysis showed that the 6-hour and 12-hour lactate clearance was higher for good neurologic outcome patients (35.3 ± 34.6% vs 6.89 ± 47.4% P = 0.01, 54.5 ± 23.7% vs 25.6 ± 43.7% P <0.01, respectively). After adjusting for potential confounding variables, the 12-hour lactate clearance still showed a statistically significant difference (P = 0.02).

Conclusion

The lactate clearance rate, and not the initial lactate level, was associated with neurological outcome in OHCA patients after therapeutic hypothermia.     

Admission hypothermia and outcome after major trauma

OBJECTIVE: Uncontrolled exposure hypothermia is believed to be deleterious in the setting of major trauma. Prevention of hypothermia in the injured patient is currently practiced in both prehospital and in-hospital settings. However, this standard is based on studies of limited patient series that were not designed to identify the independent relationship between hypothermia and mortality. Recent studies suggest that therapeutically applied hypothermia may benefit selected patient subsets. The goal of this study was to evaluate the independent association between admission hypothermia and mortality after major trauma, with adjustment for clinical confounders. DESIGN: Retrospective analysis of a statewide trauma registry. The primary outcome was death at hospital discharge. The key exposure was hypothermia, defined as body temperature /=16 yrs of age for the years 2000-2002. Transferred patients were excluded. Patients were excluded if temperature or route of temperature measurement was not known. Both the full cohort and a subset with isolated severe head injury were evaluated. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 38,520 patients, 1,921 (5.0%) were hypothermic at admission. Admission hypothermia was independently associated with increased odds of death in both the full cohort (odds ratio, 3.03; 95% confidence interval, 2.62-3.51) and the subset with isolated severe head injury (2.21; 1.62-3.03), with adjustment for age, severity and mechanism of injury, and route of temperature measurement. CONCLUSIONS: Admission hypothermia is independently associated with increased adjusted odds of death after major trauma. The increase in mortality is not completely attributable to physiologic presentation or injury pattern or severity.     

The impact of severe acidemia on neurologic outcome of cardiac arrest survivors undergoing therapeutic hypothermia

Introduction

Therapeutic Hypothermia (TH) has become a standard of care in improving neurological outcomes in cardiac arrest (CA) survivors. Previous studies have defined severe acidemia as plasma pH < 7.20. We investigated the influence of severe acidemia at the time of initiation of TH on neurological outcome in CA survivors.

Methods

A retrospective analysis was performed on 196 consecutive CA survivors (out-of-hospital CA and in-hospital CA) who underwent TH with endovascular cooling between January 2007 and October 2012. Arterial blood gas drawn prior to initiation of TH was utilized to measure pH in all patients. Shockable and non-shockable CA patients were divided into two sub-groups based on pH (pH < 7.2 and pH ≥ 7.2). The primary end-point was measured using the Pittsburgh Cerebral Performance Category (CPC) scale prior to discharge from the hospital: good (CPC 1 and 2) and poor (CPC 3 to 5) neurologic outcome.

Results

Sixty-two percent of shockable CA patients with pH ≥ 7.20 had good neurological outcome as compared to 34% patients with pH < 7.20. Shockable CA patients with pH ≥ 7.20 were 3.3 times more likely to have better neurological outcome when compared to those with pH <7.20 [p = 0.013, OR 3.3, 95% CI (1.28–8.45)]. In comparison, non-shockable CA patients with p ≥ 7.20 did not have a significantly different neurological outcome as compared to those with pH < 7.20 [p = 0.97, OR 1.02, 95% CI (0.31–3.3)].

Conclusion

Presence of severe acidemia at initiation of TH in shockable CA survivors is significantly associated with poor neurological outcomes. This effect was not observed in the non-shockable CA survivors.     

Extracerebral organ dysfunction and neurologic outcome after aneurysmal subarachnoid hemorrhage

OBJECTIVE: To analyze the influence of extracerebral organ system dysfunction after aneurysmal subarachnoid hemorrhage (SAH) on mortality and neurologic outcome. DESIGN: Observational study with retrospective data extraction. SETTING: Neurosurgical intensive care unit (NICU) at a primary level university hospital, supervised and staffed by both members of the Clinic of Neurosurgery and the Clinic of Anesthesiology and General Intensive Care. PATIENTS: Two hundred forty-two patients treated for intracranial aneurysm rupture within 7 days of the most recent SAH. INTERVENTIONS: Routine neurosurgical interventions for obliteration of the ruptured aneurysm (microsurgery, Guglielmi Detachable Coils embolization) and for treatment of posthemorrhagic hydrocephalus (ventriculostomy, cerebrospinal fluid shunt implantation). MEASUREMENTS AND MAIN RESULTS: Respiratory, renal, hepatic, cardiovascular, and hematologic organ system functions were evaluated both individually and in aggregate by using a modified version of the Multiple Organ Dysfunction (mMOD) score. Of 1,452 organ system functions assessed in 242 patients during their NICU stay, 714 organ system functions were intact (cerebral: 0, extracerebral: 714), 556 organ systems had mild-to-moderate dysfunctions (mMOD scoremax 1-2 for the affected organ system; cerebral: 153, extracerebral: 403), and 182 organ systems failed (mMOD scoremax 3 for the affected organ system; cerebral: 89, extracerebral: 93). Severity of extracerebral organ system dysfunctions correlated with the degree of neurologic impairment (Hunt and Hess [H&H] score) in a graded fashion. Similarly, the chance to develop systemic inflammatory response syndrome (SIRS) during the NICU stay increased with increasing admission H&H grade. The incidence of SIRS and septic shock was 29% and 10.3%, respectively. The mortality rate was 40.2% in patients with SIRS and 80% for patients suffering septic shock. Seventy-seven percent of extracerebral organ system failures (OSFs) occurred in conjunction with SIRS: 51% of respiratory OSFs, 97% of renal OSFs, 100% of hepatic OSFs, 96% of cardiovascular OSFs, and 73% of hematopoietic OSFs. Both CNS dysfunction and extracerebral organ system dysfunctions were significantly related to neurologic outcome. The probability of unfavorable neurologic outcome significantly increased with both decreasing cerebral perfusion pressure (CPP) and increasing severity of extracerebral organ dysfunction. CONCLUSION: Aneurysmal SAH and its neurologic sequelae accounted for the principal morbidity and mortality in the current series. Development of extracerebral organ system dysfunction was associated with a higher probability of unfavorable neurologic outcome. Systemic inflammation (SIRS) and secondary organ dysfunction were the principal non-neurologic causes of death.     

Long-term neurological outcome after cardiac arrest and therapeutic hypothermia

Aim of the studyTo analyse the neurological status of survivors after cardiac arrest (CA) treated with hypothermia.MethodsWe prospectively included all patients with CA treated with hypothermia at intensive care units (ICU) in two university hospitals and one regional hospital. All adult survivors at 6 months after CA, n = 48, were invited for neurological follow-up and 43 accepted. History, clinical status, ability testing and questionnaires were administered to screen for difficulties, including Assessment of Motor and Process Skills, Neurobehavioral Cognitive Status Examination, Frontal Lobe Assessment Battery, EQ-VAS quality of life scale, Skåne Sleep Index, Hospital Anxiety and Depression Rating Scale, Self-reported Montgomery and Åstrand Depression Rating Scale, Global Deterioration Scale, Rivermead Behavioural Memory Test, and the Cerebral Performance Categories (CPC).ResultsNo patient was found to be in a chronic vegetative state and all patients were living at home, one with extensive help. Thirty-six patients were in CPC1 at follow-up, and some degree of neurological sequelae was found in 40 patients, but was mild in all but 3. Three patients had no subjective complaints, nor could any deficits be detected. Initial defects improved over-time. Short-term memory loss, executive frontal lobe dysfunction along with mild depression and sleep rhythm disturbances were the most common findings.ConclusionsMild cognitive impairment is common following hypothermia-treated cardiac arrest but has little effect on activities of daily living or quality of life.     

Desmethyl tirilazad improves neurologic function after hypoxic ischemic brain injury in piglets

OBJECTIVE: Desmethyl tirilazad is a lipid-soluble free radical quencher. Deferoxamine reduces free radicals by chelating iron and reducing hydroxyl formation. Free radical inhibitors have shown promise in several hypoxic ischemic brain injury models, and we wished to see if this work could be extended to our newborn piglet model. DESIGN: Randomized controlled trial. SUBJECTS: Piglets (0 to 3 days old). INTERVENTION: Carotid snares and arterial and venous catheters were placed under 1.5% isoflurane anesthesia. In Experiment 1, piglets were randomly assigned to receive either 3 mg/kg desmethyl tirilazad or vehicle at -15 and 90 mins. In Experiment 2, piglets were randomly assigned to receive either 20 mg/kg desmethyl tirilazad at -15 mins followed by 8 mg/kg/hr for 90 mins or 100 mg/kg deferoxamine at -15 mins or vehicle. At time 0, both carotid arteries were clamped and blood was withdrawn to reduce the blood pressure to two-thirds normal. At 15 mins, inspired oxygen was reduced to 6%. At 30 mins, the carotid snares were released, the withdrawn blood was reinfused, and the oxygen was switched to 100%. On the third day after the hypoxic ischemic injury, the animals were killed by perfusing their brains with 10% formalin. We tested the timing of lipid peroxidation and inhibition of lipid peroxidation by these agents by freezing the brains of a subset of pigs in liquid nitrogen. MEASUREMENTS: Neurologic examination and brain pathology were scored by blinded observers. Thiobarbituric acid-reactive substance and oxidized and reduced glutathione were measured on frozen brains. MAIN RESULTS: Desmethyl tirilazad (20 mg/kg) and 100 mg/kg deferoxamine inhibit lipid peroxidation. Desmethyl tirilazad (20 mg/kg) improves neurologic exam, but 3 mg/kg Desmethyl tirilazad or 100 mg/kg deferoxamine does not. Neither desmethyl tirilazad nor deferoxamine improves pathologic results. CONCLUSIONS: High-dose desmethyl tirilazad improves neurologic function after hypoxic ischemic brain injury in the newborn piglet.     

The influence of rewarming after therapeutic hypothermia on outcome after cardiac arrest

IntroductionTreatment with hypothermia has been shown to improve outcome after cardiac arrest (CA). Current consensus is to rewarm at 0.25–0.5 °C/h and avoid fever. The aim of this study was to investigate whether active rewarming, the rate of rewarming or development of fever after treatment with hypothermia after CA was correlated with poor outcome.MethodsThis retrospective cohort study included adult patients treated with hypothermia after CA and admitted to the intensive care unit between January 2006 and January 2009. The average rewarming rate from end of hypothermia treatment (passive rewarming) or start active rewarming until 36 °C was dichotomized in a high (≥0.5 °C/h) or normal rate (<0.5 °C/h). Fever was defined as > 38 °C within 72 h after admission. Poor outcome was defined as death, vegetative state, or severe disability after 6 months.ResultsFrom 128 included patients, 56% had a poor outcome. Actively rewarmed patients (38%) had a higher risk for poor outcome, OR 2.14 (1.01–4.57), p < 0.05. However, this effect disappeared after adjustment for the confounders age and initial rhythm, OR 1.51 (0.64–3.58). A poor outcome was found in 15/21 patients (71%) with a high rewarming rate, compared to 54/103 patients (52%) with a normal rewarming rate, OR 2.61 (0.88–7.73), p = 0.08. Fever was not associated with outcome, OR 0.64 (0.31–1.30), p = 0.22.ConclusionsThis study showed that patients who needed active rewarming after therapeutic hypothermia after CA did not have a higher risk for a poor outcome. In addition, neither speed of rewarming, nor development of fever had an effect on outcome.     

Blood ammonia is a predictive biomarker of neurologic outcome in cardiac arrest patients treated with therapeutic hypothermia

Purpose

The aim of this study was to investigate the value of commonly examined laboratory measurements, including ammonia and lactate, in predicting neurologic outcome of out-of-hospital cardiac arrest (OHCA) patients treated with therapeutic hypothermia (TH).

Methods

This was a retrospective cohort study of patients with a return of spontaneous circulation after OHCA who were treated with TH between February 2007 and July 2010. We measured typical blood measurements on arrival at the emergency department. The subjects were classified into 2 groups: the good neurologic outcome group (Cerebral Performance Category [CPC] 1-2 at 1 month) and the poor neurologic outcome group (Cerebral Performance Category 3-5). We compared blood biomarker levels and basal characteristics between the 2 groups. Logistic regression analyses were performed to determine independent biomarkers that predict poor neurologic outcome.

Results

A total of 117 patients were included. Between the 2 groups, significantly different levels of blood measurements included hemoglobin level, pH, Pao₂, Paco₂, base excess, albumin, glucose, potassium, chloride, bilirubin, phosphorous, and ammonia. In multivariate analyses, blood ammonia level (>96 mg/dL; odds ratio [OR], 7.240; 95% confidence interval [CI], 1.718-30.512), noncardiac causes (OR, 46.215; 95% CI, 9.670-220.873), and time interval from collapse to return of spontaneous circulation (>33 min; OR, 5.943; 95% CI, 1.543-22.886) were significantly related to poor neurologic outcome.

Conclusion

Among the blood measurements on emergency department arrival, blood ammonia (>96 mg/dL) was the only independent predictive biomarker of poor neurologic outcome. Thus, higher blood ammonia level was associated with poor neurologic outcome in OHCA patients treated with TH.