MMWR, February 29, 2008 / 57(08);197-200:

On April 26, 2007, a patient from Alberta, Canada, died after 9 weeks in an intensive care unit (ICU) from encephalitis caused by a rabies virus variant associated with silver-haired bats. This report summarizes the clinical course of disease in that patient, who was treated using the Milwaukee Protocol, an experimental treatment protocol similar to one used for the rabies survivor described in 2005 (1). This report also describes the subsequent epidemiologic investigations by three regional public health departments in Alberta. Rabies continues to be a cause of human death in the developed and developing world. The findings in this report underscore the need for continued public education that promotes rabies prevention and postexposure prophylaxis while emphasizing the importance of bat exposure in rabies transmission.

Case Report

During August 2006, a man aged 73 years was bitten by a bat on his left shoulder while sleeping at home in rural Alberta. He killed and disposed of the bat and did not seek medical attention. The patient had no history of previous rabies vaccination and became ill on February 14, 2007, when he had onset of left shoulder pain. The pain was radicular, severe, and progressive and evolved to include left hand weakness during the next few days. The man sought care at a local emergency department on February 15, 17, and 19, and was administered analgesics.

On February 21 (the seventh day of clinical illness), the patient was admitted to the local hospital with general weakness, anorexia, and dysphagia. His family described the patient as irritable and not himself. Forty-eight hours after admission, the patient had left arm myoclonus and gasping respirations, suggestive of inspiratory spasms. His illness progressed with high fever, hypoxia, hypersalivation, and a decreased level of consciousness. He required intubation and was transferred to a tertiary-care hospital ICU on February 23 (the ninth day of clinical illness) with a presumptive diagnosis of aspiration pneumonia and sepsis. The history of a previous bat bite was not obtained at that time.

A computerized tomography scan of the head on admission to the tertiary-care hospital was unremarkable. A lumbar puncture was performed, and analysis of cerebrospinal fluid (CSF) indicated no white blood cells, normal glucose, and marginally elevated protein. A chest radiograph revealed a right lower lobe infiltrate, and treatment for presumed pneumonia with broad-spectrum antibiotics was initiated. The patient continued to deteriorate with cardiac dysrhythmias, profound hemodynamic lability, opisthotonic posturing, hypersalivation, and diffuse spasticity. Because of this evolution of the patient’s symptoms, rabies was considered as a possible diagnosis on February 26 (the 12th day of clinical illness). When asked about bites or other exposures, the patient’s family recalled that the patient had been bitten by a bat approximately 6 months before.

A nuchal biopsy specimen and saliva sample were sent to the Canadian Food Inspection Agency in Ottawa, Ontario, where the rabies diagnosis was confirmed on March 1 (the 15th day of clinical illness). Presence of viral antigen and viral RNA was detected by direct fluorescent antibody test (DFA) and reverse transcription polymerase chain reaction (RT-PCR), respectively. Subsequently, the rabies virus RNA was typed as a variant associated with silver-haired bats (Lasionycteris noctivagans).

Rabies immune globulin was administered (1,200 units intramuscularly) on March 1. After discussion with the family regarding the diagnosis, the poor prognosis, and possible management strategies, a decision was made to initiate the Milwaukee Protocol, a recently described experimental therapy for rabies (1). This regimen involves 1) induction of therapeutic coma, 2) waiting for an adaptive immune response to evolve and neutralize and clear virus from the central nervous system and periphery, and 3) supportive antiviral and metabolic therapies. In 2004, this protocol resulted in survival and good neurologic outcome for an unvaccinated female patient aged 14 years in Milwaukee, Wisconsin (1). On March 2 (the 16th day of clinical illness), the treating physicians initiated the Milwaukee Protocol, including parenteral ketamine infusion (2 mg/kg), midazolam infusion (0–20 mg/hour), ribavirin (560 µg every 8 hours), and amantadine (200 mg once daily); the protocol was modified to include L-arginine (35 g every 24 hours), enteral administration of tetrahydrobiopterin (150 mg every 8 hours), and vitamin C (500 mg once daily) to supplement possible deficiencies and to improve cerebral blood flow autoregulation. The immunologic response and peripheral viral clearance were monitored via detection of viral RNA in saliva by quantitative RT-PCR and titration of rabies virus neutralizing antibodies in sera and CSF using a rapid fluorescent focus inhibition test.

The patient’s severe hemodynamic lability improved gradually on ventilatory and low-dose pressor support. Rabies immunoglobulin G (IgG) and immunoglobulin M (IgM) were detected in serum on March 6 and in CSF on March 11, a total of 20 and 25 days, respectively, after onset of neurologic symptoms. Baseline serum and CSF tested negative for the presence of IgM and IgG against rabies virus, and subsequent development of an IgM response was thought to represent an immune response to the infection. The patient was weaned from sedation and, on April 1 (the 46th day of clinical illness), sedation was removed completely. However, no neurologic recovery occurred despite detection of low titers of virus-neutralizing antibodies (0.46–1.16 IU/mL) in CSF and normal cerebral perfusion.

Levels of virus-neutralizing antibodies in serum increased slowly and reached 0.9 IU/mL on April 24 (the 69th day of clinical illness). During the disease course, detectable rabies virus decreased markedly in the peripheral tissues, with a negative DFA on the skin biopsy and a small amount of viral RNA detected by PCR in saliva. During the same period, the patient had cardiac arrhythmias, autonomic instability, syndrome of inappropriate antidiuretic hormone secretion, hemolysis attributed to ribavirin, and ventilator-associated pneumonia.

A nuclear medicine brain death scintigraphy study revealed preserved brain perfusion; however, on April 23 (the 68th day of clinical illness), repeated magnetic resonance imaging demonstrated diffuse severe signal abnormality of the cortex, white matter, basal ganglia, and thalami. Clinical examination, including apnea testing, was consistent with brain death. After discussion with the family, life-support was withdrawn on April 26, approximately 8 weeks after initiating therapy, and the patient died. DFA staining of the autopsied brain stem and cerebral cortex demonstrated an abundance of rabies viral inclusions. These results were confirmed by RT-PCR. Microscopic examination revealed extensive and virtually complete loss of cortical neurons, whereas the cerebellum and brainstem had preservation of neurons.

Public Health Investigation

In conjunction with the admitting tertiary-care hospital, the public health departments of three Alberta health regions traced the household and health-care–associated contacts of the patient starting from 1 week before onset of neurologic symptoms, a practice consistent with previous similar investigations (2). Postexposure prophylaxis (PEP) was recommended for health-care workers and close contacts of the patient with a possible exposure (defined as a bite, scratch, or exposure of nonintact skin or mucous membrane surface to saliva, CSF, tears, or brain tissue). A total of 19 contacts received PEP. All family members (the patient’s wife and his two sons) were administered PEP with rabies immune globulin and vaccine. Sixteen health-care workers, who had reported exposures of mucous membranes or nonintact skin to the patient’s saliva, were administered PEP; 15 (six from the primary referring hospital and nine from the tertiary-care hospital) received rabies immune globulin and vaccine. One health-care worker, who had been vaccinated previously, received 2 booster vaccine doses. To date, none of the persons who received PEP have demonstrated illness consistent with rabies.

Reported by: J Johnstone, MD, L Saxinger, MD, Infectious Diseases, R McDermid, MD, S Bagshaw, MD, Critical Care, L Resch, MD, Pathology, Univ of Alberta; B Lee, MD, Alberta Provincial Public Health Laboratory; M Johnson, MD, Public Health Div, AM Joffe, MD, Occupational Health, Safety, and Wellness, Capital Health Region, Edmonton; G Benade, MD, Public Health Div, East Central Health Region, Camrose; D Johnson, MD, Public Health Div, Aspen Health Region, Westlock, Alberta; S Nadin-Davis, PhD, Canadian Food Inspection Agency, Ottawa; E Cheung, Public Health Laboratories Br, Ministry of Health and Long-Term Care, Etobicoke, Ontario, Canada. R Willoughby Jr, MD, Medical College of Wisconsin, Milwaukee, Wisconsin. R Franka, DVM, PhD, Div of Viral and Rickettsial Diseases, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, CDC.

Editorial Note:

In Canada, 24 documented human rabies cases, including the one described in this report, have occurred since 1924 (2,3). Since 1970, six of the seven cases have been attributable to rabies virus variants associated with bats (2,3). Bats are an increasingly common source of human rabies in the United States, accounting for 37 (92.5%) of the 40 indigenous cases of rabies since 1990 (4). Passive surveillance of bats in western Canada during 1985–1989 indicated that 4.8% of bats submitted for testing were positive for the presence of rabies virus; the prevalence has remained stable since 1965 (5). The rabies virus variant associated with L. noctivagans bats in North America has been implicated in multiple indigenously acquired human rabies cases in the United States in recent years and also was responsible for a case of human rabies in Quebec, Canada, in 2000 (6).

After an exposure, human rabies is preventable by local wound care and administration of PEP (3,7,8). Patients with no previous rabies vaccination require rabies immune globulin and a 5-dose series of rabies vaccine (7,8). However, as the case in this report illustrates, persons are not always aware of the importance of seeking attention and PEP after bat exposures. In addition, clinicians need to recognize that a majority of patients with human rabies transmitted by bats might have no recollection of a bat bite. Thus, PEP should be considered in circumstances in which the likelihood of a bite cannot be reasonably excluded (7,8). PEP can be administered any time after an exposure, up to the onset of neurologic illness, but effectiveness of prophylaxis decreases with time; therefore, early administration of PEP is critical. After infection, the usual incubation period for rabies is 20 to 60 days, although it can vary from several days to years (8).

Only one unvaccinated rabid patient (the girl in the Milwaukee case) has survived. Several other attempts to use the Milwaukee Protocol have been unsuccessful (9). Compared with the Milwaukee patient, the patient in this report 1) had advanced age; 2) had encephalitic disease with high levels of viral load in saliva and no detectable antibody response at the time of diagnosis; and 3) had received rabies immune globulin. Immune globulin administration during clinical rabies has not been demonstrated to be useful and is not part of the Milwaukee Protocol because of concerns that it might alter the kinetics of the immune response (10).

Sixteen health-care workers received PEP after the public health investigation. The indication for PEP includes exposure of nonintact skin or mucous membranes to potentially infectious body fluids (e.g., saliva) or neuronal tissue; standard infection-control precautions can minimize health-care workers’ risk for exposure to rabies virus (7,8). To date, no cases of transmission of rabies to persons exposed through health-care activities have been documented.

This report underscores the need for increasing public awareness of the risk for rabies after contact with bats. Underestimation of the importance of such exposures can lead to a fatal outcome. Persons bitten by a bat should immediately 1) wash the wound thoroughly with soap and water; 2) capture the animal, if this can be done safely (otherwise call local animal-control services for assistance), and submit the bat for testing; 3) report the incident to local or regional/state public health officials; and 4) visit a physician for treatment and evaluation regarding the need for PEP. Timely submission of the bat (or other possibly rabid animal) to public health officials facilitates testing for the presence of rabies virus, helps to ensure rapid administration of PEP when indicated, and minimizes the unnecessary use of PEP if the animal is not rabid.

An experimental approach to treat rabies in humans requires early diagnosis. Therefore, rabies should be included in the differential diagnosis of any unexplained acute, rapidly progressive viral encephalitis.

Rabies is a fatal but easily preventable disease that has no established effective therapy after onset of clinical disease. In addition to animal vaccination, continued public education regarding rabies exposure and timely and appropriate prophylaxis is a primary strategy for human rabies prevention.

Acknowledgments

This report is based, in part, on contributions by staff members in the Capital and Aspen Health Regions, B Aitken, East Central Health Region, Alberta; F Muldoon, M Sheen, C Fehlner-Gardiner, A Wandeler, Canadian Food Inspection Agency, Ottawa, M Shaw, T Okura, R Kandiah, Public Health Laboratories Br, Ministry of Health and Long-Term Care, Etobicoke, Ontario; and CE Rupprecht, VMD, PhD, LA Orciari, MS, M Niezgoda, MS, A Velasco-Villa, PhD, PA Yager, I Kuzmin, MD, Div of Viral and Rickettsial Diseases, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, CDC.

References

1. Willoughby RE, Tieves KS, Hoffman GM, et al. Survival after treatment of rabies with induction of coma. N Engl J Med 2005;352: 2508–14.
2. Parker R, McKay D, Hawes C, et al. Human rabies, British Columbia—January 2003. Can Commun Dis Rep 2003;29:137–8.
3. Varughese P. Human rabies in Canada—1924–2000. Can Commun Dis Rep 2000;26:210–1.
4. Blanton JD, Hanlon CA, Rupprecht CE. Rabies surveillance in the United States during 2006. J Am Vet Med Assoc 2007;231:540–56.
5. Prins B, Loewen KG. Rabies diagnosis in western Canada, 1985–1989. Can Vet J 1991;32:487–91.
6. Turgeron N, Tucci M, Deshaies D, et al. Human rabies in Montreal, Quebec—October 2000. Can Commun Dis Rep 2000;26:209–10.
7. CDC. Human rabies prevention—United States, 1999: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1999;48(No. RR-1).
8. Public Health Agency of Canada. Canadian immunization guide. 7th ed. Ottawa, Ontario: Public Health Agency of Canada; 2006:285–6. Available at http://www.phac-aspc.gc.ca/publicat/cig-gci/pdf/cig-gci-2006_e.pdf.
9. CDC. Human rabies—Indiana and California, 2006. MMWR 2007;56:361–5.
10. Jackson AC. Human disease. In: Jackson AC, Wunner WH, eds. Rabies. 2nd ed. San Diego, CA: Academic Press; 2007:309–40.

ProMEDmail, 2/28/08:  The Southern Nevada Health District is advising patients who received
injected anesthesia medication at the Endoscopy Center of Nevada      (700
Shadow Lane) of a risk for possible exposure to hepatitis C and other
bloodborne pathogens. The health district is recommending that
patients who had procedures requiring injected anesthesia at the
clinic between March 2004 and 11 Jan 2008 contact their primary care
physicians or health care providers to get tested for hepatitis C as
well as hepatitis B and HIV.

The health district received notification of 3 acute cases of
hepatitis C in January 2008 and has identified a total of 6 cases to
date; 5 of the cases had procedures requiring injected anesthesia
on the same day. Following a joint investigation with the Nevada
State Bureau of Licensure and Certification (BLC) and with
consultation from the Centers for Disease Control and Prevention, the
health district determined that unsafe injection practices related to
the administration of anesthesia medication might have exposed
patients to the blood of other patients. The exposures did not result
from the [other] medical procedures performed.

The cluster of illnesses came to the attention of the health district
in January 2008. These cases were reported to the health district by
area physicians. Nevada law requires that medical providers notify
public health officials when they identify a number of different
diseases, including hepatitis C. The common link between cases was
identified through the routine investigation of the cases reported by
medical providers, which includes an interview of the patient. Most
people infected with hepatitis C virus do not develop symptoms and do
not know that they have been infected. As a result, these infections
would not have been reported to the health district. An infection
with hepatitis C that results in the patient developing symptoms
(acute disease) is rare, so it is an unusual occurrence that brought
this problem to the attention of the health district. On average, 2
cases of acute hepatitis C are reported each year in Clark County;
6 cases have been identified in relation to this investigation.

A syringe (not a needle) that was used to administer medication to a
patient was reused on the same patient to draw up additional
medication. The process of redrawing medication using the same
syringe could have contaminated the vial from which the medicine was
drawn with the blood of the patient. The vial, which was not labeled
for use on multiple patients, was then used for a 2nd patient (with a
clean needle and syringe). If that vial was contaminated with the
blood of the 1st patient, any subsequent patients given medication
from that vial could have been exposed to bloodborne pathogens. [At
this point in the original text, the process of contamination is
illustrated by downloadable diagram. - Mod.CP]

Of the 6 known cases, 5 had procedures on the same day. Genetic
testing on 4 of the cases from that day has identified they likely
came from a common source. The patient that had a procedure on a
different day does not share a common source as the other 4. This
indicates that the problem that allowed disease transmission to occur
was not a one-time event but had recurred over an extended period.
Investigation of the clinic practices identified common practices
that would allow disease to be transmitted in this manner.

The unsafe injection practices associated with these cases were
identified during the investigation conducted in mid-January 2008.
The injection practices that led to the exposure have been
corrected, so no new patient exposures should be occurring. As it can
take several months for the symptoms of hepatitis C to appear,
additional cases might be identified despite no ongoing transmission
of disease. The investigation revealed practices that could have
exposed patients to the blood of another patient.

Although hepatitis C was the focus of the investigation, hepatitis B
and HIV can be transmitted in the same manner. It is unknown how many
people were infected at the clinic. Hepatitis C, B and HIV are
routinely found in the population. A significant number of people
might have been infected prior to their procedure. Although testing
can determine whether a person is infected, it cannot determine the
source of the infection.

Hepatitis C, B or HIV can result in a range of disease severity and
can eventually result in death. It is important that patients speak
with a physician or health care provider if they have one of these
diseases. A physician will be able to address specific risks for
serious illness and develop a plan to monitor patients’ health.

On average, 2 cases of acute hepatitis C are identified each year in
Clark County. Most people who become infected with hepatitis C
initially have mild or no symptoms and do not know that they have
been infected unless they are tested by a doctor. Only a small
percentage of people infected with hepatitis C develop acute disease
and have any outward signs of infection.

The Southern Nevada Health District is responsible for investigating
reports of illness in our community in order to take steps to protect
the health and well-being of the public. Once notified of a
reportable disease, the health district begins an investigation and
works with the appropriate agencies to address any issues identified
and make recommendations to help prevent this type of situation from
occurring again.

When proper injection practices are followed, medical procedures,
including colonoscopies or similar procedures, are generally safe.
All health care professionals and medical facilities should follow
safe injection practices and infection control procedures. Patients
can and should ask their medical providers about the practices used
in their facility.

FDA Press Release, 2/28/08:  Baxter International Inc. announced today that the company is proceeding with the voluntary recall of all remaining lots and doses of its heparin sodium injection multi-dose, single-dose vials and HEP-LOCK heparin flush products.The company initially recalled nine lots of heparin sodium injection multi-dose vials on January 17, 2008 as a precautionary measure due to a higher than usual number of reports of adverse patient reactions involving the product and suspended production earlier this month.

Given the widespread use of this blood thinner and the impact a product shortage would have on operating rooms, dialysis centers and other critical care areas, the FDA and Baxter concluded that removing additional lots and doses of Baxter’s heparin from the market earlier would have created more risk to patients requiring heparin therapy than the increased potential for experiencing an adverse reaction. Accordingly, the FDA and Baxter decided not to recall all Baxter heparin vial products at that time. The FDA has now concluded that there is sufficient capacity on the part of other suppliers that Baxter’s recall will not jeopardize access to this drug, and has told Baxter that the company can now proceed with recalling its remaining heparin sodium injection and heparin flush products.

Although the vast majority of the reports of adverse reactions have been associated with the multi-dose products, Baxter is taking the precautionary step of recalling all remaining heparin sodium injection and heparin flush products that are currently on the market. In addition to the previously recalled lots of heparin sodium injection 1000 units/mL 10mL and 30mL multi-dose vials, Baxter’s recall will now include the remaining lots of those products and heparin sodium injection 5000 units/mL 10mL multi-dose vials, heparin sodium injection 10,000 units/mL 4mL multi-dose vials, heparin sodium injection 1000 USP units/mL, 5000 USP units/mL, and 10,000 USP units/mL single-dose vials, and all HEP-LOCK and HEP-LOCK U/P, 10 USP units/mL and 100 USP units/mL vials, both preserved and preservative-free.

This recall does not involve Baxter’s heparin pre-mix IV solutions in bags: heparin sodium in 5% dextrose injection and heparin sodium in 0.9% sodium chloride injection.

“We have assurance from the U.S. Food and Drug Administration that there is an adequate supply in the market to meet the demand for these critical and lifesaving drugs,” said Peter J. Arduini, president of Baxter’s Medication Delivery business. “The safety and quality of our products is always our highest priority, and we will continue to collaborate with the FDA as we work to determine the cause of the increased rate of adverse reactions and resolve this issue.”

Nearly all reported adverse reactions have occurred in three specific areas of product use – renal dialysis, invasive cardiovascular procedures and apheresis procedures. Reported adverse patient reactions have included: stomach pain or discomfort, nausea, vomiting, diarrhea, decreased or low blood pressure, chest pain, fast heart rate, dizziness, fainting, unresponsiveness, shortness of breath, the feeling of a strong or rapid heartbeat, drug ineffectiveness, burning sensation, redness or paleness of skin, abnormal sensation of the skin, mouth or lips, flushing, increased sweating, decreased skin sensitivity, headache, feeling unwell, restlessness, watery eyes, throat swelling, thirst, bleeding tendencies and difficulty opening the mouth. Some of these reactions, particularly profound and refractory hypotension, may be severe or life-threatening.

Customers have been instructed to discontinue use and segregate the recalled product from the rest of their inventory. Customers should then contact Baxter to arrange for return and replacement product. Customers with recalled product purchased indirectly should contact their wholesaler or distributor for return and replacement product. Customers with questions may contact the Center for One Baxter at 1-800-4-BAXTER (1-800-422-9837). Representatives will be available twenty-four hours a day, seven days a week.

Important Safety Information –
Revised Directions for Using Rabies Immune Globulin (Human), HyperRAB™ S/D in Fixed Needle 2 mL Pre-filled Syringe

The Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) have been notified by Talecris Biotherapeutics, Inc. that its Rabies Immune Globulin (Human), HyperRAB™ S/D in fixed needle 2 mL pre-filled syringe does not address all dosing situations.  Specifically, the fixed needle (22 gauge, 1.25 inch) and the absence of graduations on the 2 mL pre-filled syringe do not permit administration of the recommended dose of Rabies Immune Globulin (Human), HyperRAB™ S/D in one or more of the following situations:

Healthcare providers may continue to administer HyperRAB™ S/D supplied in the 2 mL pre-filled syringe by following the “Revised Directions for Use” that are packaged with these lots.  The full “Revised Directions for Use” of these lots is available on-line: http://www.talecris.com/us/documents/FINAL_FDA_Approved_Revised_Directions_for_Syringe_Use__21-FEB-08.pdf. Talecris has discontinued manufacturing the HyperRAB™ S/D fixed needle, 2 mL pre-filled syringe.  For additional information regarding this product, please contact Talecris on-line at www.talecris.com, or call 919-412-1030, or toll free at 1-800-520-2807.Human rabies PEP (post-exposure prophylaxis) is recommended when potentially infectious material (e.g. saliva) from a rabid animal is introduced via a bite, or comes into direct contact with broken skin or mucous membranes.  More detailed information regarding evaluation for and administration of PEP is available at

http://www.cdc.gov/mmwr/preview/mmwrhtml/00056176.htm.For more information about rabies and its prevention, contact your state or local public health official or CDC at 1-800-CDC-INFO or visit www.cdc.gov/rabies.

Intro:  According to Biogen Idec and Elan, “TYSABRI^® is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations.”  Unfortunately, FDA has announced that it may cause severe liver damage.  So, if you have a patient with MS and who is turning the color of a banana, check out what meds he/she is on. 

FDA Drug Alert, 2/27/08:  Biogen Idec, Elan and FDA notified healthcare professionals of reports of clinically significant liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose of Tysabri. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. Tysabri should be discontinued in patients with jaundice or other evidence of significant liver injury. Physicians should inform patients that Tysabri may cause liver injury.

NY Times, 2/28/08:  With reports of more than 400 patients in the United States suffering serious complications after receiving the blood-thinner heparin, American investigators are trying to determine whether the raw material for the drug, made from pig intestines, became contaminated on the journey that begins in the slaughterhouses of China.The investigators are examining the records of a factory an hour from here that supplies much of the active ingredient in heparin for Baxter International, which earlier this month halted sales of multidose vials of heparin after reports of injuries and four deaths.

The owner of the factory, which is known as Changzhou SPL, says its supply chain is safe. It buys raw material from only two reputable wholesalers, it says, and audits their 10 to 12 suppliers.

“We have a collection chain in place, and we stick with that,” said David Strunce, the president of Scientific Protein Laboratories, an American company that owns a majority of Changzhou SPL. He declined repeated requests from The New York Times to identify those smaller suppliers, saying it was proprietary information.

But interviews with dozens of heparin producers and traders in several Chinese provinces, as well as a visit to a village near here dominated by tiny family workshops that process crude heparin from pig intestines, show the difficulties confronting investigators as they seek to trace the supply chain. The picture that emerges is of a chain more complex, and less orderly, than the one Mr. Strunce laid out.

The Chinese heparin market has become increasingly unsettled over the last year, as pig disease has swept through the country, depleting stocks, leading some farmers to sell sick pigs into the market and forcing heparin producers to scramble for new sources of raw material. Traders and industry experts say even big companies have been turning more often to the small village workshops, which are unregulated and often unsanitary.

One of the wholesalers named by Scientific Protein Laboratories, Ruihua Biochemical in Hangzhou, said it provided a mix of crude heparin that it manufactured and some that it bought “from small factories nearby in several villages.” The owner, Hua Ruihua, said he never inspected the small factories. “We are not the government,” he said in a telephone interview. “We have no right to inspect their pigs or intestines or facilities.”

The owner of one of those workshops, Fan Yinan, said, “I sold to Ruihua several times before, but since last September I have had no intestines.” He confirmed that “no one from Ruihua inspected my pigs or intestines.”

Asked about Ruihua Biochemical, the S.P.L. chief, Mr. Strunce, said, “We have no information to suggest that your information is true.”

This week, a spokeswoman for Baxter said the number of reports of adverse reactions to heparin had surpassed 400. A spokeswoman for the Food and Drug Administration in the United States said the agency was reviewing the new reports and did not yet have a revised count.

The authorities have not determined that problems with the heparin supply chain led to the deaths and adverse reactions, first reported last month in Missouri. Nor have investigators determined that heparin from China was the culprit. Baxter also gets some of its ingredients from a plant in Wisconsin. Neither S.P.L. nor Baxter has been accused of doing anything wrong.

Even so, the problems involving heparin have again focused attention on the quality of products from China and the gaps in regulation by both the Chinese and United States governments. S.P.L.’s plant in Changzhou was certified by American officials to export to the United States even though neither government had inspected it. The plant has been exporting heparin to Baxter since 2004.

Like many chemical companies in China that make pharmaceutical ingredients for export, S.P.L. fell into a regulatory void. A spokesman for China’s State Food and Drug Administration, Shen Chen, said his agency had not inspected the S.P.L. factory because “as far as we know, it is not a drug manufacturer; it is a producer of chemical ingredients.” Mr. Shen said his agency was helping American investigators as part of a recent agreement with American regulators.

The process of making heparin begins with the intestines of slaughtered pigs, from which mucous membrane is collected and cooked, eventually producing a dry substance known as crude heparin. Major heparin producers like S.P.L. take that substance, refine it and sell it to companies like Baxter that make the final product, which is widely used in cardiovascular surgery and dialysis.

Some experts say as much as 70 percent of China’s crude heparin — for domestic use and for export — comes from small factories in poor villages. One of the biggest areas for these workshops is here in coastal Jiangsu Province, north of Shanghai, where entire villages have become heparin production centers.

In a village called Xinwangzhuang, nearly every house along a narrow street doubles as a tiny heparin operation, where teams of four to eight women wearing aprons and white boots wash, splice, separate and process pig intestines into sausage casings and crude heparin.

The floors had large puddles and drainage channels; the workshops were dilapidated and unheated; and steam from the production process fogged up the windows and soaked the walls. There were large ovens to cook ingredients and halls lined with barrels to store enzymes, resins, intestines and wastewater.

“This is our family-style workshop,” said Zhu Jinlan, the owner of one heparin operation, who stopped sorting pig intestines and invited visitors to a back room, where she lives with her husband and child. “We’ve been doing this about 10 years.”

Experts say the small, unregulated factories could pose dangers because they do not have the same controls and rules as large slaughterhouses, which also produce crude heparin.

“If you don’t control the incoming source, it’s very hard to get rid of the contaminants,” says Liu Jian, a heparin expert at the University of North Carolina.

Mr. Strunce of S.P.L. says his company never buys directly from the crude-heparin producers, only through its wholesalers, which he called “consolidators” — Changzhou Techpool, its Chinese joint venture partner, and Ruihua. His company, he said, has records documenting all the transactions.

But here in Rugao, producers of crude heparin tell a somewhat different story. A sales manager for a major supplier, Nantong Koulong, said he sells directly to S.P.L. without going through either of the two wholesalers. “We provided crude heparin to Changzhou SPL,” said the sales manager, Chen Jianjun. Some of Koulong’s stock comes from the unregulated workshops, he said.

The owner of one such workshop, Ms. Zhu in Xinwangzhuang, said she sold to S.P.L. two years ago. She also sells to Koulong. “We are really a traditional family-style plant,” she said. “We have no certificate.”

S.P.L. said it never bought directly or indirectly from Koulong.

To the south, in Zhejiang Province, two officials of Zhejiang Willing Animal Byproducts Processing said they, too, sold to S.P.L. “We supply heparin to Changzhou SPL,” said Fang Weicai, the general manager, although he said later that he sold it privately and not under the auspices of his company.

After an outbreak of blue ear pig disease swept through 25 of China’s 31 provinces and regions last year, prices soared, and many drug suppliers had to look to the small workshops. The epidemic, said Cui Huifei, a heparin expert at the Shandong University School of Medicine, “made those biotech companies inevitably purchase from the family-style plants, for cheaper prices.”

A sales manager for another large slaughterhouse in Shandong Province, north of Jiangsu, said he was approached late last year by a buyer for S.P.L. offering what he described as rock-bottom prices for crude heparin.

“It was impossible,” said the sales manager, Wang Shengfu, who works for Shandong Jinluo Group, a major producer of crude heparin. “Only small factory-style farms could accept that low price.”

The deal was never consummated.

Mr. Strunce said S.P.L. responded to the disease outbreak by buying less raw material in China. “We were not out looking for additional heparin because we made do with what we already have,” he said, adding that the company “pays more than many people for heparin over there because we require a higher standard of heparin.”

ABSTRACT

Background Vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock, but its effect on mortality is unknown. We hypothesized that low-dose vasopressin as compared with norepinephrine would decrease mortality among patients with septic shock who were being treated with conventional (catecholamine) vasopressors. Methods In this multicenter, randomized, double-blind trial, we assigned patients who had septic shock and were receiving a minimum of 5 µg of norepinephrine per minute to receive either low-dose vasopressin (0.01 to 0.03 U per minute) or norepinephrine (5 to 15 µg per minute) in addition to open-label vasopressors. All vasopressor infusions were titrated and tapered according to protocols to maintain a target blood pressure. The primary end point was the mortality rate 28 days after the start of infusions.